Study of Telotristat Etiprate (LX1606) in Participants With Symptomatic Carcinoid Syndrome

A Phase 2, Open-Label, Multi-Center, Serial Ascending-Dose, Dose-Finding Study to Evaluate the Safety and Tolerability of LX1606 in Subjects With Symptomatic Carcinoid Syndrome

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01104415

Enrollment

Registered

2010-04-15

Start date

2010-06-15

Completion date

2014-02-12

Last updated

2019-03-15

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Carcinoid Syndrome

Brief summary

The purpose of the study is to evaluate the safety and tolerability of orally administered telotristat etiprate (LX1606) in participants with symptomatic carcinoid syndrome.

Interventions

DRUGTelotristat etiprate

Telotristat etiprate capsules orally three times daily.

Study design

Allocation

RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Males and females, aged 18 and older * Biopsy-proven metastatic carcinoid tumor of the gastrointestinal (GI) tract with disease extent confirmed by computed tomography (CT), magnetic resonance imaging (MRI), or radionuclide imaging * Symptomatic carcinoid syndrome (≥4 bowel movements per day) * Ability to provide written informed consent

Exclusion criteria

* ≥ 12 high-volume, watery bowel movements per day * Sponsor-unacceptable clinical laboratory values for hematology and liver function tests at screening * Karnofsky status ≤70% - unable to care for self * Surgery within 60 days prior to screening * A history of short bowel syndrome * Life expectancy \< 12 months * History of substance or alcohol abuse within 2 years prior to screening * Administration of any investigational drug within 30 days of screening or any therapeutic protein or antibody within 90 days of screening

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Any Treatment Emergent Adverse Events (TEAEs) and Drug-Related TEAEs in the Extension Period	Up to 124 Weeks in the Extension Period	An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related. Treatment-emergent AEs were defined as any AEs reported after the first dose of treatment on Day 1.
Number of Participants With Any Treatment Emergent Adverse Events (TEAEs) and Drug-Related TEAEs in the Core Phase	Baseline up to Week 12 in the Core Phase	An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related. Treatment-emergent AEs were defined as any AEs reported after the first dose of treatment on Day 1.

Secondary

Measure	Time frame	Description
Change From Baseline in Percentage of Days With Sensation of Urgency to Defecate	Core Phase: Baseline to Weeks 9-12; Extension Period: Baseline to Week 24	Participants assessed the urgency to defecate using a daily diary response to the following question, Have you felt or experienced a sense of urgency to pass stool today?. The change from the baseline value was calculated as the difference between the mean score (percentage of days) of the post-baseline interval (Weeks 9 to 12) and baseline. Baseline for the Extension Period was defined as non-missing assessment in Run-in period prior to the first dose of study drug.
Change From Baseline in Sensation/Severity of Nausea Using 100 mm Visual Analog Scale (VAS)	Core Phase: Baseline to Weeks 9-12; Extension Period: Baseline to Week 24	Sensation/severity of nausea was measured using a 100 mm VAS. Participants rated their perception of the sensation/severity of nausea experienced by marking a single vertical line on a VAS scale from 0 to 100 mm, where 0 = No vomiting and 100 = vomiting. The change from the baseline value was calculated as the difference between the mean score of the post-baseline interval (Weeks 9 to 12) and baseline. 0 indicates the best score, 100 indicates the worst score. Baseline for the Extension Period was defined as non-missing assessment in Run-in period prior to the first dose of study drug.
Number of Participants With an Improvement in Global Assessment of Symptoms Associated With Carcinoid Syndrome	Core Phase: Weeks 9-12; Extension Period: Week 24	Participants assessed their symptoms using a weekly subjective response to the following question, In the past 7 days, have you had adequate relief of your carcinoid syndrome bowel complaints such as diarrhea, urgent need to have a bowel movement, abdominal pain, or discomfort?. The values for improvement in global assessment of symptoms associated with carcinoid syndrome in the Core Phase were averaged from Weeks 9 to 12.
Change From Baseline in Number of Bowel Movements (BMs)	Core Phase: Baseline to Weeks 9-12; Extension Period: Baseline to Week 24	Participants recorded the number of bowel movements in a daily diary. The change from baseline value was calculated as the difference between mean numbers of BMs of the post-baseline interval (Weeks 9 to 12) and baseline. A negative change from baseline indicates improvement. Baseline for the Extension Period was defined as non-missing assessment in Run-in period prior to the first dose of study drug.
Change From Baseline in Daily Number of Cutaneous Flushing Episodes	Core Phase: Baseline to Weeks 9-12; Extension Period: Baseline to Week 24	Participants recorded the number of daily cutaneous flushing episodes experienced in the daily diary. The change from baseline value was calculated as the difference between the mean numbers of cutaneous flushing episodes of the post-baseline interval (Weeks 9 to 12) and baseline. Baseline for the Extension Period was defined as non-missing assessment in Run-in period prior to the first dose of study drug.
Number of Participants Achieving Clinically Meaningful Symptom Reduction in the Core Phase	Baseline to Week 12	Clinically meaningful symptom reduction was defined as either: a) an average of \< 4 bowel movements per day over 15 consecutive days, b) a 50% reduction from baseline in the number of bowel movements, c) a positive response to the question regarding adequate relief, or d) a 50% reduction from baseline in the number of daily flushing episodes.
Change From Baseline in Urinary 5-Hydroxyindoleacetic Acid (HIAA) Levels	Core Phase: Baseline to Week 12; Extension Period: Baseline to Weeks 20-21	Urinary 5-HIAA (u5-HIAA) is a standard test used in clinical practice to assess the neuroendocrine tumor (NET) activity and is collected as a 24-hour urine specimen. The change from baseline value for the Extension Period was calculated as the difference between mean change in 5-HIAA of the post-baseline interval (Weeks 20 to 21) and baseline. A negative change from baseline indicates improvement. Baseline for the Extension Period was defined as non-missing assessment in Run-in period prior to the first dose of study drug.
Change From Baseline in Daily Severity of Abdominal Pain or Discomfort Using 100 mm Visual Analog Scale (VAS)	Core Phase: Baseline to Weeks 9-12; Extension Period: Baseline to Week 24	The severity of abdominal pain was measured using a 100 mm VAS. Participants rated their perception of the sensation/severity of abdominal pain or experienced by marking a single vertical line on a VAS scale from 0 to 100 mm, where 0 = No vomiting and 100 = vomiting. The change from the baseline value was calculated as the difference between the mean score of the post-baseline interval (Weeks 9 to 12) and baseline. 0 indicate the best score, 100 indicates the worst score. Baseline for the Extension Period was defined as non-missing assessment in Run-in period prior to the first dose of study drug.
Change From Baseline in Stool Form/Consistency	Core Phase: Baseline to Weeks 9-12; Extension Period: Baseline to Week 24	Participants assessed stool form/consistency in a daily diary using a 6-point scale (0-none, 1-hard, 2-firm, 3-soft, 4-loose, 5-watery). The change from the baseline value was calculated as the difference between a mean score of the post-baseline interval (Weeks 9 to 12) and baseline. 0 indicates the best score and 5 indicates the worst score. A negative change from baseline indicates improvement. Baseline for the Extension Period was defined as non-missing assessment in Run-in period prior to the first dose of study drug.

Countries

Germany, United Kingdom

Participant flow

Recruitment details

A total of 15 participants were enrolled in the Core Phase (8-week Dose-escalation Period and the 4-week Stable-dose Period) from 11 sites in the United Kingdom and Germany, and 11 participants entered the Open-label Extension Period.

Participants by arm

Arm	Count
Telotristat Etiprate- Core Phase Following a 2-week Run-In Period, participants received telotristat etiprate capsules at a starting dose of 150 mg, orally three times daily (TID) for 14 days in the Core Phase. Dose escalations (250 mg, 350 mg, 500 mg) occurred serially every 14 days, up to a maximum dosage of telotristat etiprate 500 mg TID, as guided by specific clinical criteria for dose escalation. Upon completion of 12 weeks of treatment, participants were eligible to receive telotristat etiprate in the optional Open-label Extension Period.	15
Total	15

Arm

Count

Telotristat Etiprate- Core Phase

Following a 2-week Run-In Period, participants received telotristat etiprate capsules at a starting dose of 150 mg, orally three times daily (TID) for 14 days in the Core Phase. Dose escalations (250 mg, 350 mg, 500 mg) occurred serially every 14 days, up to a maximum dosage of telotristat etiprate 500 mg TID, as guided by specific clinical criteria for dose escalation. Upon completion of 12 weeks of treatment, participants were eligible to receive telotristat etiprate in the optional Open-label Extension Period.

Total

Withdrawals & dropouts

Period	Reason	FG000	FG001
Core Phase	Consent withdrawn by subjects	1	0
Extension Period	Death	0	1
Extension Period	Heart surgery/feeling miserable	0	1
Extension Period	Physician Decision	0	1
Extension Period	Progressive disease	0	4
Extension Period	Transition to Study LX1606.302	0	4

Baseline characteristics

Characteristic	Telotristat Etiprate- Core Phase
Age, Continuous	61.1 years STANDARD_DEVIATION 9.35
Race/Ethnicity, Customized White	15 Participants
Region of Enrollment Germany	9 participants
Region of Enrollment United Kingdom	6 participants
Sex: Female, Male Female	7 Participants
Sex: Female, Male Male	8 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 15	1 / 11
other Total, other adverse events	15 / 15	11 / 11
serious Total, serious adverse events	3 / 15	7 / 11

Outcome results

Primary

Number of Participants With Any Treatment Emergent Adverse Events (TEAEs) and Drug-Related TEAEs in the Core Phase

An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related. Treatment-emergent AEs were defined as any AEs reported after the first dose of treatment on Day 1.

Time frame: Baseline up to Week 12 in the Core Phase

Population: The safety set (SS) included all the enrolled participants who received at least 1 dose of study drug.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Telotristat Etiprate- Core Phase	Number of Participants With Any Treatment Emergent Adverse Events (TEAEs) and Drug-Related TEAEs in the Core Phase	Any TEAE	15 Participants
Telotristat Etiprate- Core Phase	Number of Participants With Any Treatment Emergent Adverse Events (TEAEs) and Drug-Related TEAEs in the Core Phase	Drug-Related TEAE	5 Participants

Primary

Number of Participants With Any Treatment Emergent Adverse Events (TEAEs) and Drug-Related TEAEs in the Extension Period

Time frame: Up to 124 Weeks in the Extension Period

Population: SS included all enrolled participants who had received at least 1 dose of study drug in the 124-week Extension Period.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Telotristat Etiprate- Core Phase	Number of Participants With Any Treatment Emergent Adverse Events (TEAEs) and Drug-Related TEAEs in the Extension Period	Any TEAE	11 Participants
Telotristat Etiprate- Core Phase	Number of Participants With Any Treatment Emergent Adverse Events (TEAEs) and Drug-Related TEAEs in the Extension Period	Drug-Related TEAE	4 Participants

Secondary

Change From Baseline in Daily Number of Cutaneous Flushing Episodes

Participants recorded the number of daily cutaneous flushing episodes experienced in the daily diary. The change from baseline value was calculated as the difference between the mean numbers of cutaneous flushing episodes of the post-baseline interval (Weeks 9 to 12) and baseline. Baseline for the Extension Period was defined as non-missing assessment in Run-in period prior to the first dose of study drug.