Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19 The TOGETHER Randomized Clinical Trial
et al., JAMA Network Open, doi:10.1001/jamanetworkopen.2021.6468, TOGETHER, NCT04403100, Apr 2021
The TOGETHER trial has extreme COI, impossible data, blinding failure, randomization failure, uncorrected errors, and many protocol violations. Authors do not respond to these issues and they have refused to release the data as promised. Some issues may apply only to specific arms.
Early terminated RCT in Brazil showing lower mortality and hospitalization
with HCQ, but not reaching statistical significance. Although the title includes "early
treatment", treatment was late, with most patients being over 5 days from the onset of
symptoms. Adverse events were lower in the HCQ group compared to the control group.
The TOGETHER trial has extreme COI, impossible data,
blinding failure, randomization failure, uncorrected errors, and many
protocol violations. Authors do not respond to these issues and they
have refused to release the data as promised. Some issues may apply only
to specific arms. For more details see1-5.
HCQ for COVID-19
1st treatment shown to reduce risk in
March 2020, now with p < 0.00000000001 from 424 studies, used in 59 countries.
No treatment is 100% effective. Protocols
combine treatments.
6,600+ studies for
220+ treatments. c19early.org
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CRITICALMasking description contradicts protocol.
The paper describes the trial as quadruple-masked and states that patients, investigators, healthcare practitioners, and sponsors were masked, whereas the protocol states that participant and treating-clinician blinding was not feasible because interventions differed in appearance and dosing. This materially changes risk-of-bias assessment for subjective symptoms, adherence, treatment discontinuation, co-interventions, and potentially hospitalization decisions.
CRITICALPlacebo composition contradicts protocol.
The paper states that the placebo consisted of inert talc, whereas the protocol specifically describes ascorbic acid as the control comparator. No documented amendment explaining this discrepancy was identified. This raises uncertainty about what control participants actually received and whether the control intervention changed during recruitment.
CRITICALPrespecified clinical-deterioration outcome not reported.
The protocol specifies progression to lower respiratory tract infection using oxygen-saturation deterioration and includes an initial power calculation based on this outcome, but the final publication does not report these results. This creates a substantial selective-reporting concern.
CRITICAL90-day follow-up conflicts with analysis date.
The primary outcomes are specified at 90 days, randomization is reported as continuing through October 9, 2020, but statistical analysis is stated to have occurred in December 2020. The last randomized participants therefore complete 90-day ascertainment for all patients was not possible. Figures stop at 84 days with 70-80% of participants censored.
SERIOUSMid-trial change to "early" treatment eligibility.
The <8-day symptom-duration criterion presented in the paper as an eligibility requirement was added by protocol amendment roughly eight weeks after recruitment began. Treatmetn delay is critical for a trial evaluating early antiviral treatment.
SERIOUSMain paper and supplement use different LPV/r models.
All four LPV/r hospitalization hazard ratios differ between Table 2 and eTable 1: 1.16 versus 1.17, 1.22 versus 1.23, 1.82 versus 1.84, and 2.08 versus 2.10. The supplementary estimates reproduce from the supplied coefficients and standard errors, indicating that the two tables appear to derive from different model fits or data versions rather than simple rounding.
SERIOUSResults differ significantly from those reported prior to publication.
Prior to publication, authors reported an RR for hospitalization or death of 1.0 [0.45-2.21]6.
SERIOUSTerminated while showing ≥70% probability of superiority.
This trial appears to have been terminated at 45% enrollment while showing ≥70% probability of superiority. The futility threshold was not reported, but it would be highly unusual for it to be as high as 70%7.
SERIOUSText subgroup claims contradicted by table.
The results state that neither drug showed differences in viral clearance across prespecified subgroups while citing eTable 4, yet that table contains several estimates with confidence intervals far from including 1, including ORs 0.24, 4.92, 4.75, and 0.22.
MAJORSubgroup denominators do not reconcile.
In eTable 2, age strata contain only 210 of 214 HCQ participants, 222 of 227 placebo participants, and 238 of 244 LPV/r participants, despite age being a randomization stratification factor. Diabetes strata are also short by exactly one participant in each arm.
MAJORSample-size and power assumptions changed.
The publication states that 492 participants per arm provided 80% power to detect a 37.5% hospitalization reduction, whereas the protocol states 90% power to detect a 27.5% reduction with the same sample size and control event rate.
