Protocol for the DisCoVeRy trial: multicentre, adaptive, randomised trial of the safety and efficacy of treatments for COVID-19 in hospitalised adults

Ader, Florence

doi:10.1136/bmjopen-2020-041437

Cited by 47 publications

(45 citation statements)

References 41 publications

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“…Notably, early data suggest a potential benefit for taking interferon beta on exposure to SARS-CoV-2 ; currently, trials are underway to study the efficacy of interferon beta in COVID-19. In this study, fumarates and natalizumab were each associated with reduced risk of ICU admission and/or ventilation compared with those not receiving therapy. The reason for this is unknown but may be associated with the relative anti-inflammatory vs immunosuppressive effects of these medications.…”

Section: Discussionmentioning

confidence: 70%

Outcomes and Risk Factors Associated With SARS-CoV-2 Infection in a North American Registry of Patients With Multiple Sclerosis

et al. 2021

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2 causing COVID-19 prompted the need to gather information on clinical outcomes and risk factors associated with morbidity and mortality in patients with multiple sclerosis (MS) and concomitant SARS-CoV-2 infections. OBJECTIVE To examine outcomes and risk factors associated with COVID-19 clinical severity in a large, diverse cohort of North American patients with MS. DESIGN, SETTING, AND PARTICIPANTS This analysis used deidentified, cross-sectional data on patients with MS and SARS-CoV-2 infection reported by health care professionals in North American academic and community practices between April 1, 2020, and December 12, 2020, in the COVID-19 Infections in MS Registry. Health care professionals were asked to report patients after a minimum of 7 days from initial symptom onset and after sufficient time had passed to observe the COVID-19 disease course through resolution of acute illness or death. Data collection began April 1, 2020, and is ongoing. EXPOSURES Laboratory-positive SARS-CoV-2 infection or highly suspected COVID-19. MAIN OUTCOMES AND MEASURES Clinical outcome with 4 levels of increasing severity: not hospitalized, hospitalization only, admission to the intensive care unit and/or required ventilator support, and death. RESULTS Of 1626 patients, most had laboratory-positive SARS-CoV-2 infection (1345 [82.7%]), were female (1202 [74.0%]), and had relapsing-remitting MS (1255 [80.4%]).A total of 996 patients (61.5%) were non-Hispanic White, 337 (20.8%) were Black, and 190 (11.7%) were Hispanic/Latinx. The mean (SD) age was 47.7 (13.2) years, and 797 (49.5%) had 1 or more comorbidity. The overall mortality rate was 3.3% (95% CI, 2.5%-4.3%). Ambulatory disability and older age were each independently associated with increased odds of all clinical severity levels compared with those not hospitalized after adjusting for other risk factors

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Section: Discussionmentioning

confidence: 70%

Outcomes and Risk Factors Associated With SARS-CoV-2 Infection in a North American Registry of Patients With Multiple Sclerosis

et al. 2021

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“…The trial was conducted in accordance with the Declaration of Helsinki and national laws and regulations and declared on the clinicatrials.gov registry (NCT 04315948) and on the European Clinical Trials Database (2020-000936-23). The present analysis is based on the protocol v7.0 of April, 5 th 2020, (14) with two secondary outcomes added in protocol v9.0 of June, 29 th 2020.…”

Section: Trial Design and Oversightmentioning

confidence: 99%

“…The DisCoVeRy trial is a phase 3 multicenter, open-label, randomized, adaptive, controlled trial to evaluate the clinical and the virological efficacy, as well as the safety, of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a, hydroxychloroquine, and remdesivir as compared with standard of care in adults hospitalized for COVID-19 (14). The DisCoVeRy trial is part of the international Solidarity trial consortium sponsored by the World Health Organization (WHO).…”

