Table 3.
Description of the phase III randomized clinical trials that assessed Chloroquine/Hydroxychloroquine (CQ/HCQ) as a treatment against coronavirus disease (COVID-19).
| Author | Sample | Randomized Participants | Center | Groups | Blindness | Dosage/Duration | Primary Outcome | Results | Conclusions |
|---|---|---|---|---|---|---|---|---|---|
| Beltran Gonzalez et al. (2022) [19] | Hospitalized COVID-19 individuals. | A total of 106 participants were recruited. | Single Center (Mexico). | Three arms: (i) HCQ; (ii) Ivermectin; (iii) Placebo. |
Double-blind. | (i) HCQ, 400-mg every 12-h on the first day and, subsequently, 200-mg every 12-h for four days. (ii) Ivermectin, 12-mg or 18-mg, according to patient weight. (iii) Placebo. |
The study evaluated the length of hospital stay, the number of deaths, and the presence of respiratory deterioration. Safety outcomes: Tolerance and adverse effects. |
No significant difference in hospital stay was observed between the treatment group (group i: seven versus group iii: five days); nor in respiratory deterioration (group i: 6 (18;1%) versus group iii: 9 (24.3%)) nor death [group i: 2 (6%) versus group iii: 6 (16.2%)]. | In hospitalized individuals with COVID-19 HCQ did not have an effect on hospital length of stay, death, or respiratory deterioration. |
| RECOVERY Collaborative Group et al. (2020) [25] | Hospitalized participants with clinically suspected or laboratory-confirmed COVID-19. | A total of 4716 participants were recruited. | Platform trial (176 hospitals in the United Kingdom). | (i) 1561 participants received HCQ; (ii) 3155 participants received usual care. The remainder of the participants were randomly assigned to one of the other treatment groups. |
Not blind. | - HCQ sulfate (200-mg tablet) four tablets (800-mg) at baseline and 6-h, followed by two tablets (400-mg) starting at 12-h after the initial dose and then every 12-h for the next nine days or until discharge, whichever occurred earlier. - Usual care. |
All-cause mortality on 28 days after randomization. | Death on 28 days occurred in 421 of 1561 (27.0%) participants in the HCQ group and 790 of 3155 (25.0%) participants in the usual-care group. The difference in the death rates was not statistically significant. | The HCQ group did not have a lower incidence of death 28 days post-randomization compared to those who received usual care. |
| Self et al. (2020) [26] | Hospitalized participants with positive SARS-CoV-2 RT-PCR. | A total of 479 participants were recruited. | Multicenter (34 hospitals in the USA). |
(i) 242 participants received HCQ; (ii) 237 participants received a placebo. |
Not informed. | - 400-mg HCQ twice a day for the first two doses, then 200-mg of HCQ twice a day for eight doses. - Placebo. |
Clinical status at day 14 (the scale of the COVID-19 outcome was used). | The median interquartile score of clinical status at day 14: six (HCQ) versus six (placebo) [OR (95%CI) = 1.02 (0.73 to 1.42)]. | HCQ did not improve clinical status on day 14. |
| Ader et al. (2021) [27] | Hospitalized participants with positive SARS-CoV-2 RT-PCR and pulmonary crackles or SpO2 ≤ 94% or who required supplemental oxygen. | A total of 603 participants were recruited. | Multicenter (Academic or non-academic hospitals throughout Europe). |
(i) 152 received standard of care; (ii) 150 received standard of care plus Lopinavir/Ritonavir; (iii) 150 received standard of care plus Lopinavir/Ritonavir plus Interferon-β-1a; (iv) 151 received standard of care plus HCQ. |
Open-label. | - 400-mg Lopinavir and 100-mg Ritonavir twice a day for 14 days. - 44-mcg Interferon-β-1a on days one, three, and six. - 400-mg HCQ twice on day one and 400-mg daily for nine days. |
Clinical status on day 15 was measured on the seven-point ordinal scale of the WHO. | Death at the 15-day: 7 (7%) versus 5 (5%), for control and HCQ, respectively [OR (95%CI) = 0.93 (0.62–1.41)]. | HCQ did not improve clinical status on day 15 compared to the control. |
| Arabi et al. (2021) [28] | Individuals with confirmed or suspected COVID-19 and who were also receiving respiratory or cardiovascular organ failure support in the intensive care unit. | A total of 726 participants were recruited. | Multicenter (Canada, USA, France, Germany, Ireland, Netherlands, Portugal, United Kingdom, Saudi Arabi, Australia, and New Zealand). | (i) 268 participants were assigned to Lopinavir/Ritonavir (249 included in the final analysis); (ii) 52 participants were assigned to HCQ (49 included in the final analysis); (iii) 29 participants were assigned to Lopinavir/Ritonavir plus HCQ (26 included in the final analysis); (iv) 377 participants were assigned to receive no antiviral drug (353 included in the final analysis). |
