scholarly journals Influence of Diagnostic Method on Outcomes in Phase 3 Clinical Trials of Bezlotoxumab for the Prevention of Recurrent Clostridioides difficile Infection: A Post Hoc Analysis of MODIFY I/II

2019 ◽  
Vol 6 (8) ◽  
Author(s):  
Mark H Wilcox ◽  
Galia Rahav ◽  
Erik R Dubberke ◽  
Lori Gabryelski ◽  
Kerrie Davies ◽  
...  
Keyword(s):  
Relative Difference ◽  
Test Method ◽  
Absolute Difference ◽  
Phase 3 ◽  
Post Hoc Analysis ◽  
Clostridioides Difficile ◽  
Toxigenic Culture ◽  
Clostridioides Difficile Infection ◽  
Post Hoc ◽  
The Impact

Abstract Background The optimum diagnostic test method for Clostridioides difficile infection (CDI) remains controversial due to variation in accuracy in identifying true CDI. This post hoc analysis examined the impact of CDI diagnostic testing methodology on efficacy outcomes in phase 3 MODIFY I/II trials. Methods In MODIFY I/II (NCT01241552/NCT01513239), participants received bezlotoxumab (10 mg/kg) or placebo during anti-CDI treatment for primary/recurrent CDI (rCDI). Using MODIFY I/II pooled data, initial clinical cure (ICC) and rCDI were assessed in participants diagnosed at baseline using direct detection methods (enzyme immunoassay [EIA]/cell cytotoxicity assay [CCA]) or indirect methods to determine toxin-producing ability (toxin gene polymerase chain reaction [tgPCR]/toxigenic culture). Results Of 1554 participants who received bezlotoxumab or placebo in MODIFY I/II, 781 (50.3%) and 773 (49.7%) were diagnosed by tgPCR/toxigenic culture and toxin EIA/CCA, respectively. Participants diagnosed by toxin EIA/CCA were more likely to be inpatients, older, and have severe CDI. In bezlotoxumab recipients, ICC rates were slightly higher in the toxin EIA/CCA subgroup (81.7%) vs tgPCR/toxigenic culture (78.4%). Bezlotoxumab significantly reduced the rCDI rate vs placebo in both subgroups; however, the magnitude of reduction was substantially larger in participants diagnosed by toxin EIA/CCA (relative difference, –46.6%) vs tgPCR/toxigenic culture (–29.1%). In bezlotoxumab recipients, the rCDI rate was lower in the toxin EIA/CCA subgroup (17.6%) vs tgPCR/toxigenic culture (23.6%; absolute difference, –6.0%; 95% confidence interval, –12.4 to 0.3; relative difference, –25.4%). Conclusions Diagnostic tests that detect fecal C. difficile toxins are of fundamental importance to accurately diagnosing CDI, including in clinical trial design, ensuring that therapeutic efficacy is not underestimated.

scholarly journals Exploratory Evaluation of Bezlotoxumab on Outcomes Associated With Clostridioides difficile Infection in MODIFY I/II Participants With Cancer

2020 ◽  
Vol 7 (2) ◽  
Author(s):  
Oliver A Cornely ◽  
Kathleen M Mullane ◽  
Thomas Birch ◽  
Sabine Hazan-Steinberg ◽  
Richard Nathan ◽  
...  
Keyword(s):  
Antibacterial Treatment ◽  
Absolute Difference ◽  
Cure Rate ◽  
Single Infusion ◽  
Clinical Trial Registration ◽  
Post Hoc Analysis ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection ◽  
Intent To Treat ◽  
Post Hoc

Abstract Background The incidence of Clostridioides difficile infection (CDI) is reportedly higher and the cure rate lower in individuals with cancer vs those without cancer. An exploratory post hoc analysis of the MODIFY I/II trials (NCT01241552/NCT01513239) investigated how bezlotoxumab affected the rate of CDI-related outcomes in participants with cancer. Methods Participants received a single infusion of bezlotoxumab (10 mg/kg) or placebo during anti-CDI antibacterial treatment. A post hoc analysis of CDI-related outcomes was conducted in subgroups of MODIFY I/II participants with and without cancer. Results Of 1554 participants in the modified intent-to-treat (mITT) population, 382 (24.6%) were diagnosed with cancer (bezlotoxumab 190, placebo 192). Of participants without cancer, 591 and 581 received bezlotoxumab and placebo, respectively. In the placebo group, initial clinical cure (ICC) was achieved by fewer cancer participants vs participants without cancer (71.9% vs 83.1%; absolute difference, –11.3%; 95% CI, –18.6% to –4.5%); however, CDI recurrence (rCDI) rates were similar in cancer (30.4%) and noncancer (34.0%) participants. In participants with cancer, bezlotoxumab treatment had no effect on ICC rate compared with placebo (76.8% vs 71.9%), but resulted in a statistically significant reduction in rCDI vs placebo (17.8% vs 30.4%; absolute difference, –12.6%; 95% CI, –22.5% to –2.7%). Conclusions In this post hoc analysis of participants with cancer enrolled in MODIFY I/II, the rate of rCDI in bezlotoxumab-treated participants was lower than in placebo-treated participants. Additional studies are needed to confirm these results. Clinical Trial Registration MODIFY I (NCT01241552), MODIFY II (NCT01513239).

