Table 2.

Summary of findings to date on clinical trials investigating interferon therapies for the treatment of SARS-CoV-2

	PMID	Title	Total study sample	Treatment arms	Stage of treatment administration	Primary outcomes	Location
1	32,758,689	SARS-CoV-2 clearance in SARS-CoV-2 patients with novaferon treatment: A randomized, open-label, parallel-group trial [8]	89	(a) Novaferon (b) Lopinavir/ritonavir (c) Novaferon + lopinavir/ritonavir	Hospitalized SARS-CoV-2 patients clinically classified as moderate or severe	Viral clearance rate using RT-PCR at day 9: Arm C (lopinavir/ritonavir + novaferon) had the largest viral clearance rate at day 9 (13–18% more). P-value of lopinavir/ritonavir + novaferon vs. novaferon was 0.2839	1 center, Changsha City, Hunan Province, China
2	32,862,111	Interferon β-1b in treatment of severe SARS-CoV-2: A randomized clinical trial [9]	99	(a) Interferon-β 1b + hydroxychloroquine + lopinavir/ritonavir OR atazanavir/ritonavir (b) Treatment a except interferon-β-1b	Hospitalized patients with severe SARS-CoV-2	Time to clinical improvement was measured. This was significantly shorter in the IFN group (treatment a) compared to the control group (treatment b) [9(6–10) vs. 11(9–15) days respectively, p = 0.002]	1 center, Tehran, Tehran Province, Iran
3	33,264,556	Repurposed antiviral drugs for SARS-CoV-2—Interim WHO Solidarity Trial Results [1]	2050	(a) Remdesivir (b) Hydroxychloroquine (c) Lopinavir (d) Interferon-β-1a	Hospitalized patients	In-hospital mortality before or after day 28 Interferon: 243/2050 (12.9%) Control: 216/2050 (11.0%) Odds ratio of 16.8 and variance of 113.3 Rate ratio for death: 1.16 (0.96–1.39)	405 hospitals in 30 countries (Albania, Argentina, Austria, Belgium, Brazil, Colombia, Egypt, Finland, France, Honduras, India, Indonesia, Iran, Ireland, Italy, Kuwait, Lebanon, Lithuania, Luxembourg, Malaysia, North Macedonia, Norway, Pakistan, Peru, Philippines, Saudi Arabia, South Africa, Spain, Switzerland)
4	33,620,016	Effect of a genetically engineered interferon-alpha versus traditional interferon-alpha in the treatment of moderate-to-severe SARS-CoV-2: a randomised clinical trial [10]	96	(a) Recombinant super compound interferon a (b) Interferon-alpha-2a or interferon-alpha-2b	Hospitalized patients diagnosed with moderate-to-severe SARS-CoV-2 pneumonia	Time to clinical improvement defined as the time from enrollment to an improvement of two points on a seven-category ordinal scale The primary outcome of the rSIFN-co group was statistically shorter than that of the interferon-alpha group (median, 11.5 days vs. 14.0 days; HR, 1.76; 95% CI, 1.10 to 2.81; p = 0.019)	5 centers, Wuhan City, Hubei Province, and Chengdu City, Sichuan Province, China
5	33,181,328	Randomized controlled open-label trial on the use of favipiravir combined with inhaled interferon beta-1b in hospitalized patients with moderate to severe SARS-CoV-2 pneumonia [11]	89	(a) Favipiravir + interferon beta-1b (b) Hydroxychloroquine	Hospitalized patients with moderate-to-severe SARS-CoV-2 pneumonia	Time from assignment to clinical recovery Arm (a) 7 days Arm (b) 7 days No significant difference	1 center, Muscat, Muscat Province, Oman
6	33,785,743	Peginterferon lambda-1a for treatment of outpatients with uncomplicated SARS-CoV-2: a randomized placebo-controlled trial [12]	120	(a) Peginterferon lambda-1a (b) Placebo	Asymptomatic and symptomatic patients, mild-to-severe progression	Duration until viral shedding cessation in days Arm a: 7 days (5–13) Arm b: 7 days (5–10) HR: 0.81 (0.56, 1.19) P-value = 0.29	1 center, California, USA
7	32,401,715	Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with SARS-CoV-2: an open-label, randomised, phase 2 trial [13]	127	(a) Lopinavir/ritonavir + ribavirin + interferon beta-1b (b) Lopinavir/ritonavir	Early onset of SARS-CoV-2; most patients admitted to hospital within 7 days of symptom onset	Time from start of study treatment to negative nasopharyngeal swab Combination: 7 days [IQR 5–11] Control: 12 days [8–15] Combination group had a significantly shorter median time HR 4·37 [95% CI 1·86–10·24], p = 0.0010	6 centers, Hong Kong, China
8	33,556,319	Peginterferon lambda for the treatment of outpatients with SARS-CoV-2: a phase 2, placebo-controlled randomised trial [14]	60	(a) Peginterferon lambda-1a (b) Placebo	Early-onset SARS-CoV-2 (diagnosed within 7 days of symptom onset or first positive test if asymptomatic)	Proportion of individuals with a negative mid-turbinate swab for SARS-CoV-2 at day 7 Treatment: 24 (80%) negative 19 (63%) negative p = 0.15 Unadjusted odds ratio for peginterferon lambda vs. placebo 2.32 (0.74–7.81) p = 0.15	6 centers, Toronto, Ontario, Canada
9	32,661,006	A randomized clinical trial of the efficacy and safety of interferon β-1a in treatment of severe SARS-CoV-2 [15]	81	(a) Interferon β-1a + hydroxychloroquine + lopinavir-ritonavir OR atazanavir-ritonavir (b) Treatment a except interferon-β-1b	Severe SARS-CoV-2	Time from starting the interventions to the clinical response No significant difference IFN group: 9.74 ± 5.8 Control group: 8.39 ± 4.9 Hazard ratio [HR], 1.10; 95% CI, 0.64 to 1.87 p = 0.72	1 center, Tehran, Tehran Province, Iran
10	33,189,161	Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: a randomised, double-blind, placebo-controlled, phase 2 trial [16]	101	(a) Interferon beta-1a (b) Placebo	Mild-severe SARS-CoV-2	Change in clinical condition on the WHO Ordinal Scale for Clinical Improvement Day 15/16 odds ratio 2.32 [95% CI 1.07–5.04] p = 0.033 Day 28 odds ratio: 3.15 [1.39–7.14] p = 0.006 Odds of improvement were greater in the IFN group than in the placebo group	20 centers; Hull, England; Cottingham, England; Birmingham, England; Leicester, England; Oxford, England; Manchester, England; Nottingham, England; Bradford, England; Belfast, Northern Ireland, Southampton, England; Salisbury, England; Maidenhead, England
11	33,275,267	The dual role of anti-viral therapy in the treatment of Coronavirus disease 2019	148	(a) Standard care (supplemental oxygen, ventilation, antibiotics) (b) Interferon-alpha-2b (c) Interferon-alpha-2b + lopinavir/ritonavir	Mild-severe SARS-CoV-2	Average time to two consecutive negative RT-PCR tests (viral clearance rate) Standard care, 14 days; IFN alfa-2b, 15.5 days; and IFN alfa-2b combined with lopinavir plus ritonavir 17.5 days Results suggest that early treatment with IFN alfa-2b/ later treatment with IFN alfa- 2b combined with lopinavir plus ritonavir may help fight SARS-CoV-2, but overall minimal effect of IFN administration	1 center, Beijing, China