Blind. | - 400-mg Lopinavir and 100-mg Ritonavir every 12-h for five to 14 days. - Two doses of 800-mg of HCQ 6-h apart, followed 6-h later by 400-mg 12 hourly for 12 doses. |
The ordinal scale of the number of respiratory and cardiovascular organ support-free days and hospital mortality. | The median organ support-free days among participants in Lopinavir-Ritonavir, HCQ, and combination therapy groups were 4 (−1 to 15) [OR (95%CI) = 0.73 (0.55 to 0.99)], 0 (−1 to 9) [OR (95%CI) = 0.57 (0.35 to 0.83)], and −1 (−1 to 7) [OR (95%CI) = 0.41 (0.24 to 0.72)], respectively, compared to 6 (−1 to 16) days in the control group. In-hospital mortality among participants in Lopinavir-Ritonavir, HCQ, and combination therapy was 88/249 (35.3%) [OR (95%CI) = 0.65 (0.45 to 0.95)], 17/49 (34.7%) [OR (95%CI) = 0.56 (0.36 to 0.89)], and 13/26 (50%) [OR (95%CI) = 0.36 (0.17 to 0.73)], respectively, compared to 106/353 (30%) in the control group. | In critically ill individuals infected with SARS-CoV-2, treatment with Lopinavir-Ritonavir, HCQ, or combination therapy resulted in worse outcomes compared to no COVID-19 antiviral therapy. |
| Dubée et al. (2021) [29] | Men and non-pregnant women aged +18 years with COVID-19 were confirmed by positive SARS-CoV-2 RT-PCR or chest computed tomography scan with typical features of COVID-19. Participants: (a) need for supplemental oxygen; (ii) age ≥75 years; and (iii) age between 60 and 74 years and presence of at least one co-morbidity. | A total of 250 participants were recruited. | Multicenter (France and Monaco). |
(i) 110 participants received HCQ; (ii) 116 participants received a placebo. |
Double-blind. | - 800-mg (two tablets, twice daily) on the first day and one 200-mg tablet twice daily for the following eight days (four grams total). - Placebo. |
Composite endpoint: Death and the need for invasive mechanical ventilation within 14 days following randomization. | The primary endpoint occurred in 9 (7.3%) versus 8 (6.5%) in HCQ and control groups, respectively [RR (95%CI) = 1.23 (0.43 to 3.55)]. | In order of the study’s premature discontinuation and lower-than-expected primary outcomes, no significant conclusion can be drawn on the efficacy of HCQ. |
| Hernandez-Cardenas et al. (2021) [30] | Age +18 years with COVID-19 confirmed by SARS-CoV-2 RT-PCR, symptoms onset <14 days, with lung injury requiring hospitalization with or without mechanical ventilation. | A total of 214 participants were recruited. | Multicenter (Mexico). | (i) 106 participants received HCQ; (ii) 108 participants received placebo. |
Double-blind. | - HCQ orally or by nasogastric tube—200-mg 12/12-h for 10 days. - Placebo. |
The 30-day mortality rate after randomization. | The 30-day mortality rate was 38% and 41% in the HCQ and placebo groups, respectively with a Hazard ratio of 0.89 (95%CI = 0.58 to 1.38). | No benefit or significant harm using HCQ can be demonstrated in this placebo-controlled randomized trial. |
| Pan et al. (2021) [31] | It was included participants ≥18 years, hospitalized with COVID-19, not known to have received any trial drug, not expected to be transferred elsewhere within 72-h, and no contraindication to any trial drug. | A total of 1863 participants were recruited. | Multicenter (405 hospitals in 30 countries). | (i) 954 participants received HCQ; (ii) 909 participants did not receive HCQ. |
Not blind. | - HCQ Sulfate: four tablets (800-mg) at hour zero, four tablets at hour six and starting at hour 12, two tablets (400-mg) twice daily for 10 days. - Placebo. |
In-hospital mortality in the four pairwise comparisons of each trial drug and its control. Regardless of whether it occurred before or after day 28. | No trial drug had a significant definite effect on mortality. The death occurred in 104 of 947 participants receiving HCQ and in 84 of 906 participants receiving its control. | HCQ regimen had little or no effect on hospitalized participants with COVID-19. |
