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Efficacy and Safety of Sarilumab in patients with COVID19 Pneumonia: A Randomized, Phase III Clinical Trial (SARTRE Study).

ABSTRACT: SARS-CoV-2 pneumonia is often associated with hyper-inflammation. The cytokine-storm-like is one of the targets of current therapies for coronavirus disease 2019 (COVID-19). High Interleukin-6 (IL6) blood levels have been identified in severe COVID-19 disease, but there are still uncertainties regarding the actual role of anti-IL6 antagonists in COVID-19 management. Our hypothesis was that the use of sarilumab plus corticosteroids at an early stage of the hyper-inflammatory syndrome would be beneficial and prevent progression to acute respiratory distress syndrome (ARDS). We randomly assigned (in a 1:1 ratio) COVID-19 pneumonia hospitalized patients under standard oxygen therapy and laboratory evidence of hyper-inflammation to receive sarilumab plus usual care (experimental group) or usual care alone (control group). Corticosteroids were given to all patients at a 1 mg/kg/day of methylprednisolone for at least 3 days. The primary outcome was the proportion of patients progressing to severe respiratory failure (defined as a score in the Brescia-COVID19 scale ≥ 3) up to day 15. A total of 201 patients underwent randomization: 99 patients in the sarilumab group and 102 patients in the control group. The rate of patients progressing to severe respiratory failure (Brescia-COVID scale score ≥ 3) up to day 15 was 16.16% in the Sarilumab group versus 15.69% in the control group (RR 1.03; 95% CI 0.48-2.20). No relevant safety issues were identified. In hospitalized patients with Covid-19 pneumonia, who were under standard oxygen therapy and who presented analytical inflammatory parameters, an early therapeutic intervention with sarilumab plus standard of care (including corticosteroids) was not shown to be more effective than current standard of care alone. The study was registered at EudraCT with number: 2020-002037-15.

SUBMITTER: Sancho-Lopez A

PROVIDER: S-EPMC8520759 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Efficacy and Safety of Sarilumab in patients with COVID19 Pneumonia: A Randomized, Phase III Clinical Trial (SARTRE Study).

Sancho-López Aránzazu A Caballero-Bermejo Antonio F AF Ruiz-Antorán Belén B Múñez Rubio Elena E García Gasalla Mercedes M Buades Juan J González Rozas Marta M López Veloso María M Muñoz Gómez Ana A Cuenca Abarca Ana A Durán Del Campo Pedro P Ibáñez Fátima F Díaz de Santiago Alberto A Romero Yolanda Y Calderón Jorge J Pintos Ilduara I Ferre Beltrán Adrián A Centeno Soto Gustavo G Campos José J Ramos Martínez Antonio A Avendaño-Solá Cristina C Fernández Cruz Ana A

Infectious diseases and therapy 20211017 4

<h4>Introduction</h4>SARS-CoV-2 pneumonia is often associated with hyper-inflammation. The cytokine-storm-like is one of the targets of current therapies for coronavirus disease 2019 (COVID-19). High Interleukin-6 (IL6) blood levels have been identified in severe COVID-19 disease, but there are still uncertainties regarding the actual role of anti-IL6 antagonists in COVID-19 management. Our hypothesis was that the use of sarilumab plus corticosteroids at an early stage of the hyper-inflammatory ...[more]

PMID: 34658006

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Project description:IntroductionSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), is an enveloped, single-stranded RNA virus. Favipiravir is an orally administrable antiviral drug whose mechanism of action is to selectively inhibit RNA-dependent RNA polymerase. A preliminary trial in COVID-19 patients reported significant improvements across a multitude of clinical parameters, but these findings have not been confirmed in an adequate well-controlled trial. We conducted a randomized, single-blind, placebo-controlled Phase III trial assessing the efficacy and safety of favipiravir in patients with moderate pneumonia not requiring oxygen therapy.MethodsCOVID-19 patients with moderate pneumonia (SpO2 ≥ 94%) within 10 days of onset of fever (temperature ≥ 37.5 °C) were assigned to receive either placebo or favipiravir (1800 mg twice a day on Day 1, followed by 800 mg twice a day for up to 13 days) in a ratio of 1:2. An adaptive design was used to re-estimate the sample size. The primary endpoint was a composite outcome defined as the time to improvement in temperature, oxygen saturation levels (SpO2), and findings on chest imaging, and recovery to SARS-CoV-2-negative. This endpoint was re-examined by the Central Committee under blinded conditions.ResultsA total of 156 patients were randomized. The median time of the primary endpoint was 11.9 days in the favipiravir group and 14.7 days in the placebo group, with a significant difference (p = 0.0136). Favipiravir-treated patients with known risk factors such as obesity or coexisting conditions provided better effects. Furthermore, patients with early-onset in the favipiravir group showed higher odds ratio. No deaths were documented. Although adverse events in the favipiravir group were predominantly transient, the incidence was significantly higher.ConclusionsThe results suggested favipiravir may be one of options for moderate COVID-19 pneumonia treatment. However, the risk of adverse events, including hyperuricemia, should be carefully considered.Trial registrationClinicaltrials.jp number: JapicCTI-205238.

