Relacorilant, a Selective Glucocorticoid Receptor Modulator in Development for the Treatment of Patients With Cushing Syndrome, Does Not Cause Prolongation of the Cardiac QT Interval.

OBJECTIVE: To assess the effect of relacorilant, a selective glucocorticoid receptor modulator under investigation for the treatment of patients with endogenous hypercortisolism (Cushing syndrome [CS]), on the heart rate-corrected QT interval (QTc). METHODS: Three clinical studies of relacorilant were included: (1) a first-in-human, randomized, placebo-controlled, ascending-dose (up to 500 mg of relacorilant) study in healthy volunteers; (2) a phase 1 placebo- and positive-controlled thorough QTc (TQT) study of 400 and 800 mg of relacorilant in healthy volunteers; and (3) a phase 2, open-label study of up to 400 mg of relacorilant administered daily for up to 16 weeks in patients with CS. Electrocardiogram recordings were taken, and QTc change from baseline (ΔQTc) was calculated. The association of plasma relacorilant concentration with the effect on QTc in healthy volunteers was assessed using linear mixed-effects modeling. RESULTS: Across all studies, no notable changes in the electrocardiogram parameters were observed. At all time points and with all doses of relacorilant, including supratherapeutic doses, ΔQTc was small, generally negative, and, in the placebo-controlled studies, similar to placebo. In the TQT study, placebo-corrected ΔQTc with relacorilant was small and negative, whereas placebo-corrected ΔQTc with moxifloxacin positive control showed rapid QTc prolongation. These results constituted a negative TQT study. The model-estimated slopes of the concentration-QTc relationship were slightly negative, excluding an association of relacorilant with prolonged QTc. CONCLUSION: At all doses studied, relacorilant consistently demonstrated a lack of QTc prolongation in healthy volunteers and patients with CS, including in the TQT study. Ongoing phase 3 studies will help further establish the overall benefit-risk profile of relacorilant.

Changes in migraine interictal burden following treatment with galcanezumab: Results from a phase III randomized, placebo-controlled study.

OBJECTIVE: To evaluate changes in interictal burden with galcanezumab versus placebo in patients with episodic (EM) or chronic migraine (CM). BACKGROUND: The disruptive effects of migraine occur both during attacks (ictal period) and between attacks (interictal period), affecting work, school, family, and social life. Migraine clinical trials typically assess ictal burden endpoints, neglecting interictal burden. METHODS: CONQUER was a 3-month, double-blind study that randomized adult patients with EM or CM who had experienced failure of two to four standard-of-care migraine preventive medication categories to receive monthly galcanezumab (n = 232) or placebo (n = 230), followed by 3 months of open-label galcanezumab. The mean change in interictal burden, a secondary objective, was measured using the four-item Migraine Interictal Burden Scale (MIBS-4). The total score for MIBS-4 can range from zero to 12, with scores ≥5 indicating severe interictal burden. Post hoc analyses evaluated shifts in MIBS-4 severity categories and item-level improvement. RESULTS: The MIBS-4 total score indicated severe interictal burden at baseline (mean [SD]: all patients, 5.5 [3.5]; EM, 5.0 [3.4]; CM, 6.2 [3.5]). Reductions in the MIBS-4 score were significantly greater with galcanezumab versus placebo at Month 3 (mean [SE]: all patients -1.9 [0.2] vs. -0.8 [0.2], p < 0.0001; EM, -1.8 [0.3] vs. -1.1 [0.3], p = 0.033; CM, -1.8 [0.4] vs. -0.3 [0.4], p < 0.001), with further improvement at Month 6 after all patients had received galcanezumab (mean [SE]: all patients, -2.4 [0.2] vs. -2.0 [0.2]; EM, -2.3 [0.3] vs. -2.2 [0.3]; CM, -2.1 [0.4] vs. -1.5 [0.4]). The percentage of patients with severe interictal burden decreased substantially for the galcanezumab-treated patients, from 59% (137/232) at baseline to 27% (58/217) at Month 6 (EM from 51% [70/137] to 23% [30/131]; CM from 71% [67/95] to 33% [28/86]). CONCLUSION: In addition to the known efficacy of galcanezumab in the ictal period, these findings suggest treatment with galcanezumab results in a significant reduction in interictal burden.

Effects of Galcanezumab on Health-Related Quality of Life and Disability in Patients with Previous Failure of 2-4 Migraine Preventive Medication Categories: Results from a Phase IIIb Randomized, Placebo-Controlled, Multicenter Clinical Trial (CONQUER).

