Outpatient randomized controlled trials to reduce COVID-19 hospitalization: systematic review and meta-analysis

Abstract

Problem:

This COVID-19 outpatient randomized controlled trials (RCTs) systematic review compares hospitalization outcomes amongst four treatment classes over pandemic period, geography, variants and vaccine status.

Methods:

Outpatient RCTs with hospitalization endpoint were identified in Pubmed searches through May 2023, excluding RCTs < 30 participants (PROSPERO-CRD42022369181). Risk of bias was extracted from COVID-19-NMA, with odds ratio utilized for pooled comparison.

Results:

Searches identified 281 studies with 61 published RCTs for 33 diverse interventions analyzed. RCTs were largely unvaccinated cohorts with at least one COVID-19 hospitalization risk factor. Grouping by class, monoclonal antibodies (OR=0.31 [95% CI=0.24–0.40]) had highest hospital reduction efficacy, followed by COVID-19 convalescent plasma (CCP) (OR=0.69 [95% CI=0.53 to 0.90]), small molecule antivirals (OR=0.78 [95% CI=0.48–1.33]) and repurposed drugs (OR=0.82 [95% CI- 0.72–0.93]). Earlier in disease onset interventions performed better than later. This meta-analysis allows approximate head-to-head comparisons of diverse outpatient interventions.

Conclusions:

Omicron sublineages (XBB and BQ.1.1) are resistant to monoclonal antibodies. Despite trial heterogeneity, this pooled comparison by intervention class indicated oral antivirals are the preferred outpatient treatment where available, but intravenous interventions from convalescent plasma to remdesivir are also effective and necessary in constrained medical resource settings or for acute and chronic COVID-19 in the immunocompromised.

INTRODUCTION

By May 17, 2023 the world had recorded over 766 million cases and more than 6.9 million deaths from COVID-19. In the US, some 100 million cases have been recorded, with over a million deaths, while six million hospital admissions for COVID took place between August 2020 and December 2022. A pronounced spike in hospitalizations for COVID-19 in the US took place in the first two months of 2022 with the arrival of the Omicron variant of concern (VOC).

Several approaches to reducing the risk of hospitalization have been taken during the pandemic, including administering COVID-19 convalescent plasma (CCP), monoclonal antibodies (mAbs), small molecule antivirals or repurposed drugs. Vaccination and boosters have substantially reduced the hospitalization and death risk, but outpatients at elevated severe COVID risk can still benefit from early treatment to avoid hospitalization. Randomized controlled trials (RCTs) in outpatients have tested therapeutic agents against placebo or standard of care, but very few RCTs has been conducted that compare the main outpatient treatment classes.

The first outpatient treatments for COVID-19 authorized by the FDA were for mAbs (bamlanivimab, bamlanivimab plus etesevimab¹ or casirivimab plus imdevimab²), approvals that preceded the introduction of mRNA vaccines^3,4. While many small molecules were repurposed as antivirals during the early stages of the pandemic, oral antivirals developed against SARS-CoV-2 for outpatients were not authorized and available until December 2021, when nirmatrelvir/ritonavir⁵ and molnupiravir⁶ were approved. The following month, intravenous remdesivir was also approved for outpatient use⁷. On December 2021, nearly two years after the first use of CCP, the FDA approved CCP outpatient use, but only for immunocompromised patients^8,9. The mAbs have been withdrawn due to viral variants BQ.1.* and XBB.* resistance.

The rationale of the study was to assemble in one place all outpatient COVID-19 RCT in the four classes to compare hospitalization outcomes over time, geography in relationship to variants and vaccine status. We were inclusive of smaller studies meeting criteria of RCT with endpoint hospitalization. This systematic review and meta-analysis of outpatient COVID-19 RCTs, sought to compare hospitalization outcomes amongst CCP, mAbs, antivirals or repurposed drugs as grouped classes and individual trials taking into account risk factors for progression, intervention dosage, time between symptom onset and treatment administration, and predominant variants of concern during the RCTs.

2. METHODS

2.1. Registration

The protocol has been registered in PROSPERO, the prospective register of systematic reviews and meta-analyses of the University of York (protocol registration number CRD42022369181).

2.2. Inclusion and Exclusion Criteria and Data Extraction

We included outpatient COVID-19 RCTs with outcome hospitalization or a single CCP study with life-threatening respiratory distress¹⁰, by searching MEDLINE (through PubMed), medRxiv and bioRxiv databases for the period of March 1, 2020 to May 22, 2023, with English language as the only restriction. The Medical Subject Heading (MeSH) and search query used were: “(“COVID-19” OR “SARS-CoV-2” OR “coronavirus disease 2019”) AND (“treatment” OR “therapy”) AND (“outpatient”) AND (“hospitalization”)” AND (“randomized clinical trial”). We also screened the reference list of reviewed articles for studies not captured in our initial search. We excluded case reports, case series, retrospective, propensity-matched studies, non-randomized clinical trials, review articles, meta-analyses, guidelines, studies with fewer than 30 participants, studies that did not record or had no hospitalizations, protocol only publications and articles reporting only aggregate data. Trials of COVID prevention¹¹ were excluded, even if hospitalizations were recorded. Inclusion and exclusion reasons are summarized for the 281 citations in Appendix table 1. Articles underwent a blind evaluation for inclusion by two assessors (D.S. and D.F.) and disagreements were resolved by a third senior assessor (A.C.). Figure 1 shows a PRISMA flowchart of the literature reviewing process. The following parameters were extracted by at least one reviewer from studies: baseline SARS-CoV-2 serology status, time from onset of symptoms to treatment, study dates, recruiting countries, gender, age (including the fraction of participants over age 50, 60 and 65), ethnicity, risk factors for COVID-19 progression (systemic arterial hypertension, diabetes mellitus, and obesity), sample size, dosage type of control, hospitalizations and deaths in each arm, and time to symptom resolution (Appendix Table 2). Study dates were used to infer predominant VOCs. The studies were grouped into classes by CCP, mAbs, antivirals or repurposed drugs.

Figure 1.

PRISMA flowchart for randomized controlled trials (RCT) selection in this systematic review.

** All excluded by a human

2.3. Assessment of Risk of Bias and GRADE Assessment

A risk of bias assessment of each selected RCT was performed by COVID-19-NMA initiative^12,13. Within-trial risk of bias was assessed, using the Cochrane ROB tool for RCTs¹⁴. We explored clinical heterogeneity (e.g., risk factors for progression, time between onset of symptoms and treatment administration, and predominant variants of concern at the time of the interventions) and calculated statistical heterogeneity using τ², Cochran’s Q and estimated this using the I² statistic, which examines the total variation percentage across studies due to heterogeneity rather than chance. Each study was evaluated by at least two reviewers.

We used the GRADE (The Grading of Recommendations Assessment, Development and Evaluation) system criteria to assess the quality of the body of evidence associated with specific outcomes, and constructed a ‘Summary of Findings’ table (Appendix Table 3), which defines the certainty of a body of evidence as the extent to which one can be confident that an estimate of effect or association is close to the true quantity of specific interest¹⁴. Publication bias was assessed by visual inspection of funnel plots.

2.4. Statistical Analysis

Descriptive analysis included time-to-treatment, geography (country) of the study, age, sex, race, ethnicity, seropositive, hospital type and medical high-risk conditions. The unweighted pooling ARR, RRR, NNT were calculated based on the arithmetic summation of the total hospitalization or death numbers in each therapeutic category.

Odds ratios (OR) and 95% confidence intervals (CI) were used to show the direction of effect and its significance in comparing treatment group and control groups. The studies were weighted with the Mantel-Haenszel method. The effect heterogeneity was calculated estimating the I-squared (I²) inconsistency index. If significant heterogeneity was detected (I² > 50% and Cochran’s Q test for heterogeneity was significant (p < 0.10)), a random effect model was performed; otherwise, a fixed (common) effect model was performed. Weight, heterogeneity, between-study variance, and significance level were displayed in forest plots. Robustness of hospital risk reduction utilized a leave the highest enrollment study out. The significance level was 0.05. The figures were created in Prism software, R (version 4.2.1) and its statistical package “meta” (version 6.0–0). All the data manipulation and the analyses were performed in Excel, Prism, MedCalc (version 20.106), R and REVMAN.5.

2.5. Role of the Funding Source

The study sponsors did not contribute to the study design; to the collection, analysis, and interpretation of data; to manuscript preparation, nor to the decision to submit the paper for publication.

3. RESULTS

3.1. Trial Characteristics

We reviewed in detail 61 distinct outpatient RCT publications for 70 trial arms including 33 different interventions, concluded before May 22, 2023, across waves sustained by different SARS-CoV-2 variants of concern (VOC) and different vaccination periods in diverse patient populations (Figure 2). The studies varied in reporting outcomes of hospitalization, whether all-cause or COVID-19 related (Appendix Table 2). The CCP group included 3 RCTs with all-cause hospitalization, 2 trials with COVID-19 related hospitalizations only and one trial with life-threatening respiratory distress in elderly individuals, deemed equivalent to hospital outcome (Appendix Table 2). The mAb RCTs included 4 trials with all-cause hospitalizations and 5 that used COVID-19 related hospitalizations as the outcome. The small molecule antivirals had 12 RCTs with all-cause hospitalizations and 5 with COVID-19 related hospitalizations, while 29 RCT’s of repurposed drugs used all-cause hospitalizations and 10 trials restricted to COVID-19 related hospitalizations. Here we report the hospitalizations as a composite of the two hospital types. Because inclusion criteria varied across the RCTs, control group hospitalization rates varied from 0 to 31% with a mean of 1.6% (Table 1). Three of five CCP RCTs had higher control arm hospitalization rates (11% – 31%) than all other antiviral RCTs, indicating that they studied sicker populations.⁹ (Table 1 and Figure 3). Seven of nine mAb RCTs had control arm hospitalization rates of 4.6–8.9%, the same range as CCP-CSSC-004 (6.3%)⁹. Control hospitalization rates in the molnupiravir-MOVE-OUT⁷, nirmatrelvir/ritonavir⁵ and remdesivir¹⁵ RCTs ranged from 5.3% to 9.7%. Low hospitalization rates were found in RCTs that had many vaccinees (metformin-COVID-OUT – 3.2%¹⁶) or in which most participants were seropositive (molnupiravir-PANORAMIC – 0.8%). Low control arm hospitalization rates were also found in two mAb RCTs – the bebtelovimab trial (1.6%)¹⁷ and REGN-CoV phase 1/2 (<2%), with the bebtelovimab RCT focusing on low-risk patients ¹⁷. Lower control hospitalization rates reduce power to detect absolute risk ratios.

Figure 2.

Duration and calendar months of the RCT in context of dominant variant(s) of concern and seropositivity rates. Study start and end for enrollments are charted with approximate time periods for variants of concern.

Table 1.

Hospital rates, risk reductions, NNT, numbers and symptom resolution

Study	Control hospitalizations %	hospitalizations % in intervention arm	ARR percent (95% CI)	RRR percent (95% CI)	NNT to prevent 1 hospitalization	Hospitalization (n) in control arm	total pts in control arm (n)	Hospitalization (n) in intervention arm	Total pts (n) in intervention arm	Symptom resolution: median duration-Intervention to control in days
CCP (5 RCT) % or totals	12	8.8	3.2 (0.9, 5.6)	26.8 (8.1, 41.7)	31	158	1315	116	1319
anti-Spike mAbs (8 RCT) % or totals	5.9	1.9	4.0 (3.2, 4.8)	67.8 (59.1, 74.7)	25	242	4102	88	4634
Small molecule antiviral (11 RCTs) total or average	1.8	1.3	0.5 (0.3, 0.8)	29.1 (15.9, 40.2)	187	314	17079	222	17025
Small molecule antiviral (10 RCTs-w/o Mol-Pan.) total or average	4.7	2.6	2.1 (1.3, 2.9)	44.4 (30.7, 55.3)	48	218	4595	119	4509
Repurposed drugs (20 RCTs) total or average	5.3	4.2	1.1 (0.5, 1.6)	20.1 (10.1, 28.9)	94	590	11121	483	11391
All (47 RCTs) total or average	3.9	2.6	1.2 (1.0, 1.5)	31.8 (25.9, 37.3)	81	1304	33617	909	34369
CCP-CONV-ert24	11.2	11.7	−0.5 (−7.0, 5.9)	−4.8 (−83.9, 40.3)	−188	21	188	22	188	NO difference 12 d vs 12 d
CCP-COV-Early35	9.3	5.9	3.4 (−1.8, 8.5)	36.2 (−27.9, 68.2)	29	19	204	12	202	NO difference 13 d vs 12 d
CCP-C3PO36	22.0	20.2	1.8 (−5.3, 8.9)	8.2 (−28.3, 34.4)	55	56	254	52	257	NO difference
CCP-Argentina10	31.3	16.3	15.0 (2.0, 28.0)	48.0 (5.8, 71.3)	7	25	80	13	80	Not reported
CCP-CSSC-0049	6.3	2.9	3.4 (1.0, 5.8)	54.3 (19.7, 74.0)	29	37	589	17	592	Not reported
CCP-Argentina (high titer)10	31.3	8.3	22.9 (9.3, 36.5)	73.3 (17.4, 91.4)	4	25	80	3	36	Not reported
CCP-CSSC-004 (<= 5 days) 9	9.7	1.9	7.7 (3.7, 11.7)	79.9 (48.4, 92.2)	13	25	259	5	257	Not reported
Bamlanivimab-BLAZE-11	6.3	1.6	4.7 (0.5, 8.9)	74.3 (24.7, 91.2)	21	9	143	5	309	NO difference 11 d to 11 d
Sotrovimab-COMET-ICE37	5.7	1.1	4.5 (2.4, 6.7)	80.0 (52.3, 91.6)	22	30	529	6	528	Not reported
Bamlanivimab/etesevimab-BLAZE-125	7.0	2.1	4.8 (2.3, 7.4)	69.5 (40.8, 84.3)	21	36	517	11	518	YES-8d vs 9d p=0.007
Casirivimab/imdevimab-REGEN-COV Ph 32	4.6	1.3	3.3 (2.0, 4.6)	71.3 (51.7, 82.9)	30	62	1341	18	1355	YES-10 d vs 14 p=0.0001
Casirivimab/imdevimab-REGEN-COV Ph 1/238	1.9	0.6	1.3 (−0.4, 3.1)	70.1 (−24.4, 92.8)	76	5	266	3	533	Not reported
Bebtelovimab-BLAZE-417	1.6	1.6	−0.04 (−3.1, 3.0)	−2.4 (−615.7, 85.4)	−2667	2	128	2	125	YES-6d to 8d p=0.003
Regdanvimab-CT-P5926	8.7	4.4	4.2 (−1.9, 10.3)	48.8 (−25.2, 79.0)	23	9	104	9	203	YES 6 d vs 9 d p=0.01
Regdanvimab-CT-P59–227	7.9	2.4	5.4 (3.1, 7.8)	69.1 (46.4, 82.2)	18	52	659	16	656	8 d to 13 d
Tixagevimab–cilgavimab-TACKLE39	8.9	4.4	4.5 (1.1, 7.9)	50.4 (14.3, 71.3)	22	37	415	18	407	Not reported
Molnupiravir-MOVe-OUT6	9.7	6.8	3.0 (0.1, 5.8)	30.4 (0.8, 51.2)	34	68	699	48	709	NO difference
Molnupiravir-PANORAMIC40	0.8	0.8	−0.1 (−0.3, 0.2)	−7.0 (−41.2, 18.9)	−1853	96	12484	103	12516	YES 9 d vs 15 d
Molnupiravir-Aurobindo41	0.0	0.0	NC	NC	0	0	610	0	610	Yes 10 d vs 14 d p<0.001
Nirmatrelvir/ritonavir-EPIC-HR5	6.3	0.8	5.5 (4.0, 7.1)	87.8 (74.7, 94.1)	18	66	1046	8	1039	Not reported
Remdesivir-PINETREE15	5.3	0.7	4.6 (1.8, 7.4)	86.5 (41.4, 96.9)	22	15	283	2	279	YES-Alleviation of symptoms by day 14 (rate ratio, 1.92; 95% CI, 1.26 to 2.94)
Interferon Lambda-TOGETHER42	3.9	2.3	1.7 (0.1, 3.2)	42.6 (3.4, 65.9)	60	40	1018	21	931
Interferon Lambda-ILIAD43	3.3	3.3	0 (−9.1, 9.1)	0 (−1426, 93.4)		1	30	1	30	No difference
Interferon Lambda-COVID-Lambda44	3.3	3.3	0 (−6.4, 6.4)	0 (−586.9, 85.4)		2	60	2	60	NO difference 20 d vs 20 d
Sofosbuvir and daclatasvir-SOVODAK45	14.3	3.7	10.6 (−4.2, 25.4)	74.1 (−117, 96.9)	9	4	28	1	27	NO difference in 7 d symptoms
Favipavir-Avi-Mild-1946	1.7	5.4	−3.7 (−8.4, 1.1)	−219 (−1447, 34.3)	−27	2	119	6	112	NO difference 7d vs 7d
Favipiravir-Iran47	5.1	10.5	−5.4 (−17.4, 6.6)	−105.3 (−955.6, 60.1)	−19	2	39	4	38
Favipiravir-FLARE48	0.0	1.7	−1.7 (−5.0, 1.6)	NA	−59	0	60	1	59
Favipiravir/Lopinavir/Ritonavir-FLARE48	0.0	1.6	−1.6 (−4.8, 1.5)	NA	−61	0	60	1	61
Lopinavir/Ritonavir-FLARE48	0.0	1.7	−1.7 (−5.0, 1.6)	NA	−60	0	60	1	60
Lopinavir/ritonavir-TREAT NOW49	2.7	3.2	−0.5 (−3.7, 2.6)	−19.8 (−251, 59.1)	−190	6	226	7	220	6 d to 6 d
Lopinavir/ritonavir-TOGETHER18	4.8	5.7	−0.9 (−4.9, 3.1)	−18.4 (−155.4, 45.1)	−112	11	227	14	244	NO difference by Cox proportional HR
Tenofovir Disproxil Fumarate Plus Emtricitabine-AR0-CORONA50	3.3	6.7	−3.3 (−14.3, 7.7)	−100 (−1989.8, 80.9)	−30	1	30	2	30
Metformin-COVID-OUT16	3.2	1.3	1.8 (0.1, 3.5)	57.5 (3.8, 81.3)	55	19	601	8	596	NO difference
Metformin-TOGETHER51	11.8	11.2	0.7 (−5.5, 6.8)	5.6 (−60.8, 44.6)	152	24	203	24	215	not reported
Fluvoxamine-TOGETHER21	12.8	10.1	2.7 (−0.5, 5.9)	21.1 (−4.8, 40.6)	37	97	756	75	741	NO difference-40% resolved by day 14
Fluvoxamine-STOP COVID52	8.3	0.0	8.3 (1.9, 14.7)	1 (1, 1)	12	6	72	0	80	YES (100% vs 91.7% resolved on day 7) p=0.009
Fluvoxamine-COVID-OUT16	1.7	2.0	−0.3 (−2.5, 1.9)	−17.6 (−281, 63.7)	−333	5	293	6	299	No difference (14 symptoms on 4 pt scale over 14 days)
Fluvoxamine ACTIV-653	0.3	0.1	0.18 (−0.4, 0.7)	54.7 (−398.3, 95.9)	555	2	607	1	670	12 d to 13 d
Fluvoxamine/budesonide-TOGETHER54	1.1	0.9	0.1 (−0.9, 1.1)	12.5 (−140.1, 68.1)	738	8	738	7	738	not reported
Ivermectin-TOGETHER55	14.0	11.6	2.4 (−1.2, 5.9)	16.8 (−9.9, 37.1)	42	95	679	79	679	NO difference-40% resolved by day 14
Ivermectin-COVID-OUT16	1.4	1.1	0.3 (−1.3, 1.9)	23.9 (−181, 79.4)	299	5	356	4	374	No difference (14 symptoms on 4 pt scale over 14 days
Ivermectin Iran56	5.0	7.1	−2.1 (−6.1, 1.9)	−42.3 (−178, 27.2)	−47	14	281	19	268	NO difference
Ivermectin-ACTIV-657	1.2	1.2	−0.1 (−1.1, 1.0)	−5.3 (−158, 57.0)	−1634	9	774	10	817	No difference (12d vs 13 d)
Ivermectin high dose-ACTIV-658	0.3	0.8	−0.5 (−1.4, 0.4)	−150.1 (−1188, 51.1)	−200	2	604	5	602	11 d vs 11 d no difference
Hydroxychloroquine-TOGETHER18	4.8	3.7	1.1 (−2.7, 4.9)	22.9 (−88.1, 68.4)	90	11	227	8	214	NO difference by Cox proportional HR
Hydroxychloroquine-COVID-19 PEP59	4.7	2.4	2.4 (−1.1, 5.9)	50.2 (−43.1, 82.7)	42	10	211	5	212	NO Difference in symptom severity score over 14 days
Hydroxychloroquine-AH COVID-1960	0.0	3.6	−3.6 (−7.1, −0.1)	NA	−28	0	37	4	111	NO difference 14 d vs 12 d
Hydroxychloroquine-BCN PEP-CoV-261	7.0	5.9	1.1 (−4.5, 6.7)	16.0 (−103, 65.2)	89	11	157	8	136	NO difference 10 d vs 12 d
Hydroxychloroquine-BMG62	4.8	3.4	1.4 (−4.0, 6.9)	29.9 (−154, 80.6)	69	4	83	5	148	NO difference 11 d vs 12 d
Hydroxychloroquine-Utah63	2.6	4.6	−2.0 (−6.2, 2.2)	−73.8 (−481.6, 48.0)	−51	4	151	7	152	6 d to 6 d
Hydroxychloroquine/Azithromycin-Brazil64	2.4	2.4	0 (−6.5, 6.5)	0 (−1447, 93.5)	100	1	42	1	42
Nitazoxanide-Romark22	2.6	0.5	2.0 (−0.4, 4.5)	78.8 (−79.7, 97.5)	49	5	195	1	184	Yes mild illness (13 d vs 18 d, p=0.01), NO difference for moderate illness
Colchicine-COLCORONA20	5.8	4.7	1.2 (−0.1, 2.5)	20.0 (−2.8, 37.7)	86	131	2253	104	2235	Not reported
Losartan-MN65	1.7	5.2	−3.5 (−10.1, 3.1)	−205 (−2749, 67.3)	−29	1	59	3	58
Niclosamide66	2.9	0.0	2.9 (−2.7, 8.6)	1 (1, 1)	34	1	34	0	33	NO difference 12 d vs 15 d
Aspirin-ACTIV-4B67	0.7	0.7	0.04 (−1.9, 2.0)	5.6 (−1395, 94)	2448	1	136	1	144	Not reported
2.5-mg apixaban-ACTIV-4B67	0.7	0.7	−0.01 (−2.0, 2.0)	−0.7 (−1494, 93.6)	−18360	1	136	1	135	Not reported
5-mg apixaban ACTIV-4B67	0.7	1.4	−0.7 (−3.1, 1.7)	−90.2 (−1974, 82.6)	−151	1	136	2	143	Not reported
Sulodexide68	29.4	17.7	11.7 (1.1, 22.3)	39.7 (3.5, 62.3)	9	35	119	22	124	Not reported
Enoxaparin-ETHIC69	10.5	11.4	−0.9 (−9.2, 7.4)	−8.6 (−131, 49.0)	−111	12	114	12	105	Not reported
Enoxaparin-OVID70	3.4	3.4	−0.1 (−3.3, 3.2)	−1.7 (−166, 61.2)	−1740	8	238	8	234	Not reported
Inhaled Ciclesonide-COVIS71	3.4	1.7	1.8 (−1.4, 4.9)	51.4 (−85.2, 87.2)	56	7	203	3	179	19 d to 19 d
Inhaled ciclesonide-COVERAGE72	11.2	12.7	−1.5 (−10.1, 7.1)	−13.5 (−134, 45.0)	−66	12	107	14	110	NO difference 13 d vs 12 d
Zinc73	6.0	8.6	−2.6 (−12.4, 7.2)	−43.7 (−471.4, 63.9)	−38	3	50	5	58	11 dto 10 d
Ascorbic acid73	6.0	4.2	1.8 (−6.8, 10.5)	30.6 (−297.6, 87.9)	55	3	50	2	48	12 d to 10 d
Zinc/Ascorbic acid73	6.0	12.1	−6.1 (−16.7, 4.6)	−101.1 (−637, 45.1)	−16	3	50	7	58	10 d too 10 d
Homeopathy-COVID-Simile74	6.8	2.4	4.4 (−4.3, 13.2)	65.1 (−222.6, 96.2)	23	3	44	1	42
Saliravira75	28.6	0.0	28.6 (16.7, 40.4)	1 (1, 1)	4	16	56	0	87	YES 9d vs 14 d p<0.05
Azithromycin-Atomic276	11.6	10.3	1.2 (−5.9, 8.4)	10.5 (−72.3, 53.6)	82	17	147	15	145	Not reported
Azithromycin-ACTION28	0.0	4.0	−4.0 (−7.4, −0.6)	NA	−25	0	72	5	125	No difference resolution day 14
Resveratrol77	6.0	2.0	4.0 (−3.6, 11.6)	66.7 (−210, 96.4)	25	3	50	1	50	Not reported

