Dataset Information

Lopinavir/ritonavir for treatment of non-hospitalized patients with COVID-19: a randomized clinical trial.

ABSTRACT:

Objectives

Effective and widely available therapies are still needed for outpatients with COVID-19. We aimed to evaluate the efficacy and safety of lopinavir/ritonavir (LPV/r) for early treatment of non-hospitalized individuals diagnosed with COVID-19.

Methods

This randomized, placebo (Plb)-controlled, double-blind, multi-site decentralized clinical trial enrolled non-hospitalized adults with confirmed SARS-CoV-2 infection and six or fewer days of acute respiratory infection symptoms who were randomized to either twice-daily oral LPV/r (400 mg/100 mg) or Plb for 14 days. Daily surveys on study days 1 through 16 and again on study day 28 evaluated symptoms, daily activities, and hospitalization status. The primary outcome was longitudinal change in an ordinal scale based on a combination of symptoms, activity, and hospitalization status through day 15 and was analyzed by use of a Bayesian longitudinal proportional odds logistic regression model for estimating the probability of a superior recovery for LPV/r over Plb (odds ratio >1).

Results

Between June 2020 and December 2021, 448 participants were randomized to receive either LPV/r (n = 216) or Plb (n = 221). The mean symptom duration before randomization was 4.3 days (SD 1.3). There were no differences between treatment groups through the first 15 days for the ordinal primary outcome (odds ratio 0.96; 95% credible interval: 0.66 to 1.41). There were 3.2% (n = 7) of LPV/r and 2.7% (n = 6) of Plb participants hospitalized by day 28. Serious adverse events did not differ between groups.

Conclusion

LPV/r did not significantly improve symptom resolution or reduce hospitalization in non-hospitalized participants with COVID-19.

Trial registration

ClinicalTrials.gov Identifier: NCT04372628.

SUBMITTER: Kaizer AM

PROVIDER: S-EPMC9792182 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Lopinavir/ritonavir for treatment of non-hospitalized patients with COVID-19: a randomized clinical trial.

Kaizer Alexander M AM Shapiro Nathan I NI Wild Jessica J Brown Samuel M SM Cwik B Jessica BJ Hart Kimberly W KW Jones Alan E AE Pulia Michael S MS Self Wesley H WH Smith Clay C Smith Stephanie A SA Ng Patrick C PC Thompson B Taylor BT Rice Todd W TW Lindsell Christopher J CJ Ginde Adit A AA

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 20221227

<h4>Objectives</h4>Effective and widely available therapies are still needed for outpatients with COVID-19. We aimed to evaluate the efficacy and safety of lopinavir/ritonavir (LPV/r) for early treatment of non-hospitalized individuals diagnosed with COVID-19.<h4>Methods</h4>This randomized, placebo (Plb)-controlled, double-blind, multi-site decentralized clinical trial enrolled non-hospitalized adults with confirmed SARS-CoV-2 infection and six or fewer days of acute respiratory infection sympt ...[more]

PMID: 36581186

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Project description:BackgroundNo therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2.MethodsWe conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao2) to the fraction of inspired oxygen (Fio2) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir-ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first.ResultsA total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Treatment with lopinavir-ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.31; 95% confidence interval [CI], 0.95 to 1.80). Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, -5.8 percentage points; 95% CI, -17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events.ConclusionsIn hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.).

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: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.

Project description:ObjectivesColchicine is a well-known drug, which has been used for years to treat a wide range of rheumatic and inflammatory disorders. It helps break the cycle of inflammation through diverse mechanisms including reducing Intereukin-6, Interleukin-8, Tumour Necrosis Factor-alpha besides controlling oxidative stress pathways which all are important and pathologic components in the clinical course and outcome of patients infected with COVID-19. This study aims to assess the anti-inflammatory effects of colchicine in non-severe hospitalized COVID-19 patients.Trial designProspective, randomized (1:1 ratio), double blind study with parallel group design.ParticipantsHospitalized patients with positive nasopharyngeal swab for COVID-19 infection (RT -PCR) and lung Computed tomography scan involvement compatible with COVID-19 pneumonia. The patients are not severely hypoxic, do not need intubation or invasive oxygenation.Exclusion criteriaknown hypersensitivity to colchicine; known hepatic failure; estimated glomerular filtration rate (eGFR)<30 ml/min/1.73m2 (by the CKD-EPI Creatinine Equation for Glomerular Filtration Rate (GFR) which estimates GFR based on serum creatinine. ; kidney transplant recipients, using Digoxin, QTc >450 msec. Participants will be recruited from inpatients at Labbafinejad Meidcal Center , Tehran, Iran.Intervention and comparatorEligible enrolled patients will be randomized into two groups. Group A will receive the antiretroviral Lopinavir/Ritonavir (Kaletra) while group B will receive Lopinavir/Ritonavir (Kaletra) + Colchicine 1.5 mg loading then 0.5 mg twice daily orally. All patients in both groups will receive the same amounts of essential minerals, vitamins as antioxidants, and antibiotics. Patients of both groups will be treated under optimal treatment based on the CDC and WHO guidelines and national consensus proposed in Iran including the same dosages of Lopinavir/Ritonavir, antibiotics, trace elements and antioxidants while only in group-B patients Colchicine will be added on top of this protocol.Main outcomesPrimary: Time for clinical improvement and lung CT score changes 14 days after treatment. Secondary: 14 days after treatment - C-Reactive Protein test x Neutrophil to Lymphocyte Ratio , Interleukin-6, malondialdehyde (MDA) levels reduction - Percentage of patients who require supplemental Oxygen - Mean hospital stay length RANDOMISATION: Patients will be allocated to each group (ratio 1:1) by using an online randomization tool: http://www.graphpad.com/quickcalcs/index.cfm BLINDING (MASKING): This will be a double-blind study in which participants and those assessing the final outcomes will be blinded to group assignment.Numbers to be randomised (sample size)Regarding the pandemic crisis and our center capacity to hospitalize confirmed COVID-19 patients, a total of 80 patients was found to be logical to be randomized into two groups of 40- patients.Trial statusRecruitment is ongoing. Recruitment began on 20/03/2020 and the date by which the recruitment is anticipated to be completed is 30/05/2020.Trial registrationClinicalTrials.gov Identifier: NCT04360980, registered 24/04/2020.Full protocolThe full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Dataset Information

Lopinavir/ritonavir for treatment of non-hospitalized patients with COVID-19: a randomized clinical trial.

Objectives

Methods

Results

Conclusion

Trial registration

Publications

Lopinavir/ritonavir for treatment of non-hospitalized patients with COVID-19: a randomized clinical trial.

Similar Datasets

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