TRIAL DESIGN AND OVERSIGHT
We conducted this randomized, adaptive platform trial for the investigation of the efficacy of repurposed treatments for Covid-19 among adult outpatients at high risk for hospitalization.10 The trial was designed and conducted in partnership with local public health authorities from 12 cities in Brazil in order to simultaneously test potential treatments for early Covid-19 with the use of a master protocol. A master protocol defines prospective decision criteria for discontinuing interventions for futility, stopping owing to superiority of an intervention over placebo, or adding new interventions. Interventions that have been evaluated in this trial thus far include hydroxychloroquine and lopinavir–ritonavir (both in protocol 1)11 and metformin, ivermectin administered for 1 day, ivermectin administered for 3 days, doxazosin, pegylated interferon lambda, and fluvoxamine (all in protocol 2), as compared with matching placebos. The full trial protocol with the statistical analysis plan has been published previously10 and is available with the full text of this article at NEJM.org.
The trial began recruitment for its first investigational groups on June 2, 2020. The evaluation that is reported here involved patients who had been randomly assigned to receive either ivermectin or placebo between March 23, 2021, and August 6, 2021. The initial trial protocol specified single-day administration of ivermectin, and we recruited 77 patients to this dose group. On the basis of feedback from advocacy groups, we modified the protocol to specify 3 days of administration of ivermectin. Here, we present data only on the patients who had been assigned to receive ivermectin for 3 days or placebo during the same time period. The full trial protocol was approved by local and national research ethics boards in Brazil and by the Hamilton Integrated Research Ethics Board in Canada. The CONSORT (Consolidated Standards of Reporting Trials) extension statement for adaptive design trials guided this trial report.12 All the patients provided written informed consent.
The trial was coordinated by Platform Life Sciences, and Cardresearch conducted the trial and collected the data. The first and last authors had full access to all the trial data and vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. The funders had no role in the design and conduct of the trial; the collection, management, analysis, or interpretation of the data; the preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. Ivermectin was purchased at full cost.
PATIENTS
On presentation to one of the trial outpatient care clinics, potential participants were screened to identify those meeting the eligibility criteria. Inclusion criteria were an age of 18 years or older; presentation to an outpatient care setting with an acute clinical condition consistent with Covid-19 within 7 days after symptom onset; and at least one high-risk criterion for progression of Covid-19, including an age of 50 years or older, diabetes mellitus, hypertension leading to the use of medication, cardiovascular disease, lung disease, smoking, obesity (defined as a body-mass index [the weight in kilograms divided by the square of the height in meters] of >30), organ transplantation, chronic kidney disease (stage IV) or receipt of dialysis, immunosuppressive therapy (receipt of ≥10 mg of prednisone or equivalent daily), a diagnosis of cancer within the previous 6 months, or receipt of chemotherapy for cancer. Patients who had been vaccinated against SARS-CoV-2 were eligible for participation in the trial. Further inclusion and exclusion criteria are listed in the trial protocol.10
If a patient met these eligibility criteria, trial personnel obtained written in-person informed consent and performed a rapid antigen test for SARS-CoV-2 (Panbio, Abbott Laboratories) to confirm eligibility for the trial. Before randomization, trial personnel obtained data on demographic characteristics, medical history, concomitant medications, coexisting conditions, and previous exposure to a person with Covid-19, as well as the score on the World Health Organization (WHO) clinical progression scale.13 Participants also completed the Patient-Reported Outcomes Measurement Information System (PROMIS) Global-10 health scale, which allows for the measurements of symptoms, functioning, and health-related quality of life (scores range from 5 to 20, with higher scores indicating better health-related quality of life). Normalized values are presented.
SETTING
The Supplementary Appendix, available at NEJM.org, lists the cities and investigators of the 12 participating clinical sites. Local investigators, in partnership with local public health authorities, recruited outpatients at community health facilities. Recruitment was supplemented by social media outreach.
RANDOMIZATION AND INTERVENTIONS
An independent pharmacist conducted the randomization at a central trial facility, from which the trial sites requested randomization by means of text message. Patients underwent randomization by means of a block randomization procedure for each participating site, with stratification according to age (<50 years or ≥50 years). The trial team, site staff, and patients were unaware of the randomized assignments. The active-drug and placebo pills were packaged in identically shaped bottles and labeled with alphabetic letters corresponding to ivermectin or placebo. Participants who were randomly assigned to receive placebo were assigned to a placebo regimen (ranging from 1 day to 14 days) that corresponded with that of a comparable active-treatment group in the trial. Only the pharmacist who was responsible for randomization was aware of which letter referred to which assignment.
All the patients received the usual standard care for Covid-19 provided by health care professionals in Brazil. Patients received either ivermectin at a dose of 400 μg per kilogram for 3 days or placebo beginning on the day of randomization, once per day. The placebos that were used in the trial involved regimens of 1, 3, 10, or 14 days in duration, according to the various comparator groups in the trial at the time of randomization. Patients were advised to take the pill on an empty stomach. Patients were shown a welcome video with information on the trial, ivermectin, adverse events, and follow-up procedures. Clinicians provided consultation on the management of symptoms and provided antipyretic agents; clinicians recommended antibiotic agents only if they suspected bacterial pneumonia.
OUTCOME MEASURES
The primary composite outcome was hospitalization due to Covid-19 within 28 days after randomization or an emergency department visit due to clinical worsening of Covid-19 (defined as the participant remaining under observation for >6 hours) within 28 days after randomization. Because many patients who would ordinarily have been hospitalized were prevented from admission because of limited hospital capacity during peak waves of the Covid-19 pandemic, the composite outcome was developed to measure both hospitalization and a proxy for hospitalization, observation in a Covid-19 emergency setting for more than 6 hours. This region of Brazil implemented mobile hospital-like services in the emergency settings (i.e., temporary field hospitals) with units of up to 80 beds; services included multiple-day stays, oxygenation, and mechanical ventilation. The 6-hour threshold referred only to periods of time that were recommended for observation by a clinician and was discounted for wait times. The event-adjudication committee, whose members were unaware of the randomized assignments, judged the reason for hospitalization or prolonged observation in the emergency department as being related or unrelated to the progression of Covid-19. Guidance for the validity of composite outcomes indicates that outcomes should have a similar level of patient importance.14
https://www.nejm.org/doi/full/10.1056/NEJMoa2115869
Créditos: Comité científico Covid