Figure 3.

Percent hospitalizations in control groups sorted by therapy type and descending control hospitalization rates.

3.2. Trial Outcome Comparison

Examining RCTs by agent class, statistically significant relative risk reductions in hospitalization were found in two of five CCP RCTs, six of nine mAb RCTs, four of 17 small molecule antiviral RCTs, but just 2 of 39 repurposed drug RCTs (Table 1). Except for the bebtelovimab RCT (2 hospitalizations in each arm¹⁷), mAb RCTs reduced the risk of hospitalization by 50–80% (average 75%). Two of the three small molecule antiviral drugs (remdesivir¹⁵ and nirmatrelvir/ritonavir⁵) showed very high levels of relative risk reduction - 87% and 88% respectively - but molnupiravir reduced risk of hospitalization by only 30%⁷ (excluding the large no reduction seen in the PANORAMIC RCT²⁵). The lopinavir/ritonavir combination was associated with a non-significant increase in risk of hospitalization¹⁸.

Among repurposed drug RCTs, all except metformin (58%) and sulodexide (40%), showed small and non-significant relative risk reductions of hospitalization - ivermectin¹⁹, colchicine²⁰, fluvoxamine²¹ and hydroxychloroquine¹⁸. The nitazoxanide²² RCT found one hospitalization among 184 treated participants compared to five hospitalizations among 195 controls, too few events to achieve significance.

Absolute risk reductions (ARR) and number needed to treat (NNT) to avert hospitalizations varied across studies and treatment classes (Table 1). In general, except for the repurposed drugs the absolute risk difference approximated 3% if one excludes the molnupiravir-Panoramic Study from SMA. The CCP RCTs had an ARR of 3.2% (95%CI-0.9–5.6), mAbs RCTs had an ARR of 4.0% (95%CI-3.2–4.8), small molecule antivirals excluding molnupiravir-Panoramic had ARR of 2.1% (95%CI-1.3–2.9) and the repurposed drugs had a smaller ARR at 1.1% (95%CI-0.5–1.6). The number needed to treat to prevent hospitalizations approximated 30 in the trials, with a few notably low with CCP-Argentina (NNT=7) Nirmatrelvir/ritonavir (NNT=18), except those using repurposed drugs, where NNT averaged 70 (Table 1).

3.3. Pooled Meta-analysis

In the pooled meta-analysis by class group, the CCP RCTs had a fixed effect OR of 0.69 (95% CI=0.53 to 0.9) with moderate heterogeneity (I²=43%), the mAbs had a fixed effect OR of 0.31 (95% CI=0.24–0.40) with low heterogeneity (I²=0%), the small molecule antivirals had a random effect OR of 0.78 (95% CI=0.48–1.33) with high heterogeneity (I²=69%) and the repurposed drugs had a random effect OR of 0.82 (95% CI- 0.72–0.93) with low heterogeneity (I²=0) (Figure 4, Appendix Table 4). A biologic reason to use a fixed model for CCP and mAbs is that both formulations have the same active agent as specific antibody and thus there is a high degree of similarity in these two antibody interventions. Both antiviral small molecules and repurposed drugs comparison involve many types and classes of drugs for which the random effect model for the group is biologically more plausible than treating them as fixed. The meta-analysis of all interventions had a random effect OR of 0.67 (95% CI=0.57–0.80) with high heterogeneity (I²=52%) (Appendix Figure 2). Because regional parts of the world might have different thresholds for the hospitalization outcome we grouped by region (USA, Brazil, Europe, Midde East or World) across diverse intervention classes to indicate that the intervention class had more of an effect than region (Appendix Figure 3).

Figure 4.

Odds ratio for hospitalizations with diverse therapeutic interventions, grouped according to mechanism of action (CCP, mAbs, small molecule antivirals and repurposed drugs).

Ten RCTs compared hospitalization rates in early or late interventions (dated from symptom onset) that were extractable from the published papers or supplementary data as a post-hoc analysis (Figure 5). The small molecule drugs showed no significant reduction in the OR with segregation of early treatment from late treatment. In contrast, the antibody therapies showed a difference by treatment timing. Pooling the two classes of antibody treatment, the OR for early treatment was 0.65 (95%CI=0.49–0.85), while the OR for later treatment was 0.86 (95%CI=0.66–1.12).

Figure 5.

Odds ratio for point estimates for hospitalization in RCT subgroups treated A) within 5 days since onset of symptoms and also B) over 5 days within same trial.

A) Early treatment-Fixed and random effect model B) Late treatment-Fixed and random effect model

3.4. Robustness of the Meta-analysis

Within the CCP RCTs excluding either CCP-Argentina for the nonhospital endpoint or CONV-ERT for methylene blue inactivation of antibody function only changed the OR by 0.05 with 95% CI remaining less than 1 for the fixed effect model (Appendix Figure 4). Adding the 7 all-cause hospitalizations to CSSC-004, increased the OR by 0.02 and 95% CI by 0.01, essentially no change (Appendix Figure 4). In a leave out the largest study by participants sensitivity analysis, the OR was not significantly altered in the model effects by more than 0.1 except for SMA where removal of the large Molnupirivir-Panoramic study changed common effect model OR from 0.7 to 0.54. Both the mAb and RP did not change OR results (Appendix Figure 5).

3.5. Certainty of Evidence

All four trial classes showed reduced rates of hospitalization for each group. The final certainty of the available evidence with GRADE assessment (Appendix Table 3) showed a high certainty level within CCP trials, moderate certainty with mAbs, and low certainty with small molecule antivirals and repurposed drugs. The main reason for downgrading individual and pooled studies was imprecision, related to small number of participants and the wide confidence intervals around the effect, followed by ROB (Appendix Figure 6). We did not find concerns in any of the GRADE factors for CCP RCTs, so we graded them as high level of certainty. mAbs were downgraded to moderate certainty due to ROB (in 4 of the 8 included RCTs, ROB for the outcome hospitalization was judged of some concern). In the cumulative analysis, small molecule antivirals were downgraded to low certainty of evidence because of ROB (some/high ROB in 4 RCTs) and inconsistency (due to high heterogeneity), while repurposed drugs were downgraded to low certainty due to ROB (some/high ROB in 5 of the 11 comparisons) and indirectness (due to large difference in mechanism of action of the included drugs). The ROB was independently evaluated by the COVID-19-Network Meta-Analysis (NMA) initiative for most of the RCTs (Appendix Figure 6). Funnel plot analysis with Egger Test shows a low risk of publication bias except for the mAbs, for which either the efficacy of high dose antibodies or non-reporting bias are plausible explanations (Appendix Figure 7).

3.6. Outpatient Intervention Mortality

While several RCTs showed fewer deaths in the treatment arm, no outpatient study was powered to compare differences in mortality. Because of the low rate of deaths during trials the absolute risk reductions amongst the 4 antiviral classes are all below 1% corresponding to relative risk reductions of 20%, 81%, 87% and 22% for CCP, mAbs, small molecule antivirals or repurposed drugs, respectively (Appendix Table 5).

3.7. Time To Symptom Resolution

The two most effective CCP RCTs (Argentine¹⁰ and CSSC-004⁹) did not compare time to symptom resolution, while the COV-Early²³ and ConV-ERT²⁴ RCTs reported no difference in the median time of symptom resolution in the two groups²⁴ (Table 1). The mAbs noted faster resolution by 1, 2, 3, 4 or 5 days for bamlanivimab/etesevimab²⁵, bebtelovimab¹⁷, regdanvimab²⁶, casirivimab/imdevimab², or redanvimab²⁷ respectively. The smaller bamlanivimab-only RCT did not show a difference¹. Of the three SMAs that noted reductions in hospitalizations, molnupiravir was associated with no difference in time of symptom resolution in MOVe-OUT⁷ but improvements in both PANORAMIC²⁵ and Aurobindo²⁷ RCTs. The 3-day outpatient remdesivir RCT showed that symptoms were alleviated by day 14 nearly twice as often¹⁵. The nirmatrelvir/ritonavir RCT did not report on this parameter⁵. Seven of 10 RCTs in the antiviral group did not show faster symptom resolution with intervention. The three RCTs largely performed in Brazil for fluvoxamine, ivermectin¹⁹ and hydroxychloroquine¹⁸ noted no differences in symptom resolution. Metformin did not evidence faster symptom resolution despite reducing hospitalizations. Three of the 25 RCTs reporting symptom resolution in the repurposed drug group noted faster symptom resolution.

3.8. Costs

mAbs and intravenous remdesivir schedules cost about 1000 to 2000 Euros per patient, respectively, while the oral drugs are much less than 1000 Euros per patient (Table 2). By comparison, the cost of CCP approximates 200 Euros per patient, and the cost for repurposed drugs is even lower. Considering the absolute risk reduction in hospitalization, the number needed to treat to prevent a single hospitalization is often very high, as are the associated costs. With the recently patented antivirals, costs for outpatient treatment often exceed the cost of a COVID-19 hospitalization²⁸.

Table 2.

Summary of historical efficacy of different therapeutics against SARS-CoV-2 VOCs.

	approximate cost per patient	average NNT (sourced from Table 2)	cost to prevent a single hospitalization (€)	efficacy against VOC Alpha	efficacy against VOC Delta	efficacy against VOC BA.1	efficacy against VOC BA.2	efficacy against BA.4/5	efficacy against BQ.1.1
bamlanivimab+etesesevimab	2000	21	42,000		restricted 04/2021
casirivimab+imdevimab	2000	30	60,000			restricted 01/2022
sotrovimab	1000	22	22,000				restricted 03/2022
tixagevimab+cilgavimab	1000	22	22,000						restricted 10/22
regdanvimab	300	23	6,900
bebtelovimab	2000	Not calculated (low-risk pts)	Not calculated (low-risk pts)
nirmatrelvir	635 (5 days)	18	11,435
molnupiravir	635 (5 days))	34	21,590
remdesivir	1600 (3 days)	22 (MOVE-Out)	35,200
CCP	200 (600-ml)	31	6,200
Vax-CCP

White = drug not available at that time; green = effective; orange = partially effective; red= not effective. Restriction reported refer to initial restrictions by FDA. NNT: number needed to treat.

3.9. Variants

mAbs successively lost efficacy against Delta and Omicron, with cilgavimab (the only Omicron-active ingredient in Evusheld^™) and bebtelovimab also failing against BQ.1.1 and XBB.* sublineages (Figure 6). This has led the FDA to withdraw EUAs, while EMA has not restricted usage at all. Small molecule antivirals retain in vitro efficacy against Omicron, but concerns remain: molnupiravir showed low efficacy in vivo⁶ and is mutagenic for mammals in vitro²⁹, while nirmatrelvir/ritonavir has drug/drug interaction contraindications (CYP3 metabolites especially tacrolimus, anti-cholesterol, anti-migraine or many anti-depressants) and has been associated with early virological and clinical rebounds in immunocompetent patients³⁰. CCP from unvaccinated donors does not inhibit Omicron, but CCP from donors having any sequence of vaccination and recent, within 6 months, COVID-19 or having had boosted mRNA vaccine doses universally has high Omicron-neutralizing activity.

Figure 6.

Venn diagram of mAb efficacy against Omicron sublineages. In vitro activity of currently approved mAbs against Omicron sublineages circulating as of October 2022. Specific Omicron Spike amino acid mutations causing baseline ≥ 4-fold-reduction in neutralization against mAbs are reported. Mutations for which the majority of studies are concordant are reported: the different fold-reductions for each mAb are identified across concordant studies as color coded numbers defining the mean median values of specific reduction in each study. Sourced from https://covdb.stanford.edu/page/susceptibility-data (accessed on January31, 2023

* L452R occurs in all BA.4/BA.5 lineages, but only in several BA.2. sublineages.

R346X and K444X occur in a growing number of BA.2 and BA.4/5 sublineages as a result of convergent evolution.

DISCUSSION

The paucity of head-to-head RCT comparisons amongst outpatient COVID-19 therapies makes the choice of therapy difficult. This meta-analysis allows comparison of placebo controlled RCT interventions amongst four main intervention classes-polyclonal convalescent plasma, monoclonal antibodies, small molecule antivirals and repurposed drugs. Participant features such as risk factors for COVID-19 progression (age, obesity, comorbid conditions), vaccination status and spike protein viral variation impact the hospital outcomes as a component of heterogeniety.

Outpatient RCT data confirm that most antiviral/antimicrobial therapies are more effective when given before rather than after hospital admission. In examining the full assembly of these effective, yet molecularly disparate interventions, we note the consistent importance of early outpatient treatment for patients at risk of progression to hospitalization³¹. Treatment within 5 days of illness onset was more effective than later treatment, as would be expected for an antiviral mechanism of action. An individual participant meta-analysis of CCP that investigated the effects of early compared to late treatment and of high compared to low dose antibody levels found that both early treatment and high levels of antibody combined to most effectively reduce risk of hospitalizations³².

The relative ease of conducting inpatient RCTs may have led most initial CCP, small molecule antiviral and repurposed trials – which were conducted principally by academic institutions - to be based in hospitals, often in patients treated too late for antiviral treatment to be expected to work, given that antiviral therapy must be given early in disease. The constrained resources available for clinical research by academic medicine during pandemic conditions further interfered with trial work, and several potentially valuable RCT’s with promising findings were terminated before they could provide definitive data. The findings of such trials are reported as null but often viewed as negative, notwithstanding trends towards effectiveness, and are rarely incorporated into clinical recommendations. The pharmaceutical industry – with well-established internal resources for trials and substantial economic support – was able to perform large outpatient trials of mAbs early in the pandemic. Inpatient services are generally more accessible to physician-scientists working in academic medical centers.

The choice, however, has been narrowed in recent months, and the clinical armamentarium has been reduced to small molecule antivirals, repurposed drugs and CCP, because single and double (“cocktail”) MAbs have lost effectiveness against new VOCs³³. Both vaccine-elicited and disease-elicited antibodies are polyclonal, meaning that they include various isotypes that provide functional diversity and target numerous epitopes making variant escape much more difficult with CCP. Hence, polyclonal antibody preparations are much more resilient to the relentless evolution of variants. This is in marked contrast to mAbs, which target single epitopes of SARS-CoV-2. The exquisite mAb (and receptor binding domain) specificity renders mAbs susceptible to becoming ineffective with single amino acid changes. Plasma from individuals who have been both vaccinated and boosted is characterized by high amounts of neutralizing antibodies which can be effective against practically any existing VOC, including Omicron³⁴ (so-called “heterologous immunity”, likely due to the well-known phenomenon of “epitope spreading”). Vaccine-boosted CCP has more than ten times the amount of total SARS-CoV-2 specific antibody and viral neutralizing activity compared to the pre-omicron CCP used in the effective outpatient CCP RCTs.

In addition to efficacy, other points to consider in an outpatient pandemic are tolerability, scalability and affordability. Repurposed drugs are generally well tolerated, widely available and relatively inexpensive, but, as we have shown, have limited efficacy. By contrast, small molecule antivirals are often plagued by contraindications and side effects, which make several classes of patients reliant on passive immunotherapies. Both small molecule antivirals and mAbs take time to develop and are unaffordable in low-and-middle income countries (LMIC). CCP is instead a tolerable, scalable, and affordable treatment and is usually provided in a single IV session, in contrast to remdesivir, which requires a three-day intravenous course.

On Dec. 28, 2021 the FDA expanded the authorized emergency use of convalescent plasma with high titers of anti-SARS-CoV-2 antibodies “for the treatment of COVID-19 in patients with immunosuppressive disease or receiving immunosuppressive treatment, in either the outpatient or inpatient setting.” This EUA noted that CCP was safe and effective in immunocompetent individuals and allowed under the emergency measure of the pandemic, but expanded its use in immunosuppressed individuals to outpatient use, notwithstanding the availability of oral drugs and (at that time) two remaining effective mAb treatments for the new omicron variants of concerns.

Limitations of evidence in this review process included general meta-analysis etiologies such as English only publications, limited class subgroup analysis due to low numbers like CCP or mAb, grouping diverse mechanisms of action in the SMA and RP classes which increases heterogeneity, heterogeneity loss of power when evaluating CCP and SMA due to smaller single digit number of RCTs evaluated or reporting bias towards positive successfully executed studies which might miss marginal or futile studies. While risk of bias was independently performed on more than 80% of studies by COVID-19-NMA, the RevMan program determined the missing risk of bias. Unique limitations to outpatient COVID-19 studies are diverse patient population varying in age and comorbidities, changes in outpatient standard of care and vaccination status over both the regions and period covered which led to wide variation in hospital rates which were also influenced by regional accessibility to hospitalization, depending on hospital capacity and other outpatient intervention like mAb early in pandemic. Studies also reported either all cause hospitalization or COVID-19 related hospitalization within the 2 week or 4 week outcome reporting time period as listed in appendix tables. While the pooled OR focused on just hospital rates between studies, the full data set in appendix allowing comparison of just COVID-19 related hospitalizations, pre-Alpha period trials. The outpatient RCTs reviewed here were conducted during different time-periods during the pandemic, thus targeting different variants, and enrolled participants with different vaccination statuses. Further heterogeneity was contributed by variation across the RCTs, in participant age, medical risk factors and serological status.

