Treatment of COVID-19-associated ARDS with umbilical cord-derived mesenchymal stromal cells in the STROMA-CoV-2 multicenter randomized double-blind trial: long-term safety, respiratory function, and quality of life.

BACKGROUND: The STROMA-CoV-2 study was a French phase 2b, multicenter, double-blind, randomized, placebo-controlled clinical trial that did not identify a significant efficacy of umbilical cord-derived mesenchymal stromal cells in patients with SARS-CoV-2-induced acute respiratory distress syndrome. Safety on day 28 was found to be good. The aim of our extended study was to assess the 6- and 12-month safety of UC-MSCs administration in the STROMA-CoV-2 cohort. METHODS: A detailed multi-domain assessment was conducted at 6 and 12 months following hospital discharge focusing on adverse events, lung computed tomography-scan, pulmonary and muscular functional status, and quality of life in the STROMA-CoV-2 cohort including SARS-CoV-2-related early (< 96 h) mild-to-severe acute respiratory distress syndrome. RESULTS: Between April 2020 and October 2020, 47 patients were enrolled, of whom 19 completed a 1-year follow-up. There were no significant differences in any endpoints or adverse effects between the UC-MSCs and placebo groups at the 6- and 12-month assessments. Ground-glass opacities persisted at 1 year in 5 patients (26.3%). Furthermore, diffusing capacity for carbon monoxide remained altered over 1 year, although no patient required oxygen or non-invasive ventilatory support. Quality of life revealed declines in mental, emotional and physical health throughout the follow-up period, and the six-minute walking distance remained slightly impaired at the 1-year patient assessment. CONCLUSIONS: This study suggests a favorable safety profile for the use of intravenous UC-MSCs in the context of the first French wave of SARS-CoV-2-related moderate-to-severe acute respiratory distress syndrome, with no adverse effects observed at 1 year.

FX06 to rescue SARS-CoV-2-induced acute respiratory distress syndrome: a randomized clinical trial.

BACKGROUND: Vascular leakage is a major feature of acute respiratory distress syndrome (ARDS). We aimed to evaluate the efficacy of FX06, a drug under development that stabilizes interendothelial cell junctions, at reducing vascular leakage during SARS-CoV-2-induced ARDS. METHODS: This multicenter, double-blinded, randomized trial included adults with COVID-19-associated ARDS who had received invasive mechanical ventilation for < 5 days and were randomized to receive either intravenous FX06 (400 mg/d, for 5 days) or its vehicle as placebo. The primary endpoint was the lowering-from day 1 to day 7-of the transpulmonary thermodilution-derived extravascular lung-water index (EVLWi). RESULTS: Twenty-five patients were randomized to receive FX06 and 24 the placebo. Although EVLWi was elevated at baseline (median [IQR] 15.6 mL/kg [13.5; 18.5]), its declines from day 1 to day 7 were comparable for FX06 recipients and controls (respectively, - 1.9 [- 3.3; - 0.5] vs. - 0.8 [- 5.5; - 1.1] mL/kg; estimated effect - 0.8 [- 3.1; + 2.4], p = 0.51). Cardiac indexes, pulmonary vascular permeability indexes, and fluid balances were also comparable, as were PaO2/FiO2 ratios and durations of mechanical ventilation. Adverse event rates were similar for the 2 groups, although more FX06 recipients developed ventilator-associated pneumonia (16/25 (64%) vs. 6/24 (24%), p = 0.009). CONCLUSIONS: In this unique-dosing-regimen study, FX06 did not lower SARS-CoV-2-induced pulmonary vascular leakage. Future investigations will need to evaluate its efficacy at earlier times during the disease or using other regimens. Trial registration NCT04618042. Registered 5 November 2020.

Treatment of COVID-19-associated ARDS with mesenchymal stromal cells: a multicenter randomized double-blind trial.

