Hydroxychloroquine Alone or in Combination with Cobicistat-Boosted Darunavir for Treatment of Mild COVID-19: A Cluster-Randomized Clinical Trial

Background: No therapeutics have yet been proven effective for the treatment of mild-illness caused by SARS-CoV-2. We assessed the efficacy and safety of hydroxychloroquine (HCQ) alone or in combination with cobicistat-boosted darunavir (DRVc) for treating patients with mild Covid-19. Methods: We conducted a randomized, prospective, controlled, open-label trial in three health regions of Catalonia. After confirmation of a case of Covid-19 disease, we enumerated on a list a ring of the case and all their contacts and randomly assigned the ring to either control or intervention arm on a 1:1 ratio. Here we present the methods concerning eligible index cases, which involved non-hospitalized adult patients with recently confirmed SARS-CoV-2 infection and less than seven days of symptoms. Patients were assigned to receive HCQ (800 mg on day 1, followed by 400 mg once daily for six days) in combination with DRVc (800 mg/150 mg tablets, once daily for seven days) or no antiviral treatment. The protocol was adapted during the course of the trial to use HCQ alone after findings of no benefit of the protease inhibitor lopinavir-ritonavir. Study outcomes were the reduction of viral RNA load in nasopharyngeal swabs and time to clinical improvement within 28 days of follow-up in the per-protocol population. Adverse events were assessed up to 28 days. Findings: Between Mar 17 and Apr 28, 2020, 353 Covid-19 patients met the criteria for the per-protocol analysis: 165 in the control arm and 142 in the intervention arm. The median time from symptom onset to treatment start was 3 days (IQR 2–4). The per-protocol analysis revealed no significant differences in the mean reduction of viral load in nasopharyngeal swabs at day-3 compared to baseline between the control group (-1·28 Log 10 copies/mL, SD 1·68) and the intervention group (-1·47, SD 1·50); difference -0·18 [95% CI -0.59 to 0·22]. The same pattern was observed at day-7 and -14 after treatment. Time to complete alleviation of symptoms was similar in both groups (22 vs. 20·5 days, p = 0·37). Adverse events included self-limited nausea and diarrhea. Twenty patients required hospitalization, all due to Covid-19 progression. No patients died during the study. Interpretation: In patients with mild Covid-19, no benefit was observed with HCQ alone or in combination with DRVc beyond the usual care. Future testing of other agents in randomized trials may help to identify other drugs that provide a treatment benefit. Trial Registration: This trial was part of the Barcelona Postexposupre Prophylaxis Study against SARS-CoV-2 (BCN PEP CoV-2 Study) registered with ClinicalTrials.gov, NCT04304053 and EudraCT, 2020-001031-27. Funding Statement: Crowdfunding campaign YoMeCorono (https://www.yomecorono.com/), Laboratorios Rubio, Laboratorios Gebro Pharma, Zurich Seguros, SYNLAB Barcelona, and Generalitat de Catalunya. Laboratorios Rubio also contributed to the study with the required doses of hydroxychloroquine (Dolquine®). Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: The study protocol and subsequent amendments were approved by the institutional review board of Hospital Germans Trias Pujol, (Badalona, Spain - Approval AC-20-029-HGT-CEIM) and the Spanish Agency of Medicines and Medical Devices (Madrid, Spain - Approval 66ZNRDJA98). Written informed consent was obtained from all patients.