The published mAbs RCTs assembled here showed better overall class efficacy than other outpatient interventional classes, yet mAb are now clinically ineffective against BQ.1.* and XBB.* Omicron variants. CCP and small molecule antivirals have comparable levels of effectiveness with many individual RCTS, but the latter have many contraindications and side effects. Repurposed drugs are largely either ineffective or mildly effective with just 2 RCT within the class approaching nirmatrelivir or mAbs. CCP is the remaining effective passive antibody therapy, which is especially important in the immunosuppressed but, as the trials show, early treatment with high levels of antibody, has value in other populations as well. Our clinical recommendation from this review is to use CCP on an out-patient basis in regions with no other therapy available regardless of vaccination status for those at high risk of progression to hospitalization.

Abbreviations:

CCP

COVID-19 convalescent plasma

mAb

monoclonal antibody

RCT

randomized controlled trial

VOC

variant of concern

Appendix

Description of trial participants

The median age of participants was about 50 years. The CCP group had a nonweighted trial average of median age equal to 58 years, while the anti-Spike mAbs, small molecule antivirals and repurposed drug groups younger average of median age was equal to 45 to 48 years. Most RCTs had more women than men, and 84% of all RCT 60,043 participants had Caucasian ethnicity (Appendix Table 2a,b).

The individual RCTs differed in the percentage of participants with risk factors for progression to severe COVID-19. Of the 37 RCTs reporting aggregated hospitalization risk factors, ten had 100% of participants with at least one hospitalization risk factor, while 5 had fewer than 50%. The bebtelovimab placebo-controlled RCT explicitly focused exclusively on low-risk individuals ¹. Individual risk factors such as diabetes mellitus occurred in 10 to 20% of participants in most RCTs. Obesity with BMI over 29 averaged near 40% of RCT participants in the 4 therapy groups after excluding the large single 25,000 molnupiravir-PANORAMIC RCT with 15% of participants with BMI’s over 30 (Appendix Table 2a,b) ²⁵.

Of 18 RCTs reporting seropositivity rates at baseline, 11 had < 25% screening seropositive (Appendix Table 2a,b, main text Figure 2). The molnupiravir-PANORAMIC RCT was an outlier, with 98% participant seropositives²⁵. All but one² of the RCTs enrolled within 8 days (median) of symptom onset. In RCTs of anti-Spike mAbs and small molecule antivirals, median time from illness onset to intervention was 3.5 to 4 days (Appendix Fig 1, Appendix Table 2a,b). CCP and repurposed antiviral drug RCTs enrolled within 4.5 to 5.1 days from symptom onset.

The CCP RCTs were conducted in the USA^3,4, Argentina⁵, Netherlands⁶ and Spain⁷ (Appendix Table 2). The anti-Spike mAb RCTs all had a USA component, but were largely centered in the Americas except for the sotrovimab RCT, which took place in Spain⁸. Many of the repurposed drugs and nirmatrelvir/ritonavir RCTs recruited worldwide⁹.

Four of the five CCP RCTs (COV-Early⁶, CONV-ERT⁷, Argentina⁵ and C3PO⁴), and all eight anti-Spike mAb RCTs took place in the setting of the D614G variant and the Alpha VOC (main text-Figure 2). By contrast, most of the molnupiravir, nirmatrelvir/ritonavir⁹ and interferon lambda RCTs were conducted in the setting of the Delta VOC. The ivermectin¹⁰ and fluvoxamine¹¹ RCTs ended as the Delta VOC wave began in August 2021. The remdesivir RCT spanned D614G, Alpha and Beta VOC but missed Delta¹². The CSSC-004 RCT of CCP was the longest RCT reviewed, spanning periods characterized by D614G to Delta VOC infections³.

Appendix Figure 1.

Comparison of mean interval from symptom onset to enrollment/intervention as well as per protocol interval inclusion limit for all participants.

Appendix Figure 2: Odds ratio for hospitalizations from all interventions.

Therapeutic interventions ordered according to mechanism of action (CCP, anti-Spike mAbs, small molecule antivirals and repurposed drugs

Appendix Figure 3: Odds ratio for hospitalizations from all interventions by region.

Therapeutic interventions ordered region including diverse interventions

Appendix Figure 4: Odds ratio for hospitalizations within CCP group.

A) All CCP trials excluding CCP-Argentina with a non hospital endpoint of severe respiratory distress or B) All CCP excluding CONV-ERT because of methylene blue inactivation of antibody function. C) all cause hospitalization for CSSC-004 to match all cause hospitalization for other CCP studies

Appendix Figure 5: Odds ratio for hospitalizations sensitivity analysis.

Odds ratio for hospitalizations with diverse therapeutic interventions, grouped according to mechanism of action (CCP, mAbs, small molecule antivirals and repurposed drugs) with the largest enrollment removed

Appendix Figure 6:

Risk of bias by RCT

Appendix Figure 7: Funnel plots by RCTs class.

Publication bias was examined with Egger Test for Funnel Plot asymmetry. A weighted regression model with multiplicative dispersion used standard error for prediction. A) CCP Funnel Plot Asymmetry (t=1.0879, df=3, p=0.3562). The limit estimate (as sei≥0) b=0.4699 (CI:-2.0201,2.9598) B) anti-Spike mAbs Funnel Plot Asymmetry (t=0.5087, df=7, p=0.6266). The limit estimate (as sei≥0) b=-1.2940 (CI:-2.0658, 0.5221) C) small molecule antivirals Funnel Plot Asymmetry (t=0.0695, df=15, p=0.9455). The limit estimate (as sei≥0) b= −0.2627 (CI:-0.7860, 0.2606) and D) repurposed drugs Funnel Plot Asymmetry (t=0.0645, df=37, p=0.9489). The limit estimate (as sei≥0) b= −0.2080 (CI: −0.4146, −0.0013). For anti-Spike mAbs RCTs, there is a suggestion of missing studies on the right side of the plot, where results would be unfavourable to the experimental intervention, for which either very high efficacy of high-dose anti-Spike mAbs or non-reporting bias is a plausible explanation.

Table 1.

