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Clinical Trial Results:
A Phase 3, Randomized, Placebo-controlled, Parallel-group, Multicenter, Double-blind Study to Evaluate the Efficacy and Safety of Telotristat Etiprate (LX1606) in Patients with Carcinoid Syndrome not Adequately Controlled by Somatostatin Analog (SSA) Therapy

Summary
EudraCT number	2012-003460-47
Trial protocol	GB DE NL ES IT BE FR
Global end of trial date	21 Mar 2016

Results information
Results version number	v1(current)
This version publication date	27 Jan 2018
First version publication date	27 Jan 2018
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

LX1606-301-CS

ISRCTN number

-

US NCT number

NCT01677910

WHO universal trial number (UTN)

-

Sponsor organisation name

Lexicon Pharmaceuticals, Inc.

Sponsor organisation address

8800 Technology Forest Place, The Woodlands, United States, 77381-1160

Public contact

Pablo Lapuerta, MD, Executive Vice President and Chief Medical Officer, Lexicon Pharmaceuticals, Inc., +1 (908) 360-4774, plapuerta@lexpharma.com

Scientific contact

Pablo Lapuerta, MD, Executive Vice President and Chief Medical Officer, Lexicon Pharmaceuticals, Inc., +1 (908) 360-4774, plapuerta@lexpharma.com

Is trial part of an agreed paediatric investigation plan (PIP)

No

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Analysis stage

Final

Date of interim/final analysis

21 Mar 2016

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

21 Mar 2016

Was the trial ended prematurely?

No

Main objective of the trial

The primary objective of the study was to confirm that at least 1 or more treatment groups of telotristat ethyl compared with placebo was effective in reducing the number of BMs/day from Baseline averaged over the 12-week DBT Period of the study in patients not adequately controlled by current SSA therapy.

Protection of trial subjects

All study participants were required to read and sign an Informed Consent Form.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

08 Jan 2013

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 6

Country: Number of subjects enrolled

Belgium: 1

Country: Number of subjects enrolled

Canada: 7

Country: Number of subjects enrolled

France: 11

Country: Number of subjects enrolled

Germany: 19

Country: Number of subjects enrolled

Israel: 2

Country: Number of subjects enrolled

Italy: 8

Country: Number of subjects enrolled

Netherlands: 8

Country: Number of subjects enrolled

Spain: 8

Country: Number of subjects enrolled

Sweden: 9

Country: Number of subjects enrolled

United Kingdom: 19

Country: Number of subjects enrolled

United States: 38

Worldwide total number of subjects

136

EEA total number of subjects

83

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

73

From 65 to 84 years

62

85 years and over

1

Subject disposition

Top of page

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.

Screening 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 36 week open-label extension period.

Number of subjects started

136

Number of subjects completed

135

Reason: Number of subjects

Subject Randomized twice: 1

Period 1 title

Double-Blind Treatment Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

Placebo

Arm description

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.

Arm type

Placebo

Investigational medicinal product name

placebo-matching telotristat etiprate

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

placebo-matching telotristat etiprate tablet(s) administered three times daily.

250 mg Telotristat Etiprate

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

placebo-matching telotristat etiprate

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

placebo-matching telotristat etiprate tablet(s) administered three times daily.

Investigational medicinal product name

telotristat etiprate

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

telotristat etiprate tablet(s) administered 3 times daily for 12 weeks

500 mg Telotristat Etiprate

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

telotristat etiprate

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

telotristat etiprate tablet(s) administered 3 times daily for 12 weeks

Investigational medicinal product name

placebo-matching telotristat etiprate

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

placebo-matching telotristat etiprate tablet(s) administered three times daily.

Number of subjects in period 1 ^[1]	Placebo	250 mg Telotristat Etiprate	500 mg Telotristat Etiprate
Started	45	45	45
Completed	38	42	38
Not completed	7	3	7
Physician decision	-	-	1
Adverse event, non-fatal	6	2	3
Other	-	1	-
Withdrawal of consent	1	-	3

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: One patient was randomized twice and is not included in the baseline period.

Period 2 title

Open-Label Extension Period (OLE)

Is this the baseline period?

No

Allocation method

Not applicable

Blinding used

Not blinded

Telotristat Etiprate Open-Label Extension

Arm description

Patients previously assigned to 250 mg or 500 mg three times daily of telotristat etiprate were administered two 250 mg telotristat etiprate tablets three times daily in a 36 week open-label extension (OLE) period. Patients previously assigned to placebo were administered one 250 mg telotristat etiprate tablet plus one placebo-matching tablet three times daily for one week, followed by two 250 mg telotristat etiprate tablets three times daily for 35 weeks.