BACKGROUND AND OBJECTIVES: Patients with migraine and prior preventive treatment failures have a significant burden on quality of life and disability. The CONQUER study evaluated the effects of galcanezumab on patient functioning, disability, and health status in episodic or chronic migraine with a previous failure of two to four migraine preventive medication categories. METHODS: Patients with two to four preventive migraine treatment category failures received galcanezumab 120 mg/month (240-mg loading dose) or placebo subcutaneously, for 3 months (double-blind period). In the 3-month open-label period, all patients received galcanezumab irrespective of the treatment received in the double-blind period. Changes in Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ), Migraine Disability Assessment (MIDAS), and European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) scores were assessed. RESULTS: A total of 462 patients were randomized to receive galcanezumab (N = 232) or placebo (N = 230). At month 3, improvement in the MSQ Role-Function-Restrictive score from baseline was significantly greater for galcanezumab (23.19 ± 1.34) vs placebo (10.66 ± 1.33) [p ≤ 0.0001]. Significant improvements in remaining MSQ domains and total MSQ scores were observed (p < 0.0001) during the double-blind period. MIDAS total scores were significantly (p ≤ 0.0001) reduced with galcanezumab (- 21.10 + 3.32) vs placebo (- 3.30 + 3.28). EQ-5D-5L visual analog scale scores improved for galcanezumab (3.40 + 1.31) vs placebo (- 0.09 + 1.29; p = 0.028). During the open-label period, quality of life continued to improve for galcanezumab, with patients previously assigned to placebo reaching similar results. During both study periods, similar findings were reported in subpopulations with episodic migraine and chronic migraine. CONCLUSIONS: Galcanezumab significantly improved functioning and reduced disability in patients with episodic migraine and chronic migraine and two to four migraine preventive treatment category failures. CLINICAL TRIAL REGISTRATION: NCT03559257, registration date: 6 June, 2018.

BayesWeb: a user-friendly platform for exploratory Bayesian analysis of safety signals from small clinical trials.

Safety signals observed in early-phase clinical trials can have profound implications for the development of new medical products. It is difficult to interpret the occurrence of safety signals in small clinical trials, where formal inferential procedures may be impractical. We advocate wider use of simple Bayesian methods to explore and understand safety signals from small clinical trials. We describe a new web-based application, BayesWeb.com, that makes such exploratory Bayesian methods accessible to subject-matter experts. We illustrate the use of this software with an example from a hypothetical phase I trial for a Factor VIII product for patients with hemophilia A.

Galcanezumab in Patients with Multiple Previous Migraine Preventive Medication Category Failures: Results from the Open-Label Period of the CONQUER Trial.

INTRODUCTION: Results from the open-label extension of the phase 3b CONQUER trial are presented to evaluate the effectiveness and safety of galcanezumab, a monoclonal antibody targeting calcitonin gene-related peptide, for up to 6 months in patients with multiple prior migraine preventive treatment failures. METHODS: Patients were 18-75 years old with episodic or chronic migraine and 2-4 standard-of-care migraine preventive medication category failures. After 3 months of randomized treatment with galcanezumab (120 mg/month with 240 mg loading dose; n = 232) or placebo (n = 230), patients entered a 3-month open-label extension (120 mg/month galcanezumab with a blinded 240 mg loading dose for previous-placebo patients). Primary efficacy measure was mean change from double-blind baseline in monthly migraine headache days. RESULTS: A total of 432/449 patients (96%) who entered open-label treatment completed the study. Mean change in monthly migraine headache days in the total population, which was - 1.3 for placebo and - 4.4 for galcanezumab patients at the end of double-blind treatment (p < 0.001), was - 5.2 and - 5.6, respectively, at the end of open-label treatment with galcanezumab. Among patients with episodic migraine, mean change in monthly migraine headache days had been - 0.6 for placebo and - 2.8 for galcanezumab after double-blind treatment (p < 0.001) and was - 4.5 and - 3.8, respectively, after open-label treatment. Among patients with chronic migraine, mean change in monthly migraine headache days had been - 2.5 for placebo and - 6.6 for galcanezumab after double-blind treatment (p < 0.001) and was - 6.5 and - 8.2, respectively, after open-label treatment. Adverse events were similar to those observed during double-blind placebo treatment. Review of data in elderly patients (65-75 years of age) indicated that galcanezumab was well tolerated in this age group, with no safety issues identified. CONCLUSIONS: Galcanezumab was effective and safe during open-label treatment in patients who had experienced failures of previous migraine preventives. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03559257.

Bayesian sample-size determination for two independent Poisson rates.

Because of the high cost and time constraints for clinical trials, researchers often need to determine the smallest sample size that provides accurate inferences for a parameter of interest. Although most experimenters have employed frequentist sample-size determination methods, the Bayesian paradigm offers a wide variety of sample-size determination methodologies. Bayesian sample-size determination methods are becoming increasingly more popular in clinical trials because of their flexibility and easy interpretation inferences. Recently, Bayesian approaches have been used to determine the sample size of a single Poisson rate parameter in a clinical trial setting. In this paper, we extend these results to the comparison of two Poisson rates and develop methods for sample-size determination for hypothesis testing in a Bayesian context. We have created functions in R to determine the parameters for the conjugate gamma prior and calculate the sample size for the average length criterion and average power methods. We also provide two examples that implement our sample-size determination methods using clinical data.