Included and Excluded trials in search of May 2023 281 studies

publication number	excluded reason	included in review	class	RCT per study	unique intervention	study name	ref
12		1	CCP	1	1	CCP-CONV-ert	Alemany A, Millat-Martinez P, Corbacho-Monne M, et al. High-titre methylene blue-treated convalescent plasma as an early treatment for outpatients with COVID-19: a randomised, placebo-controlled trial. Lancet Respir Med 2022; 10(3): 278–88.
92		1	CCP	1		CCP-COV-early	Gharbharan A, Jordans C, Zwaginga L, et al. Outpatient convalescent plasma therapy for high-risk patients with early COVID-19: a randomized placebo-controlled trial. Clin Microbiol Infect 2022.
132		1	CCP	1		CCP-C3PO	Korley FK, Durkalski-Mauldin V, Yeatts SD, et al. Early Convalescent Plasma for High-Risk Outpatients with Covid-19. N Engl J Med 2021; 385(21): 1951–60.
150		1	CCP	1		CCP-Argentina	Libster R, Perez Marc G, Wappner D, et al. Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults. N Engl J Med 2021; 384(7): 610–8.
252		1	CCP	1		CCP-CSSC-004	Sullivan DJ, Gebo KA, Shoham S, et al. Early Outpatient Treatment for Covid-19 with Convalescent Plasma. N Engl J Med 2022; 386(18): 1700–11.
54		1	mab	1	1	Bamlanivimab-BLAZE-1	Chen P, Nirula A, Heller B, et al. SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19. N Engl J Med 2021; 384(3): 229–37.
72		1	mab	1	1	Bebtelovimab-BLAZE-4	Dougan M, Azizad M, Chen P, et al. Bebtelovimab, alone or together with bamlanivimab and etesevimab, as a broadly neutralizing monoclonal antibody treatment for mild to moderate, ambulatory COVID-19. medRxiv 2022: 2022.03.10.22272100.
73		1	mab	1	1	Bamlanivimab/etesevimab-BLAZE-1	Dougan M, Nirula A, Azizad M, et al. Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19. N Engl J Med 2021; 385(15): 1382–92.
98		1	mab	1	1	Sotrovimab-COMET-ICE	Gupta A, Gonzalez-Rojas Y, Juarez E, et al. Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab. N Engl J Med 2021.
129		1	mab	1	1	Regdanvimab-CT-P59–2	Kim JY, Sandulescu O, Preotescu LL, et al. A Randomized Clinical Trial of Regdanvimab in High-Risk Patients With Mild-to-Moderate Coronavirus Disease 2019. Open Forum Infect Dis 2022; 9(8): ofac406.
184		1	mab	1	1	Tixagevimab–cilgavimab-TACKLE	Montgomery H, Hobbs FDR, Padilla F, et al. Efficacy and safety of intramuscular administration of tixagevimab-cilgavimab for early outpatient treatment of COVID-19 (TACKLE): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2022; 10(10): 985–96.
195		1	mab	1	1	Casirivimab/imdevimab-REGEN-COV Ph 1/2	Norton T, Ali S, Sivapalasingam S, et al. REGEN-COV Antibody Combination in Outpatients With COVID-19 – Phase 1/2 Results. medRxiv 2022: 2021.06.09.21257915.
251		1	mab	1		Regdanvimab-CT-P59	Streinu-Cercel A, Sandulescu O, Preotescu LL, et al. Efficacy and Safety of Regdanvimab (CT-P59): A Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Trial in Outpatients With Mild-to-Moderate Coronavirus Disease 2019. Open Forum Infect Dis 2022; 9(4): ofac053.
275		1	mab	1		Casirivimab/imdevimab-REGEN-COV Ph 3	Weinreich DM, Sivapalasingam S, Norton T, et al. REGEN-COV Antibody Combination and Outcomes in Outpatients with Covid-19. N Engl J Med 2021; 385(23): e81.
7		1	rp	1	1	Homeopathy-COVID-Simile	Adler UC, Adler MS, Padula AEM, et al. Homeopathy for COVID-19 in primary care: A randomized, double-blind, placebo-controlled trial (COVID-Simile study). J Integr Med 2022; 20(3): 221–9.
24		1	rp	1		Enoxaparin-OVID	Barco S, Voci D, Held U, et al. Enoxaparin for primary thromboprophylaxis in symptomatic outpatients with COVID-19 (OVID): a randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet Haematol 2022; 9(8): e585-e93.
39		1	rp	3		Metformin-COVID-OUT	Bramante CT, Huling JD, Tignanelli CJ, et al. Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19. N Engl J Med 2022; 387(7): 599–610.
48		1	rp	1	1	Niclosamide	Cairns DM, Dulko D, Griffiths JK, et al. Efficacy of Niclosamide vs Placebo in SARS-CoV-2 Respiratory Viral Clearance, Viral Shedding, and Duration of Symptoms Among Patients With Mild to Moderate COVID-19: A Phase 2 Randomized Clinical Trial. JAMA Netw Open 2022; 5(2): e2144942.
58		1	rp	1		Inhaled Ciclesonide-COVIS	Clemency BM, Varughese R, Gonzalez-Rojas Y, et al. Efficacy of Inhaled Ciclesonide for Outpatient Treatment of Adolescents and Adults With Symptomatic COVID-19: A Randomized Clinical Trial. JAMA Intern Med 2022; 182(1): 42–9.
60		1	rp	3	1	Aspirin-ACTIV-4B	Connors JM, Brooks MM, Sciurba FC, et al. Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19: The ACTIV-4B Randomized Clinical Trial. JAMA 2021; 326(17): 1703–12.
61		1	rp	1	1	Enoxaparin-ETHIC	Cools F, Virdone S, Sawhney J, et al. Thromboprophylactic low-molecular-weight heparin versus standard of care in unvaccinated, at-risk outpatients with COVID-19 (ETHIC): an open-label, multicentre, randomised, controlled, phase 3b trial. Lancet Haematol 2022; 9(8): e594-e604.
76		1	rp	1	1	Inhaled ciclesonide-COVERAGE	Duvignaud A, Lhomme E, Onaisi R, et al. Inhaled ciclesonide for outpatient treatment of COVID-19 in adults at risk of adverse outcomes: a randomised controlled trial (COVERAGE). Clin Microbiol Infect 2022; 28(7): 1010–6.
93		1	rp	1	1	Sulodexide	Gonzalez-Ochoa AJ, Raffetto JD, Hernandez AG, et al. Sulodexide in the Treatment of Patients with Early Stages of COVID-19: A Randomized Controlled Trial. Thromb Haemost 2021; 121(7): 944–54.
107		1	rp	1		Azithromycin-Atomic2	Hinks TSC, Cureton L, Knight R, et al. Azithromycin versus standard care in patients with mild-to-moderate COVID-19 (ATOMIC2): an open-label, randomised trial. Lancet Respir Med 2021; 9(10): 1130–40.
115		1	rp	1		Hydroxychloroquine-BMG	Johnston C, Brown ER, Stewart J, et al. Hydroxychloroquine with or without azithromycin for treatment of early SARS-CoV-2 infection among high-risk outpatient adults: A randomized clinical trial. EClinicalMedicine 2021; 33: 100773.
128		1	rp	1	1	Saliravira	Khorshiddoust RR, Khorshiddoust SR, Hosseinabadi T, et al. Efficacy of a multiple-indication antiviral herbal drug (Saliravira(R)) for COVID-19 outpatients: A pre-clinical and randomized clinical trial study. Biomed Pharmacother 2022; 149: 112729.
145		1	rp	1	1	Fluvoxamine-STOP COVID	Lenze EJ, Mattar C, Zorumski CF, et al. Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial. JAMA 2020; 324(22): 2292–300.
168		1	rp	1		Fluvoxamine-ACTIV-6	McCarthy MW, Naggie S, Boulware DR, et al. Effect of Fluvoxamine vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19: A Randomized Clinical Trial. JAMA 2023; 329(4): 296–305.
173		1	rp	1	1	Resveratrol	McCreary MR, Schnell PM, Rhoda DA. Randomized double-blind placebo-controlled proof-of-concept trial of resveratrol for outpatient treatment of mild coronavirus disease (COVID-19). Sci Rep 2022; 12(1): 10978.
281		1	rp	1		Hydroxychloroquine-BCN PEP-CoV-2	Mitja O, Corbacho-Monne M, Ubals M, et al. Hydroxychloroquine for Early Treatment of Adults With Mild Coronavirus Disease 2019: A Randomized, Controlled Trial. Clin Infect Dis 2021; 73(11): e4073-e81.
189		1	rp	1	1	Ivermectin high dose-ACTIV-6	Naggie S, Boulware DR, Lindsell CJ, et al. Effect of Higher-Dose Ivermectin for 6 Days vs Placebo on Time to Sustained Recovery in Outpatients With COVID-19: A Randomized Clinical Trial. JAMA 2023; 329(11): 888–97.
187		1	rp	1		Ivermectin-ACTIV-6	Naggie S, Boulware DR, Lindsell CJ, et al. Effect of Ivermectin vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19: A Randomized Clinical Trial. JAMA 2022; 328(16): 1595–603.
198		1	rp	1	1	Azithromycin-ACTION	Oldenburg CE, Pinsky BA, Brogdon J, et al. Effect of Oral Azithromycin vs Placebo on COVID-19 Symptoms in Outpatients With SARS-CoV-2 Infection: A Randomized Clinical Trial. JAMA 2021; 326(6): 490–8.
214		1	rp	1	1	Losartan-MN	Puskarich MA, Cummins NW, Ingraham NE, et al. A multi-center phase II randomized clinical trial of losartan on symptomatic outpatients with COVID-19. EClinicalMedicine 2021; 37: 100957.
219		1	rp	1	1	Metformin-TOGETHER	Reis G, Dos Santos Moreira Silva EA, Medeiros Silva DC, et al. Effect of early treatment with metformin on risk of emergency care and hospitalization among patients with COVID-19: The TOGETHER randomized platform clinical trial. Lancet Reg Health Am 2022; 6: 100142.
220		1	rp	1		Fluvoxamine/budesonide-TOGETHER	Reis G, Dos Santos Moreira Silva EA, Medeiros Silva DC, et al. Oral Fluvoxamine With Inhaled Budesonide for Treatment of Early-Onset COVID-19 : A Randomized Platform Trial. Ann Intern Med 2023; 176(5): 667–75.
221		1	rp	1		Fluvoxamine-TOGETHER	Reis G, Dos Santos Moreira-Silva EA, Silva DCM, et al. Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial. Lancet Glob Health 2022; 10(1): e42-e51.
224		1	rp	1		Ivermectin-TOGETHER	Reis G, Silva E, Silva DCM, et al. Effect of Early Treatment with Ivermectin among Patients with Covid-19. N Engl J Med 2022; 386(18): 1721–31.
227		1	rp	1		Ivermectin Iran	Rezai MS, Ahangarkani F, Hill A, et al. Non-effectiveness of Ivermectin on Inpatients and Outpatients With COVID-19; Results of Two Randomized, Double-Blinded, Placebo-Controlled Clinical Trials. Front Med (Lausanne) 2022; 9: 919708.
229		1	rp	1		Hydroxychloroquine/Azithromycin-Brazil	Rodrigues C, Freitas-Santos RS, Levi JE, et al. Hydroxychloroquine plus azithromycin early treatment of mild COVID-19 in an outpatient setting: a randomized, double-blinded, placebo-controlled clinical trial evaluating viral clearance. Int J Antimicrob Agents 2021; 58(5): 106428.
233		1	rp	1	1	Nitazoxanide-Romark	Rossignol JF, Bardin MC, Fulgencio J, Mogelnicki D, Brechot C. A randomized double-blind placebo-controlled clinical trial of nitazoxanide for treatment of mild or moderate COVID-19. EClinicalMedicine 2022; 45: 101310.
241		1	rp	1	1	Hydroxychloroquine-AH COVID-19	Schwartz I, Boesen ME, Cerchiaro G, et al. Assessing the efficacy and safety of hydroxychloroquine as outpatient treatment of COVID-19: a randomized controlled trial. CMAJ Open 2021; 9(2): E693-E702.
245		1	rp	1		Hydroxychloroquine-COVID-19 PEP	Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 : A Randomized Trial. Ann Intern Med 2020; 173(8): 623–31.
249		1	rp	1		Hydroxychloroquine-Utah	Spivak AM, Barney BJ, Greene T, et al. A Randomized Clinical Trial Testing Hydroxychloroquine for Reduction of SARS-CoV-2 Viral Shedding and Hospitalization in Early Outpatient COVID-19 Infection. Microbiol Spectr 2023; 11(2): e0467422.
257		1	rp	1	1	Colchicine-COLCORONA	Tardif JC, Bouabdallaoui N, ĽAllier PL, et al. Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial. Lancet Respir Med 2021; 9(8): 924–32.
259		1	rp	3	1	Zinc	Thomas S, Patel D, Bittel B, et al. Effect of High-Dose Zinc and Ascorbic Acid Supplementation vs Usual Care on Symptom Length and Reduction Among Ambulatory Patients With SARS-CoV-2 Infection: The COVID A to Z Randomized Clinical Trial. JAMA Netw Open 2021; 4(2): e210369.
36		1	sma	1	1	Favipiravir-Avi-Mild-19	Bosaeed M, Alharbi A, Mahmoud E, et al. Efficacy of favipiravir in adults with mild COVID-19: a randomized, double-blind, multicentre, placebo-controlled clinical trial. Clin Microbiol Infect 2022; 28(4): 602–8.
46		1	sma	1		Molnupiravir-PANORAMIC	Butler CC, Hobbs FDR, Gbinigie OA, et al. Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial. Lancet 2023; 401(10373): 281–93.
82		1	sma	1	1	Interferon Lambda-ILIAD	Feld JJ, Kandel C, Biondi MJ, et al. Peginterferon lambda for the treatment of outpatients with COVID-19: a phase 2, placebo-controlled randomised trial. Lancet Respir Med 2021; 9(5): 498–510.
95		1	sma	1	1	Remdesivir-PINETREE	Gottlieb RL, Vaca CE, Paredes R, et al. Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients. N Engl J Med 2022; 386(4): 305–15.
100		1	sma	1	1	Nirmatrelvir/ritonavir-EPIC-HR	Hammond J, Leister-Tebbe H, Gardner A, et al. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med 2022; 386(15): 1397–408.
112		1	sma	1		Interferon Lambda-COVID-Lambda	Jagannathan P, Andrews JR, Bonilla H, et al. Peginterferon Lambda-1a for treatment of outpatients with uncomplicated COVID-19: a randomized placebo-controlled trial. Nature Communications 2021; 12(1): 1967.
113		1	sma	1		Molnupiravir-MOVe-OUT	Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med 2022; 386(6): 509–20.
118		1	sma	1		Lopinavir/ritonavir-TREAT NOW	Kaizer AM, Shapiro NI, Wild J, et al. Lopinavir/ritonavir for treatment of non-hospitalized patients with COVID-19: a randomized clinical trial. Int J Infect Dis 2023; 128: 223–9.
159		1	sma	3		Favipiravir/Lopinavir/Ritonavir-FLARE	Lowe DM, Brown LK, Chowdhury K, et al. Favipiravir, lopinavir-ritonavir, or combination therapy (FLARE): A randomised, double-blind, 2 × 2 factorial placebo-controlled trial of early antiviral therapy in COVID-19. PLoS Med 2022; 19(10): e1004120.
203		1	sma	1	1	Tenofovir/Emtricitabine-AR0-CORONA	Parienti JJ, Prazuck T, Peyro-Saint-Paul L, et al. Effect of Tenofovir Disoproxil Fumarate and Emtricitabine on nasopharyngeal SARS-CoV-2 viral load burden amongst outpatients with COVID-19: A pilot, randomized, open-label phase 2 trial. EClinicalMedicine 2021; 38: 100993.
222		1	sma	2	1	Lopinavir/ritonavir-TOGETHER	Reis G, Moreira Silva E, Medeiros Silva DC, et al. Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19: The TOGETHER Randomized Clinical Trial. JAMA Netw Open 2021; 4(4): e216468.
223		1	sma	1		Interferon Lambda-TOGETHER	Reis G, Moreira Silva EAS, Medeiros Silva DC, et al. Early Treatment with Pegylated Interferon Lambda for Covid-19. N Engl J Med 2023; 388(6): 518–28.
231		1	sma	1	1	Sofosbuvir & daclatasvir-SOVODAK	Roozbeh F, Saeedi M, Alizadeh-Navaei R, et al. Sofosbuvir and daclatasvir for the treatment of COVID-19 outpatients: a double-blind, randomized controlled trial. J Antimicrob Chemother 2021; 76(3): 753–7.
260		1	sma	1	1	Molnupiravir-Aurobindo	Tippabhotla SK, Lahiri S, Rama Raju D, Kandi C, Prasad VN. Efficacy and Safety of Molnupiravir for the Treatment of Non-Hospitalized Adults With Mild COVID-19: A Randomized, Open-Label, Parallel-Group Phase 3 Trial. SSRN 2022; 4042673.
264		1	sma	1		Favipiravir-Iran	Vaezi A, Salmasi M, Soltaninejad F, Salahi M, Javanmard SH, Amra B. Favipiravir in the Treatment of Outpatient COVID-19: A Multicenter, Randomized, Triple-Blind, Placebo-Controlled Clinical Trial. Adv Respir Med 2023; 91(1): 18–25.
25	guidelines						Bassetti M, Giacobbe DR, Bruzzi P, et al. Clinical Management of Adult Patients with COVID-19 Outside Intensive Care Units: Guidelines from the Italian Society of Anti-Infective Therapy (SITA) and the Italian Society of Pulmonology (SIP). Infect Dis Ther 2021; 10(4): 1837–85.
62	guidelines						Cuker A, Tseng EK, Nieuwlaat R, et al. American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: July 2021 update on postdischarge thromboprophylaxis. Blood Adv 2022; 6(2): 664–71.
80	guidelines						Estcourt LJ, Cohn CS, Pagano MB, et al. Clinical Practice Guidelines From the Association for the Advancement of Blood and Biotherapies (AABB): COVID-19 Convalescent Plasma. Ann Intern Med 2022; 175(9): 1310–21.
139	guidelines						Kyriakoulis KG, Dimakakos E, Kyriakoulis IG, et al. Practical Recommendations for Optimal Thromboprophylaxis in Patients with COVID-19: A Consensus Statement Based on Available Clinical Trials. J Clin Med 2022; 11(20).
6	no hospitalizations						Adel Mehraban MS, Shirzad M, Mohammad Taghizadeh Kashani L, et al. Efficacy and safety of add-on Viola odorata L. in the treatment of COVID-19: A randomized double-blind controlled trial. J Ethnopharmacol 2023; 304: 116058.
15	no hospitalizations						Alizadeh Z, Keyhanian N, Ghaderkhani S, Dashti-Khavidaki S, Shokouhi Shoormasti R, Pourpak Z. A Pilot Study on Controlling Coronavirus Disease 2019 (COVID-19) Inflammation Using Melatonin Supplement. Iran J Allergy Asthma Immunol 2021; 20(4): 494–9.
29	no hospitalizations						Bechlioulis A, Markozannes G, Chionidi I, et al. The effect of SGLT2 inhibitors, GLP1 agonists, and their sequential combination on cardiometabolic parameters: A randomized, prospective, intervention study. J Diabetes Complications 2023; 37(4): 108436.
31	no hospitalizations						Ben Abdallah S, Mhalla Y, Trabelsi I, et al. Twice-Daily Oral Zinc in the Treatment of Patients With Coronavirus Disease 2019: A Randomized Double-Blind Controlled Trial. Clin Infect Dis 2023; 76(2): 185–91.
32	no hospitalizations						Bencheqroun H, Ahmed Y, Kocak M, et al. A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of ThymoQuinone Formula (TQF) for Treating Outpatient SARS-CoV-2. Pathogens 2022; 11(5).
41	no hospitalizations						Brennan CM, Nadella S, Zhao X, et al. Oral famotidine versus placebo in non-hospitalised patients with COVID-19: a randomised, double-blind, data-intense, phase 2 clinical trial. Gut 2022; 71(5): 879–88.
44	no hospitalizations						Bruno AM, Allshouse AA, Campbell HM, et al. Weight-Based Compared With Fixed-Dose Enoxaparin Prophylaxis After Cesarean Delivery: A Randomized Controlled Trial. Obstet Gynecol 2022; 140(4): 575–83.
68	no hospitalizations						De Boeck I, Cauwenberghs E, Spacova I, et al. Randomized, Double-Blind, Placebo-Controlled Trial of a Throat Spray with Selected Lactobacilli in COVID-19 Outpatients. Microbiol Spectr 2022; 10(5): e0168222.
103	no hospitalizations						Hasanpour M, Safari H, Mohammadpour AH, et al. Efficacy of Covexir(R) (Ferula foetida oleo-gum) treatment in symptomatic improvement of patients with mild to moderate COVID-19: A randomized, double-blind, placebo-controlled trial. Phytother Res 2022; 36(12): 4504–15.
125	no hospitalizations						Khan A, Iqtadar S, Mumtaz SU, et al. Oral Co-Supplementation of Curcumin, Quercetin, and Vitamin D3 as an Adjuvant Therapy for Mild to Moderate Symptoms of COVID-19-Results From a Pilot Open-Label, Randomized Controlled Trial. Front Pharmacol 2022; 13: 898062.
127	no hospitalizations						Khoo SH, FitzGerald R, Saunders G, et al. Molnupiravir versus placebo in unvaccinated and vaccinated patients with early SARS-CoV-2 infection in the UK (AGILE CST-2): a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Infect Dis 2023; 23(2): 183–95.
133	no hospitalizations						Kosmopoulos A, Bhatt DL, Meglis G, et al. A randomized trial of icosapent ethyl in ambulatory patients with COVID-19. iScience 2021; 24(9): 103040.
155	no hospitalizations						Lofgren SM, Nicol MR, Bangdiwala AS, et al. Safety of Hydroxychloroquine Among Outpatient Clinical Trial Participants for COVID-19. Open Forum Infect Dis 2020; 7(11): ofaa500.
230	no hospitalizations						Rohani M, Mozaffar H, Mesri M, Shokri M, Delaney D, Karimy M. Evaluation and comparison of vitamin A supplementation with standard therapies in the treatment of patients with COVID-19. East Mediterr Health J 2022; 28(9): 673–81.
256	no hospitalizations						Tandon M, Wu W, Moore K, et al. SARS-CoV-2 accelerated clearance using a novel nitric oxide nasal spray (NONS) treatment: A randomized trial. Lancet Reg Health Southeast Asia 2022; 3: 100036.
1	not outpt RCT						Aarnio-Peterson CM, Mara CA, Modi AC, Matthews A, Le Grange D, Shaffer A. Augmenting family based treatment with emotion coaching for adolescents with anorexia nervosa and atypical anorexia nervosa: Trial design and methodological report. Contemp Clin Trials Commun 2023; 33: 101118.
2	not outpt RCT						Abbatecola AM, Incalzi RA, Malara A, et al. Monitoring COVID-19 vaccine use in Italian long term care centers: The GeroCovid VAX study. Vaccine 2022; 40(15): 2324–30.
3	not outpt RCT						Abena PM, Decloedt EH, Bottieau E, et al. Chloroquine and Hydroxychloroquine for the Prevention or Treatment of COVID-19 in Africa: Caution for Inappropriate Off-label Use in Healthcare Settings. Am J Trop Med Hyg 2020; 102(6): 1184–8.
4	not outpt RCT						Accelerating C-TI, Vaccines-6 Study G, Naggie S. Ivermectin for Treatment of Mild-to-Moderate COVID-19 in the Outpatient Setting: A Decentralized, Placebo-controlled, Randomized, Platform Clinical Trial. medRxiv 2022.
5	not outpt RCT						Accelerating Covid-19 Therapeutic I, Vaccines-6 Study G, Naggie S. Inhaled Fluticasone for Outpatient Treatment of Covid-19: A Decentralized, Placebo-controlled, Randomized, Platform Clinical Trial. medRxiv 2022.
9	not outpt RCT						Agusti A, Guillen E, Ayora A, et al. Efficacy and safety of hydroxychloroquine in healthcare professionals with mild SARS-CoV-2 infection: Prospective, non-randomized trial. Enferm Infecc Microbiol Clin (Engl Ed) 2022; 40(6): 289–95.
10	not outpt RCT						Ainslie M, Brunette MF, Capozzoli M. Treatment Interruptions and Telemedicine Utilization in Serious Mental Illness: Retrospective Longitudinal Claims Analysis. JMIR Ment Health 2022; 9(3): e33092.
11	not outpt RCT						Akca Sumengen A, Ocakci AF. Evaluation of the effect of an education program using cartoons and comics on disease management in children with asthma: a randomized controlled study. J Asthma 2023; 60(1): 11–23.
13	not outpt RCT						Alemany A, Millat-Martinez P, Corbacho-Monne M, et al. Subcutaneous anti-COVID-19 hyperimmune immunoglobulin for prevention of disease in asymptomatic individuals with SARS-CoV-2 infection: a double-blind, placebo-controlled, randomised clinical trial. EClinicalMedicine 2023; 57: 101898.
14	not outpt RCT						Ali R, Patel A, Waqas MA, Trivedi K, Slim J. Functionality of Monoclonal Antibody Therapy in SARS-CoV-2. J Med Cases 2022; 13(8): 380–5.
16	not outpt RCT						Aref ZF, Bazeed S, Hassan MH, et al. Possible Role of Ivermectin Mucoadhesive Nanosuspension Nasal Spray in Recovery of Post-COVID-19 Anosmia. Infect Drug Resist 2022; 15: 5483–94.
17	not outpt RCT						Avezum A, Oliveira GBF, Oliveira H, et al. Hydroxychloroquine versus placebo in the treatment of non-hospitalised patients with COVID-19 (COPE - Coalition V): A double-blind, multicentre, randomised, controlled trial. Lancet Reg Health Am 2022; 11: 100243.
18	not outpt RCT						Axfors C, Schmitt AM, Janiaud P, et al. Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials. Nat Commun 2021; 12(1): 2349.
20	not outpt RCT						Bahmer T, Borzikowsky C, Lieb W, et al. Severity, predictors and clinical correlates of Post-COVID syndrome (PCS) in Germany: A prospective, multicentre, population-based cohort study. EClinicalMedicine 2022; 51: 101549.
21	not outpt RCT						Baksh S, Heath SL, Fukuta Y, et al. Symptom duration and resolution with early outpatient treatment of convalescent plasma for COVID-19: a randomized trial. J Infect Dis 2023.
22	not outpt RCT						Barati S, Feizabadi F, Khalaj H, et al. Evaluation of noscapine-licorice combination effects on cough relieving in COVID-19 outpatients: A randomized controlled trial. Front Pharmacol 2023; 14: 1102940.
23	not outpt RCT						Barchuk A, Cherkashin M, Bulina A, et al. Vaccine effectiveness against referral to hospital after SARS-CoV-2 infection in St. Petersburg, Russia, during the Delta variant surge: a test-negative case-control study. BMC Med 2022; 20(1): 312.
26	not outpt RCT						Batalik L, Dosbaba F, Hartman M, Konecny V, Batalikova K, Spinar J. Long-term exercise effects after cardiac telerehabilitation in patients with coronary artery disease: 1-year follow-up results of the randomized study. Eur J Phys Rehabil Med 2021; 57(5): 807–14.
27	not outpt RCT						Batioglu-Karaaltin A, Yigit O, Cakan D, et al. Effect of the povidone iodine, hypertonic alkaline solution and saline nasal lavage on nasopharyngeal viral load in COVID-19. Clin Otolaryngol 2023.
28	not outpt RCT						Bauer A, Schreinlechner M, Sappler N, et al. Discontinuation versus continuation of renin-angiotensin-system inhibitors in COVID-19 (ACEI-COVID): a prospective, parallel group, randomised, controlled, open-label trial. Lancet Respir Med 2021; 9(8): 863–72.
30	not outpt RCT						Behrouzi B, Bhatt DL, Cannon CP, et al. Association of Influenza Vaccination With Cardiovascular Risk: A Meta-analysis. JAMA Netw Open 2022; 5(4): e228873.
33	not outpt RCT						Bhatia T, Kumari N, Yadav A, et al. Feasibility, acceptability and evaluation of meditation to augment yoga practice among persons diagnosed with schizophrenia. Acta Neuropsychiatr 2022; 34(6): 330–43.
35	not outpt RCT						Bledsoe J, Woller SC, Brooks M, et al. Clinically stable covid-19 patients presenting to acute unscheduled episodic care venues have increased risk of hospitalization: secondary analysis of a randomized control trial. BMC Infect Dis 2023; 23(1): 325.
37	not outpt RCT						Boudreaux ED, Larkin C, Sefair AV, et al. Studying the implementation of Zero Suicide in a large health system: Challenges, adaptations, and lessons learned. Contemp Clin Trials Commun 2022; 30: 100999.
38	not outpt RCT						Bramante CT, Buse J, Tamaritz L, et al. Outpatient metformin use is associated with reduced severity of COVID-19 disease in adults with overweight or obesity. J Med Virol 2021; 93(7): 4273–9.
40	not outpt RCT						Bramante CT, Johnson SG, Garcia V, et al. Diabetes medications and associations with Covid-19 outcomes in the N3C database: A national retrospective cohort study. PLoS One 2022; 17(11): e0271574.
47	not outpt RCT						Cadegiani FA, Goren A, Wambier CG, McCoy J. Early COVID-19 therapy with azithromycin plus nitazoxanide, ivermectin or hydroxychloroquine in outpatient settings significantly improved COVID-19 outcomes compared to known outcomes in untreated patients. New Microbes New Infect 2021; 43: 100915.
50	not outpt RCT						Cavanna L, Citterio C. Randomised clinical trials on outpatient treatment of SARS-COV-2 infection: Light and shadows. Int J Clin Pract 2021; 75(12): e14896.
52	not outpt RCT						Chawla A, Birger R, Wan H, et al. Factors Influencing COVID-19 Risk: Insights From Molnupiravir Exposure-Response Modeling of Clinical Outcomes. Clin Pharmacol Ther 2023; 113(6): 1337–45.
53	not outpt RCT						Chen L, Zhou YZ, Zhou XM, et al. Evaluation of the "safe multidisciplinary app-assisted remote patient-self-testing (SMART) model" for warfarin home management during the COVID-19 pandemic: study protocol of a multi-center randomized controlled trial. BMC Health Serv Res 2021; 21(1): 875.
56	not outpt RCT						Christie LJ, Fearn N, McCluskey A, et al. Remote constraint induced therapy of the upper extremity (ReCITE): A feasibility study protocol. Front Neurol 2022; 13: 1010449.
57	not outpt RCT						Clark J, Tong SYC. In outpatients with mild to moderate COVID-19, low-dose fluvoxamine did not reduce time to sustained recovery. Ann Intern Med 2023; 176(5): JC52.
59	not outpt RCT						Cohen JB, Hanff TC, Corrales-Medina V, et al. Randomized elimination and prolongation of ACE inhibitors and ARBs in coronavirus 2019 (REPLACE COVID) Trial Protocol. J Clin Hypertens (Greenwich) 2020; 22(10): 1780–8.
63	not outpt RCT						D'Ascanio L, Vitelli F, Cingolani C, Maranzano M, Brenner MJ, Di Stadio A. Randomized clinical trial "olfactory dysfunction after COVID-19: olfactory rehabilitation therapy vs. intervention treatment with Palmitoylethanolamide and Luteolin": preliminary results. Eur Rev Med Pharmacol Sci 2021; 25(11): 4156–62.
64	not outpt RCT						da Silva RM, Gebe Abreu Cabral P, de Souza SB, et al. Serial viral load analysis by DDPCR to evaluate FNC efficacy and safety in the treatment of mild cases of COVID-19. Front Med (Lausanne) 2023; 10: 1143485.
65	not outpt RCT						Damery S, Jones J, O'Connell Francischetto E, Jolly K, Lilford R, Ferguson J. Remote Consultations Versus Standard Face-to-Face Appointments for Liver Transplant Patients in Routine Hospital Care: Feasibility Randomized Controlled Trial of myVideoClinic. J Med Internet Res 2021; 23(9): e19232.
66	not outpt RCT						Davis JS, Ferreira D, Denholm JT, Tong SY. Clinical trials for the prevention and treatment of COVID-19: current state of play. Med J Aust 2020; 213(2): 86–93.
67	not outpt RCT						Davoodi L, Abedi SM, Salehifar E, et al. Febuxostat therapy in outpatients with suspected COVID-19: A clinical trial. Int J Clin Pract 2020; 74(11): e13600.
70	not outpt RCT						Di Pierro F, Derosa G, Maffioli P, et al. Possible Therapeutic Effects of Adjuvant Quercetin Supplementation Against Early-Stage COVID-19 Infection: A Prospective, Randomized, Controlled, and Open-Label Study. Int J Gen Med 2021; 14: 2359–66.
74	not outpt RCT						Dube MP, Lemacon A, Barhdadi A, et al. Genetics of symptom remission in outpatients with COVID-19. Sci Rep 2021; 11(1): 10847.
75	not outpt RCT						Dugani SB, Kiliaki SA, Nielsen ML, et al. Post-discharge early assessment with remote video link (PEARL) initiative for patients discharged from hospital medicine services. Hosp Pract (1995) 2022; 50(5): 379–86.
77	not outpt RCT						Duvignaud A, Lhomme E, Pistone T, et al. Home Treatment of Older People with Symptomatic SARS-CoV-2 Infection (COVID-19): A structured Summary of a Study Protocol for a Multi-Arm Multi-Stage (MAMS) Randomized Trial to Evaluate the Efficacy and Tolerability of Several Experimental Treatments to Reduce the Risk of Hospitalisation or Death in outpatients aged 65 years or older (COVERAGE trial). Trials 2020; 21(1): 846.
78	not outpt RCT						Eikelboom J, Rangarajan S, Jolly SS, et al. The Anti-Coronavirus Therapies (ACT) Trials: Design, Baseline Characteristics, and Challenges. CJC Open 2022; 4(6): 568–76.
