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Drug Repurposing and Novel Antiviral Drugs for COVID-19 Management
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Shailendra Dwivedi, Aakanksha Rawat, Amit Ranjan, Ruchika Agrawal, Radhieka Misra, Sunil Kumar Gupta, Surekha Kishore, Sanjeev Misra
A randomized, double-blind, placebo-controlled phase II pilot trial of nebulized interferon beta-1a was conducted in 101 adults admitted to hospital with COVID-19. It was observed that patients receiving nebulized interferon beta-1a had significantly greater odds of clinical improvement than those who received placebo, both on day 15/16 (odds ratio [OR] 2.32 [95% CI 1·07–5·04]; P = 0·033) and on day 28 (3.15 [1.39–7.14]; P = 0·006). However, there was no significant difference between treatment groups in the odds of hospital discharge by day 28: 39 (81%) of 48 patients had been discharged in the nebulized interferon beta-1a group compared with 36 (75%) of 48 in the placebo group (OR 1·84 [95% CI 0·64–5.29]; P = 0.26) [31].
Benefit–Risk Assessment via Case Studies
Published in Qi Jiang, Weili He, Benefit-Risk Assessment Methods in Medical Product Development, 2017
Weili He, Qi Jiang, George Quartey
In study #2, all 1171 subjects enrolled had experienced one or more relapses while on treatment with interferon beta-1a (30 μg intramuscularly) once weekly during the year before study entry. The median age was 39 years, with a median disease duration of 7 years. Subjects were randomized to receive natalizumab (300 mg intravenous infusion) or placebo every 4 weeks for up to 28 months. Subjects continued taking interferon beta-1a at their normal dosing once weekly. Results showed that combination therapy resulted in a 24% reduction in the relative risk of sustained disability progression (hazard ratio, 0.76; 95% CI, 0.61 to 0.96; P = 0.02). Kaplan–Meier estimates of the cumulative probability of progression at 2 years were 23% with combination therapy and 29% with interferon beta-1a alone. Combination therapy was associated with a lower annualized rate of relapse over a 2-year period than was interferon beta-1a alone (0.34 vs. 0.75, P < 0.001) and with fewer new or enlarging lesions on T2-weighted MRI (0.9 vs. 5.4, P < 0.001). Adverse events associated with combination therapy were anxiety, pharyngitis, sinus congestion, and peripheral edema. Two cases of progressive multifocal leukoencephalopathy (PML), one of which was fatal, were diagnosed in natalizumab-treated patients (Rudick et al. 2006). For more details with regard to study design and methods, see Polman et al. (2006) and Rudick et al. (2006).
Antiviral treatment selection for SARS-CoV-2 pneumonia
Published in Expert Review of Respiratory Medicine, 2021
Matteo Bassetti, Silvia Corcione, Silvia Dettori, Andrea Lombardi, Tommaso Lupia, Antonio Vena, Francesco Giuseppe De Rosa, Andrea Gori, Daniele Roberto Giacobbe
Interferons have been proposed for the treatment of patients with COVID-19 based on their possible immunomodulatory effects and in vitro anti-SARS-CoV-2 activity [58]. In the WHO Solidarity trial, interferon beta-1a was administered subcutaneously in three doses of 44 μg over 6 days. The in-hospital mortality was 11.9% (243/2050) in the interferon beta-1a arm vs. 11.0% (216/2050) in the standard care arm, with a RR of 1.16 (95% CI 0.96 to 1.39) [40]. In the subgroup of patients not receiving mechanical ventilation at enrollment, progression to mechanical ventilation or death was similar in the two arms, with a RR of 0.99 (95% CI 0.80 to 1.24) [40]. On October 16, 2020, randomization to interferon beta-1a was ceased for futility [40]. On the other hand, some encouraging results were provided in a phase 2, double-blind RCT comparing nebulized interferon beta-1a (48 patients) vs. placebo (51 patients) for the treatment of hospitalized patients with COVID-19 [59]. The primary endpoint was a change in clinical conditions on the WHO Ordinal Scale for Clinical Improvement (OSCI) scale, with patients on the interferon beta-1a showing better improvement on the OSCI scale on day 15–16 than patients receiving placebo (odds ratio 2.32, with 95% CI from 1.07 to 5.04). No substantial differences were observed between arms in terms of tolerability, and deaths occurred in 0 and 3 patients in the interferon and placebo arms, respectively [59]. Larger RCTs remain necessary to confirm these preliminary positive findings.
Developing therapeutic strategies to promote myelin repair in multiple sclerosis
Published in Expert Review of Neurotherapeutics, 2019
Laura E. Baldassari, Jenny Feng, Benjamin L.L. Clayton, Se-Hong Oh, Ken Sakaie, Paul J. Tesar, Yanming Wang, Jeffrey A. Cohen
The phase IIb dose-finding SYNERGY trial evaluated the efficacy, safety, and tolerability of four doses of opicinumab versus placebo in RRMS or SPMS patients with evidence of inflammatory disease activity [62]. Patients also received interferon beta-1a throughout this 72-week study. The primary endpoint was the proportion of patients with three-month confirmed disability improvement, as determined by a composite of the EDSS, T25FW, 9-Hole Peg Test (9HPT), and Paced Auditory Serial Addition Test (PASAT). Improvement was defined as a ≥ 1.0-point decrease in EDSS (if baseline ≤6.0) and/or ≥15% improvement versus baseline in T25FW, 9HPT, or PASAT. Overall, 334 of the 418 randomized patients completed the study, and the primary endpoint as measured by a linear trend for a dose-response was negative [63,64]. However, there was evidence of an inverted U-shaped dose response, as only one of the opicinumab doses (30 mg/kg) demonstrated significant benefit versus placebo (odds ratio 2.06, 95% CI 1.11 to 3.84). Adverse events included dose-dependent hypersensitivity reactions and weight gain, with overall acceptable safety and tolerability [62].
Cost-utility analysis of alemtuzumab in comparison with interferon beta, fingolimod, and natalizumab treatment for relapsing-remitting multiple sclerosis in Austria
Published in Journal of Medical Economics, 2019
Evelyn Walter, Thomas Berger, Barbara Bajer-Kornek, Florian Deisenhammer
The present Markov model considered disability progression by means of 10 EDSS states. During each Markov model cycle, a patient remained in the current health state, progressed to a worse state, or improved to a better state (only possible in states 2–7). The CARE-MS trials have documented changes in EDSS score from baseline. In the untreated patient population, 11% of the interferon beta-1a-treated patients and 8% of alemtuzumab patients had SAD which did not differ between groups7, so disability accumulation did not differ in the short-term trial. In the pre-treated patient population, the rate of SAD with alemtuzumab was 13% vs 20% with interferon beta-1a. A sustainable reduction of EDSS was observed in 22% of alemtuzumab- and 9% of interferon beta-1a-treated patients8. Long-term disease progression was derived from the phase 2 CAMMS223 clinical trial which reports safety and efficacy up to 60 months from baseline15. The mean disability of alemtuzumab patients at month 60 had improved compared with baseline, whereas it had worsening effects in interferon beta-1a-treated patients15. Between month 36 and 60, the change in median disability did not differ between alemtuzumab- and interferon beta-1a-treated groups15.