Dataset Information

Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial.

ABSTRACT:

Purpose

To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19).

Methods

Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable.

Results

We randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (- 1 to 15), 0 (- 1 to 9) and-1 (- 1 to 7), respectively, compared to 6 (- 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively).

Conclusion

Among critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy.

SUBMITTER: Arabi YM

PROVIDER: S-EPMC8274471 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Publications

Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial.

Arabi Yaseen M YM Gordon Anthony C AC Derde Lennie P G LPG Nichol Alistair D AD Murthy Srinivas S Beidh Farah Al FA Annane Djillali D Swaidan Lolowa Al LA Beane Abi A Beasley Richard R Berry Lindsay R LR Bhimani Zahra Z Bonten Marc J M MJM Bradbury Charlotte A CA Brunkhorst Frank M FM Buxton Meredith M Buzgau Adrian A Cheng Allen A De Jong Menno M Detry Michelle A MA Duffy Eamon J EJ Estcourt Lise J LJ Fitzgerald Mark M Fowler Rob R Girard Timothy D TD Goligher Ewan C EC Goossens Herman H Haniffa Rashan R Higgins Alisa M AM Hills Thomas E TE Horvat Christopher M CM Huang David T DT King Andrew J AJ Lamontagne Francois F Lawler Patrick R PR Lewis Roger R Linstrum Kelsey K Litton Edward E Lorenzi Elizabeth E Malakouti Salim S McAuley Daniel F DF McGlothlin Anna A Mcguinness Shay S McVerry Bryan J BJ Montgomery Stephanie K SK Morpeth Susan C SC Mouncey Paul R PR Orr Katrina K Parke Rachael R Parker Jane C JC Patanwala Asad E AE Rowan Kathryn M KM Santos Marlene S MS Saunders Christina T CT Seymour Christopher W CW Shankar-Hari Manu M Tong Steven Y C SYC Turgeon Alexis F AF Turner Anne M AM Van de Veerdonk Frank Leo FL Zarychanski Ryan R Green Cameron C Berry Scott S Marshall John C JC McArthur Colin C Angus Derek C DC Webb Steven A SA

Intensive care medicine 20210712 8

<h4>Purpose</h4>To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19).<h4>Methods</h4>Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and ex ...[more]

PMID: 34251506

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Project description:ImportanceThe longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown.ObjectiveTo determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes.Design, setting, and participantsPrespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022.InterventionsPatients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401).Main outcomes and measuresThe main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83.ResultsAmong 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies.Conclusions and relevanceAmong critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.

Project description:ObjectivesWe evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-β-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in coronavirus 2019 disease (COVID-19) inpatients requiring oxygen and/or ventilatory support.MethodsWe conducted a phase III multicentre, open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), an add-on to the Solidarity trial (NCT04315948, EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO seven-point ordinal scale. Secondary outcomes included quantification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in respiratory specimens and pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, trials of which were stopped prematurely.ResultsThe intention-to-treat population included 583 participants-lopinavir/ritonavir (n = 145), lopinavir/ritonavir-IFN-β-1a (n = 145), hydroxychloroquine (n = 145), control (n = 148)-among whom 418 (71.7%) were male, the median age was 63 years (IQR 54-71), and 211 (36.2%) had a severe disease. The day-15 clinical status was not improved with the investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.83, (95% confidence interval (CI) 0.55-1.26, p 0.39), lopinavir/ritonavir-IFN-β-1a versus control, aOR 0.69 (95%CI 0.45-1.04, p 0.08), and hydroxychloroquine versus control, aOR 0.93 (95%CI 0.62-1.41, p 0.75). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of serious adverse events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms.ConclusionIn adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-β-1a and hydroxychloroquine improved neither the clinical status at day 15 nor SARS-CoV-2 clearance in respiratory tract specimens.