81	not outpt RCT						Fan Y, Shi Y, Zhang J, et al. The effects of narrative exposure therapy on COVID-19 patients with post-traumatic stress symptoms: A randomized controlled trial. J Affect Disord 2021; 293: 141–7.
84	not outpt RCT						Fink T, Chen Q, Chong L, Hii MW, Knowles B. Telemedicine versus face-to-face follow up in general surgery: a randomized controlled trial. ANZ J Surg 2022; 92(10): 2544–50.
85	not outpt RCT						Focosi D, Franchini M, Pirofski LA, et al. COVID-19 Convalescent Plasma and Clinical Trials: Understanding Conflicting Outcomes. Clin Microbiol Rev 2022; 35(3): e0020021.
88	not outpt RCT						Geiger I, Kammerlander C, Hofer C, et al. Implementation of an integrated care programme to avoid fragility fractures of the hip in older adults in 18 Bavarian hospitals - study protocol for the cluster-randomised controlled fracture liaison service FLS-CARE. BMC Geriatr 2021; 21(1): 43.
89	not outpt RCT						Geriak M, Haddad F, Kullar R, et al. Randomized Prospective Open Label Study Shows No Impact on Clinical Outcome of Adding Losartan to Hospitalized COVID-19 Patients with Mild Hypoxemia. Infect Dis Ther 2021; 10(3): 1323–30.
90	not outpt RCT						Gerlier C, Pilmis B, Ganansia O, Le Monnier A, Nguyen Van JC. Clinical and operational impact of rapid point-of-care SARS-CoV-2 detection in an emergency department. Am J Emerg Med 2021; 50: 713–8.
91	not outpt RCT						Ghany R, Palacio A, Dawkins E, et al. Metformin is associated with lower hospitalizations, mortality and severe coronavirus infection among elderly medicare minority patients in 8 states in USA. Diabetes Metab Syndr 2021; 15(2): 513–8.
96	not outpt RCT						Group A-TL-CS, Lundgren JD, Grund B, et al. A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19. N Engl J Med 2021; 384(10): 905–14.
97	not outpt RCT						Grundeis F, Ansems K, Dahms K, et al. Remdesivir for the treatment of COVID-19. Cochrane Database Syst Rev 2023; 1(1): CD014962.
99	not outpt RCT						Gupta A, Madhavan MV, Poterucha TJ, et al. Association Between Antecedent Statin Use and Decreased Mortality in Hospitalized Patients with COVID-19. Res Sq 2020.
101	not outpt RCT						Hanna CR, Blyth KG, Burley G, et al. Glasgow Early Treatment Arm Favirpiravir (GETAFIX) for adults with early stage COVID-19: A structured summary of a study protocol for a randomised controlled trial. Trials 2020; 21(1): 935.
102	not outpt RCT						Haran JP, Pinero JC, Zheng Y, Palma NA, Wingertzahn M. Virtualized clinical studies to assess the natural history and impact of gut microbiome modulation in non-hospitalized patients with mild to moderate COVID-19 a randomized, open-label, prospective study with a parallel group study evaluating the physiologic effects of KB109 on gut microbiota structure and function: a structured summary of a study protocol for a randomized controlled study. Trials 2021; 22(1): 245.
104	not outpt RCT						Hautmann C, Rausch J, Geldermann N, et al. Progress feedback in children and adolescents with internalizing and externalizing symptoms in routine care (OPTIE study): study protocol of a randomized parallel-group trial. BMC Psychiatry 2021; 21(1): 505.
105	not outpt RCT						Hazan S, Dave S, Gunaratne AW, et al. Effectiveness of ivermectin-based multidrug therapy in severely hypoxic, ambulatory COVID-19 patients. Future Microbiol 2022; 17: 339–50.
106	not outpt RCT						Helsingen LM, Loberg M, Refsum E, et al. Covid-19 transmission in fitness centers in Norway - a randomized trial. BMC Public Health 2021; 21(1): 2103.
108	not outpt RCT						Hosseini FS, Malektojari A, Ghazizadeh S, et al. The efficacy and safety of Ivermectin in patients with mild and moderate COVID-19: A structured summary of a study protocol for a randomized controlled trial. Trials 2021; 22(1): 4.
109	not outpt RCT						Hozayen SM, Zychowski D, Benson S, et al. Outpatient and inpatient anticoagulation therapy and the risk for hospital admission and death among COVID-19 patients. EClinicalMedicine 2021; 41: 101139.
111	not outpt RCT						Indraratna P, Biswas U, Yu J, et al. Trials and Tribulations: mHealth Clinical Trials in the COVID-19 Pandemic. Yearb Med Inform 2021; 30(1): 272–9.
114	not outpt RCT						Jering KS, Claggett BL, Pfeffer MA, et al. Prognostic Importance of NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) Following High-Risk Myocardial Infarction in the PARADISE-MI Trial. Circ Heart Fail 2023; 16(5): e010259.
116	not outpt RCT						Kadali RAK, Janagama R, Peruru S, et al. Non-life-threatening adverse effects with COVID-19 mRNA-1273 vaccine: A randomized, cross-sectional study on healthcare workers with detailed self-reported symptoms. J Med Virol 2021; 93(7): 4420–9.
117	not outpt RCT						Kaduszkiewicz H, Kochen MM, Kluge S, et al. Recommendations for the Outpatient Drug Treatment of Patients With COVID-19. Dtsch Arztebl Int 2022; 119(19): 342–9.
119	not outpt RCT						Kaizer AM, Wild J, Lindsell CJ, et al. Trial of Early Antiviral Therapies during Non-hospitalized Outpatient Window (TREAT NOW) for COVID-19: a summary of the protocol and analysis plan for a decentralized randomized controlled trial. Trials 2022; 23(1): 273.
120	not outpt RCT						Kapepula PM, Kabengele JK, Kingombe M, et al. Artemisia Spp. Derivatives for COVID-19 Treatment: Anecdotal Use, Political Hype, Treatment Potential, Challenges, and Road Map to Randomized Clinical Trials. Am J Trop Med Hyg 2020; 103(3): 960–4.
121	not outpt RCT						Karaba AH, Johnston TS, Beck E, et al. Endemic Human Coronavirus Antibody Levels Are Unchanged after Convalescent or Control Plasma Transfusion for Early Outpatient COVID-19 Treatment. mBio 2023; 14(1): e0328722.
123	not outpt RCT						Keitel V, Jensen B, Feldt T, et al. Reconvalescent plasma/camostat mesylate in early SARS-CoV-2 Q-PCR positive high-risk individuals (RES-Q-HR): a structured summary of a study protocol for a randomized controlled trial. Trials 2021; 22(1): 343.
124	not outpt RCT						Khair A, Cromwell PM, Abdelatif A, et al. Text Messaging, Telephone, or In-Person Outpatient Visit to the Surgical Clinic: A Randomized Trial. J Surg Res 2022; 280: 226–33.
126	not outpt RCT						Khoo SH, Fitzgerald R, Fletcher T, et al. Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study. J Antimicrob Chemother 2021; 76(12): 3286–95.
130	not outpt RCT						Kip KE, McCreary EK, Collins K, et al. Evolving Real-World Effectiveness of Monoclonal Antibodies for Treatment of COVID-19 : A Cohort Study. Ann Intern Med 2023; 176(4): 496–504.
134	not outpt RCT						Kramer A, Prinz C, Fichtner F, et al. Janus kinase inhibitors for the treatment of COVID-19. Cochrane Database Syst Rev 2022; 6(6): CD015209.
135	not outpt RCT						Kremsner PG, Ahuad Guerrero RA, Arana-Arri E, et al. Efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate in ten countries in Europe and Latin America (HERALD): a randomised, observer-blinded, placebo-controlled, phase 2b/3 trial. Lancet Infect Dis 2022; 22(3): 329–40.
136	not outpt RCT						Krzyzanowska MK, Julian JA, Gu CS, et al. Remote, proactive, telephone based management of toxicity in outpatients during adjuvant or neoadjuvant chemotherapy for early stage breast cancer: pragmatic, cluster randomised trial. BMJ 2021; 375: e066588.
138	not outpt RCT						Kupferschmitt A, Hinterberger T, Montanari I, et al. Relevance of the post-COVID syndrome within rehabilitation (PoCoRe): study protocol of a multicentre study with different specialisations. BMC Psychol 2022; 10(1): 189.
140	not outpt RCT						Lee MT, George J, Shahab H, Hermel M, Rana JS, Virani SS. Highlights of Cardiovascular Disease Studies Presented at the 2021 American Heart Association Scientific Sessions. Curr Atheroscler Rep 2022; 24(1): 61–72.
141	not outpt RCT						Lee TC, Bortolussi-Courval E, Belga S, et al. Inhaled corticosteroids for outpatients with COVID-19: a meta-analysis. Eur Respir J 2022; 59(5).
142	not outpt RCT						Lee TC, Morris AM, Grover SA, Murthy S, McDonald EG. Outpatient Therapies for COVID-19: How Do We Choose? Open Forum Infect Dis 2022; 9(3): ofac008.
144	not outpt RCT						Legacy M, Seely D, Conte E, et al. Dietary supplements to reduce symptom severity and duration in people with SARS-CoV-2: study protocol for a randomised, double-blind, placebo controlled clinical trial. BMJ Open 2022; 12(3): e057024.
146	not outpt RCT						Les Bujanda I, Loureiro-Amigo J, Bastons FC, et al. Treatment of COVID-19 pneumonia with glucocorticoids (CORTIVID): a structured summary of a study protocol for a randomised controlled trial. Trials 2021; 22(1): 43.
148	not outpt RCT						Levine AC, Fukuta Y, Huaman MA, et al. COVID-19 Convalescent Plasma Outpatient Therapy to Prevent Outpatient Hospitalization: A Meta-analysis of Individual Participant Data From Five Randomized Trials. Clin Infect Dis 2023.
149	not outpt RCT						Li W, Xie L, Zhu X, et al. Effectiveness and safety of Qingfei Dayuan granules for treating influenza and upper respiratory tract infections manifested by the pulmonary heat-toxin syndrome: A multicenter, randomized, double-blind, placebo-controlled trial. Front Pharmacol 2023; 14: 1133560.
151	not outpt RCT						Licchetta L, Trivisano M, Baldin E, et al. TELEmedicine for EPIlepsy Care (TELE-EPIC): protocol of a randomised, open controlled non-inferiority clinical trial. BMJ Open 2021; 11(12): e053980.
153	not outpt RCT						Liu HH, Ezekowitz MD, Columbo M, et al. The future is now: our experience starting a remote clinical trial during the beginning of the COVID-19 pandemic. Trials 2021; 22(1): 603.
156	not outpt RCT						Lokhandwala T, Acharya M, Farrelly E, Coutinho AD, Bell CF, Svedsater H. Within-trial economic analysis of resource use from COMET-ICE: A phase 3 clinical trial evaluating sotrovimab for the treatment of patients with COVID-19 at high risk of progression. J Manag Care Spec Pharm 2022; 28(11): 1261–71.
160	not outpt RCT						Lui G, Guaraldi G. Drug treatment of COVID-19 infection. Curr Opin Pulm Med 2023; 29(3): 174–83.
162	not outpt RCT						Manenti L, Maggiore U, Fiaccadori E, et al. Reduced mortality in COVID-19 patients treated with colchicine: Results from a retrospective, observational study. PLoS One 2021; 16(3): e0248276.
163	not outpt RCT						Mao Z, Li X, Dacosta-Urbieta A, et al. Economic burden and health-related quality-of-life among infants with respiratory syncytial virus infection: A multi-country prospective cohort study in Europe. Vaccine 2023; 41(16): 2707–15.
165	not outpt RCT						Mason JS, Crowell MS, Brindle RA, et al. The Effect of Blood Flow Restriction Training on Muscle Atrophy Following Meniscal Repair or Chondral Restoration Surgery in Active Duty Military: A Randomized Controlled Trial. J Sport Rehabil 2022; 31(1): 77–84.
166	not outpt RCT						Mazzaferri F, Mirandola M, Savoldi A, et al. Exploratory data on the clinical efficacy of monoclonal antibodies against SARS-CoV-2 Omicron variant of concern. Elife 2022; 11.
170	not outpt RCT						McCreary EK, Bariola JR, Minnier T, et al. Launching a comparative effectiveness adaptive platform trial of monoclonal antibodies for COVID-19 in 21 days. Contemp Clin Trials 2022; 113: 106652.
174	not outpt RCT						McCullough PA, Kelly RJ, Ruocco G, et al. Pathophysiological Basis and Rationale for Early Outpatient Treatment of SARS-CoV-2 (COVID-19) Infection. Am J Med 2021; 134(1): 16–22.
175	not outpt RCT						McKinnon JE, Wang DD, Zervos M, et al. Safety and tolerability of hydroxychloroquine in health care workers and first responders for the prevention of COVID-19: WHIP COVID-19 Study. Int J Infect Dis 2022; 116: 167–73.
176	not outpt RCT						Mesri M, Esmaeili Saber SS, Godazi M, et al. The effects of combination of Zingiber officinale and Echinacea on alleviation of clinical symptoms and hospitalization rate of suspected COVID-19 outpatients: a randomized controlled trial. J Complement Integr Med 2021; 18(4): 775–81.
179	not outpt RCT						Miguel-Cruz A, Ladurner AM, Kohls-Wiebe M, Rawani D. The Effects of 3D Immersion Technology (3Scape) on Mental Health in Outpatients From a Short-Term Assessment, Rehabilitation, and Treatment Program: Feasibility Protocol for a Randomized Controlled Trial. JMIR Res Protoc 2021; 10(9): e25017.
178	not outpt RCT						Miguel-Cruz A, Sr., Guptill C, Gregson G, et al. Determining the Effectiveness of a New Device for Hand Therapy (The FEPSim Device): Feasibility Protocol for a Randomized Controlled Trial Study. JMIR Res Protoc 2021; 10(5): e22145.
181	not outpt RCT						Mills FP, Reis G, Wilson LA, et al. Early Treatment with Fluvoxamine among Patients with COVID-19: A Cost-Consequence Model. Am J Trop Med Hyg 2023; 108(1): 101–6.
182	not outpt RCT						Miryan M, Bagherniya M, Sahebkar A, et al. Effects of curcumin-piperine co-supplementation on clinical signs, duration, severity, and inflammatory factors in patients with COVID-19: a structured summary of a study protocol for a randomised controlled trial. Trials 2020; 21(1): 1027.
183	not outpt RCT						Levine AC, Fukuta Y, Huaman MA, et al. COVID-19 Convalescent Plasma Outpatient Therapy to Prevent Outpatient Hospitalization: A Meta-analysis of Individual Participant Data From Five Randomized Trials. Clin Infect Dis 2023.
185	not outpt RCT						Levine AC, Fukuta Y, Huaman MA, et al. COVID-19 Convalescent Plasma Outpatient Therapy to Prevent Outpatient Hospitalization: A Meta-analysis of Individual Participant Data From Five Randomized Trials. medRxiv 2022.
186	not outpt RCT						Li W, Xie L, Zhu X, et al. Effectiveness and safety of Qingfei Dayuan granules for treating influenza and upper respiratory tract infections manifested by the pulmonary heat-toxin syndrome: A multicenter, randomized, double-blind, placebo-controlled trial. Front Pharmacol 2023; 14: 1133560.
190	not outpt RCT						Licchetta L, Trivisano M, Baldin E, et al. TELEmedicine for EPIlepsy Care (TELE-EPIC): protocol of a randomised, open controlled non-inferiority clinical trial. BMJ Open 2021; 11(12): e053980.
191	not outpt RCT						Lin WT, Hung SH, Lai CC, Wang CY, Chen CH. The impact of neutralizing monoclonal antibodies on the outcomes of COVID-19 outpatients: A systematic review and meta-analysis of randomized controlled trials. J Med Virol 2022; 94(5): 2222–9.
193	not outpt RCT						Liu HH, Ezekowitz MD, Columbo M, et al. The future is now: our experience starting a remote clinical trial during the beginning of the COVID-19 pandemic. Trials 2021; 22(1): 603.
196	not outpt RCT						Lofgren SM, Nicol MR, Bangdiwala AS, et al. Safety of Hydroxychloroquine among Outpatient Clinical Trial Participants for COVID-19. medRxiv 2020.
197	not outpt RCT						Lofgren SM, Nicol MR, Bangdiwala AS, et al. Safety of Hydroxychloroquine Among Outpatient Clinical Trial Participants for COVID-19. Open Forum Infect Dis 2020; 7(11): ofaa500.
200	not outpt RCT						Lokhandwala T, Acharya M, Farrelly E, Coutinho AD, Bell CF, Svedsater H. Within-trial economic analysis of resource use from COMET-ICE: A phase 3 clinical trial evaluating sotrovimab for the treatment of patients with COVID-19 at high risk of progression. J Manag Care Spec Pharm 2022; 28(11): 1261–71.
201	not outpt RCT						Lopes RD, de Barros ESPGM, Furtado RHM, et al. Randomized clinical trial to evaluate a routine full anticoagulation Strategy in Patients with Coronavirus Infection (SARS-CoV2) admitted to hospital: Rationale and design of the ACTION (AntiCoagulaTlon cOroNavirus)-Coalition IV trial. Am Heart J 2021; 238: 1–11.
202	not outpt RCT						Lother SA, Abassi M, Agostinis A, et al. Post-exposure prophylaxis or pre-emptive therapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): study protocol for a pragmatic randomized-controlled trial. Can J Anaesth 2020; 67(9): 1201–11.
204	not outpt RCT						Lui G, Guaraldi G. Drug treatment of COVID-19 infection. Curr Opin Pulm Med 2023; 29(3): 174–83.
206	not outpt RCT						Malin JJ, Weibel S, Gruell H, Kreuzberger N, Stegemann M, Skoetz N. Efficacy and safety of molnupiravir for the treatment of SARS-CoV-2 infection: a systematic review and meta-analysis. J Antimicrob Chemother 2023.
208	not outpt RCT						Manenti L, Maggiore U, Fiaccadori E, et al. Reduced mortality in COVID-19 patients treated with colchicine: Results from a retrospective, observational study. PLoS One 2021; 16(3): e0248276.
209	not outpt RCT						Mao Z, Li X, Dacosta-Urbieta A, et al. Economic burden and health-related quality-of-life among infants with respiratory syncytial virus infection: A multi-country prospective cohort study in Europe. Vaccine 2023; 41(16): 2707–15.
210	not outpt RCT						Martins-Filho PR, Ferreira LC, Heimfarth L, Araujo AAS, Quintans-Junior LJ. Efficacy and safety of hydroxychloroquine as pre-and post-exposure prophylaxis and treatment of COVID-19: A systematic review and meta-analysis of blinded, placebo-controlled, randomized clinical trials. Lancet Reg Health Am 2021; 2: 100062.
211	not outpt RCT						Mason JS, Crowell MS, Brindle RA, et al. The Effect of Blood Flow Restriction Training on Muscle Atrophy Following Meniscal Repair or Chondral Restoration Surgery in Active Duty Military: A Randomized Controlled Trial. J Sport Rehabil 2022; 31(1): 77–84.
212	not outpt RCT						Mazzaferri F, Mirandola M, Savoldi A, et al. Exploratory data on the clinical efficacy of monoclonal antibodies against SARS-CoV-2 Omicron variant of concern. Elife 2022; 11.
213	not outpt RCT						McCarthy MW, Naggie S, Boulware DR, et al. Fluvoxamine for Outpatient Treatment of COVID-19: A Decentralized, Placebo-controlled, Randomized, Platform Clinical Trial. medRxiv 2022.
215	not outpt RCT						McCoy J, Goren A, Cadegiani FA, et al. Proxalutamide Reduces the Rate of Hospitalization for COVID-19 Male Outpatients: A Randomized Double-Blinded Placebo-Controlled Trial. Front Med (Lausanne) 2021; 8: 668698.
218	not outpt RCT						McCreary EK, Bariola JR, Minnier T, et al. Launching a comparative effectiveness adaptive platform trial of monoclonal antibodies for COVID-19 in 21 days. Contemp Clin Trials 2022; 113: 106652.
225	not outpt RCT						McCreary EK, Bariola JR, Wadas RJ, et al. Association of Subcutaneous or Intravenous Administration of Casirivimab and Imdevimab Monoclonal Antibodies With Clinical Outcomes in Adults With COVID-19. JAMA Netw Open 2022; 5(4): e226920.
228	not outpt RCT						McCreary MR, Schnell PM, Rhoda DA. Randomized Double-blind Placebo-controlled Proof-of-concept Trial of Resveratrol for Outpatient Treatment of Mild Coronavirus Disease (COVID-19). Res Sq 2021.
232	not outpt RCT						McCullough PA, Kelly RJ, Ruocco G, et al. Pathophysiological Basis and Rationale for Early Outpatient Treatment of SARS-CoV-2 (COVID-19) Infection. Am J Med 2021; 134(1): 16–22.
234	not outpt RCT						McKinnon JE, Wang DD, Zervos M, et al. Safety and tolerability of hydroxychloroquine in health care workers and first responders for the prevention of COVID-19: WHIP COVID-19 Study. Int J Infect Dis 2022; 116: 167–73.
235	not outpt RCT						Mesri M, Esmaeili Saber SS, Godazi M, et al. The effects of combination of Zingiber officinale and Echinacea on alleviation of clinical symptoms and hospitalization rate of suspected COVID-19 outpatients: a randomized controlled trial. J Complement Integr Med 2021; 18(4): 775–81.
237	not outpt RCT						Migliorini F, Vaishya R, Eschweiler J, Oliva F, Hildebrand F, Maffulli N. Vitamins C and D and COVID-19 Susceptibility, Severity and Progression: An Evidence Based Systematic Review. Medicina (Kaunas) 2022; 58(7).
238	not outpt RCT						Miguel-Cruz A, Ladurner AM, Kohls-Wiebe M, Rawani D. The Effects of 3D Immersion Technology (3Scape) on Mental Health in Outpatients From a Short-Term Assessment, Rehabilitation, and Treatment Program: Feasibility Protocol for a Randomized Controlled Trial. JMIR Res Protoc 2021; 10(9): e25017.
240	not outpt RCT						Miguel-Cruz A, Sr., Guptill C, Gregson G, et al. Determining the Effectiveness of a New Device for Hand Therapy (The FEPSim Device): Feasibility Protocol for a Randomized Controlled Trial Study. JMIR Res Protoc 2021; 10(5): e22145.
242	not outpt RCT						Millat-Martinez P, Gharbharan A, Alemany A, et al. Prospective individual patient data meta-analysis of two randomized trials on convalescent plasma for COVID-19 outpatients. Nat Commun 2022; 13(1): 2583.
243	not outpt RCT						Mills FP, Reis G, Wilson LA, et al. Early Treatment with Fluvoxamine among Patients with COVID-19: A Cost-Consequence Model. Am J Trop Med Hyg 2023; 108(1): 101–6.
244	not outpt RCT						Miryan M, Bagherniya M, Sahebkar A, et al. Effects of curcumin-piperine co-supplementation on clinical signs, duration, severity, and inflammatory factors in patients with COVID-19: a structured summary of a study protocol for a randomised controlled trial. Trials 2020; 21(1): 1027.
246	not outpt RCT						Mitja O, Reis G, Boulware DR, et al. Hydroxychloroquine for treatment of non-hospitalized adults with COVID-19: A meta-analysis of individual participant data of randomized trials. Clin Transl Sci 2023; 16(3): 524–35.
247	not outpt RCT						Muschol J, Heinrich M, Heiss C, et al. Economic and Environmental Impact of Digital Health App Video Consultations in Follow-up Care for Patients in Orthopedic and Trauma Surgery in Germany: Randomized Controlled Trial. J Med Internet Res 2022; 24(11): e42839.
250	not outpt RCT						Nachega JB, Leisegang R, Kallay O, Mills EJ, Zumla A, Lester RT. Mobile Health Technology for Enhancing the COVID-19 Response in Africa: A Potential Game Changer? Am J Trop Med Hyg 2020; 103(1): 3–5.
253	not outpt RCT						Naggie S, Boulware DR, Lindsell CJ, et al. Effect of Ivermectin 600 mug/kg for 6 days vs Placebo on Time to Sustained Recovery in Outpatients with Mild to Moderate COVID-19: A Randomized Clinical Trial. medRxiv 2022.
258	not outpt RCT						Nappi F, Iervolino A, Avtaar Singh SS. Molecular Insights of SARS-CoV-2 Antivirals Administration: A Balance between Safety Profiles and Impact on Cardiovascular Phenotypes. Biomedicines 2022; 10(2).
262	not outpt RCT						Narayanan D, Parimon T. Current Therapeutics for COVID-19, What We Know about the Molecular Mechanism and Efficacy of Treatments for This Novel Virus. Int J Mol Sci 2022; 23(14).
263	not outpt RCT						Nascimento L, Mendes LA, Torres-Castro R, et al. Physical performance testing in post-COVID-19 patients: protocol for a systematic review of psychometric measurement properties. BMJ Open 2023; 13(4): e067392.
265	not outpt RCT						Ngo BT, Marik P, Kory P, et al. The time to offer treatments for COVID-19. Expert Opin Investig Drugs 2021; 30(5): 505–18.
267	not outpt RCT						Nicastri E, Marinangeli F, Pivetta E, et al. A phase 2 randomized, double-blinded, placebo-controlled, multicenter trial evaluating the efficacy and safety of raloxifene for patients with mild to moderate COVID-19. EClinicalMedicine 2022; 48: 101450.
268	not outpt RCT						Nyirenda JL, Sofroniou M, Toews I, et al. Fluvoxamine for the treatment of COVID-19. Cochrane Database Syst Rev 2022; 9(9): CD015391.
269	not outpt RCT						Ogletree ML, Chander Chiang K, Kulshrestha R, Agarwal A, Agarwal A, Gupta A. Treatment of COVID-19 Pneumonia and Acute Respiratory Distress With Ramatroban, a Thromboxane A(2) and Prostaglandin D(2) Receptor Antagonist: A Four-Patient Case Series Report. Front Pharmacol 2022; 13: 904020.
271	not outpt RCT						Oliveira GBF, Neves P, Oliveira HA, et al. Rivaroxaban in Outpatients with Mild or Moderate COVID-19: Rationale and Design of the Study CARE (CARE - Coalition COVID-19 Brazil VIII). Arq Bras Cardiol 2023; 120(3): e20220431.
272	not outpt RCT						Oliveira Junior HA, Ferri CP, Boszczowski I, et al. Rationale and Design of the COVID-19 Outpatient Prevention Evaluation (COPE - Coalition V) Randomized Clinical Trial: Hydroxychloroquine vs. Placebo in Non-Hospitalized Patients. Arq Bras Cardiol 2022; 118(2): 378–87.
273	not outpt RCT						Olson SM, Newhams MM, Halasa NB, et al. Effectiveness of Pfizer-BioNTech mRNA Vaccination Against COVID-19 Hospitalization Among Persons Aged 12–18 Years - United States, June-September 2021. MMWR Morb Mortal Wkly Rep 2021; 70(42): 1483–8.
276	not outpt RCT						Pan DZ, Odorizzi PM, Schoenichen A, et al. Remdesivir improves biomarkers associated with disease severity in COVID-19 patients treated in an outpatient setting. Commun Med (Lond) 2023; 3(1): 2.
278	not outpt RCT						Pembroke S, Rogerson S, Coyne I. Conducting a randomised controlled trial of a psychosocial intervention for adolescents with type 1 diabetes during COVID-19: recommendations to overcome the challenges complicated by inconsistent public health guidelines on research. Trials 2022; 23(1): 362.
279	not outpt RCT						Pham B, Rios P, Radhakrishnan A, et al. Comparative-effectiveness research of COVID-19 treatment: a rapid scoping review. BMJ Open 2022; 12(6): e045115.
280	not outpt RCT						Pinzon MA, Ortiz S, Holguin H, et al. Dexamethasone vs methylprednisolone high dose for Covid-19 pneumonia. PLoS One 2021; 16(5): e0252057.
51	open label						Plasse TF, Delgado B, Potts J, et al. A randomized, placebo-controlled pilot study of upamostat, a host-directed serine protease inhibitor, for outpatient treatment of COVID-19. Int J Infect Dis 2023; 128: 148–56.
79	open label						Popp M, Reis S, Schiesser S, et al. Ivermectin for preventing and treating COVID-19. Cochrane Database Syst Rev 2022; 6(6): CD015017.
157	open label						Popp M, Stegemann M, Metzendorf MI, et al. Ivermectin for preventing and treating COVID-19. Cochrane Database Syst Rev 2021; 7(7): CD015017.
248	open label						Popp M, Stegemann M, Riemer M, et al. Antibiotics for the treatment of COVID-19. Cochrane Database Syst Rev 2021; 10(10): CD015025.
254	open label						Portal-Celhay C, Forleo-Neto E, Eagan W, et al. Virologic Efficacy of Casirivimab and Imdevimab COVID-19 Antibody Combination in Outpatients With SARS-CoV-2 Infection: A Phase 2 Dose-Ranging Randomized Clinical Trial. JAMA Netw Open 2022; 5(8): e2225411.
110	propensity matcch						Powell-Jackson T, King JJC, Makungu C, et al. Infection prevention and control compliance in Tanzanian outpatient facilities: a cross-sectional study with implications for the control of COVID-19. Lancet Glob Health 2020; 8(6): e780-e9.
171	propensity matcch						Procter BC, Ross C, Pickard V, Smith E, Hanson C, McCullough PA. Clinical outcomes after early ambulatory multidrug therapy for high-risk SARS-CoV-2 (COVID-19) infection. Rev Cardiovasc Med 2020; 21(4): 611–4.
42	protocol						Puspitasari AJ, Heredia D, Coombes BJ, et al. Feasibility and Initial Outcomes of a Group-Based Teletherapy Psychiatric Day Program for Adults With Serious Mental Illness: Open, Nonrandomized Trial in the Context of COVID-19. JMIR Ment Health 2021; 8(3): e25542.
49	protocol						Rahman AE, Hossain AT, Nair H, et al. Prevalence of hypoxaemia in children with pneumonia in low-income and middle-income countries: a systematic review and meta-analysis. Lancet Glob Health 2022; 10(3): e348-e59.
94	protocol						Rahmati M, Molanouri Shamsi M, Woo W, et al. Effects of physical rehabilitation interventions in COVID-19 patients following discharge from hospital: A systematic review. J Integr Med 2023; 21(2): 149–58.
158	protocol						Rajkumar T, Freyne J, Varnfield M, et al. Remote blood pressure monitoring in high risk pregnancy - study protocol for a randomised controlled trial (REMOTE CONTROL trial). Trials 2023; 24(1): 334.
199	protocol						Reis S, Metzendorf MI, Kuehn R, et al. Nirmatrelvir combined with ritonavir for preventing and treating COVID-19. Cochrane Database Syst Rev 2022; 9(9): CD015395.
236	protocol						Reis S, Popp M, Schiesser S, et al. Anticoagulation in COVID-19 patients - An updated systematic review and meta-analysis. Thromb Res 2022; 219: 40–8.
169	retracted						Rizk JG, Gupta A, Lazo JG, Jr., et al. To Anticoagulate or Not to Anticoagulate in COVID-19: Lessons after 2 Years. Semin Thromb Hemost 2023; 49(1): 62–72.
19	review						Rohani M, Mozaffar H, Mesri M, Shokri M, Delaney D, Karimy M. Evaluation and comparison of vitamin A supplementation with standard therapies in the treatment of patients with COVID-19. East Mediterr Health J 2022; 28(9): 673–81.
34	review						Rosenthal N, Cao Z, Gundrum J, Sianis J, Safo S. Risk Factors Associated With In-Hospital Mortality in a US National Sample of Patients With COVID-19. JAMA Netw Open 2020; 3(12): e2029058.
45	review						Rubin DJ, Shah AA. Predicting and Preventing Acute Care Re-Utilization by Patients with Diabetes. Curr Diab Rep 2021; 21(9): 34.
55	review						Ruzhentsova TA, Oseshnyuk RA, Soluyanova TN, et al. Phase 3 trial of coronavir (favipiravir) in patients with mild to moderate COVID-19. Am J Transl Res 2021; 13(11): 12575–87.
69	review						Saiz-Rodriguez M, Pena T, Lazaro L, et al. Outpatient treatment of COVID-19 with steroids in the phase of mild pneumonia without the need for admission as an opportunity to modify the course of the disease: A structured summary of a randomised controlled trial. Trials 2020; 21(1): 632.
71	review						Salovaara PK, Li C, Nicholson A, Lipsitz SR, Natarajan S. Navigating COVID-19 and related challenges to completing clinical trials: Lessons from the PATRIOT and STEP-UP randomized prevention trials. Clin Trials 2023; 20(2): 153–65.
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Table 2a.

