Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, phase 3 trial.
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SUBMITTER: Kalil AC
PROVIDER: S-EPMC8523116 | biostudies-literature | 2021 Dec
REPOSITORIES: biostudies-literature
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Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, phase 3 trial.
Kalil Andre C AC Mehta Aneesh K AK Patterson Thomas F TF Erdmann Nathaniel N Gomez Carlos A CA Jain Mamta K MK Wolfe Cameron R CR Ruiz-Palacios Guillermo M GM Kline Susan S Regalado Pineda Justino J Luetkemeyer Anne F AF Harkins Michelle S MS Jackson Patrick E H PEH Iovine Nicole M NM Tapson Victor F VF Oh Myoung-Don MD Whitaker Jennifer A JA Mularski Richard A RA Paules Catharine I CI Ince Dilek D Takasaki Jin J Sweeney Daniel A DA Sandkovsky Uriel U Wyles David L DL Hohmann Elizabeth E Grimes Kevin A KA Grossberg Robert R Laguio-Vila Maryrose M Lambert Allison A AA Lopez de Castilla Diego D Kim EuSuk E Larson LuAnn L Wan Claire R CR Traenkner Jessica J JJ Ponce Philip O PO Patterson Jan E JE Goepfert Paul A PA Sofarelli Theresa A TA Mocherla Satish S Ko Emily R ER Ponce de Leon Alfredo A Doernberg Sarah B SB Atmar Robert L RL Maves Ryan C RC Dangond Fernando F Ferreira Jennifer J Green Michelle M Makowski Mat M Bonnett Tyler T Beresnev Tatiana T Ghazaryan Varduhi V Dempsey Walla W Nayak Seema U SU Dodd Lori L Tomashek Kay M KM Beigel John H JH
The Lancet. Respiratory medicine 20211018 12
<h4>Background</h4>Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19.<h4>Methods</h4>We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligib ...[more]
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Project description:BackgroundSARS-CoV-2 infections still have a significant impact on the global population. The existing vaccinations have contributed to reducing the severe disease courses, decreasing hospitalisations, and lowering the mortality rate. However, due to the variability of COVID-19 symptoms, the emergence of new variants and the uneven global distribution of vaccines there is still a great need for new therapy options. One promising approach is provided by host-directed therapies. We assessed here the efficacy and safety of MP1032, a host-directed anti-viral/anti-inflammatory drug in hospitalised patients with moderate to severe COVID-19.MethodsIn a randomised, double-blind, placebo-controlled, Phase IIa study, patients were randomised 2:1 to receive either 300 mg MP032 bid + Standard-of-Care (SoC) or placebo bid + SoC for 28 days. Eligible patients were ≥18 years old, tested positive for SARS-CoV-2, and had moderate to severe COVID-19 symptoms. The study spanned 20 sites in six countries (Bulgaria, France, Hungary, Italy, Romania, Spain), assessing disease progression according the NIAID scale as the primary outcome on day 14. Secondary objectives included disease progression (day 28), disease resolution (days 14 and 28), mortality rate, COVID-19 related parameters and safety. Exposure-response analyses were performed, linking MP1032 to COVID-19 biomarkers (eGFR, D-dimer).Findings132 patients were enrolled to receive MP1032 + SoC (n = 87) or placebo + SoC (n = 45). The patients were all white or Caucasian with a mean (median) age of 60.5 (63) years. Overall, only 10 patients were vaccinated, 5 in each group. No significant risk difference of disease progression could be detected between groups on both day 14 (9.8% MP1032 vs. 11.6% placebo) and day 28 with MH common risk differences of -0.276% (95% CI, -11.634 to 11.081; p = 0.962) and 1.722% (95% CI, -4.576 to 8.019; p = 0.592), respectively.The treatment with MP1032 + SoC was safe and well-tolerated. Overall, 182 TEAEs including 10 SAEs were reported in 53.5% (46/86) of patients of the verum group and in 57.8% (26/45) of patients of the placebo group; the SAEs occurred in 5.8% (5/86) and 6.7% (3/45) of verum and placebo patients, respectively. None of the SAEs was considered as related.InterpretationDespite the study's limitation in size and the variation in concurrent SoCs, these findings warrant further investigation of MP1032 as a host-directed anti-viral drug candidate.FundingThe study was funded by the COVID-19 Horizon Europe work programme and MetrioPharm AG.