Section: Introductionmentioning

confidence: 99%

Antiviral drugs in hospitalized patients with COVID-19 - the DisCoVeRy trial

Ader¹,

Peiffer-Smadja²,

Poissy³

et al. 2021

Preprint

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BackgroundLopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-β-1a and hydroxychloroquine efficacy for COVID-19 have been evaluated, but detailed evaluation is lacking.ObjectiveTo determine the efficacy of lopinavir/ritonavir, lopinavir/ritonavir-IFN-β-1a, hydroxychloroquine or remdesivir for improving the clinical, virological outcomes in COVID-19 inpatients.DesignOpen-label, randomized, adaptive, controlled trial.SettingMulti-center trial with patients from France.Participants583 COVID-19 inpatients requiring oxygen and/or ventilatory supportInterventionStandard of care (SoC, control), SoC plus lopinavir/ritonavir (400 mg lopinavir and 100 mg ritonavir every 12h for 14 days), SoC plus lopinavir/ritonavir plus IFN-ß-1a (44 μg of subcutaneous IFN-ß-1a on days 1, 3, and 6), SoC plus hydroxychloroquine (400 mg twice on day 1 then 400 mg once daily for 9 days) or SoC plus remdesivir (200 mg intravenously on day 1 then 100 mg once-daily for hospitalization duration or 10 days).MeasurementsThe primary outcome was the clinical status at day 15, measured by the WHO 7-point ordinal scale. Secondary outcomes included SARS-CoV-2 quantification in respiratory specimens and safety analyses.ResultsAdjusted Odds Ratio (aOR) for the WHO 7-point ordinal scale were not in favor of investigational treatments: lopinavir/ritonavir versus control, aOR 0.83, 95%CI, 0.55 to 1.26, P=0.39; lopinavir/ritonavir-IFN-β-1a versus control, aOR 0.69, 95%CI, 0.45 to 1.04, P=0.08; hydroxychloroquine versus control, aOR 0.93, 95%CI, 0.62 to 1.41, P=0.75. No significant effect on SARS-CoV-2 RNA clearance in respiratory tract was evidenced. Lopinavir/ritonavir-containing treatments were significantly associated with more SAE.LimitationsNot a placebo-controlled, no anti-inflammatory agents tested.ConclusionNo improvement of the clinical status at day 15 nor SARS-CoV-2 RNA clearance in respiratory tract specimens by studied drugs. This comforts the recent Solidarity findings.RegistrationNCT04315948.FundingPHRC 2020, Dim OneHealth, REACTing

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“…Whilst SARS-CoV-2 infection is mostly asymptomatic and/or self-limited, patients can become critically ill, as manifested by acute respiratory distress syndrome (ARDS), thromboemboli, hyperinflammation, and multi-system organ failure (MSOF) 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 . There is no treatment outside of dexamethasone, and the world is still awaiting widespread vaccination 13 , 14 , 15 , 16 , 17 , 18 . Therefore it is important to explore novel but rational therapies.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic plasma exchange in patients with life-threatening COVID-19: a randomised controlled clinical trial

Faqihi

Alharthy

Abdulaziz

et al. 2021

International Journal of Antimicrobial Agents

134

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Objective To assess the efficacy of therapeutic plasma exchange (TPE) following life-threatening COVID-19. Design, setting, and participants Open-label, randomized clinical trial of intensive care unit (ICU) patients with life-threatening COVID-19 [positive real-time-polymerase-chain-reaction test, plus acute respiratory distress syndrome (ARDS), sepsis, organ failure, hyperinflammation]. The study was terminated after 87/120 patients were enrolled. Intervention and randomization Standard treatment plus TPE (n = 43) versus standard treatment (n = 44), and stratified by peripheral arterial oxygen saturation/fraction of inspired oxygen (PaO 2 /FiO 2 ) ratio (> 150 versus ≤ 150). Main Outcomes and measures Primary outcomes were 35-day mortality and TPE safety. Secondary outcomes were association between TPE and mortality, improvement in Sequential Organ Function Assessment (SOFA) score, change in inflammatory biomarkers, days on mechanical ventilation (MV), and ICU length-of-stay. Results Eighty-seven patients [median years of age 49 (IQR: 34-63); 72 males (82.8%)] were randomized [44 to standard care; 43 to standard care plus TPE]. Days on MV (p=0.007) and ICU length-of-stay (p=0.02) were lower in the TPE group versus controls. Thirty-five-day mortality was lower in the TPE group (20.9% vs. 34.1% in controls), but this did not reach statistical significance [Kaplan-Meir analysis: p=0.582). TPE was associated with increased lymphocytes and ADAMTS-13 activity; plus decreased serum lactate, lactate dehydrogenase, ferritin, D-dimers, and interleukin-6. Multivariable regression analysis provided several predictors of 35-day mortality: PaO 2 /FiO 2 ratio [hazard ratio (HR): 0.98, 95% CI: 0.96-1.00, p=0.02], ADAMTS-13 activity (HR: 0.89, 95% CI: 0.82-0.98, p=0.01), and PE (HR: 3.57, 95% CI: 1.43-8.92, p=0.007). Post-hoc analysis revealed a significant reduction in SOFA score for TPE patients (p<0.05) compared to controls. Conclusion In critically ill COVID-19 patients the addition of TPE to standard ICU therapy was associated with faster clinical recovery and no increased 35-day mortality.

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Protocol for the DisCoVeRy trial: multicentre, adaptive, randomised trial of the safety and efficacy of treatments for COVID-19 in hospitalised adults

Cited by 47 publications

References 41 publications

Outcomes and Risk Factors Associated With SARS-CoV-2 Infection in a North American Registry of Patients With Multiple Sclerosis

Outcomes and Risk Factors Associated With SARS-CoV-2 Infection in a North American Registry of Patients With Multiple Sclerosis

Antiviral drugs in hospitalized patients with COVID-19 - the DisCoVeRy trial

Therapeutic plasma exchange in patients with life-threatening COVID-19: a randomised controlled clinical trial

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