Arm type

Experimental

Investigational medicinal product name

telotristat etiprate

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

telotristat etiprate tablet(s) administered 3 times daily.

Investigational medicinal product name

placebo-matching telotristat etiprate

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

placebo-matching telotristat etiprate tablet(s) administered three times daily.

Number of subjects in period 2 ^[2]	Telotristat Etiprate Open-Label Extension
Started	115
Completed	79
Not completed	36
Physician decision	4
Adverse event, non-fatal	15
Withdrawal of consent	9
Lost to follow-up	1
Lack of efficacy	5
Other not specified	2

Notes
[2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Not all subjects who participated in the double-blind treatment period participated in the open-label extension.

Baseline characteristics

Top of page

Reporting group title

Placebo

Reporting group description

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.

Reporting group title

250 mg Telotristat Etiprate

Reporting group description

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.

Reporting group title

500 mg Telotristat Etiprate

Reporting group description

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.

Reporting group values	Placebo	250 mg Telotristat Etiprate	500 mg Telotristat Etiprate	Total
Number of subjects	45	45	45	135
Age categorical
Units: Subjects
<65 years	25	26	22	73
≥65 years	20	19	23	62
Age continuous
Units: years
arithmetic mean (standard deviation)	63.3 ( 8.67 )	62.4 ( 9.12 )	64.9 ( 9.06 )	-
Gender categorical
Units: Subjects
Female	21	24	20	65
Male	24	21	25	70
Ethnicity
Ethnicity data was not provided for 1 participant in France.
Units: Subjects
Hispanic or Latino	0	0	1	1
Not Hispanic or Latino	45	44	44	133
No data	0	1	0	1
Race
Race data was not provided for 11 subjects in France.
Units: Subjects
White	40	41	40	121
Black or African American	1	0	0	1
Asian	0	0	0	0
American Indian or Alaska Native	1	0	0	1
Native Hawaiian or Other Pacific Islander	0	0	0	0
Other	0	0	1	1
No data	3	4	4	11
Somatostatin Analog (SSA) Therapy Schedule at Study Entry
Patients who were on a 2-week SSA therapy or receiving SSA therapy via a subcutaneous continuous infusion pump are included in the "4-week" category.
Units: Subjects
3-Week	11	11	17	39
4-Week	34	34	28	96
SSA Therapy Name at Study Entry
Units: Subjects
Octreotide	30	40	33	103
Lanreotide	15	5	12	32
Childbearing Potential
Units: Subjects
Yes	3	0	0	3
No	18	24	20	62
Not Applicable	24	21	25	70
Urinary 5-HIAA at Randomization
ULN=upper limit of normal
Units: Subjects
≤ULN	12	12	12	36
>ULN	26	26	26	78
Unknown	7	7	7	21
Country
Units: Subjects
USA	12	13	12	37
Australia	1	2	3	6
Belgium	1	0	0	1
Canada	3	2	2	7
France	3	4	4	11
Germany	5	8	6	19
Israel	2	0	0	2
Italy	1	4	3	8
Netherlands	2	3	3	8
Spain	4	3	1	8
Sweden	3	3	3	9
United Kingdom	8	3	8	19
Region
North America includes USA and Canada; Europe includes Belgium, France, Germany, Italy, Netherlands, Spain, Sweden, and United Kingdom; Rest of the World includes Australia and Israel.
Units: Subjects
North America	15	15	14	44
Europe	27	28	28	83
Rest of the World	3	2	3	8
Weight
Weight data was available for 131 subjects; N=43 subjects in the Placebo arm, N=44 subjects in the 250 mg telotristat etiprate arm and N=44 subjects in the 500 mg telotristat etiprate arm.
Units: kg
arithmetic mean (standard deviation)	70.87 ( 13.94 )	70.05 ( 14.832 )	73.44 ( 19.971 )	-
Height
Height data was available for 120 subjects; N=39 subjects in the Placebo arm, N=41 subjects in the 250 mg Telotristat Etiprate arm and N=40 subjects in the 500 mg Telotristat Etiprate arm.
Units: cm
arithmetic mean (standard deviation)	168.8 ( 10.707 )	169.32 ( 9.607 )	169.93 ( 10.436 )	-
Baseline BMI
Body Mass Index (BMI) data was available for 118 subjects; N=38 subjects in the Placebo arm, N=41 subjects in the 250 mg Telotristat Etiprate arm and N=39 subjects in the 500 mg Telotristat Etiprate arm.
Units: kg/m^2
arithmetic mean (standard deviation)	25.13 ( 4.79 )	24.26 ( 4.702 )	25.24 ( 5.352 )	-

Subject analysis set title

Safety Population

Subject analysis set type

Safety analysis

Subject analysis set description

Safety Population includes all participants who received any fraction of a dose of study drug during the study.