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Project description:ObjectiveTo describe detailed MRI results from 2 head-to-head phase III trials, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis Study I (CARE-MS I; NCT00530348) and Study II (CARE-MS II; NCT00548405), of alemtuzumab vs subcutaneous interferon β-1a (SC IFN-β-1a) in patients with active relapsing-remitting multiple sclerosis (RRMS).MethodsThe impact of alemtuzumab 12 mg vs SC IFN-β-1a 44 μg on MRI measures was evaluated in patients with RRMS who were treatment-naive (CARE-MS I) or who had an inadequate response, defined as at least one relapse, to prior therapy (CARE-MS II).ResultsBoth treatments prevented T2-hyperintense lesion volume increases from baseline. Alemtuzumab was more effective than SC IFN-β-1a on most lesion-based endpoints in both studies (p < 0.05), including decreased risk of new/enlarging T2 lesions over 2 years and gadolinium-enhancing lesions at year 2. Reduced risk of new T1 lesions (p < 0.0001) and gadolinium-enhancing lesion conversion to T1-hypointense black holes (p = 0.0078) were observed with alemtuzumab vs SC IFN-β-1a in CARE-MS II. Alemtuzumab slowed brain volume loss over 2 years in CARE-MS I (p < 0.0001) and II (p = 0.012) vs SC IFN-β-1a.ConclusionsAlemtuzumab demonstrated greater efficacy than SC IFN-β-1a on MRI endpoints in active RRMS. The superiority of alemtuzumab was more prominent during the second year of both studies. These findings complement the superior clinical efficacy of alemtuzumab over SC IFN-β-1a in RRMS.Clinicaltrialsgov identifierNCT00530348 and NCT00548405.Classification of evidenceThe results reported here provide Class I evidence that, for patients with active RRMS, alemtuzumab is superior to SC IFN-β-1a on multiple MRI endpoints.
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Project description: Not available
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Project description:Metformin is currently the first drug of choice for treatment of type II diabetes. The primary function of metformin is to decrease hepatic glucose production mainly by inhibiting gluconeogenesis. The aim of the present study was to investigate the effects of glucose alone (control groups) and glucose and metformin (treatment groups) on pancreatic islets functions. Pancreatic islets were isolated by collagenase digestion and incubated for 24 or 48 h in RPMI-1640 containing 5 mmol/l glucose (control groups 1 and 2, respectively) or 24 h with 25 mmol/l glucose (control group 3) and 15 µmol/l metformin (treatment groups 1, 2 and 3, corresponding to the control groups, respectively). Subsequently, the rate of insulin output from islets, pancreatic and duodenal homeobox 1 (Pdx-1) and insulin genes expression and islet viability were assayed. The rate of insulin secretion in a 5 mmol/l glucose concentration in the 48 h treatment group increased significantly compared with that of the 24 h treatment group (P<0.05). An increase of the glucose concentration (25 mmol/l) caused insulin secretion to increase compared with that of 5 mmol/l glucose. Pdx-1 gene expression in treatment group 2 significantly decreased compared with the control group 2 (P<0.05). The the Pdx-1 gene expression in treatment group 2 decreased compared with that of the treatment group 1. The expression of the insulin gene in treatment group 1 increased compared with control group 1, and in treatment group 2, there was a 2-fold increase in insulin gene expression compared with control group 2. The insulin gene expression in treatment group 2 increased compared with treatment group 1. The percentage of islet cell viability was increased in treatment group 3 by ~40% compared with the islet cells of treatment groups 1 and 2 (P<0/05). These data indicate that glucose and metformin have direct effects on β-cell function.
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Project description:PurposeVandetanib is an oral once-daily tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 and epidermal growth factor receptor. Vandetanib in combination with docetaxel was assessed in patients with advanced urothelial cancer (UC) who progressed on prior platinum-based chemotherapy.Patients and methodsThe primary objective was to determine whether vandetanib 100 mg plus docetaxel 75 mg/m(2) intravenously every 21 days prolonged progression-free survival (PFS) versus placebo plus docetaxel. The study was designed to detect a 60% improvement in median PFS with 80% power and one-sided α at 5%. Patients receiving docetaxel plus placebo had the option to cross over to single-agent vandetanib at progression. Overall survival (OS), overall response rate (ORR), and safety were secondary objectives.ResultsIn all, 142 patients were randomly assigned and received at least one dose of therapy. Median PFS was 2.56 months for the docetaxel plus vandetanib arm versus 1.58 months for the docetaxel plus placebo arm, and the hazard ratio for PFS was 1.02 (95% CI, 0.69 to 1.49; P = .9). ORR and OS were not different between both arms. Grade 3 or higher toxicities were more commonly seen in the docetaxel plus vandetanib arm and included rash/photosensitivity (11% v 0%) and diarrhea (7% v 0%). Among 37 patients who crossed over to single-agent vandetanib, ORR was 3% and OS was 5.2 months.ConclusionIn this platinum-pretreated population of advanced UC, the addition of vandetanib to docetaxel did not result in a significant improvement in PFS, ORR, or OS. The toxicity of vandetanib plus docetaxel was greater than that for vendetanib plus placebo. Single-agent vandetanib activity was minimal.
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