Dataset Information

Cenicriviroc for the treatment of COVID-19: first interim results of a randomised, placebo-controlled, investigator-initiated, double-blind phase II trial.

ABSTRACT:

Objectives

C-C-chemokine receptors (CCRs) are expressed on a variety of immune cells and play an important role in many immune processes, particularly leukocyte migration. Comprehensive preclinical research demonstrated CCR2/CCR5-dependent pathways as pivotal for the pathophysiology of severe COVID-19. Here we report human data on use of a chemokine receptor inhibitor in patients with COVID-19.

Methods

Interim results of a 2:1 randomised, placebo-controlled, investigator-initiated trial on the CCR2/CCR5-inhibitor Cenicriviroc (CVC) 150 mg BID orally for 28 d in hospitalised patients with moderate to severe COVID-19 are reported. The primary endpoint is the subject's responder status defined by achieving grade 1 or 2 on the 7-point ordinal scale of clinical improvement on day 15.

Results

Of the 30 patients randomised, 18 were assigned to receive CVC and 12 to placebo. Efficient CCR2- and CCR5 inhibition was demonstrated through CCL2 and CCL4 elevation in CVC-treated patients (485% and 80% increase on day 3 compared to the baseline, respectively). In the modified intention-to-treat population, 82.4% of patients (14/17) in the CVC group met the primary endpoint, as did 91.7% (11/12) in the placebo group (OR = 0.5, 95% CI = 0.04-3.41). One patient treated with CVC died of progressive acute respiratory distress syndrome, and the remaining had a favourable outcome. Overall, treatment with CVC was well tolerated, with most adverse events being grade I or II and resolving spontaneously.

Conclusions

Our interim analysis provides proof-of-concept data on CVC for COVID-19 patients as an intervention to inhibit CCR2/CCR5. Further studies are warranted to assess its clinical efficacy.

SUBMITTER: Kurth F

PROVIDER: S-EPMC9780636 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cenicriviroc for the treatment of COVID-19: first interim results of a randomised, placebo-controlled, investigator-initiated, double-blind phase II trial.

Kurth Florian F Helbig Elisa T ET Lippert Lena J LJ Thibeault Charlotte C Barbone Gianluca G Eckart Marius A MA Kluge Martin M Puengel Tobias T Demir Münevver M Röhle Robert R Keller Theresa T Ruwwe-Glösenkamp Christoph C Witzenrath Martin M Suttorp Norbert N von Kalle Christof C Sander Leif E LE Jochum Christoph C Tacke Frank F

Journal of global antimicrobial resistance 20221223

<h4>Objectives</h4>C-C-chemokine receptors (CCRs) are expressed on a variety of immune cells and play an important role in many immune processes, particularly leukocyte migration. Comprehensive preclinical research demonstrated CCR2/CCR5-dependent pathways as pivotal for the pathophysiology of severe COVID-19. Here we report human data on use of a chemokine receptor inhibitor in patients with COVID-19.<h4>Methods</h4>Interim results of a 2:1 randomised, placebo-controlled, investigator-initiated ...[more]