Demographic and clinical characteristics of recruits in the RCTs analyzed in this review.

Study	mITT	median age (range)	total female n(%)	White n(%)	Black n(%)	Hispanic n(%)	1 or more medical high risk conditons for COVID-19 progession	diabetes n(%)	hypertension n(%)	obesity or BMI >30 n(%)	median duration symptoms	Seropositive at baseline n(%)	Hospital type	Endpoint days for hosp
CCP (5 RCTs) totals or averages	2634	58	1409 (53)	2213 (84)	266 (10)	862 (33)	2074 (79)	326 (15)	606 (33)	854 (38)	4.5	73 (9)
anti-Spike mAbs (8 RCTs) totals or averages	7421	47	3944 (53)	6214 (84)	455 (6)	3113 (42)	6562 (88)	1067 (14)	1249 (17)	3197 (43)	3.5	1087 (15)
Small molecule antivirals (11 RCTs) totals or averages	33148	45.4	18116 (55)	28726 (87)	399 (1)	2458 (7)	22400 (68)	3150 (10)	6954 (21)	6271 (19)	4	25710 (77) {710/8148=9%w/o-Mol-Pan.)
Repurposed drugs (27 RCTs) totals or averages	16840	48	9595 (57)	14752 (89)	815 (5)	4212 (32)	8669 (88)	2174 (13)	4318 (27)	6615 (46)	5.1	2303 (51)
CCP-CONV-ert7	376	56	173 (46)	0	0	376 (100)	278 (74)	49 (13)	not reported	96 (26)	4.4	43 (11)	All cause	28–30
CCP-COV-Early13	406	58	187 (46)	406 (100)	0	0	278 (68)	not reported	not reported	not reported	5 (iqr4–6)	30 (8)	All cause	28–30
CCP-C3PO4	511	54	274 (54)	237 (46)	103 (20)	156 (31)	511 (100)	142 (28)	216 (42)	302 (59)	4	not reported	All cause	15
CCP-Argentina5	160	77 (65–90+)	100 (62)	0	0	160 (100)	131 (82)	36 (23)	114 (71)	12 (8)	3	not reported	hypoxia resp rate def	28–30
CCP-CSSC-0043	1181	43 (18–85)	675 (57)	934 (79)	163 (14)	170 (14)	470 (40)	99 (8)	276 (23)	444 (38)	6	not reported	COVID-19 related	28–30
Bamlanivimab-BLAZE-114	452	45 (18–86)	249 (55)	389 (86)	29 (6)	198 (44)	310 (69)		not reported	201 (44)	4	not reported	COVID-19 related + ED visit	28–30
Sotrovimab-COMET-ICE8	1057	53(17–96)	571 (54)	919 (87)	42 (4)	687 (65)	1055 (99.9)	233 (23)	not reported	665 (63)	3	not reported	All cause	28–30
Bamlanivimab/etesevimab-BLAZE-115	1035	54 (12–77+)	538 (52)	896 (87)	83 (8)	304 (29)	983 (95)	285 (28)	not reported	median 34 bmi	4	not reported	COVID-19 related	28–30
Casirivimab/imdevimab-REGEN-COV Ph 316	2696	50 (iqr 39–50)	1407 (52)	2297 (85)	143 (5)	935 (35)	2696 (100)	412 (15)	993 (37)	1559 (58)	3	620 (23)	COVID-19 related	28–30
Casirivimab/imdevimab-REGEN-COV Ph 1/217	799	42 (iqr 31–52)	423 (53)	681 (85)	74 (9)	403 (50)	483 (61)			298 (37)	3	304 (38)	All cause	28–30
Bebtelovimab-BLAZE-41	253	34	135 (53)	187 (74)	48 (19)	91 (36)	0 (0)	not reported	not reported		3	27 (11)	COVID-19 related	28–30
Regdanvimab-CT-P5918	307	51 (iqr40–60)	166 (51)	286 (87)	0	27 (8)	226 (69)	29 (9)	not reported	52 (16)	3	9 (3)	All cause	28–30
Regdanvimab-CT-P59–219	1315	48 (iqr38–59)	641 (49)	1132 (86)	7 (1)	276 (21)	880 (67)	120 (9)	443 (34)	415 (32)	4	148 (11)	All cause	28
Tixagevimab–cilgavimab-TACKLE20	822	46 (sd 15.2)	455 (50)	559 (62)	36 (4)	468 (52)	809 (90)	108 (12)	256 (28)	388 (43)	5	127 (14)	COVID-19 related	28–30
Molnupiravir-MOVe-OUT21	1408	43 (18–90)	735 (51.3)	813 (56)	75 (5)	711 (49)	1424 (99.4)	228 (15.9)%	not reported	1056(73)	3	620 (23)	All cause	28–30
Molnupiravir-PANORAMIC22	25000	57 (18–99)	15101 (59)	24270 (94)	155 (0.6)		17759 (69)	2195 (9)%	5782 (22)	3912 (15)%	3	25333 (98) 2+ doses of vaccine	All cause	28–30
Molnupiravir-Aurobindo23	1220	36 (18–60)	468 (38)	1220 (100)	0	0	90 (7.3)				3	not reported	All cause	28–30
Nirmatrelvir/ritonavir-EPIC-HR9	2085	46 (18–88)	1098 (49)	1607 (72)	110 (4.9)	1010 (45)	2085 (100)	252 (11)	739 (33)	744 (36)	3	27 (11)	COVID-19 related	28–30
Remdesivir-PINETREE12	562	50 (12–77+)	269 (48)	452 (80)	42 (7.5)	235 (41)	562 (100)	346 (62)	268 (48)	310 (55)	5	9 (3)	COVID-19 related	28–30
Interferon Lambda-TOGETHER24	1949	43 (18–92)	1113 (57)	58 (3)	28 (1)	1853 (95)	1124 (58)	181 (9)	581 (30)	719 (37)	3	1107 (58) FV	COVID-19 related	28
Interferon Lambda-ILIAD25	60	46 (iqr32–54)	35 (60)	31	6		9			12	5	5/51 (10)	COVID-19 related	14
Interferon Lambda-COVID-Lambda26	120	36 (18–71)	50 (42)	33 (28)		74 (63)		12 (10)	14 (12)		5 (iqr3–6)	49 (41)	All cause	28–30
Sofosbuvir and daclatasvir-SOVODAK27	55	<50	29 (53)	55 (100)							not reported	not reported	All cause	28–30
Favipavir-Avi-Mild-1928	231	37 (iqr32–44)	76 (33)	231 (100)	0	0		25 (11)	14 (6)	39 (17)	3	not reported	All cause	28–30
Favipiravir-Iran29	77	41	34	77 (100)	0	0	11 (14)	nr	nr	nr	4		All cause	28
Favipiravir-FLARE30	119	40	56 (47)	98 (82)			17 (14)			20 (17)	nr	74 (62)	All cause	28
Favipiravir/Lopinavir/Ritonavir-FLARE30	121	40	59 (49)	99 (82)			19 (16)			20 (17)	nr	77 (64)	All cause	28
Lopinavir/Ritonavir-FLARE30	120	40	60 (50)	98 (82)			16 (13)			20 (17)	nr	74 (62)	All cause	28
Lopinavir/ritonavir-TREAT NOW31	446	41 (19–75)	261 (59)	354 (79)	35 (8)	33 (7)	347 (78)	17 (4)	77 (17)	149 (35)	4	93 (21)	All cause	29
Lopinavir/ritonavir-TOGETHER32	471	53 (IQR 18–94)	255 (54)	14 (3)	11 (2)	428 (91)	471 (100)	92 (20)	137 (29)	198 (42)	6	not reported	COVID-19 related	90
Tenofovir Disproxil Fumarate Plus Emtricitabine-AR0-CORONA33	60	42	34 (57)					2	3		4		All cause	14
Metformin-COVID-OUT34	1197	46 (iqr 37–55)	741 (56)	1091 (82)	90 (7)			26 (2)	353 (27) cvd	646 (49)	5	690 (52fv)	COVID-19 related	28–30
Metformin-TOGETHER35	418	52 (18–90)	239 (57)	8 (2)	6 (1)	381 (91)	418 (100)	61 (15)	167 (40)	188 (45)	3		All cause	28–30
Fluvoxamine-TOGETHER11	1497	<50	862 (58)	1486 (99)	5 (1)	1486 (99)	1497 (100)	243 (16)	194 (13)	751 (50)	4	not reported	COVID-19 related	28–30
Fluvoxamine-STOP COVID36	152	46	109 (72)	106 (70)	38 (25)	5 (3)		17 (11)	30 (20)	75 (49)	4	not reported	COVID-19 related	15 (2 noncovid after day 15 to day 28
Fluvoxamine-COVID-OUT34	592	44 (iqr37–53)	358 (54)	539 (82)	51 (8)			7 (1)	172 (26) cvd	302 (46)	5	373 (56fv)	COVID-19 related	28–30
Fluvoxamine ACTIV-637	1288	48 (iqr39–58)	734 (57)	1038 (81)	96 (7)	221 (17)		115 (9)	304 (24)	469 (36)	5	861 (67)	All cause	28
Fluvoxamine/budesonide-TOGETHER38	1476	51 (18–102)	898 (61)	36 (2)	20 (1)	1419 (96)	1476 (100)	278 (19)	656 (44)	597 (42)	3	1377 (94)	All cause	28–30
Ivermectin-TOGETHER39	1349	49	791 (58)	1310 (98)	12 (1)	1310 (98)	1349 (100)	180 (13)	114 (8)	675 (50)	4	not reported	COVID-19 related	28–30
Ivermectin-COVID-OUT34	730	46 (iqr37–56)	442 (55)	662 (82)	59 (7)			13 (2)	184 (23) cvd	383 (47)	5	449 (56fv)	COVID-19 related	28–30
Ivermectin Iran40	549	35 (5–87)	294 (48)	582 (100)	0	0	112 (20)	42 (7.3)	46 (7.8)	101 (21)	3	not reported	All cause	not stated
Ivermectin-ACTIV-641	1591	47 (iqr39–56)	932 (59)	1286 (81)	113(7)	163 (10)		184	415	648	6	753 (fv47)	All cause	28–30
Ivermectin high dose-ACTIV-642	1206	48 (iqr38–58)	713 (59)	909 (75)	93 (8)	160 13)		109 (9)	317 (27)	259 (21)	5	1008 (84)	All cause	28
Hydroxychloroquine-TOGETHER32	441	53 (IQR 18–81)	243 (55)	422 (96)	7 (1)	422 (96)	441 (100)	89 (20)	210 (48)	177 (40)	6	not reported	COVID-19 related	90
Hydroxychloroquine-COVID-19 PEP43	423	40 (iqr 32–50)	238 (56)	235 (48)	15 (3)	28 (6)		15 (3)	46 (11)		2	not reported	All cause	14
Hydroxychloroquine-AH COVID-1944	148	47	66 (45)	51	12			29	41		7 (iqr5–8)	not reported	All cause	28–30
Hydroxychloroquine-BCN PEP-CoV-245	293	42 (12 sd)	201 (69)				156 (53)	20 (7)			3 (iqr 2–4)	not reported	All cause	28–30
Hydroxychloroquine-BMG46	231	37 (18–78)	131 (57)	117 (51)	26 (11)	71 (31)	129 (56)	17 (7)	27 (12)	98 (42)	6	not reported	COVID-19 related	28–30
Hydroxychloroquine-Utah47	303	42	176 (48)	165 (45)	2 (1)	158 (43)	90 (25)	28 (8)	52 914)		nr	nr	All cause	28
Hydroxychloroquine/Azithromycin-Brazil48	84	37	34	44	5	79		nr	nr	nr	4	nr	All cause	21
Nitazoxanide-Romark49	379	40 (12–83)	214 (57)	233 (61)	8 (2)	130 (34)	238 (63%)				2	38 (10)	COVID-19 related	28–30
Colchicine-COLCORONA2	4488	54 (iqr 47–61)	2421 (54)	4182 (93)	233 (5)	<10%	4488 (100)	894 (20)	1629 (36)	2052 (46)	5.3	not reported	COVID-19 related	28–30
Losartan-MN50	117	38	58	84	8	10		7	9	42	2		All cause	28
Niclosamide51	67	36 mean	26 (39)	53 (79)	4 (6)	7 (10)			5 (8)	4 (7)	not reported	not reported	All cause	28–30
Aspirin-ACTIV-4B52	280	54 (iqr 46–59)	191 (58)	250 (76)	36 (11)	93 (28)		53 (16)	109 (33)	164 (50)	10 (diagnosis)	not reported	All cause	45
2.5-mg apixaban-ACTIV-4B52	271	54 (iqr 46–59)	191 (58)	255 (78)	38 (12)	91 (28)		60 (18)	120 (37)	164 (50)	10 (diagnosis)	not reported	All cause	45
5-mg apixaban ACTIV-4B52	279	54 (iqr 46–59)	198 (6	251 (77)	36 (11)	80 (24)		55 (17)	111 (34)	164 (50)	10 (diagnosis)	not reported	All cause	45
Sulodexide53	243	55	128 (53)	243 (100)		243 (100)		50 (21)	83 (43)		3	not reported	All cause	21
Enoxaparin-ETHIC54	219	59 (iqr51–66)	96 (44)	129 (59)	5 (2)	12 (5)		50/152 (33)	114/152 (75)	109 (49)	5	not reported	All cause	21
Enoxaparin-OVID55	572	56 (iqr53–62)	217 (38)	446 (78)	3 (1)			38 (7)	115 (20)		3 (dx)	not reported	All cause	28–30
Inhaled Ciclesonide-COVIS56	400	43 (13–87)	221 (55)	345 (86)	47 (12)	172 (43)		30 (8)	89 (22)	200 (50)	NR		All cause	30
Inhaled ciclesonide-COVERAGE57	217	63 (50–86)	111 (51)	217 (100)	0	0	157 (72)	33(16)	89 (41)	52 (24)	4	not reported	All cause	28–30
Zinc58	108	43	68	73	28			10	35	54	nr	nr	All cause	28
Ascorbic acid58	98	44	64	70	23			5	22	49	nr	nr	All cause	28
Zinc/Ascorbic acid58	108	46	62	71	32			20	41	54	nr	nr	All cause	28
Homeopathy-COVID-Simile59	86	41	56			86 (100)		8	21		9	nr	All cause	27
Saliravira60	143	50 (24–80)	59 (41)	143 (100)					33 (23)		not reported	not reported	All cause	23
Azithromycin-Atomic261	292	46	143 (49)	201 (68)	11 (4)		70 (24)	25 (9)	52 (18)		6	not reported	All cause	28–30
Azithromycin-ACTION62	197	43	130 (66)	169 (86)	9 (5)	59 (30)		24 (12)	26 (13)		6	not reported	All cause	21
Resveratrol63	100	55 (45–84)	62 (59)	93 (89)	4 (4)	2 (2)	32 (30)	10 (10)		50 (50)	5	not reported	All cause	21