scholarly journals The Effects of Erratic Ratings on Placebo Response and Signal Detection in the Roche Bitopertin Phase 3 Negative Symptom Studies—A Post Hoc Analysis

2020 ◽  
Vol 1 (1) ◽  
Author(s):  
Daniel Umbricht ◽  
Alan Kott ◽  
David G Daniel
Keyword(s):  
Negative Symptom ◽  
Repeated Measures ◽  
Drug Response ◽  
Negative Symptoms ◽  
Placebo Response ◽  
Phase 3 ◽  
Post Hoc Analysis ◽  
Mixed Response ◽  
Post Hoc ◽  
The Impact

Abstract Objective In the current post hoc analyses, we assessed the impact of erratic ratings, a marker of questionable measurement quality, on placebo and drug response and drug-placebo separation in schizophrenia negative symptom trials. Methods Data were obtained from three phase 3, multi-center, 24-week, randomized, double-blind, placebo-controlled trials with bitopertin in the treatment of negative symptoms of schizophrenia. Erratic ratings were operationally defined as at least one occurrence of at least a 20% change in negative symptom factor score in the opposite direction at consecutive visits. The effect of erratic ratings on placebo and drug response and drug-placebo separation was assessed by the protocol on a subject and site-level using a mixed model repeated measures analysis. Results Placebo response was significantly increased in the presence of erratic ratings, both at the subject and site levels. Treatment response in the presence of erratic ratings was mixed and inconsistent across doses and protocols. In most cases removing data generated by subjects and sites with erratic ratings resulted in a numerical increase of drug-placebo difference favoring treatment. Additionally, in this post hoc analysis, 10 mg of bitopertin separated statistically significantly from placebo at the end of study in one of the protocols. Discussion Erratic rating patterns appear to be consistently associated with increased response to placebo and a mixed response to treatment in the bitopertin negative symptoms trials and to have degraded drug-placebo separation. As a quality indicator, they may flag the need for enhanced quality control of affected sites in clinical trials.

The Impact of Smoking on Cardiovascular Outcomes and Comorbidities in Statin-treated Patients with Coronary Artery Disease: A Post hoc Analysis of the GREACE Study

2013 ◽  
Vol 11 (5) ◽  
pp. 779-784 ◽  
Author(s):  
Vasilios G. Athyros ◽  
Konstantinos Tziomalos ◽  
Niki Katsiki ◽  
Thomas D. Gossios ◽  
Olga Giouleme ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Cardiovascular Outcomes ◽  
Post Hoc Analysis ◽  
Artery Disease ◽  
Post Hoc ◽  
The Impact

Outcomes of Passable and Non-passable Strictures in Clinical Trials of Crohn’s Disease: A Post-hoc Analysis

2021 ◽  
Author(s):  
Neeraj Narula ◽  
Emily C L Wong ◽  
Parambir S Dulai ◽  
John K Marshall ◽  
Jean-Frederic Colombel ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Activity Index ◽  
Disease Activity Index ◽  
Symptom Improvement ◽  
Logistic Regression Models ◽  
Post Hoc Analysis ◽  
Endoscopic Remission ◽  
Post Hoc ◽  
The Impact

Abstract Background and Aims There is paucity of evidence on the reversibility of Crohn’s disease [CD]-related strictures treated with therapies. We aimed to describe the clinical and endoscopic outcomes of CD patients with non-passable strictures. Methods This was a post-hoc analysis of three large CD clinical trial programmes examining outcomes with infliximab, ustekinumab, and azathioprine, which included data on 576 patients including 105 with non-passable strictures and 45 with passable strictures, as measured using the Simple Endoscopic Score for Crohn’s Disease [SES-CD]. The impact of non-passable strictures on achieving clinical remission [CR] and endoscopic remission [ER] was assessed using multivariate logistic regression models. CR was defined as a Crohn’s Disease Activity Index [CDAI] <150, clinical response as a CDAI reduction of ≥100 points, and ER as SES-CD score <3. Results After 1 year of treatment, patients with non-passable strictures demonstrated the ability to achieve passable or no strictures in 62.5% of cases, with 52.4% and 37.5% attaining CR and ER, respectively. However, patients with non-passable strictures at baseline were less likely to demonstrate symptom improvement compared with those with passable or no strictures, with reduced odds of 1-year CR (adjusted odds ratio [aOR] 0.17, 95% CI 0.03–0.99, p = 0.048). No significant differences were observed between patients with non-passable strictures at baseline and those with passable or no strictures in rates of ER [aOR 0.82, 95% CI 0.23–2.85, p = 0.751] at 1 year. Conclusions Patients with non-passable strictures can achieve symptomatic and endoscopic remission when receiving therapies used to treat CD, although they are less likely to obtain CR compared with patients without non-passable strictures. These findings support the importance of balancing the presence of non-passable strictures in trial arms.

scholarly journals Itch and Sleep Improvements with Baricitinib in Patients with Atopic Dermatitis: A Post Hoc Analysis of 3 Phase 3 Studies

2021 ◽  
Author(s):  
Timo Buhl ◽  
David Rosmarin ◽  
Esther Serra-Baldrich ◽  
Pablo Fernandez-Peñas ◽  
Atsuyuki Igarashi ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Phase 3 ◽  
Post Hoc Analysis ◽  
Post Hoc
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