Safety and efficacy of sirolimus in hospitalised patients with COVID-19 pneumonia.

BACKGROUND: There is a critical need to develop novel therapies for COVID-19. METHODS: We conducted a phase 2, multicentre, placebo-controlled, double-blind, randomised trial; hospitalised patients with hypoxemic respiratory failure due to COVID-19 and at least one poor prognostic biomarker, were given sirolimus (6 mg on Day 1 followed by 2 mg daily for 14 days or hospital discharge, whichever happens first) or placebo, in a 2:1 randomization scheme favouring sirolimus. Primary outcome was the proportion of patients alive and free from advanced respiratory support measures at Day 28. RESULTS: Between April 2020 and April 2021, 32 patients underwent randomization and 28 received either sirolimus (n = 18) or placebo (n = 10). Mean age was 57 years and 75 % of the subjects were men. Twenty-two subjects had at least one co-existing condition (Diabetes, hypertension, obesity, CHF, or asthma/COPD) associated with worse prognosis. Mean FiO2 requirement was 0.35. There was no difference in the proportion of patients who were alive and free from advanced respiratory support measures in the sirolimus group (n = 15, 83 %) compared with the placebo group (n = 8, 80 %). Although patients in the sirolimus group demonstrated faster improvement in oxygenation and spent less time in the hospital, these differences were not statistically significant. There was no between-group difference in the rate of change in serum biomarkers such as LDH, ferritin, d-dimer or lymphocyte count. There was a decreased risk of thromboembolic complications in patients on sirolimus compared with placebo. CONCLUSIONS: Larger studies are warranted to evaluate the role sirolimus in COVID-19 infection.

Safety and Efficacy of Combined Resveratrol and Sirolimus in Lymphangioleiomyomatosis.

BACKGROUND: A critical need exists to develop remission-inducing therapies for lymphangioleiomyomatosis. RESEARCH QUESTION: Is the addition of resveratrol safe and more efficacious than sirolimus alone in patients with lymphangioleiomyomatosis? STUDY DESIGN AND METHODS: We conducted a phase 2, dose-escalating, open-label trial of resveratrol in patients with lymphangioleiomyomatosis receiving a stable regimen of sirolimus. Resveratrol was started at 250 mg/d and escalated every 8 weeks to maximum dose of 1,000 mg/d over 24 weeks. The primary outcome was ≥ 42% decline in serum vascular endothelial growth factor D (VEGF-D) levels on combined therapy compared with baseline VEGF-D levels on sirolimus. Secondary objectives included an assessment of the safety profile and the effect on lung function and health-related quality of life (HRQOL). Longitudinal change in outcome measures was assessed using linear mixed models. Adverse effects were tabulated using the National Cancer Institute's Common Terminology Criteria for Adverse Events version 4. RESULTS: Twenty-five patients with lymphangioleiomyomatosis with a median age of 51 years were enrolled. Pulmonary function parameters at study inclusion were: FEV1: median absolute, 1.72 L; 64% predicted; FVC: median absolute, 2.99 L; 96% predicted; and diffusing capacity of the lungs for carbon monoxide: median absolute, 14.68 mL/mm Hg/min; 37% predicted. The median serum VEGF-D value at baseline was 617 pg/mL. Patients entered the study with a median sirolimus dose of 2 mg/d with median trough level of 6.3 ng/mL. Despite some GI side effects, the addition of resveratrol was well tolerated. Although the primary outcome was not met, a statistically significant reduction in serum VEGF-D levels and improvement in HRQOL during the study was found. INTERPRETATION: The addition of resveratrol was safe and well tolerated in patients with lymphangioleiomyomatosis taking sirolimus and was associated with modest improvement in HRQOL. Larger controlled trials of this combination might be warranted to assess definitively the usefulness of resveratrol as an additive therapy in lymphangioleiomyomatosis. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03253913; URL: www. CLINICALTRIALS: gov.