Dataset Information

Camostat Mesylate Versus Lopinavir/Ritonavir in Hospitalized Patients With COVID-19-Results From a Randomized, Controlled, Open Label, Platform Trial (ACOVACT).

ABSTRACT: Background: To date, no oral antiviral drug has proven to be beneficial in hospitalized patients with COVID-19. Methods: In this randomized, controlled, open-label, platform trial, we randomly assigned patients ≥18 years hospitalized with COVID-19 pneumonia to receive either camostat mesylate (CM) (considered standard-of-care) or lopinavir/ritonavir (LPV/RTV). The primary endpoint was time to sustained clinical improvement (≥48 h) of at least one point on the 7-category WHO scale. Secondary endpoints included length of stay (LOS), need for mechanical ventilation (MV) or death, and 29-day mortality. Results: 201 patients were included in the study (101 CM and 100 LPV/RTV) between 20 April 2020 and 14 May 2021. Mean age was 58.7 years, and 67% were male. The median time from symptom onset to randomization was 7 days (IQR 5-9). Patients in the CM group had a significantly shorter time to sustained clinical improvement (HR = 0.67, 95%-CI 0.49-0.90; 9 vs. 11 days, p = 0.008) and demonstrated less progression to MV or death [6/101 (5.9%) vs. 15/100 (15%), p = 0.036] and a shorter LOS (12 vs. 14 days, p = 0.023). A statistically nonsignificant trend toward a lower 29-day mortality in the CM group than the LPV/RTV group [2/101 (2%) vs. 7/100 (7%), p = 0.089] was observed. Conclusion: In patients hospitalized for COVID-19, the use of CM was associated with shorter time to clinical improvement, reduced need for MV or death, and shorter LOS than the use of LPV/RTV. Furthermore, research is needed to confirm the efficacy of CM in larger placebo-controlled trials. Systematic Review Registration: [https://clinicaltrials.gov/ct2/show/NCT04351724, https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001302-30/AT], identifier [NCT04351724, EUDRACT-NR: 2020-001302-30].

SUBMITTER: Karolyi M

PROVIDER: S-EPMC9354138 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Camostat Mesylate Versus Lopinavir/Ritonavir in Hospitalized Patients With COVID-19-Results From a Randomized, Controlled, Open Label, Platform Trial (ACOVACT).

Karolyi M M Pawelka E E Omid S S Koenig F F Kauer V V Rumpf B B Hoepler W W Kuran A A Laferl H H Seitz T T Traugott M M Rathkolb V V Mueller M M Abrahamowicz A A Schoergenhofer C C Hecking M M Assinger A A Wenisch C C Zeitlinger M M Jilma B B Zoufaly A A

Frontiers in pharmacology 20220722

<b>Background:</b> To date, no oral antiviral drug has proven to be beneficial in hospitalized patients with COVID-19. <b>Methods:</b> In this randomized, controlled, open-label, platform trial, we randomly assigned patients ≥18 years hospitalized with COVID-19 pneumonia to receive either camostat mesylate (CM) (considered standard-of-care) or lopinavir/ritonavir (LPV/RTV). The primary endpoint was time to sustained clinical improvement (≥48 h) of at least one point on the 7-category WHO scale. ...[more]