Project description:ObjectiveTo systematically identify, match, and compare treatment effects and study demographics from individual or meta-analysed observational studies and randomized controlled trials (RCTs) evaluating the same covid-19 treatments, comparators, and outcomes.DesignMeta-epidemiological study.Data sourcesNational Institutes of Health Covid-19 Treatment Guidelines, a living review and network meta-analysis published in The BMJ, a living systematic review with meta-analysis and trial sequential analysis in PLOS Medicine (The LIVING Project), and the Epistemonikos "Living OVerview of Evidence" (L·OVE) evidence database.Eligibility criteria for selection of studiesRCTs in The BMJ's living review that directly compared any of the three most frequently studied therapeutic interventions for covid-19 across all data sources (that is, hydroxychloroquine, lopinavir-ritonavir, or dexamethasone) for any safety and efficacy outcomes. Observational studies that evaluated the same interventions, comparisons, and outcomes that were reported in The BMJ's living review.Data extraction and synthesisSafety and efficacy outcomes from observational studies were identified and treatment effects for dichotomous (odds ratios) or continuous (mean differences or ratios of means) outcomes were calculated and, when possible, meta-analyzed to match the treatment effects from individual RCTs or meta-analyses of RCTs reported in The BMJ's living review with the same interventions, comparisons, and outcomes (that is, matched pairs). The analysis compared the distribution of study demographics and the agreement between treatment effects from matched pairs. Matched pairs were in agreement if both observational and RCT treatment effects were significantly increasing or decreasing (P<0.05) or if both treatment effects were not significant (P≥0.05).Results17 new, independent meta-analyses of observational studies were conducted that compared hydroxychloroquine, lopinavir-ritonavir, or dexamethasone with an active or placebo comparator for any safety or efficacy outcomes in covid-19 treatment. These studies were matched and compared with 17 meta-analyses of RCTs reported in The BMJ's living review. 10 additional matched pairs with only one observational study and/or one RCT were identified. Across all 27 matched pairs, 22 had adequate reporting of demographical and clinical data for all individual studies. All 22 matched pairs had studies with overlapping distributions of sex, age, and disease severity. Overall, 21 (78%) of the 27 matched pairs had treatment effects that were in agreement. Among the 17 matched pairs consisting of meta-analyses of observational studies and meta-analyses of RCTs, 14 (82%) were in agreement; seven (70%) of the 10 matched pairs consisting of at least one observational study or one RCT were in agreement. The 18 matched pairs with treatment effects for dichotomous outcomes had a higher proportion of agreement (n=16, 89%) than did the nine matched pairs with treatment effects for continuous outcomes (n=5, 56%).ConclusionsMeta-analyses of observational studies and RCTs evaluating treatments for covid-19 have summary treatment effects that are generally in agreement. Although our evaluation is limited to three covid-19 treatments, these findings suggest that meta-analyzed evidence from observational studies might complement, but should not replace, evidence collected from RCTs.

Project description:ImportanceData on the efficacy of hydroxychloroquine or lopinavir-ritonavir for the treatment of high-risk outpatients with COVID-19 in developing countries are needed.ObjectiveTo determine whether hydroxychloroquine or lopinavir-ritonavir reduces hospitalization among high-risk patients with early symptomatic COVID-19 in an outpatient setting.Design, setting, and participantsThis 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.InterventionsPatients 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 measuresThe 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.ResultsOf 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 lopinavir-ritonavir 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 [95% CI, 0.82-1.02]; lopinavir-ritonavir: OR, 1.04 [95% CI, 0.94-1.16]). At the end of the trial, there were 3 fatalities recorded, 1 in the placebo group and 2 in the lopinavir-ritonavir intervention group.Conclusions and relevanceIn this randomized clinical trial, neither hydroxychloroquine nor lopinavir-ritonavir showed any significant benefit for decreasing COVID-19-associated hospitalization or other secondary clinical outcomes. This trial suggests that expedient clinical trials can be implemented in low-income settings even during the COVID-19 pandemic.Trial registrationClinicalTrials.gov Identifier: NCT04403100.

Dataset Information

Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial.

Purpose

Methods

Results

Conclusion

Publications

Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial.

Similar Datasets

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