Carcinoid Syndrome
Conditions
Brief summary
The primary objective of the study is to confirm that at least 1 or more doses of telotristat etiprate compared to placebo is effective in reducing the number of daily bowel movements (BMs) from baseline averaged over the 12-week double-blind portion (Treatment Period) of the trial in patients not adequately controlled by current SSA therapy.
Interventions
Telotristat etiprate tablets.
DRUGPlacebo-matching telotristat etiprate
Placebo-matching telotristat etiprate tablets.
Sponsors
Lexicon Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Participants were randomized to one of three treatment arms in the double-blind treatment period. After completion of the double-blind treatment period, participants entered an open-label treatment period.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histopathologically-confirmed, well-differentiated metastatic neuroendocrine tumor * Documented history of carcinoid syndrome and currently experiencing ≥4 bowel movements per day during the Run-in period * Currently receiving stable-dose somatostatin analog (SSA) therapy * Minimum dose of long-acting release (LAR) or depot SSA therapy * Octreotide LAR at 30 mg every 4 weeks * Lanreotide Depot at 120 mg every 4 weeks * Patients who cannot tolerate SSA therapy at a level indicated above will be allowed to enter at their highest tolerated dose * Ability and willingness to provide written informed consent
Exclusion criteria
* Presence of diarrhea attributed to any condition(s) other than carcinoid syndrome * Karnofsky Performance status ≤60% * Treatment with any tumor directed therapy, including interferon, chemotherapy, mechanistic target of rapamycin (mTOR) inhibitors \<4 weeks prior to Screening, or hepatic embolization, radiotherapy, radiolabelled SSA, and/or tumor debulking \<12 weeks prior to Screening * History of short bowel syndrome (SBS) * Clinically significant cardiac arrhythmia, bradycardia, tachycardia that would compromise patient safety or the outcome of the study * Previous exposure to telotristat etiprate
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Number of Bowel Movements (BMs) Per Day Averaged Over 12 Weeks | Baseline and 12 Weeks | Participants recorded the number of bowel movements per day in a daily diary. The total number of BMs per day were averaged over the 12-week period. A negative change from Baseline indicates improvement. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Treatment Period | First dose of study drug to within 30 days of last dose of study drug in the Double-Blind Treatment Period (Up to 17.6 Weeks) | 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. A TEAE was an AE reported after the first dose of randomized treatment on Day 1. |
| Number of Participants With TEAEs in the Open-Label Extension Period | First dose of study drug to within 30 days of last dose of study drug in the Open-Label Extension Period (Up to 54.3 Weeks) | 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. A TEAE was an AE reported after the first dose of randomized treatment on Day 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Urinary 5-hydroxyindoleacetic Acid (u5-HIAA) Levels | Baseline and Week 12 | u5-HIAA is a standard test used in clinical practice to assess neuroendocrine tumor (NET) activity and is collected as a 24-hour urine specimen. A negative change from Baseline indicates improvement. |
| Change From Baseline in the Number of Daily Cutaneous Flushing Episodes Averaged Across All Time-Points | Baseline and 12 Weeks | Participants recorded the number daily flushing episodes per day in a daily diary. The total number of flushing episodes per day were averaged over the 12-week period. A negative change from Baseline indicates improvement. |
| Change From Baseline in Abdominal Pain Averaged Across All Time-Points | Baseline and 12 Weeks | Participants recorded abdominal pain in a daily diary. Participants evaluated the level of any abdominal pain using an 11-point numeric rating scale, where: 0=no pain to 10=worst pain ever experienced. The average daily abdominal pain was averaged over the 12-week period. A negative change from Baseline indicates improvement. |
Countries
Australia, Belgium, Canada, France, Germany, Israel, Italy, Netherlands, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 48 investigative sites in Australia, Belgium, Canada, France, Germany, Israel, Italy, Netherlands, Spain, Sweden, United Kingdom, and the United States from 08 January 2013 to 21 March 2016.
Pre-assignment details
Patients with Carcinoid Syndrome not adequately controlled by somatostatin analog (SSA) therapy were assigned in a 1:1:1 ratio to receive placebo, 250 mg or 500 mg telotristat etiprate (LX1606) in the double-blind period and were eligible to receive 500 mg telotristat etiprate in the 36 week open-label extension. 136 randomized;1 patient twice.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Following a 3 to 4-week run-in period on stable-dose SSA therapy (octreotide or lanreotide) participants were randomized to receive two placebo-matching telotristat etiprate tablets administered three times daily for 12 weeks in the double-blind treatment period, followed by a 36 week open-label extension period. | 45 |
| 250 mg Telotristat Etiprate Following a 3 to 4-week run-in period on stable-dose somatostatin analog (SSA) therapy (octreotide or lanreotide) participants were randomized to receive one 250 mg telotristat etiprate tablet plus one placebo-matching telotristat etiprate tablet administered three times daily for 12 Weeks in the double-blind treatment period, followed by a 36 week open-label extension period. | 45 |
| 500 mg Telotristat Etiprate Following a 3 to 4-week run-in period on stable-dose SSA therapy (octreotide or lanreotide) participants were randomized to receive, one telotristat etiprate 250 mg plus one placebo-matching telotristat etiprate tablet administered 3 times daily for 1 week, followed by two telotristat etiprate (250 mg) tablets administered three times daily for 11 weeks in the double-blind treatment period, followed by a 36 week open-label extension period. | 45 |
| Total | 135 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double-Blind Treatment Period | Adverse Event | 6 | 2 | 3 | 0 |
| Double-Blind Treatment Period | Physician Decision | 0 | 0 | 1 | 0 |
| Double-Blind Treatment Period | Reason Not Specified | 0 | 1 | 0 | 0 |
| Double-Blind Treatment Period | Withdrawal of consent | 1 | 0 | 3 | 0 |
| Open-Label Extension Period (OLE) | Adverse Event | 0 | 0 | 0 | 15 |
| Open-Label Extension Period (OLE) | Lack of Efficacy | 0 | 0 | 0 | 5 |
| Open-Label Extension Period (OLE) | Lost to Follow-up | 0 | 0 | 0 | 1 |
| Open-Label Extension Period (OLE) | Physician Decision | 0 | 0 | 0 | 4 |
| Open-Label Extension Period (OLE) | Reason not Specified | 0 | 0 | 0 | 2 |
| Open-Label Extension Period (OLE) | Withdrawal of Consent | 0 | 0 | 0 | 9 |
Baseline characteristics
| Characteristic | 250 mg Telotristat Etiprate | Total | 500 mg Telotristat Etiprate | Placebo |
|---|---|---|---|---|
| Age, Continuous | 62.4 years STANDARD_DEVIATION 9.12 | 63.2 years STANDARD_DEVIATION 9.28 | 64.9 years STANDARD_DEVIATION 9.06 | 63.3 years STANDARD_DEVIATION 8.67 |
| Age, Customized < 65 years | 26 Participants | 73 Participants | 22 Participants | 25 Participants |
| Age, Customized ≥ 65 years | 19 Participants | 62 Participants | 23 Participants | 20 Participants |
| Body Mass Index (BMI) | 24.26 kg/m^2 STANDARD_DEVIATION 4.702 | 24.87 kg/m^2 STANDARD_DEVIATION 4.931 | 25.24 kg/m^2 STANDARD_DEVIATION 5.352 | 25.13 kg/m^2 STANDARD_DEVIATION 4.79 |
| Childbearing Potential No | 24 Participants | 62 Participants | 20 Participants | 18 Participants |
| Childbearing Potential Not Applicable | 21 Participants | 70 Participants | 25 Participants | 24 Participants |
| Childbearing Potential Yes | 0 Participants | 3 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 44 Participants | 133 Participants | 44 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Height | 169.32 centimeter (cm) STANDARD_DEVIATION 9.607 | 169.35 centimeter (cm) STANDARD_DEVIATION 10.175 | 169.93 centimeter (cm) STANDARD_DEVIATION 10.436 | 168.8 centimeter (cm) STANDARD_DEVIATION 10.707 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 11 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) White | 41 Participants | 121 Participants | 40 Participants | 40 Participants |
| Region Europe | 28 Participants | 83 Participants | 28 Participants | 27 Participants |
| Region North America | 15 Participants | 44 Participants | 14 Participants | 15 Participants |
| Region Rest of the World | 2 Participants | 8 Participants | 3 Participants | 3 Participants |
| Region of Enrollment Australia | 2 participants | 6 participants | 3 participants | 1 participants |
| Region of Enrollment Belgium | 0 participants | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Canada | 2 participants | 7 participants | 2 participants | 3 participants |
| Region of Enrollment France | 4 participants | 11 participants | 4 participants | 3 participants |
| Region of Enrollment Germany | 8 participants | 19 participants | 6 participants | 5 participants |
| Region of Enrollment Israel | 0 participants | 2 participants | 0 participants | 2 participants |
| Region of Enrollment Italy | 4 participants | 8 participants | 3 participants | 1 participants |
| Region of Enrollment Netherlands | 3 participants | 8 participants | 3 participants | 2 participants |
| Region of Enrollment Spain | 3 participants | 8 participants | 1 participants | 4 participants |
| Region of Enrollment Sweden | 3 participants | 9 participants | 3 participants | 3 participants |
| Region of Enrollment United Kingdom | 3 participants | 19 participants | 8 participants | 8 participants |
| Region of Enrollment United States | 13 participants | 37 participants | 12 participants | 12 participants |
| Sex: Female, Male Female | 24 Participants | 65 Participants | 20 Participants | 21 Participants |
| Sex: Female, Male Male | 21 Participants | 70 Participants | 25 Participants | 24 Participants |
| Somatostatin Analog (SSA) Therapy Schedule at Study Entry 3-Week | 11 Participants | 39 Participants | 17 Participants | 11 Participants |
| Somatostatin Analog (SSA) Therapy Schedule at Study Entry 4-Week | 34 Participants | 96 Participants | 28 Participants | 34 Participants |
| SSA Therapy Name at Study Entry Lanreotide | 5 Participants | 32 Participants | 12 Participants | 15 Participants |
| SSA Therapy Name at Study Entry Octreotide | 40 Participants | 103 Participants | 33 Participants | 30 Participants |
| Urinary 5-hydroxyindoleacetic acid (u5-HIAA) at Randomization ≤ULN | 12 Participants | 36 Participants | 12 Participants | 12 Participants |
| Urinary 5-hydroxyindoleacetic acid (u5-HIAA) at Randomization >ULN | 26 Participants | 78 Participants | 26 Participants | 26 Participants |
| Urinary 5-hydroxyindoleacetic acid (u5-HIAA) at Randomization Unknown | 7 Participants | 21 Participants | 7 Participants | 7 Participants |
| Weight | 70.05 kilogram (kg) STANDARD_DEVIATION 14.832 | 71.46 kilogram (kg) STANDARD_DEVIATION 16.419 | 73.44 kilogram (kg) STANDARD_DEVIATION 19.971 | 70.87 kilogram (kg) STANDARD_DEVIATION 13.94 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 45 | 1 / 45 | 1 / 45 | 9 / 115 |
| other Total, other adverse events | 39 / 45 | 37 / 45 | 42 / 45 | 110 / 115 |
| serious Total, serious adverse events | 7 / 45 | 7 / 45 | 8 / 45 | 37 / 115 |
Outcome results
Primary
Change From Baseline in the Number of Bowel Movements (BMs) Per Day Averaged Over 12 Weeks
Participants recorded the number of bowel movements per day in a daily diary. The total number of BMs per day were averaged over the 12-week period. A negative change from Baseline indicates improvement.
Time frame: Baseline and 12 Weeks
Population: Participants from the Intent-to-treat population, all randomized participants, with data available were included in the analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Number of Bowel Movements (BMs) Per Day Averaged Over 12 Weeks | -0.623 counts/day | Standard Deviation 0.8275 |
| 250 mg Telotristat Etiprate | Change From Baseline in the Number of Bowel Movements (BMs) Per Day Averaged Over 12 Weeks | -1.433 counts/day | Standard Deviation 1.3652 |
| 500 mg Telotristat Etiprate | Change From Baseline in the Number of Bowel Movements (BMs) Per Day Averaged Over 12 Weeks | -1.455 counts/day | Standard Deviation 1.3098 |
Comparison: Primary analysis used a blocked 2-sample Wilcoxon rank sum statistic stratified by the urinary 5-HIAA stratification at randomization.p-value: <0.00195% CI: [-1.283, -0.337]Wilcoxon rank sum
Comparison: Primary analysis used a blocked 2-sample Wilcoxon rank sum statistic stratified by the urinary 5-HIAA stratification at randomization.p-value: <0.00195% CI: [-1.292, -0.374]Wilcoxon rank sum
Primary
Number of Participants With TEAEs in the Open-Label 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. A TEAE was an AE reported after the first dose of randomized treatment on Day 1.
Time frame: First dose of study drug to within 30 days of last dose of study drug in the Open-Label Extension Period (Up to 54.3 Weeks)
Population: Safety population, defined as all subjects who received at least one dose of study drug was used for analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With TEAEs in the Open-Label Extension Period | 110 Participants |
Primary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Treatment 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. A TEAE was an AE reported after the first dose of randomized treatment on Day 1.
Time frame: First dose of study drug to within 30 days of last dose of study drug in the Double-Blind Treatment Period (Up to 17.6 Weeks)
Population: Safety population, defined as all subjects who received at least one dose of study drug was used for analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Treatment Period | 39 Participants |
| 250 mg Telotristat Etiprate | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Treatment Period | 37 Participants |
| 500 mg Telotristat Etiprate | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Treatment Period | 42 Participants |
Secondary
Change From Baseline in Abdominal Pain Averaged Across All Time-Points
Participants recorded abdominal pain in a daily diary. Participants evaluated the level of any abdominal pain using an 11-point numeric rating scale, where: 0=no pain to 10=worst pain ever experienced. The average daily abdominal pain was averaged over the 12-week period. A negative change from Baseline indicates improvement.
Time frame: Baseline and 12 Weeks
Population: Participants from the Intent-to-treat population, all randomized participants, with available data were included in the analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Abdominal Pain Averaged Across All Time-Points | -0.226 units on a scale | Standard Deviation 1.1601 |
| 250 mg Telotristat Etiprate | Change From Baseline in Abdominal Pain Averaged Across All Time-Points | -0.489 units on a scale | Standard Deviation 1.4423 |
| 500 mg Telotristat Etiprate | Change From Baseline in Abdominal Pain Averaged Across All Time-Points | -0.333 units on a scale | Standard Deviation 1.1784 |
Secondary
Change From Baseline in the Number of Daily Cutaneous Flushing Episodes Averaged Across All Time-Points
Participants recorded the number daily flushing episodes per day in a daily diary. The total number of flushing episodes per day were averaged over the 12-week period. A negative change from Baseline indicates improvement.
Time frame: Baseline and 12 Weeks
Population: Participants from the Intent-to-treat population, all randomized participants, with data available were included in the analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Number of Daily Cutaneous Flushing Episodes Averaged Across All Time-Points | -0.164 counts/day | Standard Deviation 1.1572 |
| 250 mg Telotristat Etiprate | Change From Baseline in the Number of Daily Cutaneous Flushing Episodes Averaged Across All Time-Points | -0.296 counts/day | Standard Deviation 1.3097 |
| 500 mg Telotristat Etiprate | Change From Baseline in the Number of Daily Cutaneous Flushing Episodes Averaged Across All Time-Points | -0.525 counts/day | Standard Deviation 1.3413 |
Secondary
Change From Baseline in Urinary 5-hydroxyindoleacetic Acid (u5-HIAA) Levels
u5-HIAA is a standard test used in clinical practice to assess neuroendocrine tumor (NET) activity and is collected as a 24-hour urine specimen. A negative change from Baseline indicates improvement.
Time frame: Baseline and Week 12
Population: Participants from the Intent-to-treat population, all randomized participants, with u5-HIAA data available at Baseline and Week 12 were included in the analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Urinary 5-hydroxyindoleacetic Acid (u5-HIAA) Levels | 11.350 mg/24 hours | Standard Deviation 35.0346 |
| 250 mg Telotristat Etiprate | Change From Baseline in Urinary 5-hydroxyindoleacetic Acid (u5-HIAA) Levels | -40.134 mg/24 hours | Standard Deviation 84.7663 |
| 500 mg Telotristat Etiprate | Change From Baseline in Urinary 5-hydroxyindoleacetic Acid (u5-HIAA) Levels | -57.519 mg/24 hours | Standard Deviation 82.3273 |