Project description:BackgroundOral finasteride is a well-established treatment for men with androgenetic alopecia (AGA), but long-term therapy is not always acceptable to patients. A topical finasteride formulation has been developed to minimize systemic exposure by acting specifically on hair follicles.ObjectivesTo evaluate the efficacy and safety of topical finasteride compared with placebo, and to analyse systemic exposure and overall benefit compared with oral finasteride.MethodsThis randomized, double-blind, double dummy, parallel-group, 24-week study was conducted in adult male outpatients with AGA at 45 sites in Europe. Efficacy and safety were evaluated. Finasteride, testosterone and dihydrotestosterone (DHT) concentrations were measured.ResultsOf 458 randomized patients, 323 completed the study and 446 were evaluated for safety. Change from baseline in target area hair count (TAHC) at week 24 (primary efficacy endpoint) was significantly greater with topical finasteride than placebo (adjusted mean change 20.2 vs. 6.7 hairs; P < 0.001), and numerically similar between topical and oral finasteride. Statistically significant differences favouring topical finasteride over placebo were observed for change from baseline in TAHC at week 12 and investigator-assessed change from baseline in patient hair growth/loss at week 24. Incidence and type of adverse events, and cause of discontinuation, did not differ meaningfully between topical finasteride and placebo. No serious adverse events were treatment related. As maximum plasma finasteride concentrations were >100 times lower, and reduction from baseline in mean serum DHT concentration was lower (34.5 vs. 55.6%), with topical vs. oral finasteride, there is less likelihood of systemic adverse reactions of a sexual nature related to a decrease in DHT with topical finasteride.ConclusionTopical finasteride significantly improves hair count compared to placebo and is well tolerated. Its effect is similar to that of oral finasteride, but with markedly lower systemic exposure and less impact on serum DHT concentrations.

Project description:Importance and objectiveThe aim of this pragmatic, embedded, adaptive trial was to measure the effectiveness of the subcutaneous anti-IL-6R antibody sarilumab, when added to an evolving standard of care (SOC), for clinical management of inpatients with moderate to severe COVID-19 disease.DesignTwo-arm, randomized, open-label controlled trial comparing SOC alone to SOC plus sarilumab. The trial used a randomized play-the-winner design and was fully embedded within the electronic health record (EHR) system.Setting5 VA Medical Centers.ParticipantsHospitalized patients with clinical criteria for moderate to severe COVID-19 but not requiring mechanical ventilation, and a diagnostic test positive for SARS-CoV-2.InterventionsSarilumab, 200 or 400 mg subcutaneous injection. SOC was not pre-specified and could vary over time, e.g., to include antiviral or other anti-inflammatory drugs.Main outcomes and measuresThe primary outcome was intubation or death within 14 days of randomization. All data were extracted remotely from the EHR.ResultsAmong 162 eligible patients, 53 consented, and 50 were evaluated for the primary endpoint of intubation or death. This occurred in 5/20 and 1/30 of participants in the sarilumab and SOC arms respectively, with the majority occurring in the initial 9 participants (3/4 in the sarilumab and 1/5 in the SOC) before the sarilumab dose was increased to 400 mg and before remdesivir and dexamethasone were widely adopted. After interim review, the unblinded Data Monitoring Committee recommended that the study be stopped due to concern for safety: a high probability that rates of intubation or death were higher with addition of sarilumab to SOC (92.6%), and a very low probability (3.4%) that sarilumab would be found to be superior.Conclusions and relevanceThis randomized trial of patients hospitalized due to respiratory compromise from COVID-19 but not mechanical ventilation found no benefit from subcutaneous sarilumab when added to an evolving SOC. The numbers of patients and events were too low to allow definitive conclusions to be drawn, but this study contributes valuable information about the role of subcutaneous IL-6R inhibition in the treatment of hospitalized COVID-19 patients. Methods developed and piloted during this trial will be useful in conducting future studies more efficiently.Trial registrationClinicaltrials.gov-NCT04359901; https://clinicaltrials.gov/ct2/show/NCT04359901?cond=NCT04359901&draw=2&rank=1.

Project description:ObjectiveTo prospectively assess the efficacy, general safety, and joint safety of fasinumab, an anti-nerve growth factor monoclonal antibody, in osteoarthritis (OA) hip and/or knee pain.MethodsPatients with moderate-to-severe OA pain (knee or hip) and history of inadequate response or intolerance to analgesics were randomized to receive fasinumab (at 1 mg, 3 mg, 6 mg, or 9 mg) or placebo every 4 weeks over 16 weeks and were followed up to week 36. Efficacy end points were the change from baseline to week 16 in the pain and physical function subscale scores of the Western Ontario and McMaster Universities OA Index (WOMAC), and patient global assessment (PGA) of OA. Joints were monitored at scheduled assessments (by plain film radiography and magnetic resonance imaging) during treatment and follow-up, and if prompted, at the time of active joint symptoms.ResultsOf the 421 patients randomized, 342 completed the 36-week study. All doses of fasinumab yielded statistically significant and clinically important reductions in pain compared to placebo (least squares mean difference in WOMAC pain subscale scores at week 16 ranging -0.78 to -1.40), without any clear dose dependence. Physical function and PGA scores improved in parallel. Treatment-emergent adverse event rates were 17% with fasinumab and 10% with placebo, and 4% and 1% of patients, respectively, discontinued treatment. Arthropathies (25 in total, 7% of fasinumab-treated patients and 1% of placebo-treated patients) occurred in a dose-dependent manner, with 2 occurring in patients receiving the lowest dose of fasinumab and 10 in patients receiving the highest dose. Most of the arthropathies (16 of 25) were discovered with scheduled radiographs and not based on symptoms. Destructive arthropathy (in 1 of 337 treated patients) occurred in 1 patient who was receiving 6 mg fasimumab.ConclusionFasinumab provided improvements in OA pain and function, even in those benefitting little from previous analgesics. The observed benefit-to-risk relationship favors further clinical development to explore the lowest doses of fasinumab in patients with knee or hip OA.

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Efficacy and Safety of Sarilumab in patients with COVID19 Pneumonia: A Randomized, Phase III Clinical Trial (SARTRE Study).

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Efficacy and Safety of Sarilumab in patients with COVID19 Pneumonia: A Randomized, Phase III Clinical Trial (SARTRE Study).

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