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

Joseph S. Dillon; Matthew H. Kulke; Dieter Hörsch; Lowell B. Anthony; Richard R.P. Warner; Emily Bergsland; Staffan Welin; Thomas M. O’Dorisio; Pamela L. Kunz; Chad McKee; Pablo Lapuerta; Phillip Banks; Marianne Pavel

doi:10.1007/s12029-020-00375-2

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

Joseph S. Dillon, Matthew H. Kulke, Dieter Hörsch, Lowell B. Anthony, Richard R.P. Warner, Emily Bergsland, Staffan Welin, Thomas M. O’Dorisio, Pamela L. Kunz, Chad McKee, Pablo Lapuerta, Phillip Banks, Marianne Pavel

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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.

Original language	English
Pages (from-to)	212-221
Number of pages	10
Journal	Journal of Gastrointestinal Cancer
Volume	52
Issue number	1
DOIs	https://doi.org/10.1007/s12029-020-00375-2
State	Published - Mar 2021

Bibliographical note

Funding Information:
This work was supported by Lexicon Pharmaceuticals, Inc., The Woodlands, TX, USA. Employees of the company were involved in the study designs; the collection, analysis, and interpretation of data; the writing and review of the manuscript; and the decision to submit for publication.

Funding Information:
We thank the patients and investigators for participating in the studies. We thank James Banigan, PhD (Chameleon Communications International, with funding provided by Lexicon Pharmaceuticals, Inc.) for medical editorial assistance with this manuscript. We thank the following Lexicon employees: Shanna Jackson, RN, MBA, JD Wallace, Karie Arnold, Nam Womack, Kristi Boehm, MS, ELS, and Rosanna Fleming, MS. We would like to thank the team at INC Research (Raleigh, NC) for study conduct, monitoring, analysis, and reporting. Lastly, we thank Ipsen Pharmaceuticals, Inc., a partner of Lexicon Pharmaceuticals, Inc., for review of this manuscript for medical accuracy.

Publisher Copyright:
© 2020, The Author(s).

Keywords

Diarrhea
Malignant carcinoid syndrome
Neuroendocrine tumors
Serotonin
Telotristat ethyl
Tryptophan hydroxylase

ASJC Scopus subject areas

Oncology
Gastroenterology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s12029-020-00375-2

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Dillon, J. S., Kulke, M. H., Hörsch, D., Anthony, L. B., Warner, R. R. P., Bergsland, E., Welin, S., O’Dorisio, T. M., Kunz, P. L., McKee, C., Lapuerta, P., Banks, P., & Pavel, M. (2021). Time to Sustained Improvement in Bowel Movement Frequency with Telotristat Ethyl: Analyses of Phase III Studies in Carcinoid Syndrome. Journal of Gastrointestinal Cancer, 52(1), 212-221. https://doi.org/10.1007/s12029-020-00375-2

@article{3135b75e0a0842ee83ed924872955c92,

title = "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",

author = "Dillon, {Joseph S.} and Kulke, {Matthew H.} and Dieter H{\"o}rsch and Anthony, {Lowell B.} and Warner, {Richard R.P.} and Emily Bergsland and Staffan Welin and O{\textquoteright}Dorisio, {Thomas M.} and Kunz, {Pamela L.} and Chad McKee and Pablo Lapuerta and Phillip Banks and Marianne Pavel",

note = "Funding Information: This work was supported by Lexicon Pharmaceuticals, Inc., The Woodlands, TX, USA. Employees of the company were involved in the study designs; the collection, analysis, and interpretation of data; the writing and review of the manuscript; and the decision to submit for publication. Funding Information: We thank the patients and investigators for participating in the studies. We thank James Banigan, PhD (Chameleon Communications International, with funding provided by Lexicon Pharmaceuticals, Inc.) for medical editorial assistance with this manuscript. We thank the following Lexicon employees: Shanna Jackson, RN, MBA, JD Wallace, Karie Arnold, Nam Womack, Kristi Boehm, MS, ELS, and Rosanna Fleming, MS. We would like to thank the team at INC Research (Raleigh, NC) for study conduct, monitoring, analysis, and reporting. Lastly, we thank Ipsen Pharmaceuticals, Inc., a partner of Lexicon Pharmaceuticals, Inc., for review of this manuscript for medical accuracy. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2021",

month = mar,

doi = "10.1007/s12029-020-00375-2",

language = "English",

volume = "52",

pages = "212--221",

number = "1",

}

Dillon, JS, Kulke, MH, Hörsch, D, Anthony, LB, Warner, RRP, Bergsland, E, Welin, S, O’Dorisio, TM, Kunz, PL, McKee, C, Lapuerta, P, Banks, P & Pavel, M 2021, 'Time to Sustained Improvement in Bowel Movement Frequency with Telotristat Ethyl: Analyses of Phase III Studies in Carcinoid Syndrome', Journal of Gastrointestinal Cancer, vol. 52, no. 1, pp. 212-221. https://doi.org/10.1007/s12029-020-00375-2

TY - JOUR

T1 - Time to Sustained Improvement in Bowel Movement Frequency with Telotristat Ethyl

T2 - Analyses of Phase III Studies in Carcinoid Syndrome

AU - Dillon, Joseph S.

AU - Kulke, Matthew H.

AU - Hörsch, Dieter

AU - Anthony, Lowell B.

AU - Warner, Richard R.P.

AU - Bergsland, Emily

AU - Welin, Staffan

AU - O’Dorisio, Thomas M.

AU - Kunz, Pamela L.

AU - McKee, Chad

AU - Lapuerta, Pablo

AU - Banks, Phillip

AU - Pavel, Marianne

N1 - Funding Information: This work was supported by Lexicon Pharmaceuticals, Inc., The Woodlands, TX, USA. Employees of the company were involved in the study designs; the collection, analysis, and interpretation of data; the writing and review of the manuscript; and the decision to submit for publication. Funding Information: We thank the patients and investigators for participating in the studies. We thank James Banigan, PhD (Chameleon Communications International, with funding provided by Lexicon Pharmaceuticals, Inc.) for medical editorial assistance with this manuscript. We thank the following Lexicon employees: Shanna Jackson, RN, MBA, JD Wallace, Karie Arnold, Nam Womack, Kristi Boehm, MS, ELS, and Rosanna Fleming, MS. We would like to thank the team at INC Research (Raleigh, NC) for study conduct, monitoring, analysis, and reporting. Lastly, we thank Ipsen Pharmaceuticals, Inc., a partner of Lexicon Pharmaceuticals, Inc., for review of this manuscript for medical accuracy. Publisher Copyright: © 2020, The Author(s).

PY - 2021/3

Y1 - 2021/3

N2 - 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.

AB - 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.

KW - Diarrhea

KW - Malignant carcinoid syndrome

KW - Neuroendocrine tumors

KW - Serotonin

KW - Telotristat ethyl

KW - Tryptophan hydroxylase

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U2 - 10.1007/s12029-020-00375-2

DO - 10.1007/s12029-020-00375-2

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AN - SCOPUS:85081632135

SN - 1941-6628

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JO - Journal of Gastrointestinal Cancer

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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