MAJORPrespecified proportional-hazards safeguard unreported.
The statistical plan states that Cox analysis would be used only if the proportional-hazards assumption was satisfied and otherwise the primary outcomes would be analyzed as binary outcomes, but no proportional-hazards assessment is reported, despite median time-to-hospitalization differing markedly by arm (2.4, 3.6, 4.8 days) at near-identical cumulative rates.
MAJORRisk-factor statistics are internally inconsistent.
Table 1 reports that 56.8% of participants had multiple risk factors while simultaneously reporting a median of 1.0 risk factor per participant. If multiple means at least two on the same underlying measure, these statements are mathematically incompatible.
MAJORProtocol endpoint hierarchy is inconsistent.
Different portions of the protocol classify LRTI, viral shedding, hospitalization, and mortality differently as primary or secondary outcomes, making the prospectively specified endpoint hierarchy difficult to reconstruct.
MAJORAdverse-event narrative contradicts Table 3.
The paper states that no LPV/r or placebo participants discontinued treatment because of treatment-emergent adverse events, whereas Table 3 reports 9 LPV/r and 3 placebo withdrawals for this reason.
MAJORPrimary mortality outcome inadequately reported.
Death is explicitly designated a primary outcome alongside hospitalization, but only three raw deaths are reported in the text without a dedicated effect estimate, confidence interval, table row, or statistical analysis.
MAJORConflict and oversight disclosure.
Several authors list Cytel affiliations and the supplement states that Cytel participated in trial oversight, while the formal conflict-of-interest statement reports no conflicts.
MAJORLPV/r harm signals receive limited emphasis.
PP all-cause hospitalization HR 2.10 (0.90-4.91), male subgroup 3.39 (1.09-10.51), both deaths in the treatment arm, highest TEAE and serious-TEAE rates.
MINORFailed Cox estimates reported as hazard ratios.
For subgroups with zero placebo events, the supplement reports enormous hazard ratios such as approximately 644 million and 719 million with confidence intervals of 0 to infinity rather than identifying the estimates as non-estimable.
MINORDefinite arithmetic and transcription errors.
Table 3 reports Grade 2 adverse events as 6 + 6 + 2 = 4 although the correct total is 14 and the percentage corresponds to 14. Table 1 reports 193 dry-cough cases as 18.2%, although 193/685 equals 28.2%.
MINORCONSORT PP arithmetic is off by one.
The HCQ safety population is 207 and 8 participants are reported as having less than 80% adherence, which would leave 199, but the PP population is given as 198.
MINORAge ranges are mislabeled as IQRs.
Table 1 labels age values such as 53 (18-81) as median (IQR), although the values appear to be minimum-to-maximum ranges and the abstract explicitly describes the overall 18-94 values as a range.
MINORSite-level reporting is insufficient.
The study was conducted across multiple participating cities and centers, but site-level enrollment, outcomes, missingness, and treatment effects are not reported.
Revisions: viral clearance outcome correction. The paper reports different
values in the text and Table 2. The data repored is also impossible - 102 of 179
per-protocol participants had viral clearance versus 97 of 185 in intention-to-treat.
Since PP is a subset of ITT, this is not possible.
Viral load measured by PCR may not accurately reflect infectious virus measured by viral culture. Porter et al. show that viral load early in infection was correlated with infectious virus, but viral load late in infection could be high even with low or undetectable infectious virus. Assessing viral load later in infection may underestimate reductions in infectious virus with treatment.
Study covers lopinavir/ritonavir and HCQ.
|
risk of death, 66.0% lower, RR 0.34, p = 1.00, treatment 0 of 214 (0.0%), control 1 of 227 (0.4%), NNT 227, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
|
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risk of hospitalization, 24.0% lower, HR 0.76, p = 0.57, treatment 8 of 214 (3.7%), control 11 of 227 (4.8%), NNT 90, ITT, Cox proportional hazards.
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risk of no viral clearance, 9.9% higher, OR 1.10, p = 0.09, treatment 185, control 195, adjusted per study, inverted to make OR<1 favor treatment, day 14, intention-to-treat, RR approximated with OR, impossible data.
