Trial NCT04329832
Publication Brown SM, Ann Am Thorac Soc, 2020 (published paper)
Dates: 2020-04-03 to 2020-06-19
Funding: Public/non profit (Heart and Lung Research Foundation, Intermountain Research and Medical Foundation, Office of the Associate Vice President for Research, University of Utah Health Sciences)
Conflict of interest: Yes
| Methods | |
| RCT Blinding: Unblinded | |
| Location :
Multicenter / USA Follow-up duration (days): 28 | |
| Inclusion criteria | Report:
"We enrolled hospitalized patients with symptomatic laboratory-confirmed COVID-19, within 10 days of a positive test for COVID-19." Registry: Age >18 yr; Scheduled for admission or already admitted to an inpatient bed; Confirmed or suspected COVID-19 (Confirmed: positive assay for COVID-19 within the last 10 d; Suspected: pending assay for COVID-19 with high clinical suspicion) |
| Exclusion criteria | Report:
"Patients were excluded for ethical reasons (e.g., prisoners) or for safety reasons (e.g., known long QT, seizure disorder, renal or liver failure)." Registry: Allergy to hydroxychloroquine or azithromycin; History of bone marrow transplant ; Known G6PD deficiency ; Chronic hemodialysis or glomerular filtration rate ,20 ml/min ; Psoriasis ; Porphyria ; Concomitant use of digitalis, flecainide, amiodarone, procainamide, propafenone, cimetidine, dofetilide, phenobarbital, phenytoin, or sotalol ; History of long QT syndrome; Current known QTc .500 ms ; Seizure disorder ; Severe liver disease; Outpatient use of hydroxychloroquine or azithromycin for a chronic condition or received more than 2 d of hydroxychloroquine or azithromycin for suspected or confirmed COVID-19 ; Patient has recovered from COVID-19 and/or is being discharged from the hospital on the day of enrollment ; Pregnant or nursing ; Prisoner ; Weight < 35 kg ; Treating physician refuses to allow patient participation in the study ; Unable to obtain informed consent ; Prior enrollment in this study |
| Interventions | |
| Treatment
Hydroxychloroquine 400 mg orally twice on the first day, followed by 200 mg twice a day for the next 4 days. |
|
| Control
Azithromycin (250 mg) Duration : 5 days | |
| Participants | |
| Randomized 85 participants (n1=42 / n2= 43) | |
| Characteristics of participants N=85 Mean age : NR 52 males Severity : Mild: n=12 / Moderate: n=47/ Severe: n=13 Critical: n=13 | |
| Primary outcome | |
| In the register COVID Ordinal Outcomes Scale at 14 days | |
| In the report Day 14 COVID Ordinal Outcomes scale | |
| Documents available |
Protocol Yes. In English Statistical plan Yes Data-sharing stated Yes |
| Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review |
Some concerns |
| General comment |
In addition to the available published article, the study registry, protocol and statistical analysis plan were used in data extraction and risk of bias assessment. The trial was stopped early after enrollment of 85 patients when a separate clinical trial concluded that a clinically important effect of hydroxychloroquine over placebo was definitively excluded. There is no change from the trial registration in the intervention and control treatments and outcomes. The registry primary outcome does reflect the reported primary outcome. In the hydroxychloroquine arm, 6 (14%) received nonrandomized azithromycin after study enrollment (generally as clinician-directed treatment for suspected pneumonia.
Post-randomization concomitant medications did not differ between treatment groups (eTable 16 in Online Supplement) with one possible exception. Remdesivir (given under an emergency use authorization) may have been used significantly more often in the hydroxychloroquine than in the azithromycin arm (19% vs. 2%).
Of note: "The primary analysis was on patients in the intention to treat cohort who had no missing data for the relevant variables." "the protocol initially allowed enrollment of patients with suspected COVID-19, but no patients were enrolled under that criterion. That criterion was closed as testing became faster and more reliable. Early in the trial, azithromycin was unavailable owing to drug shortages; the original version of the protocol allowed non-randomized azithromycin if the clinician felt that it was indicated for treatment of suspected bacterial pneumonia. A protocol revision recommended use of an alternative agent (e.g., doxycycline or levofloxacin) if the clinical physician believed that a second agent was required to treat suspected bacterial pneumonia." |