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 sy