Appendix Table 2b:

Additional baseline data from RCTs-Geography, age symptom onset

Study	Enrollment Period	Study months	Geography	Enrolled	age over 65 n(%)	age over 60 n(%)	age over 50 n(%)	symptoms <= 8 days n(%)	symptoms <=7 days n(%)	symptoms <= 5 days n(%)	symptoms <= 3 days n(%)
CCP-CONV-ert7	Nov 10 2020–July 28 2021	9	Spain	376			376 (100)		376 (100)
CCP-COV-Early13			Netherlands	406			351 (86)		406 (100)
CCP-C3PO4	Aug 2020-Feb 2021	7	USA	511			511 (100)		511 (100)		246 (48)
CCP-Argentina5	Jun 4 2020 – Oct 25 2020	5	Argentina	160	160 (100)						160 (100)
CCP-CSSC-0043	June 3 2020-Oct 2021	16	USA	1225	80 (7)		410 (35)	1181 (100)		517 (44)
Bamlanivimab-BLAZE-114	June 2020-Aug 2020	3	USA	467	53 (12)					226 (50)mean
Sotrovimab-COMET-ICE8	Aug 27 2020-March 2021	6	United States, Canada, Brazil, and Spain	1057	211(20)					1057 (100)	624 (59)
Bamlanivimab/etesevimab-BLAZE-115	Sept 2020-Dec 2020	3	USA	1035	323 (31)			979 (95)
Casirivimab/imdevimab-REGEN-COV Ph 316	Sept 24 2020-Jan 17 2021	4	USA Mexico	2696	358 (13)				2696 (100)		1489 (66)
Casirivimab/imdevimab-REGEN-COV Ph 1/217	June 16, 2020 – Sept 23, 2020	3	USA	799					799 (100)	599 (75)	400 (50)
Bebtelovimab-BLAZE-41	May 2021-July 2021	3	USA	253	1 (<1)				253 (100)
Regdanvimab-CT-P5918	Oct 2020-Dec 2020	2	South Korea, Romania, Spain, USA	327		85 (26)			327 (100)
Regdanvimab-CT-P59–219	Jan 18 2021 to april 24 2021	3	world wide	1315			297 (23)			986 (75)	329 (25)
Tixagevimab–cilgavimab-TACKLE20	Jan 28, 2021–July 22, 2021,	6	USA, Latin America, Europe, and Japan.	1014	116 (13)				910 (100)
Molnupiravir-MOVe-OUT21	May 2021–Oct 2021	6	worldwide	1433		246 (17)				1408 (100)	674 (48)
Molnupiravir-PANORAMIC22	Dec 8–2021 – April 27, 2022	5	UK	25783	6838 (27)					22510 (87)
Molnupiravir-Aurobindo23	July 1, 2021 – Aug 24, 2021	2	India	1220							661 (54)
Nirmatrelvir/ritonavir-EPIC-HR9	July 1 2021 – Dec 2021	6	worldwide	2246	287(12.8)					2246 (100)	1489 (66.3)
Remdesivir-PINETREE12	Sept 2020-Apr 2021	8	USA, Spain, Denmark UK	562		170 (30)			562 (100)
Interferon Lambda-TOGETHER24	Jun 24 2021-feb 7 2022	8	Brazil	1949			752 (39)		1949 (100)		1158 (59)
Interferon Lambda-ILIAD25	May 18, 2020–Sep 4 2020	4	Canada	60					60 (100)
Interferon Lambda-COVID-Lambda26	Apil 25 2020-July 7 2020	2	USA	120
Sofosbuvir and daclatasvir-SOVODAK27	April 8 2020-May 19 2020	1	Iran	55
Favipavir-Avi-Mild-1928	July 23, 2020–Aug 4 2021	12	Saudi Arabia	245			30 (13)			231 (100)
Favipiravir-Iran29	Dec 5 2020-mar 31 2021	4	Iran	77					77 (100)
Favipiravir-FLARE30	Oct 6 2020–Nov 4 2021	13	United Kingdom	119					119 (100)	76 (64)
Favipiravir/Lopinavir/Ritonavir-FLARE30	Oct 6 2020–Nov 4 2021	13	United Kingdom	121					121 (100)	80 (66)
Lopinavir/Ritonavir-FLARE30	Oct 6 2020–Nov 4 2021	13	United Kingdom	120					120 (100)	75 (63)
Lopinavir/ritonavir-TREAT NOW31	Jun 2020-Dec 2021	18	USA	446	13 (3)		112 (25)		446 (100)	349 (78)	124 (28)
Lopinavir/ritonavir-TOGETHER32	June 2 2020-Oct 9 2020	4	Brazil	471			275	471 (100)		74 (16)
Tenofovir Disproxil Fumarate Plus Emtricitabine-AR0-CORONA33	Nov 20 2020-Mar 19 2021	4	France	60					60 (100)	45 (75)
Metformin-COVID-OUT34	Dec 30 2020 – Jan 28 2022	13	USA	1323					1197 (100)
Metformin-TOGETHER35	jan 15 2021–April 13 2021	3	Brazil	418			234 (56)		418 (100)		184 (44)
Fluvoxamine-TOGETHER11	Jan 2021 – Aug 2021	8	Brazil	1497			655 (44)		1497 (100)		638 (43)
Fluvoxamine-STOP COVID36	April 10 2020 – Aug 5 2020	4	USA	152					152 (100)	114 (75)
Fluvoxamine-COVID-OUT34	Dec 30 2020 – Jan 28 2022	13	USA	661					733 (100)
Fluvoxamine ACTIV-637	Au 6 2021-May 27 2022	10	USA	1288			541 (42)		966 (75)	644 (50)
Fluvoxamine/budesonide-TOGETHER38	Jan 15 2022-July 6 2022	6	Brazil	1476			829 (56)		1476 (100)		917 (62)
Ivermectin-TOGETHER39	March 23 – Aug 2 2021	5	Brazil	1358					1358 (100)		597 (44)
Ivermectin-COVID-OUT34	Dec 30 2020 – Jan 28 2022	13	USA	808					592 (100)
Ivermectin Iran40	Feb 19 21 – Aug 30 21	7	Iran	582							291 (50)
Ivermectin-ACTIV-641	June 23 2021 – Feb 4 2022	7	USA	1591			680 (43)	1193 (75)
Ivermectin high dose-ACTIV-642	feb 16 2022-July 22 2022	5	USA	1206					905 (75)	603 (50)	302 (25)
Hydroxychloroquine-TOGETHER32	June 2 2020-Oct 9 2020	4	Brazil	441			262 (59)	441 (100)		77 (17)
Hydroxychloroquine-COVID-19 PEP43	March 22 2020 – May 20 2020	2	USA Canada	491			99 (20)			423 (100)
Hydroxychloroquine-AH COVID-1944	April 15 2020–May 22 2020	1	Canada	148
Hydroxychloroquine-BCN PEP-CoV-245	March 17 2020-May 26 2020	2	Spain	293						293 (100)
Hydroxychloroquine-BMG46	April 15 2020-July 27 2020	3	USA	231		23 (10)			143 (62)	85 (37)
Hydroxychloroquine-Utah47	Apr 2020-Apr 2021	12	USA	303
Hydroxychloroquine/Azithromycin-Brazil48	Apr 12 2020-May 13 2020	1	Brazil	83						84 (100)
Nitazoxanide-Romark49	Aug 2020–Jan 2021	5	USA Peurto rico	379							379 (100)
Colchicine-COLCORONA2	March 2020-Dec 2020	9	Brazil, Canada, Greece, South Africa, Spain, and the USA	4488		1122 (25)		3590 (80)
Losartan-MN50	Apr 2020-Nov 2020	8	USA	117	3				117 (100)		106
Niclosamide51	Oct 1 2020-April 20 2021	7	USA	73							67 (100)
Aspirin-ACTIV-4B52	Sept 1 2020 – June 17 2021	10	USA	328		~82 (25)				82 (25)
2.5-mg apixaban-ACTIV-4B52	Sept 1 2020 – June 17 2021	10	USA	329		~82 (25)				82 (25)
5-mg apixaban ACTIV-4B52	Sept 1 2020 – June 17 2021	10	USA	328		~82 (25)				82 (25)
Sulodexide53	June 5 2020 – August 5 2020	2	Mexico	243							243 (100)
Enoxaparin-ETHIC54	Oct 27 2020 – Nov 8 2021	12	Belgium, Brazil, India, South Africa, Spain, and the UK).	219			164 (75)			121 (50)
Enoxaparin-OVID55	Aug 5 2020-Jan 14 2022	17	Switzerland and Germany	572			572 (100)			429 (dx 75)
Inhaled Ciclesonide-COVIS56	jun 11 2020-nov 3 2020	5	USA	400
Inhaled ciclesonide-COVERAGE57	Dec 29 2020-July 22 2021	7	France	217		151 (70)	217 (100)		217 (100)
Zinc58	Apr 27 2020-Oct 14 2020	6	USA	108
Ascorbic acid58	Apr 27 2020-Oct 14 2020	6	USA	98
Zinc/Ascorbic acid58	Apr 27 2020-Oct 14 2020	6	USA	108
Homeopathy-COVID-Simile59	Jun 29 2020-Ap 6 2021	10	Brazil	86
Saliravira60	Dec 21 2020 – March 1 2021	3	Iran	143
Azithromycin-Atomic261	June 3, 2020–Jan 29, 2021,	8	UK	292
Azithromycin-ACTION62	May 22 2020 – March 16 2021	9	USA	197		18 (9)			197 (100)
Resveratrol63	September 13, 2020 – December 11, 2020,	3	USA	100	16 (16)					50 (50)

Appendix Table 3.

Summary of findings table GRADE evaluation by RCT.

Patient or population: COVID-19 outpatients

Settings: Ambulatory patients with COVID-19

Intervention: COVID-19 convalescent plasma, anti-Spike mAbs, small molecule antivirals and repurposed drugs Comparison: standard of care, placebo

Study	Assumed risk-controls Illustrative comparative risks* (95% CI)	Corresponding risk-Intervention Illustrative comparative risks* (95% CI)	Effect size: OR (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
CCP-mITT all cause hospitalization: cumulative results	120 per 1000	82 per 1000 (from 63 to 108)	0.69(0.53/0.90)	2634 participants (5 RCTs)	⊕⊕⊕⊕ high (there are no concerns in any of the GRADE factors)	CCP reduces significantly need of hospitalization compared to placebo. Most information is from results at low risk of bias or with some concerns, but unlikely to lower confidence in the estimate of effect.
Anti-spike mAbs: combined results	58.9 per 1000	18.8 per 1000 (from 14.7to 22.1)	0.32(0.25/0.41)	8736 (9 trials)	⊕⊕⊕⊝ moderate (downgraded for ROB)	Anti-Spike mAbs reduce hospitalization compared to placebo
Small molecule antivirals: combined results	18.3 per 1000	14.3 per 1000 (from 8.2 to 24.3)	0.78(0.45/1.33)	34104 (17)	⊕⊝⊝⊝ very-low (downgraded for imprecision, inconsistency (I2=69) and ROB)	-It is unclear if antivirals reduce rate of hospitalization compared to placebo
Repurposed drugs combined results	53.05 per 1000	41.9 per 1000 (from 37.1 to 47.7)	0.79(0.70/0.90)	22512 (39 arms, 21 comparisons)	⊕⊕⊕⊝ moderate (downgraded for ROB)	Repurposed treatments reduce rate of hospitalization compared to placebo
CCP
CCP-CONV-ert7	111 per 1000	116 per 1000 (from 61 to 219)	1.05 (0.55/1.98)	376 (1)	⊕⊕⊕⊝ moderate (downgraded for imprecision-95% CI includes line of no effect)	CCP does not reduce hospitalization compared to placebo
CCP-COV-Early13	93 per 1000	57.6 per 1000 (from 26.9 to 120.9)	0.62 (0.29/1.30)	406 (1)	⊕⊕⊕⊝ moderate (downgraded for imprecision-95% CI includes line of no effect)	It is unclear if CCP reduces hospitalization compared to placebo
CCP-C3PO4	220 per 1000	198 per 1000 (from 127 to 301)	0.9 (0.58/1.37)	511 (1)	⊕⊕⊕⊝ moderate (downgraded for imprecision-95% CI includes line of no effect)	It is unclear if CCP reduces hospitalization compared to placebo
CCP-Argentina5	312 per 1000	133 per 1000 (from 62 to 180)	0.43 (0.20/0.91)	160 (1)	⊕⊕⊕⊝ moderate (downgraded for imprecision due to low number of participants)	CCP reduces rate of hospitalization compared to placebo
CCP-CSSC-0043	62.8 per 1000	27.6 per 1000 (from 15.7 to 49.6)	0.44 (0.25/0.79)	1181 (1)	⊕⊕⊕⊕ high (there are no concerns in any of the GRADE factors)	CCP reduces rate of hospitalization compared to placebo
Anti-Spike mAbs
Bamlanivimab14	62.9 per 1000	15 per 1000 (from 5 to 46.5)	0.24 (0.08/0.74)	919 (1 RCT)	⊕⊕⊕⊝ moderate (downgraded for imprecision)	Bamlanivimab reduces need of hospitalization compared to placebo
Sotrovimab-COMET-ICE23	56.7 per 1000	10.7 per 1000 (from 4.5 to 26)	0.19 (0.08/0.46)	1061 (1 RCT)	⊕⊕⊕⊝ moderate (downgraded for ROB)	Sotrovimab reduces need of hospitalization compared to placebo
Bamlanivimab/etesevimab15	69.3 per 1000	20 per 1000 (from 10.3 to 40.1)	0.29 (0.15/0.58)	1035 (1 RCT)	⊕⊕⊝⊝ low(downgraded for imprecision and ROB)	Bamlanivimab/etesevimab in combination reduce need of hospitalization compared to placebo
Casirivimab/imdevimab16	41.6 per 1000	11.6 per 1000 (from 7.0 to 19.1)	0.28 (0.17/0.46)	3495 (2 RCT)	⊕⊕⊝⊝ low (downgraded for ROB and imprecision due to low number of events)	Casirivimab/imdevimab in combination reduce need of hospitalization compared to placebo
Bebtelovimab-BLAZE-41	15.6 per 1000	15.9 per 1000 (from 2.1 to 115)	1.02 (0.14/7.39)	253 (1 RCT)	⊕⊕⊝⊝ low (downgraded twice for serious imprecision)	Bebtelovimab does not reduce need of hospitalization compared to placebo
Regdanvimab18,19	79.9 per 1000	26.3 per 1000 (from 5.9 to 42.3)	0.33 (0.20/0.53)	1622 (2 RCTs)	⊕⊕⊕⊝ moderate (downgraded for ROB)	Regdanviman reduces hospitalization compared to placebo
Tixagevimab–cilgavimab-TACKLE20	89.1 per 1000	41.8 per 1000 (from 24 to 74.7)	0.47 (0.27/0.84)	822 (1)	⊕⊕⊕⊝ moderate (downgraded for imprecision)	Tixagevimab-cilgavimab reduces hospitalization compared to placebo in unvaccinated adults
Small molecule antivirals
Molnupiravir21–23	11.8 per 1000	10.8 per 1000 (from 8.6 to 13.4)	0.91 (0.73/1.14)	27628 (3 RCTs)	⊕⊕⊝⊝ low (downgraded for inconsistency and imprecision)	It is unclear if Molnupiravir reduces hospitalization compared to placebo
Nirmatrelvir/ritonavir9	63 per 1000	7.5 per 1000 (from 3.7 to 15.1)	0.12 (0.06/0.24)	2085 (1)	⊕⊕⊝⊝ low (downgraded for ROB and imprecision).	Nirmatrelvir/ritonavir reduces hospitalization compared to placebo in unvaccinated adults
Remdesivir12	53 per 1000	6.8 per 1000 (from 1.5 to 50.2)	0.13 (0.03/0.57)	562 (1)	⊕⊕⊝⊝ low (downgraded for ROB and imprecision)	Remdesivir reduces hospitalization compared to placebo
Favipiravir28–30	18.3 per 1000	51.2 per 1000 (from 16.8 to 155.9)	2.80 (0.92/18.52)	427 (3)	⊕⊕⊝⊝ low (downgraded for serious imprecision)	Favipiravir does not reduce need of hospitalization compared to placebo
Favipiravir-Lopinavir/r-FLARE30	Not calculable	-	3.05 (0.12/76.39)	120 (1)	⊕⊕⊝⊝ low (downgraded for serious imprecision)	Favipiravir+Lopinavir/r does not reduce need of hospitalization compared to placebo
Peginterferon lambda24–26	38.8 per 1000	23.2 per 1000 (from 13.9 to 38.4)	0.60 (0.36/0.99)	2129 (3 RCTs)	⊕⊕⊕⊝ moderate (downgraded for ROB)	-Peginterferon lambda reduces hospitalization compared to placebo.
Sofosbuvir and daclatasvir-SOVODAK27	142.8 per 1000	32.8 per 1000 (from 2.8 to 315)	0.23 (0.02/2.21)	55 (1)	⊕⊕⊝⊝ low (downgraded for serious imprecision)	It is unclear if sofosbuvir/daclatasvir reduces hospitalization compared to placebo
Lopinavir/ritonavir30–32	33.1 per 1000	41.4 per 1000 (from 21.8 to 78.4)	1.25 (0.66/2.37)	1037 (3)	⊕⊕⊝⊝ low (downgraded for serious imprecision)	Lopinavir/ritonavir does not reduce need of hospitalization compared to placebo
Tenofovir Disproxil Fumarate Plus Emtricitabine-AR0-CORONA	33.3 per 1000	68.9 per 1000 (from 5.9 to 804.1	2.07 (0.18/24.5)	60 (1 RCT)	⊕⊝⊝⊝ very-low (downgraded for serious imprecision and ROB)	TDF+Emtricitabine does not reduce need of hospitalization compared to standard of care
Repurposed
Metformin-COVID-OUT34,35	53.4 per 1000	37.4 per 1000 (from 22.9 to 60.3)	0.70 (0.43/1.13	1615 (2 RCTs)	⊕⊕⊝⊝ low (downgraded for imprecision and inconsistency (I2=58)	It is unclear if metformin reduces hospitalization compared to placebo.
Fluvoxamine11,34,36,37	63.6 per 1000	46.4 per 1000 (from 34.3 to 62.9)	0.73 (0.54/0.99)	3518 (4 RCTs)	⊕⊕⊕⊝ moderate (downgraded for ROB)	Fluvoxamine reduces hospitalization compared to placebo
Fluvoxamine/budesonide-TOGETHER38	10.8 per 1000	9.4 per 1000 (from 3.4 to 26.1)	0.87 (0.32/2.42)	1476 (1 RCT)	⊕⊕⊕⊝ moderate (downgraded for imprecision)	It is unclear if fluvoxamine/budenoside reduces hospitalization compared to placebo.
Ivermectin10,34,40–42	46.3 per 1000	43.1 per 1000 (from 32.8 to 56.0)	0.93 (0.71/1.221	5434 (5 RCTs)	⊕⊕⊕⊝ moderate (downgraded for imprecision)	-It is unclear if Ivermectin reduces rate of hospitalization compared to placebo
Hydroxychloroquine32,43,64–66	44.0per 1000	38.7 per 1000 (from 22.8 to 65.1)	0.74 (0.45/1.23)	1536 (6 RCTs)	⊕⊕⊕⊝ moderate (downgraded for imprecision-95% CI includes line of no effect)	It is unclear if hydroxychloroquine reduces hospitalization compared to placebo
Hydroxychloroquine/azithromycin48	23.8 per 1000	23.8 per 1000 (from 1.42 to 39.2)	1.00 (0.06/16.5)	84 (1 RCT)	⊕⊕⊝⊝ low (downgraded for imprecision and ROB)	It is unclear if hydroxychloroquine/azithromycin reduces hospitalization compared to placebo
Nitazoxanide-Romark49	25.6 per 1000	5.3 per 1000 (from 0.5 to 45.8)	0.21 (0.02/1.79)	379 (1)	⊕⊝⊝⊝ very-low (downgraded for serious imprecision and ROB)	It is unclear if nitazoxanide reduces hospitalization compared to placebo
Colchicine-COLCORONA2	58.1 per 1000	45.8 per 1000 (from 35.4 to 59.8)	0.79 (0.61/1.03)	379 (1)	⊕⊕⊕⊝ moderate (downgraded for imprecision-95% CI includes line of no effect)	It is unclear if colchicine reduces hospitalization compared to placebo
Losartan-MN50	16.9 per 1000	53.5 per 1000 (from 5.4 to 529.6)	3.16 (0.32/31.34)	117 (1 RCT)	⊕⊝⊝⊝ very-low (downgraded for serious imprecision and ROB)	It is unclear if losartan reduces rate of hospitalization compared to placebo
Niclosamide51	29.4 per 1000	9.5 per 1000 (from 0.29 to 249)	0.33 (0.01/8.48)	67 (1)	⊕⊕⊝⊝ low (downgraded for serious imprecision)	It is unclear if niclosamide reduces hospitalization compared to placebo
aspirin52	7.3 per 1000	6.8 per 1000 (from 0.4 to 11)	0.94 (0.06/15.2)	280 (1)	⊕⊝⊝⊝ very-low (downgraded for serious imprecision and indirectness)	Aspirin does not reduce need of hospitalization compared to placebo
apibaxan52	7.3 per 1000	7.3 per 1000 (from 1 to 52)	1.0 (0.14/7.18)	414 (2 arms)	⊕⊝⊝⊝ very-low (downgraded for serious imprecision and indirectness)	Apibaxan 2.5–5 mg does not reduce need of hospitalization compared to placebo
Sulodexide53	294 per 1000	223.4 per 1000 (from 82.3 to 279.3)	0.52 (0.28/0.95)	243 (1)	⊕⊕⊕⊝ moderate (downgraded for imprecision)	Sulodexide reduces hospitalization compared to placebo
Enoxaparin-LMW heparin54,55	56.8 per 1000	60.2 per 1000 (from 31.8 to 115.3)	1.06 (0.56/2.03)	691 (2)	⊕⊕⊝⊝ low (downgraded for serious imprecision)	LMW heparin does not reduce hospitalization compared to placebo
Inhaled ciclesonide56,57	61.2 per 1000	55.1 per 1000 (from 27.5 to 105.2)	0.90 (0.45/1.72)	599 (2)	⊕⊝⊝⊝ very-low (downgraded for serious imprecision and ROB)	Inhaled ciclesonide does not reduce need of hospitalization compared to placebo
Zinc58	60 per 1000	88.8 per 1000 (from 20.4 to 391.2)	1.48 (0.34/6.52)	108 (1)	⊕⊝⊝⊝ very-low (downgraded for serious imprecision and ROB)	Zinc, ascorbic acid anc combination of both did not reduce rate of hospitalization compared with usual care.
Ascorbic acid58	60 per 1000	40.8 per 1000 (from 6.6 to 256.2)	0.68 (0.11/4.27)	98 (1 RCT)	⊕⊝⊝⊝ very-low (downgraded for serious imprecision and ROB)
Zinc/Ascorbic acid58	60 per 1000	129 per 1000 (from 31.8 to 528)	2.15 (0.53/8.80)	108 (1 RCT)	⊕⊝⊝⊝ very-low (downgraded for serious imprecision and ROB)
Homeopathy-COVID-Simile59	68.1 per 1000	22.5 per 1000 (from 2.0 to 227.4)	0.33 (0.03/3.34)	86 (1 RCT)	⊕⊝⊝⊝ very-low (downgraded for imprecision and serious ROB)	It is unclear if homeopathy reduces hospitalization compared to placebo
Saliravira60	285 per 1000	133.9 per 1000 (from 82.6 to 220.2)	0.47 (0.29/0.77)	143 (1)	⊕⊝⊝⊝ very-low (downgraded for serious imprecision and serious ROB)	Saliravira reduces hospitalization compared to control
Azithromycin61,62	77.6 per 1000	85.3 per 1000 (from 43.4 to 169.1)	1.10 (0.56/2.18)	489 (2)	⊕⊕⊝⊝ low (downgraded for serious imprecision)	azithromycin does not reduce hospitalization compared to placebo
Resveratrol63	60 per 1000	19.2 per 1000 (from 1.8 to 190.8)	0.32 (0.03/3.18)	100 (1)	⊕⊕⊝⊝ low (downgraded for serious imprecision)	It is unclear if resveratrol reduces hospitalization compared to placebo