| Réa-Neto et al. (2021) [32] | Individuals who were admitted to the intensive care unit or acute care room with flu symptoms and dyspnea or need for supplemental oxygen or SpO2 ≤94 on room air or computerized tomography scan compatible with COVID-19 or need for mechanical ventilation and a confirmed diagnosis of COVID-19. | A total of 142 individuals were randomized but only 105 subjects were evaluated in the modified intention to treat. | Multicenter (Brazil). |
Two groups: (i) CQ/HCQ plus standard of care; (ii) Placebo plus standard of care. |
Open Label. | (i) CQ 450-mg twice a day on day one followed by 450-mg once a day from day 2–5 OR HCQ 400-mg twice a day followed by 400-mg once daily from day 2–5 plus standard of care. (ii) Placebo plus standard of care. |
Clinical status on day 14 with a 9-point ordinal scale. | On the 14th day, the odds of having an unfavorable clinical outcome were higher in the CQ/HCQ group, even after controlling for confounding factors [OR (95%CI) = 2.45 (1.17 to 4.93)]. On the 28th day, individuals in the CQ/HCQ also presented worse clinical outcomes [OR (95%CI) = 2.47 (1.15 to 5.30)]. The mortality rate on the 28th day was not different between groups [(RR (95%CI) = 1.57 (0.79 to 3.13)]. | CQ/HCQ appears to be associated with worse clinical outcomes in severe COVID-19 individuals. |
| Ader and DisCoVeRy Study Group (2022) [33] | COVID-19 inpatients requiring oxygen and/or ventilatory support. | A total of 603 participants were recruited. | Multicenter (30 sites in France and two in Luxembourg). | (i) standard of care; (ii) standard of care plus Lopinavir/Ritonavir; (iii) standard of care plus Lopinavir/Ritonavir plus IFN-β-1a; (iv) standard of care plus HCQ. |
Not blind. | - Standard of care plus Lopinavir/Ritonavir (400-mg Lopinavir and 100-mg Ritonavir orally twice a day for 14 days). - Standard of care plus Lopinavir/Ritonavir plus Interferon-β-1a (44-mg subcutaneous Interferon -β-1a on days one, three, and six). - Standard of care plus HCQ (400-mg orally, twice on day one as a loading dose followed by 400-mg once daily for nine days). |
Clinical status at day 15 as measured on the seven-point ordinal scale of the WHO Master Protocol (v3.0, 3rd March 2020). | Adjusted OR (aOR) (95%CI) for clinical improvement were not in favor of investigational treatments: Lopinavir/Ritonavir versus control [aOR (95%CI) = 0.83 (0.55 to 1.26)]; Lopinavir/Ritonavir plus Interferon-β-1a versus control [aOR (95%CI) = 0.69 (0.45 to 1.04)]; HCQ versus control [aOR (95%CI) = 0.93 (0.62 to 1.41)]. The occurrence of serious adverse events was higher in participants allocated to the Lopinavir/Ritonavir-containing arms. |
In individuals admitted to hospital with COVID-19, Lopinavir/Ritonavir, Lopinavir/Ritonavir plus Interferon-β-1a and HCQ were not associated with clinical improvement at days 15 and 29, nor in a reduction in viral shedding, and generated more severe adverse side-effects in Lopinavir/Ritonavir-containing arms. |
| NCT04358081 (2020) [34] * | Hospitalized confirmed COVID-19 individuals. | A total of 20 § individuals were recruited. | Multicenter (USA). |
Three groups: (i) HCQ plus placebo; (ii) HCQ plus azithromycin; (iii) Placebo. |
Double-Blind. | (i) HCQ 600-mg once a day followed by 200-mg three times a day plus Azithromycin placebo. (ii) HCQ 600-mg once a day followed by 200-mg three times a day plus Azithromycin 500-mg followed by 250-mg once a day from days 2–5. (iii) HCQ and Azithromycin placebo. |
Clinical response by day 15 was defined as discharged alive or no need for mechanical ventilation or no need for supplementary oxygen therapy. | On the 15th day, 7/7 (100%) individuals achieved clinical improvement in both groups i and ii, whereas in the group iii, 4/5 (80%) achieved clinical improvement. | All the individuals treated with HCQ with or without Azithromycin presented clinical improvement on the 15th day, compared to placebo. |
95%CI, 95% confidence interval; %, percentage; aOR, adjusted odds ratio; h, hour; mcg, microgram; mg, milligram; ORs, odds ratio; RT-PCR, real-time polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SpO2, peripheral arterial oxygen saturation; USA, United States of America. § One of the patients was mis-randomized, so only 19 participants were evaluated. *, The study was obtained from the following website: https://clinicaltrials.gov/show/NCT04358081 (accessed on 22 August 2024).