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serious treatment-emergent adverse events, 2.6% lower, RR 0.97, p = 1.00, treatment 11 of 207 (5.3%), control 12 of 220 (5.5%), NNT 712.
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| Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates |
1.
Reis et al., Effect of Early Treatment with Ivermectin among Patients with Covid-19, New England Journal of Medicine, doi:10.1056/NEJMoa2115869.
2.
Reis (B) et al., RETRACTED: Effect of early treatment with metformin on risk of emergency care and hospitalization among patients with COVID-19: The TOGETHER randomized platform clinical trial, The Lancet Regional Health - Americas, doi:10.1016/j.lana.2021.100142.
3.
Reis (C) et al., Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial, The Lancet Global Health, doi:10.1016/S2214-109X(21)00448-4.
4.
Reis (D) et al., Early Treatment with Pegylated Interferon Lambda for Covid-19, New England Journal of Medicine, doi:10.1056/NEJMoa2209760.
5.
Reis (E) et al., Oral Fluvoxamine With Inhaled Budesonide for Treatment of Early-Onset COVID-19, Annals of Internal Medicine, doi:10.7326/M22-3305.
Reis et al., 22 Apr 2021, Double Blind Randomized Controlled Trial, Brazil, peer-reviewed, 18 authors, study period 2 June, 2020 - 30 September, 2020, dosage 800mg day 1, 400mg days 2-10, trial NCT04403100 (history) (TOGETHER).
Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19
JAMA Network Open, doi:10.1001/jamanetworkopen.2021.6468
IMPORTANCE Data on the efficacy of hydroxychloroquine or lopinavir-ritonavir for the treatment of high-risk outpatients with COVID-19 in developing countries are needed. OBJECTIVE To determine whether hydroxychloroquine or lopinavir-ritonavir reduces hospitalization among high-risk patients with early symptomatic COVID-19 in an outpatient setting. DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial was conducted in Brazil. Recently symptomatic adults diagnosed with respiratory symptoms from SARS-CoV-2 infection were enrolled between June 2 and September 30, 2020. The planned sample size was 1476 patients, with interim analyses planned after 500 patients were enrolled. The trial was stopped after the interim analysis for futility with a sample size of 685 patients. Statistical analysis was performed in December 2020. INTERVENTIONS Patients were randomly assigned to hydroxychloroquine (800 mg loading dose, then 400 mg daily for 9 days), lopinavir-ritonavir (loading dose of 800 mg and 200 mg, respectively, every 12 hours followed by 400 mg and 100 mg, respectively, every 12 hours for the next 9 days), or placebo.
MAIN OUTCOMES AND MEASURES The primary outcomes were COVID-19-associated hospitalization and death assessed at 90 days after randomization. COVID-19-associated hospitalization was analyzed with a Cox proportional hazards model. The trial included the following secondary outcomes: all-cause hospitalization, viral clearance, symptom resolution, and adverse events.
RESULTS Of 685 participants, 632 (92.3%) self-identified as mixed-race, 377 (55.0%) were women, and the median (range) age was 53 (18-94) years. A total of 214 participants were randomized to hydroxychloroquine; 244, lopinavir-ritonavir; and 227, placebo. At first interim analysis, the data safety monitoring board recommended stopping enrollment of both hydroxychloroquine and lopinavir-ritonavir groups because of futility. The proportion of patients hospitalized for COVID-19 was 3.7% (8 participants) in the hydroxychloroquine group, 5.7% (14 participants) in the lopinavirritonavir group, and 4.8% (11 participants) in the placebo group. We found no significant differences between interventions for COVID-19-associated hospitalization (hydroxychloroquine: hazard ratio [HR], 0.76 [95% CI, 0.30-1.88]; lopinavir-ritonavir: HR, 1.16 [95% CI, 0.53-2.56] as well as for the secondary outcome of viral clearance through day 14 (hydroxychloroquine: odds ratio [OR], 0.91
ARTICLE INFORMATION Author Contributions: Drs Reis and Mills had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Reis, E.
Conflict of Interest Disclosures: None reported. Funding/Support: The trial was supported by the Bill and Melinda Gates Foundation.
Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: Dr. Reis wishes to acknowledge particularly here the role of mayors and public health authorities in Brazil (a complete list can be found in the eAppendix of Supplement 2).
The TOGETHER Investigators
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Late treatment
is less effective
is less effective