^*The basis for the assumed risk is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect (the Risk Difference, also called ARR, absolute risk reduction)of the intervention (and its 95% CI). GRADE Working Group grades of evidenceHigh quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

OR, Odds Ratio; CIs, confidence intervals; ROB, risk of bias. GRADE, Grading of Recommendations, Assessment, Development and Evaluations

Appendix Table 4:

Hospitalized Odds Ratio statistics

Study	Hospitalization Odds ratio	Hospitalization 95 CI low	Hospitalization 95 CI high	Hospitalization significance (p)	Hospitalization z statistic
Total CCP	0.69	0.53	0.90	0.0035	2.697265
Total mAb	0.31	0.24	0.4	P<0.001	9.29792
Total antivirals	0.78	0.45	1.33	P<0.001	3.9493
Total repurposed	0.82	0.72	0.93	P<0.001	3.74264
Total	0.67	0.57	0.80	P<0.001	9.01288
CCP-CONV-ert7	1.05	0.56	1.99	0.4356	0.162033
CCP-COV-Early13	0.61	0.29	1.30	0.1021	1.269694
CCP-C3PO4	0.90	0.59	1.37	0.3078	0.502004
CCP-Argentina5	0.43	0.20	0.91	0.0140	2.197789
CCP-CSSC-0043	0.44	0.25	0.79	0.0031	2.737543
CCP-Argentina (high titer)5	0.20	0.06	0.71	0.0132	2.478
CCP-CSSC-004 (<= 5 days) 3	0.18	0.07	0.49	0.0007	3.38
Bamlanivimab-BLAZE-114	0.24	0.08	0.74	0.0066	2.479993
Sotrovimab-COMET-ICE8	0.19	0.08	0.46	0.0001	3.663844
Bamlanivimab/etesevimab-BLAZE-115	0.29	0.15	0.58	0.0002	3.534471
Casirivimab/imdevimab-REGEN-COV Ph 316	0.28	0.16	0.47	0.0000	4.734662
Casirivimab/imdevimab-REGEN-COV Ph 1/217	0.30	0.07	1.25	0.0484	1.660556
Bebtelovimab-BLAZE-41	1.02	0.14	7.39	0.4905	0.023906
Regdanvimab-CT-P5918	0.49	0.19	1.27	0.0716	1.463817
Regdanvimab-CT-P59–219	0.29	0.16	0.52	0.00001	4.22581
Tixagevimab–cilgavimab-TACKLE20	0.47	0.26	0.84	0.0057	2.528551
Molnupiravir-MOVe-OUT21	0.67	0.46	0.99	0.0223	2.00829
Molnupiravir-PANORAMIC22	1.07	0.81	1.42	0.3156	0.479984
Molnupiravir-Aurobindo23	NA	NA	NA	NA	NA
Nirmatrelvir/ritonavir-EPIC-HR9	0.12	0.06	0.24	0.0000	5.731691
Remdesivir-PINETREE12	0.13	0.03	0.57	0.0034	2.703067
Interferon Lambda-TOGETHER24	0.47	0.29	0.77	0.0011	3.054966
Interferon Lambda-ILIAD25	1.00	0.06	16.76	0.5000	0
Interferon Lambda-COVID-Lambda26	1.00	0.14	7.34	0.5000	0
Sofosbuvir and daclatasvir-SOVODAK27	0.23	0.02	2.21	0.1018	1.271414
Favipavir-Avi-Mild-1928	3.31	0.65	16.76	0.0739	1.44706
Favipiravir-Iran29	2.18	0.37	12.65	0.19324	0.86602
Favipiravir-FLARE30	3.1	0.12	77.71	0.24541	0.68902
Favipiravir/Lopinavir/Ritonavir-FLARE30	3	0.12	75.11	0.25187	0.66863
Lopinavir/Ritonavir-FLARE30	3.05	0.12	76.39	0.24865	0.67874
Lopinavir/ritonavir-TREAT NOW31	1.21	0.4	3.64	0.37059	0.3303
Lopinavir/ritonavir-TOGETHER32	1.20	0.53	2.69	0.3333	0.430926
Tenofovir Disproxil Fumarate Plus Emtricitabine-AR0-CORONA33	2.07	0.18	24.15	0.28057	0.58116
Metformin-COVID-OUT34	0.42	0.18	0.96	0.0198	2.057
Metformin-TOGETHER35	0.94	0.51	1.71	0.41626	0.21147
Fluvoxamine-TOGETHER11	0.77	0.56	1.05	0.0505	1.640023
Fluvoxamine-STOP COVID36	0.06	0.00	1.15	0.0310	1.866043
Fluvoxamine-COVID-OUT34	1.18	0.36	3.91	0.3935	0.270145
Fluvoxamine ACTIV-637	0.45	0.04	5	0.25869	0.64738
Fluvoxamine/budesonide-TOGETHER38	0.87	0.32	2.42	0.39769	0.25933
Ivermectin-TOGETHER39	0.81	0.59	1.11	0.09724	1.29742
Ivermectin-COVID-OUT34	0.76	0.20	2.85	0.3414	0.408715
Ivermectin Iran40	1.46	0.71	2.96	0.1507	1.033341
Ivermectin-ACTIV-641	1.05	0.43	2.61	0.4553	0.112309
Ivermectin high dose-ACTIV-642	2.52	0.49	13.04	0.13512	1.10252
Hydroxychloroquine-TOGETHER32	0.76	0.30	1.93	0.2840	0.570928
Hydroxychloroquine-COVID-19 PEP43	0.49	0.16	1.45	0.0971	1.298164
Hydroxychloroquine-AH COVID-1944	3.14	0.17	59.70	0.2232	0.761332
Hydroxychloroquine-BCN PEP-CoV-245	0.83	0.32	2.13	0.3486	0.389184
Hydroxychloroquine-BMG46	0.69	0.18	2.65	0.2945	0.54027
Hydroxychloroquine-Utah47	1.77	0.51	6.19	0.18429	0.89915
Hydroxychloroquine/Azithromycin-Brazil48	1	0.06	16.5	0.5	0
Nitazoxanide-Romark49	0.21	0.02	1.79	0.0766	1.428571
Colchicine-COLCORONA2	0.79	0.61	1.03	0.0407	1.742726
Losartan-MN50	3.16	0.32	31.34	0.16245	0.98443
Niclosamide51	0.33	0.01	8.48	0.2529	0.665353
Aspirin-ACTIV-4B52	0.94	0.06	15.24	0.4838	0.040562
2.5-mg apixaban-ACTIV-4B52	1.01	0.06	16.27	0.4979	0.005238
5-mg apixaban ACTIV-4B52	1.91	0.17	21.36	0.2988	0.527902
Sulodexide53	0.52	0.28	0.95	0.0167	2.128119
Enoxaparin-ETHIC54	1.10	0.47	2.56	0.4155	0.213485
Enoxaparin-OVID55	1.02	0.38	2.76	0.4862	0.034489
Inhaled Ciclesonide-COVIS56	0.48	0.12	1.87	0.14459	1.05994
Inhaled ciclesonide-COVERAGE57	1.15	0.51	2.63	0.3659	0.34277
Zinc58	1.48	0.36	6.52	0.30296	0.5159
Ascorbic acid58	0.68	0.11	4.27	0.34085	0.41015
Zinc/Ascorbic acid58	2.15	0.53	8.8	0.1435	1.06472
Homeopathy-COVID-Simile59	0.33	0.03	3.34	0.17503	0.93449
Saliravira60	0.01	0.00	0.24	0.0016	2.9467
Azithromycin-Atomic261	0.88	0.42	1.84	0.3694	0.333472
Azithromycin-ACTION62	6.62	0.36	121.45	0.1015	1.272994
Resveratrol63	0.32	0.03	3.18	0.1654	0.972432

Appendix Table 5: Deaths during RCTs.

Cumulatively, the CCP RCTs noted 10 deaths in the control arm versus 8 in CCP arm. The anti-Spike mAbs RCTs had 21 total deaths among controls and 4 in the intervention arm. The total for all small molecule antiviral RCTs was 28 in the controls and 7 in the interventions. The repurposed drugs RCTs recorded 72 deaths in the control groups and 53 in the intervention groups.

Study	ARR%	RRR%	95% CI ARR	95% CI RRR	Odds ratio	95 CI low	95 CI high	z statistic	significance (p)
Total CCP	0.15	20.2	(−0.48, 0.78)	(−101.5, 68.4)	0.8	0.31	2.02	0.47848	0.31616
Total mAb	0.45	80.8	(0.21, 0.7)	(49.4, 92.7)	0.19	0.07	0.5	3.3459	0.00041
Total antivirals	0.16	87.1	(0.1, 0.23)	(63.4, 95.4)	0.13	0.05	0.37	3.85181	0.00006
Total repurposed	0.16	21.8	(−0.1, 0.4)	(−8.3, 43.5)	0.78	0.56	1.08	1.4795	0.0695
Total	0.19	44.7	(0.11, 0.28)	(27.6, 57.8)	0.55	0.42	0.72	4.29906	0.00001
Study	Deaths control	Total control	Deaths intervent.	Total intervent.	Total both arms	% death control	% death intervent.
Total CCP	10	1315	8	1319	2634	0.76	0.61
Total mAb	23	4102	5	4634	8736	0.56	0.11
Total antivirals	31	17073	4	17031	34104	0.18	0.02
Total repurposed	81	11109	65	11396	22505	0.73	0.57
Total	131	29680	72	30363	60043	0.44	0.24
CCP-CONV-ert7	2	188	0	188	376	1.06	0
CCP-COV-Early13	0	204	1	202	406	0	0.5
CCP-C3PO4	1	254	5	257	511	0.39	1.95
CCP-Argentina5	4	80	2	80	160	5	2.5
CCP-CSSC-0043	3	589	0	592	1181	0.51	0
Bamlanivimab-BLAZE-114	0	143	0	309	452	0	0
Sotrovimab-COMET-ICE8	2	529	0	528	1057	0.38	0
Bamlanivimab/etesevimab-BLAZE-115	10	517	0	518	1035	1.93	0
Casirivimab/imdevimab-REGEN-COV Ph 316	3	1341	1	1355	2696	0.22	0.07
Casirivimab/imdevimab-REGEN-COV Ph 1/217	0	266	0	533	799	0	0
Bebtelovimab-BLAZE-41	0	128	0	125	253	0	0
Regdanvimab-CT-P5918	0	104	0	203	307	0	0
Regdanvimab-CT-P59–219	2	659	1	656	1315	0.3	0.15
Tixagevimab–cilgavimab-TACKLE20	6	415	3	407	822	1.45	0.74
Molnupiravir-MOVe-OUT21	9	699	1	709	1408	1.29	0.14
Molnupiravir-PANORAMIC22	5	12484	2	12516	25000	0.04	0.02
Molnupiravir-Aurobindo23	0	610	0	610	1220	0	0
Nirmatrelvir/ritonavir-EPIC-HR9	12	1046	0	1039	2085	1.15	0
Remdesivir-PINETREE12	1	283	0	279	562	0.35	0
Interferon Lambda-TOGETHER24	4	1018	1	931	1949	0.4	0.11
Interferon Lambda-ILIAD25	0	30	0	30	60	0	0
Interferon Lambda-COVID-Lambda26	0	60	0	60	120	0	0
Sofosbuvir and daclatasvir-SOVODAK27	0	28	0	27	55	0	0
Favipavir-Avi-Mild-1928	0	119	0	112	231	0	0
Favipiravir-Iran29	0	39	0	38	77	0	0
Favipiravir-FLARE30	0	60	0	59	119	0	0
Favipiravir/Lopinavir/Ritonavir-FLARE30	0	60	0	61	121	0	0
Lopinavir/Ritonavir-FLARE30	0	60	0	60	120	0	0
Lopinavir/ritonavir-TREAT NOW31	0	220	0	226	446	0	0
Lopinavir/ritonavir-TOGETHER32	0	227	0	244	471	0	0
Tenofovir Disproxil Fumarate Plus Emtricitabine-AR0-CORONA33	0	30	0	30	60	0	0
Metformin-COVID-OUT34	1	601	1	596	1197	0.17	0.17
Metformin-TOGETHER35	9	203	7	215	418	4.4	3.2
Fluvoxamine-TOGETHER11	25	756	17	741	1497	3.31	2.29
Fluvoxamine-STOP COVID36	0	72	0	80	152	0	0
Fluvoxamine-COVID-OUT34	0	293	0	299	592	0	0
Fluvoxamine ACTIV-637	0	599	0	662	1261	0	0
Fluvoxamine/budesonide-TOGETHER38	0	738	1	738	1476	0	0.14
Ivermectin-TOGETHER39	24	675	21	674	1349	3.56	3.12
Ivermectin-COVID-OUT34	0	356	1	374	730	0	0.27
Ivermectin Iran40	1	281	1	268	549	0.36	0.37
Ivermectin-ACTIV-641	0	774	1	817	1591	0	0.12
Ivermectin high dose-ACTIV-642	0	604	1	602	1206	0	0.17
Hydroxychloroquine-TOGETHER32	1	227	0	214	441	0.44	0
Hydroxychloroquine-COVID-19 PEP43	1	211	1	212	423	0.47	0.47
Hydroxychloroquine-AH COVID-1944	0	37	0	111	148	0	0
Hydroxychloroquine-BCN PEP-CoV-245	0	157	0	136	293	0	0
Hydroxychloroquine-BMG46	0	83	0	148	231	0	0
Hydroxychloroquine-Utah47	0	151	0	152	303	0	0
Hydroxychloroquine/Azithromycin-Brazil48	0	42	0	42	84	0	0
Nitazoxanide-Romark49	0	195	0	184	379	0	0
Colchicine-COLCORONA2	9	2253	5	2235	4488	0.4	0.22
Losartan-MN50	0	59	0	58	117	0	0
Niclosamide51	0	34	0	33	67	0	0
Aspirin-ACTIV-4B52	0	136	0	144	280	0	0
2.5-mg apixaban-ACTIV-4B52	0	136	0	135	271	0	0
5-mg apixaban ACTIV-4B52	0	136	0	143	279	0	0
Sulodexide53	7	119	3	124	243	5.88	2.42
Enoxaparin-ETHIC54	0	114	1	105	219	0	0.95
Enoxaparin-OVID55	0	238	0	234	472	0	0
Inhaled Ciclesonide-COVIS56	0	203	0	197	400	0	0
Inhaled ciclesonide-COVERAGE57	2	107	0	110	217	1.87	0
Zinc58	0	50	0	58	108	0	0
Ascorbic acid58	0	50	1	48	98	0	2.08
Zinc/Ascorbic acid58	0	50	2	58	108	0	3.45
Homeopathy-COVID-Simile59	0	44	0	42	86	0	0
Saliravira60	0	56	0	87	143	0	0
Azithromycin-Atomic261	1	147	1	145	292	0.68	0.69
Azithromycin-ACTION62	0	72	0	125	197	0	0
Resveratrol63	0	50	0	50	100	0	0

Data availability/sharing

Datasets used for this systematic review are publicly available in PubMed, medRxiv and bioRxiv. Data files used to generate figures are available upon request.