Subject analysis sets values	Safety Population
Number of subjects	135
Age categorical
Units: Subjects
<65 years
≥65 years
Age continuous
Units: years
arithmetic mean (standard deviation)	63.5 ( 8.94 )
Gender categorical
Units: Subjects
Female	65
Male	70
Ethnicity
Ethnicity data was not provided for 1 participant in France.
Units: Subjects
Hispanic or Latino	1
Not Hispanic or Latino	133
No data	1
Race
Race data was not provided for 11 subjects in France.
Units: Subjects
White	121
Black or African American	1
Asian	0
American Indian or Alaska Native	1
Native Hawaiian or Other Pacific Islander	0
Other	1
No data	11
Somatostatin Analog (SSA) Therapy Schedule at Study Entry
Patients who were on a 2-week SSA therapy or receiving SSA therapy via a subcutaneous continuous infusion pump are included in the "4-week" category.
Units: Subjects
3-Week	39
4-Week	96
SSA Therapy Name at Study Entry
Units: Subjects
Octreotide	103
Lanreotide	32
Childbearing Potential
Units: Subjects
Yes	3
No	62
Not Applicable	70
Urinary 5-HIAA at Randomization
ULN=upper limit of normal
Units: Subjects
≤ULN	36
>ULN	78
Unknown	21
Country
Units: Subjects
USA	37
Australia	6
Belgium	1
Canada	7
France	11
Germany	19
Israel	2
Italy	8
Netherlands	8
Spain	8
Sweden	9
United Kingdom	19
Region
North America includes USA and Canada; Europe includes Belgium, France, Germany, Italy, Netherlands, Spain, Sweden, and United Kingdom; Rest of the World includes Australia and Israel.
Units: Subjects
North America	44
Europe	83
Rest of the World	8
Weight
Weight data was available for 131 subjects; N=43 subjects in the Placebo arm, N=44 subjects in the 250 mg telotristat etiprate arm and N=44 subjects in the 500 mg telotristat etiprate arm.
Units: kg
arithmetic mean (standard deviation)	71.46 ( 16.419 )
Height
Height data was available for 120 subjects; N=39 subjects in the Placebo arm, N=41 subjects in the 250 mg Telotristat Etiprate arm and N=40 subjects in the 500 mg Telotristat Etiprate arm.
Units: cm
arithmetic mean (standard deviation)	169.35 ( 10.175 )
Baseline BMI
Body Mass Index (BMI) data was available for 118 subjects; N=38 subjects in the Placebo arm, N=41 subjects in the 250 mg Telotristat Etiprate arm and N=39 subjects in the 500 mg Telotristat Etiprate arm.
Units: kg/m^2
arithmetic mean (standard deviation)	24.87 ( 4.931 )

End points

Top of page

Reporting group title

Placebo

Reporting group description

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.

Reporting group title

250 mg Telotristat Etiprate

Reporting group description

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.

Reporting group title

500 mg Telotristat Etiprate

Reporting group description

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.

Reporting group title

Telotristat Etiprate Open-Label Extension

Reporting group description

Patients previously assigned to 250 mg or 500 mg three times daily of telotristat etiprate were administered two 250 mg telotristat etiprate tablets three times daily in a 36 week open-label extension (OLE) period. Patients previously assigned to placebo were administered one 250 mg telotristat etiprate tablet plus one placebo-matching tablet three times daily for one week, followed by two 250 mg telotristat etiprate tablets three times daily for 35 weeks.

Subject analysis set title

Safety Population

Subject analysis set type

Safety analysis

Subject analysis set description

Safety Population includes all participants who received any fraction of a dose of study drug during the study.

Primary: Change from Baseline in the Number of Bowel Movements (BMs) per Day Averaged over 12 Weeks

Top of page

End point title

Change from Baseline in the Number of Bowel Movements (BMs) per Day Averaged over 12 Weeks

End point description

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. Participants from the Intent-to-treat population, all randomized participants, with data available were included in the analyses.