PMID: 36572146

Similar Datasets

Project description:ObjectiveT cells play a key role in the pathogenesis of early systemic sclerosis. This study was undertaken to assess the safety and efficacy of abatacept in patients with diffuse cutaneous systemic sclerosis (dcSSc).MethodsIn this 12-month, randomized, double-blind, placebo-controlled trial, participants were randomized 1:1 to receive either subcutaneous abatacept 125 mg or matching placebo, stratified by duration of dcSSc. Escape therapy was allowed at 6 months for worsening disease. The coprimary end points were change in the modified Rodnan skin thickness score (MRSS) compared to baseline and safety over 12 months. Differences in longitudinal outcomes were assessed according to treatment using linear mixed models, with outcomes censored after initiation of escape therapy. Skin tissue obtained from participants at baseline was classified into intrinsic gene expression subsets.ResultsAmong 88 participants, the adjusted mean change in the MRSS at 12 months was -6.24 units for those receiving abatacept and -4.49 units for those receiving placebo, with an adjusted mean treatment difference of -1.75 units (P = 0.28). Outcomes for 2 secondary measures (Health Assessment Questionnaire disability index and a composite measure) were clinically and statistically significantly better with abatacept. The proportion of subjects in whom escape therapy was needed was higher in the placebo group relative to the abatacept group (36% versus 16%). In the inflammatory and normal-like skin gene expression subsets, decline in the MRSS over 12 months was clinically and significantly greater in the abatacept group versus the placebo group (P < 0.001 and P = 0.03, respectively). In the abatacept group, adverse events occurred in 35 participants versus 40 participants in the placebo group, including 2 deaths and 1 death, respectively.ConclusionIn this phase II trial, abatacept was well-tolerated, but change in the MRSS was not statistically significant. Secondary outcome measures, including gene expression subsets, showed evidence in support of abatacept. These data should be confirmed in a phase III trial.

Project description:BackgroundIn patients with COVID-19, granulocyte-macrophage colony stimulating factor (GM-CSF) might be a mediator of the hyperactive inflammatory response associated with respiratory failure and death. We aimed to evaluate whether mavrilimumab, a monoclonal antibody to the GM-CSF receptor, would improve outcomes in patients with COVID-19 pneumonia and systemic hyperinflammation.MethodsThis investigator-initiated, multicentre, double-blind, randomised trial was done at seven hospitals in the USA. Inclusion required hospitalisation, COVID-19 pneumonia, hypoxaemia, and a C-reactive protein concentration of more than 5 mg/dL. Patients were excluded if they required mechanical ventilation. Patients were randomly assigned (1:1) centrally, with stratification by hospital site, to receive mavrilimumab 6 mg/kg as a single intravenous infusion, or placebo. Participants and all clinical and research personnel were masked to treatment assignment. The primary endpoint was the proportion of patients alive and off supplemental oxygen therapy at day 14. The primary outcome and safety were analysed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT04399980, NCT04463004, and NCT04492514.FindingsBetween May 28 and Sept 15, 2020, 40 patients were enrolled and randomly assigned to mavrilimumab (n=21) or placebo (n=19). A trial of 60 patients was planned, but given slow enrolment, the study was stopped early to inform the natural history and potential treatment effect. At day 14, 12 (57%) patients in the mavrilimumab group were alive and off supplemental oxygen therapy compared with nine (47%) patients in the placebo group (odds ratio 1·48 [95% CI 0·43-5·16]; p=0·76). There were no treatment-related deaths, and adverse events were similar between groups.InterpretationThere was no significant difference in the proportion of patients alive and off oxygen therapy at day 14, although benefit or harm of mavrilimumab therapy in this patient population remains possible given the wide confidence intervals, and larger trials should be completed.FundingKiniksa Pharmaceuticals.

Project description:IntroductionCancer treatment with high-dose chemotherapy damages the mucosal barrier of the gastrointestinal (GI) tract and is associated with severe toxicity involving mucositis, severe inflammation and organ dysfunction. Currently, there is no effective prophylaxis against this. Glucagon-like peptide 1 (GLP-1), a well-known regulator of blood glucose, has been suggested in mouse studies to possess trophic effects on gut epithelial cells as well as anti-inflammatory properties. In line with this, endogenous GLP-1 levels have been shown to be inversely correlated with toxicities after haematopoietic stem cell transplantation (HSCT) and treatment with a GLP-1 receptor agonist (GLP-1RA) was shown to limit chemotherapy-induced mucositis in rodents. This present study investigates the effects of the GLP-1RA semaglutide on GI mucositis severity score in patients with lymphoma undergoing high-dose chemotherapy followed by autologous (auto) HSCT.Methods and analysisThis is a randomised, double-blind, placebo-controlled, two-centre investigator-initiated clinical study. Forty adult patients with malignant lymphoma referred for auto-HSCT will be randomised in a 1:1 manner to receive either semaglutide or placebo once-weekly for 8 weeks. This includes a run-in period of 3-4 weeks with semaglutide 0.25 mg prior to high-dose chemotherapy treatment followed by a period of 4-5 weeks with semaglutide 0.5 mg including the 1 week of high-dose chemotherapy treatment. Clinical assessment of endpoint measurements and safety will be performed weekly during treatment and in a follow-up period of 10 weeks. The primary endpoint is GI mucositis severity (mean severity grade (0-II) during week 1-4 after auto-HSCT). Secondary endpoints include C-reactive protein increment, quality of life and safety. Fever, bacteraemia, antibiotic use, weight loss, morphine consumption, duration of hospitalisation, use of parenteral nutrition, change in muscle mass and clinical and laboratory evidence of organ toxicities will also be assessed.Ethics and disseminationThe study complies with Danish and European Union legislation and is approved by the Danish Medicines Agency, the Danish National Medical Research Ethics Committee (EU CT #2022-502139-20-00) and the Danish Data Protection Agency. The study is monitored by the Capital Region of Denmark's good clinical practice unit. All results, positive, negative and inconclusive, will be disseminated at national and international scientific meetings and in peer-reviewed scientific journals.Trial registration numberNCT06449625.

Project description:BACKGROUND:Part of the pathophysiology in septic shock is a progressive activation of the endothelium and platelets leading to widespread microvascular injury with capillary leakage, microthrombi and consumption coagulopathy. Modulating the inflammatory response of endothelium and thrombocytes might attenuate this vicious cycle and improve outcome. METHOD:The CO-ILEPSS trial was a randomised, placebo-controlled, double-blind, pilot trial. Patients admitted to the intensive care unit with septic shock were randomised and allocated in a 2:1 ratio to active treatment with dual therapy of iloprost 1 ng/kg/min and eptifibatide 0.5 μg/kg/min for 48 h or placebo. The primary outcomes were changes in biomarkers reflecting endothelial activation and disruption, platelet consumption and fibrinolysis. We compared groups with mixed models, post hoc Wilcoxon signed-rank test and Mann-Whitney U test. RESULTS:We included 24 patients of which 18 (12 active, 6 placebo) completed the full 7-day trial period and were included in the per-protocol analyses of the primary outcomes. Direct comparison between groups showed no differences in the primary outcomes. Analyses of within-group delta values revealed that biomarkers of endothelial activation and disruption changed differently between groups with increasing levels of thrombomodulin (p = 0.03) and nucleosomes (p = 0.02) in the placebo group and decreasing levels of sE-Selectin (p = 0.007) and sVEGFR1 (p = 0.005) in the active treatment group. Platelet count decreased the first 48 h in the placebo group (p = 0.049) and increased from baseline to day 7 in the active treatment group (p = 0.023). Levels of fibrin monomers declined in the active treatment group within the first 48 h (p = 0.048) and onwards (p = 0.03). Furthermore, there was a significant reduction in SOFA score from 48 h (p = 0.024) and onwards in the active treatment group. Intention-to-treat analyses of all included patients showed no differences in serious adverse events including bleeding, use of blood products or mortality. CONCLUSION:Our results could indicate benefit from the experimental treatment with reduced endothelial injury, reduced platelet consumption and ensuing reduction in fibrinolytic biomarkers along with improved SOFA score. The results of the CO-ILEPSS trial are exploratory and hypothesis generating and warrant further investigation in a large-scale trial. TRIAL REGISTRATION:Clinicaltrials.com, NCT02204852 (July 30, 2014); EudraCT no. 2014-002440-41.

Dataset Information

Cenicriviroc for the treatment of COVID-19: first interim results of a randomised, placebo-controlled, investigator-initiated, double-blind phase II trial.

Objectives

Methods

Results

Conclusions

Publications

Cenicriviroc for the treatment of COVID-19: first interim results of a randomised, placebo-controlled, investigator-initiated, double-blind phase II trial.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets