Adverse events and blinding in two randomized trials of hyperbaric oxygen for persistent post-concussive symptoms

2019 ◽  
pp. 331-340
Author(s):  
Susan Churchill ◽  
◽  
Kayla Deru ◽  
Lindell K. Weaver ◽  
Steffanie H. Wilson ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Hyperbaric Oxygen ◽  
Gas Flow ◽  
Randomized Trials ◽  
Symptom Improvement ◽  
Sham Control ◽  
Serious Adverse Events ◽  
Double Blind ◽  
To Receive

Safety monitoring and successful blinding are important features of randomized, blinded clinical trials. We report chamber- and protocol-related adverse events (AEs) for participants enrolled in two randomized, double-blind clinical trials of hyperbaric oxygen (HBO2) for persistent post-concussive symptoms clinicaltrials.gov identifiers NCT01306968, HOPPS, and NCT01611194, BIMA), as well as the success of maintaining the blind with a low-pressure sham control arm. In both studies, participants were randomized to receive HBO2 (1.5 atmospheres absolute, >99% oxygen) or sham chamber sessions (1.2 atmospheres absolute, room air). In 143 participants undergoing 4,245 chamber sessions, chamber-related adverse events were rare (1.1% in the HOPPS study, 2.2% in the BIMA study). Minor, non-limiting barotrauma was the most frequently reported. Rarely, some participants experienced headache with chamber sessions. No serious adverse events were associated with chamber sessions. An allocation questionnaire completed after intervention revealed that the sham control arm adequately protected the blind in both trials. Participants based allocation assumptions on symptom improvement or lack of symptom improvement and could not discern intervention arm by pressure, smell, taste, or gas flow.

scholarly journals Natalizumab in acute ischemic stroke (ACTION II)

Neurology ◽  
2020 ◽  
Vol 95 (8) ◽  
pp. e1091-e1104 ◽  
Author(s):  
Mitchell S.V. Elkind ◽  
Roland Veltkamp ◽  
Joan Montaner ◽  
S. Claiborne Johnston ◽  
Aneesh B. Singhal ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Adverse Events ◽  
Acute Ischemic Stroke ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Excellent Outcome ◽  
Scale Scores ◽  
To Receive ◽  
Improve Patient

ObjectiveWe evaluated the effect of 2 doses of natalizumab on functional outcomes in patients with acute ischemic stroke (AIS).MethodsIn this double-blind phase 2b trial, patients with AIS aged 18–80 years with NIH Stroke Scale scores of 5–23 from 53 US and European sites were randomized 1:1:1 to receive a single dose of 300 or 600 mg IV natalizumab or placebo, with randomization stratified by treatment window (≤9 or >9 to ≤24 hours from patient's last known normal state). The primary endpoint was a composite measure of excellent outcome (modified Rankin Scale score ≤1 and Barthel Index score ≥95) at day 90 assessed in all patients receiving a full dose. Sample size was estimated from a Bayesian model; p values were not used for hypothesis testing.ResultsAn excellent outcome was less likely with natalizumab than with placebo (natalizumab 300 or 600 mg odds ratio 0.60; 95% confidence interval 0.39–0.93). There was no effect modification by time to treatment or use of thrombolysis/thrombectomy. For natalizumab 300 mg, 600 mg, or placebo, there were no differences in incidence of adverse events (90.0%, 92.1%, and 92.3%, respectively), serious adverse events (25.6%, 32.6%, and 20.9%, respectively), or deaths (6.7%, 4.5%, and 5.5%, respectively).ConclusionsNatalizumab administered ≤24 hours after AIS did not improve patient outcomes.ClinicalTrials.gov identifierNCT02730455Classification of evidenceThis study provides Class I evidence that for patients with AIS, an excellent outcome was less likely in patients treated with natalizumab than with placebo.

scholarly journals Fostamatinib for the treatment of hospitalized adults with COVD-19 A randomized trial

2021 ◽  
Author(s):  
Jeffrey R Strich ◽  
Xin Tian ◽  
Mohamed Samour ◽  
Christopher S King ◽  
Oksana Shlobin ◽  
...  
Keyword(s):  
Immune Response ◽  
Adverse Events ◽  
Kinase Inhibitor ◽  
Controlled Trial ◽  
Standard Of Care ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Reactive Protein ◽  
To Receive ◽  
Confirmatory Trials

Abstract Background Coronavirus Disease 2019 (Covid-19) requiring hospitalization is characterized by robust antibody production, dysregulated immune response and immunothrombosis. Fostamatinib, is a novel spleen tyrosine kinase inhibitor we hypothesize will ameliorate Fc activation and attenuate harmful effects of the anti-COVID-19 immune response. Methods We conducted a double-blind, randomized, placebo-controlled trial in hospitalized adults requiring oxygen with Covid-19 where patients receiving standard of care were randomized to receive fostamatinib or placebo. The primary outcome was serious adverse events by day 29. Results A total of 59 patients underwent randomization (30 to fostamatinib and 29 to placebo). Serious adverse events occurred in 10.5% of patients in the fostamatinib group compared to 22% in placebo (P = .2). Three deaths occurred by day 29, all receiving placebo. The mean change in ordinal score at day 15 was greater in the fostamatinib group (-3.6 ± 0.3 vs. -2.6 ± 0.4, P = .035) and the median length in the ICU was 3 days in the fostamatinib group vs. 7 days in placebo (P = .07). Differences in clinical improvement were most evident in patients with severe or critical disease (median days on oxygen, 10 vs. 28, P = .027). There were trends towards more rapid reductions in C-reactive protein, D-dimer, fibrinogen and ferritin levels in the fostamatinib group. Conclusion For COVID-19 requiring hospitalization, the addition of fostamatinib to standard of care was safe and patients were observed to have improved clinical outcomes compared to placebo. These results warrant further validation in larger confirmatory trials.

scholarly journals Identifying Anticipated Events of Future Clinical Trials by Leveraging Data from the Placebo Arms of Completed Trials

2020 ◽  
Author(s):  
Xiang-Lin Tan ◽  
David M. Kern ◽  
M. Soledad Cepeda
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Road Traffic ◽  
Bipolar Depression ◽  
Controlled Trial ◽  
Meta Analysis ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Summary Estimate ◽  
Safety Surveillance

Abstract Background An important component of a systematic strategy for safety surveillance is prospective identification of anticipated serious adverse events (SAEs). Developing a structured approach to identify anticipated events and estimating their incidence can help align the safety strategy and the safety surveillance efforts. Methods We developed a novel approach to identify anticipated events for a hypothetical randomized, double-blind, controlled trial in subjects with bipolar disorder using the adverse events reported in the placebo arm of trials from the ClinicalTrials.gov database. We searched the ClinicalTrials.gov database for all trials on bipolar depression with similar inclusion/exclusion criteria and study duration as our hypothetical study. The frequencies of anticipated events in placebo arms were abstracted from each trial and 95% confidence intervals (CI) were calculated using the Clopper–Pearson method. Meta-analysis with a random effects model was performed to obtain a summary estimate and 95% CI for the events identified in more than one trial. Results A total of 129 clinical trials were initially identified, and 18 were ultimately selected as they met all the selection criteria. There were 69 unique anticipated SAEs identified, and 13 out of 69 were reported in at least 2 clinical trials. The top 5 anticipated SAEs for our study were: (1) hospitalization, psychiatric symptom (3.57%); (2) suicidal behavior, overdose (3.57%), (3) cholecystitis (2.86%); (4) fall (2.86%); (5) road traffic accident, injury (2.86%). Conclusion We successfully identified the anticipated events from registered trials that included a population similar to our trial. This method for identifying anticipated events could be applied to other disease areas.

scholarly journals Cardiovascular outcomes in adults with migraine treated with eptinezumab for migraine prevention: pooled data from four randomized, double-blind, placebo-controlled studies

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Timothy R. Smith ◽  
Egilius L. H. Spierings ◽  
Roger Cady ◽  
Joe Hirman ◽  
Anders Ettrup ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Clinical Trials ◽  
Adverse Events ◽  
Vital Signs ◽  
Primary Objective ◽  
Cardiovascular Outcomes ◽  
Migraine Treatment ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Link Type

Abstract Background Patients with migraine have an increased relative risk of cardio- and cerebrovascular events, and some migraine treatments may exacerbate this risk. The primary objective of this analysis was to determine whether the rate of cardiovascular adverse events was higher for patients with migraine treated with the migraine-preventive eptinezumab, compared with patients receiving placebo. Methods Cardiovascular outcomes in patients with migraine were pooled across four clinical trials (phase 1b, phase 2, and two phase 3 trials) for use of eptinezumab as a preventive migraine treatment for up to 1 year. In all studies, treatment-emergent adverse events (TEAEs) that occurred after the first dose of study treatment (eptinezumab 100 mg, 300 mg, 1000 mg, or placebo) and vital signs were recorded through study completion. Results Cardiovascular TEAEs were rare across all four clinical trials, and rates were similar between patients receiving eptinezumab and those receiving placebo. Cardiovascular TEAEs that did occur were mild or moderate in severity; there were no serious adverse events as per FDA definition. Vital signs (systolic blood pressure, diastolic blood pressure, and heart rate) were not meaningfully different across treatment groups over the course of 56 weeks, compared to placebo. Treatment with eptinezumab did not result in significant new or changed cardiovascular medications used concomitantly compared to placebo. Conclusions In this post hoc analysis of four clinical trials for eptinezumab, doses of 100 mg, 300 mg, and 1000 mg (more than 3 times the highest approved dose) were not associated with clinically relevant changes in vital signs or significant changes in concomitant cardiovascular medication usage, and had low incidences of cardiovascular TEAEs, comparable to placebo. Trial registration NCT01772524 (Study 2), 01/21/2013; NCT02275117 (Study 5), 10/27/2014; NCT02559895 (PROMISE-1), 09/25/2017; NCT02974153 (PROMISE-2), 11/28/2016

Tonabersat, a Gap-Junction Modulator: Efficacy and Safety in Two Randomized, Placebo-Controlled, Dose-Ranging Studies of Acute Migraineceph

Cephalalgia ◽  
2009 ◽  
Vol 29 (2_suppl) ◽  
pp. 17-27 ◽  
Author(s):  
SD Silberstein ◽  
J Schoenen ◽  
H Göbel ◽  
HC Diener ◽  
AH Elkind ◽  
...  
Keyword(s):  
Adverse Events ◽  
North American ◽  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Plasma Concentrations ◽  
International Study ◽  
Maximum Plasma ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Dose Ranging

Tonabersat is a novel benzopyran derivative that blocks the cortical spreading depression proposed to be associated with migraine attacks. The ability of single oral doses of 15, 25, 40 and 80 mg of tonabersat to relieve the symptoms of moderate to severe migraine was evaluated in 859 migraineurs enrolled in two dose-ranging, double-blind, randomized, placebo-controlled, parallel-group trials, one international and the other North American. In the international study, significantly more patients given tonabersat than given placebo experienced relief of headache pain at 2 h (15 mg, 36.8%; 40 mg, 40.7%), the principal efficacy variable, and at 4 h (40 mg, 63.0%) and complete abolition of headache at 4 h (40 mg, 34.3%). None of the primary or secondary efficacy variables indicated significant differences between tonabersat and placebo in the North American study. Tonabersat was generally well tolerated, with dizziness and nausea the most common side-effects. Serious adverse events were uncommon, and no patient withdrew from either study because of adverse events. These results suggest a possible interplay between tonabersat pharmacokinetics (the relatively long time required to reach maximum plasma concentrations) and patient characteristics (previous triptan exposure) in the management of acute migraine attacks. Based on the pharmacokinetics and actions on cortical spreading depression, tonabersat may have potential value in migraine prophylaxis.

scholarly journals Safety, pharmacokinetics and antiviral activity of PGT121, a broadly neutralizing monoclonal antibody against HIV-1: a randomized, placebo-controlled, phase 1 clinical trial

2021 ◽  
Author(s):  
Kathryn E. Stephenson ◽  
Boris Julg ◽  
C. Sabrina Tan ◽  
Rebecca Zash ◽  
Stephen R. Walsh ◽  
...  
Keyword(s):  
Viral Load ◽  
T Cell ◽  
Adverse Events ◽  
Antiviral Activity ◽  
Controlled Trial ◽  
Phase 1 ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Cell Counts ◽  
Hiv 1

AbstractHuman immunodeficiency virus (HIV)-1-specific broadly neutralizing monoclonal antibodies are currently under development to treat and prevent HIV-1 infection. We performed a single-center, randomized, double-blind, dose-escalation, placebo-controlled trial of a single administration of the HIV-1 V3-glycan-specific antibody PGT121 at 3, 10 and 30 mg kg–1 in HIV-uninfected adults and HIV-infected adults on antiretroviral therapy (ART), as well as a multicenter, open-label trial of one infusion of PGT121 at 30 mg kg–1 in viremic HIV-infected adults not on ART (no. NCT02960581). The primary endpoints were safety and tolerability, pharmacokinetics (PK) and antiviral activity in viremic HIV-infected adults not on ART. The secondary endpoints were changes in anti-PGT121 antibody titers and CD4+ T-cell count, and development of HIV-1 sequence variations associated with PGT121 resistance. Among 48 participants enrolled, no treatment-related serious adverse events, potential immune-mediated diseases or Grade 3 or higher adverse events were reported. The most common reactions among PGT121 recipients were intravenous/injection site tenderness, pain and headache. Absolute and relative CD4+ T-cell counts did not change following PGT121 infusion in HIV-infected participants. Neutralizing anti-drug antibodies were not elicited. PGT121 reduced plasma HIV RNA levels by a median of 1.77 log in viremic participants, with a viral load nadir at a median of 8.5 days. Two individuals with low baseline viral loads experienced ART-free viral suppression for ≥168 days following antibody infusion, and rebound viruses in these individuals demonstrated full or partial PGT121 sensitivity. The trial met the prespecified endpoints. These data suggest that further investigation of the potential of antibody-based therapeutic strategies for long-term suppression of HIV is warranted, including in individuals off ART and with low viral load.

scholarly journals 32 Quantifying the Prevalence of Frailty in Drug Trials and the Relationship with Serious Adverse Events

2021 ◽  
Vol 50 (Supplement_1) ◽  
pp. i7-i11
Author(s):  
P Hanlon ◽  
E Butterly ◽  
J Lewsey ◽  
S Siebert ◽  
F S Mair ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Disease Severity ◽  
Negative Binomial ◽  
Frailty Index ◽  
Chronic Obstructive ◽  
Drug Trials ◽  
Phase 3 ◽  
Serious Adverse Events ◽  
Increased Risk

Abstract Introduction Frailty is common in clinical practice, but trials rarely report on participant frailty. Consequently, clinicians and guideline-developers assume frailty is largely absent from trials and have questioned the relevance of trial findings to frail people. Therefore, we examined frailty in phase 3/4 industry-sponsored clinical trials of pharmacological interventions for three exemplar conditions: type 2 diabetes mellitus (T2DM), rheumatoid arthritis (RA), and chronic obstructive pulmonary disease (COPD). Methods We constructed a 40-item frailty index (FI) in 19 clinical trials (7 T2DM, 8 RA, 4 COPD, mean age 42–65 years) using individual-level participant data. Participants with a FI >0.24 were considered “frail”. Baseline disease severity was assessed using HbA1c for T2DM, Disease Activity Score-28 (DAS28) for RA, and % predicted FEV1 for COPD. Using generalised gamma regression, we modelled FI on age, sex and disease severity. In negative binomial regression we modelled serious adverse event rates on FI, and combined results for each index condition in a random-effects meta-analysis. Results All trials included frail participants: prevalence 7–21% in T2DM trials, 33–73% in RA trials, and 15–22% in COPD trials. Increased disease severity and female sex were associated with higher FI in all trials. Frailty was associated with age in T2DM and RA trials, but not in COPD. Across all trials, and after adjusting for age, sex, and disease severity, higher FI predicted increased risk of serious adverse events; the pooled incidence rate ratios (per 0.1-point increase in FI scale) were 1.46 (95% CI 1.21–1.75), 1.45 (1.13–1.87) and 1.99 (1.43–2.76) for T2DM, RA and COPD, respectively. Conclusion Frailty is identifiable and prevalent among middle aged and older participants in phase 3/4 drug trials and has clinically important safety implications. Trial data may be harnessed to better understand chronic disease management in people living with frailty.

scholarly journals Phase III double-blind study comparing the efficacy and safety of proposed biosimilar MYL-1402O and reference bevacizumab in stage IV non-small-cell lung cancer

2021 ◽  
Vol 13 ◽  
pp. 175883592110458
Author(s):  
Mark A. Socinski ◽  
Cornelius F. Waller ◽  
Tazeen Idris ◽  
Igor Bondarenko ◽  
Alexander Luft ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Phase Iii ◽  
European Medicines Agency ◽  
Small Cell Lung ◽  
Serious Adverse Events ◽  
Double Blind

Purpose: This phase III study compared the efficacy and safety of proposed biosimilar MYL-1402O with reference bevacizumab (BEV), as first-line treatment for patients with stage IV non-squamous non-small-cell lung cancer. Patients and methods: Patients were randomly assigned (1:1) to receive MYL-1402O or bevacizumab with carboplatin-paclitaxel up to 18 weeks (6 cycles), followed by up to 24 weeks (8 cycles) of bevacizumab monotherapy. The primary objective was comparison of overall response rate (ORR), based on independently reviewed best tumor responses as assessed during the first 18 weeks. ORR was analyzed per US Food and Drug Administration (ratio of ORR) and European Medicines Agency (difference in ORRs) requirements for equivalence evaluation. Secondary end points included progression-free survival, disease control rate, duration of response, overall survival, safety, and immunogenicity over a period of 42 weeks, and pharmacokinetics (up to 18 weeks). Results: A total of 671 patients were included in the intent-to-treat population. The ratio of ORR was 0.96 [confidence interval (CI) 0.83, 1.12] and the difference in ORR was −1.6 (CI −9.0, 5.9) between treatment arms; CIs were within the predefined equivalence margins. Overall, the incidence of treatment-emergent adverse events and serious adverse events was comparable. Treatment-emergent anti-drug antibody (ADA) positivity was transient, with no notable differences between treatment arms (6.5% versus 4.8% ADA positivity rate in MYL-1402O versus BEV, respectively). The incidence of neutralizing antibody post-baseline was lower in the MYL-1402O arm (0.6%) compared to the bevacizumab arm (2.5%). Conclusions: MYL-1402O is therapeutically equivalent to bevacizumab, based on the ORR analyses, with comparable secondary endpoints. Trial Registry Information EU Clinical Trials Register, Registration # EudraCT no. 2015-005141-32 https://www.clinicaltrialsregister.eu/ctr-search/search?query=2015-005141-32 Plain language summary Previous studies established bioequivalence of the proposed bevacizumab biosimilar MYL-1402O to reference bevacizumab. In this randomized, double-blind, phase III trial, MYL-1402O ( n = 337) demonstrated comparable efficacy to bevacizumab ( n = 334) in treating advanced non-squamous non-small-cell lung cancer per Food and Drug Administration and European Medicines Agency requirements for equivalence; the ratio of objective response rate (ORR) was 0.96 [90% confidence interval (CI) 0.83, 1.12] and the difference in ORR (MYL-1402O:bevacizumab) was −1.6 (95% CI −9.0, 5.9). Median progression-free survival at 42 weeks was comparable: 7.6 (7.0, 9.5) with MYL-1402O versus 9.0 (7.2, 9.7) months ( p = 0.0906) with bevacizumab, by independent review. Treatment-emergent adverse events leading to death (2.4% vs 1.5%), serious adverse events (17.6% vs 16.7%), and antidrug antibodies (6.5% vs 4.8%), were comparable in the MYL-1402O vs bevacizumab arms, respectively. The incidence of neutralizing antibody post-baseline was lower with MYL-1402O (0.6%) than with bevacizumab (2.5%). These findings confirm therapeutic equivalence of MYL-1402O to bevacizumab, providing opportunities for improving access to bevacizumab.

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