End point type

Primary

End point timeframe

Baseline and 12 Weeks

End point values	Placebo	250 mg Telotristat Etiprate	500 mg Telotristat Etiprate
Number of subjects analysed	45	45	45
Units: counts/day
arithmetic mean (standard deviation)	-0.623 ( 0.8275 )	-1.433 ( 1.3652 )	-1.455 ( 1.3098 )

Statistical Analysis 1

Statistical analysis description

Primary analysis used a blocked 2-sample Wilcoxon rank sum statistic stratified by the urinary 5-HIAA stratification at randomization. Mean difference is calculated as LX1606-Placebo

Comparison groups

250 mg Telotristat Etiprate v Placebo

Number of subjects included in analysis

90

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Wilcoxon rank sum

Parameter type

Mean difference (net)

Point estimate

-0.81

Confidence interval

level

95%

sides

2-sided

lower limit

-1.283

upper limit

0.337

Statistical Analysis 2

Statistical analysis description

Primary analysis used a blocked 2-sample Wilcoxon rank sum statistic stratified by the urinary 5-HIAA stratification at randomization. Mean difference is calculated as LX1606-Placebo

Comparison groups

Placebo v 500 mg Telotristat Etiprate

Number of subjects included in analysis

90

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Wilcoxon rank sum

Parameter type

Mean difference (net)

Point estimate

-0.833

Confidence interval

level

95%

sides

2-sided

lower limit

-1.292

upper limit

-0.374

Primary: Number of Participants with Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period

Top of page

End point title

Number of Participants with Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period ^[1]

End point description

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. Safety population, defined as all subjects who received at least one dose of study drug was used for analysis.

End point type

Primary

End point timeframe

First dose of study drug to within 30 days of last dose of study drug in the Double-Blind Period (Up to 17.6 Weeks)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses are reported for this endpoint.

End point values	Placebo	250 mg Telotristat Etiprate	500 mg Telotristat Etiprate
Number of subjects analysed	45	45	45
Units: Participants	39	37	42

No statistical analyses for this end point

Primary: Number of Participants with TEAEs in the Open-Label Extension Period

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End point title

Number of Participants with TEAEs in the Open-Label Extension Period ^[2]

End point description

An 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. Safety population, defined as all subjects who received at least one dose of study drug was used for analysis.

End point type

Primary

End point timeframe

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)

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses are reported for this endpoint.

End point values	Telotristat Etiprate Open-Label Extension
Number of subjects analysed	115
Units: Participants	110

No statistical analyses for this end point

Secondary: Change from Baseline in Urinary 5-hydroxyindoleacetic Acid (u5-HIAA) Levels

Top of page

End point title

Change from Baseline in Urinary 5-hydroxyindoleacetic Acid (u5-HIAA) Levels

End point description

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. 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.

End point type

Secondary

End point timeframe

Baseline and Week 12

End point values	Placebo	250 mg Telotristat Etiprate	500 mg Telotristat Etiprate
Number of subjects analysed	30	32	31
Units: mg/24 hours
arithmetic mean (standard deviation)	11.35 ( 35.0346 )	-40.134 ( 84.7663 )	-57.519 ( 82.3273 )

No statistical analyses for this end point

Secondary: Change form Baseline in the Number of Daily Cutaneous Flushing Episodes Averaged Across all Time-Points

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End point title

Change form Baseline in the Number of Daily Cutaneous Flushing Episodes Averaged Across all Time-Points

End point description

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. Participants from the Intent-to-treat population, all randomized participants, with data available were included in the analyses.

End point type

Secondary

End point timeframe

Baseline and 12 Weeks

End point values	Placebo	250 mg Telotristat Etiprate	500 mg Telotristat Etiprate
Number of subjects analysed	45	45	45
Units: counts/day
arithmetic mean (standard deviation)	-0.164 ( 1.1572 )	-0.296 ( 1.3097 )	-0.525 ( 1.3413 )

No statistical analyses for this end point

Secondary: Change form Baseline in Abdominal Pain Averaged Across all Time-Points

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End point title

Change form Baseline in Abdominal Pain Averaged Across all Time-Points

End point description

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. Participants from the Intent-to-treat population, all randomized participants, with available data were included in the analyses.

End point type

Secondary

End point timeframe

Baseline and 12 Weeks

End point values	Placebo	250 mg Telotristat Etiprate	500 mg Telotristat Etiprate
Number of subjects analysed	45	45	45
Units: units on a scale
arithmetic mean (standard deviation)	-0.226 ( 1.1601 )	-0.489 ( 1.4423 )	-0.333 ( 1.1784 )

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

First dose of study drug to within 30 days of last dose of study drug (Up to 72.2 Weeks)

Adverse event reporting additional description

Data for the double-blind treatment period and the open-label extension period were analyzed separately. In the Non-Serious Adverse Event section, a result of "0" for a preferred term means that there are no participants in that arm above the 5% threshold.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

15.1

Reporting group title

Placebo

Reporting group description

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.