BACKGROUND: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced acute respiratory distress syndrome (ARDS) causes high mortality. Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) have potentially relevant immune-modulatory properties, whose place in ARDS treatment is not established. This phase 2b trial was undertaken to assess the efficacy of UC-MSCs in patients with SARS-CoV-2-induced ARDS. METHODS: This multicentre, double-blind, randomized, placebo-controlled trial (STROMA-CoV-2) recruited adults (≥ 18 years) with SARS-CoV-2-induced early (< 96 h) mild-to-severe ARDS in 10 French centres. Patients were randomly assigned to receive three intravenous infusions of 106 UC-MSCs/kg or placebo (0.9% NaCl) over 5 days after recruitment. For the modified intention-to-treat population, the primary endpoint was the partial pressure of oxygen to fractional inspired oxygen (PaO2/FiO2)-ratio change between baseline (day (D) 0) and D7. RESULTS: Among the 107 patients screened for eligibility from April 6, 2020, to October 29, 2020, 45 were enrolled, randomized and analyzed. PaO2/FiO2 changes between D0 and D7 did not differ significantly between the UC-MSCs and placebo groups (medians [IQR] 54.3 [- 15.5 to 93.3] vs 25.3 [- 33.3 to 104.6], respectively; ANCOVA estimated treatment effect 7.4, 95% CI - 44.7 to 59.7; P = 0.77). Six (28.6%) of the 21 UC-MSCs recipients and six of 24 (25%) placebo-group patients experienced serious adverse events, none of which were related to UC-MSCs treatment. CONCLUSIONS: D0-to-D7 PaO2/FiO2 changes for intravenous UC-MSCs-versus placebo-treated adults with SARS-CoV-2-induced ARDS did not differ significantly. Repeated UC-MSCs infusions were not associated with any serious adverse events during treatment or thereafter (until D28). Larger trials enrolling patients earlier during the course of their ARDS are needed to further assess UC-MSCs efficacy in this context. TRIAL REGISTRATION: NCT04333368. Registered 01 April 2020, https://clinicaltrials.gov/ct2/history/NCT04333368 .

Circulating Receptor Activator of Nuclear Factor kB Ligand and triglycerides are associated with progression of lower limb arterial calcification in type 2 diabetes: a prospective, observational cohort study.

BACKGROUND: Lower limb arterial calcification is a frequent, underestimated but serious complication of diabetes. The DIACART study is a prospective cohort study designed to evaluate the determinants of the progression of lower limb arterial calcification in 198 patients with type 2 diabetes. METHODS: Lower limb arterial calcification scores were determined by computed tomography at baseline and after a mean follow up of 31.20 ± 3.86 months. Serum RANKL (Receptor Activator of Nuclear factor kB Ligand) and bone remodeling, inflammatory and metabolic parameters were measured at baseline. The predictive effect of these markers on calcification progression was analyzed by a multivariate linear regression model. RESULTS: At baseline, mean ± SD and median lower limb arterial calcification scores were, 2364 ± 5613 and 527 respectively and at the end of the study, 3739 ± 6886 and 1355 respectively. Using multivariate analysis, the progression of lower limb arterial log calcification score was found to be associated with (ß coefficient [slope], 95% CI, p-value) baseline log(calcification score) (1.02, 1.00-1.04, p < 0.001), triglycerides (0.11, 0.03-0.20, p = 0.007), log(RANKL) (0.07, 0.02-0.11, p = 0.016), previous ischemic cardiomyopathy (0.36, 0.15-0.57, p = 0.001), statin use (0.39, 0.06-0.72, p = 0.023) and duration of follow up (0.04, 0.01-0.06, p = 0.004). CONCLUSION: In patients with type 2 diabetes, lower limb arterial calcification is frequent and can progress rapidly. Circulating RANKL and triglycerides are independently associated with this progression. These results open new therapeutic perspectives in peripheral diabetic calcifying arteriopathy. Trial registration NCT02431234.

A phase III double-blind placebo-controlled randomized study of dexamphetamine sulfate for fatigue in primary brain tumors patients: An ANOCEF trial (DXA).

BACKGROUND: Most patients suffering from a primary brain tumor (PBT) complain of chronic fatigue affecting their quality of life (QOL). We hypothesized that dexamphetamine sulfate, a psychostimulant drug, could improve fatigue in PBT patients. METHODS: A double-blind, phase III, multi-institutional, placebo-controlled randomized trial (1:1 allocation) assessed the efficacy and tolerability of dexamphetamine at a dosage of 30 mg/day in PBT patients with stable disease who complained of severe fatigue, defined as a Multidimensional Fatigue Inventory (MFI-20) score ≥60. The primary outcome was the variation of the MFI 20 score between inclusion and the evaluation at 3 months in nonprogressive patients. Mood, QOL and cognitive function were also evaluated. RESULTS: From April 2013 to November 2016, 46 patients were enrolled in the study, 41 of whom were evaluable for analysis (dexamphetamine group: 22; placebo group: 19). Tolerance was generally good, with no treatment-related deaths and no grade 4 toxicity. Patients in the dexamphetamine arm complained more frequently of psychiatric side effects (mostly hyperactivity, anxiety, sleep disorder, and irritability) than patients in the placebo arm (P = .018). There were no statistically significant differences at 3 months between the dexamphetamine and placebo arms in any of the outcomes (MFI-20, Norris Visual Analog Scale, Hospital Anxiety and Depression Scale (HADS), QOL (EORTC QLQ-C30/BN 20), Marin's Apathy Evaluation Scale, and cognitive evaluations). CONCLUSION: Dexamphetamine at a dosage of up to 30 mg/day for 3 months has acceptable tolerability in PBT patients but does not improve fatigue, cognitive function, or QOL.