Conditions: Carcinoid Syndrome
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 124
Healthy volunteers: no

Brief summary:
The primary objective of this study is to evaluate the long-term safety and tolerability of orally administered telotristat etiprate.

Detailed description:

Arms:
arm 1: One telotristat etiprate (250 mg) tablet administered three times daily. arm 2: Two telotristat etiprate (250 mg) tablets administered three times daily.

Interventions: intervention 1: Telotristat etiprate
Intervention descriptions: intervention 1: Telotristat etiprate tablet (250 mg)

Protocol document:
Prot_000.pdf: 
 
Official Title: 
A Multicenter, Long-term Extension Study to Further Evaluate the 
Safety and Tolerability of Telotristat Etiprate (LX1606)   
NCT Number: 
NCT02026063 
Document Dates: 
Protocol Amendment/Version 4: 02 November 2015 (North America 
only) 
Protocol Amendment/Version 3: 06 May 2015 (Germany and UK sites 
only) 
Protocol Amendment/Version 2: 08 October 2014 
Protocol Amendment/Version 1: 31 January 2014 
 
 


16. 
APPENDICES 
16.1 
STUDY INFORMATION 
16.1.1 
Protocol and protocol amendments 
 
Protocol Amendment 4 dated 02Nov2015 (North America sites only) 
Summary of Changes for Protocol Amendment 4 
Protocol Amendment 3 dated 06May2015 (Germany and UK sites only) 
Summary of Changes for Protocol Amendment 3 
Protocol Amendment 2 dated 08Oct2014 
Protocol Amendment 2 dated 21Jan2015 (France only) 
Summary of Changes for Protocol Amendment 2 
 
Protocol Amendment 1 dated 31Jan2014 
Protocol Amendment 1 dated 30Dec2014 (France only) 
Protocol Amendment 1 Addendum  dated 13Apr2015 (the Netherlands only) 
Summary of Changes for Protocol Amendment 1 
 
Original Protocol dated 14Jun2013 
 
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CLINICAL STUDY PROTOCOL 
Protocol Number: 
LX1606.1-302-CS 
LX1606.302 (Abbreviated number) 
EudraCT Number 
2013-002596-18 
Investigational Phase: 
3 
Protocol Title: 
A Multicenter, Long-term Extension Study to Further 
Evaluate the Safety and Tolerability of Telotristat Etiprate 
(LX1606) 
Study Name: 
TELEPATH (Telotristat Etiprate – Expanded Treatment 
for Patients with Carcinoid Syndrome) 
Amendment 4 Date: 
02 November 2015 (North America only) 
Amendment 3 Date: 
06 May 2015 (Germany and UK sites only) 
Amendment 2 Date: 
08 October 2014 
Amendment 1 Date: 
31 January 2014 
Original Version Date: 
14 June 2013 
Sponsor: 
Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Place 
The Woodlands, TX 77381-1160 
Telephone: 001 (281) 863-3000 
Safety Hotline: 001 (877) 372-3597 
Safety Data Facsimile: 001 (832) 442-5917 
 
 
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Lexicon 
Protocol No. LXJ606.302 
Investigator Signature Page 
Protocol Number: 
Protocol Title: 
Amendment 4 Date: 
Amendment 3 Date: 
Amendment 2 Date: 
Amendment 1 Date: 
Original Version Date: 
Sponsor: 
LX 1606.1-302-CS 
LX 1606.302 (Abbreviated number) 
A Multicenter, Long-term Extension Study to Further 
Evaluate the Safety and Tolerability ofTelotristat Etiprate 
(LXI606) 
02 November 2015 (North America only) 
06 May 2015 (Germany and UK sites only) 
08 October 20 14 
31 January 2014 
14 June 2013 
Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Place 
The Woodlands, TX 77381-1160 
Telephone:OO I (281) 863-3000 
Safety Hotline: 001 (877) 372-3597 
Safety Data Facsimile: 00 I (832) 442-5917 
By my signature below, I hereby attest that I have read and that I understand and will abide by 
all the conditions, instructions, and restrictions contained in the attached protocol and will 
conduct the study in accordance with International Conference on Harmonisation (ICH) E6 
Good Clinical Practice (GCP) guidance. 
Additionally, I will not initiate this study without written and dated approval from the 
appropriate Institutional Review Board (IRB)/ Ethic Review Committee (ERC), and I 
understand that any changes in the protocol must be approved in writing by the Sponsor, the 
IRB/ERC, and, in certain cases the Food and Drug Administration (FDA) or other applicable 
regulatory agencies, before they can be implemented, except where necessary to eliminate 
hazards to patients. 
Principal Investigator's Signature 
 M.D. 
Lexicon 
t-
 
 (Printed Name) 
02 November 20 IS 
CONFIDENTIAL 
Date 
Date 
Page 2 of 58 
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Protocol No. LX1606.302 
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1. 
Synopsis 
Name of Study Drug 
Telotristat etiprate 
Protocol Number 
LX1606.1-302-CS 
LX1606.302 (Abbreviated number) 
Protocol Title  
 
A Multicenter, Long-term Extension Study to Further Evaluate the 
Safety and Tolerability of Telotristat Etiprate (LX1606) 
Primary Objective 
The primary objective of this study is to evaluate the long-term 
safety and tolerability of orally administered telotristat etiprate   
Secondary Objective 
To evaluate changes in patients’ quality of life (QOL) through Week 
84  
Phase of Development 
3 
Methodology 
 
The study will be conducted as a multicenter, open-label, long-term 
extension study to further evaluate long-term safety and tolerability 
of telotristat etiprate. 
Patients currently participating in any LX1606 Phase 2 carcinoid 
syndrome (CS) study may enter into this extension study upon 
institutional or local approval of the protocol. Patients participating 
in a Phase 3 CS study may enter into this extension study at the 
Week 48 visit. All patients who enter into this extension study will 
be exempt from any follow-up visit required by the original study 
and will not experience an interruption in study drug due to the 
transition from the original study to LX1606.1-302-CS. 
Following confirmation of eligibility, patients will complete a series 
of visit assessments in order to establish Baseline symptoms. 
Patients will then continue on open-label study drug at the same dose 
level and regimen as identified in their original study.  
Downward dose adjustment will be permitted during the study if 
evidence of intolerability emerges. Patients who experience 
intolerability at the 250 mg tid dose level must be discontinued from 
the study. Patients may return to the previous dosing at the discretion 
of the Investigator and in consultation with the Medical Monitor. 
Upon completion or early withdrawal from treatment, all patients 
will be required to complete a 14-day Follow-up Period, during 
which no study drug will be administered.  
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A Data Safety Monitoring Board (DSMB) will review safety data 
quarterly throughout the study.  
Number of Patients 
Up to 130 patients are expected to participate in this study.  
Patients 
Eligible patients are defined as those that are currently participating 
in a Phase 2 or Phase 3 telotristat etiprate carcinoid syndrome study. 
Number of Study Sites 
Approximately 50 sites 
Treatments 
Telotristat etiprate, 250-mg tablet, administered at the same dose 
level and regimen identified in the patient’s original study 
Route of Administration 
Oral 
Duration of Participation 
All patients will participate in the Treatment Period until such time 
telotristat etiprate has received regulatory approval to be marketed 
and is available via prescription or 31 March 2017, whichever occurs 
first. Based upon the expected dates for eligible patients’ entry into 
this study, overall duration of participation will last up to 169 weeks 
including the Treatment Period and Follow-up Period. 
Inclusion Criteria 
Patients must meet all of the following criteria to be considered 
eligible to participate in the study: 
1. Ongoing participation in a Phase 2 study (ie, LX1606.1-202-CS, 
LX1606.1-203-CS) or Phase 3 study (ie, LX1606.1-301-CS, 
LX1606.1-303-CS) 
2. Patients of childbearing potential must agree to use an adequate 
method of contraception (defined as having a failure rate of <1% 
per year) during the study and for 12 weeks after the Follow-up 
visit. Adequate methods of contraception for patients or partner 
include condoms with spermicide gel, diaphragm with 
spermicide gel, coil (intrauterine device), surgical sterilization, 
vasectomy, oral contraceptive pill, depot progesterone injections, 
progesterone implant, and abstinence during the study and for 12 
weeks after the Follow-up Visit. 
a. Childbearing potential is defined as those who have not 
undergone surgical sterilization, or those who are not 
considered postmenopausal. Postmenopause is defined as 
absence of menstruation for at least 2 years. If necessary, 
follicle-stimulating hormone (FSH) results >50 IU/L at entry 
are confirmatory in the absence of a clear postmenopausal 
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history. 
3. Ability and willingness to provide written informed consent 
prior to participation in any study-related procedure 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded 
from participating in the study:   
1. Major protocol violations in regard to dosing compliance or 
telotristat etiprate tolerability concerns in a Phase 2 study (ie, 
LX1606.1-202-CS, LX1606.1-203-CS) or Phase 3 study (ie, 
LX1606.1-301-CS, LX1606.1-303-CS) 
2. Positive pregnancy test 
3. Presence of any clinically significant findings at entry for 
medical history, laboratory values, or physical examination 
(relative to patient population) that, in the Investigator’s or 
Medical Monitor’s opinion, would compromise patient safety or 
the outcome of the study 
4. Patients who are currently committed to an institution by virtue 
of an order issued either by judicial or administrative authorities 
Statistical Methods 
Descriptive analysis methods will be used to summarize the data. 
Continuous variables will be summarized by the N, mean, standard 
deviation, median, minimum, and maximum values. Categorical 
variables will be summarized as counts and related percentages. Data 
tabulations will be categorized by the treatment received on Day 1 of 
this study and combined across all treated patients. Primary analyses 
of the data will be based on the Safety population which includes all 
patients treated on Day 1 of this study. Supportive analyses of the 
efficacy data will be made on a Per Protocol population.  
Data will be summarized per study visit as the actual (raw) outcomes 
and change from Baseline scores, where applicable. Day 1 of this 
study will serve as the Baseline assessment.  
Study Assessments 
Safety 
Safety assessments include monitoring of adverse events, clinical 
laboratory tests, vital signs measurements, 12-lead electrocardiogram 
(ECG), and physical examinations. 
Efficacy 
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Efficacy assessments will include patient reported quality of life 
measures as captured in the European Organization for Research and 
Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-
C30 and the module specific for gastrointestinal symptoms of 
carcinoid neuroendocrine tumors (GI.NET21) and subjective global 
assessment of symptoms associated with CS 
Pharmacodynamics 
Pharmacodynamic (PD) assessments include determination of 5-
HIAA levels in plasma  
Efficacy Data Analysis 
 
All efficacy and PD variables will be summarized descriptively and 
listed. 
Statistical tests and estimates of within patient effects for the 
efficacy and PD measures will be derived from application of a 
mixed linear model with repeated measures. The form of the model 
will be specific to measurement properties of the dependent variable. 
Non-parametric methods will be used to supplement the tests and 
estimates from the mixed linear model. 
Exploratory analyses of treatment group differences may be 
performed by use of propensity score models. The treatments groups 
will correspond to patients’ telotristat etiprate dose level on Day 1 of 
this study.  
Safety Data Analysis 
 
Statistical analysis of the safety data will involve examination of the 
descriptive statistics and individual patient listings for any effects of 
study treatment on clinical tolerability and safety. Reporting of these 
data will be based on the Safety population. Summaries will be 
prepared by treatment group, and as needed, by study visit. 
Treatment-emergent adverse event summaries will include the 
overall incidence (by system organ class and preferred term), events 
by maximum intensity, event by relationship to study treatment, 
events leading to discontinuation of study drug, and serious adverse 
events. 
Vital signs, ECG, physical examination findings, and laboratory 
parameters (hematology, chemistry, and urinalysis) will be 
summarized descriptively at each time point. Actual and change 
from Baseline data will be calculated and summarized. In addition, 
shift table analysis will be applied to the laboratory data. 
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Table of Contents 
 
1. 
Synopsis .............................................................................................................................. 3 
2. 
List of Abbreviations and Definitions of Terms ............................................................... 10 
Definitions of Terms ................................................................................................................ 12 
3. 
Introduction ...................................................................................................................... 13 
3.1 
Background on Telotristat Etiprate (LX1606) and Disease ................................ 13 
3.2 
Clinical Trials of Telotristat Etiprate (LX1606) in Humans ............................... 14 
3.2.1 
Phase 1 Studies .............................................................................. 14 
3.2.2 
Phase 2 Studies .............................................................................. 16 
3.2.3 
Ongoing Studies ............................................................................. 18 
3.3 
Rationale for Current Study ................................................................................ 18 
3.3.1 
Rationale for Selection of Dose ..................................................... 18 
3.3.2 
Benefit/Risk Assessment ................................................................ 19 
3.4 
Rationale for Study Design and Control Groups ................................................ 20 
4. 
Study Objectives ............................................................................................................... 20 
4.1 
Primary Objective ............................................................................................... 20 
4.2 
Secondary Objective(s) ....................................................................................... 20 
4.3 
Safety Objectives ................................................................................................ 20 
5. 
Investigational Plan .......................................................................................................... 21 
5.1 
Overall Study Design .......................................................................................... 21 
6. 
Study Population .............................................................................................................. 21 
6.1 
Inclusion Criteria ................................................................................................ 22 
6.2 
Exclusion Criteria ............................................................................................... 22 
6.3 
Criteria for Stopping Treatment/Study Withdrawal ............................................ 23 
6.4 
Criteria for Termination of the Study .................................................................. 23 
6.5 
Clinical Stopping Rules ...................................................................................... 24 
6.6 
Method of Assigning Patients to Treatment ........................................................ 24 
6.7 
Blinding and Unblinding of Study Medication ................................................... 24 
6.8 
Replacement of Patients ...................................................................................... 24 
7. 
Treatment .......................................................................................................................... 25 
7.1.1 
Telotristat Etiprate (LX1606) ......................................................... 25 
7.1.1.1 
Identity ......................................................................... 25 
7.1.1.2 
Packaging, Labeling, and Storage ................................ 25 
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7.2 
Prior and Concomitant Medications ................................................................... 25 
7.2.1 
Prior Medications ........................................................................... 25 
7.2.2 
Concomitant Medications .............................................................. 25 
7.2.3 
Prohibited Medications or Concomitant Therapy .......................... 26 
7.3 
Administration of Study Medication .................................................................. 26 
7.3.1 
Treatment Compliance ................................................................... 26 
7.4 
Dose Adjustment ................................................................................................. 26 
8. 
Study Procedures .............................................................................................................. 26 
8.1 
Restrictions during Study .................................................................................... 27 
8.2 
Description of Study Assessments ...................................................................... 27 
8.2.1 
Efficacy Assessments ..................................................................... 27 
8.2.1.1 
EORTC QLQ-C30 & GI.NET21 ................................. 27 
8.2.1.2 
Subjective Global Assessment ..................................... 27 
8.2.2 
Clinical Laboratory Assessment .................................................... 27 
8.2.2.1 
Monitoring Hepatic Function ....................................... 28 
8.2.3 
Pharmacodynamic Assessments..................................................... 29 
8.2.3.1 
Plasma 5-HIAA ............................................................ 29 
8.2.4 
Safety Assessments ........................................................................ 29 
8.2.4.1 
Vital Sign Measurements ............................................. 29 
8.2.4.2 
Physical Examinations ................................................. 30 
8.2.4.3 
Electrocardiograms ...................................................... 30 
8.2.4.4 
Adverse Events of Special Interest .............................. 30 
8.2.4.4.1 
Central Nervous System Events ............... 30 
8.2.4.4.1.1 Depression Detection .......... 31 
8.3 
Other Assessments .............................................................................................. 31 
8.3.1 
Chromogranin A (CgA).................................................................. 31 
8.3.2 
Disease Progression ....................................................................... 31 
8.3.3 
Quality of Sleep Assessment .......................................................... 31 
8.4 
Appropriateness of Assessments ......................................................................... 31 
8.4.1 
Blood Collection ............................................................................ 31 
9. 
Safety Reporting ............................................................................................................... 32 
9.1 
Adverse Events ................................................................................................... 33 
9.2 
Serious Adverse Events (SAEs) .......................................................................... 35 
9.2.1 
Hospitalization as an SAE ............................................................. 37 
9.3 
Suspected Unexpected Serious Adverse Reactions (SUSARs) .......................... 37 
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9.4 
Precautions .......................................................................................................... 38 
9.4.1 
Pregnancy ....................................................................................... 38 
10. Statistical Methodology .................................................................................................... 38 
10.1 
Determination of Sample Size ............................................................................ 38 
10.2 
Analysis Populations ........................................................................................... 39 
10.3 
Study Endpoints .................................................................................................. 39 
10.3.1 
Primary and Secondary Endpoints ................................................. 39 
10.3.2 
Safety Endpoints ............................................................................ 39 
10.4 
Statistical Methods .............................................................................................. 39 
10.4.1 
Efficacy Analyses ........................................................................... 40 
10.4.2 
Safety Analyses .............................................................................. 40 
10.4.2.1 
Adverse Events ............................................................ 40 
10.4.2.2 
Clinical Laboratory Parameters ................................... 41 
10.4.2.3 
Vital Sign Measurements ............................................. 41 
10.4.2.4 
Electrocardiograms ...................................................... 41 
10.4.3 
Pharmacodynamic Analyses .......................................................... 41 
10.4.4 
Baseline Characteristics and Other Summaries ............................. 41 
10.4.5 
Interim Analysis ............................................................................. 42 
11. Study Management ........................................................................................................... 42 
11.1 
Monitoring .......................................................................................................... 42 
11.2 
Audits and Inspections ........................................................................................ 43 
11.3 
Amendments ....................................................................................................... 43 
11.4 
Record Keeping .................................................................................................. 43 
11.4.1 
Drug Accountability ....................................................................... 43 
11.4.2 
Health Insurance Portability Accountability Act of 1996 and 
Subsequent Updates ....................................................................... 44 
11.4.3 
Financial Disclosure....................................................................... 44 
11.4.4 
Access to Original Records ............................................................ 44 
11.4.5 
Retention of Study Documents ...................................................... 44 
12. Administrative Structure of the Study .............................................................................. 45 
13. Appendix A – Schedule of Events .................................................................................... 46 
14. Appendix B – Amount of Blood to be Collected from Each Patient ............................... 47 
15. Appendix C – EORTC QLQ-C30 .................................................................................... 48 
16. Appendix D – EORTC QLQ - GI.NET21 ........................................................................ 50 
17. Appendix E – Ethical Standards ....................................................................................... 51 
18. Appendix F – Investigator Obligations ............................................................................ 53 
19. References ........................................................................................................................ 58 
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2. 
List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
5-HIAA 
5-hydroxyindoleacetic acid 
5-HT 
serotonin 
AE 
adverse event 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
ALP 
alkaline phosphatase 
AST 
aspartate transaminase 
bid 
twice daily 
BM 
bowel movements 
BMI 
body mass index 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CgA 
chromogranin A 
CNS 
central nervous system 
CRF 
case report form 
CRO 
contract research organization 
CS 
carcinoid syndrome 
CT 
computed tomography 
DSMB 
Data Safety Monitoring Board 
EC 
enterochromaffin 
ECG 
electrocardiogram 
ERC 
Ethics Review Committee 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HEENT 
head, eyes, ears, nose, and throat 
Hgb 
hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
IBD 
inflammatory bowel disease 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
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Abbreviation 
Definition 
Continued on the next page 
 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IMP 
Investigational Medicinal Product 
IWRS 
interactive web response system 
LAR 
long-acting release 
LS 
least square 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCP 
multiple comparison procedure 
MRI 
magnetic resonance imaging 
NET 
neuroendocrine tumor 
NRS 
numeric rating scale 
OOR 
out-of-range 
OTC 
over-the-counter 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
qd 
once daily 
SAE 
serious adverse event 
SBS 
short bowel syndrome 
SOP 
standard operating procedure 
SSA 
somatostatin analog 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
tid 
3 times daily 
TPH 
tryptophan hydroxylase 
ULN 
upper limit of the normal reference range 
WRS 
Wilcoxon rank sum 
 
 
 
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Definitions of Terms  
Term 
Definition 
LX1606 Hippurate 
telotristat etiprate 
LP-778902 
active moiety of LX1606 
LX1606 
telotristat ethyl: the ethyl-ester prodrug of the active moiety LP-
778902; a serotonin synthesis inhibitor being developed by 
Lexicon Pharmaceuticals, Inc. 
QTcF 
corrected QT interval using Fredericia’s formula 
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3. 
Introduction 
3.1 
Background on Telotristat Etiprate (LX1606) and Disease 
Serotonin (5-HT) plays a critical role in regulating several major physiological processes of 
the gastrointestinal tract, including aspects of secretion, motility, inflammation and sensation. 
Enterochromaffin (EC) cells release 5-HT when the intestinal wall is stimulated by 
intraluminal pressure or chemicals. Through multiple classes of receptors, 5-HT is believed to 
initiate directly, or facilitate, peristaltic and secretory reflexes. 5-HT is also reportedly 
involved in the pathophysiology of various types of functional gastrointestinal (GI) disorders, 
valvular heart disease, and may play a role in the pathophysiology of inflammatory bowel 
disease (IBD).  
Carcinoid tumors are mostly derived from EC cells of the midgut, and often produce and 
release large amounts of 5-HT. Such excess of 5-HT is believed to be responsible for the 
severe diarrhea and eventual valvular heart damage and mesenteric fibrosis in patients with 
carcinoid syndrome (CS).1-3 Inhibition of tryptophan hydroxylase (TPH) activity in carcinoid 
tumors should lead to a reduction of peripheral 5-HT in afflicted patients and thus an 
amelioration of the pathophysiology and symptomology of CS. A peripheral TPH inhibitor, 
such as telotristat etiprate, should alleviate the symptoms due to excess 5-HT in carcinoid 
patients without central nervous system (CNS)-related adverse events (AEs). 
Approximately 90% of the body's 5-HT is found in the EC cells of the GI tract, with the 
remainder distributed between the platelets and CNS.4 TPH catalyzes the biopterin-dependent 
monooxygenation of tryptophan to 5-hydroxytryptophan, which is subsequently 
decarboxylated to form 5-HT. Expression of TPH is limited to a few specialized tissues:  
raphe neurons, pinealocytes, mast cells, mononuclear leukocytes, beta cells of the islets of 
Langerhans, and intestinal and pancreatic EC cells.5 Two isoforms of the enzyme exist, TPH1 
and TPH2. TPH1 is exclusively located in the EC cells of the GI tract and pineal gland and is 
the rate limiting enzyme responsible for the majority of systemic 5-HT production and is also 
responsible for 5-HT synthesis in carcinoid tumors. TPH2 is located in the central and enteric 
nervous systems and is the rate-limiting enzyme in the production of neuronal 5-HT. 
The oral TPH inhibitor, telotristat etiprate, represents a novel approach to potentially lessen 
the pathophysiology of CS by reducing 5-HT levels via inhibition of TPH. Telotristat etiprate 
was designed specifically as a prodrug in order to gain greater systemic exposure, opening 
the potential application for indications in which hyperserotonemia is thought to contribute to 
the disorder, such as CS. Preclinical pharmacology studies of telotristat etiprate were 
designed to evaluate the compound’s mechanism of action and effects in vivo. Telotristat 
etiprate is the ethyl-ester prodrug of the active moiety LP-778902. Telotristat etiprate was 
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designed as a prodrug in order to enhance peripheral exposure without crossing the blood-
brain barrier. In vivo, telotristat etiprate is readily converted through esterase activity to its 
corresponding acid, LP-778902. LP-778902 has an in vitro potency of 0.028 μM on purified 
human TPH1 enzyme and 0.032 μM on purified human TPH2 enzyme. Therefore, telotristat 
etiprate is a robust inhibitor of TPH both in vitro and in vivo and has been shown in Phase 2 
studies to provide clinical benefit to patients with carcinoid tumors and associated CS.  
Telotristat etiprate is being developed to manage GI symptoms and possibly other symptoms 
associated with CS. Currently, the standard of care for patients with CS is symptom 
management using somatostatin analogs (SSA), which are available in both short- and long-
acting release (LAR) formulations. Somatostatin analogs such as octreotide are indicated for 
the control of flushing, diarrhea, and other symptoms associated with CS. Common side 
effects of the long-acting depot form of the drug are pain at the site of the injection, reported 
in as many as 30 to 50% of carcinoid patients at the 20 and 30 mg dose levels, and less 
commonly, stomach cramps, nausea, vomiting, headaches, dizziness, and fatigue.6 Other side 
effects identified in the product labeling include biliary tract abnormalities (gallstones, 
sludge, and dilatation), hypothyroidism, dietary fat malabsorption, and hyper or 
hypoglycemia.7 In addition to the morbidity associated with parenterally administered agents, 
tachyphylaxis will occur in the majority of patients, resulting in recurrent symptoms. 
There are currently no specific oral treatments indicated for the management of symptoms 
associated with CS. As a result of the morbidity associated with SSAs and the associated 
tachyphylaxis, there is an unmet medical need to provide symptom management and modify 
the pathophysiology of patients with metastatic CS. Inhibition of the excessive 5-HT 
produced by these tumors with an orally delivered agent such as telotristat etiprate could 
provide significant benefit as an additional treatment option for patients and clinicians.  
3.2 
Clinical Trials of Telotristat Etiprate (LX1606) in Humans 
Telotristat etiprate has been studied in single/multiple doses in Phase 1 studies, approximately 
259 healthy volunteers participated in Phase 1 trials with 237 subjects receiving telotristat 
etiprate. In Phase 2, 38 patients with CS and 49 patients with ulcerative colitis received 
telotristat etiprate during the evaluation of 3 clinical studies.   Additionally, over 200 patients 
with carcinoid syndrome have been enrolled and are being evaluated in ongoing Phase 3 
studies. 
3.2.1 
Phase 1 Studies 
Telotristat etiprate has been evaluated in 9 completed Phase 1 clinical studies to date. A single 
ascending dose tolerability study explored a dose range of 50 to 1500 mg (LX1606.1-101-
NRM), and a multiple ascending dose tolerability study explored a dose range of 100 mg (qd) 
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to 1500 mg (500 mg tid) over 14 days (LX1606.1-102-NRM). Both studies were conducted 
in healthy, normal volunteers in a randomized, double-blind, placebo controlled fashion, 
utilizing whole blood 5-HT and 24-hour urinary 5-HIAA levels as biomarkers of 
pharmacologic response. A two-way crossover study of 2 oral formulations of 250 mg given 
as a single dose (LX1606.1-103-NRM) was conducted in healthy, normal volunteers as a 
randomized, open-label study, utilizing PK parameters as a marker of comparability of the 
capsule versus tablet formulation. A study designed to evaluate the pharmacokinetics, 
metabolism, and routes and extent of elimination of LX1606 telotristat etiprate and its 
primary metabolite (LP-778902) after a single oral dose of 500 mg 14C-LX1606 was 
conducted in 8 healthy male volunteers (LX1606.1-104-NRM). A thorough QT study 
(LX1606.1-105-NRM), a food-effect study (LX1606.1-107-NRM), and 3 drug-drug 
interaction studies (LX1606.1-106-NRM; LX1606.1-108-NRM; LX1606.1-109-NRM) were 
also all conducted in healthy, normal volunteers. Telotristat etiprate was well tolerated with 
drug-related GI AEs (primarily nausea) becoming dose-limiting at the 1500 mg single dose 
level. Multiple doses of telotristat etiprate over 14 days are well tolerated up to 1500 mg daily 
dose, administered as 500 mg tid. Telotristat etiprate is readily converted to the active 
metabolite LP-778902. At the doses evaluated, extremely low levels of telotristat etiprate are 
present in circulation, with most samples containing ≤ 10 ng/mL of the prodrug and many 
samples being below the limit of quantitation (0.5 ng/mL). Urinary 5-HIAA levels showed a 
statistically significant reduction of approximately 50-60% relative to placebo over 14 days at 
dose levels ≥ 500 mg telotristat etiprate. Similarly whole blood 5-HT declined in a dose-
dependent fashion over 14 days. The results of the thorough QT study clearly demonstrated 
that telotristat etiprate is negative for QT prolongation as defined by the ICH E14 guidance. 
The results of LX1606.1-106-NRM suggest that telotristat etiprate is not a P-glycoprotein 1 
(P-gp) inhibitor as per FDA Guidance for Industry – Drug Interaction Studies (February 
2012), where P-gp inhibitors are defined as those drugs that increase the AUC of 
fexofenadine by ≥1.25 fold. However, telotristat etiprate did exhibit a lower level of P-gp 
inhibition that is unlikely to be clinically meaningful. LX1606.1-107-NRM confirms a food 
effect is seen with telotristat etiprate such that systemic exposure to telotristat ethyl and 
metabolite LP-778902 is significantly increased following administration in the fed state 
compared to the fasted state. Results of LX1606.1-108-NRM do not support inhibitory 
activity of steady-state telotristat ethyl concentrations on CYP3A4; however, systemic 
exposure to midazolam was significantly lower when midazolam was coadministered with 
telotristat etiprate. It is believed this observation is the result of a reduction in midazolam 
absorption. Coadministration of octreotide acetate with telotristat etiprate is addressed in 
LX1606.1-109-NRM. Systemic exposure to both telotristat ethyl and metabolite LP-778902 
is significantly reduced compared to administration of telotristat etiprate alone, thereby 
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suggesting a drug-drug interaction. However, it is not known whether the long-acting depot 
formulation of octreotide acetate would exhibit a similar interaction with telotristat etiprate as 
what was seen with the subcutaneous injections of octreotide acetate used in this study. 
3.2.2 
Phase 2 Studies 
In Phase 2 studies in patients with CS, dose levels of 150, 250, 350, or 500 mg tid telotristat 
etiprate were evaluated. All dose levels were generally well tolerated. The Phase 2 clinical 
trial results indicated that treatment using telotristat etiprate in patients with CS may lead to 
improvements in BM frequency, stool consistency, urgency to defecate, abdominal pain, 
diarrhea, flushing, and reductions in 5-HIAA. 
LX1606.1-202-CS was a randomized, double-blind, placebo-controlled, multiple ascending 
dose study conducted in 2 parts in order to evaluate a total of 23 patients at a dose range of 
450 to 1500 mg given as 150, 250, 350, or 500 mg tid (telotristat etiprate or matching 
placebo) on a background therapy of octreotide. In Part 1, 16 patients were randomly 
assigned 3:1 into 4 sequential cohorts. Each cohort evaluated 1 of the following daily doses 
given as 150, 250, 350, or 500 mg tid over a course of 4 weeks. During the study, all patients 
continued on a stable-dose background therapy of octreotide. In Part 2, an additional 7 
patients were randomly assigned 3:1 in order to evaluate 500 mg tid, the highest tolerated 
dose as determined in Part 1. Upon completion of the initial 4-week double-blind, placebo-
controlled portion (the Core Phase), eligible patients had the option to continue into an open-
label Extension Period (the Extension Phase). 
For the LX1606-treated patients combined (n=18) in the randomized placebo-controlled 
LX1606.1-202-CS study, 5 patients (33.3%) experienced a reduction in BM frequency of at 
least 30% versus no patients (0.0%) for the placebo group (n=5). A complete biochemical 
response, defined as at least a 50% reduction from Baseline in urinary 5-HIAA (mg/24 hours) 
or normalization post-Baseline urinary 5-HIAA (mg/24 hours) value <ULN for cases where 
the Baseline value was elevated, was achieved by 9 of 16 patients (56.3%) versus no patients 
(0.0%) on placebo.  
LX1606 was well tolerated by patients enrolled in this study. Across both the Core Phase and 
the Extension Phase, greater than half (73.9% and 52.6%, respectively) of the TEAEs 
reported were mild or moderate in intensity. TEAEs were reported most frequently within the 
GI disorders class, the most frequently reported TEAE was diarrhea, followed by nausea. No 
clinically significant changes from baseline in laboratory parameters, vital signs, physical 
examination findings, or ECG results were observed throughout the study, except for alkaline 
phosphatase (ALP) and gamma-glutamyltransferase (GGT) levels. Mean ALP and GGT 
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levels remained elevated compared with Baseline during both study periods, but no relevant 
clinical outcomes were observed.  
During the Core Phase, no dose-response relationship was observed in frequencies of any 
TEAEs, severe TEAEs or related TEAEs among the treatment groups that received placebo 
or various dosages of LX1606. One patient each in the placebo arm (20.0%) and the active 
treatment arm (5.6%) discontinued the study drug due to TEAEs. There were no fatal SAEs 
during the Core Phase. One patient in the LX1606 350 mg tid group experienced 2 SAEs 
(severe nausea and vomiting) that were reported as possibly related to study drug; both events 
resolved after symptomatic treatment. 
During the Extension Phase, eight patients experienced a total of 20 SAEs. One patient 
experienced 4 TEAEs that led to discontinuation. There was 1 fatal SAE of disease 
progression. None of the SAEs were reported as related to study drug. 
LX1606.1-203-CS was an open-label, serial ascending, multiple dose, individual titration 
study that evaluated the same dose ranges as the LX1606.1-202-CS study in a total of 15 
patients. Patients were serially escalated to the next dose level every 2 weeks until a 
maximally tolerated dose (MTD) or 500 mg tid was reached. Once a MTD had been 
determined, the patient would remain on the dose for an additional 4 weeks. Patients then had 
the option to continue into an Extension Period.  
In this open-label study, there was evidence of clinically meaningful improvement in the GI-
related symptoms associated with carcinoid syndrome, reflected by decreases in BM 
frequency, improvements in stool consistency, reductions in urgency to defecate, and 
reductions in flushing. Patients reported adequate relief of their symptoms, and physicians 
reported global clinical improvement. Reductions in u5-HIAA were observed. Most patients 
continued into the long-term Extension Period, with no evidence of loss of efficacy over time. 
Most patients reached the 500 mg tid dose level during this study. No MTD was identified. 
Adverse events were those expected for the patient population under treatment, and no 
clinically significant trends in laboratory values, vital sign measurements, ECG results, or 
physical examination findings were observed. There was 1 fatal SAE of neoplasm 
progression; no SAE was reported as related to study drug. 
LX1606.1-204-UC evaluated patients with acute, mild to moderate ulcerative colitis 
experiencing active flares were enrolled in a randomized, double-blind, placebo-controlled 
study designed to evaluate the safety and efficacy of telotristat etiprate. Patients were 
maintained on a stable-dose of aminosalicylate therapy for 8 weeks and randomly assigned to 
receive 1 of 2 dosages of telotristat etiprate (500 mg once daily or 500 mg tid) or placebo; 59 
patients were enrolled in the study. Adverse events were those expected for the ulcerative 
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colitis patient population and no clinically significant trends in laboratory values, vital sign 
measurements, ECG results, or physical examination findings were observed.  
Although results from the study provide a clear signal of activity of the mechanism of action 
of telotristat etiprate in this patient population, they were not accompanied by other findings 
that would indicate a large impact on disease modification. Detailed information regarding 
the completed clinical studies can be found in the Investigator Brochure.8 
3.2.3 
Ongoing Studies 
LX1606.1-301-CS is intended to evaluate patients who are currently on a background of SSA 
therapy and still experiencing breakthrough symptoms such as a frequency of BMs ≥4 per 
day on average: (1) the efficacy of telotristat etiprate on reducing the number of BMs; (2) the 
efficacy of telotristat etiprate on a number of clinically relevant secondary endpoints; and, (3) 
the safety of telotristat etiprate over the 12-week double-blind portion (Treatment Period) of 
the study. Upon completion of the Treatment Period, patients will continue into a 36-week 
open-label Extension Period.  
LX1606.1-303-CS is intended to evaluate patients with carcinoid syndrome whose primary 
symptoms are not GI related and may be naïve to SSA therapy: (1) the safety of telotristat 
etiprate over the 12-week double-blind portion (Treatment Period) of the study; (2) percent 
(%) change from Baseline in 24-hour u5-HIAA levels at Week 12; (3) the effects of telotristat 
etiprate on a number of clinically relevant secondary endpoints. Upon completion of the 
Treatment Period, patients will continue into a 36-week open-label Extension Period. 
Detailed information regarding the ongoing clinical studies can be found in the Investigator 
Brochure.8 
3.3 
Rationale for Current Study 
3.3.1 
Rationale for Selection of Dose 
The dose levels of telotristat etiprate selected for this study are consistent with prior clinical 
study experience and based upon clinical safety and pharmacodynamic (PD) data from 2 
Phase 2 multiple ascending-dose studies in patients with symptomatic CS (LX1606.1-202-CS 
and LX1606.1-203-CS).  
Based upon observations noted in Section 3.2, it is anticipated that the doses to be utilized in 
this protocol will be safe and well tolerated and may provide clinical benefit to patients with 
CS. 
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3.3.2 
Benefit/Risk Assessment 
Clinical experience with telotristat etiprate (treated subjects) consists of completed single and 
multiple ascending dose studies in 259 normal subjects, 2 Phase 2 studies (38 patients with 
symptomatic CS) and ongoing Phase 3 studies in patients with symptomatic CS. 
In healthy volunteer studies, single doses up to 1000 mg were found to be generally well 
tolerated, while at the 1500 mg dose level GI-related adverse events increased. A similar 
adverse event profile was observed after multiple dose administration over 14 days with GI 
events predominating. Mild, dose-dependent increases in hepatic transaminase levels (≤2 x 
ULN) were observed with increased frequency in relation to dose, with 1 subject requiring 
withdrawal from therapy at the 500 mg bid dose level. Most subjects that were observed to 
have increased transaminase levels did not exceed >2 x ULN. No abnormalities in total 
bilirubin were observed at any dose level. GI events have been the most commonly observed 
events to date. The adverse event profile in normal subjects may differ significantly from 
what is observed in patients with hyperserotonemia. All adverse events resolved without 
sequelae. In addition, there were no significant changes in vital signs or ECG. No physical 
examination abnormalities were noted in studies to date. There were no serious adverse 
events reported in healthy volunteers. 
In patients with CS, dose escalations have proceeded up to and including 500 mg tid. To date, 
there has been no evidence of dose-limiting intolerability. Dose levels have been generally 
well tolerated.  
Phase 3 clinical trials are currently underway to provide further data to support the Phase 2 
study results. Currently 210 patients have been randomized to the placebo-controlled trials 
(LX1606.1-301-CS and LX1606.1-303-CS). After completing participation in 1 of the Phase 
2 or Phase 3 studies, eligible patients with CS will have the option of continuing treatment 
with the study drug in this long-term, open-label Extension study (LX1606.1-302-CS).  
Based upon observations from preclinical and clinical studies conducted to date, it is 
anticipated that orally administered telotristat etiprate will be well tolerated at dose levels 
required to influence peripheral 5-HT production. Potential adverse events primarily involve 
the GI tract, and could include alterations in gut motility that may result in nausea, vomiting, 
diarrhea, and constipation. Regular and ongoing clinical and laboratory assessments should 
detect any of these events, and depending on the type of event, further dose adjustment or 
discontinuation from the trial would occur. Central nervous system effects are not anticipated 
at dose levels planned for evaluation, but careful monitoring for any such effect has been 
included in the study. As elevations in hepatic transaminase levels were observed with 
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multiple dosing in normal subjects, monitoring clinical laboratory tests of hepatic function 
will be incorporated into clinical trials conducted in CS patients. 
The Phase 2 clinical trial results indicated that treatment may lead to improvements in BM 
frequency, stool consistency, urgency to defecate, abdominal pain, diarrhea, flushing, and 
reductions in 5-HIAA. These potential benefits relate to a unique mechanism of action. 
Symptomatic improvement may lead to a better quality of life (QOL) for patients with few 
treatment options available, and a reduction in serotonin may help reduce the risk of 
carcinoid heart disease. Overall, the benefit/risk profile of telotristat etiprate is expected to be 
favorable for participation in this clinical study. 
3.4 
Rationale for Study Design and Control Groups 
Currently, no approved therapy exists for the treatment of symptoms driven by underlying 
serotonin pathophysiology of CS in patients whose disease is refractory to SSA therapy or for 
those patients who are unable to tolerate SSA therapy or who are unwilling to take SSA 
therapy. 
This study will allow for continued access to telotristat etiprate after patients have completed 
the required study visits in ongoing Phase 2 and Phase 3 studies. Continuation of CS patients 
into this study will allow for the collection of additional long-term safety and efficacy data, 
while providing access to patients who may be receiving benefit. The treatment duration is 
supported by results of chronic toxicology studies (6-month rat and 9-month dog) and the 
current safety profile from completed and ongoing clinical trials. 
4. 
Study Objectives 
4.1 
Primary Objective 
The primary objective of the study is to evaluate the long-term safety and tolerability of 
orally administered telotristat etiprate. 
4.2 
Secondary Objective(s) 
The secondary objective of this study is to evaluate changes in patients’ QOL through Week 
84. 
4.3 
Safety Objectives 
Evaluation of overall safety will be assessed as: 
 Incidence of treatment-emergent adverse events (TEAEs) 
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 Changes from Baseline in clinical laboratory results, vital signs results, physical 
examinations, and ECG findings. 
5. 
Investigational Plan 
5.1 
Overall Study Design 
The study will be conducted as a multicenter, open-label, long-term extension study to further 
evaluate long-term safety and tolerability of telotristat etiprate. 
Patients currently participating in any LX1606 Phase 2 CS study may enter into this 
extension study upon institutional or local approval of the protocol. Patients participating in a 
Phase 3 CS study may enter into this extension study at the Week 48 visit. All patients who 
enter into this extension study will be exempt from any follow-up visit required by the 
original study and will not experience an interruption in study drug due to the transition from 
the original protocol to LX1606.1-302-CS. 
Following confirmation of eligibility, patients will complete a series of visit assessments in 
order to establish Baseline symptoms. Patients will then continue on open-label LX1606 at 
the same dose level identified in the original study.  
All patients will receive telotristat etiprate for at least 52 weeks and may continue treatment 
in the trial until such time telotristat etiprate has received regulatory approval to be marketed 
and is available via prescription or until 31 March 2017, whichever occurs first. Patients who 
reach this timeline event will be deemed to have completed the Treatment Period and will 
advance to the End-of-Study (EOS) visit as identified in Appendix A – Schedule of Events, 
regardless of where they are in the visit schedule and when their last study visit occurred. 
Upon completion, all patients will be required to complete a 14-day Follow-up Period, during 
which no study drug will be administered.  
Downward dose adjustment will be permitted during the study if evidence of intolerability 
emerges. Patients who experience intolerability at the 250 mg tid dose level must be 
discontinued from the study. Patients may return to the previous dosing at the discretion of 
the Investigator and in consultation with the Medical Monitor. 
A Data Safety Monitoring Board (DSMB) will review safety data quarterly throughout the 
study.  
6. 
Study Population 
Adult patients who are currently participating in ongoing Phase 2 or Phase 3 telotristat 
etiprate CS clinical protocols will be enrolled into the study. Up to 130 patients are expected 
to enroll in this study. Approximately 50 sites worldwide will participate in the study. Patients 
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may continue allowed medications as background therapy provided they remain on stable- 
doses throughout the Treatment Period. 
6.1 
Inclusion Criteria 
Patients must meet all of the following criteria to be considered eligible to participate in the 
study: 
1. Ongoing participation in a Phase 2 study (ie, LX1606.1-202-CS, LX1606.1-203-CS) 
or Phase 3 study (ie, LX1606.1-301-CS, LX1606.1-303-CS)  
2. Patients of childbearing potential must agree to use an adequate method of 
contraception (defined as having a failure rate of <1% per year) during the study and 
for 12 weeks after the Follow-up visit. Adequate methods of contraception for 
patients or partner include condoms with spermicide gel, diaphragm with spermicide 
gel, coil (intrauterine device), surgical sterilization, vasectomy, oral contraceptive pill, 
depot progesterone injections, progesterone implant, and abstinence during the study 
and for 12 weeks after the Follow-up Visit.  
a. Childbearing potential is defined as those who have not undergone surgical 
sterilization, or those who are not considered postmenopausal. Postmenopause 
is defined as absence of menstruation for at least 2 years. If necessary, follicle-
stimulating hormone (FSH) results >50 IU/L at Baseline Day 1 are 
confirmatory in the absence of a clear postmenopausal history. 
3. Ability and willingness to provide written informed consent prior to participation in 
any study-related procedure. 
6.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participating in the 
study:   
1. Major protocol violations in regard to dosing compliance or telotristat etiprate 
tolerability concerns in a Phase 2 study (ie, LX1606.1-202-CS, LX1606.1-203-CS) or 
Phase 3 study (ie, LX1606.1-301-CS, LX1606.1-303-CS)  
2. Positive pregnancy test 
3. Presence of any clinically significant findings at entry for medical history, laboratory 
values, or physical examination (relative to patient population) that, in the 
Investigator’s or Medical Monitor’s opinion, would compromise patient safety or the 
outcome of the study 
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4. Patients who are currently committed to an institution by virtue of an order issued 
either by judicial or administrative authorities 
6.3 
Criteria for Stopping Treatment/Study Withdrawal 
A patient may also be discontinued from the study for the following medical or 
administrative reasons: 
 Withdrawal of consent by the patient or legal guardian 
 Noncompliance, including refusal of the study medication and/or failure to adhere to 
the study requirements as in the study protocol 
 Investigator decides that, in the interest of the patient, it is not medically acceptable to 
continue participation in the study 
 The Sponsor terminates the study (Section 6.4) 
 Pregnancy (Section 9.4.1) 
Note:  If patients voluntarily withdraw or are discontinued from study treatment before 
completing the entire duration of the Treatment Period, they should be encouraged to 
continue clinic visits according to the study schedule.  
Patients who discontinue study treatment and who are not willing to continue clinic visits (eg, 
withdrawal of consent) should be encouraged to complete End-of-Study (EOS) assessments 
as identified in Appendix A – Schedule of Events and agree to report any SAEs (Section 9.2) 
that occur within 30 days following the last dose of telotristat etiprate. 
The date the patient discontinues study treatment, the primary reason for study treatment 
discontinuation, study termination, and/or termination of participation (eg, withdrawal of 
consent), will be captured within the Case Report Form (CRF). 
When patients withdraw consent from study participation, it must be recorded on the CRF 
whether the withdrawal of consent applies to specific aspects of the study such as 
discontinuation of study treatment, participation in study visits, contact by study personnel, or 
access to information about potential SAEs. If specific consent has not been withdrawn, study 
personnel should contact the patient (or a previously approved designee such as a caregiver, 
partner, or family member) at the scheduled Follow-up visit to inquire about health status. 
6.4 
Criteria for Termination of the Study 
If the Sponsor, Investigator, study monitor, DSMB, or regulatory officials discover conditions 
arising during the study that indicate that the patient safety and/or scientific value of the study 
and/or quality of the study drugs have been compromised, the study should be halted or the 
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study center’s participation should be terminated. Conditions that may warrant termination of 
the study include, but are not limited to, the following: 
 The discovery of an unexpected, serious, or unacceptable risk to the patients enrolled in 
the study; 
 A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product for carcinoid syndrome or any other indication for any 
reason; 
 Failure of the Investigator to enroll patients into the study at an acceptable rate; 
 Failure of the Investigator to comply with pertinent governing body regulations; 
 Submission of knowingly false information from the research facility to the Sponsor, 
study monitor, medical officer, or regulatory official; and, 
 Insufficient adherence to protocol requirements.  
Study termination and Follow-up would be performed in compliance with applicable 
governing body regulations. 
6.5 
Clinical Stopping Rules 
Criteria for individual patient withdrawal or study termination are summarized in Sections 
6.3 and 6.4, respectively. 
6.6 
Method of Assigning Patients to Treatment  
Patients will enter the study at the same dose level and regimen as identified in the prior 
Phase 2 or Phase 3 CS study. Randomization will not be used to assign patients to study 
treatments. 
6.7 
Blinding and Unblinding of Study Medication 
This is an open-label study.  
6.8 
Replacement of Patients 
Patients who do not complete the study will not be replaced. 
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7. 
Treatment 
7.1.1 
Telotristat Etiprate (LX1606) 
7.1.1.1 
Identity 
Telotristat etiprate (LX1606 Hippurate) is the salt form of the drug substance. LX1606 
Hippurate is a crystalline white to off-white to tan solid with a melting point of 147°C. 
LX1606 is insoluble in water within the pH range of 5 to 9 (≤2 mg/L). It undergoes 
hydrolysis under strongly basic or strongly acidic conditions.  
Study drug dosage form consists of white coated debossed oval tablets containing 250 mg 
LX1606. 
7.1.1.2 
Packaging, Labeling, and Storage 
Patients will receive 250-mg telotristat etiprate tablets packaged in 100 cc high density 
polyethylene bottles with child-resistant polypropylene screw caps and heat-induction seal 
liners.  
Telotristat etiprate should be stored between 15 to 25°C (59 to 77°F), with excursions 
allowed up to 30C. 
7.2 
Prior and Concomitant Medications 
7.2.1 
Prior Medications 
All medications and other treatments taken by patients within 30 days prior to entry will be 
recorded on the CRF.  
7.2.2 
Concomitant Medications 
All concomitant medications taken by patients during the study will be recorded on the CRF. 
Treatment with prescription or over-the-counter (OTC) antidiarrheal therapy, bile acid 
sequestrants, or pancreatic enzyme is permitted; however, the use of these concomitant 
therapies should be associated with a documented history of disease (eg, fat malabsorption, 
bile acid malabsorption, or steatorrhea).  
 Medical management of patients and their concomitant medications is allowed at the 
discretion of the Investigator. However, should the need arise to modify/adjust a patient’s 
therapy due to a concern for patient safety and/or tolerability the Medical Monitor should be 
contacted. The Investigator and Medical Monitor will make a determination if such a change 
would impact the safety of the patient and the integrity of the study. The Medical Monitor 
will determine if the patient can continue in the study. 
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7.2.3 
Prohibited Medications or Concomitant Therapy 
None 
7.3 
Administration of Study Medication 
All patients will be instructed to take the study medication with food. “With food” means 
taking telotristat etiprate tablets within 15 minutes before or within 1 hour after a meal or 
snack. Patients will be instructed to take study drug 3 times daily during waking hours, with 
doses spaced approximately 6 hours apart.  
Study medication and instructions will be dispensed to patients at each visit as described in 
the schedule of study procedures (Appendix A). 
7.3.1 
Treatment Compliance  
Patients will be asked to bring their unused or unopened study medication to each visit 
(Appendix A). At each visit and in the presence of the patient, study site personnel will count 
returned tablets and reconcile the counts against planned number of doses for that interval. 
Site personnel will clarify any discrepancy and record this information within the CRF.  
Patients must maintain at least 75% compliance in dosing to be deemed as compliant. In the 
event of a missed or vomited dose, patients will take their subsequent dose of study drug at 
the next scheduled time point, following the tid dosing regimen of approximately every 6 
hours. A dose outside of a 3-hour window should be considered missed. Missed or vomited 
doses will not be made up.  
7.4 
Dose Adjustment 
Downward dose adjustment of telotristat etiprate will be permitted if evidence of 
intolerability emerges. After a period at the lowered dose level, patients may resume the 
previous dosing level at the discretion of the Investigator after consultation with the Medical 
Monitor. Patients who experience intolerability at the 250 mg tid dose level must be 
discontinued from study treatment. Interruptions or delays in dosing throughout the entire 
study may be permitted after consultation with the Medical Monitor, at which time the patient 
will be reassessed for study continuation, dosage reduction, or discontinuation. 
8. 
Study Procedures 
A schedule of study assessments is provided in Appendix A. 
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8.1 
Restrictions during Study 
Patients should be advised to avoid food and drink containing grapefruit for 2-3 hours prior to 
and following dosing while participating in the study. 
8.2 
Description of Study Assessments 
8.2.1 
Efficacy Assessments 
Efficacy assessments include the patient reported QOL measures; EORTC QLQ-C30 
(Appendix C) & GI.NET21 (Appendix D) questionnaires and subjective global assessment of 
symptoms associated with CS. 
A description of the efficacy assessments is provided below. 
8.2.1.1 
EORTC QLQ-C30 & GI.NET21 
Patients will complete the questionnaires during each visit as indicated in Appendix A. 
8.2.1.2 
Subjective Global Assessment 
A subjective global assessment of symptoms associated with CS will be evaluated using 2 
methods at each visit as indicated in Appendix A.  
Patients will first be asked to respond to the following question:  “In the past 7 days, have 
you had adequate relief of your carcinoid syndrome bowel complaints such as diarrhea, 
urgent need to have a bowel movement, abdominal pain, or discomfort?”. 
Then patients will be asked the following question to assess global symptoms associated with 
CS on an 11-point scale: “Rate the severity of your overall carcinoid symptoms over the past 
7 days on a scale from 0-10, where 0 = no symptoms and 10 = worst symptoms ever 
experienced.” 
8.2.2 
Clinical Laboratory Assessment  
Clinical laboratory assessments will consist of hematology (complete blood count [CBC] 
with differential and platelet counts), blood chemistry (complete metabolic panel and liver 
function tests), and urinalysis. All laboratory tests will be performed by a central laboratory, 
with the exception of the urine pregnancy test, which will be performed by the study site with 
the provided laboratory kit.  
The incidence of clinically significant laboratory values, as well as clinically significant shifts 
in laboratory values, should be reported as an AE in the patient’s CRF (see also Section 9.1 
for reporting of AEs related to laboratory abnormalities). The Investigator will assess any 
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clinically significant values relevant to the patient population to determine if termination of 
the study drug is required. 
8.2.2.1 
Monitoring Hepatic Function 
Patients with clinically significant abnormalities in liver function tests should be excluded 
from participating; however, the patient’s clinical situation as a whole should be taken into 
account when evaluating hepatic transaminase elevations, which may represent a 
consequence of the underlying disease and/or therapeutic interventions. Patients with 
abnormalities in liver function test results, as defined below, should be further assessed by the 
Investigator and may have additional tests performed by the central laboratory as clinically 
indicated. The following describes the Sponsor’s recommended approach to evaluating these 
events. This approach is not meant to replace the Investigator’s clinical judgment.  
These guidelines apply to the following events: 
1) A new confirmed result (after Day 1 dosing) of ALT or AST >3 x ULN (in 
patients previously within normal range) 
OR 
2) A confirmed increase in transaminases above the patient’s previous Baseline to a 
degree that is significant in the clinical judgment of the Investigator and ALT or 
AST >3 x ULN (in patients with previous abnormal liver-test results) 
OR 
3) Any occurrence of an elevation of ALT or AST >3 x ULN and total bilirubin >2 x 
ULN (in any patient) 
For any such event, the Investigator should discuss the Follow-up approach with the Medical 
Monitor.  
The Sponsor’s recommended approach is as follows: 
1. Schedule the patient for a Follow-up visit within 3 days following the receipt of 
laboratory results to assess the patient and conduct further evaluation, to include the 
following: 
a. Obtain repeat testing of ALT, AST, total bilirubin, and ALP through the central 
laboratory. 
b. Reassess the patient through patient interview and physical examination to 
uncover new or emerging risk factors of liver injury including an increased use 
of alcohol, gallbladder disease, hemochromatosis, fatty liver, use of 
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hepatotoxic concomitant medications (including acetaminophen), occupational 
exposures, liver metastases, and other causes for potential clues as to the 
underlying etiology of the event. 
c. Continue to monitor the patient’s transaminases and total bilirubin regularly 
until the liver function test values return to Baseline levels.  
Additional recommendations include: 
 Consider referral to a hepatologist or gastroenterologist 
 Consider reimaging (eg, ultrasound, CT, or MRI) the liver and biliary tract 
 Consider additional laboratory testing as clinically indicated. Laboratory assays 
available to the Investigator for further workup are described in the laboratory manual 
Upon completion of hepatic assessment, the Investigator should review results with the 
Medical Monitor and assess continued study participation. 
8.2.3 
Pharmacodynamic Assessments 
8.2.3.1 
Plasma 5-HIAA 
Fasting blood samples (≥6 hours) for measurement of 5-HIAA in plasma will be collected 
and analyzed by a specialty laboratory. All sample processing information will be supplied by 
the laboratory in a separate document/study manual. Efforts should be made to schedule these 
visits in the morning, with instructions to the patient to arrive in a fasted state and not dose 
prior to the blood draw. 
8.2.4 
Safety Assessments 
In addition to the clinical laboratory assessments described in Section 8.2.2, monitoring of 
AEs is also considered a safety assessment and is described in detail in Section 9. Clinically 
significant changes compared with Baseline findings for these variables should be reported as 
AEs on the CRF. Clinically significant changes compared with Baseline values, which are 
determined to be AEs, should be followed until the event has resolved, the condition has 
stabilized, etiology of the event is determined to be not related to study drug, or the patient is 
lost to Follow-up. 
8.2.4.1 
Vital Sign Measurements 
Measurement of vital signs will include assessment of blood pressure, respiratory rate, pulse 
rate, and oral temperature. Vital sign measurements should not be conducted with the 
30 minutes immediately following any phlebotomy. 
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Efforts should be made to standardize blood pressure collection across all patients and visits. 
Patients should be seated for at least 5 minutes prior to collection. All measurements should 
be assessed on the same arm, and by the same technician where possible. 
Additional measurements may be obtained if clinically indicated. Vital sign measurements 
will be measured as indicated in Appendix A. 
8.2.4.2 
Physical Examinations 
Complete physical examinations will be performed as outlined in Appendix A. Complete 
physical examinations will include a minimum of a review of the patient’s general 
appearance, head, eyes, ears, nose, and throat (HEENT), neck, heart, lungs, abdomen, back 
and extremities, skin, and general neurological system.  
Symptom-oriented physical examinations will be performed at all other time points and as 
clinically indicated.  
In addition, weight will be captured during each physical examination. Efforts should be 
made to standardize weight collection across all patients and visits. Patients should be 
instructed to remove shoes and heavy clothing (eg, heavy coats, jackets) prior to 
measurement. For weight collection, an effort should be made to use the same scale 
throughout the study where possible. In instances where multiple scales may be used, efforts 
should be made to reset the scale to zero prior to collection of weight measurement. 
8.2.4.3 
Electrocardiograms 
Electrocardiograms (12-lead ECGs) will be performed as specified in Appendix A. 
8.2.4.4 
Adverse Events of Special Interest 
Monitoring of these events will be the responsibility of the DSMB. The process of data 
collection and assessment of the events will be detailed in a separate DSMB charter.  
Additional information will be collected if episodes of any of the following AEs of special 
interest occur. 
8.2.4.4.1 
Central Nervous System Events 
Central nervous system events of special interest may include any clinically significant 
changes in mood, physical affect, or exacerbation of preexisting CNS conditions (eg, 
depression, migraine headaches). 
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8.2.4.4.1.1 
Depression Detection 
Patients will be evaluated beginning at Day 1 (Baseline) and at each subsequent visit for 
indications of depression. During each visit the patient will first be asked to respond to the 
question “During the past month, have you often been bothered by feeling down, depressed, 
or hopeless?” Followed by “During the past month, have you often been bothered by little 
interest or pleasure in doing things?” A positive response prior to Day 1 dosing will be 
evaluated by the Investigator in order to assess if the response is clinically significant. 
Positive responses assessed as clinically significant prior to Day 1 dosing will be captured on 
the medical history CRF page. Positive responses following the first dose will be evaluated 
by the Investigator in order to assess if an AE has occurred. Positive responses assessed to be 
an AE will be followed as an AE of special interest.  
8.3 
Other Assessments 
8.3.1 
Chromogranin A (CgA) 
Blood samples for measurement of chromogranin A (CgA) levels will be collected as 
indicated in Appendix A. 
8.3.2 
Disease Progression 
Data will also be collected on measures of disease progression as performed as standard of 
care including, but not limited to interpretation of clinical scans (eg, PET, CAT, MRI scans of 
tumor), or Investigator assessment of disease status, while the patient is enrolled in the study.     
8.3.3 
Quality of Sleep Assessment 
Quality of sleep will also be evaluated beginning Day 1 (Baseline) and at each subsequent 
visit thereafter. Patients will be asked to respond to the following question “Since your last 
visit, how many times a night (on average) do you wake up due to your CS symptoms?” 
based on the following scale 0, 1, 2, 3, 4, >4.  
8.4 
Appropriateness of Assessments 
The assessments used in this study conform to the usual clinical and laboratory assessments 
of patients with CS participating in clinical trials and are typical of a Phase 3 study.  
8.4.1 
Blood Collection 
An attempt should be made to collect all samples as per the schedule outlined in Appendix A. 
Any portion of samples remaining after the required tests for this study have been completed 
will be destroyed. 
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The estimated amount of blood scheduled for collection per patient, over the course of the 
study, may be found in Appendix B. 
9. 
Safety Reporting 
Medical queries should be addressed to the Medical Monitor responsible for the region. 
Sites in North America: 
, MD 
  
INC Research 
 
Phone: 
 
 
 
Sites outside North America:  
, MD, PhD 
 
INC Research 
 
 
The Netherlands 
Phone: 
 
Mobile: 
 
 
 
, MD, PhD 
Medical Monitor 
INC Research, LLC 
 
 
Czech Republic 
Phone: 
 
Fax: 
 
 
After-hours emergency medical coverage is available to site personnel should the regional 
Medical Monitor and regional backup Medical Monitor be unavailable. 
 