Reporting group title

250 mg Telotristat Etiprate

Reporting group description

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.

Reporting group title

500 mg Telotristat Etiprate

Reporting group description

Following a 3 to 4-week run-in period on stable-dose SSA therapy (octreotide or lanreotide) participants were randomized to receive, one 250 mg telotristat etiprate tablet plus one placebo-matching telotristat etiprate tablet administered 3 times daily for 1 week, followed by two 250 mg telotristat etiprate tablets administered three times daily for 11 weeks in the double-blind treatment period.

Reporting group title

Telotristat Etiprate Open-Label Extension

Reporting group description

Patients previously assigned to 250 mg or 500 mg three times daily of telotristat etiprate were administered two 250 mg telotristat etiprate tablets three times daily in a 36 week open-label extension (OLE) period. Patients previously assigned to placebo were administered one 250 mg telotristat etiprate tablet plus one placebo-matching tablet three times daily for one week, followed by two 250 mg telotristat etiprate tablets three times daily for 35 weeks.

Serious adverse events	Placebo	250 mg Telotristat Etiprate	500 mg Telotristat Etiprate	Telotristat Etiprate Open-Label Extension
Total subjects affected by serious adverse events
subjects affected / exposed	7 / 45 (15.56%)	7 / 45 (15.56%)	8 / 45 (17.78%)	37 / 115 (32.17%)
number of deaths (all causes)	3	1	1	9
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Carcinoid tumour
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
Pancreatic neuroendocrine tumour metastatic
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 45 (2.22%)	0 / 45 (0.00%)	0 / 115 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Tumour pain
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	2 / 115 (1.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neuroendocrine tumour
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertensive crisis
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Superior vena cava syndrome
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Skin neoplasm excision
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 45 (2.22%)	0 / 45 (0.00%)	0 / 115 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Radiotherapy
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	3 / 115 (2.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chemotherapy
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrostomy
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nephrostomy tube placement
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgery
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Therapeutic embolisation
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Disease progression
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 45 (2.22%)	1 / 45 (2.22%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
Pyrexia
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 45 (2.22%)	0 / 45 (0.00%)	0 / 115 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	3 / 115 (2.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Multi-organ failure
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Pain
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 45 (2.22%)	0 / 45 (0.00%)	0 / 115 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 45 (2.22%)	0 / 115 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Investigation
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	2 / 45 (4.44%)	1 / 45 (2.22%)	4 / 115 (3.48%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood potassium decreased
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholangiogram
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transaminases increased
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Muscle injury
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post embolisation syndrome
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Carcinoid heart disease
subjects affected / exposed	1 / 45 (2.22%)	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 115 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 45 (2.22%)	0 / 115 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
Cardiovascular disorder
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 115 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Sensory disturbance
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 45 (2.22%)	0 / 115 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 45 (2.22%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cognitive disorder
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Presyncope
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia of malignant disease
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Disseminated intravascular coagulation
subjects affected / exposed	0 / 45 (0.00%)	1 / 45 (2.22%)	0 / 45 (0.00%)	0 / 115 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 45 (2.22%)	0 / 45 (0.00%)	5 / 115 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	5 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 45 (2.22%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 115 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 45 (2.22%)	0 / 115 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Faecaloma
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	2 / 115 (1.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Haematemesis
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ileal perforation
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine perforation
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Peritoneal adhesions
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subileus
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colonic stenosis
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct stenosis
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 45 (2.22%)	0 / 45 (0.00%)	0 / 115 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholestasis
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 45 (2.22%)	0 / 45 (0.00%)	0 / 115 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Cholecystitis acute
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 45 (2.22%)	0 / 45 (0.00%)	0 / 115 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure acute
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 45 (2.22%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
Haemorrhage urinary tract
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Carcinoid syndrome
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 45 (2.22%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Musculoskeletal and connective tissue disorders
Flank pain
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 115 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Sepsis
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
Peritonitis
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	2 / 115 (1.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Catheter site infection
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis bacterial
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyonephrosis
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Urinary tract infection
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypokalemia
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 45 (0.00%)	1 / 45 (2.22%)	0 / 115 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cachexia
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 115 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 45 (2.22%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Hyponatraemia
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 115 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Placebo	250 mg Telotristat Etiprate	500 mg Telotristat Etiprate	Telotristat Etiprate Open-Label Extension
Total subjects affected by non serious adverse events
subjects affected / exposed	39 / 45 (86.67%)	37 / 45 (82.22%)	42 / 45 (93.33%)	110 / 115 (95.65%)
Investigations
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 45 (0.00%)	4 / 45 (8.89%)	4 / 45 (8.89%)	9 / 115 (7.83%)
occurrences all number	0	5	4	9
Alanine aminotransferase increased
subjects affected / exposed	0 / 45 (0.00%)	1 / 45 (2.22%)	3 / 45 (6.67%)	0 / 115 (0.00%)
occurrences all number	0	1	4	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	3 / 45 (6.67%)	0 / 115 (0.00%)
occurrences all number	0	0	3	0
Vascular disorders
Flushing
alternative assessment type: Non-systematic
subjects affected / exposed	2 / 45 (4.44%)	3 / 45 (6.67%)	3 / 45 (6.67%)	7 / 115 (6.09%)
occurrences all number	2	4	4	11
Hypertension
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	6 / 115 (5.22%)
occurrences all number	0	0	0	7
Nervous system disorders
Headache
alternative assessment type: Non-systematic
subjects affected / exposed	2 / 45 (4.44%)	5 / 45 (11.11%)	5 / 45 (11.11%)	12 / 115 (10.43%)
occurrences all number	2	5	6	13
Dizziness
alternative assessment type: Non-systematic
subjects affected / exposed	2 / 45 (4.44%)	0 / 45 (0.00%)	4 / 45 (8.89%)	0 / 115 (0.00%)
occurrences all number	2	0	6	0
Memory impairment
alternative assessment type: Non-systematic
subjects affected / exposed	3 / 45 (6.67%)	0 / 45 (0.00%)	1 / 45 (2.22%)	0 / 115 (0.00%)
occurrences all number	3	0	1	0
General disorders and administration site conditions
Fatigue
alternative assessment type: Non-systematic
subjects affected / exposed	4 / 45 (8.89%)	4 / 45 (8.89%)	7 / 45 (15.56%)	13 / 115 (11.30%)
occurrences all number	4	4	7	13
Asthenia
alternative assessment type: Non-systematic
subjects affected / exposed	3 / 45 (6.67%)	2 / 45 (4.44%)	1 / 45 (2.22%)	11 / 115 (9.57%)
occurrences all number	3	2	1	14
Oedema peripheral
alternative assessment type: Non-systematic
subjects affected / exposed	2 / 45 (4.44%)	3 / 45 (6.67%)	2 / 45 (4.44%)	10 / 115 (8.70%)
occurrences all number	2	3	2	12
Pyrexia
alternative assessment type: Non-systematic
subjects affected / exposed	2 / 45 (4.44%)	3 / 45 (6.67%)	0 / 45 (0.00%)	8 / 115 (6.96%)
occurrences all number	2	4	0	9
General physical health deterioration
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	8 / 115 (6.96%)
occurrences all number	0	0	0	9
Gastrointestinal disorders
Nausea
alternative assessment type: Non-systematic
subjects affected / exposed	5 / 45 (11.11%)	6 / 45 (13.33%)	14 / 45 (31.11%)	27 / 115 (23.48%)
occurrences all number	10	8	19	41
Abdominal pain
alternative assessment type: Non-systematic
subjects affected / exposed	8 / 45 (17.78%)	5 / 45 (11.11%)	10 / 45 (22.22%)	35 / 115 (30.43%)
occurrences all number	10	5	10	50
Vomiting
subjects affected / exposed	4 / 45 (8.89%)	2 / 45 (4.44%)	5 / 45 (11.11%)	16 / 115 (13.91%)
occurrences all number	5	2	8	23
Abdominal pain upper
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	3 / 45 (6.67%)	5 / 45 (11.11%)	13 / 115 (11.30%)
occurrences all number	0	3	7	14
Abdominal distension
alternative assessment type: Non-systematic
subjects affected / exposed	3 / 45 (6.67%)	2 / 45 (4.44%)	1 / 45 (2.22%)	13 / 115 (11.30%)
occurrences all number	3	2	1	17
Diarrhoea
alternative assessment type: Non-systematic
subjects affected / exposed	3 / 45 (6.67%)	3 / 45 (6.67%)	0 / 45 (0.00%)	11 / 115 (9.57%)
occurrences all number	3	3	0	17
Flatulence
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 45 (2.22%)	3 / 45 (6.67%)	2 / 45 (4.44%)	11 / 115 (9.57%)
occurrences all number	1	3	2	11
Dyspepsia
alternative assessment type: Non-systematic
subjects affected / exposed	3 / 45 (6.67%)	1 / 45 (2.22%)	1 / 45 (2.22%)	0 / 115 (0.00%)
occurrences all number	3	1	1	0
Constipation
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	8 / 115 (6.96%)
occurrences all number	0	0	0	11
Respiratory, thoracic and mediastinal disorders
Dyspnoea
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	2 / 45 (4.44%)	5 / 45 (11.11%)	7 / 115 (6.09%)
occurrences all number	0	2	5	7
Cough
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 45 (2.22%)	1 / 45 (2.22%)	3 / 45 (6.67%)	0 / 115 (0.00%)
occurrences all number	1	1	4	0
Epistaxis
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	3 / 45 (6.67%)	0 / 115 (0.00%)
occurrences all number	0	0	3	0
Skin and subcutaneous tissue disorders
Rash
alternative assessment type: Non-systematic
subjects affected / exposed	3 / 45 (6.67%)	0 / 45 (0.00%)	1 / 45 (2.22%)	0 / 115 (0.00%)
occurrences all number	3	0	1	0
Psychiatric disorders
Depression
alternative assessment type: Non-systematic
subjects affected / exposed	3 / 45 (6.67%)	2 / 45 (4.44%)	7 / 45 (15.56%)	10 / 115 (8.70%)
occurrences all number	3	2	7	13
Depressed mood
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	9 / 115 (7.83%)
occurrences all number	0	0	0	9
Decreased interest
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	7 / 115 (6.09%)
occurrences all number	0	0	0	8
Insomnia
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	6 / 115 (5.22%)
occurrences all number	0	0	0	6
Musculoskeletal and connective tissue disorders
Back pain
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	9 / 115 (7.83%)
occurrences all number	0	0	0	13
Arthralgia
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	8 / 115 (6.96%)
occurrences all number	0	0	0	9
Muscle spasms
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	6 / 115 (5.22%)
occurrences all number	0	0	0	7
Infections and infestations
Nasopharyngitis
subjects affected / exposed	1 / 45 (2.22%)	2 / 45 (4.44%)	3 / 45 (6.67%)	6 / 115 (5.22%)
occurrences all number	1	2	3	7
Pneumonia
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	3 / 45 (6.67%)	0 / 115 (0.00%)
occurrences all number	0	0	3	0
Urinary tract infection
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 45 (0.00%)	10 / 115 (8.70%)
occurrences all number	0	0	0	12
Metabolism and nutrition disorders
Decreased appetite
alternative assessment type: Non-systematic
subjects affected / exposed	2 / 45 (4.44%)	3 / 45 (6.67%)	7 / 45 (15.56%)	13 / 115 (11.30%)
occurrences all number	2	3	7	13
Hypokalaemia
subjects affected / exposed	3 / 45 (6.67%)	3 / 45 (6.67%)	5 / 45 (11.11%)	8 / 115 (6.96%)
occurrences all number	3	3	6	9

More information

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Were there any global substantial amendments to the protocol? Yes

01 Aug 2012

Amendment 1: 1. Added 2 exclusion criteria for the purposes of screening patients who may not have had carcinoid syndrome (CS)-related diarrhea. Specifically, exclusion criteria #15 and #16 were revised to clarify that only clinically significant findings that would compromise patient safety or the outcome of the study were to result in patient exclusion 2. Modified text to clarify how patients with missing or uninterpretable urinary 5-hydroxyindoleacetic acid (u5-HIAA) results would be stratified 3. Modified text regarding the use of concomitant medications to clarify the use of over-the-counter antidiarrheal therapy, bile acid sequestrants, and pancreatic enzymes 4. Added text to clarify that select study visits may have been performed outside of investigative site at the discretion of the Investigator and Sponsor 5. Added stool sampling to the Screening laboratory assessments 6. Added text to specify that additional information was collected if episodes of adverse events of special interest (AESIs) occurred 7. Defined central nervous system (CNS) events to include any clinically significant changes in mood, physical affect, or exacerbation of preexisting CNS conditions (eg, depression, migraine headaches) as AESIs 8. Revised the analysis section to clarify that the Run-in and DBT Periods of the study were to be reported separately from the OLE Period

11 Apr 2013

Amendment 2: 1. Modified the secondary endpoint describing durability and additional endpoints for changes in bowel movement (BM) frequency to reflect a 30% change in response of desired criteria. Based on review of new data from completed Phase 2 studies by key opinion leaders in the field, a 30% change in response criteria was considered clinically relevant. The leaders had cited precedent for this proportion of change in prior studies of medications to control diarrhea 2. Added information on patient symptomatology and clinical relevance of symptom improvement through semi-structured patient interviews 3. Increased the number of study sites anticipated to participate to 70 4. Added definition of childbearing potential to the inclusion criteria 5. Added information regarding benefit/risk assessment to the Introduction Section 6. Added text to specify that a Data Safety Monitoring Board (DSMB) may have terminated the study if warranted 7. Revised text to remove reference to the interactive voice response system as only a web-based system (IWRS) was to be utilized for this study 8. Revised treatment compliance text to include criteria for defining a missed dose; specifically, “A dose outside of a 3-hour window should have been considered missed” 9. Added restrictions for grapefruit just for 2-3 hours before and following dosing in the study 10. Added text to allow rescreening of patients at the discretion of the Medical Monitor who were excluded during the Screening Period 11. Added text to describe the patient Exit Interview Substudy 12. Added a section to provide guidance to Investigators when monitoring/evaluating hepatic function 13. Modified instructions on how blood pressure, height, and weight measurements should have been collected 14. Updated safety reporting information 15. Added additional details regarding pharmacokinetic (PK) sampling

06 Sep 2013

Amendment 3: 1. Revised the wording of the primary endpoint to correctly reflect that the planned analysis was to evaluate individual treatment groups versus placebo for a reduction of bowel movements (BMs) from an initial Baseline value 2. Secondary endpoints were revised to align with the clinical importance of additional pathological and physical manifestations of carcinoid syndrome (CS). The other efficacy objectives were adjusted to accommodate changes to the planned analysis 3. Replaced the term “refractory” with the term “not adequately controlled” for the patient population expected to participate. Although early signs of tachyphylaxis were exhibited in the planned patient population, patients who were eligible to participate in this study may have experienced some benefit from their background somatostatin analog therapy and, thus, were no longer adequately controlled 4. Allowed patients who had undergone tumor-directed therapies and experienced little or no reduction in BMs to participate 5. Increased the number of study sites anticipated to participate to 100 6. Clarified the PK objective and clarified that details of the population PK analyses were to be prepared in a separate document 7. Provided updated information on new and completed studies 8. Provided additional information for the withdrawal of patients 9. Added text to require capturing individual missed doses 10. Added assessment of a patient’s clotting profile via prothrombin time and international normalized ratio laboratory values at Screening 11. Added parameters for depression detection and quality of sleep assessment during the DBT Period 12. Provided clarification that patients who become pregnant should have been discontinued from study treatment immediately 13. Clarified sample size calculations and statistical testing

17 Apr 2014

Amendment 4: 1. Modified portions of the statistical methodology to ensure consistency between the protocol and the Statistical Analysis Plan (SAP). Specifically, updates were made in order to describe which population was used in the sensitivity analyses of the primary efficacy endpoint, as well as to provide clarification on the summary of plasma concentration and pharmacokinetic (PK) parameters for the data collected from patients with intensive PK assessments 2. The name of the study drug (active metabolite and ethyl esterprodrug of the active metabolite) was modified throughout to correctly represent the adoption of the United States Adopted Name naming convention, and additional text was added to clarify that the identified dose of each tablet is representative of free base (ie, the ethyl ester prodrug) 3. Clarified the expected frequency of the Data Safety Monitoring Board (DSMB) meetings 4. Updated safety reporting text regarding relation to study drug and definition of an SAE 5. Statistical text was modified to describe disposition of AEs identified as adverse events of special interest (AESI) 6. Clarified the minimum dose requirement of SSA therapy in regards to inclusion criterion number 5 7. Added restrictions for both food and drink containing grapefruit to 2 to 3 hours before and after dosing

20 Jan 2015

Amendment 5: 1. Modified the exclusion criterion to remove the corrected QT interval using Fridericia’s formula (QTcF) limitation of 450 msec 2. Clarified AESIs 3. Clarified the manner in which responses to questions designed to detect early signs of depression were to be managed 4. Clarified definition of AEs not related to study drug 5. Included a fifth classification for AEs, entitled “unlikely related” 6. Further defined the criteria for reporting a hospitalization as an SAE 7. Further defined how primary and secondary endpoints were to be analyzed and reported

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

During the open-label extension there was no placebo control, so safety results should be interpreted with caution.

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