PMID: 35935856

Similar Datasets

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:BackgroundLopinavir-ritonavir has been proposed as a treatment for COVID-19 on the basis of in vitro activity, preclinical studies, and observational studies. Here, we report the results of a randomised trial to assess whether lopinavir-ritonavir improves outcomes in patients admitted to hospital with COVID-19.MethodsIn this randomised, controlled, open-label, platform trial, a range of possible treatments was compared with usual care in patients admitted to hospital with COVID-19. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients were randomly allocated to either usual standard of care alone or usual standard of care plus lopinavir-ritonavir (400 mg and 100 mg, respectively) by mouth for 10 days or until discharge (or one of the other RECOVERY treatment groups: hydroxychloroquine, dexamethasone, or azithromycin) using web-based simple (unstratified) randomisation with allocation concealment. Randomisation to usual care was twice that of any of the active treatment groups (eg, 2:1 in favour of usual care if the patient was eligible for only one active group, 2:1:1 if the patient was eligible for two active groups). The primary outcome was 28-day all-cause mortality. Analyses were done on an intention-to-treat basis in all randomly assigned participants. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.FindingsBetween March 19, 2020, and June 29, 2020, 1616 patients were randomly allocated to receive lopinavir-ritonavir and 3424 patients to receive usual care. Overall, 374 (23%) patients allocated to lopinavir-ritonavir and 767 (22%) patients allocated to usual care died within 28 days (rate ratio 1·03, 95% CI 0·91-1·17; p=0·60). Results were consistent across all prespecified subgroups of patients. We observed no significant difference in time until discharge alive from hospital (median 11 days [IQR 5 to >28] in both groups) or the proportion of patients discharged from hospital alive within 28 days (rate ratio 0·98, 95% CI 0·91-1·05; p=0·53). Among patients not on invasive mechanical ventilation at baseline, there was no significant difference in the proportion who met the composite endpoint of invasive mechanical ventilation or death (risk ratio 1·09, 95% CI 0·99-1·20; p=0·092).InterpretationIn patients admitted to hospital with COVID-19, lopinavir-ritonavir was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death. These findings do not support the use of lopinavir-ritonavir for treatment of patients admitted to hospital with COVID-19.FundingMedical Research Council and National Institute for Health Research.

Project description:BackgroundThe outbreak of COVID-19 (caused by SARS-Cov-2) is very serious, and no effective antiviral treatment has yet been confirmed. The adage "old drug, new trick" in this context may suggest the important therapeutic potential of existing drugs. We found that the lopinavir/ritonavir treatment recommended in the fifth edition of the Treatment Plan of China can only help to improve a minority of throat-swab nucleic-acid results (3/15) in hospitals. Our previous use of chloroquine to treat patients with COVID-19 infection showed an improvement in more throat-swab nucleic-acid results (5/10) than the use of lopinavir/ritonavir.Methods/designThis is a prospective, open-label, randomized controlled, multicenter clinical study. The study consists of three phases: a screening period, a treatment period of no more than 10 days, and a follow-up period for each participant. Participants with COVID-19 infection who are eligible for selection for the study will be randomly allocated to the trial group or the control group. The control group will be given lopinavir/ritonavir treatment for no more than 10 days. The trial group will be given chloroquine phosphate treatment for no more than 10 days. The primary outcome is the clinical recovery time at no more than 28 days after the completion of therapy and follow-up. The secondary outcomes include the rate of treatment success after the completion of therapy and follow-up, the time of treatment success after no more than 28 days, the rate of serious adverse events during the completion of therapy and follow-up, and the time to return to normal temperature (calculated from the onset of illness) during the completion of therapy and follow-up. Comparisons will be performed using two-sided tests with a statistical significance level of 5%.DiscussionThis experiment should reveal the efficacy and safety of using chloroquine versus lopinavir/ritonavir for patients with mild/general COVID-19 infection. If the new treatment including chloroquine shows a higher rate of throat-swab SARS-CoV-2 real-time fluorescent reverse transcription polymerase chain reaction (RT-PCR) negativity and is safe, it could be tested as a future COVID-19 treatment.Trial registrationChinese Clinical Trial Registry, ID: ChiCTR2000029741 . Registered on 11 February 2020.

