Time to Sustained Improvement in Bowel Movement Frequency with Telotristat Ethyl: Analyses of Phase III Studies in Carcinoid Syndrome

Abstract

Background: Telotristat ethyl is approved to treat carcinoid syndrome diarrhea in combination with somatostatin analogs. In TELESTAR and TELECAST phase III studies, patients with carcinoid syndrome received telotristat ethyl 250 or 500 mg 3 times per day (tid) or placebo tid in addition to somatostatin analogs. The aim of this prespecified analysis was to examine the time to reductions in bowel movements (BMs) in the TELESTAR and TELECAST studies using survival analysis methods.

Methods: First occurrence of sustained response was defined as the time to the first day of 2 consecutive weeks with a mean BM frequency improvement of ≥ 30% from baseline during the 12-week double-blind treatment periods. Time to first ≥ 30% worsening in BM frequency was also measured. Treatments were compared with the log-rank test; Cox regression models provided point and confidence interval estimates of the hazard ratios for each trial.

Results: In TELESTAR and TELECAST, majority of patients (69%) on telotristat ethyl experienced a sustained ≥ 30% improvement in BM frequency. The median time to sustained reduction of at least 30% in BM frequency was significantly faster (fewer days to onset) for telotristat ethyl compared with placebo in both TELESTAR (250 mg, HR = 2.3 [95% CI, 1.3-4.1, P = 0.004]; 500 mg, HR = 2.2 [95% CI, 1.2-3.9, P = 0.009]) and TELECAST (250 mg, HR = 3.9 [95% CI, 1.6-11.1, P = 0.003]; 500 mg, HR = 4.2 [95% CI, 1.7-11.7, P = 0.002]). In TELECAST, 42% of patients on placebo experienced sustained worsening in BM frequency compared with 20% on telotristat ethyl; no significant difference was observed in TELESTAR.

Conclusion: The time of onset of sustained BM frequency improvement mean and range are important when considering use of telotristat ethyl in patients with carcinoid syndrome diarrhea. Telotristat ethyl may also reduce sustained worsening in BM frequency.

Trial registration: ClinicalTrials.gov Identifiers: NCT01677910, NCT02063659.

Keywords: Diarrhea; Malignant carcinoid syndrome; Neuroendocrine tumors; Serotonin; Telotristat ethyl; Tryptophan hydroxylase.

Conflict of interest statement

Joseph S. Dillon: Lexicon Pharmaceuticals, Inc. (RF); Matthew H. Kulke: Lexicon Pharmaceuticals, Inc. (C/A), Ipsen Bioscience (C/A), Novartis Pharmaceuticals (C/A); Dieter Hörsch: Lexicon Pharmaceuticals, Inc. (H), Ipsen Pharmaceuticals, Inc. (RF, H); Lowell B. Anthony: Lexicon Pharmaceuticals, Inc. (RF, H); Richard R. P. Warner: Lexicon Pharmaceuticals, Inc. (RF); Emily Bergsland: UpToDate (IP), Novartis (RF); Staffan Welin: Ipsen (C/A), Novartis (C/A); Pamela L. Kunz: Lexicon Pharmaceuticals, Inc. (C/A), Advanced Accelerator Applications (RF), Genentech (RF), Ipsen (RF), Merck (RF), Incyte (RF); Chad McKee: Lexicon Pharmaceuticals, Inc. (E, OI); Pablo Lapuerta: Lexicon Pharmaceuticals, Inc. (E, OI); Phillip Banks: Lexicon Pharmaceuticals, Inc. (E, OI); Marianne Pavel: Novartis Pharmaceuticals (RF, H), Ipsen (RF, H), Lexicon Pharmaceuticals, Inc. (H), Pfizer, Inc. (H). Thomas M. O’Dorisio indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board.

Figures

Fig. 1

Kaplan–Meier curves for improvement in BM frequency. Probability with time that a patient would not have a sustained ≥ 30% improvement in BM frequency for patients in the TELESTAR (a) and TELECAST (b) studies. A sustained ≥ 30% improvement from baseline was defined as the time from the first DBT dose date to the first day of a consecutive 14-day period with BM frequency at least 30% below the individual baseline BM frequency. Patients having no ≥ 30% improvement were censored on the last day of the last week a valid assessment of the endpoint can be made. Shapes indicate censored values. Abbreviations: BM, bowel movement; DBT, double-blind treatment; tid, three times per day

Fig. 2

Kaplan–Meier curves for worsening in BM frequency. Probability with time that a patient would not have a ≥ 30% worsening in BM frequency for patients participating in the TELESTAR (a) and TELECAST (b) studies. The time to ≥ 30% worsening from baseline was defined as the time from the first DBT dose date to the first day of a consecutive 14-day period with BM frequency at least 30% above the individual baseline BM frequency. Patients having no ≥ 30% worsening were censored on the last day of the last week a valid assessment of the endpoint can be made. Shapes indicate censored values. Abbreviations: BM, bowel movement; DBT, double-blind treatment; tid, three times per day

Fig. 3

Mean change from baseline in stool form at six weeks for patients who experienced ≥ 30% reduction, 0–30% reduction, or no reduction in baseline BM frequency in the TELESTAR (a) and TELECAST (b) studies. The data from six weeks is presented, as both trials reached the median time to sustained improvement in BM frequency by this point. Abbreviations: BM, bowel movement; SE, standard error; tid, three times per day

Fig. 4

Proportion of days with reports of urgency/immediate need to defecate at 6 weeks for patients who experienced ≥ 30% reduction, 0–30% reduction, or no reduction in baseline BM frequency in the TELESTAR (a) and TELECAST (b) studies. The data from six weeks is presented, as both trials reached the median time to sustained improvement in BM frequency by this point. Abbreviations: BM, bowel movement; SE, standard error; tid, three times per day