We included asymptomatic adults (≥18 years of age) who had a latest historical past of close-contact publicity to a PCR-confirmed case affected person with Covid-19 (i.e., >15 minutes inside 2 m, as much as 7 days earlier than enrollment), who had no Covid-19–like signs in the course of the 2 weeks earlier than enrollment, and who had an elevated danger of an infection (e.g., a well being care employee, a family contact, a nursing-home employee, or a nursing-home resident). Trial candidates had been examined by PCR assay for SARS-CoV-2 an infection at baseline. We included candidates with both a detrimental or constructive PCR take a look at at baseline to evaluate the prophylactic and preemptive impact of hydroxychloroquine remedy, respectively. All eligibility standards are listed within the Supplementary Appendix and the trial protocol, each accessible with the total textual content of this text at NEJM.org.
Trial Design and Oversight
This was an open-label, part 3, cluster-randomized trial performed from March 17 to April 28, 2020, in the course of the early levels of the Covid-19 outbreak, in three of 9 well being administrative areas in Catalonia, Spain (whole goal inhabitants, 4,206,440) (Fig. S1 within the Supplementary Appendix). Trial candidates had been screened with the usage of the digital registry of the nationwide well being data system.13
The trial was supported by the crowdfunding marketing campaign YoMeCorono (https://www.yomecorono.com/), Generalitat de Catalunya, Zurich Seguros, Synlab Diagnósticos, Laboratorios Rubió, and Laboratorios Gebro Pharma. Laboratorios Rubió donated and equipped the hydroxychloroquine (Dolquine). The sponsors had no function within the conduct of the trial, the evaluation, or the choice to submit the manuscript for publication. The trial protocol and subsequent amendments had been permitted by the institutional evaluation board at Hospital Germans Trias i Pujol and the Spanish Company of Medicines and Medical Gadgets. All of the contributors supplied written knowledgeable consent.
We outlined trial clusters (referred to as rings) of wholesome individuals (contacts) who had been epidemiologically linked to a PCR-positive case affected person with Covid-19 (index case affected person). All of the contacts in a hoop concurrently underwent cluster randomization (in a 1:1 ratio) to both the hydroxychloroquine group or the usual-care group. Contacts within the former group acquired hydroxychloroquine (Dolquine) at a dose of 800 mg on day 1, adopted by 400 mg as soon as day by day for six days; the dosing routine was based mostly on pharmacokinetic simulations. Contacts within the usual-care group acquired no particular remedy. After cluster randomization, we verified the choice standards of particular person candidates, obtained knowledgeable consent, and revealed the trial-group assignments. In accordance with nationwide tips, all of the contacts had been quarantined.
All of the contacts had been visited at residence or within the office on day 1 (enrollment) and day 14 (ultimate consequence measurement) for evaluation of well being standing and assortment of nasopharyngeal swabs. Signs had been monitored by phone on days Three and seven. Contacts in whom signs developed at any time level had been visited at residence inside 24 hours for evaluation of well being standing and assortment of nasopharyngeal swabs. Security (i.e., frequency and severity of antagonistic occasions), treatment adherence (i.e., remedy and variety of doses taken), and crossover (i.e., unplanned conversion from common care to hydroxychloroquine) had been assessed with the usage of contact reviews collected in phone interviews on days 3, 7, and 28.
All testing of nasopharyngeal swabs for SARS-CoV-2 and analyses to find out viral load had been carried out by technicians who had been unaware of earlier PCR outcomes, trial-group assignments, and response. PCR amplification was based mostly on the 2019 Novel Coronavirus Actual-Time RT [reverse transcriptase]–PCR Diagnostic Panel tips of the Facilities for Illness Management and Prevention.14 For quantification, an ordinary curve was constructed with the usage of 1:5 serial dilutions of a SARS-CoV-2 plasmid (with recognized focus) and run in parallel with 300 examine samples. The accuracy of the qualitative estimate (i.e., cycle threshold [Ct] values) was decided by correlation with the quantitative measure on 300 samples (Fig. S2). The coefficient of correlation between the 2 strategies was 0.93, which permitted the usage of qualitative Ct information to estimate viral load in contacts. Detection of IgM and IgG antibodies was carried out by way of fingertip blood testing on the day 14 go to with the usage of a fast take a look at (VivaDiag COVID-19).15
The first consequence was the onset of a PCR-confirmed, symptomatic Covid-19 episode, outlined as symptomatic sickness (at the very least one of many following signs: fever, cough, issue respiratory, myalgia, headache, sore throat, new olfactory or style dysfunction, or diarrhea) and a constructive RT-PCR take a look at for SARS-CoV-2. The first consequence was assessed in all asymptomatic contacts, no matter the baseline PCR end result; in a publish hoc evaluation, we explored the result individually in contacts with a constructive baseline PCR take a look at and people with a detrimental baseline PCR take a look at. The time till the first occasion was outlined because the variety of days till the onset of symptomatic sickness from the date of publicity and from the date of randomization.
The secondary consequence was the incidence of SARS-CoV-2 an infection, outlined as both the RT-PCR detection of SARS-CoV-2 in a nasopharyngeal specimen or the presence of any of the aforementioned signs appropriate with Covid-19. The rationale for this consequence was to embody definitions of Covid-19 used elsewhere.12,16 Contacts who had been hospitalized or who died and whose hospital and very important information listed Covid-19 as the principle prognosis (together with PCR affirmation) had been additionally thought of for the first and secondary outcomes.
With an enrollment goal of 95 clusters per trial group17 ― 15 contacts per cluster and intraclass correlation of 1.0 ― the preliminary design supplied an influence of 90% to detect a between-group distinction of 10 proportion points within the incidence of PCR-confirmed, symptomatic Covid-19, with an anticipated incidence of 5% within the hydroxychloroquine group and 15% within the usual-care group. Owing to the restricted data accessible by March 2020 concerning the cluster dimension and the incidence of Covid-19 after publicity, the protocol prespecified a sample-size reestimation on the interim evaluation. Reestimation was aimed toward sustaining the power (at 80% energy) to detect a between-group distinction of three.5 proportion points within the incidence of primary-outcome occasions (3.0% within the hydroxychloroquine group and 6.5% within the usual-care group), yielding 320 clusters per trial group with 3.5 contacts per cluster, an intraclass correlation of 1.0, and no provision for crossover.
The first efficacy evaluation was carried out within the intention-to-treat inhabitants. A number of imputation by chained equations was utilized to account for lacking information.18,19 The belief that unobserved values had been lacking at random was deemed to be applicable as a result of we couldn’t discover any sample among the many lacking values.20 A whole-case evaluation and a per-protocol evaluation had been performed as sensitivity analyses. The cumulative incidence of trial outcomes was in contrast on the particular person degree with the usage of a binomial regression model with strong sandwich commonplace errors to account for grouping inside clusters.21 We outlined a generalized linear model with a binomial distribution and a log-link perform to estimate the chance ratio as a measure of impact.22 The analyses had been adjusted for the baseline variables of age, intercourse, geographic area, and time of publicity. We carried out further prespecified analyses to evaluate the consistency of remedy results in subgroups outlined in accordance with the viral load of the contact at baseline, viral load of the index case affected person, place of publicity, and time of publicity to the index case affected person. The reported confidence intervals haven’t been adjusted for a number of comparisons and can’t be used to deduce results. Survival curves in accordance with trial group for time-to-event outcomes had been in contrast with the usage of a Cox proportional-hazards model with a cluster-level frailty time period to regulate for clustering.23 The importance threshold was set at a two-sided alpha value of 0.05, except in any other case indicated. All statistical analyses had been performed with R software program, model 220.127.116.11