Project description:BackgroundSince the beginning of the COVID-19 pandemic, no direct antiviral treatment is effective as post-exposure prophylaxis (PEP). Lopinavir/ritonavir (LPV/r) was repurposed as a potential PEP agent against COVID-19.MethodsWe conducted a pragmatic open-label, parallel, cluster-randomised superiority trial in four sites in Switzerland and Brazil between March 2020 to March 2021. Clusters were randomised to receive LPV/r PEP (400/100 mg) twice daily for 5 days or no PEP (surveillance). Exposure to SARS-CoV-2 was defined as a close contact of >15 minutes in <2 metres distance or having shared a closed space for ≥2 hours with a person with confirmed SARS-CoV-2 infection. The primary outcome is the occurrence of COVID-19 defined by a SARS-CoV-2 infection (positive oropharyngeal SARS-CoV-2 PCR and/or a seroconversion) and ≥1 compatible symptom within 21 days post-enrolment. ClinicalTrials.gov (Identifier: NCT04364022); Swiss National Clinical Trial Portal: SNCTP 000003732.FindingsOf 318 participants, 157 (49.4%) were women; median age was 39 (interquartile range, 28-50) years. A total of 209 (179 clusters) participants were randomised to LPV/r PEP and 109 (95 clusters) to surveillance. Baseline characteristics were similar, with the exception of baseline SARS-CoV-2 PCR positivity, which was 3-fold more frequent in the LPV/r arm (34/209 [16.3%] vs 6/109 [5.5%], respectively). During 21-day follow-up, 48/318 (15.1%) participants developed COVID-19: 35/209 (16.7%) in the LPV/r group and 13/109 (11.9%) in the surveillance group (unadjusted hazard ratio 1.44; 95% CI, 0.76-2.73). In the primary endpoint analysis, which was adjuted for baseline imbalance, the hazard ratio for developing COVID-19 in the LPV/r group vs surveillance was 0.60 (95% CI, 0.29-1.26; p =0.18).InterpretationThe role of LPV/r as PEP for COVID-19 remains unanswered. Although LPV/r over 5 days did not significantly reduce the incidence of COVID-19 in exposed individuals, we observed a change in the directionality of the effect in favour of LPV/r after adjusting for baseline imbalance. LPV/r for this indication merits further testing against SARS-CoV-2 in clinical trials.FundingSwiss National Science Foundation (project no.: 33IC30_166819) and the Private Foundation of Geneva University Hospitals (Edmond Rothschild (Suisse) SA, Union Bancaire Privée and the Fondation pour la recherche et le traitement médical).

Project description:BackgroundNevirapine-based antiretroviral therapy is the predominant (and often the only) regimen available for children in resource-limited settings. Nevirapine resistance after exposure to the drug for prevention of maternal-to-child human immunodeficiency virus (HIV) transmission is common, a problem that has led to the recommendation of ritonavir-boosted lopinavir in such settings. Regardless of whether there has been prior exposure to nevirapine, the performance of nevirapine versus ritonavir-boosted lopinavir in young children has not been rigorously established.MethodsIn a randomized trial conducted in six African countries and India, we compared the initiation of HIV treatment with zidovudine, lamivudine, and either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 2 to 36 months of age who had no prior exposure to nevirapine. The primary end point was virologic failure or discontinuation of treatment by study week 24.ResultsA total of 288 children were enrolled; the median percentage of CD4+ T cells was 15%, and the median plasma HIV type 1 (HIV-1) RNA level was 5.7 log(10) copies per milliliter. The percentage of children who reached the primary end point was significantly higher in the nevirapine group than in the ritonavir-boosted lopinavir group (40.8% vs. 19.3%; P<0.001). Among the nevirapine-treated children with virologic failure for whom data on resistance were available, more than half (19 of 32) had resistance at the time of virologic failure. In addition, the time to a protocol-defined toxicity end point was shorter in the nevirapine group (P=0.04), as was the time to death (P=0.06).ConclusionsOutcomes were superior with ritonavir-boosted lopinavir among young children with no prior exposure to nevirapine. Factors that may have contributed to the suboptimal results with nevirapine include elevated viral load at baseline, selection for nevirapine resistance, background regimen of nucleoside reverse-transcriptase inhibitors, and the standard ramp-up dosing strategy. The results of this trial present policymakers with difficult choices. (Funded by the National Institute of Allergy and Infectious Diseases and others; P1060 ClinicalTrials.gov number, NCT00307151.).

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.).

Dataset Information

Camostat Mesylate Versus Lopinavir/Ritonavir in Hospitalized Patients With COVID-19-Results From a Randomized, Controlled, Open Label, Platform Trial (ACOVACT).

Publications

Camostat Mesylate Versus Lopinavir/Ritonavir in Hospitalized Patients With COVID-19-Results From a Randomized, Controlled, Open Label, Platform Trial (ACOVACT).

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets