Carcinoid Syndrome
Conditions
Brief summary
The purpose of the study is to evaluate the effect of telotristat etiprate versus placebo on the incidence of treatment-emergent adverse events and on 5-hydroxyindoleacetic acid (5-HIAA) levels.
Interventions
Telotristat etiprate tablets
DRUGPlacebo
Placebo-matching telotristat etiprate tablets
Sponsors
Lexicon Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients ≥ 18 years of age * All patients of reproductive potential must agree to use an adequate method of contraception during the study and for 12 weeks after the Follow-up visit. * Histopathologically-confirmed, well-differentiated metastatic neuroendocrine tumor * Documented history of carcinoid syndrome * Patient is able and willing to provide written informed consent prior to participation
Exclusion criteria
* Presence of diarrhea attributed to any condition other than carcinoid syndrome. * Presence of 12 or more watery bowel movements per day * Positive stool examination for enteric pathogens, pathogenic ova or parasites, of Clostridium difficile at Screening * Karnofsky Performance Status ≤ 60% * Presence of any clinically significant laboratory, medical history, or physical examination findings deemed unacceptable by the Investigator * A history of short bowel syndrome * History of constipation within 2 years of Screening * Life expectancy \< 12 months from Screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 17.1 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. |
| Primary: Percent Change From Baseline in Urinary 5-hydroxyindoleacetic Acid (u5-HIAA) Levels | Baseline and 12 Weeks | 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. |
| Number of Participants With Treatment-Emergent Adverse Events (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 52.6 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| Change From Baseline in the Number of Daily BMs Averaged Over the 12-Week Double-Blind Period, Among Participants Who Were Not Receiving SSA Therapy at Baseline | 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. |
| Change in the Frequency of Rescue Short-acting, Somatostatin Analog (SSA) Used to Treat Carcinoid Syndrome Symptoms Averaged Across All Time-Points | Baseline and 12 weeks | The frequency (the number of times) the participant used rescue with SSA to control symptoms was recorded in a daily diary. The daily number of rescue treatments with SSA was averaged over the 12- week period. A negative change from Baseline (less use of SSA) indicates improvement. |
| Change From Baseline in Stool Form/Consistency Averaged Across All Time-Points | Baseline and 12 Weeks | Participants assessed stool form/consistency of a BM using the Bristol Stool Form Scale where: 1=hard lumps to 7=watery liquid. The daily scores were averaged over the 12-week period. A negative change 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. |
Countries
Australia, Belgium, Canada, France, Germany, Israel, Netherlands, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 31 investigative sites in Australia, Belgium, Canada, France, Germany, Israel, Netherlands, Spain, Sweden, United Kingdom, and the United States from 11 Mar 2014 to 29 Mar 2016.
Pre-assignment details
Participants with Carcinoid Syndrome not adequately controlled by somatostatin analog (SSA) therapy were randomly assigned in a 1:1:1 ratio to receive placebo, 250 mg or 500 mg telotristat etiprate (LX1606) in the double-blind treatment period and were eligible to receive 500 mg telotristat etiprate in the open-label extension period.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Following a 3 to 4-week run-in period, participants were randomized to receive two placebo-matching telotristat etiprate tablets administered three times daily for 12 weeks, followed by a 36 week open-label extension period. | 26 |
| 250 mg Telotristat Etiprate Following a 3 to 4-week run-in period, participants were randomized to receive one 250 mg telotristat etiprate tablet and one placebo-matching telotristat etiprate tablet administered three times daily for 12 weeks, followed by a 36 week open-label extension period. | 25 |
| 500 mg Telotristat Etiprate Following a 3 to 4-week run-in period, participants were randomized to receive one 250 mg telotristat etiprate tablet and one placebo-matching telotristat etiprate tablet administered three times daily for one week, followed by two 250 mg telotristat etiprate tablets administered three times daily for 11 weeks in the 12 week double-blind treatment period, followed by a 36 week open-label extension period. | 25 |
| Total | 76 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double-Blind Treatment Period | Adverse Event | 1 | 2 | 0 | 0 |
| Double-Blind Treatment Period | Physician Decision | 1 | 0 | 0 | 0 |
| Double-Blind Treatment Period | Withdrawal of consent | 0 | 1 | 3 | 0 |
| Open-Label Extension Period (OLE) | Adverse Event | 0 | 0 | 0 | 7 |
| Open-Label Extension Period (OLE) | Lack of Efficacy | 0 | 0 | 0 | 1 |
| Open-Label Extension Period (OLE) | Physician Decision | 0 | 0 | 0 | 1 |
| 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 | Placebo | 500 mg Telotristat Etiprate |
|---|---|---|---|---|
| Age, Continuous | 63.6 years STANDARD_DEVIATION 12.62 | 62.8 years STANDARD_DEVIATION 11.52 | 62.2 years STANDARD_DEVIATION 10.32 | 62.7 years STANDARD_DEVIATION 11.97 |
| Age, Customized < 65 years | 14 Participants | 41 Participants | 12 Participants | 15 Participants |
| Age, Customized ≥ 65 years | 11 Participants | 35 Participants | 14 Participants | 10 Participants |
| Baseline Body Mass Index (BMI) | 25.96 kg/m^2 STANDARD_DEVIATION 5.258 | 26.16 kg/m^2 STANDARD_DEVIATION 6.521 | 26.28 kg/m^2 STANDARD_DEVIATION 4.364 | 26.21 kg/m^2 STANDARD_DEVIATION 9.213 |
| Childbearing Potential No | 7 Participants | 27 Participants | 11 Participants | 9 Participants |
| Childbearing Potential Not Applicable | 14 Participants | 42 Participants | 13 Participants | 15 Participants |
| Childbearing Potential Yes | 4 Participants | 7 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants | 75 Participants | 25 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Height | 169.74 cm STANDARD_DEVIATION 10.025 | 169.76 cm STANDARD_DEVIATION 9.327 | 169.48 cm STANDARD_DEVIATION 9.765 | 170.08 cm STANDARD_DEVIATION 8.525 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 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 | 0 Participants | 0 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 | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 25 Participants | 73 Participants | 25 Participants | 23 Participants |
| Region Europe | 16 Participants | 44 Participants | 16 Participants | 12 Participants |
| Region North America | 6 Participants | 18 Participants | 4 Participants | 8 Participants |
| Region Rest of the World | 3 Participants | 14 Participants | 6 Participants | 5 Participants |
| Region of Enrollment Australia | 0 Participants | 7 Participants | 4 Participants | 3 Participants |
| Region of Enrollment Belgium | 2 Participants | 5 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Canada | 1 Participants | 2 Participants | 0 Participants | 1 Participants |
| Region of Enrollment France | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment Germany | 2 Participants | 7 Participants | 3 Participants | 2 Participants |
| Region of Enrollment Israel | 3 Participants | 7 Participants | 2 Participants | 2 Participants |
| Region of Enrollment Netherlands | 2 Participants | 6 Participants | 3 Participants | 1 Participants |
| Region of Enrollment Spain | 5 Participants | 10 Participants | 1 Participants | 4 Participants |
| Region of Enrollment Sweden | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United Kingdom | 3 Participants | 13 Participants | 7 Participants | 3 Participants |
| Region of Enrollment United States | 5 Participants | 16 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Female | 11 Participants | 34 Participants | 13 Participants | 10 Participants |
| Sex: Female, Male Male | 14 Participants | 42 Participants | 13 Participants | 15 Participants |
| Somatostatin Analog (SSA) Therapy Schedule at Study Entry 3-Week | 7 Participants | 22 Participants | 6 Participants | 9 Participants |
| Somatostatin Analog (SSA) Therapy Schedule at Study Entry 4-Week | 15 Participants | 46 Participants | 20 Participants | 11 Participants |
| Somatostatin Analog (SSA) Therapy Schedule at Study Entry Not on SSA | 3 Participants | 8 Participants | 0 Participants | 5 Participants |
| SSA Therapy Name at Study Entry Lanreotide | 5 Participants | 22 Participants | 14 Participants | 3 Participants |
| SSA Therapy Name at Study Entry Not Applicable | 3 Participants | 8 Participants | 0 Participants | 5 Participants |
| SSA Therapy Name at Study Entry Octreotide | 17 Participants | 45 Participants | 12 Participants | 16 Participants |
| SSA Therapy Name at Study Entry Unknown | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Urinary 5-Hydroxyindoleacetic acid (5-HIAA) at Randomization ≤ ULN | 5 Participants | 22 Participants | 9 Participants | 8 Participants |
| Urinary 5-Hydroxyindoleacetic acid (5-HIAA) at Randomization > ULN | 18 Participants | 52 Participants | 17 Participants | 17 Participants |
| Urinary 5-Hydroxyindoleacetic acid (5-HIAA) at Randomization Unknown | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Weight | 74.74 kg STANDARD_DEVIATION 17.839 | 75.94 kg STANDARD_DEVIATION 20.442 | 76.38 kg STANDARD_DEVIATION 16.959 | 76.69 kg STANDARD_DEVIATION 26.188 |
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 | 0 / 26 | 0 / 25 | 0 / 25 | 0 / 67 |
| other Total, other adverse events | 21 / 26 | 25 / 25 | 22 / 25 | 61 / 67 |
| serious Total, serious adverse events | 5 / 26 | 1 / 25 | 3 / 25 | 17 / 67 |
Outcome results
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 17.1 Weeks)
Population: Safety population, defined as all participants 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 | 21 Participants |
| 250 mg Telotristat Etiprate | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Treatment Period | 25 Participants |
| 500 mg Telotristat Etiprate | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Treatment Period | 22 Participants |
Primary
Number of Participants With Treatment-Emergent Adverse Events (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 52.6 Weeks)
Population: Safety population, defined as all participants 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 Open-Label Extension Period | 61 Participants |
Primary
Primary: Percent 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 12 Weeks
Population: Participants from the Intent-to-treat population, all randomized participants, with data available for this endpoint were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Primary: Percent Change From Baseline in Urinary 5-hydroxyindoleacetic Acid (u5-HIAA) Levels | 97.721 percentage change of mg/24 hours | Standard Deviation 397.0107 |
| 250 mg Telotristat Etiprate | Primary: Percent Change From Baseline in Urinary 5-hydroxyindoleacetic Acid (u5-HIAA) Levels | -33.164 percentage change of mg/24 hours | Standard Deviation 58.4754 |
| 500 mg Telotristat Etiprate | Primary: Percent Change From Baseline in Urinary 5-hydroxyindoleacetic Acid (u5-HIAA) Levels | -76.466 percentage change of mg/24 hours | Standard Deviation 17.3714 |
Comparison: The primary analysis used a blocked 2-sample Wilcoxon rank sum statistic stratified by the u5-HIAA at randomization.p-value: <0.00195% CI: [-84.955, -25.119]Wilcoxon rank sum
Comparison: The primary analysis used a blocked 2-sample Wilcoxon rank sum statistic stratified by the u5-HIAA at randomization.p-value: <0.00195% CI: [-113.104, -63.863]Wilcoxon rank sum
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 data available for this endpoint were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Abdominal Pain Averaged Across All Time-Points | -0.063 score on a scale | Standard Deviation 0.7823 |
| 250 mg Telotristat Etiprate | Change From Baseline in Abdominal Pain Averaged Across All Time-Points | -0.234 score on a scale | Standard Deviation 0.9697 |
| 500 mg Telotristat Etiprate | Change From Baseline in Abdominal Pain Averaged Across All Time-Points | 0.025 score on a scale | Standard Deviation 0.7744 |
Secondary
Change From Baseline in Stool Form/Consistency Averaged Across All Time-Points
Participants assessed stool form/consistency of a BM using the Bristol Stool Form Scale where: 1=hard lumps to 7=watery liquid. The daily scores were averaged over the 12-week period. A negative change indicates improvement.
Time frame: Baseline and 12 Weeks
Population: Participants from the Intent-to-treat population, all randomized participants, with data available for this endpoint were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Stool Form/Consistency Averaged Across All Time-Points | 0.006 score on a scale | Standard Deviation 0.4127 |
| 250 mg Telotristat Etiprate | Change From Baseline in Stool Form/Consistency Averaged Across All Time-Points | -0.196 score on a scale | Standard Deviation 0.7012 |
| 500 mg Telotristat Etiprate | Change From Baseline in Stool Form/Consistency Averaged Across All Time-Points | -0.597 score on a scale | Standard Deviation 0.8605 |
Secondary
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 for this endpoint were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Number of Bowel Movements (BMs) Per Day Averaged Over 12 Weeks | 0.050 counts/day | Standard Deviation 0.3263 |
| 250 mg Telotristat Etiprate | Change From Baseline in the Number of Bowel Movements (BMs) Per Day Averaged Over 12 Weeks | -0.452 counts/day | Standard Deviation 0.694 |
| 500 mg Telotristat Etiprate | Change From Baseline in the Number of Bowel Movements (BMs) Per Day Averaged Over 12 Weeks | -0.595 counts/day | Standard Deviation 0.724 |
Secondary
Change From Baseline in the Number of Daily BMs Averaged Over the 12-Week Double-Blind Period, Among Participants Who Were Not Receiving SSA Therapy at Baseline
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 for this endpoint were included in the analysis.The Placebo arm is not included because all participants in the Placebo arm were receiving SSA therapy at Baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Number of Daily BMs Averaged Over the 12-Week Double-Blind Period, Among Participants Who Were Not Receiving SSA Therapy at Baseline | -0.906 counts/day | Standard Deviation 0.5925 |
| 250 mg Telotristat Etiprate | Change From Baseline in the Number of Daily BMs Averaged Over the 12-Week Double-Blind Period, Among Participants Who Were Not Receiving SSA Therapy at Baseline | -0.98 counts/day | Standard Deviation 1.154 |
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 for this endpoint were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Number of Daily Cutaneous Flushing Episodes Averaged Across All Time-Points | -0.333 counts/day | Standard Deviation 1.2203 |
| 250 mg Telotristat Etiprate | Change From Baseline in the Number of Daily Cutaneous Flushing Episodes Averaged Across All Time-Points | -0.061 counts/day | Standard Deviation 0.9754 |
| 500 mg Telotristat Etiprate | Change From Baseline in the Number of Daily Cutaneous Flushing Episodes Averaged Across All Time-Points | 0.114 counts/day | Standard Deviation 2.0992 |
Secondary
Change in the Frequency of Rescue Short-acting, Somatostatin Analog (SSA) Used to Treat Carcinoid Syndrome Symptoms Averaged Across All Time-Points
The frequency (the number of times) the participant used rescue with SSA to control symptoms was recorded in a daily diary. The daily number of rescue treatments with SSA was averaged over the 12- week period. A negative change from Baseline (less use of SSA) indicates improvement.
Time frame: Baseline and 12 weeks
Population: Participants from the Intent-to-treat population, all randomized participants, with data available for this endpoint were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in the Frequency of Rescue Short-acting, Somatostatin Analog (SSA) Used to Treat Carcinoid Syndrome Symptoms Averaged Across All Time-Points | -0.013 counts/day | Standard Deviation 0.1359 |
| 250 mg Telotristat Etiprate | Change in the Frequency of Rescue Short-acting, Somatostatin Analog (SSA) Used to Treat Carcinoid Syndrome Symptoms Averaged Across All Time-Points | -0.065 counts/day | Standard Deviation 0.3542 |
| 500 mg Telotristat Etiprate | Change in the Frequency of Rescue Short-acting, Somatostatin Analog (SSA) Used to Treat Carcinoid Syndrome Symptoms Averaged Across All Time-Points | 0.006 counts/day | Standard Deviation 0.103 |