Sites in North America dial 1-877-462-0134. 
 
Sites outside North America dial the country prefix number plus 1-877-462-0134. Prefix 
numbers are determined by accessing the AT&T Direct on-line link 
http://www.usa.att.com/traveler/access_numbers/country/index.jsp. Note: These calls are not 
toll-free. 
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9.1 
Adverse Events 
It is the responsibility of the Investigator to document all AEs that occur during the study. 
Adverse event is defined as any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. 
Life-threatening adverse event or life-threatening suspected adverse reaction: An adverse 
event or suspected adverse reaction is considered "life-threatening" if, in the view of either 
the Investigator or Sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred 
in a more severe form, might have caused death. 
An AE includes any noxious, pathological, or unintended change in anatomical, 
physiological, or metabolic functions as indicated by physical signs or symptoms occurring in 
any phase of the clinical study whether or not considered related to the study medication. 
This definition includes an exacerbation of preexisting medical conditions or events, 
historical condition not present prior to study treatment, which reappear following study 
treatment, intercurrent illnesses, hypersensitivity reactions, drug interaction, or the significant 
worsening of the disease under investigation that is not recorded elsewhere in the CRF. 
Anticipated day-to-day fluctuations of pre-existing conditions that do not represent a 
clinically significant exacerbation or worsening need not be considered AEs. 
Any laboratory abnormality fulfilling the criteria for a SAE (Section 9.2) should be reported 
as such, in addition to being recorded as an AE. Any treatment-emergent abnormal laboratory 
result which is clinically significant, ie, meeting 1 or more of the following conditions, 
should be recorded as a single diagnosis AE: 
 Is considered to be an SAE, 
 Results in discontinuation from study treatment, or 
 Results in a requirement for a change in concomitant therapy (ie, addition of concomitant 
therapy) 
In the event of medically significant unexplained abnormal laboratory test values, the tests 
should be repeated and followed up until they have returned to the normal range and/or an 
adequate explanation of the abnormality is determined.  
TEAEs are defined as any AEs reported after the first dose of study drug on Day 1. Adverse 
events reported after consent of a patient, but before administration of study medication, will 
be reported in the Medical History. 
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AEs should not be solicited with leading questions that suggest specific signs or symptoms. 
Rather, AEs should be solicited by asking the patient a non-leading question such as: “Do you 
feel different in any way since receiving the dose or since the last assessment?” 
The Investigator will evaluate all AEs with regard to the maximum intensity and relationship 
to study drug, as follows: 
 Maximum intensity  
Maximum intensity should be assigned using 1 of the following 3 severity grades: 
o 
Mild: aware of event but easily tolerated 
o 
Moderate: discomfort, enough to cause interference with usual activity 
o 
Severe: incapacitating: patient unable to work or perform usual activities 
 Relationship to study drug 
Not related:  
o 
Does not follow a reasonable temporal sequence from administration of the drug 
o 
Event is reasonably explained by other factors, including underlying disease, 
complications, concomitant drugs, or concurrent treatment; there is no reasonable 
causal link that drug caused the event. 
Unlikely related: 
o 
Temporal sequence from administration of the study drug to event onset suggests a 
doubtful or improbable causal relationship 
o 
Alternative explanation (including underlying disease, complications, concomitant 
drugs, or concurrent treatment) is plausible and more likely 
Possibly related:  
o 
That follows a reasonable temporal sequence from administration of the drug 
(including the course after withdrawal of the drug), or 
o 
For which the possibility of the study drug being the causative factor (eg, existence 
of similar reports attributed to the suspected drug and its analogues; reactions 
attributable to the pharmacological effect) could not be excluded, although other 
factors such as underlying disease, complications, concomitant drugs, or concurrent 
treatment are presumable. 
Probably related: 
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o 
That follows a reasonable temporal sequence from administration of the drug 
(including the course after withdrawal of the drug), and 
o 
For which the possibility of factors other than the drug, such as underlying disease, 
complications, concomitant drugs, or concurrent treatment, could not be excluded as 
the cause. 
Definitely related: 
o 
Follows a clear temporal sequence from administration of the study drug. 
o 
Could not be possibly explained by the known characteristics of the patient’s 
clinical state, environmental or toxic factors, or other modes of therapy 
administered to the patient. 
o 
Disappears or decreases on cessation or reduction in dose of the study drug. 
o 
Reappears or worsens when the study drug is re-administered. 
o 
Follows a response pattern known to be associated with administration of the study 
drug. 
The degree of certainty with which an AE is attributed to treatment with study medication (or 
alternative causes, eg, natural history of the underlying diseases, concomitant therapy, etc.) 
will be determined by how well the event can be understood in terms of known 
pharmacology of the study medication and/or reaction of similar nature being previously 
observed with the study medication or the class of study medication. 
All AEs should be followed for at least 30 days following the last dose of study drug or until 
the event has resolved, the condition has stabilized, or the patient is lost to Follow-up. For 
each patient for whom an AE was reported that did not resolve before the end of the reporting 
period, Follow-up information on the subsequent course of events must be submitted to the 
Sponsor. This requirement indicates that follow-up may be required for some AEs after the 
patient has completed his/her participation in the study 
9.2 
Serious Adverse Events (SAEs) 
An SAE is defined as any event that results in any of the following outcomes: 
1. Death 
2. A life-threatening adverse event; 
3. Inpatient hospitalization or prolonging of an existing hospitalization (see Section 9.2.1 
for information on hospitalization as an SAE);  
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4. A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; or 
5. A congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed above. 
Any SAE must be reported by telephone or facsimile within 24 hours of discovery of the 
event. Investigators should not wait to receive additional information to fully document the 
event before notifying the Sponsor of an SAE at: 
Sites in North America must report to: 
Safety Data Facsimile: 001 (832) 442-5917 
 
Email address (in case of fax failure): drugsafetyfax@lexpharma.com 
 
Sites outside North America must report to the country specific toll-free fax numbers 
identified below: 
Australia: 
 
Belgium: 
 
Brazil: 
 
France: 
 
Germany:
 
Israel: 
 
Italy: 
 
Netherlands: 
 
Spain: 
 
Sweden: 
 
United Kingdom: 
 
 
Email Address (in case of fax failure):  
 
 
The telephone report should be followed by full written summary detailing relevant aspects 
of the SAE in question using the provided SAE report form. Where applicable, information 
from relevant hospital case records and autopsy reports should be obtained. The SAE should 
also be recorded on the AE page of the patient’s CRF. 
An SAE that occurs after completion of the study but, in the opinion of the Investigator, is 
related to the study medication, should be reported as described for an SAE. If an AE does 
not meet the regulatory definition of “serious” but is considered by the Investigator to be 
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related to the study medication and of such clinical concern as to influence the overall 
assessment of safety, it must be reported as defined for an SAE. 
All patients (including discontinued patients) with a SAE must be followed until the event 
resolves or reaches a new Baseline, but for a minimum of 30 days after the last dose of study 
drug. 
9.2.1 
Hospitalization as an SAE 
Hospitalization is defined as any in-patient overnight stay in a hospital. A hospitalization in 
and of itself does not constitute an SAE. The condition which caused the hospitalization must 
be evaluated and determined to be an AE. Although an AE which results in hospitalization is 
an SAE, patients are hospitalized for a variety of reasons which may not be associated with or 
considered an SAE (eg, convenience, logistics, preference, etc). Therefore, each case of 
hospitalization must be evaluated separately. 
For example, the following would not be considered SAEs: 
 Hospitalization for a preexisting condition which did not worsen (eg, cataract surgery) 
 Hospitalization solely for a procedure or treatment that was not performed to treat an 
AE 
 Hospitalization for a condition that does not normally require treatment, but electively 
done (eg, cosmetic surgery) 
 Hospitalization strictly for convenience reasons or observations (eg, procedures only 
performed in a hospital because of the distance the subject lives from the hospital) 
9.3 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
The FDA and/or other applicable Regulatory Authorities and all participating Investigators 
will be notified by a written Investigational New Drug Application (IND) safety report and/or 
other applicable regulatory report (eg, SUSAR) of any suspected adverse reaction that is both 
serious and unexpected, no later than 15 calendar days from the “date learned” of the event. 
In addition, all applicable regulatory bodies will be notified within 7 calendar days of any 
unexpected fatal or life-threatening suspected adverse reaction.  
An adverse reaction is defined as any untoward and unintended response to an investigational 
medicinal product (IMP) related to any dose administered. This definition also covers 
medication errors and uses outside what is foreseen in the protocol, including misuse and 
abuse of the product. The definition also implies a reasonable possibility of a causal 
relationship between the event and the IMP.  
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An unexpected adverse reaction is any adverse drug event, which is not listed in the current 
Investigator’s Brochure or is not listed at the specificity or severity that has been observed. 
For example, (A) a single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (eg, angioedema, hepatic injury, Stevens-Johnson Syndrome); 
(B) 1 or more occurrences of an event that is not commonly associated with drug exposure, 
but is otherwise uncommon in the population exposed to the drug (eg, tendon rupture); (C) an 
aggregate analysis of specific events observed in a clinical trial (such as known consequences 
of the underlying disease or condition under investigation or other events that commonly 
occur in the study population independent of drug therapy) that indicates those events occur 
more frequently in the drug treatment group than in a concurrent or historical control group. 
An untoward and unintended response to a non-IMP is by definition not a SUSAR. 
9.4 
Precautions 
9.4.1 
Pregnancy 
Any patient (or patient’s partner) who becomes pregnant during the study should be followed 
through delivery or termination of the pregnancy. In addition, patients who become pregnant 
during the study must be discontinued from the study treatment immediately.  
In pregnancies that progress to term, any congenital abnormalities/birth defects in the 
offspring of a patient who received study medication should be reported as an SAE. The 
outcome of the pregnancy and the presence or absence of a congenital abnormality will be 
documented by completion of a Pregnancy Questionnaire and a Pregnancy Outcome Form in 
accordance with GCP and ICH guidelines and the Sponsor’s SOPs.  
Female patients should also notify the Investigator if they become pregnant within 30 days 
after last dose of study medication. Male patients should notify the Investigator if a female 
partner becomes pregnant within 30 days after last dose of study medication. The Sponsor 
must be notified of all pregnancies reported to the Investigator (see Section 9.2 for contact 
information). 
10. 
Statistical Methodology 
10.1 
Determination of Sample Size 
No formal sample size calculation was made. The number of patients expected to participate 
in this study was calculated from estimated enrollment rates from other carcinoid cancer trials 
employed in the LX1606 clinical program. 
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10.2 
Analysis Populations 
Per protocol: A Per Protocol population will consist of those patients that receive study 
treatment and have no major protocol violation that would interfere with the collection or 
interpretation of the efficacy data. The primary analyses of efficacy will be based on the 
safety population; the per-protocol population will be used in a supplemental manner.  
Safety: The safety population consists of all patients receiving any fraction of a dose of study 
drug during this study.  
10.3 
Study Endpoints 
10.3.1 
Primary and Secondary Endpoints 
The primary endpoint is to evaluate the long-term safety and tolerability of orally 
administered telotristat etiprate. 
The secondary endpoint is to evaluate changes in patients’ QOL over 84 weeks of therapy.  
10.3.2 
Safety Endpoints 
Safety endpoints are as follows:  
 Incidence of TEAEs, suspected adverse reaction, AEs leading to discontinuation from the 
study, SAEs, and deaths 
 Actual and change from Baseline in clinical laboratory results  
 Actual and change from Baseline in vital signs results  
 Actual and change from Baseline in physical examinations 
 Actual and change from Baseline in ECG findings 
10.4 
Statistical Methods 
Descriptive analysis methods will be used to summarize the data. Continuous variables will 
be summarized by the N, mean, standard deviation, median, minimum, and maximum values. 
Categorical variables will be summarized as counts and related percentages. Data tabulations 
will be categorized by the treatment received on Day 1 of this study, where appropriate, and 
combined across all treated patients. All data will be listed. 
Primary analyses of the data will be based on the Safety population which includes all 
patients treated with any fraction of study drug during this study. Supportive analyses of the 
efficacy data will be made on a Per Protocol population. This dataset will include the Safety 
population, but limited to those patients that have at least one assessment post Day 1 and do 
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not have any protocol violations that would interfere with collection or interpretation of the 
data. The Per Protocol analysis will be applied to the QOL measures, subjective global 
assessment, and plasma 5-HIAA values. 
Data will be summarized per study visit as the actual (raw) outcomes and change from 
Baseline scores, where applicable. Day 1 of this study will serve as the Baseline assessment. 
10.4.1 
Efficacy Analyses 
All efficacy and PD variables will be summarized descriptively and listed. 
Statistical tests and estimates of within patient effects for these measures will be derived from 
application of a mixed linear model with repeated measures. The model will be generalized to 
handle missing data and specific to the measurement properties of the dependent variable. 
There is no plan to impute data for missing observations for any variable. Non-parametric 
methods will be used to supplement the tests and estimates from the mixed linear model. 
Exploratory analyses of treatment group differences may be performed by use of propensity 
score models. The treatments groups will correspond to how patients were dosed on Day 1 of 
this study.  
10.4.2 
Safety Analyses 
Statistical analysis of the safety data will involve examination of the descriptive statistics and 
individual patient listings for any effects of study treatment on clinical tolerability and safety. 
Reporting of these data will be based on the Safety population. Summaries will be prepared 
by treatment group (corresponding to the LX1606 dose given on Day 1), pooled across all 
patients, and as needed, by study visit. All safety data will be listed. 
Treatment-emergent adverse event summaries will include the overall incidence (by system 
organ class and preferred term), events by maximum intensity, events by relationship to study 
treatment, events leading to discontinuation of study drug, events leading to study 
discontinuation, and SAEs. 
Vital signs, ECG, and laboratory parameters (hematology, chemistry, and urinalysis) will be 
summarized descriptively at each time point. Actual and change from Baseline data will be 
calculated and summarized. In addition, shift table analysis will be applied to the laboratory 
data and summarized. 
10.4.2.1 
Adverse Events 
All AEs will be coded and listed by body system and preferred term based on the Medical 
Dictionary for Regulatory Activities (MedDRA). Summaries using descriptive statistics will 
be provided for treatment-emergent AEs, drug-related AEs and AEs by intensity. Treatment-
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emergent AEs are those events not present at Baseline, but occurring after the start of study 
drug, or if existing at Baseline, increasing in intensity after initiation study drug. Summaries 
made by intensity will select the event with the highest intensity when multiple occurrences 
of the same event are reported for the same patient. In a similar manner, summaries prepared 
by drug relationship will select the event with the greatest degree of relationship when a 
study reports multiple occurrences of the same event. On-study deaths will be reported for 
deaths occurring during the active phase of the treatment period and 30 days after stopping 
study drug. Also, deaths occurring outside the 30-day window, but secondary to an AE 
reported within the 30-day post treatment period, will be reported as well.  
Listings will be provided for deaths, SAEs, and discontinuations due to AEs. Additional 
summaries or listings of AEs may also be provided. 
10.4.2.2 
Clinical Laboratory Parameters 
Laboratory results will be reported in conventional units in all tables, figures, and listings. 
Laboratory results falling out of the normal range will be marked as high or low in the 
listings. Actual and changes from Baseline (Day 1) in clinical laboratory results will be 
summarized by using descriptive statistics. Summaries of shifts from Baseline to abnormal 
clinical laboratory results will also be provided. Actual and change from Baseline in 
chromogranin A levels will be summarized descriptively as well. 
10.4.2.3 
Vital Sign Measurements 
Actual and changes from Baseline (Day 1) in vital signs results will be summarized by using 
descriptive statistics. 
10.4.2.4 
Electrocardiograms 
Clinically significant changes in ECGs compared to Baseline, as determined by the 
Investigator, will be summarized by using descriptive statistics. Actual and change from 
Baseline (Day 1 predose values) to each time point in corrected QT interval (QTcF) will be 
summarized as well. 
10.4.3 
Pharmacodynamic Analyses 
Analysis and summarization of the plasma 5-HIAA data are described in Section 10.4.1. 
10.4.4 
Baseline Characteristics and Other Summaries 
Treatment group differences will be summarized descriptively for demographic data, prior 
and concomitant medications, treatment compliance, and final disposition. Data collected 
from assessments of tumor status, when available, will be listed. 
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Protocol deviations will provided as listings. 
10.4.5 
Interim Analysis 
An independent DSMB will be charged with reviewing interim safety data on a quarterly 
basis and reporting its recommendations to Lexicon Pharmaceuticals, Inc. Appropriate 
procedures will be detailed in a DSMB Charter that defines accessibility and disclosure of the 
interim study results. 
The study may be analyzed and reported in multiple phases. The first report will summarize 
data obtained from all patients providing information up to a specified data cut-off point. The 
following reports will update the initial report by including data from the remaining portion 
of the study. The first reporting of the data may be taken as an interim analysis in terms of the 
procedural efforts needed to summarize these data, but it will not serve as a means to modify 
study conduct or the final analysis.   
11. 
Study Management 
The Investigator is responsible for completing and maintaining adequate and accurate CRFs 
and source documentation. Source documentation constitutes original records, which may 
include: progress notes, medication administration records, laboratory reports, ECG tracings, 
and discharge summaries.  
All data on the CRF must be recorded in accordance with the CRF guidelines. If a correction 
is necessary, it should be made by the Investigator or a designated qualified individual as 
specified within the guideline. All CRFs should be completed in their entirety and stored in a 
secure location. The Investigator must sign the Investigator’s statement in each patient’s CRF 
indicating that the data reported are accurate. 
At the study site, clinical research associates will verify 100% of CRFs in their entirety 
against source documentation. Computer programmed edit checks will be run against the 
database to check for discrepancies and reasonableness of the data, and the safety database 
will be reconciled with the clinical database. All issues resulting from the computer generated 
checks and the safety database reconciliation will be resolved according to standard data 
management practices in conjunction with the Sponsor, clinical study personnel, and the 
study Investigators. 
11.1 
Monitoring 
The Sponsor is responsible for ensuring the proper conduct of the study with regard to ethics, 
protocol adherence, site procedures, integrity of the data, and applicable laws and/or 
regulations. At regular intervals during the study and following completion of the study, the 
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Sponsor’s study monitors will contact the study site via visits to the site, telephone calls, 
and/or letters in order to review study progress, CRF completion, and address any concerns 
or questions regarding the study conduct. During monitoring visits, the following aspects of 
study conduct will be carefully reviewed: informed consent of patients, patient recruitment, 
patient compliance with the study procedures, source data verification, drug accountability, 
use of concomitant therapy by patients, AE and SAE documentation and reporting, and 
quality of data. Records pertaining to these aspects are expected to be kept current. 
The Investigator must make study data accessible to the clinical monitor, to other authorized 
representatives of the Sponsor, and to regulatory inspectors 
11.2 
Audits and Inspections 
The Sponsor, regulatory authority, or IRB/ERC may visit the study site at any time during the 
study or after completion of the study to perform audits or inspections. The purpose of a 
Sponsor audit or regulatory inspection is to systematically and independently examine all 
study-related activities and documents to determine whether these activities were conducted 
according to the protocol, GCP, ICH guidelines, and any other applicable regulatory 
requirements. Investigators should contact the Sponsor immediately if contacted by a 
regulatory agency about an inspection at their site. 
11.3 
Amendments 
Any amendments to the protocol will be written and approved by the Sponsor. All 
amendments must be submitted to the IRB/ERC for approval prior to implementing the 
changes. In some instances, an amendment may require changes to the informed consent 
form, which also must be submitted for IRB/ERC approval prior to administration to patients. 
If any changes to the CRF are required, the Sponsor will issue supplemental or revised CRF 
pages. 
11.4 
Record Keeping 
11.4.1 
Drug Accountability  
The Investigator must maintain accurate records of receipt of study drug, dispensing 
information (date, lot, and dose for each patient), and the prompt return or destruction of 
unused supplies. If the Investigator cannot account for all clinical supplies at the termination 
of the study, a written explanation must be provided.  
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11.4.2 
Health Insurance Portability Accountability Act of 1996 and 
Subsequent Updates 
The Investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of patient health information, including, but not limited to, 
the Standards for Individually Identifiable Health Information, 45 Code of Federal 
Regulations (CFR) Parts 160 and 164 (the Health Insurance Portability Accountability Act of 
1996 [HIPAA] Privacy Regulation and any applicable updates). The Investigator shall ensure 
that study patients authorize the use and disclosure of protected health information in 
accordance with HIPAA Privacy Regulation and in a form satisfactory to the Sponsor. 
11.4.3 
Financial Disclosure 
The Investigator shall provide to the Sponsor sufficient accurate financial information to 
allow the Sponsor to submit complete and accurate financial certification or disclosure 
statements to the FDA and/or other applicable regulatory agencies. The Investigator shall 
promptly update this information if any relevant changes occur in the course of the study or 
for 1 year following completion of the study. 
11.4.4 
Access to Original Records 
It is an expectation of regulatory authorities that monitors, auditors, and representatives of 
national and international government regulatory agency bodies have access to original 
source documentation (see examples in Section 11) to ensure data integrity. “Original” in this 
context is defined as the first documentation of an observation and does not differentiate 
between hard copy and electronic records. 
11.4.5 
Retention of Study Documents 
According to 21 CFR Part 312.62 and ICH E6, study-related records must be retained for at 
least 2 years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region, or at least 
2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. These documents should be retained for a longer period, however, if 
required by applicable regulatory requirements or by an agreement with the Sponsor. 
The Investigator must not destroy any study-related records without receiving approval from 
the Sponsor. The Investigator must notify the Sponsor in the event of accidental loss or 
destruction of any study records. If the Investigator leaves the institution where the study was 
conducted, the Sponsor must be contacted to arrange alternative record storage options. 
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12. 
Administrative Structure of the Study 
The study will be monitored by Sponsor personnel or Sponsor representative. The following 
functions for this study will be performed by organizations designated by the Sponsor: data 
management and statistical analysis, including PD analysis and reporting.
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13. 
Appendix A – Schedule of Events 
 
Baseline 
Day 11
Week 12 Week 24 Week 36 Week 48 Week 60 Week 72 Week 84 Week 96
Week 
108
Week 
120
Week 
132
Week 
144
Week 
156
Week 
168
Tolerance (days)
NA
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
+ 21
± 5
Inclusion/Exclusion criteria
X
Medical history
X
Physical examination incl. weight
X
X3
X3
X3
X
X3
X3
X
X3
X3
X3
X
X3
X3
X3
X
 X5
Urine pregnancy test2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology, Blood chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 X5
Urinalysis
X
X
X
X
X
 X5
Chromogranin A
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
X
X
 X5
Subjective Global Assessment
X
X
X
X
X
X
X
X
EORTC QLQ-C30 & GI.NET21
X
X
X
X
X
Sleep and Depression Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma 5-HIAA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispensation of LX1606
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1Eligibility will be determined at last visit of the original protocol; Day 1 will replace the next scheduled visit in the original protocol schedule. Visits should coincide with LAR injections for those patients receiving SSA therapy. 
2Females of child-bearing potential only. 3Brief physical examination only (symptom-oriented, including weight). 4Visit to be performed for subjects who withdraw early and will not return for a 2-week follow-up visit; in all 
other cases the End-of-Study (EOS) visit should be performed followed by the follow-up visit 2 weeks after the final dose. 5To be performed only if evaluation at EOS is abnormal. 6All patients will receive LX1606 for at least 
52 weeks and may continue treatment in the trial until such time telotristat etiprate has received regulatory approval to be marketed and is available via prescription or until 31 March 2017, whichever occurs first. Patients who 
reach this timeline event will be deemed to have completed the Treatment Period and will advance to the EOS visit, regardless of where they are in the visit schedule and when their last study visit occurred. The EOS visit should 
be performed within 21 calendar days following the completion of the Treatment Period.
Treatment Period6
EOS 4
Procedure
2-Week 
Follow-up
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14. 
 Appendix B – Amount of Blood to be Collected from Each Patient 
 
 
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15. 
Appendix C – EORTC QLQ-C30 
 
 
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16. 
Appendix D – EORTC QLQ - GI.NET21 
 
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17. 
Appendix E – Ethical Standards 
Ethics and Regulatory Considerations 
This study will be conducted according to GCP, 21 CFR Part 50, (Protection of Human 
Subjects), 21 CFR Part 56 (Institutional Review Boards), International Conference on 
Harmonisation Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance, the 
Nuremberg Code, and the Declaration of Helsinki.  
General Instructions 
The FDA regulates studies of drugs, biologics, and medical devices. Consequently, these 
studies are subject to GCP regulations and guidance issued by the FDA and are included in, 
but not limited to, the following parts of the CFR and guideline document: 
 21 CFR Part 11 – Electronic Records 
 21 CFR Part 50 – Protection of Human Subjects 
 21 CFR Part 54 – Financial Disclosure 
 21 CFR Part 56 – Institutional Review Boards 
 21 CFR Part 312 – Investigational New Drug Application 
 Current FDA Guideline for the Monitoring of Clinical Investigations 
 Current Guidance for Institutional Review Boards and Clinical Investigators 
 ICH E6 – Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance  
Studies conducted in the European Union are also regulated by Volume 10 of the publications 
“The rules governing medicinal products in the European Union”. 
Copies of these materials are available from the Sponsor upon request. The purpose of these 
regulations and legal obligations is to define the standards and principles for the proper 
conduct of clinical trials that have been developed by the medical, scientific, and regulatory 
communities. They are not intended to impede or restrict clinical research.  
The ethical standards defined within GCP are intended to ensure that: 
 human subjects are provided with an adequate understanding of the possible risks of their 
participation in the study, and that they have a free choice to participate or not; 
 the study is conducted with diligence and in conformance with the protocol in such a way 
as to insure the integrity of the findings; 
 the potential benefits of the research justify the risks. 
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Lexicon Pharmaceuticals, Inc. is the Sponsor of the IND. The Sponsor is responsible for the 
following: 
 selecting qualified Investigators, 
 providing Investigators with the information they need to properly conduct an 
investigation, 
 ensuring proper monitoring of the investigation, 
 ensuring that the study is conducted according to the general investigational plan and 
protocols contained in the IND, 
 maintaining the IND, and  
 ensuring that regulatory authorities and all participating Investigators are properly 
informed of significant new information regarding adverse effects or risks associated with 
the drug being studied 
 ensuring the study is conducted in accordance to FDA and ICH guidelines and all 
applicable regulations 
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18. 
Appendix F – Investigator Obligations 
Per Title 21 of the US Government Code of Federal Regulations (21 CFR) Parts 50 and 56 
and ICH E6, the study protocol and the final version of the subject informed consent form 
will be approved by the IRB/ERC before enrollment of any subjects. The opinion of the 
IRB/ERC will be dated and given in writing. A copy of the letter of approval from the 
IRB/ERC and a copy of the approved informed consent form will be received by the Sponsor 
prior to shipment of study medication supplies to the Investigator. 
The Investigator will ensure that the IRB/ERC will be promptly informed of all changes in 
the research activity and of all unanticipated problems including risk to subjects. The 
Investigator will also ensure that no changes will be made to the protocol without IRB/ERC 
approval. 
As a part of the IRB/ERC requirement for continuing review of approved research, the 
Investigator will be responsible for submitting periodic progress reports to the IRB/ERC at 
intervals appropriate to the degree of subject risk involved, but no less than once per year. 
Written informed consent must be given freely and obtained from every subject prior to 
clinical trial participation. The rights, safety, and well-being of the trial subjects are the most 
important considerations and should prevail over interests of science and society. 
As described in GCP guidelines, study personnel involved in conducting this trial will be 
qualified by education, training, and experience to perform their respective task(s). Study 
personnel will not include individuals against whom sanctions have been invoked after 
scientific misconduct or fraud (eg, loss of medical licensure, debarment). Quality assurance 
systems and procedures will be implemented to assure the quality of every aspect of the 
study. 
Principal Investigators must provide Lexicon with a fully executed Form FDA 1572 
(statement of Investigator) and all updates on a new fully executed Form FDA 1572. 
Principal Investigators must provide Lexicon with his/her own curriculum vitae and current 
curriculum vitae for each sub-Investigator listed on Form FDA 1572. 
Protection of Human Subjects (21 CFR Part 50 and ICH E6)  
Informed consent must be obtained from every subject before entry into a clinical study. It 
must be given freely and not under duress. Consent must be documented by use of an 
IRB/ERC-approved consent form and signed by the subject or the subject’s legally authorized 
representative. The US Department of Health and Human Services suggests that when minors 
are involved, a parent or guardian should sign the consent form. If the minor is an adolescent, 
his signature should also be included. Non-English-speaking subjects must be presented with 
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a consent form written in a language that they understand. A copy of the signed consent form 
must be given to the subject signing it. Another copy must be kept in the Investigator’s files 
and made available to regulatory authority representatives upon request. If, for any reason, 
subject risk is increased as the study progresses, a revised, IRB/ERC-approved consent form 
must be signed by the subject. Before the study begins, a sample of the consent form must be 
provided to the Sponsor for review. The FDA and/or other applicable regulatory agencies 
may reject otherwise scientifically valid studies if proper informed consent has not been 
obtained from all subjects. 
Only in the case of a life-threatening incident may an investigational product be used without 
prior signed consent. In such an emergency situation, separate certifications must be written 
both by a physician not participating in the study and by the Investigator. The certifications, 
along with the protocol and informed consent, must be sent to the IRB/ERC within 5 working 
days. In this situation, the Investigator may not administer any subsequent product to that 
subject until informed consent and IRB/ERC approval are obtained. 
Informed Consent 
Written informed consent must be obtained from each subject prior to entry in the study. One 
copy of the signed informed consent document will be given to the subject, and another will 
be retained by the Investigator. Additionally, the subject must be allowed adequate time to 
consider the potential risks and benefits associated with his/her participation in the study.  
In situations where the subject is not legally competent to provide consent (ie, mentally 
incapacitated), written consent must be obtained from a parent, legal guardian, or legal 
representative. In these situations, the consent must be signed and dated by a witness. 
The informed consent document must have been reviewed and approved by the Sponsor and 
by the Investigator’s IRB/ERC prior to the initiation of the study. The document must contain 
the 8 basic elements of informed consent and may contain the 6 additional elements 
described in 21 CFR Part 50. Every consent form must include the following 8 elements: 
 A statement that the study involves research, an explanation of the purpose of the research 
and the expected duration of the subject’s participation, a description of the procedures to 
be followed, and identification of any procedures that are experimental 
 A description of any reasonably foreseeable risks or discomforts to the subject 
 A description of any benefits to the subject or to others that may reasonably be expected 
from the research 
 A disclosure of appropriate alternative procedures or course of treatment, if any, that 
might be advantageous to the subject 
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 A statement describing the extent, if any, to which confidentiality of records identifying 
the subject will be maintained and noting the possibility that the FDA and/or other 
applicable regulatory authority representatives may inspect the records 
 An explanation as to whether any compensation or medical treatments are available if 
injury occurs for research involving more than minimal risk. The explanation should 
involve a description of the compensation or treatment available, or a statement 
describing where further information may be obtained 
 An explanation of whom to contact for answers to pertinent questions about the research 
and the subject’s rights and whom to contact in the event of a research related injury 
 A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the subject is otherwise entitled, and that the subject 
may discontinue participation at any time without penalty or loss of benefits to which the 
subject is otherwise entitled. 
When appropriate, 1 or more of the following elements of information shall also be included 
in the consent form: 
 A statement that the particular treatment or procedure may involve risks to the subject (or 
to the embryo or fetus, if the subject is or may become pregnant) which are currently 
unforeseeable 
 Anticipated circumstances under which the subject’s participation may be terminated by 
the Investigator without regard to the subject’s consent 
 Any additional costs the subject may incur from participation in the research 
 The consequences of a subject’s decision to withdraw from the research and procedures 
for orderly termination of participation by the subject 
 A statement that significant new findings developed during the course of the research that 
may relate to the subject’s willingness to continue participation will be provided to the 
subject 
 The approximate number of subjects involved in the study 
The Declaration of Helsinki includes further details regarding the specific requirements for 
informed consent.  
Nothing in these regulations is intended to limit the authority of a physician to provide 
emergency medical care to the extent the physician is permitted to do so under applicable 
federal, state, or local laws. 
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The informed consent requirements in these regulations are not intended to preempt any 
applicable federal, state, or local laws that require additional information to be disclosed in 
order that informed consent be legally effective. Some states, such as California and Oregon, 
require further action on the Investigator’s part concerning subject consent. 
Study Documentation 
IRB/ERC Review/Approval 
The protocol and informed consent for this study, including advertisements used to recruit 
subjects, must be reviewed and approved by an appropriate IRB/ERC prior to enrollment of 
subjects in the study. It is the responsibility of the Investigator to assure that all aspects of the 
ethical review are conducted in accordance with the current Declaration of Helsinki, ICH, 
GCP, and/or local laws, whichever provide the greatest level of protection. A letter 
documenting the IRB/ERC approval which specifically identifies the study/protocol and a list 
of the committee members must be received by the Sponsor prior to initiation of the study. 
Amendments to the protocol will be subject to the same requirements as the original protocol. 
A progress report with a request for re-evaluation and re-approval will be submitted by the 
Investigator to the IRB/ERC at intervals required by the IRB/ERC, and not less than 
annually. A copy of the report will be sent to the Sponsor.  
When the Sponsor provides the Investigator with a Safety Report, the Investigator must 
promptly forward a copy to the IRB/ERC. 
After completion or termination of the study, the Investigator will submit a final report to the 
IRB/ERC and to the Sponsor, if required. This report should include: deviations from the 
protocol, the number and types of subjects evaluated, the number of subjects who 
discontinued (with reasons), results of the study, if known, and significant AEs, including 
deaths. 
Study Files 
The Investigator is required to maintain complete and accurate study documentation in 
compliance with current Good Clinical Practice standards and all applicable federal, state, 
and local laws, rules, and regulations related to the conduct of a clinical study. Study 
documents include, but are not limited to, the Investigator’s Brochure, drug accountability 
records, Sponsor/Investigator correspondence, IRB/ERC correspondence, protocol and 
amendments, information regarding monitoring activities, subject exclusion records, CRFs, 
and data queries. 
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Confidentiality 
The anonymity of subjects must be maintained. Patients will be identified by their initials and 
an assigned subject number on CRFs and other documents submitted to the clinical monitor. 
Documents that will be submitted to the clinical monitor and that identify the subject (eg, the 
signed informed consent document) must be maintained in strict confidence by the Principal 
Investigator, except to the extent necessary to allow auditing by regulatory authorities, the 
clinical monitor, or Sponsor personnel. 
All information regarding the nature of the proposed investigation provided by the Sponsor to 
the Investigator (with the exception of information required by law or regulations to be 
disclosed to the IRB/ERC, the subject, or the regulatory authority) must be kept in confidence 
by the Investigator. 
Drug Accountability 
The Investigator or designee is responsible for accountability of the investigational product at 
the site. The Investigator or designee must maintain records of the product’s delivery to the 
site, inventory at the site, use by each subject, and return to the Sponsor or alternative 
disposition of any unused product. These records must include dates, quantities, 
batch/serial/lot numbers, and expiration dates (if applicable). 
The Investigator should ensure that the investigational product is used only in accordance 
with the protocol 
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19.
References
1.
Bhattacharyya S, Toumpanakis C, Chilkunda D, Caplin ME, Davar J. Risk factors for
the development and progression of carcinoid heart disease. Am J Cardiol. 2011;
107(8):1221-6. Epub 2011 Feb 4.
2.
Møller JE, Connolly HM, Rubin J, Seward JB, Modesto K, Pellikka PA. Factors
associated with progression of carcinoid heart disease. N Engl J Med.
2003;348(11):1005-15.
3.
Druce M, Rockall A, Grossman AB. Fibrosis and carcinoid syndrome: from causation to
future therapy. Nat Rev Endocrinol. 2009;5(5):276-83 .
4.
DePonti F. Pharmacology of serotonin: what a clinician should know. Gut.
2004;53:1520-35.
5.
Cote F, et al. Disruption of the nonneuronal tph 1 gene demonstrates the importance of
peripheral serotonin in cardiac function. Proc Natl Acad Sci. 2003;100(23):13525-30.
6.
De Vries H, et al. Diagnostic, surgical, and medical aspect of the midgut carcinoids.
Cancer Treat Rev. 2002;28:11-25.
7.
Sandostatin LAR® depot product label. Revised July 2014. Accessed at: 
http://www.pharma.us.novartis.com/product/pi/pdf/sandostatin_lar.pdf
8.
Investigator Brochure LX1606, Lexicon Pharmaceuticals, Inc.
9.
Dmitrienko A, Tamhane A, Wiens B. General multistage gatekeeping procedures.
Biometrical Journal. 2008;50:667-77
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CLINICAL PROTOCOL AMENDMENT 4  
STUDY LX1606.302 
 
 
A Multicenter, Long-term Extension Study to Further Evaluate the Safety and 
Tolerability of Telotristat Etiprate (LX1606) 
 
 
PROTOCOL NO.: 
LX1606.1-302-CS 
LX1606.302 (Abbreviated number) 
 
 
EudraCT Number: 
2013-002596-18 
 
 
INVESTIGATIONAL PHASE: 
3 
 
 
SPONSOR: 
Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Place 
The Woodlands, TX 77381-1160 
Telephone: 001 (281) 863-3000 
Safety Hotline: 001 (877) 372-3597 
Safety Data Facsimile: 001 (832) 442-5917 
 
 
 
PROTOCOL AMENDMENT 4 DATE: 
02 November 2015 (North America only) 
PROTOCOL AMENDMENT 3 DATE: 
06 May 2015 (Germany and UK sites only) 
PROTOCOL AMENDMENT 2 DATE: 
08 October 2014 
PROTOCOL AMENDMENT 1 DATE: 
31 January 2014 
ORIGINAL VERSION DATE: 
14 June 2013 
 
 
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Amendment Changes 
 
Rationale 
 
A protocol amendment is proposed to provide additional continued access to telotristat etiprate 
for patients who are enrolled in the LX1606.1-302-CS study.  This amendment will allow 
treatment with telotristat etiprate until such time telotristat etiprate has received regulatory 
approval to be marketed and is available via prescription or 31 March 2017, whichever occurs 
first. Based upon the expected dates for eligible patients’ entry into this study, overall duration of 
participation will last up to 169 weeks including the Treatment Period and Follow-up Period. 
As a result of the extended duration of the study, the protocol has been modified to reflect that 
patient reported quality of life (QOL) measures will be analyzed through Week 84 of the study.  
These QOL assessments include the EORTC QLQ-C30 & GI.NET21 questionnaires and the 
subjective global assessment of symptoms associated with carcinoid syndrome (CS). 
In addition, modifications have been made to: (1) revise the number of patients expected to 
participate;  (2) decrease the number of study sites anticipated to participate; (3) clarify the 
nature of major protocol violations in the lead-in study that would meet exclusion criteria under 
this study; (4) update the clinical trial experience and safety information based on completed 
Phase 1 and Phase 2 studies; (5) correct errant language that unintentionally associates the term 
“efficacy” with the primary objectives of the protocol; (6) clarify the upper limit of allowable 
temperature excursion for the storage of study drug; (7) clarify the manner in which responses to 
questions designed to detect early signs of depression are managed; (8) clarify the definition of 
AEs not related to study drug; (9) include a fifth classification for AEs, “unlikely related”; (10) 
revise the description of safety analyses; (11) update Schedule of Events to reflect new 
assessments; and (12) update the amount of blood to be collected.  
The following administrative changes have also been made: 
 Minor formatting, capitalization, punctuation, abbreviation, grammatical, and spelling 
errors have been corrected 
 Definition of Terms has been updated to define telotristat etiprate as the hippurate salt 
form of the LX1606 drug substance 
 Due to the revision of some section headings, renumbering has occurred as appropriate  
 The Table of Contents has been updated as appropriate 
In response to these changes, the following sections have been revised as follows (changes are 
indicated in italics):  
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1. SYNOPSIS – Secondary Objective, page 3 – This section was modified to reflect that 
patient reported QOL data will be collected and evaluated through Week 84.  The 
revised section now reads: 
“To evaluate changes in patients’ quality of life (QOL) through Week 84” 
2. SYNOPSIS – Number of Patients, page 4 – This section was modified to update the 
anticipated study enrollment.  The revised section now reads: 
“Up to 130 patients are expected to participate in this study.” 
3. SYNOPSIS – Number of Study Sites, page 4 – This section was modified to decrease 
the number of study sites expected to participate.  The revised section now reads: 
“Approximately 50 sites” 
4. SYNOPSIS – Duration of Participation, page 4 – This section was modified to reflect 
the further extension of the study Treatment Period.  The revised section now reads: 
“All patients will participate in the Treatment Period until such time telotristat etiprate has 
received regulatory approval to be marketed and is available via prescription or 31 March 2017, 
whichever occurs first. Based upon the expected dates for eligible patients’ entry into this study, 
overall duration of participation will last up to 169 weeks including the Treatment Period and 
Follow-up Period.” 
5. SYNOPSIS – Exclusion Criteria, page 5 and STUDY POPULATION – Exclusion 
Criteria, Section 6.2, pages 22, Criterion #1 – This criterion has been modified to 
clarify the nature of major protocol violations in the lead-in study that would meet 
exclusion criteria under this study. The revised criterion now reads: 
“Major protocol violations in regard to dosing compliance or telotristat etiprate tolerability 
concerns in a Phase 2 study (ie, LX1606.1-202-CS, LX1606.1-203-CS) or Phase 3 study (ie, 
LX1606.1-301-CS, LX1606.1-303-CS)” 
6. INTRODUCTION – Clinical Trials of Telotristat Etiprate (LX1606) in Humans, 
Section 3.2, page 14 – This section was revised to reflect the total number of healthy 
volunteers and patients with either carcinoid syndrome or ulcerative colitis that 
have participated in completed Phase 1 and Phase 2 trials.  The revised section now 
reads: 
“Telotristat etiprate has been studied in single/multiple doses in Phase 1 studies, approximately 
259 healthy volunteers participated in Phase 1 trials with 237 subjects receiving telotristat 
etiprate. In Phase 2, 38 patients with CS and 49 patients with ulcerative colitis received 
telotristat etiprate during the evaluation of 3 clinical studies.   Additionally, over 200 patients 
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with carcinoid syndrome have been enrolled and are being evaluated in ongoing Phase 3 
studies.” 
7.  INTRODUCTION – Section 3.2.1 Phase 1 Studies, pages 14-16 – This section was 
revised in its entirety to update the clinical trial experience and safety information 
based on completed Phase 1 studies.  The revised section now reads: 
“Telotristat etiprate has been evaluated in 9 completed Phase 1 clinical studies to date. A single 
ascending dose tolerability study explored a dose range of 50 to 1500 mg (LX1606.1-101-NRM), 
and a multiple ascending dose tolerability study explored a dose range of 100 mg (qd) to 1500 
mg (500 mg tid) over 14 days (LX1606.1-102-NRM). Both studies were conducted in healthy, 
normal volunteers in a randomized, double-blind, placebo controlled fashion, utilizing whole 
blood 5-HT and 24-hour urinary 5-HIAA levels as biomarkers of pharmacologic response. A 
two-way crossover study of 2 oral formulations of 250 mg given as a single dose (LX1606.1-103-
NRM) was conducted in healthy, normal volunteers as a randomized, open-label study, utilizing 
PK parameters as a marker of comparability of the capsule versus tablet formulation. A study 
designed to evaluate the pharmacokinetics, metabolism, and routes and extent of elimination of 
LX1606 telotristat etiprate and its primary metabolite (LP-778902) after a single oral dose of 
500 mg 14C-LX1606 was conducted in 8 healthy male volunteers (LX1606.1-104-NRM). A 
thorough QT study (LX1606.1-105-NRM), a food-effect study (LX1606.1-107-NRM), and 3 drug-
drug interaction studies (LX1606.1-106-NRM; LX1606.1-108-NRM; LX1606.1-109-NRM) were 
also all conducted in healthy, normal volunteers. Telotristat etiprate was well tolerated with 
drug-related GI AEs (primarily nausea) becoming dose-limiting at the 1500 mg single dose level. 
Multiple doses of telotristat etiprate over 14 days are well tolerated up to 1500 mg daily dose, 
administered as 500 mg tid. Telotristat etiprate is readily converted to the active metabolite LP-
778902. At the doses evaluated, extremely low levels of telotristat etiprate are present in 
circulation, with most samples containing ≤ 10 ng/mL of the prodrug and many samples being 
below the limit of quantitation (0.5 ng/mL). Urinary 5-HIAA levels showed a statistically 
significant reduction of approximately 50-60% relative to placebo over 14 days at dose levels ≥ 
500 mg telotristat etiprate. Similarly whole blood 5-HT declined in a dose-dependent fashion 
over 14 days. The results of the thorough QT study clearly demonstrated that telotristat etiprate 
is negative for QT prolongation as defined by the ICH E14 guidance. The results of LX1606.1-
106-NRM suggest that telotristat etiprate is not a P-glycoprotein 1 (P-gp) inhibitor as per FDA 
Guidance for Industry – Drug Interaction Studies (February 2012), where P-gp inhibitors are 
defined as those drugs that increase the AUC of fexofenadine by ≥1.25 fold. However, telotristat 
etiprate did exhibit a lower level of P-gp inhibition that is unlikely to be clinically meaningful. 
LX1606.1-107-NRM confirms a food effect is seen with telotristat etiprate such that systemic 
exposure to telotristat ethyl and metabolite LP-778902 is significantly increased following 
administration in the fed state compared to the fasted state. Results of LX1606.1-108-NRM do 
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not support inhibitory activity of steady-state telotristat ethyl concentrations on CYP3A4; 
however, systemic exposure to midazolam was significantly lower when midazolam was 
coadministered with telotristat etiprate. It is believed this observation is the result of a reduction 
in midazolam absorption. Coadministration of octreotide acetate with telotristat etiprate is 
addressed in LX1606.1-109-NRM. Systemic exposure to both telotristat ethyl and metabolite LP-
778902 is significantly reduced compared to administration of telotristat etiprate alone, thereby 
suggesting a drug-drug interaction. However, it is not known whether the long-acting depot 
formulation of octreotide acetate would exhibit a similar interaction with telotristat etiprate as 
what was seen with the subcutaneous injections of octreotide acetate used in this study. 
8. INTRODUCTION – Section 3.2.2 Phase 2 Studies, pages 16-18 – This section was 
revised to update the clinical trial experience and safety information based on 
completed Phase 2 studies.  The revised section now reads: 
“In Phase 2 studies in patients with CS, dose levels of 150, 250, 350, or 500 mg tid telotristat 
etiprate were evaluated. All dose levels were generally well tolerated. The Phase 2 clinical trial 
results indicated that treatment using telotristat etiprate in patients with CS may lead to 
improvements in BM frequency, stool consistency, urgency to defecate, abdominal pain, 
diarrhea, flushing, and reductions in 5-HIAA. 
LX1606.1-202-CS was a randomized, double-blind, placebo-controlled, multiple ascending dose 
study conducted in 2 parts in order to evaluate a total of 23 patients at a dose range of 450 to 
1500 mg given as 150, 250, 350, or 500 mg tid (telotristat etiprate or matching placebo) on a 
background therapy of octreotide. In Part 1, 16 patients were randomly assigned 3:1 into 4 
sequential cohorts. Each cohort evaluated 1 of the following daily doses given as 150, 250, 350, 
or 500 mg tid over a course of 4 weeks. During the study, all patients continued on a stable-dose 
background therapy of octreotide. In Part 2, an additional 7 patients were randomly assigned 3:1 
in order to evaluate 500 mg tid, the highest tolerated dose as determined in Part 1. Upon 
completion of the initial 4-week double-blind, placebo-controlled portion (the Core Phase), 
eligible patients had the option to continue into an open-label Extension Period (the Extension 
Phase). 
For the LX1606-treated patients combined (n=18) in the randomized placebo-controlled 
LX1606.1-202-CS study, 5 patients (33.3%) experienced a reduction in BM frequency of at least 
30% versus no patients (0.0%) for the placebo group (n=5). A complete biochemical response, 
defined as at least a 50% reduction from Baseline in urinary 5-HIAA (mg/24 hours) or 
normalization post-Baseline urinary 5-HIAA (mg/24 hours) value <ULN for cases where the 
Baseline value was elevated, was achieved by 9 of 16 patients (56.3%) versus no patients (0.0%) 
on placebo. 
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LX1606 was well tolerated by patients enrolled in this study. Across both the Core Phase and the 
Extension Phase, greater than half (73.9% and 52.6%, respectively) of the TEAEs reported were 
mild or moderate in intensity. TEAEs were reported most frequently within the GI disorders 
class, the most frequently reported TEAE was diarrhea, followed by nausea. No clinically 
significant changes from baseline in laboratory parameters, vital signs, physical examination 
findings, or ECG results were observed throughout the study, except for alkaline phosphatase 
(ALP) and gamma-glutamyltransferase (GGT) levels. Mean ALP and GGT levels remained 
elevated compared with Baseline during both study periods, but no relevant clinical outcomes 
were observed.  
During the Core Phase, no dose-response relationship was observed in frequencies of any 
TEAEs, severe TEAEs or related TEAEs among the treatment groups that received placebo or 
various dosages of LX1606. One patient each in the placebo arm (20.0%) and the active 
treatment arm (5.6%) discontinued the study drug due to TEAEs. There were no fatal SAEs 
during the Core Phase. One patient in the LX1606 350 mg tid group experienced 2 SAEs (severe 
nausea and vomiting) that were reported as possibly related to study drug; both events resolved 
after symptomatic treatment. 
During the Extension Phase, eight patients experienced a total of 20 SAEs. One patient 
experienced 4 TEAEs that led to discontinuation. There was 1 fatal SAE of disease progression. 
None of the SAEs were reported as related to study drug. 
LX1606.1-203-CS was an open-label, serial ascending, multiple dose, individual titration study 
that evaluated the same dose ranges as the LX1606.1-202-CS study in a total of 15 patients. 
Patients were serially escalated to the next dose level every 2 weeks until a maximally tolerated 
dose (MTD) or 500 mg tid was reached. Once a MTD had been determined, the patient would 
remain on the dose for an additional 4 weeks. Patients then had the option to continue into an 
Extension Period.  
In this open-label study, there was evidence of clinically meaningful improvement in the GI-
related symptoms associated with carcinoid syndrome, reflected by decreases in BM frequency, 
improvements in stool consistency, reductions in urgency to defecate, and reductions in flushing. 
Patients reported adequate relief of their symptoms, and physicians reported global clinical 
improvement. Reductions in u5-HIAA were observed. Most patients continued into the long-term 
Extension Period, with no evidence of loss of efficacy over time. 
Most patients reached the 500 mg tid dose level during this study. No MTD was identified. 
Adverse events were those expected for the patient population under treatment, and no clinically 
significant trends in laboratory values, vital sign measurements, ECG results, or physical 
examination findings were observed. There was 1 fatal SAE of neoplasm progression; no SAE 
was reported as related to study drug. 
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LX1606.1-204-UC evaluated patients with acute, mild to moderate ulcerative colitis 
experiencing active flares were enrolled in a randomized, double-blind, placebo-controlled study 
designed to evaluate the safety and efficacy of telotristat etiprate. Patients were maintained on a 
stable-dose of aminosalicylate therapy for 8 weeks and randomly assigned to receive 1 of 2 
dosages of telotristat etiprate (500 mg once daily or 500 mg tid) or placebo; 59 patients were 
enrolled in the study. Adverse events were those expected for the ulcerative colitis patient 
population and no clinically significant trends in laboratory values, vital sign measurements, 
ECG results, or physical examination findings were observed. 
Although results from the study provide a clear signal of activity of the mechanism of action of 
telotristat etiprate in this patient population, they were not accompanied by other findings that 
would indicate a large impact on disease modification. Detailed information regarding the 
completed clinical studies can be found in the Investigator Brochure.8” 
9. INTRODUCTION – Ongoing Studies, Section 3.2.3, page 18 – This section was 
revised to reference the Investigator Brochure.  The following paragraph has been 
inserted at the end of this section: 
“Detailed information regarding the ongoing clinical studies can be found in the Investigator 
Brochure.8” 
10. INTRODUCTION – Benefit/Risk Assessment, Section 3.3.2, pages 19-20 – This 
section was revised to reflect the total number of subjects that have been exposed to 
telotristat etiprate in Phase 1, Phase 2, and Phase 3 studies. In addition, some textual 
clarifications were made to better reflect the observed and anticipated benefits and 
risks associated with telotristat etiprate. The revised section now reads: 
“Clinical experience with telotristat etiprate (treated subjects) consists of completed single and 
multiple ascending dose studies in 259 normal subjects, 2 Phase 2 studies (38 patients with 
symptomatic CS) and ongoing Phase 3 studies in patients with symptomatic CS. 
In healthy volunteer studies, single doses up to 1000 mg were found to be generally well 
tolerated, while at the 1500 mg dose level GI-related adverse events increased. A similar adverse 
event profile was observed after multiple dose administration over 14 days with GI events 
predominating. Mild, dose-dependent increases in hepatic transaminase levels (≤2 x ULN) were 
observed with increased frequency in relation to dose, with 1 subject requiring withdrawal from 
therapy at the 500 mg bid dose level. Most subjects that were observed to have increased 
transaminase levels did not exceed >2 x ULN. No abnormalities in total bilirubin were observed 
at any dose level. GI events have been the most commonly observed events to date. The adverse 
event profile in normal subjects may differ significantly from what is observed in patients with 
hyperserotonemia. All adverse events resolved without sequelae. In addition, there were no 
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significant changes in vital signs or ECG. No physical examination abnormalities were noted in 
studies to date. There were no serious adverse events reported in healthy volunteers. 
In patients with CS, dose escalations have proceeded up to and including 500 mg tid. To date, 
there has been no evidence of dose-limiting intolerability. Dose levels have been generally well 
tolerated.  
Phase 3 clinical trials are currently underway to provide further data to support the Phase 2 
study results. Currently 210 patients have been randomized to the placebo-controlled trials 
(LX1606.1-301-CS and LX1606.1-303-CS). After completing participation in 1 of the Phase 2 or 
Phase 3 studies, eligible patients with CS will have the option of continuing treatment with the 
study drug in this long-term, open-label Extension study (LX1606.1-302-CS).  
Based upon observations from preclinical and clinical studies conducted to date, it is anticipated 
that orally administered telotristat etiprate will be well tolerated at dose levels required to 
influence peripheral 5-HT production. Potential adverse events primarily involve the GI tract, 
and could include alterations in gut motility that may result in nausea, vomiting, diarrhea, and 
constipation. Regular and ongoing clinical and laboratory assessments should detect any of these 
events, and depending on the type of event, further dose adjustment or discontinuation from the 
trial would occur. Central nervous system effects are not anticipated at dose levels planned for 
evaluation, but careful monitoring for any such effect has been included in the study. As 
elevations in hepatic transaminase levels were observed with multiple dosing in normal subjects, 
monitoring clinical laboratory tests of hepatic function will be incorporated into clinical trials 
conducted in CS patients. 
The Phase 2 clinical trial results indicated that treatment may lead to improvements in BM 
frequency, stool consistency, urgency to defecate, abdominal pain, diarrhea, flushing, and 
reductions in 5-HIAA. These potential benefits relate to a unique mechanism of action. 
Symptomatic improvement may lead to a better quality of life (QOL) for patients with few 
treatment options available, and a reduction in serotonin may help reduce the risk of carcinoid 
heart disease. Overall the benefit/risk profile of telotristat etiprate is expected to be favorable for 
participation in this clinical study.” 
11. STUDY OBJECTIVES – Efficacy Objectives, Section 4.1, page 20 – This section 
header was deleted to correct errant language that unintentionally associates the 
term “efficacy” with the primary objectives of the protocol.  As a result of the 
deletion, section headers for Primary Objective, Section 4.1.1, page 20, Secondary 
Objective(s), Section 4.1.2, page 20, and Safety Objectives, Section 4.2, page 20 were 
updated.  The revised section headers now read as in the following comparison 
table: 
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Section 
Previous Headings (Amendment 2, 
dated 31 January 2014) with Revisions 
Marked in Track Change Mode 
New Headings (Amendment 4, 
dated 02 November 2015) as 
Revised 
Section 4./ 
Study Objectives 
(page 20) 
4. Study Objectives
4. 1 Efficacy Objectives 
4.1.1 Primary Objective 
4.1.2 Secondary Objective(s) 
4.23 Safety Objectives 
4. Study Objectives
4.1 Primary Objective 
4.2 Secondary Objective(s) 
4.3 Safety Objectives 
added text / deleted text 
12. STUDY OBJECTIVES – Secondary Objective(s), Section 4.2, page 20 – This section
was modified to reflect that patient reported QOL data will be collected and
evaluated through Week 84.  The revised section now reads:
“The secondary objective of this study is to evaluate changes in patients’ QOL through Week 84.” 
13. INVESTIGATIONAL PLAN – Overall Study Design, Section 5.1, paragraphs 3 and
4, page 21 - This section was revised to insert paragraph 3 describing the minimum
treatment duration of 52 weeks, which may continue to the earlier of marketing
approval with prescription availability or 31 March 2017.  The inserted text also
defines the completion of the Treatment Period. The paragraph describing the
patients’ completion of a Follow-up Period was moved to immediately follow the
inserted text and revised to address only patients who complete the Treatment
Period since the management of discontinued patients is already described
elsewhere in the protocol.  The following paragraph was been inserted, followed by
the relocated paragraph:
“All patients will receive telotristat etiprate for at least 52 weeks and may continue treatment in 
the trial until such time telotristat etiprate has received regulatory approval to be marketed and 
is available via prescription or until 31 March 2017, whichever occurs first. Patients who reach 
this timeline event will be deemed to have completed the Treatment Period and will advance to 
the End-of-Study (EOS) visit as identified in Appendix A – Schedule of Events, regardless of 
where they are in the visit schedule and when their last study visit occurred. 
Upon completion, all patients will be required to complete a 14-day Follow-up Period, during 
which no study drug will be administered.” 
14. STUDY POPULATION – Section 6, pages 21-22 – This section was revised to
update both the number of patients and the number of study sites expected to
participate in the study.  The revised section now reads:
“Adult patients who are currently participating in ongoing Phase 2 or Phase 3 telotristat etiprate 
CS clinical protocols will be enrolled into the study. Up to 130 patients are expected to enroll in 
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Protocol No.  LX1606.302 A4 
02 November 2015 
CONFIDENTIAL
Page 10 of 14 
this study. Approximately 50 sites worldwide will participate in the study. Patients may continue 
allowed medications as background therapy provided they remain on stable- doses throughout 
the Treatment Period.” 
15. TREATMENT – Packaging, Labeling, and Storage, Section 7.1.1.2, page 25,
paragraph 2 – This paragraph was revised to clarify the upper limit of allowable
temperature excursion for the storage of study drug. The revised paragraph now
reads:
“Telotristat etiprate should be stored between 15 to 25°C (59 to 77°F), with excursions allowed 
up to 30C.” 
16. STUDY PROCEDURES – Efficacy Assessments, Section 8.2.1, pages 26-27,
paragraph – This paragraph was revised to correct parenthetic references to
protocol appendices. The paragraph now reads:
“Efficacy assessments include the patient reported QOL measures; EORTC QLQ-C30 (Appendix 
C) & GI.NET21 (Appendix D) questionnaires and subjective global assessment of symptoms
associated with CS.”  
17. STUDY PROCEDURES – Subjective Global Assessment, Section 8.2.1.2, page 26 –
This section was revised to reference Appendix A – Schedule of Events, which
reflects that the Subjective Global Assessment will be conducted through Week 84.
The following paragraph now reads:
“A subjective global assessment of symptoms associated with CS will be evaluated using 
2 methods at each visit as indicated in Appendix A.” 
18. STUDY PROCEDURES – Depression Detection, Section 8.2.4.4.1.1, pages 30-31 –
This section has been modified to clarify how responses to the questions should be
assessed and documented. The section now reads:
“Patients will be evaluated beginning at Day 1 (Baseline) and at each subsequent visit for 
indications of depression. During each visit the patient will first be asked to respond to the 
question “During the past month, have you often been bothered by feeling down, depressed, or 
hopeless?” Followed by “During the past month, have you often been bothered by little interest 
or pleasure in doing things?” A positive response prior to Day 1 dosing will be evaluated by the 
Investigator in order to assess if the response is clinically significant. Positive responses 
assessed as clinically significant prior to Day 1 dosing will be captured on the medical history 
CRF page. Positive responses following the first dose will be evaluated by the Investigator in 
order to assess if an AE has occurred. Positive responses assessed to be an AE will be followed 
as an AE of special interest.” 
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Protocol No.  LX1606.302 A4 
02 November 2015 
CONFIDENTIAL
Page 11 of 14 
19. SAFETY REPORTING – Adverse Events, Section 9.1, Relationship to Study Drug,
page 34 – This section has been modified to provide clarification on categorizing
events that are not related. In addition, a 5th classification “unlikely related” has
been added. The revised and added text reads:
“Not related:  
o
Does not follow a reasonable temporal sequence from administration of the drug
o
Event is reasonably explained by other factors, including underlying disease, complications,
concomitant drugs, or concurrent treatment; there is no reasonable causal link that drug
caused the event.
Unlikely related: 
o
Temporal sequence from administration of the study drug to event onset suggests a doubtful
or improbable causal relationship
o
Alternative explanation (including underlying disease, complications, concomitant drugs, or
concurrent treatment) is plausible and more likely”
20. STATISTICAL METHODOLOGY – Efficacy Endpoints, Section 10.3.1, page 39 –
This section was renamed to correct errant language that unintentionally associates
the term “efficacy” with the primary objectives of the protocol. In addition, the
second paragraph was revised to more precisely reflect the study period over which
patient reported QOL data will be evaluated.  The revised section now reads as in
the following comparison table:
Section 
Previous Section Heading and 
Content (Amendment 2, dated 31 
January 2014) with Revisions 
Marked in Track Change Mode 
New Section Heading and Content 
(Amendment 4, dated 02 November 
2015) as Revised 
Section 10.3.1/ 
Efficacy Endpoints 
(page 39) 
10.3.1 Efficacy Primary and 
Secondary Endpoints 
The primary efficacy endpoint is to 
evaluate the long-term safety and 
tolerability of orally administered 
telotristat etiprate. 
Secondary efficacy The secondary 
endpoint is to evaluate changes in 
patients’ QOL over multiple years 84 
weeks of therapy. 
10.3.1 Primary and Secondary 
Endpoints 
The primary endpoint is to evaluate 
the long-term safety and tolerability 
of orally administered telotristat 
etiprate. 
The secondary endpoint is to evaluate 
changes in patients’ QOL over 84 
weeks of therapy. 
added text / deleted text 
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Protocol No.  LX1606.302 A4 
02 November 2015 
CONFIDENTIAL
Page 12 of 14 
21. STATISTICAL METHODOLOGY – Safety Analyses, Section 10.4.2, page 40,
paragraph 2 – This paragraph was updated to better reflect what treatment-
emergent adverse event summaries will include.  The revised paragraph now reads:
“Treatment-emergent adverse event summaries will include the overall incidence (by system 
organ class and preferred term), events by maximum intensity, events by relationship to study 
treatment, events leading to discontinuation of study drug, events leading to study 
discontinuation, and SAEs.” 
22. APPENDIX A – Schedule of Events, Section 13, page 45 – The Schedule of Events
has been updated to reflect the following changes:

Addition of Week 96, Week 108, Week 120, Week 132, Week 144, Week 156, and Week
168 visits

Addition of dispensation of LX1606 at Week 84

Separation of EOS visit from Week 84 as a stand-alone visit

Revision of the table footnote to clarify the conduct of the EOS visit and reflect the
management of the Treatment Period for patients who reach the timeline event of marketing
approval with prescription availability or 31 March 2017, whichever occurs first

Renaming of Extension Period to Treatment Period to be consistent with the protocol
Changes are indicated by highlighted cells in ‘Revised Appendix A – Schedule of Events’ table 
below. 
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Protocol No.  LX1606.302 A2 
 
08 October 2014 
 
CONFIDENTIAL 
 
 
 
 
 
Page 13 of 14 
Revised Appendix A – Schedule of Events  
 
 
added text / deleted text 
 
 
Baseline 
Day 1
1
Week 12 Week 24 Week 36 Week 48 Week 60 Week 72 Week 84 
/ EOS
Week 96
Week 
108
Week 
120
Week 
132
Week 
144
Week 
156
Week 
168
Tolerance (days)
NA
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5+ 21
± 5
Inclusion/Exclusion criteria
X
Medical history
X
Physical examination incl. weight
X
X3
X3
X3
X
X3
X3
X
X3
X3
X3
X
X3
X3
X3
X
 X5
Urine pregnancy test2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology, Blood chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 X5
Urinalysis
X
X
X
X
X
 X5
Chromogranin A
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
X
X
 X5
Subjective Global Assessment
X
X
X
X
X
X
X
X
EORTC QLQ-C30 & GI.NET21
X
X
X
X
X
Sleep and Depression Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma 5-HIAA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispensation of LX1606
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ExtensionTreatment Period6
EOS
4
Procedure
2-Week 
Follow-up
4
1Eligibility will be determined at last visit of the original protocol; Day 1 will replace the next scheduled visit in the original protocol schedule. Visits should coincide with LAR injections for those patients receiving SSA therapy. 
2Females of child-bearing potential only. 3Brief physical examination only (symptom-oriented, including weight). 4Visit to be performed for subjects who withdraw early and will not return for a 2-week follow-up visit; in all 
other cases the End-of-Study (EOS) visit should be performed followed by the follow-up visit 2 weeks postdoseafter the final dose. 5To be performed only if evaluation at Week 84/EOS is abnormal. 6All patients will receive 
LX1606 for at least 52 weeks and may continue treatment in the trial until such time telotristat etiprate has received regulatory approval to be marketed and is available via prescription or until 31 March 2017, whichever occurs 
first. Patients who reach this timeline event will be deemed to have completed the Treatment Period and will advance to the EOS visit, regardless of where they are in the visit schedule and when their last study visit occurred. 
The EOS visit should be performed within 21 calendar days following the completion of the Treatment Period.
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Protocol No.  LX1606.302 A2 
 
08 October 2014 
 
CONFIDENTIAL 
 
 
 
 
 
Page 14 of 14 
 
23. APPENDIX B – Amount of Blood to be Collected from Each Patient, Section 14, page 46 – This section has been modified to 
reflect the maximum estimated volume of blood that may be collected from each patient based upon changes reflected in 
Appendix A. Changes are indicated by highlighted cells. The revised table now reads: 
 
 
 
 
Sample volume (mL)
Number of samples*
Estimated total volume (mL)
Safety
Hematology
2
17
34
Blood chemistry
6
17
102
Other
CgA
2
5
10
Pharmacodynamic
Plasma 5-HIAA
4
17
68
214
Assessment
Total 
*Maximum number of samples is indicated
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CLINICAL STUDY PROTOCOL 
Protocol Number: 
LX1606.1-302-CS 
LX1606.302 (Abbreviated number) 
EudraCT Number 
2013-002596-18 
Investigational Phase: 
3 
Protocol Title: 
A Multicenter, Long-term Extension Study to Further 
Evaluate the Safety and Tolerability of Telotristat Etiprate 
(LX1606) 
Study Name: 
TELEPATH (Telotristat Etiprate – Expanded Treatment 
for Patients with Carcinoid Syndrome) 
Amendment 3 Date: 
06 May 2015 (Germany and UK sites only) 
Amendment 2 Date: 
08 October 2014 
Amendment 1 Date: 
31 January 2014 
Original Version Date: 
14 June 2013 
Sponsor: 
Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Place 
The Woodlands, TX 77381-1160 
Telephone: 001 (281) 863-3000 
Safety Hotline: 001 (877) 372-3597 
Safety Data Facsimile: 001 (832) 442-5917 
 
 
 
 
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Protocol No. LX1606.302 
06 May 2015 
CONFIDENTIAL 
Page 3 of 56 
1. 
Synopsis 
Name of Study Drug 
Telotristat etiprate 
Protocol Number 
LX1606.1-302-CS 
LX1606.302 (Abbreviated number) 
Protocol Title  
 
A Multicenter, Long-term Extension Study to Further Evaluate the 
Safety and Tolerability of Telotristat Etiprate (LX1606) 
Primary Objective 
The primary objective of this study is to evaluate the long-term 
safety and tolerability of orally administered telotristat etiprate   
Secondary Objective 
To evaluate changes in patients’ quality of life (QOL) through Week 
84  
Phase of Development 
3 
Methodology 
 
The study will be conducted as a multicenter, open-label, long-term 
extension study to further evaluate long-term safety and tolerability 
of telotristat etiprate. 
Patients currently participating in any LX1606 Phase 2 carcinoid 
syndrome (CS) study may enter into this extension study upon 
institutional or local approval of the protocol. Patients participating 
in a Phase 3 CS study may enter into this extension study at the 
Week 48 visit. All patients who enter into this extension study will 
be exempt from any follow-up visit required by the original study 
and will not experience an interruption in study drug due to the 
transition from the original study to LX1060.1-302-CS. 
Following confirmation of eligibility, patients will complete a series 
of visit assessments in order to establish Baseline symptoms. 
Patients will then continue on open-label study drug at the same dose 
level and regimen as identified in their original study.  
Downward dose adjustment will be permitted during the study if 
evidence of intolerability emerges. Patients who experience 
intolerability at the 250 mg tid dose level must be discontinued from 
the study. Patients may return to the previous dosing at the discretion 
of the Investigator and in consultation with the Medical Monitor. 
Upon completion or early withdrawal from treatment, all patients 
will be required to complete a 14-day Follow-up Period, during 
which no study drug will be administered.  
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Protocol No. LX1606.302 
06 May 2015 
CONFIDENTIAL 
Page 4 of 56 
A Data Safety Monitoring Board (DSMB) will review safety data 
quarterly throughout the study.  
Number of Patients 
Up to 100 patients are expected to participate in this study.  
Patients 
Eligible patients are defined as those that are currently participating 
in a Phase 2 or Phase 3 telotristat etiprate carcinoid syndrome study. 
Number of Study Sites 
Approximately 70 sites 
Treatments 
Telotristat etiprate, 250-mg tablet, administered at the same dose 
level and regimen identified in the patient’s original study 
Route of Administration 
Oral 
Duration of Participation 
All patients will participate for at least 86 weeks including Treatment 
and Follow-up. Patients who are scheduled to complete the 
Treatment Period prior to 31 March 2016 will have the option to 
extend the Treatment Period until 31 March 2016. 
Inclusion Criteria 
Patients must meet all of the following criteria to be considered 
eligible to participate in the study: 
1. Ongoing participation in a Phase 2 (eg, LX1606.1-202-CS, 
LX1606.1-203-CS) or Phase 3 (eg, LX1606.1-301-CS, 
LX1606.1-303-CS) study 
2. Patients of childbearing potential must agree to use an adequate 
method of contraception (defined as having a failure rate of <1% 
per year) during the study and for 12 weeks after the Follow-up 
visit. Adequate methods of contraception for patients or partner 
include condoms with spermicide gel, diaphragm with 
spermicide gel, coil (intrauterine device), surgical sterilization, 
vasectomy, oral contraceptive pill, depot progesterone injections, 
progesterone implant, and abstinence during the study and for 12 
weeks after the Follow-up Visit. 
a. Childbearing potential is defined as those who have not 
undergone surgical sterilization, or those who are not 
considered postmenopausal. Postmenopause is defined as 
absence of menstruation for at least 2 years. If necessary, 
follicle-stimulating hormone (FSH) results >50 IU/L at entry 
are confirmatory in the absence of a clear postmenopausal 
history. 
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Protocol No. LX1606.302 
06 May 2015 
CONFIDENTIAL 
Page 5 of 56 
3. Ability and willingness to provide written informed consent 
prior to participation in any study-related procedure 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded 
from participating in the study:   
1. Major protocol violations or telotristat etiprate tolerability 
concerns in a Phase 2 (eg, LX1606.1-202-CS, LX1606.1-203-
CS) or Phase 3 (eg, LX1606.1-301-CS, LX1606.1-303-CS) 
study 
2. Positive pregnancy test 
3. Presence of any clinically significant findings at entry for 
medical history, laboratory values, or physical examination 
(relative to patient population) that, in the Investigator’s or 
Medical Monitor’s opinion, would compromise patient safety or 
the outcome of the study 
4. Patients who are currently committed to an institution by virtue 
of an order issued either by judicial or administrative authorities 
Statistical Methods 
Descriptive analysis methods will be used to summarize the data. 
Continuous variables will be summarized by the N, mean, standard 
deviation, median, minimum, and maximum values. Categorical 
variables will be summarized as counts and related percentages. Data 
tabulations will be categorized by the treatment received on Day 1 of 
this study and combined across all treated patients. Primary analyses 
of the data will be based on the Safety population which includes all 
patients treated on Day 1 of this study. Supportive analyses of the 
efficacy data will be made on a Per Protocol population.  
Data will be summarized per study visit as the actual (raw) outcomes 
and change from Baseline scores, where applicable. Day 1 of this 
study will serve as the Baseline assessment.  
Study Assessments 
Safety 
Safety assessments include monitoring of adverse events, clinical 
laboratory tests, vital signs measurements, 12-lead ECG, and 
physical examinations 
Efficacy 
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Protocol No. LX1606.302 
06 May 2015 
CONFIDENTIAL 
Page 6 of 56 
Efficacy assessments will include patient reported quality of life 
measures as captured in the European Organization for Research and 
Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-
C30 and the module specific for gastrointestinal symptoms of 
carcinoid neuroendocrine tumors (GI.NET21) and subjective global 
assessment of symptoms associated with CS 
Pharmacodynamics 
Pharmacodynamic (PD) assessments include determination of 5-
HIAA levels in plasma  
Efficacy Data Analysis 
 
All efficacy and PD variables will be summarized descriptively and 
listed. 
Statistical tests and estimates of within patient effects for the 
efficacy and PD measures will be derived from application of a 
mixed linear model with repeated measures. The form of the model 
will be specific to measurement properties of the dependent variable. 
Non-parametric methods will be used to supplement the tests and 
estimates from the mixed linear model. 
Exploratory analyses of treatment group differences may be 
performed by use of propensity score models. The treatments groups 
will correspond to patients’ telotristat etiprate dose level on Day 1 of 
this study.  
Safety Data Analysis 
 
Statistical analysis of the safety data will involve examination of the 
descriptive statistics and individual patient listings for any effects of 
study treatment on clinical tolerability and safety. Reporting of these 
data will be based on the Safety population. Summaries will be 
prepared by treatment group, and as needed, by study visit. 
Treatment-emergent adverse event summaries will include the 
overall incidence (by system organ class and preferred term), events 
by maximum intensity, event by relationship to study treatment, 
events leading to discontinuation of study drug, and serious adverse 
events. 
Vital signs, ECG, and laboratory parameters (hematology, chemistry, 
and urinalysis) will be summarized descriptively at each time point. 
Actual and change from Baseline data will be calculated and 
summarized. In addition, shift table analysis will be applied to the 
laboratory data. 
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Protocol No. LX1606.302 
06 May 2015 
CONFIDENTIAL 
Page 7 of 56 
Table of Contents 
1. 
Synopsis .............................................................................................................................. 3 
2. 
List of Abbreviations and Definitions of Terms ............................................................... 10 
3. 
Introduction ...................................................................................................................... 12 
3.1 
Background on Telotristat Etiprate (LX1606) and Disease ................................ 12 
3.2 
Clinical Trials of Telotristat Etiprate (LX1606) in Humans ............................... 13 
3.2.1 
Phase 1 Studies .............................................................................. 13 
3.2.2 
Phase 2 Studies .............................................................................. 15 
3.2.3 
Ongoing Studies ............................................................................. 16 
3.3 
Rationale for Current Study ................................................................................ 17 
3.3.1 
Rationale for Selection of Dose ..................................................... 17 
3.3.2 
Benefit/Risk Assessment ................................................................ 17 
3.4 
Rationale for Study Design and Control Groups ................................................ 18 
4. 
Study Objectives ............................................................................................................... 19 
4.1 
Efficacy Objectives ............................................................................................. 19 
4.1.1 
Primary Objective .......................................................................... 19 
4.1.2 
Secondary Objective(s) .................................................................. 19 
4.2 
Safety Objectives ................................................................................................ 19 
5. 
Investigational Plan .......................................................................................................... 19 
5.1 
Overall Study Design .......................................................................................... 19 
6. 
Study Population .............................................................................................................. 20 
6.1 
Inclusion Criteria ................................................................................................ 20 
6.2 
Exclusion Criteria ............................................................................................... 21 
6.3 
Criteria for Stopping Treatment/Study Withdrawal ............................................ 21 
6.4 
Criteria for Termination of the Study .................................................................. 22 
6.5 
Clinical Stopping Rules ...................................................................................... 23 
6.6 
Method of Assigning Patients to Treatment ........................................................ 23 
6.7 
Blinding and Unblinding of Study Medication ................................................... 23 
6.8 
Replacement of Patients ...................................................................................... 23 
7. 
Treatment .......................................................................................................................... 23 
7.1.1 
Telotristat Etiprate (LX1606) ......................................................... 23 
7.1.1.1 
Identity ......................................................................... 23 
7.1.1.2 
Packaging, Labeling, and Storage ................................ 23 
7.2 
Prior and Concomitant Medications ................................................................... 24 
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Protocol No. LX1606.302 
06 May 2015 
CONFIDENTIAL 
Page 8 of 56 
7.2.1 
Prior Medications ........................................................................... 24 
7.2.2 
Concomitant Medications .............................................................. 24 
7.2.3 
Prohibited Medications or Concomitant Therapy .......................... 24 
7.3 
Administration of Study Medication .................................................................. 24 
7.3.1 
Treatment Compliance ................................................................... 24 
7.4 
Dose Adjustment ................................................................................................. 25 
8. 
Study Procedures .............................................................................................................. 25 
8.1 
Restrictions during Study .................................................................................... 25 
8.2 
Description of Study Assessments ...................................................................... 25 
8.2.1 
Efficacy Assessments ..................................................................... 25 
8.2.1.1 
EORTC QLQ-C30 & GI.NET21 ................................. 25 
8.2.1.2 
Subjective Global Assessment ..................................... 25 
8.2.2 
Clinical Laboratory Assessment .................................................... 26 
8.2.2.1 
Monitoring Hepatic Function ....................................... 26 
8.2.3 
Pharmacodynamic Assessments..................................................... 28 
8.2.3.1 
Plasma 5-HIAA ............................................................ 28 
8.2.4 
Safety Assessments ........................................................................ 28 
8.2.4.1 
Vital Sign Measurements ............................................. 28 
8.2.4.2 
Physical Examinations ................................................. 28 
8.2.4.3 
Electrocardiograms ...................................................... 29 
8.2.4.4 
Adverse Events of Special Interest .............................. 29 
8.2.4.4.1 
Central Nervous System Events ............... 29 
8.2.4.4.1.1 Depression Detection .......... 29 
8.3 
Other Assessments .............................................................................................. 29 
8.3.1 
Chromogranin A (CgA).................................................................. 29 
8.3.2 
Disease Progression ....................................................................... 30 
8.3.3 
Quality of Sleep Assessment .......................................................... 30 
8.4 
Appropriateness of Assessments ......................................................................... 30 
8.4.1 
Blood Collection ............................................................................ 30 
9. 
Safety Reporting ............................................................................................................... 30 
9.1 
Adverse Events ................................................................................................... 31 
9.2 
Serious Adverse Events (SAEs) .......................................................................... 34 
9.2.1 
Hospitalization as an SAE ............................................................. 35 
9.3 
Suspected Unexpected Serious Adverse Reactions (SUSARs) .......................... 36 
9.4 
Precautions .......................................................................................................... 36 
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Protocol No. LX1606.302 
06 May 2015 
CONFIDENTIAL 
Page 9 of 56 
9.4.1 
Pregnancy ....................................................................................... 36 
10. Statistical Methodology .................................................................................................... 37 
10.1 
Determination of Sample Size ............................................................................ 37 
10.2 
Analysis Populations ........................................................................................... 37 
10.3 
Study Endpoints .................................................................................................. 37 
10.3.1 
Efficacy Endpoints ......................................................................... 37 
10.3.2 
Safety Endpoints ............................................................................ 37 
10.4 
Statistical Methods .............................................................................................. 38 
10.4.1 
Efficacy Analyses ........................................................................... 38 
10.4.2 
Safety Analyses .............................................................................. 38 
10.4.2.1 
Adverse Events ............................................................ 39 
10.4.2.2 
Clinical Laboratory Parameters ................................... 39 
10.4.2.3 
Vital Sign Measurements ............................................. 39 
10.4.2.4 
Electrocardiograms ...................................................... 40 
10.4.3 
Pharmacodynamic Analyses .......................................................... 40 
10.4.4 
Baseline Characteristics and Other Summaries ............................. 40 
10.4.5 
Interim Analysis ............................................................................. 40 
11. Study Management ........................................................................................................... 40 
11.1 
Monitoring .......................................................................................................... 41 
11.2 
Audits and Inspections ........................................................................................ 41 
11.3 
Amendments ....................................................................................................... 41 
11.4 
Record Keeping .................................................................................................. 42 
11.4.1 
Drug Accountability ....................................................................... 42 
11.4.2 
Health Insurance Portability Accountability Act of 1996 and 
Subsequent Updates ....................................................................... 42 
11.4.3 
Financial Disclosure ....................................................................... 42 
11.4.4 
Access to Original Records ............................................................ 42 
11.4.5 
Retention of Study Documents ...................................................... 43 
12. Administrative Structure of the Study .............................................................................. 43 
13. Appendix A – Schedule of Events .................................................................................... 44 
14. Appendix B – Amount of Blood to be Collected from Each Patient ............................... 45 
15. Appendix C – EORTC QLQ-C30 .................................................................................... 46 
16. Appendix D – EORTC QLQ - GI.NET21 ........................................................................ 48 
17. Appendix E – Ethical Standards ....................................................................................... 49 
18. Appendix F – Investigator Obligations ............................................................................ 51 
19. References ........................................................................................................................ 56 
 
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2. 
List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
5-HIAA 
5-hydroxyindoleacetic acid 
5-HT 
serotonin 
AE 
adverse event 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
ALP 
alkaline phosphatase 
AST 
aspartate transaminase 
bid 
twice daily 
BM 
bowel movements 
BMI 
body mass index 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CgA 
chromogranin A 
CNS 
central nervous system 
CRF 
case report form 
CRO 
contract research organization 
CS 
carcinoid syndrome 
CT 
computed tomography 
DSMB 
Data Safety Monitoring Board 
EC 
enterochromaffin 
ECG 
electrocardiogram 
ERC 
Ethic Review Committee 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HEENT 
head, eyes, ears, nose, and throat 
Hgb 
hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
IBD 
inflammatory bowel disease 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
Continued on the next page 
 
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Abbreviation 
Definition 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IMP 
Investigational Medicinal Product 
IWRS 
interactive web response system 
LAR 
long-acting release 
LS 
least square 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCP 
multiple comparison procedure 
MRI 
magnetic resonance imaging 
NET 
neuroendocrine tumor 
NRS 
numeric rating scale 
OOR 
out-of-range 
OTC 
over-the-counter 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
qd 
once daily 
SAE 
serious adverse event 
SBS 
short bowel syndrome 
SOP 
standard operating procedure 
SSA 
somatostatin analog 
SUSAR 
suspected unexpected serious adverse reactions 
TEAE 
treatment-emergent adverse events 
tid 
3 times daily 
TPH 
tryptophan hydroxylase 
ULN 
upper limit of the normal reference range 
WRS 
Wilcoxon rank sum 
 
Definitions of Terms  
Term 
Definition 
LP-778902 
active moiety of LX1606 
LX1606 
telotristat ethyl: the ethyl-ester prodrug of the active moiety LP-
778902; a serotonin synthesis inhibitor being developed by Lexicon 
Pharmaceuticals, Inc. 
QTcF 
corrected QT interval using Fredericia’s formula 
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3. 
Introduction 
3.1 
Background on Telotristat Etiprate (LX1606) and Disease 
Serotonin (5-HT) plays a critical role in regulating several major physiological processes of 
the gastrointestinal tract, including aspects of secretion, motility, inflammation and sensation. 
Enterochromaffin (EC) cells release 5-HT when the intestinal wall is stimulated by 
intraluminal pressure or chemicals. Through multiple classes of receptors, 5-HT is believed to 
initiate directly, or facilitate, peristaltic and secretory reflexes. 5-HT is also reportedly 
involved in the pathophysiology of various types of functional gastrointestinal (GI) disorders, 
valvular heart disease, and may play a role in the pathophysiology of inflammatory bowel 
disease (IBD).  
Carcinoid tumors are mostly derived from EC cells of the midgut, and often produce and 
release large amounts of 5-HT. Such excess of 5-HT is believed to be responsible for the 
severe diarrhea and eventual valvular heart damage and mesenteric fibrosis in patients with 
carcinoid syndrome (CS).1-3 Inhibition of tryptophan hydroxylase (TPH) activity in carcinoid 
tumors should lead to a reduction of peripheral 5-HT in afflicted patients and thus an 
amelioration of the pathophysiology and symptomology of CS. A peripheral TPH inhibitor, 
such as telotristat etiprate, should alleviate the symptoms due to excess 5-HT in carcinoid 
patients without central nervous system (CNS)-related adverse events (AEs). 
Approximately 90% of the body's 5-HT is found in the EC cells of the GI tract, with the 
remainder distributed between the platelets and CNS.4 TPH catalyzes the biopterin-dependent 
monooxygenation of tryptophan to 5-hydroxytryptophan, which is subsequently 
decarboxylated to form 5-HT. Expression of TPH is limited to a few specialized tissues:  
raphe neurons, pinealocytes, mast cells, mononuclear leukocytes, beta cells of the islets of 
Langerhans, and intestinal and pancreatic EC cells.5 Two isoforms of the enzyme exist, TPH1 
and TPH2. TPH1 is exclusively located in the EC cells of the GI tract and pineal gland and is 
the rate limiting enzyme responsible for the majority of systemic 5-HT production and is also 
responsible for 5-HT synthesis in carcinoid tumors. TPH2 is located in the central and enteric 
nervous systems and is the rate-limiting enzyme in the production of neuronal 5-HT. 
The oral TPH inhibitor, telotristat etiprate, represents a novel approach to potentially lessen 
the pathophysiology of CS by reducing 5-HT levels via inhibition of TPH. Telotristat etiprate 
was designed specifically as a prodrug in order to gain greater systemic exposure, opening 
the potential application for indications in which hyperserotonemia is thought to contribute to 
the disorder, such as CS. Preclinical pharmacology studies of telotristat etiprate were 
designed to evaluate the compound’s mechanism of action and effects in vivo. Telotristat 
etiprate is the ethyl-ester prodrug of the active moiety LP-778902. Telotristat etiprate was 
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designed as a prodrug in order to enhance peripheral exposure without crossing the blood-
brain barrier. In vivo, telotristat etiprate is readily converted through esterase activity to its 
corresponding acid, LP-778902. LP-778902 has an in vitro potency of 0.028 μM on purified 
human TPH1 enzyme and 0.032 μM on purified human TPH2 enzyme. Therefore, telotristat 
etiprate is a robust inhibitor of TPH both in vitro and in vivo and has been shown in Phase 2 
studies to provide clinical benefit to patients with carcinoid tumors and associated CS.  
Telotristat etiprate is being developed to manage GI symptoms and possibly other symptoms 
associated with CS. Currently, the standard of care for patients with CS is symptom 
management using somatostatin analogs (SSA), which are available in both short- and long-
acting release (LAR) formulations. Somatostatin analogs such as octreotide are indicated for 
the control of flushing, diarrhea, and other symptoms associated with CS. Common side 
effects of the long-acting depot form of the drug are pain at the site of the injection, reported 
in as many as 30 to 50% of carcinoid patients at the 20 and 30 mg dose levels, and less 
commonly, stomach cramps, nausea, vomiting, headaches, dizziness, and fatigue.6 Other side 
effects identified in the product labeling include biliary tract abnormalities (gallstones, 
sludge, and dilatation), hypothyroidism, dietary fat malabsorption, and hyper or 
hypoglycemia.7 In addition to the morbidity associated with parenterally administered agents, 
tachyphylaxis will occur in the majority of patients, resulting in recurrent symptoms. 
There are currently no specific oral treatments indicated for the management of symptoms 
associated with CS. As a result of the morbidity associated with SSAs and the associated 
tachyphylaxis, there is an unmet medical need to provide symptom management and modify 
the pathophysiology of patients with metastatic CS. Inhibition of the excessive 5-HT 
produced by these tumors with an orally delivered agent such as telotristat etiprate could 
provide significant benefit as an additional treatment option for patients and clinicians.  
3.2 
Clinical Trials of Telotristat Etiprate (LX1606) in Humans 
Telotristat etiprate has been studied in single/multiple doses in Phase 1 studies, approximately 
117 healthy volunteers participated in Phase 1 trials with 96 subjects receiving telotristat 
etiprate and 21 subjects receiving placebo. In addition, 37 patients with CS have received 
telotristat etiprate during the clinical development program in Phase 2.  An additional 59 
patients with ulcerative colitis have been enrolled into an ongoing Phase 2 study to evaluate 
telotristat etiprate versus placebo in patients with ulcerative colitis experiencing active flares. 
3.2.1 
Phase 1 Studies 
LX1606.1-101-NRM utilized telotristat etiprate as a single oral dose and was noted to be safe 
and well tolerated up to doses of 1,000 mg. At doses of ≥1,000 mg, an increase in GI AEs 
was observed, which were assessed as at least possibly related to study drug. These AEs led 
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to a decision not to escalate the dose beyond 1,500 mg. No serious adverse events (SAEs) or 
deaths were reported and no patient discontinued due to an AE. Twenty-three patients 
experienced at least 1 AE. The majority of the AEs were assessed as mild. The most common 
AEs were diarrhea and nausea. Random out-of-range laboratory values at various time points 
in several patients occurred without any apparent trend. There were no other clinically 
significant vital signs, laboratory or physical examination findings.  
LX1606.1-102-NRM utilized telotristat etiprate as multiple oral doses over 14 days and was 
tolerated up to the maximum dose assessed, 500 mg tid; 1,500 mg total dose daily. Most AEs 
were mild, the most common being nausea and headache; all resolved. Most AEs were at 
least possibly related to study treatment. Four AEs required treatment with concomitant 
medication, 3 AEs of constipation and 1 of headache. No deaths or SAEs were reported. One 
patient was discontinued due to an AE of abnormal liver function. There were no apparent 
trends or clinically significant findings observed upon review of vital signs and 
electrocardiogram (ECG) data. There were no clinically significant abnormal physical 
examination findings. 
Overall, in LX1606.1-102-NRM, treatment with telotristat etiprate was associated with mild 
elevations, generally ≤2x the upper limit of normal (ULN), in alanine transaminase (ALT) 
and aspartate transaminase (AST), with elevations in values observed earlier in the higher 
dose cohorts. Results were assessed as clinically significant for only 1 patient, in Cohort 4, 
who was withdrawn on Day 10. The trend was most pronounced in Cohort 5, in which 5 out 
of 6 patients who received telotristat etiprate had increases in ALT values which were above 
normal range and 4 patients had increases in AST values which were above normal range at 
Day 14. Mean increases in ALT and AST appeared earlier in the study for Cohorts 4 and 5 
than in the other cohorts, and were noted for all cohorts by Day 12. All patients had normal 
ALT and AST values at Baseline and most elevated transaminases returned to normal range 
within 48 hours after the last dose of study drug. No changes in alkaline phosphatase (ALP) 
or total bilirubin were observed in any patient. 
LX1606.1-103-NRM evaluated 2 oral formulations of telotristat etiprate in an open-label 
crossover study. Each formulation was given as a single oral dose followed by a 5-day 
washout and then patients were given a single oral dose of the second formulation. During 
this study, there were no deaths or SAEs reported and no AEs lead to discontinuation. The 
most commonly reported AE was diarrhea. No clinically significant observations or changes 
in other safety parameters (eg, clinical laboratory evaluations, vital signs, physical 
examinations, ECGs, and AEs) were identified in the patient population during the study 
conduct. 
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LX1606.1-104-NRM was designed to evaluate the pharmacokinetics, metabolism, and routes 
and extent of elimination of telotristat ethyl and its primary metabolite (LP-778902) in 8 
healthy male subjects after a single oral dose of 500 mg radio-labeled telotristat etiprate 
(14C-LX1606). This study has been completed and the results will be discussed in the annual 
update of the Investigator Brochure. 
3.2.2 
Phase 2 Studies 
LX1606.1-202-CS was a randomized, double-blind, placebo-controlled, multiple ascending 
dose study conducted in 2 parts in order to evaluate a total of 23 patients at a dose range of 
450 to 1500 mg given as 150, 250, 350, or 500 mg tid (telotristat etiprate or matching 
placebo) on a background therapy of octreotide. In Part 1, 16 patients were randomly 
assigned 3:1 into 4 sequential cohorts. Each cohort evaluated 1 of the following daily doses 
given as 150, 250, 350, or 500 mg tid over a course of 4 weeks. During the study, all patients 
continued on a stable-dose background therapy of octreotide. In Part 2, an additional 7 
patients were randomly assigned 3:1 in order to evaluate 500 mg tid, the highest tolerated 
dose as determined in Part 1. Upon completion of the initial 4-week portion, eligible patients 
had the option to continue into an open-label Extension Period. 
There was 1 treatment emergent SAE assessed as possibly related to study drug which 
occurred in the 350 mg tid dose group. The patient had a history of nausea and vomiting and 
was hospitalized for exacerbation of these conditions.  
Telotristat etiprate was generally well tolerated with no evidence of dose-limiting tolerability. 
Adverse events were mostly mild to moderate and with similar frequencies between 
treatment groups and placebo. No significant changes in vital signs, ECG, or physical exam 
findings were noted after administration of telotristat etiprate at any dose level. The most 
common AEs were GI-related and reported as diarrhea, nausea, and abdominal pain, 
respectively. The modest elevations in transaminases seen in the Phase 1 multiple ascending 
dose study (LX1606.1-102-NRM) were not apparent in this 4-week study in patients with CS.  
Patients that received telotristat etiprate achieved a clinical response (28%) defined as at least 
a 30% reduction in bowel movements (BMs) for at least 2 weeks; a biochemical response 
(56%) defined as at least a 50% reduction or normalization of urinary 5-hydroxyindoleacetic 
acid (5-HIAA); and reported adequate relief at Week 4 (46%) while no placebo patients 
experienced clinical response, biochemical response, or adequate relief. 
LX1606.1-203 was an open-label, serial ascending, multiple dose, individual titration study 
that evaluated the same dose ranges as the LX1606.1-202-CS study in a total of 15 patients. 
Patients were serially escalated to the next dose level every 2 weeks until a maximally 
tolerated dose or 500 mg tid was reached. Once a dose had been determined, the patient 
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would remain on the dose for an additional 4 weeks. Patients then had the option to continue 
into an Extension Period.  
Telotristat etiprate was generally safe and well-tolerated in subjects with CS in the 
LX1606.1-203 study. Most AEs were mild to moderate in severity and assessed as unrelated 
to study drug. Events in the Gastrointestinal Disorders system organ class were common, as 
is anticipated with the underlying illness. 
Statistically significant reductions from Baseline in the mean number of BMs/day were 
observed in this study throughout the entire dose-escalation and stable-dose phases, as were 
improvements in stool form. Telotristat etiprate produced an improvement in global 
assessment of GI symptoms associated with CS in the majority of subjects (12 of 15 subjects, 
80%) across the 12-week period. The global assessment of GI symptoms was based on the 
following question, “In the past 7 days, have you had adequate relief of your carcinoid 
syndrome bowel complaints such as diarrhea, urgent need to have a BM, abdominal pain or 
discomfort?” In addition, subjects experienced statistically significant decreases in the mean 
daily number of cutaneous flushing episodes. 
Thirteen subjects (86.7%) experienced a complete biochemical response (defined as a ≥50% 
reduction from Baseline in u5-HIAA levels at 1 or more time points). Consistent with the 
proposed mechanism of action for telotristat etiprate, a complete biochemical response 
correlated closely with measures of clinical response, such as number of bowel movements 
per day. 
LX1606.1-204-UC evaluated patients with active flares of ulcerative colitis. Doses under 
evaluation are 500 mg once daily (qd) and 500 mg tid vs. placebo; 59 patients were enrolled 
for an 8-week treatment period. This study has been completed and the results will be 
discussed in the annual update of the Investigator Brochure. 
Detailed information regarding the completed clinical studies can be found in the Investigator 
Brochure.8 
3.2.3 
Ongoing Studies 
The open-label extension portions in LX1606.1-202-CS and LX1606.1-203-CS remain 
ongoing. 
LX1606.1-301-CS is intended to evaluate patients who are currently on a background of SSA 
therapy and still experiencing breakthrough symptoms such as an increased frequency of 
BMs ≥4 per day on average: (1) the efficacy of telotristat etiprate on reducing the number of 
BMs; (2) the efficacy of telotristat etiprate on a number of clinically relevant secondary 
endpoints; and, (3) the safety of telotristat etiprate over the 12-week double-blind portion 
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(Treatment Period) of the study. Upon completion of the Treatment Period, patients will 
continue into a 36-week open-label Extension Period (Extension Period).  
LX1606.1-303-CS is intended to evaluate patients with carcinoid syndrome whose primary 
symptoms are not GI related and may be naïve to SSA therapy: (1) the safety of telotristat 
etiprate over the 12-week double-blind portion (Treatment Period) of the study; (2) percent 
(%) change from Baseline in 24-hour u5-HIAA levels at Week 12; (3) the effects of telotristat 
etiprate on a number of clinically relevant secondary endpoints. Upon completion of the 
Treatment Period, patients will continue into a 36-week open-label Extension Period. 
3.3 
Rationale for Current Study 
3.3.1 
Rationale for Selection of Dose 
The dose levels of telotristat etiprate selected for this study are consistent with prior clinical 
study experience and based upon clinical safety and pharmacodynamic (PD) data from 2 
Phase 2 multiple ascending-dose studies in patients with symptomatic CS (LX1606.1-202-CS 
and LX1606.1-203-CS).  
Based upon observations noted in Section 3.2, it is anticipated that the doses to be utilized in 
this protocol will be safe and well tolerated and may provide clinical benefit to patients with 
CS. 
3.3.2 
Benefit/Risk Assessment 
Clinical experience with telotristat etiprate (treated subjects) consists of completed single and 
multiple ascending dose studies in 96 normal subjects (44 in single dose studies and 52 in the 
multiple dose study), 2 Phase 2 studies (37 patients with symptomatic CS) and 2 ongoing 
Phase 3 studies in patients with symptomatic CS. 
In healthy volunteer studies, single doses up to 1000 mg were found to be generally well 
tolerated, while at the 1500 mg dose level GI-related adverse events increased. A similar 
adverse event profile was observed after multiple dose administration over 14 days with GI 
events predominating. Mild, dose-dependent increases in hepatic transaminase levels (≤2 x 
ULN) were observed with increased frequency in relation to dose, with 1 subject requiring 
withdrawal from therapy at the 500 mg bid dose level. Most subjects that were observed to 
have increased transaminase levels did not exceed >2 x ULN. No abnormalities in total 
bilirubin were observed at any dose level. GI events have been the most commonly observed 
events to date. The adverse event profile in normal subjects may differ significantly from 
what is observed in patients with hyperserotonemia. All adverse events resolved without 
sequelae. In addition, there were no significant changes in vital signs or ECG. No physical 
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examination abnormalities were noted in studies to date. There were no serious adverse 
events reported in healthy volunteers. 
In patients with CS, dose escalations have proceeded up to and including 500 mg tid. To date, 
there has been no evidence of dose-limiting intolerability. Dose levels have been generally 
well tolerated with no evidence to suggest elevations in hepatic transaminase levels. Based 
upon observations from preclinical and clinical studies conducted to date, it is anticipated that 
orally administered telotristat etiprate will be well tolerated at dose levels required to 
influence peripheral 5-HT production in patients with symptomatic CS. Potential adverse 
events primarily involve the GI tract, and could include alterations in gut motility, nausea, 
vomiting, diarrhea, constipation, abdominal bloating, and/or pain. Regular and ongoing 
clinical and laboratory assessments should detect any of these events, and depending on the 
type of event, further dose adjustment or discontinuation from the trial would occur. Although 
CNS effects are not anticipated at dose levels planned for evaluation, standard adverse event 
questioning and/or physical examination should reveal any subtle CNS findings. As 
elevations in hepatic transaminase levels were observed with multiple dosing in normal 
subjects, monitoring clinical laboratory tests of hepatic function will be incorporated into 
clinical trials conducted in CS patients. 
Treatment has the potential to improve several signs and symptoms of CS. The Phase 2 
clinical trial results indicated that treatment may lead to improvements in BM frequency, 
stool consistency, urgency, abdominal pain, diarrhea, flushing, and reductions in 5-HIAA. 
These potential benefits relate to a unique mechanism of action. Symptomatic improvement 
may lead to a better quality of life (QOL) for patients with few treatment options available, 
and a reduction in serotonin may help reduce the risk of carcinoid heart disease. Overall the 
benefit/risk profile of telotristat etiprate is expected to be favorable for participation in this 
clinical study. 
3.4 
Rationale for Study Design and Control Groups 
Currently, no approved therapy exists for the treatment of symptoms driven by underlying 
serotonin pathophysiology of CS in patients whose disease is refractory to SSA therapy or for 
those patients who are unable to tolerate SSA therapy or who are unwilling to take SSA 
therapy. 
This study will allow for continued access to telotristat etiprate after patients have completed 
the required study visits in ongoing Phase 2 and Phase 3 studies. Continuation of CS patients 
into this study will allow for the collection of additional long-term safety and efficacy data, 
while providing access to patients who may be receiving benefit. The treatment duration is 
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supported by results of chronic toxicology studies (6-month rat and 9-month dog) and the 
current safety profile from completed and ongoing clinical trials. 
4. 
Study Objectives 
4.1 
Efficacy Objectives 
4.1.1 
Primary Objective 
The primary objective of the study is to evaluate the long-term safety and tolerability of 
orally administered telotristat etiprate. 
4.1.2 
Secondary Objective(s) 
The secondary objective of this study is to evaluate changes in patients’ QOL through Week 
84. 
4.2 
Safety Objectives 
Evaluation of overall safety will be assessed as: 
 Incidence of treatment-emergent adverse events (TEAEs) 
 Changes from Baseline in clinical laboratory results, vital signs results, and ECG 
findings 
5. 
Investigational Plan 
5.1 
Overall Study Design 
The study will be conducted as a multicenter, open-label, long-term extension study to further 
evaluate long-term safety and tolerability of telotristat etiprate. 
Patients currently participating in any LX1606 Phase 2 CS study may enter into this 
extension study upon institutional or local approval of the protocol. Patients participating in a 
Phase 3 CS study may enter into this extension study at the Week 48 visit. All patients who 
enter into this extension study will be exempt from any follow-up visit required by the 
original study and will not experience an interruption in study drug due to the transition from 
the original protocol to LX1606.1-302-CS. 
Following confirmation of eligibility, patients will complete a series of visit assessments in 
order to establish Baseline symptoms. Patients will then continue on open-label LX1606 at 
the same dose level identified in the original study.  
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All patients will receive telotristat etiprate for at least 84 weeks. However, patients who will 
complete 84 weeks of treatment prior to 31 March 2016 may continue to receive telotristat 
etiprate in the trial until 31 March 2016.    
Upon completion or early withdrawal from treatment, all patients will be required to 
complete a 14-day Follow-up Period, during which no study drug will be administered.  
Downward dose adjustment will be permitted during the study if evidence of intolerability 
emerges. Patients who experience intolerability at the 250 mg tid dose level must be 
discontinued from the study. Patients may return to the previous dosing at the discretion of 
the Investigator and in consultation with the Medical Monitor. 
A Data Safety Monitoring Board (DSMB) will review safety data quarterly throughout the 
study.  
6. 
Study Population 
Adult patients who are currently participating in ongoing Phase 2 or Phase 3 telotristat 
etiprate CS clinical protocols will be enrolled into the study. Up to 100 patients are expected 
to enroll in this study. Approximately 70 sites worldwide will participate in the study. Patients 
may continue allowed medications as background therapy provided they remain on stable- 
doses throughout the Treatment Period. 
6.1 
Inclusion Criteria 
Patients must meet all of the following criteria to be considered eligible to participate in the 
study: 
1. Ongoing participation in a Phase 2 (eg, LX1606.1-202-CS, LX1606.1-203-CS) or 
Phase 3 (eg, LX1606.1-301-CS, LX1606.1-303-CS) study  
2. Patients of childbearing potential must agree to use an adequate method of 
contraception (defined as having a failure rate of <1% per year) during the study and 
for 12 weeks after the Follow-up visit. Adequate methods of contraception for 
patients or partner include condoms with spermicide gel, diaphragm with spermicide 
gel, coil (intrauterine device), surgical sterilization, vasectomy, oral contraceptive pill, 
depot progesterone injections, progesterone implant, and abstinence during the study 
and for 12 weeks after the Follow-up Visit.  
a. Childbearing potential is defined as those who have not undergone surgical 
sterilization, or those who are not considered postmenopausal. Postmenopause 
is defined as absence of menstruation for at least 2 years. If necessary, follicle-
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stimulating hormone (FSH) results >50 IU/L at Baseline Day 1 are 
confirmatory in the absence of a clear postmenopausal history. 
3. Ability and willingness to provide written informed consent prior to participation in 
any study-related procedure. 
6.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participating in the 
study:   
1. Major protocol violations or telotristat etiprate tolerability concerns in a Phase 2 (eg, 
LX1606.1-202-CS, LX1606.1-203-CS) or Phase 3 (eg, LX1606.1-301-CS, 
LX1606.1-303-CS) study  
2. Positive pregnancy test 
3. Presence of any clinically significant findings at entry for medical history, laboratory 
values, or physical examination (relative to patient population) that, in the 
Investigator’s or Medical Monitor’s opinion, would compromise patient safety or the 
outcome of the study 
4. Patients who are currently committed to an institution by virtue of an order issued 
either by judicial or administrative authorities 
6.3 
Criteria for Stopping Treatment/Study Withdrawal 
A patient may also be discontinued from the study for the following medical or 
administrative reasons: 
 Withdrawal of consent by the patient or legal guardian 
 Noncompliance, including refusal of the study medication and/or failure to adhere to 
the study requirements as in the study protocol 
 Investigator decides that, in the interest of the patient, it is not medically acceptable to 
continue participation in the study 
 The Sponsor terminates the study (Section 6.4) 
 Pregnancy (Section 9.4.1) 
Note:  If a patients voluntarily withdraws or is discontinued from study treatment before 
completing the entire duration of the Treatment Period, they should be encouraged to 
continue clinic visits according to the study schedule.  
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Patients who discontinue study treatment, and who are not willing to continue clinic visits 
(eg, withdrawal of consent) should be encouraged to complete End-of-Study (EOS) 
assessments as identified in Appendix A – Schedule of Events and agree to report any SAEs 
(Section 9.2) that occur within 30 days following the last dose of telotristat etiprate. 
The date the patient discontinues study treatment, the primary reason for study treatment 
discontinuation, study termination, and/or termination of participation (eg, withdrawal of 
consent), will be captured within the Case Report Form (CRF). 
When patients withdraw consent from study participation, it must be recorded on the CRF 
whether the withdrawal of consent applies to specific aspects of the study such as 
discontinuation of study treatment, participation in study visits, contact by study personnel, or 
access to information about potential SAEs. If specific consent has not been withdrawn, study 
personnel should contact the patient (or a previously approved designee such as a caregiver, 
partner, or family member) at the scheduled Follow-up visit to inquire about health status. 
6.4 
Criteria for Termination of the Study 
If the Sponsor, Investigator, study monitor, DSMB, or regulatory officials discover conditions 
arising during the study that indicate that the patient safety and/or scientific value of the study 
and/or quality of the study drugs have been compromised, the study should be halted or the 
study center’s participation should be terminated. Conditions that may warrant termination of 
the study include, but are not limited to, the following: 
 The discovery of an unexpected, serious, or unacceptable risk to the patients enrolled in 
the study; 
 A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product for carcinoid syndrome or any other indication for any 
reason; 
 Failure of the Investigator to enroll patients into the study at an acceptable rate; 
 Failure of the Investigator to comply with pertinent governing body regulations; 
 Submission of knowingly false information from the research facility to the Sponsor, 
study monitor, medical officer, or regulatory official; and, 
 Insufficient adherence to protocol requirements.  
Study termination and Follow-up would be performed in compliance with applicable 
governing body regulations. 
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6.5 
Clinical Stopping Rules 
Criteria for individual patient withdrawal or study termination are summarized in Sections 
6.3 and 6.4, respectively. 
6.6 
Method of Assigning Patients to Treatment  
Patients will enter the study at the same dose level and regimen as identified in the prior 
Phase 2 or Phase 3 CS study. Randomization will not be used to assign patients to study 
treatments. 
6.7 
Blinding and Unblinding of Study Medication 
This is an open-label study.  
6.8 
Replacement of Patients 
Patients who do not complete the study will not be replaced. 
7. 
Treatment 
7.1.1 
Telotristat Etiprate (LX1606) 
7.1.1.1 
Identity 
Telotristat etiprate (LX1606 hippurate) is the salt form of the drug substance. LX1606 
hippurate is a crystalline white to off-white to tan solid with a melting point of 147°C. 
LX1606 is insoluble in water within the pH range of 5 to 9 (≤2 mg/L). It undergoes 
hydrolysis under strongly basic or strongly acidic conditions. The solubility of LX1606 
hippurate in water is about 22 mg/L at 25°C. 
Study drug dosage form consists of white coated debossed oval tablets containing 250 mg 
LX1606. 
7.1.1.2 
Packaging, Labeling, and Storage 
Patients will receive 250-mg telotristat etiprate tablets packaged in 100 cc high density 
polyethylene bottles with child-resistant polypropylene screw caps and heat-induction seal 
liners.  
Telotristat etiprate should be stored between 15 to 25°C (59 to 77°F). 
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7.2 
Prior and Concomitant Medications 
7.2.1 
Prior Medications 
All medications and other treatments taken by patients within 30 days prior to entry will be 
recorded on the CRF.  
7.2.2 
Concomitant Medications 
All concomitant medications taken by patients during the study will be recorded on the CRF. 
Treatment with prescription or over-the-counter (OTC) antidiarrheal therapy, bile acid 
sequestrants, or pancreatic enzyme is permitted; however, the use of these concomitant 
therapies should be associated with a documented history of disease (eg, fat malabsorption, 
bile acid malabsorption, or steatorrhea).  
 Medical management of patients and their concomitant medications is allowed at the 
discretion of the Investigator. However, should the need arise to modify/adjust a patient’s 
therapy due to a concern for patient safety and/or tolerability the Medical Monitor should be 
contacted. The Investigator and Medical Monitor will make a determination if such a change 
would impact the safety of the patient and the integrity of the study. The Medical Monitor 
will determine if the patient can continue in the study. 
7.2.3 
Prohibited Medications or Concomitant Therapy 
None 
7.3 
Administration of Study Medication 
All patients will be instructed to take the study medication with food. “With food” means 
taking telotristat etiprate tablets within 15 minutes before or within 1 hour after a meal or 
snack. Patients will be instructed to take study drug 3 times daily during waking hours, with 
doses spaced approximately 6 hours apart.  
Study medication and instructions will be dispensed to patients at each visit as described in 
the schedule of study procedures (Appendix A). 
7.3.1 
Treatment Compliance  
Patients will be asked to bring their unused or unopened study medication to each visit 
(Appendix A). At each visit and in the presence of the patient, study site personnel will count 
returned tablets and reconcile the counts against planned number of doses for that interval. 
Site personnel will clarify any discrepancy and record this information within the CRF.  
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Patients must maintain at least 75% compliance in dosing to be deemed as compliant. In the 
event of a missed or vomited dose, patients will take their subsequent dose of study drug at 
the next scheduled time point, following the tid dosing regimen of approximately every 6 
hours. A dose outside of a 3-hour window should be considered missed. Missed or vomited 
doses will not be made up.  
7.4 
Dose Adjustment 
Downward dose adjustment of telotristat etiprate will be permitted if evidence of 
intolerability emerges. After a period at the lowered dose level, patients may resume the 
previous dosing level at the discretion of the Investigator after consultation with the Medical 
Monitor. Patients who experience intolerability at the 250 mg tid dose level must be 
discontinued from study treatment. Interruptions or delays in dosing throughout the entire 
study may be permitted after consultation with the Medical Monitor, at which time the patient 
will be reassessed for study continuation, dosage reduction, or discontinuation. 
8. 
Study Procedures 
A schedule of study assessments is provided in Appendix A. 
8.1 
Restrictions during Study 
Patients should be advised to avoid food and drink containing grapefruit for 2-3 hours prior to 
and following dosing while participating in the study. 
8.2 
Description of Study Assessments 
8.2.1 
Efficacy Assessments 
Efficacy assessments include the patient reported QOL measures; EORTC QLQ-C30 
(Appendix D) & GI.NET21 (Appendix E) questionnaires and subjective global assessment of 
symptoms associated with CS. 
A description of the efficacy assessments is provided below. 
8.2.1.1 
EORTC QLQ-C30 & GI.NET21 
Patients will complete the questionnaires during each visit as indicated in Appendix A. 
8.2.1.2 
Subjective Global Assessment 
A subjective global assessment of symptoms associated with CS will be evaluated using 2 
methods at each visit as indicated in Appendix A.  
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Patients will first be asked to respond to the following question:  “In the past 7 days, have 
you had adequate relief of your carcinoid syndrome bowel complaints such as diarrhea, 
urgent need to have a bowel movement, abdominal pain, or discomfort?”. 
Then patients will be asked the following question to assess global symptoms associated with 
CS on an 11-point scale: “Rate the severity of your overall carcinoid symptoms over the past 
7 days on a scale from 0-10, where 0 = no symptoms and 10 = worst symptoms ever 
experienced.” 
8.2.2 
Clinical Laboratory Assessment  
Clinical laboratory assessments will consist of hematology (complete blood count [CBC] 
with differential and platelet counts), blood chemistry (complete metabolic panel and liver 
function tests), and urinalysis. All laboratory tests will be performed by a central laboratory, 
with the exception of the urine pregnancy test, which will be performed by the study site with 
the provided laboratory kit.  
The incidence of clinically significant laboratory values, as well as clinically significant shifts 
in laboratory values, should be reported as an AE in the patient’s CRF (see also Section 9.1 
for reporting of AEs related to laboratory abnormalities). The Investigator will assess any 
clinically significant values relevant to the patient population to determine if termination of 
the study drug is required. 
8.2.2.1 
Monitoring Hepatic Function 
Patients with clinically significant abnormalities in liver function tests should be excluded 
from participating; however, the patient’s clinical situation as a whole should be taken into 
account when evaluating hepatic transaminase elevations, which may represent a 
consequence of the underlying disease and/or therapeutic interventions. Patients with 
abnormalities in liver function test results, as defined below, should be further assessed by the 
Investigator and may have additional tests performed by the central laboratory as clinically 
indicated. The following describes the Sponsor’s recommended approach to evaluating these 
events. This approach is not meant to replace the Investigator’s clinical judgment.  
These guidelines apply to the following events: 
1) A new confirmed result (after Day 1 dosing) of ALT or AST >3 x ULN (in 
patients previously within normal range) 
OR 
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2) A confirmed increase in transaminases above the patient’s previous Baseline to a 
degree that is significant in the clinical judgment of the Investigator and ALT or 
AST >3 x ULN (in patients with previous abnormal liver-test results) 
OR 
3) Any occurrence of an elevation of ALT or AST >3 x ULN and total bilirubin >2 x 
ULN (in any patient) 
For any such event, the Investigator should discuss the Follow-up approach with the Medical 
Monitor.  
The Sponsor’s recommended approach is as follows: 
1. Schedule the patient for a Follow-up visit within 3 days following the receipt of 
laboratory results to assess the patient and conduct further evaluation, to include the 
following: 
a. Obtain repeat testing of ALT, AST, total bilirubin, and ALP through the central 
laboratory. 
b. Reassess the patient through patient interview and physical examination to 
uncover new or emerging risk factors of liver injury including an increased use 
of alcohol, gallbladder disease, hemochromatosis, fatty liver, use of 
hepatotoxic concomitant medications (including acetaminophen), occupational 
exposures, liver metastases, and other causes for potential clues as to the 
underlying etiology of the event. 
c. Continue to monitor the patient’s transaminases and total bilirubin regularly 
until the liver function test values return to Baseline levels.  
Additional recommendations include: 
 Consider referral to a hepatologist or gastroenterologist 
 Consider reimaging (eg, ultrasound, CT, or MRI) the liver and biliary tract 
 Consider additional laboratory testing as clinically indicated. Laboratory assays 
available to the Investigator for further workup are described in the laboratory manual 
Upon completion of hepatic assessment, the Investigator should review results with the 
Medical Monitor and assess continued study participation. 
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8.2.3 
Pharmacodynamic Assessments 
8.2.3.1 
Plasma 5-HIAA 
Fasting blood samples (≥6 hours) for measurement of 5-HIAA in plasma will be collected 
and analyzed by a specialty laboratory. All sample processing information will be supplied by 
the laboratory in a separate document/study manual. Efforts should be made to schedule these 
visits in the morning, with instructions to the patient to arrive in a fasted state and not dose 
prior to the blood draw. 
8.2.4 
Safety Assessments 
In addition to the clinical laboratory assessments described in Section 8.2.2, monitoring of 
AEs is also considered a safety assessment and is described in detail in Section 9. Clinically 
significant changes compared with Baseline findings for these variables should be reported as 
AEs on the CRF. Clinically significant changes compared with Baseline values, which are 
determined to be AEs, should be followed until the event has resolved, the condition has 
stabilized, etiology of the event is determined to be not related to study drug, or the patient is 
lost to Follow-up. 
8.2.4.1 
Vital Sign Measurements 
Measurement of vital signs will include assessment of blood pressure, respiratory rate, pulse 
rate, and oral temperature. Vital sign measurements should not be conducted with the 
30 minutes immediately following any phlebotomy. 
Efforts should be made to standardize blood pressure collection across all patients and visits. 
Patients should be seated for at least 5 minutes prior to collection. All measurements should 
be assessed on the same arm, and by the same technician where possible. 
Additional measurements may be obtained if clinically indicated. Vital sign measurements 
will be measured as indicated in Appendix A. 
8.2.4.2 
Physical Examinations 
Complete physical examinations will be performed as outlined in Appendix A. Complete 
physical examinations will include a minimum of a review of the patient’s general 
appearance, head, eyes, ears, nose, and throat (HEENT), neck, heart, lungs, abdomen, back 
and extremities, skin, and general neurological system.  
Symptom-oriented physical examinations will be performed at all other time points and as 
clinically indicated.  
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In addition, weight will be captured during each physical examination. Efforts should be 
made to standardize weight collection across all patients and visits. Patients should be 
instructed to remove shoes and heavy clothing (eg, heavy coats, jackets) prior to 
measurement. For weight collection, an effort should be made to use the same scale 
throughout the study where possible. In instances where multiple scales may be used, efforts 
should be made to reset the scale to zero prior to collection of weight measurement. 
8.2.4.3 
Electrocardiograms 
Electrocardiograms (12-lead ECGs) will be performed as specified in Appendix A. 
8.2.4.4 
Adverse Events of Special Interest 
Monitoring of these events will be the responsibility of the DSMB. The process of data 
collection and assessment of the events will be detailed in a separate DSMB charter.  
Additional information will be collected if episodes of any of the following AEs of special 
interest occur. 
8.2.4.4.1 
Central Nervous System Events 
Central nervous system events of special interest may include any clinically significant 
changes in mood, physical affect, or exacerbation of preexisting CNS conditions (eg, 
depression, migraine headaches). 
8.2.4.4.1.1 
Depression Detection 
Patients will be evaluated beginning at Day 1 (Baseline) and at each subsequent visit for 
indications of depression. During each visit the patient will first be asked to respond to the 
question “During the past month, have you often been bothered by feeling down, depressed, 
or hopeless?” Followed by “During the past month, have you often been bothered by little 
interest or pleasure in doing things?” A positive response prior to Day 1 dosing will be 
captured on the medical history CRF page. Positive responses following the first dose will be 
captured as an AE and will be followed as an AE of special interest.  
8.3 
Other Assessments 
8.3.1 
Chromogranin A (CgA) 
Blood samples for measurement of chromogranin A (CgA) levels will be collected as 
indicated in Appendix A. 
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8.3.2 
Disease Progression 
Data will also be collected on measures of disease progression as performed as standard of 
care including, but not limited to: interpretation of clinical scans (eg, PET, CAT, MRI scans 
of tumor), or Investigator assessment of disease status, while the patient is enrolled in the 
study.     
8.3.3 
Quality of Sleep Assessment 
Quality of sleep will also be evaluated beginning Day 1 (Baseline) and at each subsequent 
visit thereafter. Patients will be asked to respond to the following question “Since your last 
visit, how many times a night (on average) do you wake up due to your CS symptoms?” 
based on the following scale 0, 1, 2, 3, 4, >4.  
8.4 
Appropriateness of Assessments 
The assessments used in this study conform to the usual clinical and laboratory assessments 
of patients with CS participating in clinical trials and are typical of a Phase 3 study.  
8.4.1 
Blood Collection 
An attempt should be made to collect all samples as per the schedule outlined in Appendix A. 
Any portion of samples remaining after the required tests for this study have been completed 
will be destroyed. 
The estimated amount of blood scheduled for collection per patient, over the course of the 
study, may be found in Appendix B. 
9. 
Safety Reporting 
Medical queries should be addressed to the Medical Monitor responsible for the region. 
Sites in North America: 
, MD 
  
INC Research 
 
 
Phone: 
 
 
 
Sites outside North America:  
, MD, PhD 
 
INC Research 
 
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The Netherlands 
Phone: 
 
Mobile: 
 
 
 
, MD, PhD 
Medical Monitor 
INC Research, LLC 
 
 
Czech Republic 
Phone: 
 
Fax: 
 
 
After-hours emergency medical coverage is available to site personnel should the regional 
Medical Monitor and regional backup Medical Monitor be unavailable. 
 
Sites in North America dial 1-877-462-0134. 
 
Sites outside North America dial the country prefix number plus 1-877-462-0134. Prefix 
numbers are determined by accessing the AT&T Direct on-line link 
http://www.usa.att.com/traveler/access_numbers/country/index.jsp. Note: These calls are not 
toll-free. 
9.1 
Adverse Events 
It is the responsibility of the Investigator to document all AEs that occur during the study. 
Adverse event is defined as any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. 
Life-threatening adverse event or life-threatening suspected adverse reaction: An adverse 
event or suspected adverse reaction is considered "life-threatening" if, in the view of either 
the Investigator or Sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred 
in a more severe form, might have caused death. 
An AE includes any noxious, pathological, or unintended change in anatomical, 
physiological, or metabolic functions as indicated by physical signs or symptoms occurring in 
any phase of the clinical study whether or not considered related to the study medication. 
This definition includes an exacerbation of preexisting medical conditions or events, 
historical condition not present prior to study treatment, which reappear following study 
treatment, intercurrent illnesses, hypersensitivity reactions, drug interaction, or the significant 
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worsening of the disease under investigation that is not recorded elsewhere in the CRF. 
Anticipated day-to-day fluctuations of pre-existing conditions that do not represent a 
clinically significant exacerbation or worsening need not be considered AEs. 
Any laboratory abnormality fulfilling the criteria for a SAE (Section 9.2) should be reported 
as such, in addition to being recorded as an AE. Any treatment-emergent abnormal laboratory 
result which is clinically significant, ie, meeting 1 or more of the following conditions, 
should be recorded as a single diagnosis AE: 
 Is considered to be an SAE, 
 Results in discontinuation from study treatment, or 
 Results in a requirement for a change in concomitant therapy (ie, addition of concomitant 
therapy) 
In the event of medically significant unexplained abnormal laboratory test values, the tests 
should be repeated and followed up until they have returned to the normal range and/or an 
adequate explanation of the abnormality is determined.  
TEAEs are defined as any AEs reported after the first dose of study drug on Day 1. Adverse 
events reported after consent of a patient, but before administration of study medication, will 
be reported in the Medical History. 
AEs should not be solicited with leading questions that suggest specific signs or symptoms. 
Rather, AEs should be solicited by asking the patient a non-leading question such as: “Do you 
feel different in any way since receiving the dose or since the last assessment?” 
The Investigator will evaluate all AEs with regard to the maximum intensity and relationship 
to study drug, as follows: 
 Maximum intensity  
Maximum intensity should be assigned using 1 of the following 3 severity grades: 
o 
Mild: aware of event but easily tolerated 
o 
Moderate: discomfort, enough to cause interference with usual activity 
o 
Severe: incapacitating: patient unable to work or perform usual activities 
 Relationship to study drug 
Not related:  
o 
Does not follow a reasonable temporal sequence from administration of the drug 
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o 
Could be reasonably explained by other factors, including underlying disease, 
complications, concomitant drugs, or concurrent treatment. 
Possibly related:  
o 
That follows a reasonable temporal sequence from administration of the drug 
(including the course after withdrawal of the drug), or 
o 
For which the possibility of the study drug being the causative factor (eg, existence 
of similar reports attributed to the suspected drug and its analogues; reactions 
attributable to the pharmacological effect) could not be excluded, although other 
factors such as underlying disease, complications, concomitant drugs, or concurrent 
treatment are presumable. 
Probably related: 
o 
That follows a reasonable temporal sequence from administration of the drug 
(including the course after withdrawal of the drug), and 
o 
For which the possibility of factors other than the drug, such as underlying disease, 
complications, concomitant drugs, or concurrent treatment, could not be excluded as 
the cause. 
Definitely related: 
o 
Follows a clear temporal sequence from administration of the study drug. 
o 
Could not be possibly explained by the known characteristics of the patient’s 
clinical state, environmental or toxic factors, or other modes of therapy 
administered to the patient. 
o 
Disappears or decreases on cessation or reduction in dose of the study drug. 
o 
Reappears or worsens when the study drug is re-administered. 
o 
Follows a response pattern known to be associated with administration of the study 
drug. 
The degree of certainty with which an AE is attributed to treatment with study medication (or 
alternative causes, eg, natural history of the underlying diseases, concomitant therapy, etc.) 
will be determined by how well the event can be understood in terms of known 
pharmacology of the study medication and/or reaction of similar nature being previously 
observed with the study medication or the class of study medication. 
All AEs should be followed for at least 30 days following the last dose of study drug or until 
the event has resolved, the condition has stabilized, or the patient is lost to Follow-up. For 
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each patient for whom an AE was reported that did not resolve before the end of the reporting 
period, Follow-up information on the subsequent course of events must be submitted to the 
Sponsor. This requirement indicates that follow-up may be required for some AEs after the 
patient has completed his/her participation in the study 
9.2 
Serious Adverse Events (SAEs) 
An SAE is defined as any event that results in any of the following outcomes: 
1. Death 
2. A life-threatening adverse event; 
3. Inpatient hospitalization or prolonging of an existing hospitalization (see Section 9.2.1 
for information on hospitalization as an SAE);  
4. A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; or 
5. A congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed above. 
Any SAE must be reported by telephone or facsimile within 24 hours of discovery of the 
event. Investigators should not wait to receive additional information to fully document the 
event before notifying the Sponsor of an SAE at: 
Sites in North America must report to: 
Safety Data Facsimile: 001 (832) 442-5917 
Safety Hotline: 001 (877) 372-3597 
 
Email address (in case of fax failure): drugsafetyfax@lexpharma.com 
 
Sites outside North America must report to the country specific toll-free fax numbers 
identified below: 
Australia: 
 
Belgium: 
 
Brazil: 
 
France:
 
Germany: 
 
Israel: 
 
Italy:
 
Netherlands: 
 
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Spain: 
 
Sweden: 
 
United Kingdom: 
 
 
Email Address (in case of fax failure):  
 
 
The telephone report should be followed by full written summary detailing relevant aspects 
of the SAE in question using the provided SAE report form. Where applicable, information 
from relevant hospital case records and autopsy reports should be obtained. The SAE should 
also be recorded on the AE page of the patient’s CRF. 
An SAE that occurs after completion of the study but, in the opinion of the Investigator, is 
related to the study medication, should be reported as described for an SAE. If an AE does 
not meet the regulatory definition of “serious” but is considered by the Investigator to be 
related to the study medication and of such clinical concern as to influence the overall 
assessment of safety, it must be reported as defined for an SAE. 
All patients (including discontinued patients) with a SAE must be followed until the event 
resolves or reaches a new Baseline, but for a minimum of 30 days after the last dose of study 
drug. 
9.2.1 
Hospitalization as an SAE 
Hospitalization is defined as any in-patient overnight stay in a hospital. A hospitalization in 
and of itself does not constitute an SAE. The condition which caused the hospitalization must 
be evaluated and determined to be an AE. Although an AE which results in hospitalization is 
an SAE, patients are hospitalized for a variety of reasons which may not be associated with or 
considered an SAE (eg, convenience, logistics, preference, etc). Therefore, each case of 
hospitalization must be evaluated separately. 
For example, the following would not be considered SAEs: 
 Hospitalization for a preexisting condition which did not worsen (eg, cataract surgery) 
 Hospitalization solely for a procedure or treatment that was not performed to treat an 
AE 
 Hospitalization for a condition that does not normally require treatment, but electively 
done (eg, cosmetic surgery) 
 Hospitalization strictly for convenience reasons or observations (eg, procedures only 
performed in a hospital because of the distance the subject lives from the hospital) 
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9.3 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
The FDA and/or other applicable Regulatory Authorities and all participating Investigators 
will be notified by a written Investigational New Drug Application (IND) safety report and/or 
other applicable regulatory report (eg, SUSAR) of any suspected adverse reaction that is both 
serious and unexpected, no later than 15 calendar days from the “date learned” of the event. 
In addition, all applicable regulatory bodies will be notified within 7 calendar days of any 
unexpected fatal or life-threatening suspected adverse reaction.  
An adverse reaction is defined as any untoward and unintended response to an investigational 
medicinal product (IMP) related to any dose administered. This definition also covers 
medication errors and uses outside what is foreseen in the protocol, including misuse and 
abuse of the product. The definition also implies a reasonable possibility of a causal 
relationship between the event and the IMP.  
An unexpected adverse reaction is any adverse drug event, which is not listed in the current 
Investigator’s Brochure or is not listed at the specificity or severity that has been observed. 
For example, (A) a single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (eg, angioedema, hepatic injury, Stevens-Johnson Syndrome); 
(B) 1 or more occurrences of an event that is not commonly associated with drug exposure, 
but is otherwise uncommon in the population exposed to the drug (eg, tendon rupture); (C) an 
aggregate analysis of specific events observed in a clinical trial (such as known consequences 
of the underlying disease or condition under investigation or other events that commonly 
occur in the study population independent of drug therapy) that indicates those events occur 
more frequently in the drug treatment group than in a concurrent or historical control group. 
An untoward and unintended response to a non-IMP is by definition not a SUSAR. 
9.4 
Precautions 
9.4.1 
Pregnancy 
Any patient (or patient’s partner) who becomes pregnant during the study should be followed 
through delivery or termination of the pregnancy. In addition, patients who become pregnant 
during the study must be discontinued from the study treatment immediately.  
In pregnancies that progress to term, any congenital abnormalities/birth defects in the 
offspring of a patient who received study medication should be reported as an SAE. The 
outcome of the pregnancy and the presence or absence of a congenital abnormality will be 
documented by completion of a Pregnancy Questionnaire and a Pregnancy Outcome Form in 
accordance with GCP and ICH guidelines and the Sponsor’s SOPs.  
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Female patients should also notify the Investigator if they become pregnant within 30 days 
after last dose of study medication. Male patients should notify the Investigator if a female 
partner becomes pregnant within 30 days after last dose of study medication. The Sponsor 
must be notified of all pregnancies reported to the Investigator (see Section 9.2 for contact 
information). 
10. 
Statistical Methodology 
10.1 
Determination of Sample Size 
No formal sample size calculation was made. The number of patients expected to participate 
in this study was calculated from estimated enrollment rates from other carcinoid cancer trials 
employed in the LX1606 clinical program. 
10.2 
Analysis Populations 
Per protocol: A Per Protocol population will consist of those patients that receive study 
treatment and have no major protocol violation that would interfere with the collection or 
interpretation of the efficacy data. The primary analyses of efficacy will be based on the 
safety population; the per-protocol population will be used in a supplemental manner.  
Safety: The safety population consists of all patients receiving any fraction of a dose of study 
drug during this study.  
10.3 
Study Endpoints 
10.3.1 
Efficacy Endpoints 
The primary efficacy endpoint is to evaluate the long-term safety and tolerability of orally 
administered telotristat etiprate. 
Secondary efficacy endpoint is to evaluate changes in patients’ QOL over 84 weeks of 
therapy.  
10.3.2 
Safety Endpoints 
Safety endpoints are as follows:  
 Incidence of TEAEs, suspected adverse reaction, AEs leading to discontinuation from the 
study, SAEs, and deaths 
 Actual and change from Baseline in clinical laboratory results  
 Actual and change from Baseline in vital signs results  
 Actual and change from Baseline in physical examinations 
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 Actual and change from Baseline in ECG findings 
10.4 
Statistical Methods 
Descriptive analysis methods will be used to summarize the data. Continuous variables will 
be summarized by the N, mean, standard deviation, median, minimum, and maximum values. 
Categorical variables will be summarized as counts and related percentages. Data tabulations 
will be categorized by the treatment received on Day 1 of this study and combined across all 
treated patients. All data will be listed. 
Primary analyses of the data will be based on the Safety population which includes all 
patients treated with any fraction of study drug during this study. Supportive analyses of the 
efficacy data will be made on a Per Protocol population. This dataset will include the Safety 
population, but limited to those patients that have at least one assessment post Day 1 and do 
not have any protocol violations that would interfere with collection or interpretation of the 
data. The Per Protocol analysis will be applied to the QOL measures, subjective global 
assessment, and plasma 5-HIAA values. 
Data will be summarized per study visit as the actual (raw) outcomes and change from 
Baseline scores, where applicable. Day 1 of this study will serve as the Baseline assessment. 
10.4.1 
Efficacy Analyses 
All efficacy and PD variables will be summarized descriptively and listed. 
Statistical tests and estimates of within patient effects for these measures will be derived from 
application of a mixed linear model with repeated measures. The model will be generalized to 
handle missing data and specific to the measurement properties of the dependent variable. 
There is no plan to impute data for missing observations for any variable. Non-parametric 
methods will be used to supplement the tests and estimates from the mixed linear model. 
Exploratory analyses of treatment group differences may be performed by use of propensity 
score models. The treatments groups will correspond to how patients were dosed on Day 1 of 
this study.  
10.4.2 
Safety Analyses 
Statistical analysis of the safety data will involve examination of the descriptive statistics and 
individual patient listings for any effects of study treatment on clinical tolerability and safety. 
Reporting of these data will be based on the Safety population. Summaries will be prepared 
by treatment group (corresponding to the LX1606 dose given on Day 1), pooled across all 
patients, and as needed, by study visit. All safety data will be listed. 
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Treatment-emergent adverse event summaries will include the overall incidence (by system 
organ class and preferred term), events by maximum intensity, event by relationship to study 
treatment, events leading to discontinuation of study drug, and serious adverse events. 
Vital signs, ECG, and laboratory parameters (hematology, chemistry, and urinalysis) will be 
summarized descriptively at each time point. Actual and change from Baseline data will be 
calculated and summarized. In addition, shift table analysis will be applied to the laboratory 
data and summarized. 
10.4.2.1 
Adverse Events 
All AEs will be coded and listed by body system and preferred term based on the Medical 
Dictionary for Regulatory Activities (MedDRA). Summaries using descriptive statistics will 
be provided for treatment-emergent AEs, drug-related AEs and AEs by intensity. Treatment-
emergent AEs are those events not present at Baseline, but occurring after the start of study 
drug, or if existing at Baseline, increasing in intensity after initiation study drug. Summaries 
made by intensity will select the event with the highest intensity when multiple occurrences 
of the same event are reported for the same patient. In a similar manner, summaries prepared 
by drug relationship will select the event with the greatest degree of relationship when a 
study reports multiple occurrences of the same event. On-study deaths will be reported for 
deaths occurring during the active phase of the treatment period and 30 days after stopping 
study drug. Also, deaths occurring outside the 30-day window, but secondary to an AE 
reported within the 30-day post treatment period, will be reported as well.  
Listings will be provided for deaths, SAEs, and discontinuations due to AEs. Additional 
summaries or listings of AEs may also be provided. 
10.4.2.2 
Clinical Laboratory Parameters 
Laboratory results will be reported in conventional units in all tables, figures, and listings. 
Laboratory results falling out of the normal range will be marked as high or low in the 
listings. Actual and changes from Baseline (Day 1) in clinical laboratory results will be 
summarized by using descriptive statistics. Summaries of shifts from Baseline to abnormal 
clinical laboratory results will also be provided. Actual and change from Baseline in 
chromogranin A levels will be summarized descriptively as well. 
10.4.2.3 
Vital Sign Measurements 
Actual and changes from Baseline (Day 1) in vital signs results will be summarized by using 
descriptive statistics. 
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10.4.2.4 
Electrocardiograms 
Clinically significant changes in ECGs compared to Baseline, as determined by the 
Investigator, will be summarized by using descriptive statistics. Actual and change from 
Baseline (Day 1 predose values) to each time point in corrected QT interval (QTcF) will be 
summarized as well. 
10.4.3 
Pharmacodynamic Analyses 
Analysis and summarization of the plasma 5-HIAA data are described in Section 10.4.1. 
10.4.4 
Baseline Characteristics and Other Summaries 
Treatment group differences will be summarized descriptively for demographic data, prior 
and concomitant medications, treatment compliance, and final disposition. Data collected 
from assessments of tumor status, when available, will be listed. 
Protocol deviations will provided as listings. 
10.4.5 
Interim Analysis 
An independent DSMB will be charged with reviewing interim safety data on a quarterly 
basis and reporting its recommendations to Lexicon Pharmaceuticals, Inc. Appropriate 
procedures will be detailed in a DSMB Charter that defines accessibility and disclosure of the 
interim study results. 
The study may be analyzed and reported in multiple phases. The first report will summarize 
data obtained from all patients providing information up to a specified data cut-off point. The 
following reports will update the initial report by including data from the remaining portion 
of the study. The first reporting of the data may be taken as an interim analysis in terms of the 
procedural efforts needed to summarize these data, but it will not serve as a means to modify 
the analysis/study conduct.   
11. 
Study Management 
The Investigator is responsible for completing and maintaining adequate and accurate CRFs 
and source documentation. Source documentation constitutes original records, which may 
include: progress notes, medication administration records, laboratory reports, ECG tracings, 
and discharge summaries.  
All data on the CRF must be recorded in accordance with the CRF guidelines. If a correction 
is necessary, it should be made by the Investigator or a designated qualified individual as 
specified within the guideline. All CRFs should be completed in their entirety and stored in a 
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secure location. The Investigator must sign the Investigator’s statement in each patient’s CRF 
indicating that the data reported are accurate. 
At the study site, clinical research associates will verify 100% of CRFs in their entirety 
against source documentation. Computer programmed edit checks will be run against the 
database to check for discrepancies and reasonableness of the data, and the safety database 
will be reconciled with the clinical database. All issues resulting from the computer generated 
checks and the safety database reconciliation will be resolved according to standard data 
management practices in conjunction with the Sponsor, clinical study personnel, and the 
study Investigators. 
11.1 
Monitoring 
The Sponsor is responsible for ensuring the proper conduct of the study with regard to ethics, 
protocol adherence, site procedures, integrity of the data, and applicable laws and/or 
regulations. At regular intervals during the study and following completion of the study, the 
Sponsor’s study monitors will contact the study site via visits to the site, telephone calls, 
and/or letters in order to review study progress, CRF completion, and address any concerns 
or questions regarding the study conduct. During monitoring visits, the following aspects of 
study conduct will be carefully reviewed: informed consent of patients, patient recruitment, 
patient compliance with the study procedures, source data verification, drug accountability, 
use of concomitant therapy by patients, AE and SAE documentation and reporting, and 
quality of data. Records pertaining to these aspects are expected to be kept current. 
The Investigator must make study data accessible to the clinical monitor, to other authorized 
representatives of the Sponsor, and to regulatory inspectors 
11.2 
Audits and Inspections 
The Sponsor, regulatory authority, or IRB/ERC may visit the study site at any time during the 
study or after completion of the study to perform audits or inspections. The purpose of a 
Sponsor audit or regulatory inspection is to systematically and independently examine all 
study-related activities and documents to determine whether these activities were conducted 
according to the protocol, GCP, ICH guidelines, and any other applicable regulatory 
requirements. Investigators should contact the Sponsor immediately if contacted by a 
regulatory agency about an inspection at their site. 
11.3 
Amendments 
Any amendments to the protocol will be written and approved by the Sponsor. All 
amendments must be submitted to the IRB/ERC for approval prior to implementing the 
changes. In some instances, an amendment may require changes to the informed consent 
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form, which also must be submitted for IRB/ERC approval prior to administration to patients. 
If any changes to the CRF are required, the Sponsor will issue supplemental or revised CRF 
pages. 
11.4 
Record Keeping 
11.4.1 
Drug Accountability  
The Investigator must maintain accurate records of receipt of study drug, dispensing 
information (date, lot, and dose for each patient), and the prompt return or destruction of 
unused supplies. If the Investigator cannot account for all clinical supplies at the termination 
of the study, a written explanation must be provided.  
11.4.2 
Health Insurance Portability Accountability Act of 1996 and 
Subsequent Updates 
The Investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of patient health information, including, but not limited to, 
the Standards for Individually Identifiable Health Information, 45 Code of Federal 
Regulations (CFR) Parts 160 and 164 (the Health Insurance Portability Accountability Act of 
1996 [HIPAA] Privacy Regulation and any applicable updates). The Investigator shall ensure 
that study patients authorize the use and disclosure of protected health information in 
accordance with HIPAA Privacy Regulation and in a form satisfactory to the Sponsor. 
11.4.3 
Financial Disclosure 
The Investigator shall provide to the Sponsor sufficient accurate financial information to 
allow the Sponsor to submit complete and accurate financial certification or disclosure 
statements to the FDA and/or other applicable regulatory agencies. The Investigator shall 
promptly update this information if any relevant changes occur in the course of the study or 
for 1 year following completion of the study. 
11.4.4 
Access to Original Records 
It is an expectation of regulatory authorities that monitors, auditors, and representatives of 
national and international government regulatory agency bodies have access to original 
source documentation (see examples in Section 11) to ensure data integrity. “Original” in this 
context is defined as the first documentation of an observation and does not differentiate 
between hard copy and electronic records. 
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11.4.5 
Retention of Study Documents 
According to 21 CFR Part 312.62 and ICH E6, study-related records must be retained for at 
least 2 years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region, or at least 
2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. These documents should be retained for a longer period, however, if 
required by applicable regulatory requirements or by an agreement with the Sponsor. 
The Investigator must not destroy any study-related records without receiving approval from 
the Sponsor. The Investigator must notify the Sponsor in the event of accidental loss or 
destruction of any study records. If the Investigator leaves the institution where the study was 
conducted, the Sponsor must be contacted to arrange alternative record storage options. 
12. 
Administrative Structure of the Study 
The study will be monitored by Sponsor personnel or Sponsor representative. The following 
functions for this study will be performed by organizations designated by the Sponsor: data 
management and statistical analysis, including PD analysis and reporting.
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13. 
Appendix A – Schedule of Events 
Baseline Day 
11
Week 12
Week 24
Week 36
Week 48
Week 60
Week 72
Week 84 / 
EOS
Week 966
Week 1086
Tolerance (days)
NA
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
Inclusion/Exclusion criteria
X
Medical history
X
Physical examination incl. weight
X
X3
X3
X3
X
X3
X3
X
X3
X3
 X5
Urine pregnancy test2
X
X
X
X
X
X
X
X
X
X
X
Hematology, Blood chemistry
X
X
X
X
X
X
X
X
X
X
 X5
Urinalysis
X
X
X
 X5
Chromogranin A
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
 X5
Subjective Global Assessment
X
X
X
X
X
X
X
X
X
EORTC QLQ-C30 & GI.NET21
X
X
X
X
X
Sleep and Depression Assessment
X
X
X
X
X
X
X
X
X
X
X
Plasma 5-HIAA
X
X
X
X
X
X
X
X
X
X
X
Dispensation of LX1606
X
X
X
X
X
X
X
X
X
 
 
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
Optional Extension
2-Week Follow-up4
1Eligibility will be determined at last visit of the original protocol; Day 1 will replace the next scheduled visit in the original protocol schedule. Visits should coincide with LAR injections 
for those patients receiving SSA therapy. 2Females of child-bearing potential only. 3Brief physical examination only (symptom-oriented, including weight). 4Visit to be performed for 
subjects who withdraw early and will not return for a 2-week follow-up visit; in all other cases the EOS visit should be performed followed by the follow-up visit 2 weeks postdose. 5To be 
performed only if evaluation at Week 84/EOS is abnormal. 6Week 96 and Week 108 visits may be performed up until 31 March 2016 for patients who would otherwise complete 84 weeks of 
treatment in the study prior to 31 March 2016.
Procedure
Extension Period
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14. 
 Appendix B – Amount of Blood to be Collected from Each Patient 
Assessment 
Sample volume 
(mL) 
Number of 
samples* 
Estimated total volume 
(mL) 
Safety 
Hematology 
2 
11 
22 
  
Blood chemistry 
6 
11 
66 
Other 
CgA 
2 
3 
6 
Pharmacodynamic Plasma 5-HIAA 
4 
11 
44 
Total  
138 
*Maximum number of samples is indicated 
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15. 
Appendix C – EORTC QLQ-C30 
 
 
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16. 
Appendix D – EORTC QLQ - GI.NET21 
 
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17. 
Appendix E – Ethical Standards 
Ethics and Regulatory Considerations 
This study will be conducted according to GCP, 21 CFR Part 50, (Protection of Human 
Subjects), 21 CFR Part 56 (Institutional Review Boards), International Conference on 
Harmonisation Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance, the 
Nuremberg Code, and the Declaration of Helsinki.  
General Instructions 
The FDA regulates studies of drugs, biologics, and medical devices. Consequently, these 
studies are subject to GCP regulations and guidance issued by the FDA and are included in, 
but not limited to, the following parts of the CFR and guideline document: 
 21 CFR Part 11 – Electronic Records 
 21 CFR Part 50 – Protection of Human Subjects 
 21 CFR Part 54 – Financial Disclosure 
 21 CFR Part 56 – Institutional Review Boards 
 21 CFR Part 312 – Investigational New Drug Application 
 Current FDA Guideline for the Monitoring of Clinical Investigations 
 Current Guidance for Institutional Review Boards and Clinical Investigators 
 ICH E6 – Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance  
Studies conducted in the European Union are also regulated by Volume 10 of the publications 
“The rules governing medicinal products in the European Union”. 
Copies of these materials are available from the Sponsor upon request. The purpose of these 
regulations and legal obligations is to define the standards and principles for the proper 
conduct of clinical trials that have been developed by the medical, scientific, and regulatory 
communities. They are not intended to impede or restrict clinical research.  
The ethical standards defined within GCP are intended to ensure that: 
 human subjects are provided with an adequate understanding of the possible risks of their 
participation in the study, and that they have a free choice to participate or not; 
 the study is conducted with diligence and in conformance with the protocol in such a way 
as to insure the integrity of the findings; 
 the potential benefits of the research justify the risks. 
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Lexicon Pharmaceuticals, Inc. is the Sponsor of the IND. The Sponsor is responsible for the 
following: 
 selecting qualified Investigators, 
 providing Investigators with the information they need to properly conduct an 
investigation, 
 ensuring proper monitoring of the investigation, 
 ensuring that the study is conducted according to the general investigational plan and 
protocols contained in the IND, 
 maintaining the IND, and  
 ensuring that regulatory authorities and all participating Investigators are properly 
informed of significant new information regarding adverse effects or risks associated with 
the drug being studied 
 ensuring the study is conducted in accordance to FDA and ICH guidelines and all 
applicable regulations 
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18. 
Appendix F – Investigator Obligations 
Per Title 21 of the US Government Code of Federal Regulations (21 CFR) Parts 50 and 56 
and ICH E6, the study protocol and the final version of the subject informed consent form 
will be approved by the IRB/ERC before enrollment of any subjects. The opinion of the 
IRB/ERC will be dated and given in writing. A copy of the letter of approval from the 
IRB/ERC and a copy of the approved informed consent form will be received by the Sponsor 
prior to shipment of study medication supplies to the Investigator. 
The Investigator will ensure that the IRB/ERC will be promptly informed of all changes in 
the research activity and of all unanticipated problems including risk to subjects. The 
Investigator will also ensure that no changes will be made to the protocol without IRB/ERC 
approval. 
As a part of the IRB/ERC requirement for continuing review of approved research, the 
Investigator will be responsible for submitting periodic progress reports to the IRB/ERC at 
intervals appropriate to the degree of subject risk involved, but no less than once per year. 
Written informed consent must be given freely and obtained from every subject prior to 
clinical trial participation. The rights, safety, and well-being of the trial subjects are the most 
important considerations and should prevail over interests of science and society. 
As described in GCP guidelines, study personnel involved in conducting this trial will be 
qualified by education, training, and experience to perform their respective task(s). Study 
personnel will not include individuals against whom sanctions have been invoked after 
scientific misconduct or fraud (eg, loss of medical licensure, debarment). Quality assurance 
systems and procedures will be implemented to assure the quality of every aspect of the 
study. 
Principal Investigators must provide Lexicon with a fully executed Form FDA 1572 
(statement of Investigator) and all updates on a new fully executed Form FDA 1572. 
Principal Investigators must provide Lexicon with his/her own curriculum vitae and current 
curriculum vitae for each sub-Investigator listed on Form FDA 1572. 
Protection of Human Subjects (21 CFR Part 50 and ICH E6)  
Informed consent must be obtained from every subject before entry into a clinical study. It 
must be given freely and not under duress. Consent must be documented by use of an 
IRB/ERC-approved consent form and signed by the subject or the subject’s legally authorized 
representative. The US Department of Health and Human Services suggests that when minors 
are involved, a parent or guardian should sign the consent form. If the minor is an adolescent, 
his signature should also be included. Non-English-speaking subjects must be presented with 
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a consent form written in a language that they understand. A copy of the signed consent form 
must be given to the subject signing it. Another copy must be kept in the Investigator’s files 
and made available to regulatory authority representatives upon request. If, for any reason, 
subject risk is increased as the study progresses, a revised, IRB/ERC-approved consent form 
must be signed by the subject. Before the study begins, a sample of the consent form must be 
provided to the Sponsor for review. The FDA and/or other applicable regulatory agencies 
may reject otherwise scientifically valid studies if proper informed consent has not been 
obtained from all subjects. 
Only in the case of a life-threatening incident may an investigational product be used without 
prior signed consent. In such an emergency situation, separate certifications must be written 
both by a physician not participating in the study and by the Investigator. The certifications, 
along with the protocol and informed consent, must be sent to the IRB/ERC within 5 working 
days. In this situation, the Investigator may not administer any subsequent product to that 
subject until informed consent and IRB/ERC approval are obtained. 
Informed Consent 
Written informed consent must be obtained from each subject prior to entry in the study. One 
copy of the signed informed consent document will be given to the subject, and another will 
be retained by the Investigator. Additionally, the subject must be allowed adequate time to 
consider the potential risks and benefits associated with his/her participation in the study.  
In situations where the subject is not legally competent to provide consent (ie, mentally 
incapacitated), written consent must be obtained from a parent, legal guardian, or legal 
representative. In these situations, the consent must be signed and dated by a witness. 
The informed consent document must have been reviewed and approved by the Sponsor and 
by the Investigator’s IRB/ERC prior to the initiation of the study. The document must contain 
the 8 basic elements of informed consent and may contain the 6 additional elements 
described in 21 CFR Part 50. Every consent form must include the following 8 elements: 
 A statement that the study involves research, an explanation of the purpose of the research 
and the expected duration of the subject’s participation, a description of the procedures to 
be followed, and identification of any procedures that are experimental 
 A description of any reasonably foreseeable risks or discomforts to the subject 
 A description of any benefits to the subject or to others that may reasonably be expected 
from the research 
 A disclosure of appropriate alternative procedures or course of treatment, if any, that 
might be advantageous to the subject 
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 A statement describing the extent, if any, to which confidentiality of records identifying 
the subject will be maintained and noting the possibility that the FDA and/or other 
applicable regulatory authority representatives may inspect the records 
 An explanation as to whether any compensation or medical treatments are available if 
injury occurs for research involving more than minimal risk. The explanation should 
involve a description of the compensation or treatment available, or a statement 
describing where further information may be obtained 
 An explanation of whom to contact for answers to pertinent questions about the research 
and the subject’s rights and whom to contact in the event of a research related injury 
 A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the subject is otherwise entitled, and that the subject 
may discontinue participation at any time without penalty or loss of benefits to which the 
subject is otherwise entitled. 
When appropriate, 1 or more of the following elements of information shall also be included 
in the consent form: 
 A statement that the particular treatment or procedure may involve risks to the subject (or 
to the embryo or fetus, if the subject is or may become pregnant) which are currently 
unforeseeable 
 Anticipated circumstances under which the subject’s participation may be terminated by 
the Investigator without regard to the subject’s consent 
 Any additional costs the subject may incur from participation in the research 
 The consequences of a subject’s decision to withdraw from the research and procedures 
for orderly termination of participation by the subject 
 A statement that significant new findings developed during the course of the research that 
may relate to the subject’s willingness to continue participation will be provided to the 
subject 
 The approximate number of subjects involved in the study 
The Declaration of Helsinki includes further details regarding the specific requirements for 
informed consent.  
Nothing in these regulations is intended to limit the authority of a physician to provide 
emergency medical care to the extent the physician is permitted to do so under applicable 
federal, state, or local laws. 
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The informed consent requirements in these regulations are not intended to preempt any 
applicable federal, state, or local laws that require additional information to be disclosed in 
order that informed consent be legally effective. Some states, such as California and Oregon, 
require further action on the Investigator’s part concerning subject consent. 
Study Documentation 
IRB/ERC Review/Approval 
The protocol and informed consent for this study, including advertisements used to recruit 
subjects, must be reviewed and approved by an appropriate IRB/ERC prior to enrollment of 
subjects in the study. It is the responsibility of the Investigator to assure that all aspects of the 
ethical review are conducted in accordance with the current Declaration of Helsinki, ICH, 
GCP, and/or local laws, whichever provide the greatest level of protection. A letter 
documenting the IRB/ERC approval which specifically identifies the study/protocol and a list 
of the committee members must be received by the Sponsor prior to initiation of the study. 
Amendments to the protocol will be subject to the same requirements as the original protocol. 
A progress report with a request for re-evaluation and re-approval will be submitted by the 
Investigator to the IRB/ERC at intervals required by the IRB/ERC, and not less than 
annually. A copy of the report will be sent to the Sponsor.  
When the Sponsor provides the Investigator with a Safety Report, the Investigator must 
promptly forward a copy to the IRB/ERC. 
After completion or termination of the study, the Investigator will submit a final report to the 
IRB/ERC and to the Sponsor, if required. This report should include: deviations from the 
protocol, the number and types of subjects evaluated, the number of subjects who 
discontinued (with reasons), results of the study, if known, and significant AEs, including 
deaths. 
Study Files 
The Investigator is required to maintain complete and accurate study documentation in 
compliance with current Good Clinical Practice standards and all applicable federal, state, 
and local laws, rules, and regulations related to the conduct of a clinical study. Study 
documents include, but are not limited to, the Investigator’s Brochure, drug accountability 
records, Sponsor/Investigator correspondence, IRB/ERC correspondence, protocol and 
amendments, information regarding monitoring activities, subject exclusion records, CRFs, 
and data queries. 
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Confidentiality 
The anonymity of subjects must be maintained. Patients will be identified by their initials and 
an assigned subject number on CRFs and other documents submitted to the clinical monitor. 
Documents that will be submitted to the clinical monitor and that identify the subject (eg, the 
signed informed consent document) must be maintained in strict confidence by the Principal 
Investigator, except to the extent necessary to allow auditing by regulatory authorities, the 
clinical monitor, or Sponsor personnel. 
All information regarding the nature of the proposed investigation provided by the Sponsor to 
the Investigator (with the exception of information required by law or regulations to be 
disclosed to the IRB/ERC, the subject, or the regulatory authority) must be kept in confidence 
by the Investigator. 
Drug Accountability 
The Investigator or designee is responsible for accountability of the investigational product at 
the site. The Investigator or designee must maintain records of the product’s delivery to the 
site, inventory at the site, use by each subject, and return to the Sponsor or alternative 
disposition of any unused product. These records must include dates, quantities, 
batch/serial/lot numbers, and expiration dates (if applicable). 
The Investigator should ensure that the investigational product is used only in accordance 
with the protocol 
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19. 
References 
1. 
Bhattacharyya S, Toumpanakis C, Chilkunda D, Caplin ME, Davar J. Risk factors for 
the development and progression of carcinoid heart disease. Am J Cardiol. 2011; 
107(8):1221-6. Epub 2011 Feb 4. 
2. 
Møller JE, Connolly HM, Rubin J, Seward JB, Modesto K, Pellikka PA. Factors 
associated with progression of carcinoid heart disease. N Engl J Med. 
2003;348(11):1005-15. 
3. 
Druce M, Rockall A, Grossman AB. Fibrosis and carcinoid syndrome: from causation to 
future therapy. Nat Rev Endocrinol. 2009;5(5):276-83 . 
4. 
DePonti F. Pharmacology of serotonin: what a clinician should know. Gut. 
2004;53:1520-35. 
5. 
Cote F, et al. Disruption of the nonneuronal tph 1 gene demonstrates the importance of 
peripheral serotonin in cardiac function. Proc Natl Acad Sci. 2003;100(23):13525-30. 
6. 
De Vries H, et al. Diagnostic, surgical, and medical aspect of the midgut carcinoids. 
Cancer Treat Rev. 2002;28:11-25. 
7. 
Sandostatin LAR® depot product label. Revised July 2014. Accessed at: 
http://www.pharma.us.novartis.com/product/pi/pdf/sandostatin_lar.pdf  
8. 
Investigator Brochure LX1606, Lexicon Pharmaceuticals, Inc.  
9. 
Dmitrienko A, Tamhane A, Wiens B. General multistage gatekeeping procedures. 
Biometrical Journal. 2008;50:667-77 
 
 
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Protocol No.  LX1606.302 A3 
 
06 May 2015 
CONFIDENTIAL 
 
 
 
Page 1 of 6 
 
 
CLINICAL PROTOCOL AMENDMENT 3  
STUDY LX1606.302 
 
 
A Multicenter, Long-term Extension Study to Further Evaluate the Safety and 
Tolerability of Telotristat Etiprate (LX1606) 
 
 
PROTOCOL NO.: 
LX1606.1-302-CS 
LX1606.302 (Abbreviated number) 
 
 
EudraCT Number: 
2013-002596-18 
 
 
INVESTIGATIONAL PHASE: 
3 
 
 
SPONSOR: 
Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Place 
The Woodlands, TX 77381-1160 
Telephone: 001 (281) 863-3000 
Safety Hotline: 001 (877) 372-3597 
Safety Data Facsimile: 001 (832) 442-5917 
 
 
 
PROTOCOL AMENDMENT 3 DATE: 
06 May 2015 (Germany and UK sites only) 
PROTOCOL AMENDMENT 2 DATE: 
08 October 2014 
PROTOCOL AMENDMENT 1 DATE: 
31 January 2014 
ORIGINAL VERSION DATE: 
14 June 2013 
 
 
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Protocol No.  LX1606.302 A3 
 
06 May 2015 
CONFIDENTIAL 
 
 
 
Page 2 of 6 
Amendment Changes 
 
Rationale 
 
Data readout from an interim analysis of the placebo-controlled, double-blind treatment phase of 
Lexicon Pharmaceutical, Inc.’s (Lexicon’s) pivotal Phase 3 study for telotristat etiprate, 
LX1606.1-301-CS, is anticipated during the third quarter of 2015, results of which are 
anticipated to inform and guide decisions regarding the development and regulatory path for 
telotristat etiprate.  During this time, the earliest enrollees of this LX1606.1-302-CS study are 
scheduled to complete the protocol-prescribed 84-week Treatment Period.  A protocol 
amendment is proposed to provide additional continued access to telotristat etiprate for patients 
who are enrolled in the LX1606.1-302-CS study and scheduled to complete the Treatment Period 
prior to 31 March 2016.  This amendment will provide these patients the option to extend the 
Treatment Period until 31 March 2016.   
As a result of the extended duration of study, the protocol has been modified to reflect that 
patient reported quality of life (QOL) measures will be analyzed through Week 84 of the study.  
These QOL assessments include the EORTC QLQ-C30 & GI.NET21 questionnaires and the 
subjective global assessment of symptoms associated with carcinoid syndrome (CS).   
Modifications have also been made to: (1) update the Schedule of Events to reflect additional 
visits required for patients who elect to extend the Treatment Period to 31 March 2016; and (2) 
revise the maximum amount of blood to be collected from patients who attend the additional 
visits.  
The following administrative changes have also been made: 
 Document versioning has been updated to reflect the new amendment number and date 
 The Table of Contents has been updated as appropriate 
In response to these changes, the following sections have been revised as follows (changes are 
indicated in italics):  
1. SYNOPSIS – Secondary Objective, page 3 – This section was modified to reflect that 
patient reported QOL data will be collected and evaluated through Week 84.  The 
revised section now reads: 
“To evaluate changes in patients’ quality of life (QOL) through Week 84” 
2. SYNOPSIS – Duration of Participation, page 4 – This section has been modified to 
reflect the minimum study duration of 86 weeks for all patients and the optional 
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Protocol No.  LX1606.302 A3 
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Page 3 of 6
extended Treatment Period for patients who are scheduled to complete the 
Treatment Period prior to 31 March 2016. The revised section now reads: 
“All patients will participate for at least 86 weeks including Treatment and Follow-up. Patients 
who are scheduled to complete the Treatment Period prior to 31 March 2016 will have the 
option to extend the Treatment Period until 31 March 2016.” 
3. STUDY OBJECTIVES – Secondary Objective(s), Section 4.1.2, page 13 – This
section was modified to reflect that patient reported QOL data will be collected and
evaluated through Week 84.  The revised section now reads:
“The secondary objective of this study is to evaluate changes in patients’ QOL through Week 84.” 
4. INVESTIGATIONAL PLAN – Overall Study Design, Section 5.1, page 21 – This
section was revised to reflect the minimum treatment duration of 84 weeks for all
patients and the option for patients who are scheduled to complete the Treatment
Period prior to 31 March 2016 to continue to receive study drug until 31 March
2016.  The paragraph describing the patients’ completion of a Follow-up Period was
moved to immediately follow the inserted text.  The following paragraph has been
inserted, followed by the relocated paragraph:
“All patients will receive telotristat etiprate for at least 84 weeks. However, patients who will 
complete 84 weeks of treatment prior to 31 March 2016 may continue to receive telotristat 
etiprate in the trial until 31 March 2016. 
Upon completion or early withdrawal from treatment, all patients will be required to complete a 
14-day Follow-up Period, during which no study drug will be administered.” 
5. STUDY PROCEDURES – Subjective Global Assessment, Section 8.2.1.2, page 26 –
This section was revised to reference Appendix A – Schedule of Events, which
reflects that the Subjective Global Assessment will be conducted through Week 84.
The following paragraph now reads:
“A subjective global assessment of symptoms associated with CS will be evaluated using 
2 methods at each visit as indicated in Appendix A.” 
6. STATISTICAL METHODOLOGY – Efficacy Endpoints, Section 10.3.1, page 38 –
This section was revised to more precisely reflect the study period over which
patient reported QOL data will be evaluated.  The following paragraph now reads:
“Secondary efficacy endpoint is to evaluate changes in patients’ QOL over 84 weeks of therapy.” 
7. APPENDIX A – Schedule of Events, Section 13, page 45 – The Schedule of Events
has been updated to reflect the following changes:
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
Addition of Optional Extension Week 96 and Week 108 for patients scheduled to complete
84 weeks of participation in the study prior to 31 March 2016

Dispensation of LX1606 at Week 84 and Optional Extension Week 96

Update footnote to reflect new Optional Extension visits
Changes are indicated by highlighted cells in ‘Revised Appendix A – Schedule of Events’ table 
below. 
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Protocol No.  LX1606.302 A3 
 
06 May 2015 
 
CONFIDENTIAL 
 
 
 
 
 
Page 5 of 6 
Revised Appendix A – Schedule of Events  
 
Baseline Day 
11
Week 12
Week 24
Week 36
Week 48
Week 60
Week 72
Week 84 / 
EOS
Week 966
Week 1086
Tolerance (days)
NA
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
Inclusion/Exclusion criteria
X
Medical history
X
Physical examination incl. weight
X
X3
X3
X3
X
X3
X3
X
X3
X3
 X5
Urine pregnancy test2
X
X
X
X
X
X
X
X
X
X
X
Hematology, Blood chemistry
X
X
X
X
X
X
X
X
X
X
 X5
Urinalysis
X
X
X
 X5
Chromogranin A
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
 X5
Subjective Global Assessment
X
X
X
X
X
X
X
X
X
EORTC QLQ-C30 & GI.NET21
X
X
X
X
X
Sleep and Depression Assessment
X
X
X
X
X
X
X
X
X
X
X
Plasma 5-HIAA
X
X
X
X
X
X
X
X
X
X
X
Dispensation of LX1606
X
X
X
X
X
X
X
X
X
 
 
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
Optional Extension
2-Week Follow-up4
1Eligibility will be determined at last visit of the original protocol; Day 1 will replace the next scheduled visit in the original protocol schedule. Visits should coincide with LAR injections 
for those patients receiving SSA therapy. 2Females of child-bearing potential only. 3Brief physical examination only (symptom-oriented, including weight). 4Visit to be performed for 
subjects who withdraw early and will not return for a 2-week follow-up visit; in all other cases the EOS visit should be performed followed by the follow-up visit 2 weeks postdose. 5To be 
performed only if evaluation at Week 84/EOS is abnormal. 6Week 96 and Week 108 visits may be performed up until 31 March 2016 for patients who would otherwise complete 84 weeks of 
treatment in the study prior to 31 March 2016.
Procedure
Extension Period
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Protocol No.  LX1606.302 A3 
 
06 May 2015 
 
CONFIDENTIAL 
 
 
 
 
 
Page 6 of 6 
8. Appendix B – Amount of Blood to be Collected from Each Patient, Section 14, page 46 – This section has been modified 
to reflect estimated volume of blood collected based upon changes reflected in Appendix A. Changes are indicated by 
highlighted cells. The revised table now reads:  
Safety
Hematology
2
11
22
Blood chemistry
6
11
66
Other
CgA
2
3
6
Pharmacodynamic Plasma 5-HIAA
4
11
44
138
*Maximum number of samples is indicated
Total 
Assessment
Sample volume (mL)
Number of samples*
Estimated total volume (mL)
 
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CLINICAL STUDY PROTOCOL 
Protocol Number: 
LX1606.1-302-CS 
LX1606.302 (Abbreviated number) 
EudraCT Number 
2013-002596-18 
Investigational Phase: 
3 
Protocol Title: 
A Multicenter, Long-term Extension Study to Further 
Evaluate the Safety and Tolerability of Telotristat Etiprate 
(LX1606) 
Study Name: 
TELEPATH (Telotristat Etiprate – Expanded Treatment 
for Patients with Carcinoid Syndrome) 
Amendment 2 Date: 
08 October 2014 
Amendment 1 Date: 
31 January 2014 
Original Version Date: 
14 June 2013 
Sponsor: 
Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Place 
The Woodlands, TX 77381-1160 
Telephone: 001 (281) 863-3000 
Safety Hotline: 001 (877) 372-3597 
Safety Data Facsimile: 001 (832) 442-5917 
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Page 3 of 57 
1. 
Synopsis 
Name of Study Drug 
Telotristat etiprate 
Protocol Number 
LX1606.1-302-CS 
LX1606.302 (Abbreviated number) 
Protocol Title  
 
A Multicenter, Long-term Extension Study to Further Evaluate the 
Safety and Tolerability of Telotristat Etiprate (LX1606) 
Primary Objective 
The primary objective of this study is to evaluate the long-term 
safety and tolerability of orally administered telotristat etiprate   
Secondary Objective 
To evaluate long-term changes in patients’ quality of life (QOL)  
Phase of Development 
3 
Methodology 
 
The study will be conducted as a multicenter, open-label, long-term 
extension study to further evaluate long-term safety and tolerability 
of telotristat etiprate. 
Patients currently participating in any LX1606 Phase 2 carcinoid 
syndrome (CS) study may enter into this extension study upon 
institutional or local approval of the protocol. Patients participating 
in a Phase 3 CS study may enter into this extension study at the 
Week 48 visit. All patients who enter into this extension study will 
be exempt from any follow-up visit required by the original study 
and will not experience an interruption in study drug due to the 
transition from the original study to LX1060.1-302-CS. 
Following confirmation of eligibility, patients will complete a series 
of visit assessments in order to establish Baseline symptoms. 
Patients will then continue on open-label study drug at the same dose 
level and regimen as identified in their original study.  
Downward dose adjustment will be permitted during the study if 
evidence of intolerability emerges. Patients who experience 
intolerability at the 250 mg tid dose level must be discontinued from 
the study. Patients may return to the previous dosing at the discretion 
of the Investigator and in consultation with the Medical Monitor. 
Upon completion or early withdrawal from treatment, all patients 
will be required to complete a 14-day Follow-up Period, during 
which no study drug will be administered.  
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A Data Safety Monitoring Board (DSMB) will review safety data 
quarterly throughout the study.  
Number of Patients 
Up to 100 patients are expected to participate in this study.  
Patients 
Eligible patients are defined as those that are currently participating 
in a Phase 2 or Phase 3 telotristat etiprate carcinoid syndrome study. 
Number of Study Sites 
Approximately 70 sites 
Treatments 
Telotristat etiprate, 250-mg tablet, administered at the same dose 
level and regimen identified in the patient’s original study 
Route of Administration 
Oral 
Duration of Participation 
Up to 86 weeks including Treatment and Follow-up 
Inclusion Criteria 
Patients must meet all of the following criteria to be considered 
eligible to participate in the study: 
1. Ongoing participation in a Phase 2 (eg, LX1606.1-202-CS, 
LX1606.1-203-CS) or Phase 3 (eg, LX1606.1-301-CS, 
LX1606.1-303-CS) study 
2. Patients of childbearing potential must agree to use an adequate 
method of contraception (defined as having a failure rate of <1% 
per year) during the study and for 12 weeks after the Follow-up 
visit. Adequate methods of contraception for patients or partner 
include condoms with spermicide gel, diaphragm with 
spermicide gel, coil (intrauterine device), surgical sterilization, 
vasectomy, oral contraceptive pill, depot progesterone injections, 
progesterone implant, and abstinence during the study and for 12 
weeks after the Follow-up Visit. 
a. Childbearing potential is defined as those who have not 
undergone surgical sterilization, or those who are not 
considered postmenopausal. Postmenopause is defined as 
absence of menstruation for at least 2 years. If necessary, 
follicle-stimulating hormone (FSH) results >50 IU/L at entry 
are confirmatory in the absence of a clear postmenopausal 
history. 
3. Ability and willingness to provide written informed consent 
prior to participation in any study-related procedure 
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Protocol No. LX1606.302 
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Exclusion Criteria 
Patients who meet any of the following criteria will be excluded 
from participating in the study:   
1. Major protocol violations or telotristat etiprate tolerability 
concerns in a Phase 2 (eg, LX1606.1-202-CS, LX1606.1-203-
CS) or Phase 3 (eg, LX1606.1-301-CS, LX1606.1-303-CS) 
study 
2. Positive pregnancy test 
3. Presence of any clinically significant findings at entry for 
medical history, laboratory values, or physical examination 
(relative to patient population) that, in the Investigator’s or 
Medical Monitor’s opinion, would compromise patient safety or 
the outcome of the study 
4. Patients who are currently committed to an institution by virtue 
of an order issued either by judicial or administrative authorities 
Statistical Methods 
Descriptive analysis methods will be used to summarize the data. 
Continuous variables will be summarized by the N, mean, standard 
deviation, median, minimum, and maximum values. Categorical 
variables will be summarized as counts and related percentages. Data 
tabulations will be categorized by the treatment received on Day 1 of 
this study and combined across all treated patients. Primary analyses 
of the data will be based on the Safety population which includes all 
patients treated on Day 1 of this study. Supportive analyses of the 
efficacy data will be made on a Per Protocol population.  
Data will be summarized per study visit as the actual (raw) outcomes 
and change from Baseline scores, where applicable. Day 1 of this 
study will serve as the Baseline assessment.  
Study Assessments 
Safety 
Safety assessments include monitoring of adverse events, clinical 
laboratory tests, vital signs measurements, 12-lead ECG, and 
physical examinations 
Efficacy 
Efficacy assessments will include patient reported quality of life 
measures as captured in the European Organization for Research and 
Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-
C30 and the module specific for gastrointestinal symptoms of 
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carcinoid neuroendocrine tumors (GI.NET21) and subjective global 
assessment of symptoms associated with CS 
Pharmacodynamics 
Pharmacodynamic (PD) assessments include determination of 5-
HIAA levels in plasma 
Efficacy Data Analysis 
 
All efficacy and PD variables will be summarized descriptively and 
listed. 
Statistical tests and estimates of within patient effects for the 
efficacy and PD measures will be derived from application of a 
mixed linear model with repeated measures. The form of the model 
will be specific to measurement properties of the dependent variable. 
Non-parametric methods will be used to supplement the tests and 
estimates from the mixed linear model. 
Exploratory analyses of treatment group differences may be 
performed by use of propensity score models. The treatments groups 
will correspond to patients’ telotristat etiprate dose level on Day 1 of 
this study.  
Safety Data Analysis 
 
Statistical analysis of the safety data will involve examination of the 
descriptive statistics and individual patient listings for any effects of 
study treatment on clinical tolerability and safety. Reporting of these 
data will be based on the Safety population. Summaries will be 
prepared by treatment group, and as needed, by study visit. 
Treatment-emergent adverse event summaries will include the 
overall incidence (by system organ class and preferred term), events 
by maximum intensity, event by relationship to study treatment, 
events leading to discontinuation of study drug, and serious adverse 
events. 
Vital signs, ECG, and laboratory parameters (hematology, chemistry, 
and urinalysis) will be summarized descriptively at each time point. 
Actual and change from Baseline data will be calculated and 
summarized. In addition, shift table analysis will be applied to the 
laboratory data. 
 
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Table of Contents 
1. 
Synopsis .............................................................................................................................. 3 
2. 
List of Abbreviations and Definitions of Terms ............................................................... 10 
Definitions of Terms ................................................................................................................ 11 
3. 
Introduction ...................................................................................................................... 13 
3.1 
Background on Telotristat Etiprate (LX1606) and Disease ................................ 13 
3.2 
Clinical Trials of Telotristat Etiprate (LX1606) in Humans ............................... 14 
3.2.1 
Phase 1 Studies .............................................................................. 14 
3.2.2 
Phase 2 Studies .............................................................................. 16 
3.2.3 
Ongoing Studies ............................................................................. 17 
3.3 
Rationale for Current Study ................................................................................ 18 
3.3.1 
Rationale for Selection of Dose ..................................................... 18 
3.3.2 
Benefit/Risk Assessment ................................................................ 18 
3.4 
Rationale for Study Design and Control Groups ................................................ 19 
4. 
Study Objectives ............................................................................................................... 20 
4.1 
Efficacy Objectives ............................................................................................. 20 
4.1.1 
Primary Objective .......................................................................... 20 
4.1.2 
Secondary Objective(s) .................................................................. 20 
4.2 
Safety Objectives ................................................................................................ 20 
5. 
Investigational Plan .......................................................................................................... 20 
5.1 
Overall Study Design .......................................................................................... 20 
6. 
Study Population .............................................................................................................. 21 
6.1 
Inclusion Criteria ................................................................................................ 21 
6.2 
Exclusion Criteria ............................................................................................... 22 
6.3 
Criteria for Stopping Treatment/Study Withdrawal ............................................ 22 
6.4 
Criteria for Termination of the Study .................................................................. 23 
6.5 
Clinical Stopping Rules ...................................................................................... 23 
6.6 
Method of Assigning Patients to Treatment ........................................................ 24 
6.7 
Blinding and Unblinding of Study Medication ................................................... 24 
6.8 
Replacement of Patients ...................................................................................... 24 
7. 
Treatment .......................................................................................................................... 24 
7.1.1 
Telotristat Etiprate (LX1606) ......................................................... 24 
7.1.1.1 
Identity ......................................................................... 24 
7.1.1.2 
Packaging, Labeling, and Storage ................................ 24 
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7.2 
Prior and Concomitant Medications ................................................................... 24 
7.2.1 
Prior Medications ........................................................................... 24 
7.2.2 
Concomitant Medications .............................................................. 25 
7.2.3 
Prohibited Medications or Concomitant Therapy .......................... 25 
7.3 
Administration of Study Medication .................................................................. 25 
7.3.1 
Treatment Compliance ................................................................... 25 
7.4 
Dose Adjustment ................................................................................................. 26 
8. 
Study Procedures .............................................................................................................. 26 
8.1 
Restrictions during Study .................................................................................... 26 
8.2 
Description of Study Assessments ...................................................................... 26 
8.2.1 
Efficacy Assessments ..................................................................... 26 
8.2.1.1 
EORTC QLQ-C30 & GI.NET21 ................................. 26 
8.2.1.2 
Subjective Global Assessment ..................................... 26 
8.2.2 
Clinical Laboratory Assessment .................................................... 27 
8.2.2.1 
Monitoring Hepatic Function ....................................... 27 
8.2.3 
Pharmacodynamic Assessments..................................................... 28 
8.2.3.1 
Plasma 5-HIAA ............................................................ 28 
8.2.4 
Safety Assessments ........................................................................ 28 
8.2.4.1 
Vital Sign Measurements ............................................. 29 
8.2.4.2 
Physical Examinations ................................................. 29 
8.2.4.3 
Electrocardiograms ...................................................... 29 
8.2.4.4 
Adverse Events of Special Interest .............................. 29 
8.2.4.4.1 
Central Nervous System Events ............... 30 
8.2.4.4.1.1 Depression Detection .......... 30 
8.3 
Other Assessments .............................................................................................. 30 
8.3.1 
Chromogranin A (CgA).................................................................. 30 
8.3.2 
Disease Progression ....................................................................... 30 
8.3.3 
Quality of Sleep Assessment .......................................................... 30 
8.4 
Appropriateness of Assessments ......................................................................... 30 
8.4.1 
Blood Collection ............................................................................ 31 
9. 
Safety Reporting ............................................................................................................... 31 
9.1 
Adverse Events ................................................................................................... 32 
9.2 
Serious Adverse Events (SAEs) .......................................................................... 34 
9.2.1 
Hospitalization as an SAE ............................................................. 36 
9.3 
Suspected Unexpected Serious Adverse Reactions (SUSARs) .......................... 36 
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9.4 
Precautions .......................................................................................................... 37 
9.4.1 
Pregnancy ....................................................................................... 37 
10. Statistical Methodology .................................................................................................... 37 
10.1 
Determination of Sample Size ............................................................................ 37 
10.2 
Analysis Populations ........................................................................................... 38 
10.3 
Study Endpoints .................................................................................................. 38 
10.3.1 
Efficacy Endpoints ......................................................................... 38 
10.3.2 
Safety Endpoints ............................................................................ 38 
10.4 
Statistical Methods .............................................................................................. 38 
10.4.1 
Efficacy Analyses ........................................................................... 39 
10.4.2 
Safety Analyses .............................................................................. 39 
10.4.2.1 
Adverse Events ............................................................ 39 
10.4.2.2 
Clinical Laboratory Parameters ................................... 40 
10.4.2.3 
Vital Sign Measurements ............................................. 40 
10.4.2.4 
Electrocardiograms ...................................................... 40 
10.4.3 
Pharmacodynamic Analyses .......................................................... 40 
10.4.4 
Baseline Characteristics and Other Summaries ............................. 40 
10.4.5 
Interim Analysis ............................................................................. 41 
11. Study Management ........................................................................................................... 41 
11.1 
Monitoring .......................................................................................................... 41 
11.2 
Audits and Inspections ........................................................................................ 42 
11.3 
Amendments ....................................................................................................... 42 
11.4 
Record Keeping .................................................................................................. 42 
11.4.1 
Drug Accountability ....................................................................... 42 
11.4.2 
Health Insurance Portability Accountability Act of 1996 and 
Subsequent Updates ....................................................................... 43 
11.4.3 
Financial Disclosure....................................................................... 43 
11.4.4 
Access to Original Records ............................................................ 43 
11.4.5 
Retention of Study Documents ...................................................... 43 
12. Administrative Structure of the Study .............................................................................. 44 
13. Appendix A – Schedule of Events .................................................................................... 45 
14. Appendix B – Amount of Blood to be Collected from Each Patient ............................... 46 
15. Appendix C – EORTC QLQ-C30 .................................................................................... 47 
16. Appendix D – EORTC QLQ - GI.NET21 ........................................................................ 49 
17. Appendix E – Ethical Standards ....................................................................................... 50 
18. Appendix F – Investigator Obligations ............................................................................ 52 
19. References ........................................................................................................................ 57 
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2. 
List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
5-HIAA 
5-hydroxyindoleacetic acid 
5-HT 
serotonin 
AE 
adverse event 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
ALP 
alkaline phosphatase 
AST 
aspartate transaminase 
bid 
twice daily 
BM 
bowel movements 
BMI 
body mass index 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CgA 
chromogranin A 
CNS 
central nervous system 
CRF 
case report form 
CRO 
contract research organization 
CS 
carcinoid syndrome 
CT 
computed tomography 
DSMB 
Data Safety Monitoring Board 
EC 
enterochromaffin 
ECG 
electrocardiogram 
ERC 
Ethic Review Committee 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HEENT 
head, eyes, ears, nose, and throat 
Hgb 
hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
IBD 
inflammatory bowel disease 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
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Abbreviation 
Definition 
Continued on the next page 
 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IMP 
Investigational Medicinal Product 
IWRS 
interactive web response system 
LAR 
long-acting release 
LS 
least square 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCP 
multiple comparison procedure 
MRI 
magnetic resonance imaging 
NET 
neuroendocrine tumor 
NRS 
numeric rating scale 
OOR 
out-of-range 
OTC 
over-the-counter 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
qd 
once daily 
SAE 
serious adverse event 
SBS 
short bowel syndrome 
SOP 
standard operating procedure 
SSA 
somatostatin analog 
SUSAR 
suspected unexpected serious adverse reactions 
TEAE 
treatment-emergent adverse events 
tid 
3 times daily 
TPH 
tryptophan hydroxylase 
ULN 
upper limit of the normal reference range 
WRS 
Wilcoxon rank sum 
Definitions of Terms  
Term 
Definition 
LP-778902 
active moiety of LX1606 
LX1606 
telotristat ethyl: the ethyl-ester prodrug of the active moiety LP-
778902; a serotonin synthesis inhibitor being developed by Lexicon 
Pharmaceuticals, Inc. 
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Term 
Definition 
QTcF 
corrected QT interval using Fredericia’s formula 
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3. 
Introduction 
3.1 
Background on Telotristat Etiprate (LX1606) and Disease 
Serotonin (5-HT) plays a critical role in regulating several major physiological processes of 
the gastrointestinal tract, including aspects of secretion, motility, inflammation and sensation. 
Enterochromaffin (EC) cells release 5-HT when the intestinal wall is stimulated by 
intraluminal pressure or chemicals. Through multiple classes of receptors, 5-HT is believed to 
initiate directly, or facilitate, peristaltic and secretory reflexes. 5-HT is also reportedly 
involved in the pathophysiology of various types of functional gastrointestinal (GI) disorders, 
valvular heart disease, and may play a role in the pathophysiology of inflammatory bowel 
disease (IBD).  
Carcinoid tumors are mostly derived from EC cells of the midgut, and often produce and 
release large amounts of 5-HT. Such excess of 5-HT is believed to be responsible for the 
severe diarrhea and eventual valvular heart damage and mesenteric fibrosis in patients with 
carcinoid syndrome (CS).1-3 Inhibition of tryptophan hydroxylase (TPH) activity in carcinoid 
tumors should lead to a reduction of peripheral 5-HT in afflicted patients and thus an 
amelioration of the pathophysiology and symptomology of CS. A peripheral TPH inhibitor, 
such as telotristat etiprate, should alleviate the symptoms due to excess 5-HT in carcinoid 
patients without central nervous system (CNS)-related adverse events (AEs). 
Approximately 90% of the body's 5-HT is found in the EC cells of the GI tract, with the 
remainder distributed between the platelets and CNS.4 TPH catalyzes the biopterin-dependent 
monooxygenation of tryptophan to 5-hydroxytryptophan, which is subsequently 
decarboxylated to form 5-HT. Expression of TPH is limited to a few specialized tissues:  
raphe neurons, pinealocytes, mast cells, mononuclear leukocytes, beta cells of the islets of 
Langerhans, and intestinal and pancreatic EC cells.5 Two isoforms of the enzyme exist, TPH1 
and TPH2. TPH1 is exclusively located in the EC cells of the GI tract and pineal gland and is 
the rate limiting enzyme responsible for the majority of systemic 5-HT production and is also 
responsible for 5-HT synthesis in carcinoid tumors. TPH2 is located in the central and enteric 
nervous systems and is the rate-limiting enzyme in the production of neuronal 5-HT. 
The oral TPH inhibitor, telotristat etiprate, represents a novel approach to potentially lessen 
the pathophysiology of CS by reducing 5-HT levels via inhibition of TPH. Telotristat etiprate 
was designed specifically as a prodrug in order to gain greater systemic exposure, opening 
the potential application for indications in which hyperserotonemia is thought to contribute to 
the disorder, such as CS. Preclinical pharmacology studies of telotristat etiprate were 
designed to evaluate the compound’s mechanism of action and effects in vivo. Telotristat 
etiprate is the ethyl-ester prodrug of the active moiety LP-778902. Telotristat etiprate was 
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designed as a prodrug in order to enhance peripheral exposure without crossing the blood-
brain barrier. In vivo, telotristat etiprate is readily converted through esterase activity to its 
corresponding acid, LP-778902. LP-778902 has an in vitro potency of 0.028 μM on purified 
human TPH1 enzyme and 0.032 μM on purified human TPH2 enzyme. Therefore, telotristat 
etiprate is a robust inhibitor of TPH both in vitro and in vivo and has been shown in Phase 2 
studies to provide clinical benefit to patients with carcinoid tumors and associated CS.  
Telotristat etiprate is being developed to manage GI symptoms and possibly other symptoms 
associated with CS. Currently, the standard of care for patients with CS is symptom 
management using somatostatin analogs (SSA), which are available in both short- and long-
acting release (LAR) formulations. Somatostatin analogs such as octreotide are indicated for 
the control of flushing, diarrhea, and other symptoms associated with CS. Common side 
effects of the long-acting depot form of the drug are pain at the site of the injection, reported 
in as many as 30 to 50% of carcinoid patients at the 20 and 30 mg dose levels, and less 
commonly, stomach cramps, nausea, vomiting, headaches, dizziness, and fatigue.6 Other side 
effects identified in the product labeling include biliary tract abnormalities (gallstones, 
sludge, and dilatation), hypothyroidism, dietary fat malabsorption, and hyper or 
hypoglycemia.7 In addition to the morbidity associated with parenterally administered agents, 
tachyphylaxis will occur in the majority of patients, resulting in recurrent symptoms. 
There are currently no specific oral treatments indicated for the management of symptoms 
associated with CS. As a result of the morbidity associated with SSAs and the associated 
tachyphylaxis, there is an unmet medical need to provide symptom management and modify 
the pathophysiology of patients with metastatic CS. Inhibition of the excessive 5-HT 
produced by these tumors with an orally delivered agent such as telotristat etiprate could 
provide significant benefit as an additional treatment option for patients and clinicians.  
3.2 
Clinical Trials of Telotristat Etiprate (LX1606) in Humans 
Telotristat etiprate has been studied in single/multiple doses in Phase 1 studies, approximately 
117 healthy volunteers participated in Phase 1 trials with 96 subjects receiving telotristat 
etiprate and 21 subjects receiving placebo. In addition, 37 patients with CS have received 
telotristat etiprate during the clinical development program in Phase 2.  An additional 59 
patients with ulcerative colitis have been enrolled into an ongoing Phase 2 study to evaluate 
telotristat etiprate versus placebo in patients with ulcerative colitis experiencing active flares. 
3.2.1 
Phase 1 Studies 
LX1606.1-101-NRM utilized telotristat etiprate as a single oral dose and was noted to be safe 
and well tolerated up to doses of 1,000 mg. At doses of ≥1,000 mg, an increase in GI AEs 
was observed, which were assessed as at least possibly related to study drug. These AEs led 
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to a decision not to escalate the dose beyond 1,500 mg. No serious adverse events (SAEs) or 
deaths were reported and no patient discontinued due to an AE. Twenty-three patients 
experienced at least 1 AE. The majority of the AEs were assessed as mild. The most common 
AEs were diarrhea and nausea. Random out-of-range laboratory values at various time points 
in several patients occurred without any apparent trend. There were no other clinically 
significant vital signs, laboratory or physical examination findings.  
LX1606.1-102-NRM utilized telotristat etiprate as multiple oral doses over 14 days and was 
tolerated up to the maximum dose assessed, 500 mg tid; 1,500 mg total dose daily. Most AEs 
were mild, the most common being nausea and headache; all resolved. Most AEs were at 
least possibly related to study treatment. Four AEs required treatment with concomitant 
medication, 3 AEs of constipation and 1 of headache. No deaths or SAEs were reported. One 
patient was discontinued due to an AE of abnormal liver function. There were no apparent 
trends or clinically significant findings observed upon review of vital signs and 
electrocardiogram (ECG) data. There were no clinically significant abnormal physical 
examination findings. 
Overall, in LX1606.1-102-NRM, treatment with telotristat etiprate was associated with mild 
elevations, generally ≤2x the upper limit of normal (ULN), in alanine transaminase (ALT) 
and aspartate transaminase (AST), with elevations in values observed earlier in the higher 
dose cohorts. Results were assessed as clinically significant for only 1 patient, in Cohort 4, 
who was withdrawn on Day 10. The trend was most pronounced in Cohort 5, in which 5 out 
of 6 patients who received telotristat etiprate had increases in ALT values which were above 
normal range and 4 patients had increases in AST values which were above normal range at 
Day 14. Mean increases in ALT and AST appeared earlier in the study for Cohorts 4 and 5 
than in the other cohorts, and were noted for all cohorts by Day 12. All patients had normal 
ALT and AST values at Baseline and most elevated transaminases returned to normal range 
within 48 hours after the last dose of study drug. No changes in alkaline phosphatase (ALP) 
or total bilirubin were observed in any patient. 
LX1606.1-103-NRM evaluated 2 oral formulations of telotristat etiprate in an open-label 
crossover study. Each formulation was given as a single oral dose followed by a 5-day 
washout and then patients were given a single oral dose of the second formulation. During 
this study, there were no deaths or SAEs reported and no AEs lead to discontinuation. The 
most commonly reported AE was diarrhea. No clinically significant observations or changes 
in other safety parameters (eg, clinical laboratory evaluations, vital signs, physical 
examinations, ECGs, and AEs) were identified in the patient population during the study 
conduct. 
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LX1606.1-104-NRM was designed to evaluate the pharmacokinetics, metabolism, and routes 
and extent of elimination of telotristat ethyl and its primary metabolite (LP-778902) in 8 
healthy male subjects after a single oral dose of 500 mg radio-labeled telotristat etiprate 
(14C-LX1606). This study has been completed and the results will be discussed in the annual 
update of the Investigator Brochure. 
3.2.2 
Phase 2 Studies 
LX1606.1-202-CS was a randomized, double-blind, placebo-controlled, multiple ascending 
dose study conducted in 2 parts in order to evaluate a total of 23 patients at a dose range of 
450 to 1500 mg given as 150, 250, 350, or 500 mg tid (telotristat etiprate or matching 
placebo) on a background therapy of octreotide. In Part 1, 16 patients were randomly 
assigned 3:1 into 4 sequential cohorts. Each cohort evaluated 1 of the following daily doses 
given as 150, 250, 350, or 500 mg tid over a course of 4 weeks. During the study, all patients 
continued on a stable-dose background therapy of octreotide. In Part 2, an additional 7 
patients were randomly assigned 3:1 in order to evaluate 500 mg tid, the highest tolerated 
dose as determined in Part 1. Upon completion of the initial 4-week portion, eligible patients 
had the option to continue into an open-label Extension Period. 
There was 1 treatment emergent SAE assessed as possibly related to study drug which 
occurred in the 350 mg tid dose group. The patient had a history of nausea and vomiting and 
was hospitalized for exacerbation of these conditions.  
Telotristat etiprate was generally well tolerated with no evidence of dose-limiting tolerability. 
Adverse events were mostly mild to moderate and with similar frequencies between 
treatment groups and placebo. No significant changes in vital signs, ECG, or physical exam 
findings were noted after administration of telotristat etiprate at any dose level. The most 
common AEs were GI-related and reported as diarrhea, nausea, and abdominal pain, 
respectively. The modest elevations in transaminases seen in the Phase 1 multiple ascending 
dose study (LX1606.1-102-NRM) were not apparent in this 4-week study in patients with CS.  
Patients that received telotristat etiprate achieved a clinical response (28%) defined as at least 
a 30% reduction in bowel movements (BMs) for at least 2 weeks; a biochemical response 
(56%) defined as at least a 50% reduction or normalization of urinary 5-hydroxyindoleacetic 
acid (5-HIAA); and reported adequate relief at Week 4 (46%) while no placebo patients 
experienced clinical response, biochemical response, or adequate relief. 
LX1606.1-203 was an open-label, serial ascending, multiple dose, individual titration study 
that evaluated the same dose ranges as the LX1606.1-202-CS study in a total of 15 patients. 
Patients were serially escalated to the next dose level every 2 weeks until a maximally 
tolerated dose or 500 mg tid was reached. Once a dose had been determined, the patient 
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would remain on the dose for an additional 4 weeks. Patients then had the option to continue 
into an Extension Period.  
Telotristat etiprate was generally safe and well-tolerated in subjects with CS in the 
LX1606.1-203 study. Most AEs were mild to moderate in severity and assessed as unrelated 
to study drug. Events in the Gastrointestinal Disorders system organ class were common, as 
is anticipated with the underlying illness. 
Statistically significant reductions from Baseline in the mean number of BMs/day were 
observed in this study throughout the entire dose-escalation and stable-dose phases, as were 
improvements in stool form. Telotristat etiprate produced an improvement in global 
assessment of GI symptoms associated with CS in the majority of subjects (12 of 15 subjects, 
80%) across the 12-week period. The global assessment of GI symptoms was based on the 
following question, “In the past 7 days, have you had adequate relief of your carcinoid 
syndrome bowel complaints such as diarrhea, urgent need to have a BM, abdominal pain or 
discomfort?” In addition, subjects experienced statistically significant decreases in the mean 
daily number of cutaneous flushing episodes. 
Thirteen subjects (86.7%) experienced a complete biochemical response (defined as a ≥50% 
reduction from Baseline in u5-HIAA levels at 1 or more time points). Consistent with the 
proposed mechanism of action for telotristat etiprate, a complete biochemical response 
correlated closely with measures of clinical response, such as number of bowel movements 
per day. 
LX1606.1-204-UC evaluated patients with active flares of ulcerative colitis. Doses under 
evaluation are 500 mg once daily (qd) and 500 mg tid vs. placebo; 59 patients were enrolled 
for an 8-week treatment period. This study has been completed and the results will be 
discussed in the annual update of the Investigator Brochure. 
Detailed information regarding the completed clinical studies can be found in the Investigator 
Brochure.8 
3.2.3 
Ongoing Studies 
The open-label extension portions in LX1606.1-202-CS and LX1606.1-203-CS remain 
ongoing. 
LX1606.1-301-CS is intended to evaluate patients who are currently on a background of SSA 
therapy and still experiencing breakthrough symptoms such as an increased frequency of 
BMs ≥4 per day on average: (1) the efficacy of telotristat etiprate on reducing the number of 
BMs; (2) the efficacy of telotristat etiprate on a number of clinically relevant secondary 
endpoints; and, (3) the safety of telotristat etiprate over the 12-week double-blind portion 
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(Treatment Period) of the study. Upon completion of the Treatment Period, patients will 
continue into a 36-week open-label Extension Period (Extension Period).  
LX1606.1-303-CS is intended to evaluate patients with carcinoid syndrome whose primary 
symptoms are not GI related and may be naïve to SSA therapy: (1) the safety of telotristat 
etiprate over the 12-week double-blind portion (Treatment Period) of the study; (2) percent 
(%) change from Baseline in 24-hour u5-HIAA levels at Week 12; (3) the effects of telotristat 
etiprate on a number of clinically relevant secondary endpoints. Upon completion of the 
Treatment Period, patients will continue into a 36-week open-label Extension Period. 
3.3 
Rationale for Current Study 
3.3.1 
Rationale for Selection of Dose 
The dose levels of telotristat etiprate selected for this study are consistent with prior clinical 
study experience and based upon clinical safety and pharmacodynamic (PD) data from 2 
Phase 2 multiple ascending-dose studies in patients with symptomatic CS (LX1606.1-202-CS 
and LX1606.1-203-CS).  
Based upon observations noted in Section 3.2, it is anticipated that the doses to be utilized in 
this protocol will be safe and well tolerated and may provide clinical benefit to patients with 
CS. 
3.3.2 
Benefit/Risk Assessment 
Clinical experience with telotristat etiprate (treated subjects) consists of completed single and 
multiple ascending dose studies in 96 normal subjects (44 in single dose studies and 52 in the 
multiple dose study), 2 Phase 2 studies (37 patients with symptomatic CS) and 2 ongoing 
Phase 3 studies in patients with symptomatic CS. 
In healthy volunteer studies, single doses up to 1000 mg were found to be generally well 
tolerated, while at the 1500 mg dose level GI-related adverse events increased. A similar 
adverse event profile was observed after multiple dose administration over 14 days with GI 
events predominating. Mild, dose-dependent increases in hepatic transaminase levels (≤2 x 
ULN) were observed with increased frequency in relation to dose, with 1 subject requiring 
withdrawal from therapy at the 500 mg bid dose level. Most subjects that were observed to 
have increased transaminase levels did not exceed >2 x ULN. No abnormalities in total 
bilirubin were observed at any dose level. GI events have been the most commonly observed 
events to date. The adverse event profile in normal subjects may differ significantly from 
what is observed in patients with hyperserotonemia. All adverse events resolved without 
sequelae. In addition, there were no significant changes in vital signs or ECG. No physical 
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examination abnormalities were noted in studies to date. There were no serious adverse 
events reported in healthy volunteers. 
In patients with CS, dose escalations have proceeded up to and including 500 mg tid. To date, 
there has been no evidence of dose-limiting intolerability. Dose levels have been generally 
well tolerated with no evidence to suggest elevations in hepatic transaminase levels. Based 
upon observations from preclinical and clinical studies conducted to date, it is anticipated that 
orally administered telotristat etiprate will be well tolerated at dose levels required to 
influence peripheral 5-HT production in patients with symptomatic CS. Potential adverse 
events primarily involve the GI tract, and could include alterations in gut motility, nausea, 
vomiting, diarrhea, constipation, abdominal bloating, and/or pain. Regular and ongoing 
clinical and laboratory assessments should detect any of these events, and depending on the 
type of event, further dose adjustment or discontinuation from the trial would occur. Although 
CNS effects are not anticipated at dose levels planned for evaluation, standard adverse event 
questioning and/or physical examination should reveal any subtle CNS findings. As 
elevations in hepatic transaminase levels were observed with multiple dosing in normal 
subjects, monitoring clinical laboratory tests of hepatic function will be incorporated into 
clinical trials conducted in CS patients. 
Treatment has the potential to improve several signs and symptoms of CS. The Phase 2 
clinical trial results indicated that treatment may lead to improvements in BM frequency, 
stool consistency, urgency, abdominal pain, diarrhea, flushing, and reductions in 5-HIAA. 
These potential benefits relate to a unique mechanism of action. Symptomatic improvement 
may lead to a better quality of life (QOL) for patients with few treatment options available, 
and a reduction in serotonin may help reduce the risk of carcinoid heart disease. Overall the 
benefit/risk profile of telotristat etiprate is expected to be favorable for participation in this 
clinical study. 
3.4 
Rationale for Study Design and Control Groups 
Currently, no approved therapy exists for the treatment of symptoms driven by underlying 
serotonin pathophysiology of CS in patients whose disease is refractory to SSA therapy or for 
those patients who are unable to tolerate SSA therapy or who are unwilling to take SSA 
therapy. 
This study will allow for continued access to telotristat etiprate after patients have completed 
the required study visits in ongoing Phase 2 and Phase 3 studies. Continuation of CS patients 
into this study will allow for the collection of additional long-term safety and efficacy data, 
while providing access to patients who may be receiving benefit. The treatment duration is 
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supported by results of chronic toxicology studies (6-month rat and 9-month dog) and the 
current safety profile from completed and ongoing clinical trials. 
4. 
Study Objectives 
4.1 
Efficacy Objectives 
4.1.1 
Primary Objective 
The primary objective of the study is to evaluate the long-term safety and tolerability of 
orally administered telotristat etiprate. 
4.1.2 
Secondary Objective(s) 
The secondary objective of this study is to evaluate changes in patients’ QOL. 
4.2 
Safety Objectives 
Evaluation of overall safety will be assessed as: 
 Incidence of treatment-emergent adverse events (TEAEs) 
 Changes from Baseline in clinical laboratory results, vital signs results, and ECG 
findings 
5. 
Investigational Plan 
5.1 
Overall Study Design 
The study will be conducted as a multicenter, open-label, long-term extension study to further 
evaluate long-term safety and tolerability of telotristat etiprate. 
Patients currently participating in any LX1606 Phase 2 CS study may enter into this 
extension study upon institutional or local approval of the protocol. Patients participating in a 
Phase 3 CS study may enter into this extension study at the Week 48 visit. All patients who 
enter into this extension study will be exempt from any follow-up visit required by the 
original study and will not experience an interruption in study drug due to the transition from 
the original protocol to LX1060.1-302-CS. 
Following confirmation of eligibility, patients will complete a series of visit assessments in 
order to establish Baseline symptoms. Patients will then continue on open-label LX1606 at 
the same dose level identified in the original study.  
Downward dose adjustment will be permitted during the study if evidence of intolerability 
emerges. Patients who experience intolerability at the 250 mg tid dose level must be 
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discontinued from the study. Patients may return to the previous dosing at the discretion of 
the Investigator and in consultation with the Medical Monitor. 
Upon completion or early withdrawal from treatment, all patients will be required to 
complete a 14-day Follow-up Period, during which no study drug will be administered.  
A Data Safety Monitoring Board (DSMB) will review safety data quarterly throughout the 
study.  
6. 
Study Population 
Adult patients who are currently participating in ongoing Phase 2 or Phase 3 telotristat 
etiprate CS clinical protocols will be enrolled into the study. Up to 100 patients are expected 
to enroll in this study. Approximately 70 sites worldwide will participate in the study. Patients 
may continue allowed medications as background therapy provided they remain on stable- 
doses throughout the Treatment Period. 
6.1 
Inclusion Criteria 
Patients must meet all of the following criteria to be considered eligible to participate in the 
study: 
1. Ongoing participation in a Phase 2 (eg, LX1606.1-202-CS, LX1606.1-203-CS) or 
Phase 3 (eg, LX1606.1-301-CS, LX1606.1-303-CS) study  
2. Patients of childbearing potential must agree to use an adequate method of 
contraception (defined as having a failure rate of <1% per year) during the study and 
for 12 weeks after the Follow-up visit. Adequate methods of contraception for 
patients or partner include condoms with spermicide gel, diaphragm with spermicide 
gel, coil (intrauterine device), surgical sterilization, vasectomy, oral contraceptive pill, 
depot progesterone injections, progesterone implant, and abstinence during the study 
and for 12 weeks after the Follow-up Visit.  
a. Childbearing potential is defined as those who have not undergone surgical 
sterilization, or those who are not considered postmenopausal. Postmenopause 
is defined as absence of menstruation for at least 2 years. If necessary, follicle-
stimulating hormone (FSH) results >50 IU/L at Baseline Day 1 are 
confirmatory in the absence of a clear postmenopausal history. 
3. Ability and willingness to provide written informed consent prior to participation in 
any study-related procedure. 
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6.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participating in the 
study:   
1. Major protocol violations or telotristat etiprate tolerability concerns in a Phase 2 (eg, 
LX1606.1-202-CS, LX1606.1-203-CS) or Phase 3 (eg, LX1606.1-301-CS, 
LX1606.1-303-CS) study  
2. Positive pregnancy test 
3. Presence of any clinically significant findings at entry for medical history, laboratory 
values, or physical examination (relative to patient population) that, in the 
Investigator’s or Medical Monitor’s opinion, would compromise patient safety or the 
outcome of the study 
4. Patients who are currently committed to an institution by virtue of an order issued 
either by judicial or administrative authorities 
6.3 
Criteria for Stopping Treatment/Study Withdrawal 
A patient may also be discontinued from the study for the following medical or 
administrative reasons: 
 Withdrawal of consent by the patient or legal guardian 
 Noncompliance, including refusal of the study medication and/or failure to adhere to 
the study requirements as in the study protocol 
 Investigator decides that, in the interest of the patient, it is not medically acceptable to 
continue participation in the study 
 The Sponsor terminates the study (Section 6.4) 
 Pregnancy (Section 9.4.1) 
Note:  If a patients voluntarily withdraws or is discontinued from study treatment before 
completing the entire duration of the Treatment Period, they should be encouraged to 
continue clinic visits according to the study schedule.  
Patients who discontinue study treatment, and who are not willing to continue clinic visits 
(eg, withdrawal of consent) should be encouraged to complete End-of-Study (EOS) 
assessments as identified in Appendix A – Schedule of Events and agree to report any SAEs 
(Section 9.2) that occur within 30 days following the last dose of telotristat etiprate. 
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The date the patient discontinues study treatment, the primary reason for study treatment 
discontinuation, study termination, and/or termination of participation (eg, withdrawal of 
consent), will be captured within the Case Report Form (CRF). 
When patients withdraw consent from study participation, it must be recorded on the CRF 
whether the withdrawal of consent applies to specific aspects of the study such as 
discontinuation of study treatment, participation in study visits, contact by study personnel, or 
access to information about potential SAEs. If specific consent has not been withdrawn, study 
personnel should contact the patient (or a previously approved designee such as a caregiver, 
partner, or family member) at the scheduled Follow-up visit to inquire about health status. 
6.4 
Criteria for Termination of the Study 
If the Sponsor, Investigator, study monitor, DSMB, or regulatory officials discover conditions 
arising during the study that indicate that the patient safety and/or scientific value of the study 
and/or quality of the study drugs have been compromised, the study should be halted or the 
study center’s participation should be terminated. Conditions that may warrant termination of 
the study include, but are not limited to, the following: 
 The discovery of an unexpected, serious, or unacceptable risk to the patients enrolled in 
the study; 
 A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product for carcinoid syndrome or any other indication for any 
reason; 
 Failure of the Investigator to enroll patients into the study at an acceptable rate; 
 Failure of the Investigator to comply with pertinent governing body regulations; 
 Submission of knowingly false information from the research facility to the Sponsor, 
study monitor, medical officer, or regulatory official; and, 
 Insufficient adherence to protocol requirements.  
Study termination and Follow-up would be performed in compliance with applicable 
governing body regulations. 
6.5 
Clinical Stopping Rules 
Criteria for individual patient withdrawal or study termination are summarized in Sections 
6.3 and 6.4, respectively. 
 
 
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6.6 
Method of Assigning Patients to Treatment  
Patients will enter the study at the same dose level and regimen as identified in the prior 
Phase 2 or Phase 3 CS study. Randomization will not be used to assign patients to study 
treatments. 
6.7 
Blinding and Unblinding of Study Medication 
This is an open-label study.  
6.8 
Replacement of Patients 
Patients who do not complete the study will not be replaced. 
7. 
Treatment 
7.1.1 
Telotristat Etiprate (LX1606) 
7.1.1.1 
Identity 
Telotristat etiprate (LX1606 hippurate) is the salt form of the drug substance. LX1606 
hippurate is a crystalline white to off-white to tan solid with a melting point of 147°C. 
LX1606 is insoluble in water within the pH range of 5 to 9 (≤2 mg/L). It undergoes 
hydrolysis under strongly basic or strongly acidic conditions. The solubility of LX1606 
hippurate in water is about 22 mg/L at 25°C. 
Study drug dosage form consists of white coated debossed oval tablets containing 250 mg 
LX1606. 
7.1.1.2 
Packaging, Labeling, and Storage 
Patients will receive 250-mg telotristat etiprate tablets packaged in 100 cc high density 
polyethylene bottles with child-resistant polypropylene screw caps and heat-induction seal 
liners.  
Telotristat etiprate should be stored between 15 to 25°C (59 to 77°F). 
7.2 
Prior and Concomitant Medications 
7.2.1 
Prior Medications 
All medications and other treatments taken by patients within 30 days prior to entry will be 
recorded on the CRF.  
 
 
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7.2.2 
Concomitant Medications 
All concomitant medications taken by patients during the study will be recorded on the CRF. 
Treatment with prescription or over-the-counter (OTC) antidiarrheal therapy, bile acid 
sequestrants, or pancreatic enzyme is permitted; however, the use of these concomitant 
therapies should be associated with a documented history of disease (eg, fat malabsorption, 
bile acid malabsorption, or steatorrhea).  
 Medical management of patients and their concomitant medications is allowed at the 
discretion of the Investigator. However, should the need arise to modify/adjust a patient’s 
therapy due to a concern for patient safety and/or tolerability the Medical Monitor should be 
contacted. The Investigator and Medical Monitor will make a determination if such a change 
would impact the safety of the patient and the integrity of the study. The Medical Monitor 
will determine if the patient can continue in the study. 
7.2.3 
Prohibited Medications or Concomitant Therapy 
None 
7.3 
Administration of Study Medication 
All patients will be instructed to take the study medication with food. “With food” means 
taking telotristat etiprate tablets within 15 minutes before or within 1 hour after a meal or 
snack. Patients will be instructed to take study drug 3 times daily during waking hours, with 
doses spaced approximately 6 hours apart.  
Study medication and instructions will be dispensed to patients at each visit as described in 
the schedule of study procedures (Appendix A). 
7.3.1 
Treatment Compliance  
Patients will be asked to bring their unused or unopened study medication to each visit 
(Appendix A). At each visit and in the presence of the patient, study site personnel will count 
returned tablets and reconcile the counts against planned number of doses for that interval. 
Site personnel will clarify any discrepancy and record this information within the CRF.  
Patients must maintain at least 75% compliance in dosing to be deemed as compliant. In the 
event of a missed or vomited dose, patients will take their subsequent dose of study drug at 
the next scheduled time point, following the tid dosing regimen of approximately every 6 
hours. A dose outside of a 3-hour window should be considered missed. Missed or vomited 
doses will not be made up.  
 
 
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7.4 
Dose Adjustment 
Downward dose adjustment of telotristat etiprate will be permitted if evidence of 
intolerability emerges. After a period at the lowered dose level, patients may resume the 
previous dosing level at the discretion of the Investigator after consultation with the Medical 
Monitor. Patients who experience intolerability at the 250 mg tid dose level must be 
discontinued from study treatment. Interruptions or delays in dosing throughout the entire 
study may be permitted after consultation with the Medical Monitor, at which time the patient 
will be reassessed for study continuation, dosage reduction, or discontinuation. 
8. 
Study Procedures 
A schedule of study assessments is provided in Appendix A. 
8.1 
Restrictions during Study 
Patients should be advised to avoid food and drink containing grapefruit for 2-3 hours prior to 
and following dosing while participating in the study. 
8.2 
Description of Study Assessments 
8.2.1 
Efficacy Assessments 
Efficacy assessments include the patient reported QOL measures; EORTC QLQ-C30 
(Appendix D) & GI.NET21 (Appendix E) questionnaires and subjective global assessment of 
symptoms associated with CS. 
A description of the efficacy assessments is provided below. 
8.2.1.1 
EORTC QLQ-C30 & GI.NET21 
Patients will complete the questionnaires during each visit as indicated in Appendix A. 
8.2.1.2 
Subjective Global Assessment 
A subjective global assessment of symptoms associated with CS will be evaluated using 2 
methods at each visit.  
Patients will first be asked to respond to the following question:  “In the past 7 days, have 
you had adequate relief of your carcinoid syndrome bowel complaints such as diarrhea, 
urgent need to have a bowel movement, abdominal pain, or discomfort?”. 
Then patients will be asked the following question to assess global symptoms associated with 
CS on an 11-point scale: “Rate the severity of your overall carcinoid symptoms over the past 
7 days on a scale from 0-10, where 0 = no symptoms and 10 = worst symptoms ever 
experienced.” 
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8.2.2 
Clinical Laboratory Assessment  
Clinical laboratory assessments will consist of hematology (complete blood count [CBC] 
with differential and platelet counts), blood chemistry (complete metabolic panel and liver 
function tests), and urinalysis. All laboratory tests will be performed by a central laboratory, 
with the exception of the urine pregnancy test, which will be performed by the study site with 
the provided laboratory kit.  
The incidence of clinically significant laboratory values, as well as clinically significant shifts 
in laboratory values, should be reported as an AE in the patient’s CRF (see also Section 9.1 
for reporting of AEs related to laboratory abnormalities). The Investigator will assess any 
clinically significant values relevant to the patient population to determine if termination of 
the study drug is required. 
8.2.2.1 
Monitoring Hepatic Function 
Patients with clinically significant abnormalities in liver function tests should be excluded 
from participating; however, the patient’s clinical situation as a whole should be taken into 
account when evaluating hepatic transaminase elevations, which may represent a 
consequence of the underlying disease and/or therapeutic interventions. Patients with 
abnormalities in liver function test results, as defined below, should be further assessed by the 
Investigator and may have additional tests performed by the central laboratory as clinically 
indicated. The following describes the Sponsor’s recommended approach to evaluating these 
events. This approach is not meant to replace the Investigator’s clinical judgment.  
These guidelines apply to the following events: 
1) A new confirmed result (after Day 1 dosing) of ALT or AST >3 x ULN (in 
patients previously within normal range) 
OR 
2) A confirmed increase in transaminases above the patient’s previous Baseline to a 
degree that is significant in the clinical judgment of the Investigator and ALT or 
AST >3 x ULN (in patients with previous abnormal liver-test results) 
OR 
3) Any occurrence of an elevation of ALT or AST >3 x ULN and total bilirubin >2 x 
ULN (in any patient) 
For any such event, the Investigator should discuss the Follow-up approach with the Medical 
Monitor.  
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The Sponsor’s recommended approach is as follows: 
1. Schedule the patient for a Follow-up visit within 3 days following the receipt of 
laboratory results to assess the patient and conduct further evaluation, to include the 
following: 
a. Obtain repeat testing of ALT, AST, total bilirubin, and ALP through the central 
laboratory. 
b. Reassess the patient through patient interview and physical examination to 
uncover new or emerging risk factors of liver injury including an increased use 
of alcohol, gallbladder disease, hemochromatosis, fatty liver, use of 
hepatotoxic concomitant medications (including acetaminophen), occupational 
exposures, liver metastases, and other causes for potential clues as to the 
underlying etiology of the event. 
c. Continue to monitor the patient’s transaminases and total bilirubin regularly 
until the liver function test values return to Baseline levels.  
Additional recommendations include: 
 Consider referral to a hepatologist or gastroenterologist 
 Consider reimaging (eg, ultrasound, CT, or MRI) the liver and biliary tract 
 Consider additional laboratory testing as clinically indicated. Laboratory assays 
available to the Investigator for further workup are described in the laboratory manual 
Upon completion of hepatic assessment, the Investigator should review results with the 
Medical Monitor and assess continued study participation. 
8.2.3 
Pharmacodynamic Assessments 
8.2.3.1 
Plasma 5-HIAA 
Fasting blood samples (≥6 hours) for measurement of 5-HIAA in plasma will be collected 
and analyzed by a specialty laboratory. All sample processing information will be supplied by 
the laboratory in a separate document/study manual. Efforts should be made to schedule these 
visits in the morning, with instructions to the patient to arrive in a fasted state and not dose 
prior to the blood draw. 
8.2.4 
Safety Assessments 
In addition to the clinical laboratory assessments described in Section 8.2.2, monitoring of 
AEs is also considered a safety assessment and is described in detail in Section 9. Clinically 
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significant changes compared with Baseline findings for these variables should be reported as 
AEs on the CRF. Clinically significant changes compared with Baseline values, which are 
determined to be AEs, should be followed until the event has resolved, the condition has 
stabilized, etiology of the event is determined to be not related to study drug, or the patient is 
lost to Follow-up. 
8.2.4.1 
Vital Sign Measurements 
Measurement of vital signs will include assessment of blood pressure, respiratory rate, pulse 
rate, and oral temperature. Vital sign measurements should not be conducted with the 
30 minutes immediately following any phlebotomy. 
Efforts should be made to standardize blood pressure collection across all patients and visits. 
Patients should be seated for at least 5 minutes prior to collection. All measurements should 
be assessed on the same arm, and by the same technician where possible. 
Additional measurements may be obtained if clinically indicated. Vital sign measurements 
will be measured as indicated in Appendix A. 
8.2.4.2 
Physical Examinations 
Complete physical examinations will be performed as outlined in Appendix A. Complete 
physical examinations will include a minimum of a review of the patient’s general 
appearance, head, eyes, ears, nose, and throat (HEENT), neck, heart, lungs, abdomen, back 
and extremities, skin, and general neurological system.  
Symptom-oriented physical examinations will be performed at all other time points and as 
clinically indicated.  
In addition, weight will be captured during each physical examination. Efforts should be 
made to standardize weight collection across all patients and visits. Patients should be 
instructed to remove shoes and heavy clothing (eg, heavy coats, jackets) prior to 
measurement. For weight collection, an effort should be made to use the same scale 
throughout the study where possible. In instances where multiple scales may be used, efforts 
should be made to reset the scale to zero prior to collection of weight measurement. 
8.2.4.3 
Electrocardiograms 
Electrocardiograms (12-lead ECGs) will be performed as specified in Appendix A. 
8.2.4.4 
Adverse Events of Special Interest 
Monitoring of these events will be the responsibility of the DSMB. The process of data 
collection and assessment of the events will be detailed in a separate DSMB charter.  
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Additional information will be collected if episodes of any of the following AEs of special 
interest occur. 
8.2.4.4.1 
Central Nervous System Events 
Central nervous system events of special interest may include any clinically significant 
changes in mood, physical affect, or exacerbation of preexisting CNS conditions (eg, 
depression, migraine headaches). 
8.2.4.4.1.1 
Depression Detection 
Patients will be evaluated beginning at Day 1 (Baseline) and at each subsequent visit for 
indications of depression. During each visit the patient will first be asked to respond to the 
question “During the past month, have you often been bothered by feeling down, depressed, 
or hopeless?” Followed by “During the past month, have you often been bothered by little 
interest or pleasure in doing things?” A positive response prior to Day 1 dosing will be 
captured on the medical history CRF page. Positive responses following the first dose will be 
captured as an AE and will be followed as an AE of special interest.  
8.3 
Other Assessments 
8.3.1 
Chromogranin A (CgA) 
Blood samples for measurement of chromogranin A (CgA) levels will be collected as 
indicated in Appendix A. 
8.3.2 
Disease Progression 
Data will also be collected on measures of disease progression as performed as standard of 
care including, but not limited to: interpretation of clinical scans (eg, PET, CAT, MRI scans 
of tumor), or Investigator assessment of disease status, while the patient is enrolled in the 
study.     
8.3.3 
Quality of Sleep Assessment 
Quality of sleep will also be evaluated beginning Day 1 (Baseline) and at each subsequent 
visit thereafter. Patients will be asked to respond to the following question “Since your last 
visit, how many times a night (on average) do you wake up due to your CS symptoms?” 
based on the following scale 0, 1, 2, 3, 4, >4.  
8.4 
Appropriateness of Assessments 
The assessments used in this study conform to the usual clinical and laboratory assessments 
of patients with CS participating in clinical trials and are typical of a Phase 3 study.  
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8.4.1 
Blood Collection 
An attempt should be made to collect all samples as per the schedule outlined in Appendix A. 
Any portion of samples remaining after the required tests for this study have been completed 
will be destroyed. 
The estimated amount of blood scheduled for collection per patient, over the course of the 
study, may be found in Appendix B. 
9. 
Safety Reporting 
Medical queries should be addressed to the Medical Monitor responsible for the region. 
Sites in North America: 
, MD 
  
INC Research 
 
 
Phone: 
 
 
 
Sites outside North America:  
, MD, PhD 
 
INC Research 
 
The Netherlands 
Phone: 
 
Mobile: 
 
 
 
, MD, PhD 
Medical Monitor 
INC Research, LLC 
 
 
Czech Republic 
Phone: 
 
Fax: 
 
 
After-hours emergency medical coverage is available to site personnel should the regional 
Medical Monitor and regional backup Medical Monitor be unavailable. 
 
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Sites in North America dial 1-877-462-0134. 
 
Sites outside North America dial the country prefix number plus 1-877-462-0134. Prefix 
numbers are determined by accessing the AT&T Direct on-line link 
http://www.usa.att.com/traveler/access_numbers/country/index.jsp. Note: These calls are not 
toll-free. 
9.1 
Adverse Events 
It is the responsibility of the Investigator to document all AEs that occur during the study. 
Adverse event is defined as any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. 
Life-threatening adverse event or life-threatening suspected adverse reaction: An adverse 
event or suspected adverse reaction is considered "life-threatening" if, in the view of either 
the Investigator or Sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred 
in a more severe form, might have caused death. 
An AE includes any noxious, pathological, or unintended change in anatomical, 
physiological, or metabolic functions as indicated by physical signs or symptoms occurring in 
any phase of the clinical study whether or not considered related to the study medication. 
This definition includes an exacerbation of preexisting medical conditions or events, 
historical condition not present prior to study treatment, which reappear following study 
treatment, intercurrent illnesses, hypersensitivity reactions, drug interaction, or the significant 
worsening of the disease under investigation that is not recorded elsewhere in the CRF. 
Anticipated day-to-day fluctuations of pre-existing conditions that do not represent a 
clinically significant exacerbation or worsening need not be considered AEs. 
Any laboratory abnormality fulfilling the criteria for a SAE (Section 9.2) should be reported 
as such, in addition to being recorded as an AE. Any treatment-emergent abnormal laboratory 
result which is clinically significant, ie, meeting 1 or more of the following conditions, 
should be recorded as a single diagnosis AE: 
 Is considered to be an SAE, 
 Results in discontinuation from study treatment, or 
 Results in a requirement for a change in concomitant therapy (ie, addition of concomitant 
therapy) 
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In the event of medically significant unexplained abnormal laboratory test values, the tests 
should be repeated and followed up until they have returned to the normal range and/or an 
adequate explanation of the abnormality is determined.  
TEAEs are defined as any AEs reported after the first dose of study drug on Day 1. Adverse 
events reported after consent of a patient, but before administration of study medication, will 
be reported in the Medical History. 
AEs should not be solicited with leading questions that suggest specific signs or symptoms. 
Rather, AEs should be solicited by asking the patient a non-leading question such as: “Do you 
feel different in any way since receiving the dose or since the last assessment?” 
The Investigator will evaluate all AEs with regard to the maximum intensity and relationship 
to study drug, as follows: 
 Maximum intensity  
Maximum intensity should be assigned using 1 of the following 3 severity grades: 
o 
Mild: aware of event but easily tolerated 
o 
Moderate: discomfort, enough to cause interference with usual activity 
o 
Severe: incapacitating: patient unable to work or perform usual activities 
 Relationship to study drug 
Not related:  
o 
Does not follow a reasonable temporal sequence from administration of the drug 
o 
Could be reasonably explained by other factors, including underlying disease, 
complications, concomitant drugs, or concurrent treatment. 
Possibly related:  
o 
That follows a reasonable temporal sequence from administration of the drug 
(including the course after withdrawal of the drug), or 
o 
For which the possibility of the study drug being the causative factor (eg, existence 
of similar reports attributed to the suspected drug and its analogues; reactions 
attributable to the pharmacological effect) could not be excluded, although other 
factors such as underlying disease, complications, concomitant drugs, or concurrent 
treatment are presumable. 
Probably related: 
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o 
That follows a reasonable temporal sequence from administration of the drug 
(including the course after withdrawal of the drug), and 
o 
For which the possibility of factors other than the drug, such as underlying disease, 
complications, concomitant drugs, or concurrent treatment, could not be excluded as 
the cause. 
Definitely related: 
o 
Follows a clear temporal sequence from administration of the study drug. 
o 
Could not be possibly explained by the known characteristics of the patient’s 
clinical state, environmental or toxic factors, or other modes of therapy 
administered to the patient. 
o 
Disappears or decreases on cessation or reduction in dose of the study drug. 
o 
Reappears or worsens when the study drug is re-administered. 
o 
Follows a response pattern known to be associated with administration of the study 
drug. 
The degree of certainty with which an AE is attributed to treatment with study medication (or 
alternative causes, eg, natural history of the underlying diseases, concomitant therapy, etc.) 
will be determined by how well the event can be understood in terms of known 
pharmacology of the study medication and/or reaction of similar nature being previously 
observed with the study medication or the class of study medication. 
All AEs should be followed for at least 30 days following the last dose of study drug or until 
the event has resolved, the condition has stabilized, or the patient is lost to Follow-up. For 
each patient for whom an AE was reported that did not resolve before the end of the reporting 
period, Follow-up information on the subsequent course of events must be submitted to the 
Sponsor. This requirement indicates that follow-up may be required for some AEs after the 
patient has completed his/her participation in the study 
9.2 
Serious Adverse Events (SAEs) 
An SAE is defined as any event that results in any of the following outcomes: 
1. Death 
2. A life-threatening adverse event; 
3. Inpatient hospitalization or prolonging of an existing hospitalization (see Section 9.2.1 
for information on hospitalization as an SAE);  
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4. A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; or 
5. A congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed above. 
Any SAE must be reported by telephone or facsimile within 24 hours of discovery of the 
event. Investigators should not wait to receive additional information to fully document the 
event before notifying the Sponsor of an SAE at: 
Sites in North America must report to: 
Safety Data Facsimile: 001 (832) 442-5917 
Safety Hotline: 001 (877) 372-3597 
 
Email address (in case of fax failure): drugsafetyfax@lexpharma.com 
 
Sites outside North America must report to the country specific toll-free fax numbers 
identified below: 
Australia: 
 
Belgium: 
 
Brazil:
 
France: 
 
Germany: 
 
Israel: 
 
Italy: 
 
Netherlands: 
 
Spain: 
 
Sweden: 
 
United Kingdom: 
 
 
Email Address (in case of fax failure):  
 
 
The telephone report should be followed by full written summary detailing relevant aspects 
of the SAE in question using the provided SAE report form. Where applicable, information 
from relevant hospital case records and autopsy reports should be obtained. The SAE should 
also be recorded on the AE page of the patient’s CRF. 
An SAE that occurs after completion of the study but, in the opinion of the Investigator, is 
related to the study medication, should be reported as described for an SAE. If an AE does 
not meet the regulatory definition of “serious” but is considered by the Investigator to be 
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related to the study medication and of such clinical concern as to influence the overall 
assessment of safety, it must be reported as defined for an SAE. 
All patients (including discontinued patients) with a SAE must be followed until the event 
resolves or reaches a new Baseline, but for a minimum of 30 days after the last dose of study 
drug. 
9.2.1 
Hospitalization as an SAE 
Hospitalization is defined as any in-patient overnight stay in a hospital. A hospitalization in 
and of itself does not constitute an SAE. The condition which caused the hospitalization must 
be evaluated and determined to be an AE. Although an AE which results in hospitalization is 
an SAE, patients are hospitalized for a variety of reasons which may not be associated with or 
considered an SAE (eg, convenience, logistics, preference, etc). Therefore, each case of 
hospitalization must be evaluated separately. 
For example, the following would not be considered SAEs: 
 Hospitalization for a preexisting condition which did not worsen (eg, cataract surgery) 
 Hospitalization solely for a procedure or treatment that was not performed to treat an 
AE 
 Hospitalization for a condition that does not normally require treatment, but electively 
done (eg, cosmetic surgery) 
 Hospitalization strictly for convenience reasons or observations (eg, procedures only 
performed in a hospital because of the distance the subject lives from the hospital) 
9.3 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
The FDA and/or other applicable Regulatory Authorities and all participating Investigators 
will be notified by a written Investigational New Drug Application (IND) safety report and/or 
other applicable regulatory report (eg, SUSAR) of any suspected adverse reaction that is both 
serious and unexpected, no later than 15 calendar days from the “date learned” of the event. 
In addition, all applicable regulatory bodies will be notified within 7 calendar days of any 
unexpected fatal or life-threatening suspected adverse reaction.  
An adverse reaction is defined as any untoward and unintended response to an investigational 
medicinal product (IMP) related to any dose administered. This definition also covers 
medication errors and uses outside what is foreseen in the protocol, including misuse and 
abuse of the product. The definition also implies a reasonable possibility of a causal 
relationship between the event and the IMP.  
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An unexpected adverse reaction is any adverse drug event, which is not listed in the current 
Investigator’s Brochure or is not listed at the specificity or severity that has been observed. 
For example, (A) a single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (eg, angioedema, hepatic injury, Stevens-Johnson Syndrome); 
(B) 1 or more occurrences of an event that is not commonly associated with drug exposure, 
but is otherwise uncommon in the population exposed to the drug (eg, tendon rupture); (C) an 
aggregate analysis of specific events observed in a clinical trial (such as known consequences 
of the underlying disease or condition under investigation or other events that commonly 
occur in the study population independent of drug therapy) that indicates those events occur 
more frequently in the drug treatment group than in a concurrent or historical control group. 
An untoward and unintended response to a non-IMP is by definition not a SUSAR. 
9.4 
Precautions 
9.4.1 
Pregnancy 
Any patient (or patient’s partner) who becomes pregnant during the study should be followed 
through delivery or termination of the pregnancy. In addition, patients who become pregnant 
during the study must be discontinued from the study treatment immediately.  
In pregnancies that progress to term, any congenital abnormalities/birth defects in the 
offspring of a patient who received study medication should be reported as an SAE. The 
outcome of the pregnancy and the presence or absence of a congenital abnormality will be 
documented by completion of a Pregnancy Questionnaire and a Pregnancy Outcome Form in 
accordance with GCP and ICH guidelines and the Sponsor’s SOPs.  
Female patients should also notify the Investigator if they become pregnant within 30 days 
after last dose of study medication. Male patients should notify the Investigator if a female 
partner becomes pregnant within 30 days after last dose of study medication. The Sponsor 
must be notified of all pregnancies reported to the Investigator (see Section 9.2 for contact 
information). 
10. 
Statistical Methodology 
10.1 
Determination of Sample Size 
No formal sample size calculation was made. The number of patients expected to participate 
in this study was calculated from estimated enrollment rates from other carcinoid cancer trials 
employed in the LX1606 clinical program. 
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10.2 
Analysis Populations 
Per protocol: A Per Protocol population will consist of those patients that receive study 
treatment and have no major protocol violation that would interfere with the collection or 
interpretation of the efficacy data. The primary analyses of efficacy will be based on the 
safety population; the per-protocol population will be used in a supplemental manner.  
Safety: The safety population consists of all patients receiving any fraction of a dose of study 
drug during this study.  
10.3 
Study Endpoints 
10.3.1 
Efficacy Endpoints 
The primary efficacy endpoint is to evaluate the long-term safety and tolerability of orally 
administered telotristat etiprate. 
Secondary efficacy endpoint is to evaluate changes in patients’ QOL over multiple years of 
therapy.  
10.3.2 
Safety Endpoints 
Safety endpoints are as follows:  
 Incidence of TEAEs, suspected adverse reaction, AEs leading to discontinuation from the 
study, SAEs, and deaths 
 Actual and change from Baseline in clinical laboratory results  
 Actual and change from Baseline in vital signs results  
 Actual and change from Baseline in physical examinations 
 Actual and change from Baseline in ECG findings 
10.4 
Statistical Methods 
Descriptive analysis methods will be used to summarize the data. Continuous variables will 
be summarized by the N, mean, standard deviation, median, minimum, and maximum values. 
Categorical variables will be summarized as counts and related percentages. Data tabulations 
will be categorized by the treatment received on Day 1 of this study and combined across all 
treated patients. All data will be listed. 
Primary analyses of the data will be based on the Safety population which includes all 
patients treated with any fraction of study drug during this study. Supportive analyses of the 
efficacy data will be made on a Per Protocol population. This dataset will include the Safety 
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population, but limited to those patients that have at least one assessment post Day 1 and do 
not have any protocol violations that would interfere with collection or interpretation of the 
data. The Per Protocol analysis will be applied to the QOL measures, subjective global 
assessment, and plasma 5-HIAA values. 
Data will be summarized per study visit as the actual (raw) outcomes and change from 
Baseline scores, where applicable. Day 1 of this study will serve as the Baseline assessment. 
10.4.1 
Efficacy Analyses 
All efficacy and PD variables will be summarized descriptively and listed. 
Statistical tests and estimates of within patient effects for these measures will be derived from 
application of a mixed linear model with repeated measures. The model will be generalized to 
handle missing data and specific to the measurement properties of the dependent variable. 
There is no plan to impute data for missing observations for any variable. Non-parametric 
methods will be used to supplement the tests and estimates from the mixed linear model. 
Exploratory analyses of treatment group differences may be performed by use of propensity 
score models. The treatments groups will correspond to how patients were dosed on Day 1 of 
this study.  
10.4.2 
Safety Analyses 
Statistical analysis of the safety data will involve examination of the descriptive statistics and 
individual patient listings for any effects of study treatment on clinical tolerability and safety. 
Reporting of these data will be based on the Safety population. Summaries will be prepared 
by treatment group (corresponding to the LX1606 dose given on Day 1), pooled across all 
patients, and as needed, by study visit. All safety data will be listed. 
Treatment-emergent adverse event summaries will include the overall incidence (by system 
organ class and preferred term), events by maximum intensity, event by relationship to study 
treatment, events leading to discontinuation of study drug, and serious adverse events. 
Vital signs, ECG, and laboratory parameters (hematology, chemistry, and urinalysis) will be 
summarized descriptively at each time point. Actual and change from Baseline data will be 
calculated and summarized. In addition, shift table analysis will be applied to the laboratory 
data and summarized. 
10.4.2.1 
Adverse Events 
All AEs will be coded and listed by body system and preferred term based on the Medical 
Dictionary for Regulatory Activities (MedDRA). Summaries using descriptive statistics will 
be provided for treatment-emergent AEs, drug-related AEs and AEs by intensity. Treatment-
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emergent AEs are those events not present at Baseline, but occurring after the start of study 
drug, or if existing at Baseline, increasing in intensity after initiation study drug. Summaries 
made by intensity will select the event with the highest intensity when multiple occurrences 
of the same event are reported for the same patient. In a similar manner, summaries prepared 
by drug relationship will select the event with the greatest degree of relationship when a 
study reports multiple occurrences of the same event. On-study deaths will be reported for 
deaths occurring during the active phase of the treatment period and 30 days after stopping 
study drug. Also, deaths occurring outside the 30-day window, but secondary to an AE 
reported within the 30-day post treatment period, will be reported as well.  
Listings will be provided for deaths, SAEs, and discontinuations due to AEs. Additional 
summaries or listings of AEs may also be provided. 
10.4.2.2 
Clinical Laboratory Parameters 
Laboratory results will be reported in conventional units in all tables, figures, and listings. 
Laboratory results falling out of the normal range will be marked as high or low in the 
listings. Actual and changes from Baseline (Day 1) in clinical laboratory results will be 
summarized by using descriptive statistics. Summaries of shifts from Baseline to abnormal 
clinical laboratory results will also be provided. Actual and change from Baseline in 
chromogranin A levels will be summarized descriptively as well. 
10.4.2.3 
Vital Sign Measurements 
Actual and changes from Baseline (Day 1) in vital signs results will be summarized by using 
descriptive statistics. 
10.4.2.4 
Electrocardiograms 
Clinically significant changes in ECGs compared to Baseline, as determined by the 
Investigator, will be summarized by using descriptive statistics. Actual and change from 
Baseline (Day 1 predose values) to each time point in corrected QT interval (QTcF) will be 
summarized as well. 
10.4.3 
Pharmacodynamic Analyses 
Analysis and summarization of the plasma 5-HIAA data are described in Section 10.4.1. 
10.4.4 
Baseline Characteristics and Other Summaries 
Treatment group differences will be summarized descriptively for demographic data, prior 
and concomitant medications, treatment compliance, and final disposition. Data collected 
from assessments of tumor status, when available, will be listed. 
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Protocol deviations will provided as listings. 
10.4.5 
Interim Analysis 
An independent DSMB will be charged with reviewing interim safety data on a quarterly 
basis and reporting its recommendations to Lexicon Pharmaceuticals, Inc. Appropriate 
procedures will be detailed in a DSMB Charter that defines accessibility and disclosure of the 
interim study results. 
The study may be analyzed and reported in multiple phases. The first report will summarize 
data obtained from all patients providing information up to a specified data cut-off point. The 
following reports will update the initial report by including data from the remaining portion 
of the study. The first reporting of the data may be taken as an interim analysis in terms of the 
procedural efforts needed to summarize these data, but it will not serve as a means to modify 
the analysis/study conduct.   
11. 
Study Management 
The Investigator is responsible for completing and maintaining adequate and accurate CRFs 
and source documentation. Source documentation constitutes original records, which may 
include: progress notes, medication administration records, laboratory reports, ECG tracings, 
and discharge summaries.  
All data on the CRF must be recorded in accordance with the CRF guidelines. If a correction 
is necessary, it should be made by the Investigator or a designated qualified individual as 
specified within the guideline. All CRFs should be completed in their entirety and stored in a 
secure location. The Investigator must sign the Investigator’s statement in each patient’s CRF 
indicating that the data reported are accurate. 
At the study site, clinical research associates will verify 100% of CRFs in their entirety 
against source documentation. Computer programmed edit checks will be run against the 
database to check for discrepancies and reasonableness of the data, and the safety database 
will be reconciled with the clinical database. All issues resulting from the computer generated 
checks and the safety database reconciliation will be resolved according to standard data 
management practices in conjunction with the Sponsor, clinical study personnel, and the 
study Investigators. 
11.1 
Monitoring 
The Sponsor is responsible for ensuring the proper conduct of the study with regard to ethics, 
protocol adherence, site procedures, integrity of the data, and applicable laws and/or 
regulations. At regular intervals during the study and following completion of the study, the 
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Sponsor’s study monitors will contact the study site via visits to the site, telephone calls, 
and/or letters in order to review study progress, CRF completion, and address any concerns 
or questions regarding the study conduct. During monitoring visits, the following aspects of 
study conduct will be carefully reviewed: informed consent of patients, patient recruitment, 
patient compliance with the study procedures, source data verification, drug accountability, 
use of concomitant therapy by patients, AE and SAE documentation and reporting, and 
quality of data. Records pertaining to these aspects are expected to be kept current. 
The Investigator must make study data accessible to the clinical monitor, to other authorized 
representatives of the Sponsor, and to regulatory inspectors 
11.2 
Audits and Inspections 
The Sponsor, regulatory authority, or IRB/ERC may visit the study site at any time during the 
study or after completion of the study to perform audits or inspections. The purpose of a 
Sponsor audit or regulatory inspection is to systematically and independently examine all 
study-related activities and documents to determine whether these activities were conducted 
according to the protocol, GCP, ICH guidelines, and any other applicable regulatory 
requirements. Investigators should contact the Sponsor immediately if contacted by a 
regulatory agency about an inspection at their site. 
11.3 
Amendments 
Any amendments to the protocol will be written and approved by the Sponsor. All 
amendments must be submitted to the IRB/ERC for approval prior to implementing the 
changes. In some instances, an amendment may require changes to the informed consent 
form, which also must be submitted for IRB/ERC approval prior to administration to patients. 
If any changes to the CRF are required, the Sponsor will issue supplemental or revised CRF 
pages. 
11.4 
Record Keeping 
11.4.1 
Drug Accountability  
The Investigator must maintain accurate records of receipt of study drug, dispensing 
information (date, lot, and dose for each patient), and the prompt return or destruction of 
unused supplies. If the Investigator cannot account for all clinical supplies at the termination 
of the study, a written explanation must be provided.  
 
 
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11.4.2 
Health Insurance Portability Accountability Act of 1996 and 
Subsequent Updates 
The Investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of patient health information, including, but not limited to, 
the Standards for Individually Identifiable Health Information, 45 Code of Federal 
Regulations (CFR) Parts 160 and 164 (the Health Insurance Portability Accountability Act of 
1996 [HIPAA] Privacy Regulation and any applicable updates). The Investigator shall ensure 
that study patients authorize the use and disclosure of protected health information in 
accordance with HIPAA Privacy Regulation and in a form satisfactory to the Sponsor. 
11.4.3 
Financial Disclosure 
The Investigator shall provide to the Sponsor sufficient accurate financial information to 
allow the Sponsor to submit complete and accurate financial certification or disclosure 
statements to the FDA and/or other applicable regulatory agencies. The Investigator shall 
promptly update this information if any relevant changes occur in the course of the study or 
for 1 year following completion of the study. 
11.4.4 
Access to Original Records 
It is an expectation of regulatory authorities that monitors, auditors, and representatives of 
national and international government regulatory agency bodies have access to original 
source documentation (see examples in Section 11) to ensure data integrity. “Original” in this 
context is defined as the first documentation of an observation and does not differentiate 
between hard copy and electronic records. 
11.4.5 
Retention of Study Documents 
According to 21 CFR Part 312.62 and ICH E6, study-related records must be retained for at 
least 2 years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region, or at least 
2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. These documents should be retained for a longer period, however, if 
required by applicable regulatory requirements or by an agreement with the Sponsor. 
The Investigator must not destroy any study-related records without receiving approval from 
the Sponsor. The Investigator must notify the Sponsor in the event of accidental loss or 
destruction of any study records. If the Investigator leaves the institution where the study was 
conducted, the Sponsor must be contacted to arrange alternative record storage options. 
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12. 
Administrative Structure of the Study 
The study will be monitored by Sponsor personnel or Sponsor representative. The following 
functions for this study will be performed by organizations designated by the Sponsor: data 
management and statistical analysis, including PD analysis and reporting.
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13. 
Appendix A – Schedule of Events 
Baseline Day 
11
Week 12
Week 24
Week 36
Week 48
Week 60
Week 72
Week 84 /
EOS
Tolerance (days)
NA
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
Inclusion/Exclusion criteria
X
Medical history
X
Physical examination incl. weight
X
X3
X3
X3
X
X3
X3
X
 X5
Urine pregnancy test2
X
X
X
X
X
X
X
X
X
Hematology, Blood chemistry
X
X
X
X
X
X
X
X
 X5
Urinalysis
X
X
X
 X5
Chromogranin A
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
ECG
X
X
X
 X5
Subjective Global Assessment
X
X
X
X
X
X
X
X
X
EORTC QLQ-C30 & GI.NET21
X
X
X
X
X
Sleep and Depression Assessment
X
X
X
X
X
X
X
X
X
Plasma 5-HIAA
X
X
X
X
X
X
X
X
X
Dispensation of LX1606
X
X
X
X
X
X
X
 
Concomitant medications
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
Procedure
Extension Period
2-Week 
Follow-up4
1Eligibility will be determined at last visit of the original protocol; Day 1 will replace the next scheduled visit in the original protocol schedule. Visits 
should coincide with LAR injections for those patients receiving SSA therapy. 2Females of child-bearing potential only. 3Brief physical examination only 
(symptom-oriented, including weight). 4Visit to be performed for subjects who withdraw early and will not return for a 2-week follow-up visit; in all other 
cases the EOS visit should be performed followed by the follow-up visit 2 weeks postdose. 5To be performed only if evaluation at Week 84/EOS is 
abnormal. 
 
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14. 
Appendix B – Amount of Blood to be Collected from Each Patient 
Safety
Hematology
2
9
18
Blood chemistry
6
9
54
Other
CgA
2
3
6
Pharmacodynamic Plasma 5-HIAA
4
9
36
114
*Maximum number of samples is indicated
Total 
Assessment
Sample volume (mL)
Number of samples*
Estimated total volume (mL)
 
 
 
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15. 
Appendix C – EORTC QLQ-C30 
 
 
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16. 
Appendix D – EORTC QLQ - GI.NET21 
 
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17. 
Appendix E – Ethical Standards 
Ethics and Regulatory Considerations 
This study will be conducted according to GCP, 21 CFR Part 50, (Protection of Human 
Subjects), 21 CFR Part 56 (Institutional Review Boards), International Conference on 
Harmonisation Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance, the 
Nuremberg Code, and the Declaration of Helsinki.  
General Instructions 
The FDA regulates studies of drugs, biologics, and medical devices. Consequently, these 
studies are subject to GCP regulations and guidance issued by the FDA and are included in, 
but not limited to, the following parts of the CFR and guideline document: 
 21 CFR Part 11 – Electronic Records 
 21 CFR Part 50 – Protection of Human Subjects 
 21 CFR Part 54 – Financial Disclosure 
 21 CFR Part 56 – Institutional Review Boards 
 21 CFR Part 312 – Investigational New Drug Application 
 Current FDA Guideline for the Monitoring of Clinical Investigations 
 Current Guidance for Institutional Review Boards and Clinical Investigators 
 ICH E6 – Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance  
Studies conducted in the European Union are also regulated by Volume 10 of the publications 
“The rules governing medicinal products in the European Union”. 
Copies of these materials are available from the Sponsor upon request. The purpose of these 
regulations and legal obligations is to define the standards and principles for the proper 
conduct of clinical trials that have been developed by the medical, scientific, and regulatory 
communities. They are not intended to impede or restrict clinical research.  
The ethical standards defined within GCP are intended to ensure that: 
 human subjects are provided with an adequate understanding of the possible risks of their 
participation in the study, and that they have a free choice to participate or not; 
 the study is conducted with diligence and in conformance with the protocol in such a way 
as to insure the integrity of the findings; 
 the potential benefits of the research justify the risks. 
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Lexicon Pharmaceuticals, Inc. is the Sponsor of the IND. The Sponsor is responsible for the 
following: 
 selecting qualified Investigators, 
 providing Investigators with the information they need to properly conduct an 
investigation, 
 ensuring proper monitoring of the investigation, 
 ensuring that the study is conducted according to the general investigational plan and 
protocols contained in the IND, 
 maintaining the IND, and  
 ensuring that regulatory authorities and all participating Investigators are properly 
informed of significant new information regarding adverse effects or risks associated with 
the drug being studied 
 ensuring the study is conducted in accordance to FDA and ICH guidelines and all 
applicable regulations 
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18. 
Appendix F – Investigator Obligations 
Per Title 21 of the US Government Code of Federal Regulations (21 CFR) Parts 50 and 56 
and ICH E6, the study protocol and the final version of the subject informed consent form 
will be approved by the IRB/ERC before enrollment of any subjects. The opinion of the 
IRB/ERC will be dated and given in writing. A copy of the letter of approval from the 
IRB/ERC and a copy of the approved informed consent form will be received by the Sponsor 
prior to shipment of study medication supplies to the Investigator. 
The Investigator will ensure that the IRB/ERC will be promptly informed of all changes in 
the research activity and of all unanticipated problems including risk to subjects. The 
Investigator will also ensure that no changes will be made to the protocol without IRB/ERC 
approval. 
As a part of the IRB/ERC requirement for continuing review of approved research, the 
Investigator will be responsible for submitting periodic progress reports to the IRB/ERC at 
intervals appropriate to the degree of subject risk involved, but no less than once per year. 
Written informed consent must be given freely and obtained from every subject prior to 
clinical trial participation. The rights, safety, and well-being of the trial subjects are the most 
important considerations and should prevail over interests of science and society. 
As described in GCP guidelines, study personnel involved in conducting this trial will be 
qualified by education, training, and experience to perform their respective task(s). Study 
personnel will not include individuals against whom sanctions have been invoked after 
scientific misconduct or fraud (eg, loss of medical licensure, debarment). Quality assurance 
systems and procedures will be implemented to assure the quality of every aspect of the 
study. 
Principal Investigators must provide Lexicon with a fully executed Form FDA 1572 
(statement of Investigator) and all updates on a new fully executed Form FDA 1572. 
Principal Investigators must provide Lexicon with his/her own curriculum vitae and current 
curriculum vitae for each sub-Investigator listed on Form FDA 1572. 
Protection of Human Subjects (21 CFR Part 50 and ICH E6)  
Informed consent must be obtained from every subject before entry into a clinical study. It 
must be given freely and not under duress. Consent must be documented by use of an 
IRB/ERC-approved consent form and signed by the subject or the subject’s legally authorized 
representative. The US Department of Health and Human Services suggests that when minors 
are involved, a parent or guardian should sign the consent form. If the minor is an adolescent, 
his signature should also be included. Non-English-speaking subjects must be presented with 
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a consent form written in a language that they understand. A copy of the signed consent form 
must be given to the subject signing it. Another copy must be kept in the Investigator’s files 
and made available to regulatory authority representatives upon request. If, for any reason, 
subject risk is increased as the study progresses, a revised, IRB/ERC-approved consent form 
must be signed by the subject. Before the study begins, a sample of the consent form must be 
provided to the Sponsor for review. The FDA and/or other applicable regulatory agencies 
may reject otherwise scientifically valid studies if proper informed consent has not been 
obtained from all subjects. 
Only in the case of a life-threatening incident may an investigational product be used without 
prior signed consent. In such an emergency situation, separate certifications must be written 
both by a physician not participating in the study and by the Investigator. The certifications, 
along with the protocol and informed consent, must be sent to the IRB/ERC within 5 working 
days. In this situation, the Investigator may not administer any subsequent product to that 
subject until informed consent and IRB/ERC approval are obtained. 
Informed Consent 
Written informed consent must be obtained from each subject prior to entry in the study. One 
copy of the signed informed consent document will be given to the subject, and another will 
be retained by the Investigator. Additionally, the subject must be allowed adequate time to 
consider the potential risks and benefits associated with his/her participation in the study.  
In situations where the subject is not legally competent to provide consent (ie, mentally 
incapacitated), written consent must be obtained from a parent, legal guardian, or legal 
representative. In these situations, the consent must be signed and dated by a witness. 
The informed consent document must have been reviewed and approved by the Sponsor and 
by the Investigator’s IRB/ERC prior to the initiation of the study. The document must contain 
the 8 basic elements of informed consent and may contain the 6 additional elements 
described in 21 CFR Part 50. Every consent form must include the following 8 elements: 
 A statement that the study involves research, an explanation of the purpose of the research 
and the expected duration of the subject’s participation, a description of the procedures to 
be followed, and identification of any procedures that are experimental 
 A description of any reasonably foreseeable risks or discomforts to the subject 
 A description of any benefits to the subject or to others that may reasonably be expected 
from the research 
 A disclosure of appropriate alternative procedures or course of treatment, if any, that 
might be advantageous to the subject 
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 A statement describing the extent, if any, to which confidentiality of records identifying 
the subject will be maintained and noting the possibility that the FDA and/or other 
applicable regulatory authority representatives may inspect the records 
 An explanation as to whether any compensation or medical treatments are available if 
injury occurs for research involving more than minimal risk. The explanation should 
involve a description of the compensation or treatment available, or a statement 
describing where further information may be obtained 
 An explanation of whom to contact for answers to pertinent questions about the research 
and the subject’s rights and whom to contact in the event of a research related injury 
 A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the subject is otherwise entitled, and that the subject 
may discontinue participation at any time without penalty or loss of benefits to which the 
subject is otherwise entitled. 
When appropriate, 1 or more of the following elements of information shall also be included 
in the consent form: 
 A statement that the particular treatment or procedure may involve risks to the subject (or 
to the embryo or fetus, if the subject is or may become pregnant) which are currently 
unforeseeable 
 Anticipated circumstances under which the subject’s participation may be terminated by 
the Investigator without regard to the subject’s consent 
 Any additional costs the subject may incur from participation in the research 
 The consequences of a subject’s decision to withdraw from the research and procedures 
for orderly termination of participation by the subject 
 A statement that significant new findings developed during the course of the research that 
may relate to the subject’s willingness to continue participation will be provided to the 
subject 
 The approximate number of subjects involved in the study 
The Declaration of Helsinki includes further details regarding the specific requirements for 
informed consent.  
Nothing in these regulations is intended to limit the authority of a physician to provide 
emergency medical care to the extent the physician is permitted to do so under applicable 
federal, state, or local laws. 
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The informed consent requirements in these regulations are not intended to preempt any 
applicable federal, state, or local laws that require additional information to be disclosed in 
order that informed consent be legally effective. Some states, such as California and Oregon, 
require further action on the Investigator’s part concerning subject consent. 
Study Documentation 
IRB/ERC Review/Approval 
The protocol and informed consent for this study, including advertisements used to recruit 
subjects, must be reviewed and approved by an appropriate IRB/ERC prior to enrollment of 
subjects in the study. It is the responsibility of the Investigator to assure that all aspects of the 
ethical review are conducted in accordance with the current Declaration of Helsinki, ICH, 
GCP, and/or local laws, whichever provide the greatest level of protection. A letter 
documenting the IRB/ERC approval which specifically identifies the study/protocol and a list 
of the committee members must be received by the Sponsor prior to initiation of the study. 
Amendments to the protocol will be subject to the same requirements as the original protocol. 
A progress report with a request for re-evaluation and re-approval will be submitted by the 
Investigator to the IRB/ERC at intervals required by the IRB/ERC, and not less than 
annually. A copy of the report will be sent to the Sponsor.  
When the Sponsor provides the Investigator with a Safety Report, the Investigator must 
promptly forward a copy to the IRB/ERC. 
After completion or termination of the study, the Investigator will submit a final report to the 
IRB/ERC and to the Sponsor, if required. This report should include: deviations from the 
protocol, the number and types of subjects evaluated, the number of subjects who 
discontinued (with reasons), results of the study, if known, and significant AEs, including 
deaths. 
Study Files 
The Investigator is required to maintain complete and accurate study documentation in 
compliance with current Good Clinical Practice standards and all applicable federal, state, 
and local laws, rules, and regulations related to the conduct of a clinical study. Study 
documents include, but are not limited to, the Investigator’s Brochure, drug accountability 
records, Sponsor/Investigator correspondence, IRB/ERC correspondence, protocol and 
amendments, information regarding monitoring activities, subject exclusion records, CRFs, 
and data queries. 
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Confidentiality 
The anonymity of subjects must be maintained. Patients will be identified by their initials and 
an assigned subject number on CRFs and other documents submitted to the clinical monitor. 
Documents that will be submitted to the clinical monitor and that identify the subject (eg, the 
signed informed consent document) must be maintained in strict confidence by the Principal 
Investigator, except to the extent necessary to allow auditing by regulatory authorities, the 
clinical monitor, or Sponsor personnel. 
All information regarding the nature of the proposed investigation provided by the Sponsor to 
the Investigator (with the exception of information required by law or regulations to be 
disclosed to the IRB/ERC, the subject, or the regulatory authority) must be kept in confidence 
by the Investigator. 
Drug Accountability 
The Investigator or designee is responsible for accountability of the investigational product at 
the site. The Investigator or designee must maintain records of the product’s delivery to the 
site, inventory at the site, use by each subject, and return to the Sponsor or alternative 
disposition of any unused product. These records must include dates, quantities, 
batch/serial/lot numbers, and expiration dates (if applicable). 
The Investigator should ensure that the investigational product is used only in accordance 
with the protocol 
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19. 
References 
1. 
Bhattacharyya S, Toumpanakis C, Chilkunda D, Caplin ME, Davar J. Risk factors for 
the development and progression of carcinoid heart disease. Am J Cardiol. 2011; 
107(8):1221-6. Epub 2011 Feb 4. 
2. 
Møller JE, Connolly HM, Rubin J, Seward JB, Modesto K, Pellikka PA. Factors 
associated with progression of carcinoid heart disease. N Engl J Med. 
2003;348(11):1005-15. 
3. 
Druce M, Rockall A, Grossman AB. Fibrosis and carcinoid syndrome: from causation to 
future therapy. Nat Rev Endocrinol. 2009;5(5):276-83 . 
4. 
DePonti F. Pharmacology of serotonin: what a clinician should know. Gut. 
2004;53:1520-35. 
5. 
Cote F, et al. Disruption of the nonneuronal tph 1 gene demonstrates the importance of 
peripheral serotonin in cardiac function. Proc Natl Acad Sci. 2003;100(23):13525-30. 
6. 
De Vries H, et al. Diagnostic, surgical, and medical aspect of the midgut carcinoids. 
Cancer Treat Rev. 2002;28:11-25. 
7. 
Sandostatin LAR® depot product label. Revised July 2014. Accessed at: 
http://www.pharma.us.novartis.com/product/pi/pdf/sandostatin_lar.pdf  
8. 
Investigator Brochure LX1606, Lexicon Pharmaceuticals, Inc.  
9. 
Dmitrienko A, Tamhane A, Wiens B. General multistage gatekeeping procedures. 
Biometrical Journal. 2008;50:667-77 
 
 
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CLINICAL STUDY PROTOCOL 
Protocol Number: 
LX1606.1-302-CS 
LX1606.302 (Abbreviated number) 
EudraCT Number 
2013-002596-18 
Investigational Phase: 
3 
Protocol Title: 
A Multicenter, Long-term Extension Study to Further 
Evaluate the Safety and Tolerability of Telotristat Etiprate 
(LX1606) 
Study Name: 
TELEPATH (Telotristat Etiprate – Expanded Treatment 
for Patients with Carcinoid Syndrome) 
Amendment 2 Date: 
21 January 2015 (France only) 
Amendment 1 Date: 
30 December 2014 (France only) 
Original Version Date: 
14 June 2013 
Sponsor: 
Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Place 
The Woodlands, TX 77381-1160 
Telephone: 001 (281) 863-3000 
Safety Hotline: 001 (877) 372-3597 
Safety Data Facsimile: 001 (832) 442-5917 
 
 
 
 
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1. 
Synopsis 
Name of Study Drug 
Telotristat etiprate 
Protocol Number 
LX1606.1-302-CS 
LX1606.302 (Abbreviated number) 
Protocol Title  
 
A Multicenter, Long-term Extension Study to Further Evaluate the 
Safety and Tolerability of Telotristat Etiprate (LX1606) 
Primary Objective 
The primary objective of this study is to evaluate the long-term 
safety and tolerability of orally administered telotristat etiprate   
Secondary Objective 
To evaluate long-term changes in patients’ quality of life (QOL)  
Phase of Development 
3 
Methodology 
 
The study will be conducted as a multicenter, open-label, long-term 
extension study to further evaluate long-term safety and tolerability 
of telotristat etiprate. 
Patients currently participating in any LX1606 Phase 2 carcinoid 
syndrome (CS) study may enter into this extension study upon 
institutional or local approval of the protocol. Patients participating 
in a Phase 3 CS study may enter into this extension study at the 
Week 48 visit. All patients who enter into this extension study will 
be exempt from any follow-up visit required by the original study 
and will not experience an interruption in study drug due to the 
transition from the original study to LX1060.1-302-CS. 
Following confirmation of eligibility, patients will complete a series 
of visit assessments in order to establish Baseline symptoms. 
Patients will then continue on open-label study drug at the same dose 
level and regimen as identified in their original study.  
Downward dose adjustment will be permitted during the study if 
evidence of intolerability emerges. Patients who experience 
intolerability at the 250 mg tid dose level must be discontinued from 
the study. Patients may return to the previous dosing at the discretion 
of the Investigator and in consultation with the Medical Monitor. 
Upon completion or early withdrawal from treatment, all patients 
will be required to complete a 14-day Follow-up Period, during 
which no study drug will be administered.  
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A Data Safety Monitoring Board (DSMB) will review safety data 
quarterly throughout the study.  
Number of Patients 
Up to 100 patients are expected to participate in this study.  
Patients 
Eligible patients are defined as those that are currently participating 
in a Phase 2 or Phase 3 telotristat etiprate carcinoid syndrome study. 
Number of Study Sites 
Approximately 70 sites 
Treatments 
Telotristat etiprate, 250-mg tablet, administered at the same dose 
level and regimen identified in the patient’s original study 
Route of Administration 
Oral 
Duration of Participation 
Up to 86 weeks including Treatment and Follow-up 
Inclusion Criteria 
Patients must meet all of the following criteria to be considered 
eligible to participate in the study: 
1. Ongoing participation in a Phase 2 (eg, LX1606.1-202-CS, 
LX1606.1-203-CS) or Phase 3 (eg, LX1606.1-301-CS, 
LX1606.1-303-CS) study 
2. Patients of childbearing potential must agree to use an adequate 
method of contraception (defined as having a failure rate of <1% 
per year) during the study and for 12 weeks after the Follow-up 
visit. Adequate methods of contraception for patients or partner 
include condoms with spermicide gel, diaphragm with 
spermicide gel, coil (intrauterine device), surgical sterilization, 
vasectomy, oral contraceptive pill, depot progesterone injections, 
progesterone implant, and abstinence during the study and for 12 
weeks after the Follow-up Visit. 
a. Childbearing potential is defined as those who have not 
undergone surgical sterilization, or those who are not 
considered postmenopausal. Postmenopause is defined as 
absence of menstruation for at least 2 years. If necessary, 
follicle-stimulating hormone (FSH) results >50 IU/L at entry 
are confirmatory in the absence of a clear postmenopausal 
history. 
3. Ability and willingness to provide written informed consent 
prior to participation in any study-related procedure 
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Exclusion Criteria 
Patients who meet any of the following criteria will be excluded 
from participating in the study:   
1. Major protocol violations or telotristat etiprate tolerability 
concerns in a Phase 2 (eg, LX1606.1-202-CS, LX1606.1-203-
CS) or Phase 3 (eg, LX1606.1-301-CS, LX1606.1-303-CS) 
study 
2. Positive pregnancy test 
3. Presence of any clinically significant findings at entry for 
medical history, laboratory values, or physical examination 
(relative to patient population) that, in the Investigator’s or 
Medical Monitor’s opinion, would compromise patient safety or 
the outcome of the study 
4. Patients who are currently committed to an institution by virtue 
of an order issued either by judicial or administrative authorities 
Statistical Methods 
Descriptive analysis methods will be used to summarize the data. 
Continuous variables will be summarized by the N, mean, standard 
deviation, median, minimum, and maximum values. Categorical 
variables will be summarized as counts and related percentages. Data 
tabulations will be categorized by the treatment received on Day 1 of 
this study and combined across all treated patients. Primary analyses 
of the data will be based on the Safety population which includes all 
patients treated on Day 1 of this study. Supportive analyses of the 
efficacy data will be made on a Per Protocol population.  
Data will be summarized per study visit as the actual (raw) outcomes 
and change from Baseline scores, where applicable. Day 1 of this 
study will serve as the Baseline assessment.  
Study Assessments 
Safety 
Safety assessments include monitoring of adverse events, clinical 
laboratory tests, vital signs measurements, 12-lead ECG, and 
physical examinations 
Efficacy 
Efficacy assessments will include patient reported quality of life 
measures as captured in the European Organization for Research and 
Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-
C30 and the module specific for gastrointestinal symptoms of 
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carcinoid neuroendocrine tumors (GI.NET21) and subjective global 
assessment of symptoms associated with CS 
Pharmacodynamics 
Pharmacodynamic (PD) assessments include determination of 5-
HIAA levels in plasma 
Efficacy Data Analysis 
 
All efficacy and PD variables will be summarized descriptively and 
listed. 
Statistical tests and estimates of within patient effects for the 
efficacy and PD measures will be derived from application of a 
mixed linear model with repeated measures. The form of the model 
will be specific to measurement properties of the dependent variable. 
Non-parametric methods will be used to supplement the tests and 
estimates from the mixed linear model. 
Exploratory analyses of treatment group differences may be 
performed by use of propensity score models. The treatments groups 
will correspond to patients’ telotristat etiprate dose level on Day 1 of 
this study.  
Safety Data Analysis 
 
Statistical analysis of the safety data will involve examination of the 
descriptive statistics and individual patient listings for any effects of 
study treatment on clinical tolerability and safety. Reporting of these 
data will be based on the Safety population. Summaries will be 
prepared by treatment group, and as needed, by study visit. 
Treatment-emergent adverse event summaries will include the 
overall incidence (by system organ class and preferred term), events 
by maximum intensity, event by relationship to study treatment, 
events leading to discontinuation of study drug, and serious adverse 
events. 
Vital signs, ECG, and laboratory parameters (hematology, chemistry, 
and urinalysis) will be summarized descriptively at each time point. 
Actual and change from Baseline data will be calculated and 
summarized. In addition, shift table analysis will be applied to the 
laboratory data. 
 
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Table of Contents 
1. 
Synopsis .............................................................................................................................. 3 
2. 
List of Abbreviations and Definitions of Terms ............................................................... 11 
Definitions of Terms ................................................................................................................ 12 
3. 
Introduction ...................................................................................................................... 13 
3.1 
Background on Telotristat Etiprate (LX1606) and Disease ................................ 13 
3.2 
Clinical Trials of Telotristat Etiprate (LX1606) in Humans ............................... 14 
3.2.1 
Phase 1 Studies .............................................................................. 14 
3.2.2 
Phase 2 Studies .............................................................................. 16 
3.2.3 
Ongoing Studies ............................................................................. 17 
3.3 
Rationale for Current Study ................................................................................ 18 
3.3.1 
Rationale for Selection of Dose ..................................................... 18 
3.3.2 
Benefit/Risk Assessment ................................................................ 18 
3.4 
Rationale for Study Design and Control Groups ................................................ 19 
4. 
Study Objectives ............................................................................................................... 20 
4.1 
Efficacy Objectives ............................................................................................. 20 
4.1.1 
Primary Objective .......................................................................... 20 
4.1.2 
Secondary Objective(s) .................................................................. 20 
4.2 
Safety Objectives ................................................................................................ 20 
5. 
Investigational Plan .......................................................................................................... 20 
5.1 
Overall Study Design .......................................................................................... 20 
6. 
Study Population .............................................................................................................. 21 
6.1 
Inclusion Criteria ................................................................................................ 21 
6.2 
Exclusion Criteria ............................................................................................... 22 
6.3 
Criteria for Stopping Treatment/Study Withdrawal ............................................ 22 
6.4 
Criteria for Termination of the Study .................................................................. 23 
6.5 
Clinical Stopping Rules ...................................................................................... 23 
6.6 
Method of Assigning Patients to Treatment ........................................................ 23 
6.7 
Blinding and Unblinding of Study Medication ................................................... 24 
6.8 
Replacement of Patients ...................................................................................... 24 
7. 
Treatment .......................................................................................................................... 24 
7.1.1 
Telotristat Etiprate (LX1606) ......................................................... 24 
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7.1.1.1 
Identity ......................................................................... 24 
7.1.1.2 
Packaging, Labeling, and Storage ................................ 24 
7.2 
Prior and Concomitant Medications ................................................................... 24 
7.2.1 
Prior Medications ........................................................................... 24 
7.2.2 
Concomitant Medications .............................................................. 24 
7.2.3 
Prohibited Medications or Concomitant Therapy .......................... 25 
7.3 
Administration of Study Medication .................................................................. 25 
7.3.1 
Treatment Compliance ................................................................... 25 
7.4 
Dose Adjustment ................................................................................................. 25 
8. 
Study Procedures .............................................................................................................. 26 
8.1 
Restrictions during Study .................................................................................... 26 
8.2 
Description of Study Assessments ...................................................................... 26 
8.2.1 
Efficacy Assessments ..................................................................... 26 
8.2.1.1 
EORTC QLQ-C30 & GI.NET21 ................................. 26 
8.2.1.2 
Subjective Global Assessment ..................................... 26 
8.2.2 
Clinical Laboratory Assessment .................................................... 26 
8.2.2.1 
Monitoring Hepatic Function ....................................... 27 
8.2.3 
Pharmacodynamic Assessments..................................................... 28 
8.2.3.1 
Plasma 5-HIAA ............................................................ 28 
8.2.4 
Safety Assessments ........................................................................ 28 
8.2.4.1 
Vital Sign Measurements ............................................. 29 
8.2.4.2 
Physical Examinations ................................................. 29 
8.2.4.3 
Electrocardiograms ...................................................... 29 
8.2.4.4 
Adverse Events of Special Interest .............................. 29 
8.2.4.4.1 
Central Nervous System Events ............... 30 
8.2.4.4.1.1  Depression Detection .......... 30 
8.3 
Other Assessments .............................................................................................. 30 
8.3.1 
Chromogranin A (CgA).................................................................. 30 
8.3.2 
Disease Progression ....................................................................... 30 
8.3.3 
Quality of Sleep Assessment .......................................................... 30 
8.4 
Appropriateness of Assessments ......................................................................... 30 
8.4.1 
Blood Collection ............................................................................ 31 
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9. 
Safety Reporting ............................................................................................................... 31 
9.1 
Adverse Events ................................................................................................... 32 
9.2 
Serious Adverse Events (SAEs) .......................................................................... 34 
9.2.1 
Hospitalization as an SAE ............................................................. 36 
9.3 
Suspected Unexpected Serious Adverse Reactions (SUSARs) .......................... 36 
9.4 
Precautions .......................................................................................................... 37 
9.4.1 
Pregnancy ....................................................................................... 37 
10.  Statistical Methodology .................................................................................................... 37 
10.1 
Determination of Sample Size ............................................................................ 37 
10.2 
Analysis Populations ........................................................................................... 38 
10.3 
Study Endpoints .................................................................................................. 38 
10.3.1 
Efficacy Endpoints ......................................................................... 38 
10.3.2 
Safety Endpoints ............................................................................ 38 
10.4 
Statistical Methods .............................................................................................. 38 
10.4.1 
Efficacy Analyses ........................................................................... 39 
10.4.2 
Safety Analyses .............................................................................. 39 
10.4.2.1 
Adverse Events ............................................................ 39 
10.4.2.2 
Clinical Laboratory Parameters ................................... 40 
10.4.2.3 
Vital Sign Measurements ............................................. 40 
10.4.2.4 
Electrocardiograms ...................................................... 40 
10.4.3 
Pharmacodynamic Analyses .......................................................... 40 
10.4.4 
Baseline Characteristics and Other Summaries ............................. 40 
10.4.5 
Interim Analysis ............................................................................. 41 
11.  Study Management ........................................................................................................... 41 
11.1 
Monitoring .......................................................................................................... 41 
11.2 
Audits and Inspections ........................................................................................ 42 
11.3 
Amendments ....................................................................................................... 42 
11.4 
Record Keeping .................................................................................................. 42 
11.4.1 
Drug Accountability ....................................................................... 42 
11.4.2 
Health Insurance Portability Accountability Act of 1996 and 
Subsequent Updates ....................................................................... 42 
11.4.3 
Financial Disclosure ....................................................................... 43 
11.4.4 
Access to Original Records ............................................................ 43 
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11.4.5 
Retention of Study Documents ...................................................... 43 
12.  Administrative Structure of the Study .............................................................................. 43 
13.  Appendix A – Schedule of Events .................................................................................... 45 
14.  Appendix B – Amount of Blood to be Collected from Each Patient ............................... 46 
15.  Appendix C – EORTC QLQ-C30 .................................................................................... 47 
16.  Appendix D – EORTC QLQ - GI.NET21 ........................................................................ 49 
17.  Appendix E – Ethical Standards ....................................................................................... 50 
18.  Appendix F – Investigator Obligations ............................................................................ 52 
19.  Appendix G – Guidance on the Selection of Patients ...................................................... 57 
20.  Appendix H - Guidance on the Use of Pro-serotonergic Drugs as Concomitant 
Medications ...................................................................................................................... 58 
21.  References ........................................................................................................................ 59 
 
 
 
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2. 
List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
5-HIAA 
5-hydroxyindoleacetic acid 
5-HT 
serotonin 
AE 
adverse event 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
ALP 
alkaline phosphatase 
AST 
aspartate transaminase 
bid 
twice daily 
BM 
bowel movements 
BMI 
body mass index 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CgA 
chromogranin A 
CNS 
central nervous system 
CRF 
case report form 
CRO 
contract research organization 
CS 
carcinoid syndrome 
CT 
computed tomography 
DSMB 
Data Safety Monitoring Board 
EC 
enterochromaffin 
ECG 
electrocardiogram 
ERC 
Ethic Review Committee 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HEENT 
head, eyes, ears, nose, and throat 
Hgb 
hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
IBD 
inflammatory bowel disease 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
Continued on the next page 
 
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Abbreviation 
Definition 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IMP 
Investigational Medicinal Product 
IWRS 
interactive web response system 
LAR 
long-acting release 
LS 
least square 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCP 
multiple comparison procedure 
MRI 
magnetic resonance imaging 
NET 
neuroendocrine tumor 
NRS 
numeric rating scale 
OOR 
out-of-range 
OTC 
over-the-counter 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
qd 
once daily 
SAE 
serious adverse event 
SBS 
short bowel syndrome 
SOP 
standard operating procedure 
SSA 
somatostatin analog 
SUSAR 
suspected unexpected serious adverse reactions 
TEAE 
treatment-emergent adverse events 
tid 
3 times daily 
TPH 
tryptophan hydroxylase 
ULN 
upper limit of the normal reference range 
WRS 
Wilcoxon rank sum 
 
Definitions of Terms  
Term 
Definition 
LP-778902 
active moiety of LX1606 
LX1606 
telotristat ethyl: the ethyl-ester prodrug of the active moiety LP-
778902; a serotonin synthesis inhibitor being developed by Lexicon 
Pharmaceuticals, Inc. 
QTcF 
corrected QT interval using Fredericia’s formula 
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3. 
Introduction 
3.1 
Background on Telotristat Etiprate (LX1606) and Disease 
Serotonin (5-HT) plays a critical role in regulating several major physiological processes of 
the gastrointestinal tract, including aspects of secretion, motility, inflammation and sensation. 
Enterochromaffin (EC) cells release 5-HT when the intestinal wall is stimulated by 
intraluminal pressure or chemicals. Through multiple classes of receptors, 5-HT is believed to 
initiate directly, or facilitate, peristaltic and secretory reflexes. 5-HT is also reportedly 
involved in the pathophysiology of various types of functional gastrointestinal (GI) disorders, 
valvular heart disease, and may play a role in the pathophysiology of inflammatory bowel 
disease (IBD).  
Carcinoid tumors are mostly derived from EC cells of the midgut, and often produce and 
release large amounts of 5-HT. Such excess of 5-HT is believed to be responsible for the 
severe diarrhea and eventual valvular heart damage and mesenteric fibrosis in patients with 
carcinoid syndrome (CS).1-3 Inhibition of tryptophan hydroxylase (TPH) activity in carcinoid 
tumors should lead to a reduction of peripheral 5-HT in afflicted patients and thus an 
amelioration of the pathophysiology and symptomology of CS. A peripheral TPH inhibitor, 
such as telotristat etiprate, should alleviate the symptoms due to excess 5-HT in carcinoid 
patients without central nervous system (CNS)-related adverse events (AEs). 
Approximately 90% of the body's 5-HT is found in the EC cells of the GI tract, with the 
remainder distributed between the platelets and CNS.4 TPH catalyzes the biopterin-dependent 
monooxygenation of tryptophan to 5-hydroxytryptophan, which is subsequently 
decarboxylated to form 5-HT. Expression of TPH is limited to a few specialized tissues:  
raphe neurons, pinealocytes, mast cells, mononuclear leukocytes, beta cells of the islets of 
Langerhans, and intestinal and pancreatic EC cells.5 Two isoforms of the enzyme exist, TPH1 
and TPH2. TPH1 is exclusively located in the EC cells of the GI tract and pineal gland and is 
the rate limiting enzyme responsible for the majority of systemic 5-HT production and is also 
responsible for 5-HT synthesis in carcinoid tumors. TPH2 is located in the central and enteric 
nervous systems and is the rate-limiting enzyme in the production of neuronal 5-HT. 
The oral TPH inhibitor, telotristat etiprate, represents a novel approach to potentially lessen 
the pathophysiology of CS by reducing 5-HT levels via inhibition of TPH. Telotristat etiprate 
was designed specifically as a prodrug in order to gain greater systemic exposure, opening 
the potential application for indications in which hyperserotonemia is thought to contribute to 
the disorder, such as CS. Preclinical pharmacology studies of telotristat etiprate were 
designed to evaluate the compound’s mechanism of action and effects in vivo. Telotristat 
etiprate is the ethyl-ester prodrug of the active moiety LP-778902. Telotristat etiprate was 
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designed as a prodrug in order to enhance peripheral exposure without crossing the blood-
brain barrier. In vivo, telotristat etiprate is readily converted through esterase activity to its 
corresponding acid, LP-778902. LP-778902 has an in vitro potency of 0.028 μM on purified 
human TPH1 enzyme and 0.032 μM on purified human TPH2 enzyme. Therefore, telotristat 
etiprate is a robust inhibitor of TPH both in vitro and in vivo and has been shown in Phase 2 
studies to provide clinical benefit to patients with carcinoid tumors and associated CS.  
Telotristat etiprate is being developed to manage GI symptoms and possibly other symptoms 
associated with CS. Currently, the standard of care for patients with CS is symptom 
management using somatostatin analogs (SSA), which are available in both short- and long-
acting release (LAR) formulations. Somatostatin analogs such as octreotide are indicated for 
the control of flushing, diarrhea, and other symptoms associated with CS. Common side 
effects of the long-acting depot form of the drug are pain at the site of the injection, reported 
in as many as 30 to 50% of carcinoid patients at the 20 and 30 mg dose levels, and less 
commonly, stomach cramps, nausea, vomiting, headaches, dizziness, and fatigue.6 Other side 
effects identified in the product labeling include biliary tract abnormalities (gallstones, 
sludge, and dilatation), hypothyroidism, dietary fat malabsorption, and hyper or 
hypoglycemia.7 In addition to the morbidity associated with parenterally administered agents, 
tachyphylaxis will occur in the majority of patients, resulting in recurrent symptoms. 
There are currently no specific oral treatments indicated for the management of symptoms 
associated with CS. As a result of the morbidity associated with SSAs and the associated 
tachyphylaxis, there is an unmet medical need to provide symptom management and modify 
the pathophysiology of patients with metastatic CS. Inhibition of the excessive 5-HT 
produced by these tumors with an orally delivered agent such as telotristat etiprate could 
provide significant benefit as an additional treatment option for patients and clinicians.  
3.2 
Clinical Trials of Telotristat Etiprate (LX1606) in Humans 
Telotristat etiprate has been studied in single/multiple doses in Phase 1 studies, approximately 
117 healthy volunteers participated in Phase 1 trials with 96 subjects receiving telotristat 
etiprate and 21 subjects receiving placebo. In addition, 37 patients with CS have received 
telotristat etiprate during the clinical development program in Phase 2.  An additional 59 
patients with ulcerative colitis have been enrolled into an ongoing Phase 2 study to evaluate 
telotristat etiprate versus placebo in patients with ulcerative colitis experiencing active flares. 
3.2.1 
Phase 1 Studies 
LX1606.1-101-NRM utilized telotristat etiprate as a single oral dose and was noted to be safe 
and well tolerated up to doses of 1,000 mg. At doses of ≥1,000 mg, an increase in GI AEs 
was observed, which were assessed as at least possibly related to study drug. These AEs led 
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to a decision not to escalate the dose beyond 1,500 mg. No serious adverse events (SAEs) or 
deaths were reported and no patient discontinued due to an AE. Twenty-three patients 
experienced at least 1 AE. The majority of the AEs were assessed as mild. The most common 
AEs were diarrhea and nausea. Random out-of-range laboratory values at various time points 
in several patients occurred without any apparent trend. There were no other clinically 
significant vital signs, laboratory or physical examination findings.  
LX1606.1-102-NRM utilized telotristat etiprate as multiple oral doses over 14 days and was 
tolerated up to the maximum dose assessed, 500 mg tid; 1,500 mg total dose daily. Most AEs 
were mild, the most common being nausea and headache; all resolved. Most AEs were at 
least possibly related to study treatment. Four AEs required treatment with concomitant 
medication, 3 AEs of constipation and 1 of headache. No deaths or SAEs were reported. One 
patient was discontinued due to an AE of abnormal liver function. There were no apparent 
trends or clinically significant findings observed upon review of vital signs and 
electrocardiogram (ECG) data. There were no clinically significant abnormal physical 
examination findings. 
Overall, in LX1606.1-102-NRM, treatment with telotristat etiprate was associated with mild 
elevations, generally ≤2x the upper limit of normal (ULN), in alanine transaminase (ALT) 
and aspartate transaminase (AST), with elevations in values observed earlier in the higher 
dose cohorts. Results were assessed as clinically significant for only 1 patient, in Cohort 4, 
who was withdrawn on Day 10. The trend was most pronounced in Cohort 5, in which 5 out 
of 6 patients who received telotristat etiprate had increases in ALT values which were above 
normal range and 4 patients had increases in AST values which were above normal range at 
Day 14. Mean increases in ALT and AST appeared earlier in the study for Cohorts 4 and 5 
than in the other cohorts, and were noted for all cohorts by Day 12. All patients had normal 
ALT and AST values at Baseline and most elevated transaminases returned to normal range 
within 48 hours after the last dose of study drug. No changes in alkaline phosphatase (ALP) 
or total bilirubin were observed in any patient. 
LX1606.1-103-NRM evaluated 2 oral formulations of telotristat etiprate in an open-label 
crossover study. Each formulation was given as a single oral dose followed by a 5-day 
washout and then patients were given a single oral dose of the second formulation. During 
this study, there were no deaths or SAEs reported and no AEs lead to discontinuation. The 
most commonly reported AE was diarrhea. No clinically significant observations or changes 
in other safety parameters (eg, clinical laboratory evaluations, vital signs, physical 
examinations, ECGs, and AEs) were identified in the patient population during the study 
conduct. 
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LX1606.1-104-NRM was designed to evaluate the pharmacokinetics, metabolism, and routes 
and extent of elimination of telotristat ethyl and its primary metabolite (LP-778902) in 8 
healthy male subjects after a single oral dose of 500 mg radio-labeled telotristat etiprate 
(14C-LX1606). This study has been completed and the results will be discussed in the annual 
update of the Investigator Brochure. 
3.2.2 
Phase 2 Studies 
LX1606.1-202-CS was a randomized, double-blind, placebo-controlled, multiple ascending 
dose study conducted in 2 parts in order to evaluate a total of 23 patients at a dose range of 
450 to 1500 mg given as 150, 250, 350, or 500 mg tid (telotristat etiprate or matching 
placebo) on a background therapy of octreotide. In Part 1, 16 patients were randomly 
assigned 3:1 into 4 sequential cohorts. Each cohort evaluated 1 of the following daily doses 
given as 150, 250, 350, or 500 mg tid over a course of 4 weeks. During the study, all patients 
continued on a stable-dose background therapy of octreotide. In Part 2, an additional 7 
patients were randomly assigned 3:1 in order to evaluate 500 mg tid, the highest tolerated 
dose as determined in Part 1. Upon completion of the initial 4-week portion, eligible patients 
had the option to continue into an open-label Extension Period. 
There was 1 treatment emergent SAE assessed as possibly related to study drug which 
occurred in the 350 mg tid dose group. The patient had a history of nausea and vomiting and 
was hospitalized for exacerbation of these conditions.  
Telotristat etiprate was generally well tolerated with no evidence of dose-limiting tolerability. 
Adverse events were mostly mild to moderate and with similar frequencies between 
treatment groups and placebo. No significant changes in vital signs, ECG, or physical exam 
findings were noted after administration of telotristat etiprate at any dose level. The most 
common AEs were GI-related and reported as diarrhea, nausea, and abdominal pain, 
respectively. The modest elevations in transaminases seen in the Phase 1 multiple ascending 
dose study (LX1606.1-102-NRM) were not apparent in this 4-week study in patients with CS.  
Patients that received telotristat etiprate achieved a clinical response (28%) defined as at least 
a 30% reduction in bowel movements (BMs) for at least 2 weeks; a biochemical response 
(56%) defined as at least a 50% reduction or normalization of urinary 5-hydroxyindoleacetic 
acid (5-HIAA); and reported adequate relief at Week 4 (46%) while no placebo patients 
experienced clinical response, biochemical response, or adequate relief. 
LX1606.1-203 was an open-label, serial ascending, multiple dose, individual titration study 
that evaluated the same dose ranges as the LX1606.1-202-CS study in a total of 15 patients. 
Patients were serially escalated to the next dose level every 2 weeks until a maximally 
tolerated dose or 500 mg tid was reached. Once a dose had been determined, the patient 
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would remain on the dose for an additional 4 weeks. Patients then had the option to continue 
into an Extension Period.  
Telotristat etiprate was generally safe and well-tolerated in subjects with CS in the 
LX1606.1-203 study. Most AEs were mild to moderate in severity and assessed as unrelated 
to study drug. Events in the Gastrointestinal Disorders system organ class were common, as 
is anticipated with the underlying illness. 
Statistically significant reductions from Baseline in the mean number of BMs/day were 
observed in this study throughout the entire dose-escalation and stable-dose phases, as were 
improvements in stool form. Telotristat etiprate produced an improvement in global 
assessment of GI symptoms associated with CS in the majority of subjects (12 of 15 subjects, 
80%) across the 12-week period. The global assessment of GI symptoms was based on the 
following question, “In the past 7 days, have you had adequate relief of your carcinoid 
syndrome bowel complaints such as diarrhea, urgent need to have a BM, abdominal pain or 
discomfort?” In addition, subjects experienced statistically significant decreases in the mean 
daily number of cutaneous flushing episodes. 
Thirteen subjects (86.7%) experienced a complete biochemical response (defined as a ≥50% 
reduction from Baseline in u5-HIAA levels at 1 or more time points). Consistent with the 
proposed mechanism of action for telotristat etiprate, a complete biochemical response 
correlated closely with measures of clinical response, such as number of bowel movements 
per day. 
LX1606.1-204-UC evaluated patients with active flares of ulcerative colitis. Doses under 
evaluation are 500 mg once daily (qd) and 500 mg tid vs. placebo; 59 patients were enrolled 
for an 8-week treatment period. This study has been completed and the results will be 
discussed in the annual update of the Investigator Brochure. 
Detailed information regarding the completed clinical studies can be found in the Investigator 
Brochure.8 
3.2.3 
Ongoing Studies 
The open-label extension portions in LX1606.1-202-CS and LX1606.1-203-CS remain 
ongoing. 
LX1606.1-301-CS is intended to evaluate patients who are currently on a background of SSA 
therapy and still experiencing breakthrough symptoms such as an increased frequency of 
BMs ≥4 per day on average: (1) the efficacy of telotristat etiprate on reducing the number of 
BMs; (2) the efficacy of telotristat etiprate on a number of clinically relevant secondary 
endpoints; and, (3) the safety of telotristat etiprate over the 12-week double-blind portion 
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(Treatment Period) of the study. Upon completion of the Treatment Period, patients will 
continue into a 36-week open-label Extension Period (Extension Period).  
LX1606.1-303-CS is intended to evaluate patients with carcinoid syndrome whose primary 
symptoms are not GI related and may be naïve to SSA therapy: (1) the safety of telotristat 
etiprate over the 12-week double-blind portion (Treatment Period) of the study; (2) percent 
(%) change from Baseline in 24-hour u5-HIAA levels at Week 12; (3) the effects of telotristat 
etiprate on a number of clinically relevant secondary endpoints. Upon completion of the 
Treatment Period, patients will continue into a 36-week open-label Extension Period. 
3.3 
Rationale for Current Study 
3.3.1 
Rationale for Selection of Dose 
The dose levels of telotristat etiprate selected for this study are consistent with prior clinical 
study experience and based upon clinical safety and pharmacodynamic (PD) data from 2 
Phase 2 multiple ascending-dose studies in patients with symptomatic CS (LX1606.1-202-CS 
and LX1606.1-203-CS).  
Based upon observations noted in Section 3.2, it is anticipated that the doses to be utilized in 
this protocol will be safe and well tolerated and may provide clinical benefit to patients with 
CS. 
3.3.2 
Benefit/Risk Assessment 
Clinical experience with telotristat etiprate (treated subjects) consists of completed single and 
multiple ascending dose studies in 96 normal subjects (44 in single dose studies and 52 in the 
multiple dose study), 2 Phase 2 studies (37 patients with symptomatic CS) and 2 ongoing 
Phase 3 studies in patients with symptomatic CS. 
In healthy volunteer studies, single doses up to 1000 mg were found to be generally well 
tolerated, while at the 1500 mg dose level GI-related adverse events increased. A similar 
adverse event profile was observed after multiple dose administration over 14 days with GI 
events predominating. Mild, dose-dependent increases in hepatic transaminase levels (≤2 x 
ULN) were observed with increased frequency in relation to dose, with 1 subject requiring 
withdrawal from therapy at the 500 mg bid dose level. Most subjects that were observed to 
have increased transaminase levels did not exceed >2 x ULN. No abnormalities in total 
bilirubin were observed at any dose level. GI events have been the most commonly observed 
events to date. The adverse event profile in normal subjects may differ significantly from 
what is observed in patients with hyperserotonemia. All adverse events resolved without 
sequelae. In addition, there were no significant changes in vital signs or ECG. No physical 
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examination abnormalities were noted in studies to date. There were no serious adverse 
events reported in healthy volunteers. 
In patients with CS, dose escalations have proceeded up to and including 500 mg tid. To date, 
there has been no evidence of dose-limiting intolerability. Dose levels have been generally 
well tolerated with no evidence to suggest elevations in hepatic transaminase levels. Based 
upon observations from preclinical and clinical studies conducted to date, it is anticipated that 
orally administered telotristat etiprate will be well tolerated at dose levels required to 
influence peripheral 5-HT production in patients with symptomatic CS. Potential adverse 
events primarily involve the GI tract, and could include alterations in gut motility, nausea, 
vomiting, diarrhea, constipation, abdominal bloating, and/or pain. Regular and ongoing 
clinical and laboratory assessments should detect any of these events, and depending on the 
type of event, further dose adjustment or discontinuation from the trial would occur. Although 
CNS effects are not anticipated at dose levels planned for evaluation, standard adverse event 
questioning and/or physical examination should reveal any subtle CNS findings. As 
elevations in hepatic transaminase levels were observed with multiple dosing in normal 
subjects, monitoring clinical laboratory tests of hepatic function will be incorporated into 
clinical trials conducted in CS patients. 
Treatment has the potential to improve several signs and symptoms of CS. The Phase 2 
clinical trial results indicated that treatment may lead to improvements in BM frequency, 
stool consistency, urgency, abdominal pain, diarrhea, flushing, and reductions in 5-HIAA. 
These potential benefits relate to a unique mechanism of action. Symptomatic improvement 
may lead to a better quality of life (QOL) for patients with few treatment options available, 
and a reduction in serotonin may help reduce the risk of carcinoid heart disease. Overall the 
benefit/risk profile of telotristat etiprate is expected to be favorable for participation in this 
clinical study. 
3.4 
Rationale for Study Design and Control Groups 
Currently, no approved therapy exists for the treatment of symptoms driven by underlying 
serotonin pathophysiology of CS in patients whose disease is refractory to SSA therapy or for 
those patients who are unable to tolerate SSA therapy or who are unwilling to take SSA 
therapy. 
This study will allow for continued access to telotristat etiprate after patients have completed 
the required study visits in ongoing Phase 2 and Phase 3 studies. Continuation of CS patients 
into this study will allow for the collection of additional long-term safety and efficacy data, 
while providing access to patients who may be receiving benefit. The treatment duration is 
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supported by results of chronic toxicology studies (6-month rat and 9-month dog) and the 
current safety profile from completed and ongoing clinical trials. 
4. 
Study Objectives 
4.1 
Efficacy Objectives 
4.1.1 
Primary Objective 
The primary objective of the study is to evaluate the long-term safety and tolerability of 
orally administered telotristat etiprate. 
4.1.2 
Secondary Objective(s) 
The secondary objective of this study is to evaluate changes in patients’ QOL. 
4.2 
Safety Objectives 
Evaluation of overall safety will be assessed as: 
 Incidence of treatment-emergent adverse events (TEAEs) 
 Changes from Baseline in clinical laboratory results, vital signs results, and ECG 
findings 
5. 
Investigational Plan 
5.1 
Overall Study Design 
The study will be conducted as a multicenter, open-label, long-term extension study to further 
evaluate long-term safety and tolerability of telotristat etiprate. 
Patients currently participating in any LX1606 Phase 2 CS study may enter into this 
extension study upon institutional or local approval of the protocol. Patients participating in a 
Phase 3 CS study may enter into this extension study at the Week 48 visit. All patients who 
enter into this extension study will be exempt from any follow-up visit required by the 
original study and will not experience an interruption in study drug due to the transition from 
the original protocol to LX1060.1-302-CS. 
Following confirmation of eligibility, patients will complete a series of visit assessments in 
order to establish Baseline symptoms. Patients will then continue on open-label LX1606 at 
the same dose level identified in the original study.  
Downward dose adjustment will be permitted during the study if evidence of intolerability 
emerges. Patients who experience intolerability at the 250 mg tid dose level must be 
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discontinued from the study. Patients may return to the previous dosing at the discretion of 
the Investigator and in consultation with the Medical Monitor. 
Upon completion or early withdrawal from treatment, all patients will be required to 
complete a 14-day Follow-up Period, during which no study drug will be administered.  
A Data Safety Monitoring Board (DSMB) will review safety data quarterly throughout the 
study.  
6. 
Study Population 
Adult patients who are currently participating in ongoing Phase 2 or Phase 3 telotristat 
etiprate CS clinical protocols will be enrolled into the study. Up to 100 patients are expected 
to enroll in this study. Approximately 70 sites worldwide will participate in the study. Patients 
may continue allowed medications as background therapy provided they remain on stable- 
doses throughout the Treatment Period. 
6.1 
Inclusion Criteria 
Patients must meet all of the following criteria to be considered eligible to participate in the 
study: 
1. Ongoing participation in a Phase 2 (eg, LX1606.1-202-CS, LX1606.1-203-CS) or 
Phase 3 (eg, LX1606.1-301-CS, LX1606.1-303-CS) study  
2. Patients of childbearing potential must agree to use an adequate method of 
contraception (defined as having a failure rate of <1% per year) during the study and 
for 12 weeks after the Follow-up visit. Adequate methods of contraception for 
patients or partner include condoms with spermicide gel, diaphragm with spermicide 
gel, coil (intrauterine device), surgical sterilization, vasectomy, oral contraceptive pill, 
depot progesterone injections, progesterone implant, and abstinence during the study 
and for 12 weeks after the Follow-up Visit.  
a. Childbearing potential is defined as those who have not undergone surgical 
sterilization, or those who are not considered postmenopausal. Postmenopause 
is defined as absence of menstruation for at least 2 years. If necessary, follicle-
stimulating hormone (FSH) results >50 IU/L at Baseline Day 1 are 
confirmatory in the absence of a clear postmenopausal history. 
3. Ability and willingness to provide written informed consent prior to participation in 
any study-related procedure. 
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6.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participating in the 
study:   
1. Major protocol violations or telotristat etiprate tolerability concerns in a Phase 2 (eg, 
LX1606.1-202-CS, LX1606.1-203-CS) or Phase 3 (eg, LX1606.1-301-CS, 
LX1606.1-303-CS) study  
2. Positive pregnancy test 
3. Presence of any clinically significant findings at entry for medical history, laboratory 
values, or physical examination (relative to patient population) that, in the 
Investigator’s or Medical Monitor’s opinion, would compromise patient safety or the 
outcome of the study 
4. Patients who are currently committed to an institution by virtue of an order issued 
either by judicial or administrative authorities 
6.3 
Criteria for Stopping Treatment/Study Withdrawal 
A patient may also be discontinued from the study for the following medical or 
administrative reasons: 
 Withdrawal of consent by the patient or legal guardian 
 Noncompliance, including refusal of the study medication and/or failure to adhere to 
the study requirements as in the study protocol 
 Investigator decides that, in the interest of the patient, it is not medically acceptable to 
continue participation in the study 
 The Sponsor terminates the study (Section 6.4) 
 Pregnancy (Section 9.4.1) 
Note:  If a patients voluntarily withdraws or is discontinued from study treatment before 
completing the entire duration of the Treatment Period, they should be encouraged to 
continue clinic visits according to the study schedule.  
Patients who discontinue study treatment, and who are not willing to continue clinic visits 
(eg, withdrawal of consent) should be encouraged to complete End-of-Study (EOS) 
assessments as identified in Appendix A – Schedule of Events and agree to report any SAEs 
(Section 9.2) that occur within 30 days following the last dose of telotristat etiprate. 
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The date the patient discontinues study treatment, the primary reason for study treatment 
discontinuation, study termination, and/or termination of participation (eg, withdrawal of 
consent), will be captured within the Case Report Form (CRF). 
When patients withdraw consent from study participation, it must be recorded on the CRF 
whether the withdrawal of consent applies to specific aspects of the study such as 
discontinuation of study treatment, participation in study visits, contact by study personnel, or 
access to information about potential SAEs. If specific consent has not been withdrawn, study 
personnel should contact the patient (or a previously approved designee such as a caregiver, 
partner, or family member) at the scheduled Follow-up visit to inquire about health status. 
6.4 
Criteria for Termination of the Study 
If the Sponsor, Investigator, study monitor, DSMB, or regulatory officials discover conditions 
arising during the study that indicate that the patient safety and/or scientific value of the study 
and/or quality of the study drugs have been compromised, the study should be halted or the 
study center’s participation should be terminated. Conditions that may warrant termination of 
the study include, but are not limited to, the following: 
 The discovery of an unexpected, serious, or unacceptable risk to the patients enrolled in 
the study; 
 A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product for carcinoid syndrome or any other indication for any 
reason; 
 Failure of the Investigator to enroll patients into the study at an acceptable rate; 
 Failure of the Investigator to comply with pertinent governing body regulations; 
 Submission of knowingly false information from the research facility to the Sponsor, 
study monitor, medical officer, or regulatory official; and, 
 Insufficient adherence to protocol requirements.  
Study termination and Follow-up would be performed in compliance with applicable 
governing body regulations. 
6.5 
Clinical Stopping Rules 
Criteria for individual patient withdrawal or study termination are summarized in Sections 
6.3 and 6.4, respectively. 
6.6 
Method of Assigning Patients to Treatment  
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Patients will enter the study at the same dose level and regimen as identified in the prior 
Phase 2 or Phase 3 CS study. Randomization will not be used to assign patients to study 
treatments. 
6.7 
Blinding and Unblinding of Study Medication 
This is an open-label study.  
6.8 
Replacement of Patients 
Patients who do not complete the study will not be replaced. 
7. 
Treatment 
7.1.1 
Telotristat Etiprate (LX1606) 
7.1.1.1 
Identity 
Telotristat etiprate (LX1606 hippurate) is the salt form of the drug substance. LX1606 
hippurate is a crystalline white to off-white to tan solid with a melting point of 147°C. 
LX1606 is insoluble in water within the pH range of 5 to 9 (≤2 mg/L). It undergoes 
hydrolysis under strongly basic or strongly acidic conditions. The solubility of LX1606 
hippurate in water is about 22 mg/L at 25°C. 
Study drug dosage form consists of white coated debossed oval tablets containing 250 mg 
LX1606. 
7.1.1.2 
Packaging, Labeling, and Storage 
Patients will receive 250-mg telotristat etiprate tablets packaged in 100 cc high density 
polyethylene bottles with child-resistant polypropylene screw caps and heat-induction seal 
liners.  
Telotristat etiprate should be stored between 15 to 25°C (59 to 77°F). 
7.2 
Prior and Concomitant Medications 
7.2.1 
Prior Medications 
All medications and other treatments taken by patients within 30 days prior to entry will be 
recorded on the CRF.  
7.2.2 
Concomitant Medications 
All concomitant medications taken by patients during the study will be recorded on the CRF. 
Treatment with prescription or over-the-counter (OTC) antidiarrheal therapy, bile acid 
sequestrants, or pancreatic enzyme is permitted; however, the use of these concomitant 
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therapies should be associated with a documented history of disease (eg, fat malabsorption, 
bile acid malabsorption, or steatorrhea).  
 Medical management of patients and their concomitant medications is allowed at the 
discretion of the Investigator. However, should the need arise to modify/adjust a patient’s 
therapy due to a concern for patient safety and/or tolerability the Medical Monitor should be 
contacted. The Investigator and Medical Monitor will make a determination if such a change 
would impact the safety of the patient and the integrity of the study. The Medical Monitor 
will determine if the patient can continue in the study. 
7.2.3 
Prohibited Medications or Concomitant Therapy 
None 
7.3 
Administration of Study Medication 
All patients will be instructed to take the study medication with food. “With food” means 
taking telotristat etiprate tablets within 15 minutes before or within 1 hour after a meal or 
snack. Patients will be instructed to take study drug 3 times daily during waking hours, with 
doses spaced approximately 6 hours apart.  
Study medication and instructions will be dispensed to patients at each visit as described in 
the schedule of study procedures (Appendix A). 
7.3.1 
Treatment Compliance  
Patients will be asked to bring their unused or unopened study medication to each visit 
(Appendix A). At each visit and in the presence of the patient, study site personnel will count 
returned tablets and reconcile the counts against planned number of doses for that interval. 
Site personnel will clarify any discrepancy and record this information within the CRF.  
Patients must maintain at least 75% compliance in dosing to be deemed as compliant. In the 
event of a missed or vomited dose, patients will take their subsequent dose of study drug at 
the next scheduled time point, following the tid dosing regimen of approximately every 6 
hours. A dose outside of a 3-hour window should be considered missed. Missed or vomited 
doses will not be made up.  
7.4 
Dose Adjustment 
Downward dose adjustment of telotristat etiprate will be permitted if evidence of 
intolerability emerges. After a period at the lowered dose level, patients may resume the 
previous dosing level at the discretion of the Investigator after consultation with the Medical 
Monitor. Patients who experience intolerability at the 250 mg tid dose level must be 
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discontinued from study treatment. Interruptions or delays in dosing throughout the entire 
study may be permitted after consultation with the Medical Monitor, at which time the patient 
will be reassessed for study continuation, dosage reduction, or discontinuation. 
8. 
Study Procedures 
A schedule of study assessments is provided in Appendix A. 
8.1 
Restrictions during Study 
Patients should be advised to avoid food and drink containing grapefruit for 2-3 hours prior to 
and following dosing while participating in the study. 
8.2 
Description of Study Assessments 
8.2.1 
Efficacy Assessments 
Efficacy assessments include the patient reported QOL measures; EORTC QLQ-C30 
(Appendix D) & GI.NET21 (Appendix E) questionnaires and subjective global assessment of 
symptoms associated with CS. 
A description of the efficacy assessments is provided below. 
8.2.1.1 
EORTC QLQ-C30 & GI.NET21 
Patients will complete the questionnaires during each visit as indicated in Appendix A. 
8.2.1.2 
Subjective Global Assessment 
A subjective global assessment of symptoms associated with CS will be evaluated using 2 
methods at each visit.  
Patients will first be asked to respond to the following question:  “In the past 7 days, have 
you had adequate relief of your carcinoid syndrome bowel complaints such as diarrhea, 
urgent need to have a bowel movement, abdominal pain, or discomfort?”. 
Then patients will be asked the following question to assess global symptoms associated with 
CS on an 11-point scale: “Rate the severity of your overall carcinoid symptoms over the past 
7 days on a scale from 0-10, where 0 = no symptoms and 10 = worst symptoms ever 
experienced.” 
8.2.2 
Clinical Laboratory Assessment  
Clinical laboratory assessments will consist of hematology (complete blood count [CBC] 
with differential and platelet counts), blood chemistry (complete metabolic panel and liver 
function tests), and urinalysis. All laboratory tests will be performed by a central laboratory, 
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with the exception of the urine pregnancy test, which will be performed by the study site with 
the provided laboratory kit.  
The incidence of clinically significant laboratory values, as well as clinically significant shifts 
in laboratory values, should be reported as an AE in the patient’s CRF (see also Section 9.1 
for reporting of AEs related to laboratory abnormalities). The Investigator will assess any 
clinically significant values relevant to the patient population to determine if termination of 
the study drug is required. 
8.2.2.1 
Monitoring Hepatic Function 
Patients with clinically significant abnormalities in liver function tests should be excluded 
from participating; however, the patient’s clinical situation as a whole should be taken into 
account when evaluating hepatic transaminase elevations, which may represent a 
consequence of the underlying disease and/or therapeutic interventions. Patients with 
abnormalities in liver function test results, as defined below, should be further assessed by the 
Investigator and may have additional tests performed by the central laboratory as clinically 
indicated. The following describes the Sponsor’s recommended approach to evaluating these 
events. This approach is not meant to replace the Investigator’s clinical judgment.  
These guidelines apply to the following events: 
1) A new confirmed result (after Day 1 dosing) of ALT or AST >3 x ULN (in 
patients previously within normal range) 
OR 
2) A confirmed increase in transaminases above the patient’s previous Baseline to a 
degree that is significant in the clinical judgment of the Investigator and ALT or 
AST >3 x ULN (in patients with previous abnormal liver-test results) 
OR 
3) Any occurrence of an elevation of ALT or AST >3 x ULN and total bilirubin >2 x 
ULN (in any patient) 
For any such event, the Investigator should discuss the Follow-up approach with the Medical 
Monitor.  
The Sponsor’s recommended approach is as follows: 
1. Schedule the patient for a Follow-up visit within 3 days following the receipt of 
laboratory results to assess the patient and conduct further evaluation, to include the 
following: 
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a. Obtain repeat testing of ALT, AST, total bilirubin, and ALP through the central 
laboratory. 
b. Reassess the patient through patient interview and physical examination to 
uncover new or emerging risk factors of liver injury including an increased use 
of alcohol, gallbladder disease, hemochromatosis, fatty liver, use of 
hepatotoxic concomitant medications (including acetaminophen), occupational 
exposures, liver metastases, and other causes for potential clues as to the 
underlying etiology of the event. 
c. Continue to monitor the patient’s transaminases and total bilirubin regularly 
until the liver function test values return to Baseline levels.  
Additional recommendations include: 
 Consider referral to a hepatologist or gastroenterologist 
 Consider reimaging (eg, ultrasound, CT, or MRI) the liver and biliary tract 
 Consider additional laboratory testing as clinically indicated. Laboratory assays 
available to the Investigator for further workup are described in the laboratory manual 
Upon completion of hepatic assessment, the Investigator should review results with the 
Medical Monitor and assess continued study participation. 
8.2.3 
Pharmacodynamic Assessments 
8.2.3.1 
Plasma 5-HIAA 
Fasting blood samples (≥6 hours) for measurement of 5-HIAA in plasma will be collected 
and analyzed by a specialty laboratory. All sample processing information will be supplied by 
the laboratory in a separate document/study manual. Efforts should be made to schedule these 
visits in the morning, with instructions to the patient to arrive in a fasted state and not dose 
prior to the blood draw. 
8.2.4 
Safety Assessments 
In addition to the clinical laboratory assessments described in Section 8.2.2, monitoring of 
AEs is also considered a safety assessment and is described in detail in Section 9. Clinically 
significant changes compared with Baseline findings for these variables should be reported as 
AEs on the CRF. Clinically significant changes compared with Baseline values, which are 
determined to be AEs, should be followed until the event has resolved, the condition has 
stabilized, etiology of the event is determined to be not related to study drug, or the patient is 
lost to Follow-up. 
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8.2.4.1 
Vital Sign Measurements 
Measurement of vital signs will include assessment of blood pressure, respiratory rate, pulse 
rate, and oral temperature. Vital sign measurements should not be conducted with the 
30 minutes immediately following any phlebotomy. 
Efforts should be made to standardize blood pressure collection across all patients and visits. 
Patients should be seated for at least 5 minutes prior to collection. All measurements should 
be assessed on the same arm, and by the same technician where possible. 
Additional measurements may be obtained if clinically indicated. Vital sign measurements 
will be measured as indicated in Appendix A. 
8.2.4.2 
Physical Examinations 
Complete physical examinations will be performed as outlined in Appendix A. Complete 
physical examinations will include a minimum of a review of the patient’s general 
appearance, head, eyes, ears, nose, and throat (HEENT), neck, heart, lungs, abdomen, back 
and extremities, skin, and general neurological system.  
Symptom-oriented physical examinations will be performed at all other time points and as 
clinically indicated.  
In addition, weight will be captured during each physical examination. Efforts should be 
made to standardize weight collection across all patients and visits. Patients should be 
instructed to remove shoes and heavy clothing (eg, heavy coats, jackets) prior to 
measurement. For weight collection, an effort should be made to use the same scale 
throughout the study where possible. In instances where multiple scales may be used, efforts 
should be made to reset the scale to zero prior to collection of weight measurement. 
8.2.4.3 
Electrocardiograms 
Electrocardiograms (12-lead ECGs) will be performed as specified in Appendix A. 
8.2.4.4 
Adverse Events of Special Interest 
Monitoring of these events will be the responsibility of the DSMB. The process of data 
collection and assessment of the events will be detailed in a separate DSMB charter.  
Additional information will be collected if episodes of any of the following AEs of special 
interest occur. 
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8.2.4.4.1 
Central Nervous System Events 
Central nervous system events of special interest may include any clinically significant 
changes in mood, physical affect, or exacerbation of preexisting CNS conditions (eg, 
depression, migraine headaches). 
8.2.4.4.1.1 
Depression Detection 
Patients will be evaluated beginning at Day 1 (Baseline) and at each subsequent visit for 
indications of depression. During each visit the patient will first be asked to respond to the 
question “During the past month, have you often been bothered by feeling down, depressed, 
or hopeless?” Followed by “During the past month, have you often been bothered by little 
interest or pleasure in doing things?” A positive response prior to Day 1 dosing will be 
captured on the medical history CRF page. Positive responses following the first dose will be 
captured as an AE and will be followed as an AE of special interest.  
8.3 
Other Assessments 
8.3.1 
Chromogranin A (CgA) 
Blood samples for measurement of chromogranin A (CgA) levels will be collected as 
indicated in Appendix A. 
8.3.2 
Disease Progression 
Data will also be collected on measures of disease progression as performed as standard of 
care including, but not limited to: interpretation of clinical scans (eg, PET, CAT, MRI scans 
of tumor), or Investigator assessment of disease status, while the patient is enrolled in the 
study.     
8.3.3 
Quality of Sleep Assessment 
Quality of sleep will also be evaluated beginning Day 1 (Baseline) and at each subsequent 
visit thereafter. Patients will be asked to respond to the following question “Since your last 
visit, how many times a night (on average) do you wake up due to your CS symptoms?” 
based on the following scale 0, 1, 2, 3, 4, >4.  
8.4 
Appropriateness of Assessments 
The assessments used in this study conform to the usual clinical and laboratory assessments 
of patients with CS participating in clinical trials and are typical of a Phase 3 study.  
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8.4.1 
Blood Collection 
An attempt should be made to collect all samples as per the schedule outlined in Appendix A. 
Any portion of samples remaining after the required tests for this study have been completed 
will be destroyed. 
The estimated amount of blood scheduled for collection per patient, over the course of the 
study, may be found in Appendix B. 
9. 
Safety Reporting 
Medical queries should be addressed to the Medical Monitor responsible for the region. 
Sites in North America: 
, MD 
  
INC Research 
 
 
Phone: 
 
 
 
Sites outside North America:  
, MD, PhD 
 
INC Research 
 
The Netherlands 
Phone:
 
Mobile: 
 
 
 
, MD, PhD 
Medical Monitor 
INC Research, LLC 
 
 
Czech Republic 
Phone: 
 
Fax: 
 
 
After-hours emergency medical coverage is available to site personnel should the regional 
Medical Monitor and regional backup Medical Monitor be unavailable. 
 
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Sites in North America dial 1-877-462-0134. 
 
Sites outside North America dial the country prefix number plus 1-877-462-0134. Prefix 
numbers are determined by accessing the AT&T Direct on-line link 
http://www.usa.att.com/traveler/access_numbers/country/index.jsp. Note: These calls are not 
toll-free. 
9.1 
Adverse Events 
It is the responsibility of the Investigator to document all AEs that occur during the study. 
Adverse event is defined as any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. 
Life-threatening adverse event or life-threatening suspected adverse reaction: An adverse 
event or suspected adverse reaction is considered "life-threatening" if, in the view of either 
the Investigator or Sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred 
in a more severe form, might have caused death. 
An AE includes any noxious, pathological, or unintended change in anatomical, 
physiological, or metabolic functions as indicated by physical signs or symptoms occurring in 
any phase of the clinical study whether or not considered related to the study medication. 
This definition includes an exacerbation of preexisting medical conditions or events, 
historical condition not present prior to study treatment, which reappear following study 
treatment, intercurrent illnesses, hypersensitivity reactions, drug interaction, or the significant 
worsening of the disease under investigation that is not recorded elsewhere in the CRF. 
Anticipated day-to-day fluctuations of pre-existing conditions that do not represent a 
clinically significant exacerbation or worsening need not be considered AEs. 
Any laboratory abnormality fulfilling the criteria for a SAE (Section 9.2) should be reported 
as such, in addition to being recorded as an AE. Any treatment-emergent abnormal laboratory 
result which is clinically significant, ie, meeting 1 or more of the following conditions, 
should be recorded as a single diagnosis AE: 
 Is considered to be an SAE, 
 Results in discontinuation from study treatment, or 
 Results in a requirement for a change in concomitant therapy (ie, addition of concomitant 
therapy) 
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In the event of medically significant unexplained abnormal laboratory test values, the tests 
should be repeated and followed up until they have returned to the normal range and/or an 
adequate explanation of the abnormality is determined.  
TEAEs are defined as any AEs reported after the first dose of study drug on Day 1. Adverse 
events reported after consent of a patient, but before administration of study medication, will 
be reported in the Medical History. 
AEs should not be solicited with leading questions that suggest specific signs or symptoms. 
Rather, AEs should be solicited by asking the patient a non-leading question such as: “Do you 
feel different in any way since receiving the dose or since the last assessment?” 
The Investigator will evaluate all AEs with regard to the maximum intensity and relationship 
to study drug, as follows: 
 Maximum intensity  
Maximum intensity should be assigned using 1 of the following 3 severity grades: 
o 
Mild: aware of event but easily tolerated 
o 
Moderate: discomfort, enough to cause interference with usual activity 
o 
Severe: incapacitating: patient unable to work or perform usual activities 
 Relationship to study drug 
Not related:  
o 
Does not follow a reasonable temporal sequence from administration of the drug 
o 
Could be reasonably explained by other factors, including underlying disease, 
complications, concomitant drugs, or concurrent treatment. 
Possibly related:  
o 
That follows a reasonable temporal sequence from administration of the drug 
(including the course after withdrawal of the drug), or 
o 
For which the possibility of the study drug being the causative factor (eg, existence 
of similar reports attributed to the suspected drug and its analogues; reactions 
attributable to the pharmacological effect) could not be excluded, although other 
factors such as underlying disease, complications, concomitant drugs, or concurrent 
treatment are presumable. 
Probably related: 
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o 
That follows a reasonable temporal sequence from administration of the drug 
(including the course after withdrawal of the drug), and 
o 
For which the possibility of factors other than the drug, such as underlying disease, 
complications, concomitant drugs, or concurrent treatment, could not be excluded as 
the cause. 
Definitely related: 
o 
Follows a clear temporal sequence from administration of the study drug. 
o 
Could not be possibly explained by the known characteristics of the patient’s 
clinical state, environmental or toxic factors, or other modes of therapy 
administered to the patient. 
o 
Disappears or decreases on cessation or reduction in dose of the study drug. 
o 
Reappears or worsens when the study drug is re-administered. 
o 
Follows a response pattern known to be associated with administration of the study 
drug. 
The degree of certainty with which an AE is attributed to treatment with study medication (or 
alternative causes, eg, natural history of the underlying diseases, concomitant therapy, etc.) 
will be determined by how well the event can be understood in terms of known 
pharmacology of the study medication and/or reaction of similar nature being previously 
observed with the study medication or the class of study medication. 
All AEs should be followed for at least 30 days following the last dose of study drug or until 
the event has resolved, the condition has stabilized, or the patient is lost to Follow-up. For 
each patient for whom an AE was reported that did not resolve before the end of the reporting 
period, Follow-up information on the subsequent course of events must be submitted to the 
Sponsor. This requirement indicates that follow-up may be required for some AEs after the 
patient has completed his/her participation in the study 
9.2 
Serious Adverse Events (SAEs) 
An SAE is defined as any event that results in any of the following outcomes: 
1. Death 
2. A life-threatening adverse event; 
3. Inpatient hospitalization or prolonging of an existing hospitalization (see Section 9.2.1 
for information on hospitalization as an SAE);  
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4. A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; or 
5. A congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed above. 
Any SAE must be reported by telephone or facsimile within 24 hours of discovery of the 
event. Investigators should not wait to receive additional information to fully document the 
event before notifying the Sponsor of an SAE at: 
Sites in North America must report to: 
Safety Data Facsimile: 001 (832) 442-5917 
Safety Hotline: 001 (877) 372-3597 
 
Email address (in case of fax failure): drugsafetyfax@lexpharma.com 
 
Sites outside North America must report to the country specific toll-free fax numbers 
identified below: 
Australia: 
 
Belgium: 
 
Brazil:
 
France:
 
Germany:
 
Israel: 
 
Italy: 
 
Netherlands: 
 
Spain: 
 
Sweden: 
 
United Kingdom: 
 
 
Email Address (in case of fax failure):  
 
 
The telephone report should be followed by full written summary detailing relevant aspects 
of the SAE in question using the provided SAE report form. Where applicable, information 
from relevant hospital case records and autopsy reports should be obtained. The SAE should 
also be recorded on the AE page of the patient’s CRF. 
An SAE that occurs after completion of the study but, in the opinion of the Investigator, is 
related to the study medication, should be reported as described for an SAE. If an AE does 
not meet the regulatory definition of “serious” but is considered by the Investigator to be 
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related to the study medication and of such clinical concern as to influence the overall 
assessment of safety, it must be reported as defined for an SAE. 
All patients (including discontinued patients) with a SAE must be followed until the event 
resolves or reaches a new Baseline, but for a minimum of 30 days after the last dose of study 
drug. 
9.2.1 
Hospitalization as an SAE 
Hospitalization is defined as any in-patient overnight stay in a hospital. A hospitalization in 
and of itself does not constitute an SAE. The condition which caused the hospitalization must 
be evaluated and determined to be an AE. Although an AE which results in hospitalization is 
an SAE, patients are hospitalized for a variety of reasons which may not be associated with or 
considered an SAE (eg, convenience, logistics, preference, etc). Therefore, each case of 
hospitalization must be evaluated separately. 
For example, the following would not be considered SAEs: 
 Hospitalization for a preexisting condition which did not worsen (eg, cataract surgery) 
 Hospitalization solely for a procedure or treatment that was not performed to treat an 
AE 
 Hospitalization for a condition that does not normally require treatment, but electively 
done (eg, cosmetic surgery) 
 Hospitalization strictly for convenience reasons or observations (eg, procedures only 
performed in a hospital because of the distance the subject lives from the hospital) 
9.3 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
The FDA and/or other applicable Regulatory Authorities and all participating Investigators 
will be notified by a written Investigational New Drug Application (IND) safety report and/or 
other applicable regulatory report (eg, SUSAR) of any suspected adverse reaction that is both 
serious and unexpected, no later than 15 calendar days from the “date learned” of the event. 
In addition, all applicable regulatory bodies will be notified within 7 calendar days of any 
unexpected fatal or life-threatening suspected adverse reaction.  
An adverse reaction is defined as any untoward and unintended response to an investigational 
medicinal product (IMP) related to any dose administered. This definition also covers 
medication errors and uses outside what is foreseen in the protocol, including misuse and 
abuse of the product. The definition also implies a reasonable possibility of a causal 
relationship between the event and the IMP.  
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An unexpected adverse reaction is any adverse drug event, which is not listed in the current 
Investigator’s Brochure or is not listed at the specificity or severity that has been observed. 
For example, (A) a single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (eg, angioedema, hepatic injury, Stevens-Johnson Syndrome); 
(B) 1 or more occurrences of an event that is not commonly associated with drug exposure, 
but is otherwise uncommon in the population exposed to the drug (eg, tendon rupture); (C) an 
aggregate analysis of specific events observed in a clinical trial (such as known consequences 
of the underlying disease or condition under investigation or other events that commonly 
occur in the study population independent of drug therapy) that indicates those events occur 
more frequently in the drug treatment group than in a concurrent or historical control group. 
An untoward and unintended response to a non-IMP is by definition not a SUSAR. 
9.4 
Precautions 
9.4.1 
Pregnancy 
Any patient (or patient’s partner) who becomes pregnant during the study should be followed 
through delivery or termination of the pregnancy. In addition, patients who become pregnant 
during the study must be discontinued from the study treatment immediately.  
In pregnancies that progress to term, any congenital abnormalities/birth defects in the 
offspring of a patient who received study medication should be reported as an SAE. The 
outcome of the pregnancy and the presence or absence of a congenital abnormality will be 
documented by completion of a Pregnancy Questionnaire and a Pregnancy Outcome Form in 
accordance with GCP and ICH guidelines and the Sponsor’s SOPs.  
Female patients should also notify the Investigator if they become pregnant within 30 days 
after last dose of study medication. Male patients should notify the Investigator if a female 
partner becomes pregnant within 30 days after last dose of study medication. The Sponsor 
must be notified of all pregnancies reported to the Investigator (see Section 9.2 for contact 
information). 
10. 
Statistical Methodology 
10.1 
Determination of Sample Size 
No formal sample size calculation was made. The number of patients expected to participate 
in this study was calculated from estimated enrollment rates from other carcinoid cancer trials 
employed in the LX1606 clinical program. 
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10.2 
Analysis Populations 
Per protocol: A Per Protocol population will consist of those patients that receive study 
treatment and have no major protocol violation that would interfere with the collection or 
interpretation of the efficacy data. The primary analyses of efficacy will be based on the 
safety population; the per-protocol population will be used in a supplemental manner.  
Safety: The safety population consists of all patients receiving any fraction of a dose of study 
drug during this study.  
10.3 
Study Endpoints 
10.3.1 
Efficacy Endpoints 
The primary efficacy endpoint is to evaluate the long-term safety and tolerability of orally 
administered telotristat etiprate. 
Secondary efficacy endpoint is to evaluate changes in patients’ QOL over multiple years of 
therapy.  
10.3.2 
Safety Endpoints 
Safety endpoints are as follows:  
 Incidence of TEAEs, suspected adverse reaction, AEs leading to discontinuation from the 
study, SAEs, and deaths 
 Actual and change from Baseline in clinical laboratory results  
 Actual and change from Baseline in vital signs results  
 Actual and change from Baseline in physical examinations 
 Actual and change from Baseline in ECG findings 
10.4 
Statistical Methods 
Descriptive analysis methods will be used to summarize the data. Continuous variables will 
be summarized by the N, mean, standard deviation, median, minimum, and maximum values. 
Categorical variables will be summarized as counts and related percentages. Data tabulations 
will be categorized by the treatment received on Day 1 of this study and combined across all 
treated patients. All data will be listed. 
Primary analyses of the data will be based on the Safety population which includes all 
patients treated with any fraction of study drug during this study. Supportive analyses of the 
efficacy data will be made on a Per Protocol population. This dataset will include the Safety 
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population, but limited to those patients that have at least one assessment post Day 1 and do 
not have any protocol violations that would interfere with collection or interpretation of the 
data. The Per Protocol analysis will be applied to the QOL measures, subjective global 
assessment, and plasma 5-HIAA values. 
Data will be summarized per study visit as the actual (raw) outcomes and change from 
Baseline scores, where applicable. Day 1 of this study will serve as the Baseline assessment. 
10.4.1 
Efficacy Analyses 
All efficacy and PD variables will be summarized descriptively and listed. 
Statistical tests and estimates of within patient effects for these measures will be derived from 
application of a mixed linear model with repeated measures. The model will be generalized to 
handle missing data and specific to the measurement properties of the dependent variable. 
There is no plan to impute data for missing observations for any variable. Non-parametric 
methods will be used to supplement the tests and estimates from the mixed linear model. 
Exploratory analyses of treatment group differences may be performed by use of propensity 
score models. The treatments groups will correspond to how patients were dosed on Day 1 of 
this study.  
10.4.2 
Safety Analyses 
Statistical analysis of the safety data will involve examination of the descriptive statistics and 
individual patient listings for any effects of study treatment on clinical tolerability and safety. 
Reporting of these data will be based on the Safety population. Summaries will be prepared 
by treatment group (corresponding to the LX1606 dose given on Day 1), pooled across all 
patients, and as needed, by study visit. All safety data will be listed. 
Treatment-emergent adverse event summaries will include the overall incidence (by system 
organ class and preferred term), events by maximum intensity, event by relationship to study 
treatment, events leading to discontinuation of study drug, and serious adverse events. 
Vital signs, ECG, and laboratory parameters (hematology, chemistry, and urinalysis) will be 
summarized descriptively at each time point. Actual and change from Baseline data will be 
calculated and summarized. In addition, shift table analysis will be applied to the laboratory 
data and summarized. 
10.4.2.1 
Adverse Events 
All AEs will be coded and listed by body system and preferred term based on the Medical 
Dictionary for Regulatory Activities (MedDRA). Summaries using descriptive statistics will 
be provided for treatment-emergent AEs, drug-related AEs and AEs by intensity. Treatment-
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emergent AEs are those events not present at Baseline, but occurring after the start of study 
drug, or if existing at Baseline, increasing in intensity after initiation study drug. Summaries 
made by intensity will select the event with the highest intensity when multiple occurrences 
of the same event are reported for the same patient. In a similar manner, summaries prepared 
by drug relationship will select the event with the greatest degree of relationship when a 
study reports multiple occurrences of the same event. On-study deaths will be reported for 
deaths occurring during the active phase of the treatment period and 30 days after stopping 
study drug. Also, deaths occurring outside the 30-day window, but secondary to an AE 
reported within the 30-day post treatment period, will be reported as well.  
Listings will be provided for deaths, SAEs, and discontinuations due to AEs. Additional 
summaries or listings of AEs may also be provided. 
10.4.2.2 
Clinical Laboratory Parameters 
Laboratory results will be reported in conventional units in all tables, figures, and listings. 
Laboratory results falling out of the normal range will be marked as high or low in the 
listings. Actual and changes from Baseline (Day 1) in clinical laboratory results will be 
summarized by using descriptive statistics. Summaries of shifts from Baseline to abnormal 
clinical laboratory results will also be provided. Actual and change from Baseline in 
chromogranin A levels will be summarized descriptively as well. 
10.4.2.3 
Vital Sign Measurements 
Actual and changes from Baseline (Day 1) in vital signs results will be summarized by using 
descriptive statistics. 
10.4.2.4 
Electrocardiograms 
Clinically significant changes in ECGs compared to Baseline, as determined by the 
Investigator, will be summarized by using descriptive statistics. Actual and change from 
Baseline (Day 1 predose values) to each time point in corrected QT interval (QTcF) will be 
summarized as well. 
10.4.3 
Pharmacodynamic Analyses 
Analysis and summarization of the plasma 5-HIAA data are described in Section 10.4.1. 
10.4.4 
Baseline Characteristics and Other Summaries 
Treatment group differences will be summarized descriptively for demographic data, prior 
and concomitant medications, treatment compliance, and final disposition. Data collected 
from assessments of tumor status, when available, will be listed. 
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Protocol deviations will provided as listings. 
10.4.5 
Interim Analysis 
An independent DSMB will be charged with reviewing interim safety data on a quarterly 
basis and reporting its recommendations to Lexicon Pharmaceuticals, Inc. Appropriate 
procedures will be detailed in a DSMB Charter that defines accessibility and disclosure of the 
interim study results. 
The study may be analyzed and reported in multiple phases. The first report will summarize 
data obtained from all patients providing information up to a specified data cut-off point. The 
following reports will update the initial report by including data from the remaining portion 
of the study. The first reporting of the data may be taken as an interim analysis in terms of the 
procedural efforts needed to summarize these data, but it will not serve as a means to modify 
the analysis/study conduct.   
11. 
Study Management 
The Investigator is responsible for completing and maintaining adequate and accurate CRFs 
and source documentation. Source documentation constitutes original records, which may 
include: progress notes, medication administration records, laboratory reports, ECG tracings, 
and discharge summaries.  
All data on the CRF must be recorded in accordance with the CRF guidelines. If a correction 
is necessary, it should be made by the Investigator or a designated qualified individual as 
specified within the guideline. All CRFs should be completed in their entirety and stored in a 
secure location. The Investigator must sign the Investigator’s statement in each patient’s CRF 
indicating that the data reported are accurate. 
At the study site, clinical research associates will verify 100% of CRFs in their entirety 
against source documentation. Computer programmed edit checks will be run against the 
database to check for discrepancies and reasonableness of the data, and the safety database 
will be reconciled with the clinical database. All issues resulting from the computer generated 
checks and the safety database reconciliation will be resolved according to standard data 
management practices in conjunction with the Sponsor, clinical study personnel, and the 
study Investigators. 
11.1 
Monitoring 
The Sponsor is responsible for ensuring the proper conduct of the study with regard to ethics, 
protocol adherence, site procedures, integrity of the data, and applicable laws and/or 
regulations. At regular intervals during the study and following completion of the study, the 
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Sponsor’s study monitors will contact the study site via visits to the site, telephone calls, 
and/or letters in order to review study progress, CRF completion, and address any concerns 
or questions regarding the study conduct. During monitoring visits, the following aspects of 
study conduct will be carefully reviewed: informed consent of patients, patient recruitment, 
patient compliance with the study procedures, source data verification, drug accountability, 
use of concomitant therapy by patients, AE and SAE documentation and reporting, and 
quality of data. Records pertaining to these aspects are expected to be kept current. 
The Investigator must make study data accessible to the clinical monitor, to other authorized 
representatives of the Sponsor, and to regulatory inspectors 
11.2 
Audits and Inspections 
The Sponsor, regulatory authority, or IRB/ERC may visit the study site at any time during the 
study or after completion of the study to perform audits or inspections. The purpose of a 
Sponsor audit or regulatory inspection is to systematically and independently examine all 
study-related activities and documents to determine whether these activities were conducted 
according to the protocol, GCP, ICH guidelines, and any other applicable regulatory 
requirements. Investigators should contact the Sponsor immediately if contacted by a 
regulatory agency about an inspection at their site. 
11.3 
Amendments 
Any amendments to the protocol will be written and approved by the Sponsor. All 
amendments must be submitted to the IRB/ERC for approval prior to implementing the 
changes. In some instances, an amendment may require changes to the informed consent 
form, which also must be submitted for IRB/ERC approval prior to administration to patients. 
If any changes to the CRF are required, the Sponsor will issue supplemental or revised CRF 
pages. 
11.4 
Record Keeping 
11.4.1 
Drug Accountability  
The Investigator must maintain accurate records of receipt of study drug, dispensing 
information (date, lot, and dose for each patient), and the prompt return or destruction of 
unused supplies. If the Investigator cannot account for all clinical supplies at the termination 
of the study, a written explanation must be provided.  
11.4.2 
Health Insurance Portability Accountability Act of 1996 and 
Subsequent Updates 
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The Investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of patient health information, including, but not limited to, 
the Standards for Individually Identifiable Health Information, 45 Code of Federal 
Regulations (CFR) Parts 160 and 164 (the Health Insurance Portability Accountability Act of 
1996 [HIPAA] Privacy Regulation and any applicable updates). The Investigator shall ensure 
that study patients authorize the use and disclosure of protected health information in 
accordance with HIPAA Privacy Regulation and in a form satisfactory to the Sponsor. 
11.4.3 
Financial Disclosure 
The Investigator shall provide to the Sponsor sufficient accurate financial information to 
allow the Sponsor to submit complete and accurate financial certification or disclosure 
statements to the FDA and/or other applicable regulatory agencies. The Investigator shall 
promptly update this information if any relevant changes occur in the course of the study or 
for 1 year following completion of the study. 
11.4.4 
Access to Original Records 
It is an expectation of regulatory authorities that monitors, auditors, and representatives of 
national and international government regulatory agency bodies have access to original 
source documentation (see examples in Section 11) to ensure data integrity. “Original” in this 
context is defined as the first documentation of an observation and does not differentiate 
between hard copy and electronic records. 
11.4.5 
Retention of Study Documents 
According to 21 CFR Part 312.62 and ICH E6, study-related records must be retained for at 
least 2 years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region, or at least 
2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. These documents should be retained for a longer period, however, if 
required by applicable regulatory requirements or by an agreement with the Sponsor. 
The Investigator must not destroy any study-related records without receiving approval from 
the Sponsor. The Investigator must notify the Sponsor in the event of accidental loss or 
destruction of any study records. If the Investigator leaves the institution where the study was 
conducted, the Sponsor must be contacted to arrange alternative record storage options. 
12. 
Administrative Structure of the Study 
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The study will be monitored by Sponsor personnel or Sponsor representative. The following 
functions for this study will be performed by organizations designated by the Sponsor: data 
management and statistical analysis, including PD analysis and reporting.
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13. 
Appendix A – Schedule of Events 
Baseline Day 
11
Week 12
Week 24
Week 36
Week 48
Week 60
Week 72
Week 84 /
EOS
Tolerance (days)
NA
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
Inclusion/Exclusion criteria
X
Medical history
X
Physical examination incl. weight
X
X3
X3
X3
X
X3
X3
X
 X5
Urine pregnancy test2
X
X
X
X
X
X
X
X
X
Serum pregnancy test2
Hematology, Blood chemistry
X
X
X
X
X
X
X
X
 X5
Urinalysis
X
X
X
 X5
Chromogranin A
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
ECG
X
X
X
 X5
Subjective Global Assessment
X
X
X
X
X
X
X
X
X
EORTC QLQ-C30 & GI.NET21
X
X
X
X
X
Sleep and Depression Assessment
X
X
X
X
X
X
X
X
X
Plasma 5-HIAA
X
X
X
X
X
X
X
X
X
Dispensation of LX1606
X
X
X
X
X
X
X
 
Concomitant medications
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
Procedure
Extension Period
2-Week 
Follow-up4
1Eligibility will be determined at last visit of the original protocol; Day 1 will replace the next scheduled visit in the original protocol schedule. Visits 
should coincide with LAR injections for those patients receiving SSA therapy. 2Females of child-bearing potential only. 3Brief physical examination only 
(symptom-oriented, including weight). 4Visit to be performed for subjects who withdraw early and will not return for a 2-week follow-up visit; in all other 
cases the EOS visit should be performed followed by the follow-up visit 2 weeks postdose. 5To be performed only if evaluation at Week 4884/EOS is 
abnormal. 
 
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14. 
Appendix B – Amount of Blood to be Collected from Each Patient 
Safety
Hematology
2
9
18
Blood chemistry
6
9
54
Other
CgA
2
3
6
Pharmacodynamic Plasma 5-HIAA
4
9
36
114
*Maximum number of samples is indicated
Total 
Assessment
Sample volume (mL)
Number of samples*
Estimated total volume (mL)
 
 
 
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15. 
Appendix C – EORTC QLQ-C30 
 
 
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16. 
Appendix D – EORTC QLQ - GI.NET21 
 
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17. 
Appendix E – Ethical Standards 
Ethics and Regulatory Considerations 
This study will be conducted according to GCP, 21 CFR Part 50, (Protection of Human 
Subjects), 21 CFR Part 56 (Institutional Review Boards), International Conference on 
Harmonisation Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance, the 
Nuremberg Code, and the Declaration of Helsinki.  
General Instructions 
The FDA regulates studies of drugs, biologics, and medical devices. Consequently, these 
studies are subject to GCP regulations and guidance issued by the FDA and are included in, 
but not limited to, the following parts of the CFR and guideline document: 
 21 CFR Part 11 – Electronic Records 
 21 CFR Part 50 – Protection of Human Subjects 
 21 CFR Part 54 – Financial Disclosure 
 21 CFR Part 56 – Institutional Review Boards 
 21 CFR Part 312 – Investigational New Drug Application 
 Current FDA Guideline for the Monitoring of Clinical Investigations 
 Current Guidance for Institutional Review Boards and Clinical Investigators 
 ICH E6 – Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance  
Studies conducted in the European Union are also regulated by Volume 10 of the publications 
“The rules governing medicinal products in the European Union”. 
Copies of these materials are available from the Sponsor upon request. The purpose of these 
regulations and legal obligations is to define the standards and principles for the proper 
conduct of clinical trials that have been developed by the medical, scientific, and regulatory 
communities. They are not intended to impede or restrict clinical research.  
The ethical standards defined within GCP are intended to ensure that: 
 human subjects are provided with an adequate understanding of the possible risks of their 
participation in the study, and that they have a free choice to participate or not; 
 the study is conducted with diligence and in conformance with the protocol in such a way 
as to insure the integrity of the findings; 
 the potential benefits of the research justify the risks. 
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Lexicon Pharmaceuticals, Inc. is the Sponsor of the IND. The Sponsor is responsible for the 
following: 
 selecting qualified Investigators, 
 providing Investigators with the information they need to properly conduct an 
investigation, 
 ensuring proper monitoring of the investigation, 
 ensuring that the study is conducted according to the general investigational plan and 
protocols contained in the IND, 
 maintaining the IND, and  
 ensuring that regulatory authorities and all participating Investigators are properly 
informed of significant new information regarding adverse effects or risks associated with 
the drug being studied 
 ensuring the study is conducted in accordance to FDA and ICH guidelines and all 
applicable regulations 
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18. 
Appendix F – Investigator Obligations 
Per Title 21 of the US Government Code of Federal Regulations (21 CFR) Parts 50 and 56 
and ICH E6, the study protocol and the final version of the subject informed consent form 
will be approved by the IRB/ERC before enrollment of any subjects. The opinion of the 
IRB/ERC will be dated and given in writing. A copy of the letter of approval from the 
IRB/ERC and a copy of the approved informed consent form will be received by the Sponsor 
prior to shipment of study medication supplies to the Investigator. 
The Investigator will ensure that the IRB/ERC will be promptly informed of all changes in 
the research activity and of all unanticipated problems including risk to subjects. The 
Investigator will also ensure that no changes will be made to the protocol without IRB/ERC 
approval. 
As a part of the IRB/ERC requirement for continuing review of approved research, the 
Investigator will be responsible for submitting periodic progress reports to the IRB/ERC at 
intervals appropriate to the degree of subject risk involved, but no less than once per year. 
Written informed consent must be given freely and obtained from every subject prior to 
clinical trial participation. The rights, safety, and well-being of the trial subjects are the most 
important considerations and should prevail over interests of science and society. 
As described in GCP guidelines, study personnel involved in conducting this trial will be 
qualified by education, training, and experience to perform their respective task(s). Study 
personnel will not include individuals against whom sanctions have been invoked after 
scientific misconduct or fraud (eg, loss of medical licensure, debarment). Quality assurance 
systems and procedures will be implemented to assure the quality of every aspect of the 
study. 
Principal Investigators must provide Lexicon with a fully executed Form FDA 1572 
(statement of Investigator) and all updates on a new fully executed Form FDA 1572. 
Principal Investigators must provide Lexicon with his/her own curriculum vitae and current 
curriculum vitae for each sub-Investigator listed on Form FDA 1572. 
Protection of Human Subjects (21 CFR Part 50 and ICH E6)  
Informed consent must be obtained from every subject before entry into a clinical study. It 
must be given freely and not under duress. Consent must be documented by use of an 
IRB/ERC-approved consent form and signed by the subject or the subject’s legally authorized 
representative. The US Department of Health and Human Services suggests that when minors 
are involved, a parent or guardian should sign the consent form. If the minor is an adolescent, 
his signature should also be included. Non-English-speaking subjects must be presented with 
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a consent form written in a language that they understand. A copy of the signed consent form 
must be given to the subject signing it. Another copy must be kept in the Investigator’s files 
and made available to regulatory authority representatives upon request. If, for any reason, 
subject risk is increased as the study progresses, a revised, IRB/ERC-approved consent form 
must be signed by the subject. Before the study begins, a sample of the consent form must be 
provided to the Sponsor for review. The FDA and/or other applicable regulatory agencies 
may reject otherwise scientifically valid studies if proper informed consent has not been 
obtained from all subjects. 
Only in the case of a life-threatening incident may an investigational product be used without 
prior signed consent. In such an emergency situation, separate certifications must be written 
both by a physician not participating in the study and by the Investigator. The certifications, 
along with the protocol and informed consent, must be sent to the IRB/ERC within 5 working 
days. In this situation, the Investigator may not administer any subsequent product to that 
subject until informed consent and IRB/ERC approval are obtained. 
Informed Consent 
Written informed consent must be obtained from each subject prior to entry in the study. One 
copy of the signed informed consent document will be given to the subject, and another will 
be retained by the Investigator. Additionally, the subject must be allowed adequate time to 
consider the potential risks and benefits associated with his/her participation in the study.  
In situations where the subject is not legally competent to provide consent (ie, mentally 
incapacitated), written consent must be obtained from a parent, legal guardian, or legal 
representative. In these situations, the consent must be signed and dated by a witness. 
The informed consent document must have been reviewed and approved by the Sponsor and 
by the Investigator’s IRB/ERC prior to the initiation of the study. The document must contain 
the 8 basic elements of informed consent and may contain the 6 additional elements 
described in 21 CFR Part 50. Every consent form must include the following 8 elements: 
 A statement that the study involves research, an explanation of the purpose of the research 
and the expected duration of the subject’s participation, a description of the procedures to 
be followed, and identification of any procedures that are experimental 
 A description of any reasonably foreseeable risks or discomforts to the subject 
 A description of any benefits to the subject or to others that may reasonably be expected 
from the research 
 A disclosure of appropriate alternative procedures or course of treatment, if any, that 
might be advantageous to the subject 
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 A statement describing the extent, if any, to which confidentiality of records identifying 
the subject will be maintained and noting the possibility that the FDA and/or other 
applicable regulatory authority representatives may inspect the records 
 An explanation as to whether any compensation or medical treatments are available if 
injury occurs for research involving more than minimal risk. The explanation should 
involve a description of the compensation or treatment available, or a statement 
describing where further information may be obtained 
 An explanation of whom to contact for answers to pertinent questions about the research 
and the subject’s rights and whom to contact in the event of a research related injury 
 A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the subject is otherwise entitled, and that the subject 
may discontinue participation at any time without penalty or loss of benefits to which the 
subject is otherwise entitled. 
When appropriate, 1 or more of the following elements of information shall also be included 
in the consent form: 
 A statement that the particular treatment or procedure may involve risks to the subject (or 
to the embryo or fetus, if the subject is or may become pregnant) which are currently 
unforeseeable 
 Anticipated circumstances under which the subject’s participation may be terminated by 
the Investigator without regard to the subject’s consent 
 Any additional costs the subject may incur from participation in the research 
 The consequences of a subject’s decision to withdraw from the research and procedures 
for orderly termination of participation by the subject 
 A statement that significant new findings developed during the course of the research that 
may relate to the subject’s willingness to continue participation will be provided to the 
subject 
 The approximate number of subjects involved in the study 
The Declaration of Helsinki includes further details regarding the specific requirements for 
informed consent.  
Nothing in these regulations is intended to limit the authority of a physician to provide 
emergency medical care to the extent the physician is permitted to do so under applicable 
federal, state, or local laws. 
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The informed consent requirements in these regulations are not intended to preempt any 
applicable federal, state, or local laws that require additional information to be disclosed in 
order that informed consent be legally effective. Some states, such as California and Oregon, 
require further action on the Investigator’s part concerning subject consent. 
Study Documentation 
IRB/ERC Review/Approval 
The protocol and informed consent for this study, including advertisements used to recruit 
subjects, must be reviewed and approved by an appropriate IRB/ERC prior to enrollment of 
subjects in the study. It is the responsibility of the Investigator to assure that all aspects of the 
ethical review are conducted in accordance with the current Declaration of Helsinki, ICH, 
GCP, and/or local laws, whichever provide the greatest level of protection. A letter 
documenting the IRB/ERC approval which specifically identifies the study/protocol and a list 
of the committee members must be received by the Sponsor prior to initiation of the study. 
Amendments to the protocol will be subject to the same requirements as the original protocol. 
A progress report with a request for re-evaluation and re-approval will be submitted by the 
Investigator to the IRB/ERC at intervals required by the IRB/ERC, and not less than 
annually. A copy of the report will be sent to the Sponsor.  
When the Sponsor provides the Investigator with a Safety Report, the Investigator must 
promptly forward a copy to the IRB/ERC. 
After completion or termination of the study, the Investigator will submit a final report to the 
IRB/ERC and to the Sponsor, if required. This report should include: deviations from the 
protocol, the number and types of subjects evaluated, the number of subjects who 
discontinued (with reasons), results of the study, if known, and significant AEs, including 
deaths. 
Study Files 
The Investigator is required to maintain complete and accurate study documentation in 
compliance with current Good Clinical Practice standards and all applicable federal, state, 
and local laws, rules, and regulations related to the conduct of a clinical study. Study 
documents include, but are not limited to, the Investigator’s Brochure, drug accountability 
records, Sponsor/Investigator correspondence, IRB/ERC correspondence, protocol and 
amendments, information regarding monitoring activities, subject exclusion records, CRFs, 
and data queries. 
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Confidentiality 
The anonymity of subjects must be maintained. Patients will be identified by their initials and 
an assigned subject number on CRFs and other documents submitted to the clinical monitor. 
Documents that will be submitted to the clinical monitor and that identify the subject (eg, the 
signed informed consent document) must be maintained in strict confidence by the Principal 
Investigator, except to the extent necessary to allow auditing by regulatory authorities, the 
clinical monitor, or Sponsor personnel. 
All information regarding the nature of the proposed investigation provided by the Sponsor to 
the Investigator (with the exception of information required by law or regulations to be 
disclosed to the IRB/ERC, the subject, or the regulatory authority) must be kept in confidence 
by the Investigator. 
Drug Accountability 
The Investigator or designee is responsible for accountability of the investigational product at 
the site. The Investigator or designee must maintain records of the product’s delivery to the 
site, inventory at the site, use by each subject, and return to the Sponsor or alternative 
disposition of any unused product. These records must include dates, quantities, 
batch/serial/lot numbers, and expiration dates (if applicable). 
The Investigator should ensure that the investigational product is used only in accordance 
with the protocol 
 
 
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19. 
Appendix G – Guidance on the Selection of Patients  
This long-term study in France is intended for patients who experience clinical benefit in 
their prior experience with telotristat etiprate, either in study LX1606.1-301-CS or 
LX1606.303.1-303-CS. 
Clinical benefit should be present for subjects to meet entry criteria #3 described in section 
6.1 of the protocol: ability and willingness to provide written consent prior to participation in 
any study-related procedure.  
In this study population, clinical benefit may be represented by any of the following:  
 Reduction in bowel movement frequency, or 
 A positive response on the subjective global assessment of adequate relief, or  
 A reduction in urinary 5-HIAA either in study LX1606.1-301-CS or LX1606.1-303-
CS. 
Reduction in bowel movement frequency: a reduction of at least 30% in bowel movement 
frequency from baseline to the end of study LX1606.1-301-CS or LX1606.303.1-303-CS 
may represent clinical benefit. In patients with carcinoid syndrome, benefits of this 
magnitude have been associated with improvements in patient-reported outcomes. 
A positive response on the subjective global assessment of adequate relief: An answer of 
“yes” to the question “In the past 7 days, have you had adequate relief of your carcinoid 
syndrome bowel complaints such as diarrhea, urgent need to have a bowel movement, 
abdominal pain, or discomfort?” at the time of completing participation in LX1606.1-301-CS 
or LX1606.303.1-303-CS is a clinical benefit. 
A reduction in urinary 5-HIAA either in study LX1606.1-301-CS or LX1606.1-303-CS: 
Normalization of urinary 5-HIAA or a reduction of at least 50% in urinary 5-HIAA is a 
clinical benefit for patients at risk of the development of new or progressive carcinoid heart 
disease. 
In addition to the absence of the above signs of benefit, a lack of clinical benefit may reflect 
itself in one of the criteria for stopping treatment or study withdrawal (section 6.3 of the 
protocol): withdrawal of consent, refusal of the study medication, or an investigator decision 
that it is not medically acceptable to continue participation in the study. 
 
 
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20. 
Appendix H - Guidance on the Use of Pro-serotonergic Drugs as 
Concomitant Medications 
Serotonin-synthesis reuptake inhibitors (SSRis) are associated with serotonin syndrome, and 
patients with carcinoid syndrome may be at higher risk of this complication.  
There is some experience with the use of SSRis with telotristat etiprate. In study LX1606.1-
202-CS there were 8 patients on SSRis at baseline, and one patient had an SSRi added during 
the study. There were no reports of serotonin syndrome. However, since the experience was 
relatively limited, caution should be given to the use of SSRis as a concomitant medication in 
study LX1606.1-302-CS. 
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21. 
References 
1. 
Bhattacharyya S, Toumpanakis C, Chilkunda D, Caplin ME, Davar J. Risk factors for 
the development and progression of carcinoid heart disease. Am J Cardiol. 2011; 
107(8):1221-6. Epub 2011 Feb 4. 
2. 
Møller JE, Connolly HM, Rubin J, Seward JB, Modesto K, Pellikka PA. Factors 
associated with progression of carcinoid heart disease. N Engl J Med. 
2003;348(11):1005-15. 
3. 
Druce M, Rockall A, Grossman AB. Fibrosis and carcinoid syndrome: from causation to 
future therapy. Nat Rev Endocrinol. 2009;5(5):276-83 . 
4. 
DePonti F. Pharmacology of serotonin: what a clinician should know. Gut. 
2004;53:1520-35. 
5. 
Cote F, et al. Disruption of the nonneuronal tph 1 gene demonstrates the importance of 
peripheral serotonin in cardiac function. Proc Natl Acad Sci. 2003;100(23):13525-30. 
6. 
De Vries H, et al. Diagnostic, surgical, and medical aspect of the midgut carcinoids. 
Cancer Treat Rev. 2002;28:11-25. 
7. 
Sandostatin LAR® depot product label. Revised July 2014. Accessed at: 
http://www.pharma.us.novartis.com/product/pi/pdf/sandostatin_lar.pdf  
8. 
Investigator Brochure LX1606, Lexicon Pharmaceuticals, Inc.  
9. 
Dmitrienko A, Tamhane A, Wiens B. General multistage gatekeeping procedures. 
Biometrical Journal. 2008;50:667-77 
 
 
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Protocol No.  LX1606.302 A2 
 
08 October 2014 
CONFIDENTIAL 
 
 
 
Page 1 of 8 
 
 
CLINICAL PROTOCOL AMENDMENT 2  
STUDY LX1606.302 
 
 
A Multicenter, Long-term Extension Study to Further Evaluate the Safety and 
Tolerability of Telotristat Etiprate (LX1606) 
 
 
PROTOCOL NO.: 
LX1606.1-302-CS 
LX1606.302 (Abbreviated number) 
 
 
EudraCT Number: 
2013-002596-18 
 
 
INVESTIGATIONAL PHASE: 
3 
 
 
SPONSOR: 
Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Place 
The Woodlands, TX 77381-1160 
Telephone: 001 (281) 863-3000 
Safety Hotline: 001 (877) 372-3597 
Safety Data Facsimile: 001 (832) 442-5917 
 
 
 
PROTOCOL AMENDMENT 2 DATE: 
08 October 2014 
PROTOCOL AMENDMENT 1 DATE: 
31 January 2014 
ORIGINAL VERSION DATE: 
14 June 2013 
 
 
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Protocol No.  LX1606.302 A2 
 
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Page 2 of 8 
Amendment Changes 
 
Rationale 
 
A protocol amendment is proposed to provide additional continued access to telotristat etiprate 
for patients who are enrolled in the LX1606.1-302-CS protocol.  This amendment will allow 
treatment with telotristat etiprate for an additional 36 weeks following the completion of the 
original protocol. The total duration of participation is now defined as up to 86 weeks including 
the Treatment and Follow-up phases. 
Modifications have also been made to: (1) revise the number of healthy volunteers that have 
participated in a Phase 1 study;  (2) denote that recently completed studies; (3) clarify that 
Screening should denote Baseline (Day 1) as there is no Screening period in this study; (4) 
clarify the criteria for the termination of the study; (5) clarify how change in concomitant 
medications should be approached; (6) clarify how blood pressure measurement should be 
collected; (7) further define reporting requirements for hospitalization; (8) denote that the study 
may be reported in multiple phases; (9) update Schedule of Events to reflect new assessments; 
(10) update amount of blood to be collected.  
The following administrative changes have also been made: 
 LX1606 is identified as telotristat etiprate throughout the document for consistency 
 Minor formatting, capitalization, and punctuation have been corrected 
 Definition of Terms has been updated to accurately identify LX1606 
 Due to the insertion of new sections, renumbering has occurred as appropriate  
 Table of contents has been updated as appropriate 
In response to these changes, the following sections have been revised as follows (changes are 
indicated in italics):  
1. SYNOPSIS – Duration of Participation, page 4 – This section was modified to reflect 
study duration of 86 weeks.  The revised section now reads: 
“Up to 86 weeks including Treatment and Follow-up” 
2. SYNOPSIS – Exclusion Criteria, page 5 and STUDY POPULATION – Exclusion 
Criterion, Section 6.2, pages 20-21, Criterion #1 – This criterion has been modified 
to clarify that patients with telotristat etiprate tolerability concerns will be excluded 
from the study. The revised criterion now reads: 
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“Major protocol violations or telotristat etiprate tolerability concerns in a Phase 2 (eg, 
LX1606.1-202-CS, LX1606.1-203-CS) or Phase 3 (eg, LX1606.1-301-CS, LX1606.1-303-CS) 
study” 
3. INTRODUCTION – Clinical Trials of Telotristat Etiprate (LX1606) in Humans, 
Section 3.2, page 13 – This section was revised to reflect number of healthy 
volunteers that have participated in Phase 1 trials.  The revised section now reads: 
“Telotristat etiprate has been studied in single/multiple doses in Phase 1 studies, approximately 
117 healthy volunteers participated in Phase 1 trials with 96 subjects receiving telotristat etiprate 
and 21 subjects receiving placebo. In addition, 37 patients with CS have received telotristat 
etiprate during the clinical development program in Phase 2.  An additional 59 patients with 
ulcerative colitis have been enrolled into an ongoing Phase 2 study to evaluate telotristat etiprate 
versus placebo in patients with ulcerative colitis experiencing active flares.” 
4. INTRODUCTION – Phase 1 Studies, Section 3.2.1, pages 13-14 – This section was 
revised to reflect a recently completed Phase 1 study.  The following paragraph has 
been inserted: 
“LX1606.1-104-NRM was designed to evaluate the pharmacokinetics, metabolism, and routes 
and extent of elimination of telotristat ethyl and its primary metabolite (LP-778902) in 8 healthy 
male subjects after a single oral dose of 500 mg radio-labeled telotristat etiprate (14C-LX1606). 
This study has been completed and the results will be discussed in the annual update of the 
Investigator Brochure.” 
5. INTRODUCTION – Phase 2 Studies, Section 3.2.2, pages 15-16 – This section was 
revised to reflect a recently completed Phase 2 study.  The following paragraph has 
been inserted: 
“LX1606.1-204-UC evaluated patients with active flares of ulcerative colitis. Doses under 
evaluation are 500 mg once daily (qd) and 500 mg tid vs. placebo; 59 patients were enrolled for 
an 8-week treatment period. This study has been completed and the results will be discussed in 
the annual update of the Investigator Brochure.” 
6. INTRODUCTION – Ongoing Studies, Section 3.2.3, pages 16-17 – This section was 
revised to reflect a recently completed Phase 2 study.  The following paragraph has 
been removed: 
“LX1606.1-204-UC is currently evaluating patients with active flares of ulcerative colitis. Doses 
under evaluation are 500 mg once daily (qd) and 500 mg tid vs. placebo; 59 patients have been 
enrolled for an 8-week treatment period.” 
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7. INTRODUCTION – Benefit/Risk Assessment, Section 3.3.2, pages 17-18, 1st 
paragraph – This paragraph was revised to reflect number of healthy volunteers 
that have participated in Phase 1 trials.  The following paragraph now reads: 
“Clinical experience with telotristat etiprate (treated subjects) consists of completed single and 
multiple ascending dose studies in 96 normal subjects (44 in single dose studies and 52 in the 
multiple dose study), 2 Phase 2 studies (37 patients with symptomatic CS) and 2 ongoing Phase 
3 studies in patients with symptomatic CS.” 
8. STUDY POPULATION – Inclusion Criteria, Section 6.1, page 20, Criterion #2.a. – 
This criterion has been modified to clarify Baseline Day 1. The revised criterion now 
reads: 
“Childbearing potential is defined as those who have not undergone surgical sterilization, or 
those who are not considered postmenopausal. Postmenopause is defined as absence of 
menstruation for at least 2 years. If necessary, follicle-stimulating hormone (FSH) results >50 
IU/L at Baseline Day 1 are confirmatory in the absence of a clear postmenopausal history.” 
9. STUDY POPULATION – Criteria for Termination of the Study, Section 6.4, page 
22, bullet #2 – This bullet was modified to clarify that termination of the study may 
result in a Sponsor decision to suspend or discontinue development for carcinoid 
syndrome or any other indication.  The revised bullet now reads: 
“A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product for carcinoid syndrome or any other indication for any reason;”  
10. TREATMENT –Concomitant Medications, Section 7.2.2, pages 23-24, 2nd 
paragraph – This paragraph was revised to clarify how changes to concomitant 
medications should be addressed. The revised paragraph now reads: 
“Medical management of patients and their concomitant medications is allowed at the discretion 
of the Investigator. However, should the need arise to modify/adjust a patient’s therapy due to a 
concern for patient safety and/or tolerability the Medical Monitor should be contacted. The 
Investigator and Medical Monitor will make a determination if such a change would impact the 
safety of the patient and the integrity of the study. The Medical Monitor will determine if the 
patient can continue in the study.” 
11. STUDY PROCEDURES – Vital Sign Measurements, Section 8.2.4.1, pages 27-28, 
2nd paragraph – This paragraph was revised to remove the requirement to capture 
the measurement by using Sponsor provided equipment. The paragraph now reads: 
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“Efforts should be made to standardize blood pressure collection across all patients and visits. 
Patients should be seated for at least 5 minutes prior to collection. All measurements should be 
assessed on the same arm, and by the same technician where possible.”  
12. SAFETY REPORTING – Serious Adverse Events (SAEs), Section 9.2, pages 33-34,
bullet #3 – This bullet was modified to include reference to a new section defining
hospitalization as an SAE.  The revised bullet now reads:
“Inpatient hospitalization or prolonging of an existing hospitalization (see Section 9.2.1 
for information on hospitalization as an SAE);” 
13. SAFETY REPORTING – Hospitalization as an SAE, Section 9.2.1, pages 34 – This
section was inserted to further define hospitalization and subsequent reporting
expectations. The new section now reads:
“Hospitalization is defined as any in-patient overnight stay in a hospital. A hospitalization in and 
of itself does not constitute an SAE. The condition which caused the hospitalization must be 
evaluated and determined to be an AE. Although an AE which results in hospitalization is an 
SAE, patients are hospitalized for a variety of reasons which may not be associated with or 
considered an SAE (eg, convenience, logistics, preference, etc). Therefore, each case of 
hospitalization must be evaluated separately. 
For example, the following would not be considered SAEs: 

Hospitalization for a preexisting condition which did not worsen (eg, cataract surgery)

Hospitalization solely for a procedure or treatment that was not performed to treat an AE

Hospitalization for a condition that does not normally require treatment, but electively
done (eg, cosmetic surgery)

Hospitalization strictly for convenience reasons or observations (eg, procedures only
performed in a hospital because of the distance the subject lives from the hospital)”
14. STATISTICAL METHODOLOGY – Interim Analysis, Section 10.4.5, page 39, 2nd
paragraph – This paragraph was modified to provide information regarding how
the study will be reported.  The revised paragraph now reads:
“The study may be analyzed and reported in multiple phases. The first report will summarize data 
obtained from all patients providing information up to a specified data cut-off point. The 
following reports will update the initial report by including data from the remaining portion of 
the study. The first reporting of the data may be taken as an interim analysis in terms of the 
procedural efforts needed to summarize these data, but it will not serve as a means to modify the 
analysis/study conduct.”   
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Protocol No.  LX1606.302 A2 
 
08 October 2014 
CONFIDENTIAL 
 
 
 
Page 6 of 8 
15. APPENDIX A – Schedule of Events, Section 13, page 43 – The Schedule of Events 
has been updated to reflect the following changes: 
 Dispensation of LX1606 at Week 48 
 Remove EOS from Week 48  
 Remove serum pregnancy testing from the study 
 Add urine pregnancy tests to be conducted for females of child-bearing potential at all study 
weeks 
 Addition of Week 60, Week 72, and Week 84/EOS visits 
 Update footnote to reflect new EOS visit 
Changes are indicated by highlighted cells in ‘Revised Appendix A – Schedule of Events’ table 
below. 
 
 
 
 
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Protocol No.  LX1606.302 A2 
 
08 October 2014 
 
CONFIDENTIAL 
 
 
 
 
 
Page 7 of 8 
Revised Appendix A – Schedule of Events  
 
Baseline Day 
11
Week 12
Week 24
Week 36
Week 48
Week 60
Week 72
Week 84 /
EOS
Tolerance (days)
NA
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
Inclusion/Exclusion criteria
X
Medical history
X
Physical examination incl. weight
X
X3
X3
X3
X
X3
X3
X
 X5
Urine pregnancy test2
X
X
X
X
X
X
X
X
X
Serum pregnancy test2
 
 
 
 
Hematology, Blood chemistry
X
X
X
X
X
X
X
X
 X5
Urinalysis
X
X
X
 X5
Chromogranin A
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
ECG
X
X
X
 X5
Subjective Global Assessment
X
X
X
X
X
X
X
X
X
EORTC QLQ-C30 & GI.NET21
X
X
X
X
X
Sleep and Depression Assessment
X
X
X
X
X
X
X
X
X
Plasma 5-HIAA
X
X
X
X
X
X
X
X
X
Dispensation of LX1606
X
X
X
X
X
X
X
 
Concomitant medications
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
Procedure
Extension Period
2-Week 
Follow-up4
1Eligibility will be determined at last visit of the original protocol; Day 1 will replace the next scheduled visit in the original protocol schedule. Visits 
should coincide with LAR injections for those patients receiving SSA therapy. 2Females of child-bearing potential only. 3Brief physical examination only 
(symptom-oriented, including weight). 4Visit to be performed for subjects who withdraw early and will not return for a 2-week follow-up visit; in all other 
cases the EOS visit should be performed followed by the follow-up visit 2 weeks postdose. 5To be performed only if evaluation at Week 4884/EOS is 
abnormal. 
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Protocol No.  LX1606.302 A2 
 
08 October 2014 
 
CONFIDENTIAL 
 
 
 
 
 
Page 8 of 8 
16. Appendix B – Amount of Blood to be Collected from Each Patient, Section 14, page 44 – This section has been modified 
to reflect estimated volume of blood collected based upon changes reflected in Appendix A. Changes are indicated by 
highlighted cells. The revised table now reads:  
Safety
Hematology
2
9
18
Blood chemistry
6
9
54
Other
CgA
2
3
6
Serum Pregnancy
2
0
0
Pharmacodynamic Plasma 5-HIAA
4
9
36
114
*Maximum number of samples is indicated
Total 
Assessment
Sample volume (mL)
Number of samples*
Estimated total volume (mL)
 
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CLINICAL STUDY PROTOCOL 
Protocol Number: 
LX1606.1-302-CS 
LX1606.302 (Abbreviated number) 
EudraCT Number 
2013-002596-18 
Investigational Phase: 
3 
Protocol Title: 
A Multicenter, Long-term Extension Study to Further 
Evaluate the Safety and Tolerability of Telotristat Etiprate 
(LX1606) 
Study Name: 
TELEPATH (Telotristat Etiprate – Expanded Treatment 
for Patients with Carcinoid Syndrome) 
Amendment 1 Date: 
31 January 2014 
Original Version Date: 
14 June 2013 
Sponsor: 
Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Place 
The Woodlands, TX 77381-1160 
Telephone: 001 (281) 863-3000 
Safety Hotline: 001 (877) 372-3597 
Safety Data Facsimile: 001 (832) 442-5917 
 
 
 
 
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Protocol No. LX1606.302 
 31 January 2014 
CONFIDENTIAL 
Page 3 of 55 
1. 
Synopsis 
Name of Study Drug 
Telotristat etiprate 
Protocol Number 
LX1606.1-302-CS 
LX1606.302 (Abbreviated number) 
Protocol Title  
 
A Multicenter, Long-term Extension Study to Further Evaluate the 
Safety and Tolerability of Telotristat Etiprate (LX1606) 
Primary Objective 
The primary objective of this study is to evaluate the long-term 
safety and tolerability of orally administered telotristat etiprate   
Secondary Objective 
To evaluate long-term changes in patients’ quality of life (QOL)  
Phase of Development 
3 
Methodology 
 
The study will be conducted as a multicenter, open-label, long-term 
extension study to further evaluate long-term safety and tolerability 
of telotristat etiprate. 
Patients currently participating in any LX1606 Phase 2 carcinoid 
syndrome (CS) study may enter into this extension study upon 
institutional or local approval of the protocol. Patients participating 
in a Phase 3 CS study may enter into this extension study at the 
Week 48 visit. All patients who enter into this extension study will 
be exempt from any follow-up visit required by the original study 
and will not experience an interruption in study drug due to the 
transition from the original study to LX1060.1-302-CS. 
Following confirmation of eligibility, patients will complete a series 
of visit assessments in order to establish Baseline symptoms. 
Patients will then continue on open-label study drug at the same dose 
level and regimen as identified in their original study.  
Downward dose adjustment will be permitted during the study if 
evidence of intolerability emerges. Patients who experience 
intolerability at the 250 mg tid dose level must be discontinued from 
the study. Patients may return to the previous dosing at the discretion 
of the Investigator and in consultation with the Medical Monitor. 
Upon completion or early withdrawal from treatment, all patients 
will be required to complete a 14-day Follow-up Period, during 
which no study drug will be administered.  
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Protocol No. LX1606.302 
 31 January 2014 
CONFIDENTIAL 
Page 4 of 55 
A Data Safety Monitoring Board (DSMB) will review safety data 
quarterly throughout the study.  
Number of Patients 
Up to 100 patients are expected to participate in this study.  
Patients 
Eligible patients are defined as those that are currently participating 
in a Phase 2 or Phase 3 telotristat etiprate carcinoid syndrome study. 
Number of Study Sites 
Approximately 70 sites 
Treatments 
Telotristat etiprate, 250 mg  tablet, administered at the same dose 
level and regimen identified in the patient’s original study 
Route of Administration 
Oral 
Duration of Participation 
Up to 50 weeks including Treatment and Follow-up 
Inclusion Criteria 
Patients must meet all of the following criteria to be considered 
eligible to participate in the study: 
1. Ongoing participation in a Phase 2 (eg, LX1606.1-202-CS, 
LX1606.1-203-CS) or Phase 3 (eg, LX1606.1-301-CS, 
LX1606.1-303-CS) study 
2. Patients of childbearing potential must agree to use an adequate 
method of contraception (defined as having a failure rate of <1% 
per year) during the study and for 12 weeks after the Follow-up 
visit. Adequate methods of contraception for patients or partner 
include condoms with spermicide gel, diaphragm with 
spermicide gel, coil (intrauterine device), surgical sterilization, 
vasectomy, oral contraceptive pill, depot progesterone injections, 
progesterone implant, and abstinence during the study and for 12 
weeks after the Follow-up Visit. 
a. Childbearing potential is defined as those who have not 
undergone surgical sterilization, or those who are not 
considered postmenopausal. Postmenopause is defined as 
absence of menstruation for at least 2 years. If necessary, 
follicle-stimulating hormone (FSH) results >50 IU/L at entry 
are confirmatory in the absence of a clear postmenopausal 
history. 
3. Ability and willingness to provide written informed consent 
prior to participation in any study-related procedure 
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Protocol No. LX1606.302 
 31 January 2014 
CONFIDENTIAL 
Page 5 of 55 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded 
from participating in the study:   
1. Major protocol violations or tolerability concerns in a Phase 2 
(eg, LX1606.1-202-CS, LX1606.1-203-CS) or Phase 3 (eg, 
LX1606.1-301-CS, LX1606.1-303-CS) study 
2. Positive pregnancy test 
3. Presence of any clinically significant findings at entry for 
medical history, laboratory values, or physical examination 
(relative to patient population) that, in the Investigator’s or 
Medical Monitor’s opinion, would compromise patient safety or 
the outcome of the study 
4. Patients who are currently committed to an institution by virtue 
of an order issued either by judicial or administrative authorities 
Statistical Methods 
Descriptive analysis methods will be used to summarize the data. 
Continuous variables will be summarized by the N, mean, standard 
deviation, median, minimum, and maximum values. Categorical 
variables will be summarized as counts and related percentages. Data 
tabulations will be categorized by the treatment received on Day 1 of 
this study and combined across all treated patients. Primary analyses 
of the data will be based on the Safety population which includes all 
patients treated on Day 1 of this study. Supportive analyses of the 
efficacy data will be made on a Per Protocol population.  
Data will be summarized per study visit as the actual (raw) outcomes 
and change from Baseline scores, where applicable. Day 1 of this 
study will serve as the Baseline assessment.  
Study Assessments 
Safety 
Safety assessments include monitoring of adverse events, clinical 
laboratory tests, vital signs measurements, 12-lead ECG, and 
physical examinations 
Efficacy 
Efficacy assessments will include patient reported quality of life 
measures as captured in the European Organization for Research and 
Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-
C30 and the module specific for gastrointestinal symptoms of 
carcinoid neuroendocrine tumors (GI.NET21) and subjective global 
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Protocol No. LX1606.302 
 31 January 2014 
CONFIDENTIAL 
Page 6 of 55 
assessment of symptoms associated with CS 
Pharmacodynamics 
Pharmacodynamic (PD) assessments include determination of 5-
HIAA levels in plasma 
Efficacy Data Analysis 
 
All efficacy and PD variables will be summarized descriptively and 
listed. 
Statistical tests and estimates of within patient effects for the 
efficacy and PD measures will be derived from application of a 
mixed linear model with repeated measures. The form of the model 
will be specific to measurement properties of the dependent variable. 
Non-parametric methods will be used to supplement the tests and 
estimates from the mixed linear model. 
Exploratory analyses of treatment group differences may be 
performed by use of propensity score models. The treatments groups 
will correspond to patients’ LX1606 dose level on Day 1 of this 
study.  
Safety Data Analysis 
 
Statistical analysis of the safety data will involve examination of the 
descriptive statistics and individual patient listings for any effects of 
study treatment on clinical tolerability and safety. Reporting of these 
data will be based on the Safety population. Summaries will be 
prepared by treatment group, and as needed, by study visit. 
Treatment-emergent adverse event summaries will include the 
overall incidence (by system organ class and preferred term), events 
by maximum intensity, event by relationship to study treatment, 
events leading to discontinuation of study drug, and serious adverse 
events. 
Vital signs, ECG, and laboratory parameters (hematology, chemistry, 
and urinalysis) will be summarized descriptively at each time point. 
Actual and change from Baseline data will be calculated and 
summarized. In addition, shift table analysis will be applied to the 
laboratory data. 
 
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Protocol No. LX1606.302 
 31 January 2014 
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Page 7 of 55 
Table of Contents 
1. 
Synopsis ......................................................................................................................... 3 
2. 
List of Abbreviations and Definitions of Terms ........................................................... 10 
Definitions of Terms ................................................................................................................ 11 
3. 
Introduction .................................................................................................................. 12 
3.1 
Background on Telotristat Etiprate (LX1606) and Disease .......................... 12 
3.2 
Clinical Trials of Telotristat Etiprate (LX1606) in Humans ......................... 13 
3.2.1 
 Phase 1 Studies ............................................................................................ 13 
3.2.2 
 Phase 2 Studies ............................................................................................ 15 
3.3 
Rationale for Current Study .......................................................................... 17 
3.3.1 
Rationale for Selection of Dose ..................................................... 17 
3.3.2 
Benefit/Risk Assessment ................................................................ 17 
3.4 
Rationale for Study Design and Control Groups .......................................... 18 
4. 
Study Objectives .......................................................................................................... 19 
4.1 
Efficacy Objectives ....................................................................................... 19 
4.1.1 
Primary Objective .......................................................................... 19 
4.1.2 
Secondary Objective(s) .................................................................. 19 
4.2 
Safety Objectives .......................................................................................... 19 
5. 
Investigational Plan ...................................................................................................... 19 
5.1 
Overall Study Design .................................................................................... 19 
6. 
Study Population .......................................................................................................... 20 
6.1 
Inclusion Criteria .......................................................................................... 20 
6.2 
Exclusion Criteria ......................................................................................... 20 
6.3 
Criteria for Stopping Treatment/Study Withdrawal ...................................... 21 
6.4 
Criteria for Termination of the Study ............................................................ 22 
6.5 
Clinical Stopping Rules ................................................................................ 22 
6.6 
Method of Assigning Patients to Treatment .................................................. 22 
6.7 
Blinding and Unblinding of Study Medication ............................................. 22 
6.8 
Replacement of Patients ................................................................................ 23 
7. 
Treatment ..................................................................................................................... 23 
7.1.1 
Telotristat Etiprate (LX1606) ......................................................... 23 
7.1.1.1 
Identity ......................................................................... 23 
7.1.1.2 
Packaging, Labeling, and Storage ................................ 23 
7.2 
Prior and Concomitant Medications ............................................................. 23 
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Protocol No. LX1606.302 
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7.2.1 
Prior Medications ........................................................................... 23 
7.2.2 
Concomitant Medications .............................................................. 23 
7.2.3 
Prohibited Medications or Concomitant Therapy .......................... 24 
7.3 
Administration of Study Medication ............................................................ 24 
7.3.1 
Treatment Compliance ................................................................... 24 
7.4 
Dose Adjustment ........................................................................................... 24 
8. 
Study Procedures ......................................................................................................... 24 
8.1 
Restrictions during Study .............................................................................. 25 
8.2 
Description of Study Assessments ................................................................ 25 
8.2.1 
Efficacy Assessments ..................................................................... 25 
8.2.1.1 
EORTC QLQ-C30 & GI.NET21 ................................. 25 
8.2.1.2 
Subjective Global Assessment ..................................... 25 
8.2.2 
Clinical Laboratory Assessment .................................................... 25 
8.2.2.1 
Monitoring Hepatic Function ....................................... 26 
8.2.3 
Pharmacodynamic Assessments..................................................... 27 
8.2.3.1 
Plasma 5-HIAA ............................................................ 27 
8.2.4 
Safety Assessments ........................................................................ 27 
8.2.4.1 
Vital Sign Measurements ............................................. 27 
8.2.4.2 
Physical Examinations ................................................. 28 
8.2.4.3 
Electrocardiograms ...................................................... 28 
8.2.4.4 
Adverse Events of Special Interest .............................. 28 
8.2.4.4.1 
Central Nervous System Events ........... 28 
8.2.4.4.1.1 
Depression Detection ......................................................................... 29 
8.3 
Other Assessments ........................................................................................ 29 
8.3.1   
Chromogranin A (CgA)................................................................................. 29 
8.3.2 
Disease Progression ...................................................................................... 29 
8.3.3 
Quality of Sleep Assessment ......................................................................... 29 
8.4  
Appropriateness of Assessments ................................................................... 29 
8.4.1  
Blood Collection ............................................................................ 29 
9. 
Safety Reporting .......................................................................................................... 30 
9.1 
Adverse Events ............................................................................................. 30 
9.2 
Serious Adverse Events (SAEs) .................................................................... 33 
9.3 
Suspected Unexpected Serious Adverse Reactions (SUSARs) .................... 34 
9.4 
Precautions .................................................................................................... 35 
9.4.1 
Pregnancy ....................................................................................... 35 
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Protocol No. LX1606.302 
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Page 9 of 55 
10. 
Statistical Methodology ............................................................................................... 36 
10.1 
Determination of Sample Size ...................................................................... 36 
10.2 
Analysis Populations ..................................................................................... 36 
10.3 
Study Endpoints ............................................................................................ 36 
10.3.1 
Efficacy Endpoints ......................................................................... 36 
10.3.2 
Safety Endpoints ............................................................................ 36 
10.4 
Statistical Methods ........................................................................................ 36 
10.4.1 
Efficacy Analyses ........................................................................... 37 
10.4.2 
Safety Analyses .............................................................................. 37 
10.4.2.1 
Adverse Events ............................................................ 38 
10.4.2.2 
Clinical Laboratory Parameters ................................... 38 
10.4.2.3 
Vital Sign Measurements ............................................. 38 
10.4.2.4 
Electrocardiograms ...................................................... 38 
10.4.3 
Pharmacodynamic Analyses .......................................................... 39 
10.4.4 
Baseline Characteristics and Other Summaries ............................. 39 
10.4.5 
Interim Analysis ............................................................................. 39 
11. 
Study Management ...................................................................................................... 39 
11.1 
Monitoring .................................................................................................... 40 
11.2 
Audits and Inspections .................................................................................. 40 
11.3 
Amendments ................................................................................................. 40 
11.4 
Record Keeping ............................................................................................ 41 
11.4.1 
Drug Accountability ....................................................................... 41 
11.4.2 
Health Insurance Portability Accountability Act of 1996 and 
Subsequent Updates ....................................................................... 41 
11.4.3 
Financial Disclosure ....................................................................... 41 
11.4.4 
Access to Original Records ............................................................ 41 
11.4.5 
Retention of Study Documents ...................................................... 41 
12. 
Administrative Structure of the Study ......................................................................... 42 
13. 
Appendix A – Schedule of Events ............................................................................... 43 
14. 
Appendix B – Amount of Blood to be Collected from Each Patient ........................... 44 
15. 
Appendix C – EORTC QLQ-C30 ................................................................................ 45 
16. 
Appendix D – EORTC QLQ - GI.NET21 ................................................................... 47 
17. 
Appendix E – Ethical Standards .................................................................................. 48 
18. 
Appendix F – Investigator Obligations ........................................................................ 50 
19. 
References .................................................................................................................... 55 
 
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Protocol No. LX1606.302 
 31 January 2014 
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Page 10 of 55 
2. 
List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
5-HIAA 
5-hydroxyindoleacetic acid 
5-HT 
serotonin 
AE 
adverse event 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
ALP 
alkaline phosphatase 
AST 
aspartate transaminase 
bid 
twice daily 
BM 
bowel movements 
BMI 
body mass index 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CgA 
chromogranin A 
CNS 
central nervous system 
CRF 
case report form 
CRO 
contract research organization 
CS 
carcinoid syndrome 
CT 
computed tomography 
DSMB 
Data Safety Monitoring Board 
EC 
enterochromaffin 
ECG 
electrocardiogram 
ERC 
Ethic Review Committee 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HEENT 
head, eyes, ears, nose, and throat 
Hgb 
hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
IBD 
inflammatory bowel disease 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
Continued on the next page 
 
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Protocol No. LX1606.302 
 31 January 2014 
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Page 11 of 55 
Abbreviation 
Definition 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IMP 
Investigational Medicinal Product 
IWRS 
interactive web response system 
LAR 
long-acting release 
LS 
least square 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCP 
multiple comparison procedure 
MRI 
magnetic resonance imaging 
NET 
neuroendocrine tumor 
NRS 
numeric rating scale 
OOR 
out-of-range 
OTC 
over-the-counter 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
qd 
once daily 
SAE 
serious adverse event 
SBS 
short bowel syndrome 
SOP 
standard operating procedure 
SSA 
somatostatin analog 
SUSAR 
suspected unexpected serious adverse reactions 
TEAE 
treatment-emergent adverse events 
tid 
3 times daily 
TPH 
tryptophan hydroxylase 
ULN 
upper limit of the normal reference range 
WRS 
Wilcoxon rank sum 
 
Definitions of Terms  
Term 
Definition 
LP-778902 
active moiety of LX1606 
LX1606 
ethyl-ester prodrug of the active moiety LP-778902; a serotonin 
synthesis inhibitor being developed by Lexicon Pharmaceuticals, Inc. 
QTcF 
corrected QT interval using Fredericia’s formula 
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Protocol No. LX1606.302 
 31 January 2014 
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Page 12 of 55 
3. 
Introduction 
3.1 
Background on Telotristat Etiprate (LX1606) and Disease 
Serotonin (5-HT) plays a critical role in regulating several major physiological processes of 
the gastrointestinal tract, including aspects of secretion, motility, inflammation and sensation. 
Enterochromaffin (EC) cells release 5-HT when the intestinal wall is stimulated by 
intraluminal pressure or chemicals. Through multiple classes of receptors, 5-HT is believed to 
initiate directly, or facilitate, peristaltic and secretory reflexes. 5-HT is also reportedly 
involved in the pathophysiology of various types of functional gastrointestinal (GI) disorders, 
valvular heart disease, and may play a role in the pathophysiology of inflammatory bowel 
disease (IBD).  
Carcinoid tumors are mostly derived from EC cells of the midgut, and often produce and 
release large amounts of 5-HT. Such excess of 5-HT is believed to be responsible for the 
severe diarrhea and eventual valvular heart damage and mesenteric fibrosis in patients with 
carcinoid syndrome (CS).1-3 Inhibition of tryptophan hydroxylase (TPH) activity in carcinoid 
tumors should lead to a reduction of peripheral 5-HT in afflicted patients and thus an 
amelioration of the pathophysiology and symptomology of CS. A peripheral TPH inhibitor, 
such as telotristat etiprate, should alleviate the symptoms due to excess 5-HT in carcinoid 
patients without central nervous system (CNS)-related adverse events (AEs). 
Approximately 90% of the body's 5-HT is found in the EC cells of the GI tract, with the 
remainder distributed between the platelets and CNS.4 TPH catalyzes the biopterin-dependent 
monooxygenation of tryptophan to 5-hydroxytryptophan, which is subsequently 
decarboxylated to form 5-HT. Expression of TPH is limited to a few specialized tissues:  
raphe neurons, pinealocytes, mast cells, mononuclear leukocytes, beta cells of the islets of 
Langerhans, and intestinal and pancreatic EC cells.5 Two isoforms of the enzyme exist, TPH1 
and TPH2. TPH1 is exclusively located in the EC cells of the GI tract and pineal gland and is 
the rate limiting enzyme responsible for the majority of systemic 5-HT production and is also 
responsible for 5-HT synthesis in carcinoid tumors. TPH2 is located in the central and enteric 
nervous systems and is the rate-limiting enzyme in the production of neuronal 5-HT. 
The oral TPH inhibitor, telotristat etiprate, represents a novel approach to potentially lessen 
the pathophysiology of CS by reducing 5-HT levels via inhibition of TPH. Telotristat etiprate 
was designed specifically as a prodrug in order to gain greater systemic exposure, opening 
the potential application for indications in which hyperserotonemia is thought to contribute to 
the disorder, such as CS. Preclinical pharmacology studies of telotristat etiprate were 
designed to evaluate the compound’s mechanism of action and effects in vivo. Telotristat 
etiprate is the ethyl-ester prodrug of the active moiety LP-778902. Telotristat etiprate was 
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designed as a prodrug in order to enhance peripheral exposure without crossing the blood-
brain barrier. In vivo, telotristat etiprate is readily converted through esterase activity to its 
corresponding acid, LP-778902. LP-778902 has an in vitro potency of 0.028 μM on purified 
human TPH1 enzyme and 0.032 μM on purified human TPH2 enzyme. Therefore, telotristat 
etiprate is a robust inhibitor of TPH both in vitro and in vivo and has been shown in Phase 2 
studies to provide clinical benefit to patients with carcinoid tumors and associated CS.  
Telotristat etiprate is being developed to manage GI symptoms and possibly other symptoms 
associated with CS. Currently, the standard of care for patients with CS is symptom 
management using somatostatin analogs (SSA), which are available in both short- and long-
acting release (LAR) formulations. Somatostatin analogs such as octreotide are indicated for 
the control of flushing, diarrhea, and other symptoms associated with CS. Common side 
effects of the long-acting depot form of the drug are pain at the site of the injection, reported 
in as many as 30 to 50% of carcinoid patients at the 20 and 30 mg dose levels, and less 
commonly, stomach cramps, nausea, vomiting, headaches, dizziness, and fatigue.6 Other side 
effects identified in the product labeling include biliary tract abnormalities (gallstones, 
sludge, and dilatation), hypothyroidism, dietary fat malabsorption, and hyper or 
hypoglycemia.7 In addition to the morbidity associated with parenterally administered agents, 
tachyphylaxis will occur in the majority of patients, resulting in recurrent symptoms. 
There are currently no specific oral treatments indicated for the management of symptoms 
associated with CS. As a result of the morbidity associated with SSAs and the associated 
tachyphylaxis, there is an unmet medical need to provide symptom management and modify 
the pathophysiology of patients with metastatic CS. Inhibition of the excessive 5-HT 
produced by these tumors with an orally delivered agent such as telotristat etiprate could 
provide significant benefit as an additional treatment option for patients and clinicians.  
3.2 
Clinical Trials of Telotristat Etiprate (LX1606) in Humans 
Telotristat etiprate has been studied in single/multiple doses in Phase 1 studies, approximately 
109 healthy volunteers participated in Phase 1 trials with 88 subjects receiving telotristat 
etiprate and 21 subjects receiving placebo. In addition, 37 patients with CS have received 
telotristat etiprate during the clinical development program in Phase 2.  An additional 59 
patients with ulcerative colitis have been enrolled into an ongoing Phase 2 study to evaluate 
telotristat etiprate versus placebo in patients with ulcerative colitis experiencing active flares. 
3.2.1 
 Phase 1 Studies 
LX1606.1-101-NRM utilized telotristat etiprate as a single oral dose and was noted to be safe 
and well tolerated up to doses of 1,000 mg. At doses of ≥1,000 mg, an increase in GI AEs 
was observed, which were assessed as at least possibly related to study drug. These AEs led 
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to a decision not to escalate the dose beyond 1,500 mg. No serious adverse events (SAEs) or 
deaths were reported and no patient discontinued due to an AE. Twenty-three patients 
experienced at least 1 AE. The majority of the AEs were assessed as mild. The most common 
AEs were diarrhea and nausea. Random out-of-range laboratory values at various time points 
in several patients occurred without any apparent trend. There were no other clinically 
significant vital signs, laboratory or physical examination findings.  
LX1606.1-102-NRM utilized telotristat etiprate as multiple oral doses over 14 days and was 
tolerated up to the maximum dose assessed, 500 mg tid; 1,500 mg total dose daily. Most AEs 
were mild, the most common being nausea and headache; all resolved. Most AEs were at 
least possibly related to study treatment. Four AEs required treatment with concomitant 
medication, 3 AEs of constipation and 1 of headache. No deaths or SAEs were reported. One 
patient was discontinued due to an AE of abnormal liver function. There were no apparent 
trends or clinically significant findings observed upon review of vital signs and 
electrocardiogram (ECG) data. There were no clinically significant abnormal physical 
examination findings. 
Overall, in LX1606.1-102-NRM, treatment with telotristat etiprate was associated with mild 
elevations, generally ≤2x the upper limit of normal (ULN), in alanine transaminase (ALT) 
and aspartate transaminase (AST), with elevations in values observed earlier in the higher 
dose cohorts. Results were assessed as clinically significant for only 1 patient, in Cohort 4, 
who was withdrawn on Day 10. The trend was most pronounced in Cohort 5, in which 5 out 
of 6 patients who received telotristat etiprate had increases in ALT values which were above 
normal range and 4 patients had increases in AST values which were above normal range at 
Day 14. Mean increases in ALT and AST appeared earlier in the study for Cohorts 4 and 5 
than in the other cohorts, and were noted for all cohorts by Day 12. All patients had normal 
ALT and AST values at Baseline and most elevated transaminases returned to normal range 
within 48 hours after the last dose of study drug. No changes in alkaline phosphatase (ALP) 
or total bilirubin were observed in any patient. 
LX1606.1-103-NRM evaluated 2 oral formulations of telotristat etiprate in an open-label 
crossover study. Each formulation was given as a single oral dose followed by a 5-day 
washout and then patients were given a single oral dose of the second formulation. During 
this study, there were no deaths or SAEs reported and no AEs lead to discontinuation. The 
most commonly reported AE was diarrhea. No clinically significant observations or changes 
in other safety parameters (eg, clinical laboratory evaluations, vital signs, physical 
examinations, ECGs, and AEs) were identified in the patient population during the study 
conduct. 
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3.2.2 
 Phase 2 Studies 
LX1606.1-202-CS was a randomized, double-blind, placebo-controlled, multiple ascending 
dose study conducted in 2 parts in order to evaluate a total of 23 patients at a dose range of 
450 to 1500 mg given as 150, 250, 350, or 500 mg tid (telotristat etiprate or matching 
placebo) on a background therapy of octreotide. In Part 1, 16 patients were randomly 
assigned 3:1 into 4 sequential cohorts. Each cohort evaluated 1 of the following daily doses 
given as 150, 250, 350, or 500 mg tid over a course of 4 weeks. During the study, all patients 
continued on a stable-dose background therapy of octreotide. In Part 2, an additional 7 
patients were randomly assigned 3:1 in order to evaluate 500 mg tid, the highest tolerated 
dose as determined in Part 1. Upon completion of the initial 4-week portion, eligible patients 
had the option to continue into an open-label Extension Period. 
There was 1 treatment emergent SAE assessed as possibly related to study drug which 
occurred in the 350 mg tid dose group. The patient had a history of nausea and vomiting and 
was hospitalized for exacerbation of these conditions.  
Telotristat etiprate was generally well tolerated with no evidence of dose-limiting tolerability. 
Adverse events were mostly mild to moderate and with similar frequencies between 
treatment groups and placebo. No significant changes in vital signs, ECG, or physical exam 
findings were noted after administration of telotristat etiprate at any dose level. The most 
common AEs were GI-related and reported as diarrhea, nausea, and abdominal pain, 
respectively. The modest elevations in transaminases seen in the Phase 1 multiple ascending 
dose study (LX1606.1-102-NRM) were not apparent in this 4-week study in patients with CS.  
Patients that received telotristat etiprate achieved a clinical response (28%) defined as at least 
a 30% reduction in bowel movements (BMs) for at least 2 weeks; a biochemical response 
(56%) defined as at least a 50% reduction or normalization of urinary 5-hydroxyindoleacetic 
acid (5-HIAA); and reported adequate relief at Week 4 (46%) while no placebo patients 
experienced clinical response, biochemical response, or adequate relief. 
LX1606.1-203 was an open-label, serial ascending, multiple dose, individual titration study 
that evaluated the same dose ranges as the LX1606.1-202-CS study in a total of 15 patients. 
Patients were serially escalated to the next dose level every 2 weeks until a maximally 
tolerated dose or 500 mg tid was reached. Once a dose had been determined, the patient 
would remain on the dose for an additional 4 weeks. Patients then had the option to continue 
into an Extension Period.  
Telotristat etiprate was generally safe and well-tolerated in subjects with CS in the 
LX1606.1-203 study. Most AEs were mild to moderate in severity and assessed as unrelated 
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to study drug. Events in the Gastrointestinal Disorders SOC were common, as is anticipated 
with the underlying illness. 
Statistically significant reductions from Baseline in the mean number of BMs/day were 
observed in this study throughout the entire dose-escalation and stable-dose phases, as were 
improvements in stool form. Telotristat etiprate produced an improvement in global 
assessment of GI symptoms associated with CS in the majority of subjects (12 of 15 subjects, 
80%) across the 12-week period. The global assessment of GI symptoms was based on the 
following question, “In the past 7 days, have you had adequate relief of your carcinoid 
syndrome bowel complaints such as diarrhea, urgent need to have a BM, abdominal pain or 
discomfort?” In addition, subjects experienced statistically significant decreases in the mean 
daily number of cutaneous flushing episodes. 
Thirteen subjects (86.7%) experienced a complete biochemical response (defined as a ≥50% 
reduction from Baseline in u5-HIAA levels at 1 or more time points). Consistent with the 
proposed mechanism of action for telotristat etiprate, a complete biochemical response 
correlated closely with measures of clinical response, such as number of bowel movements 
per day. 
Detailed information regarding the completed clinical studies can be found in the Investigator 
Brochure.8 
3.2.3   
Ongoing Studies 
The open-label extension portions in LX1606.1-202-CS and LX1606.1-203-CS remain 
ongoing. 
LX1606.1-204-UC is currently evaluating patients with active flares of ulcerative colitis. 
Doses under evaluation are 500 mg once daily (qd) and 500 mg tid vs. placebo; 59 patients 
have been enrolled for an 8-week treatment period.  
LX1606.1-301-CS is intended to evaluate patients who are currently on a background of SSA 
therapy and still experiencing breakthrough symptoms such as an increased frequency of 
BMs ≥ 4 per day on average: (1) the efficacy of telotristat etiprate on reducing the number of 
BMs; (2) the efficacy of telotristat etiprate on a number of clinically relevant secondary 
endpoints; and, (3) the safety of telotristat etiprate over the 12-week double-blind portion 
(Treatment Period) of the study. Upon completion of the Treatment Period, patients will 
continue into a 36-week open-label Extension Period (Extension Period).  
LX1606.1-303-CS is intended to evaluate patients with carcinoid syndrome whose primary 
symptoms are not GI related and may be naïve to SSA therapy: (1) the safety of telotristat 
etiprate over the 12-week double-blind portion (Treatment Period) of the study; (2) percent 
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(%) change  from Baseline in 24-hour u5-HIAA levels at Week 12; (3) the effects of 
telotristat etiprate on a number of clinically relevant secondary endpoints. Upon completion 
of the Treatment Period, patients will continue into a 36-week open-label Extension Period. 
3.3 
Rationale for Current Study 
3.3.1 
Rationale for Selection of Dose 
The dose levels of telotristat etiprate selected for this study are consistent with prior clinical 
study experience and based upon clinical safety and pharmacodynamic (PD) data from 2 
Phase 2 multiple ascending-dose studies in patients with symptomatic CS (LX1606.1-202-CS 
and LX1606.1-203-CS).  
Based upon observations noted in Section 3.2, it is anticipated that the doses to be utilized in 
this protocol will be safe and well tolerated and may provide clinical benefit to patients with 
CS. 
3.3.2 
Benefit/Risk Assessment 
Clinical experience with telotristat etiprate (treated subjects) consists of completed single and 
multiple ascending dose studies in 88 normal subjects (36 in single dose studies and 52 in the 
multiple dose study), two Phase 2 studies (37 patients with symptomatic CS) and 2 ongoing 
Phase 3 studies in patients with symptomatic CS. 
In healthy volunteer studies, single doses up to 1000 mg were found to be generally well 
tolerated, while at the 1500 mg dose level GI-related adverse events increased. A similar 
adverse event profile was observed after multiple dose administration over 14 days with GI 
events predominating. Mild, dose-dependent increases in hepatic transaminase levels (≤2 x 
ULN) were observed with increased frequency in relation to dose, with 1 subject requiring 
withdrawal from therapy at the 500 mg bid dose level. Most subjects that were observed to 
have increased transaminase levels did not exceed >2 x ULN. No abnormalities in total 
bilirubin were observed at any dose level. GI events have been the most commonly observed 
events to date. The adverse event profile in normal subjects may differ significantly from 
what is observed in patients with hyperserotonemia. All adverse events resolved without 
sequelae. In addition, there were no significant changes in vital signs or ECG. No physical 
examination abnormalities were noted in studies to date. There were no serious adverse 
events reported in healthy volunteers. 
In patients with CS, dose escalations have proceeded up to and including 500 mg tid. To date, 
there has been no evidence of dose-limiting intolerability. Dose levels have been generally 
well tolerated with no evidence to suggest elevations in hepatic transaminase levels. Based 
upon observations from preclinical and clinical studies conducted to date, it is anticipated that 
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orally administered telotristat etiprate will be well tolerated at dose levels required to 
influence peripheral 5-HT production in patients with symptomatic CS. Potential adverse 
events primarily involve the GI tract, and could include alterations in gut motility, nausea, 
vomiting, diarrhea, constipation, abdominal bloating, and/or pain. Regular and ongoing 
clinical and laboratory assessments should detect any of these events, and depending on the 
type of event, further dose adjustment or discontinuation from the trial would occur. Although 
CNS effects are not anticipated at dose levels planned for evaluation, standard adverse event 
questioning and/or physical examination should reveal any subtle CNS findings. As 
elevations in hepatic transaminase levels were observed with multiple dosing in normal 
subjects, monitoring clinical laboratory tests of hepatic function will be incorporated into 
clinical trials conducted in CS patients. 
Treatment has the potential to improve several signs and symptoms of CS. The Phase 2 
clinical trial results indicated that treatment may lead to improvements in BM frequency, 
stool consistency, urgency, abdominal pain, diarrhea, flushing, and reductions in 5-HIAA. 
These potential benefits relate to a unique mechanism of action. Symptomatic improvement 
may lead to a better quality of life (QOL) for patients with few treatment options available, 
and a reduction in serotonin may help reduce the risk of carcinoid heart disease. Overall the 
benefit/risk profile of telotristat etiprate is expected to be favorable for participation in this 
clinical study. 
3.4 
Rationale for Study Design and Control Groups 
Currently, no approved therapy exists for the treatment of symptoms driven by underlying 
serotonin pathophysiology of CS in patients whose disease is refractory to SSA therapy or for 
those patients who are unable to tolerate SSA therapy or who are unwilling to take SSA 
therapy. 
This study will allow for continued access to telotristat etiprate after patients have completed 
the required study visits in ongoing Phase 2 and Phase 3 studies. Continuation of CS patients 
into this study will allow for the collection of additional long-term safety and efficacy data, 
while providing access to patients who may be receiving benefit. The treatment duration is 
supported by results of chronic toxicology studies (6-month rat and 9-month dog) and the 
current safety profile from completed and ongoing clinical trials. 
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4. 
Study Objectives 
4.1 
Efficacy Objectives 
4.1.1 
Primary Objective 
The primary objective of the study is to evaluate the long-term safety and tolerability of 
orally administered telotristat etiprate. 
4.1.2 
Secondary Objective(s) 
The secondary objective of this study is to evaluate changes in patients’ QOL. 
4.2 
Safety Objectives 
Evaluation of overall safety will be assessed as: 
• Incidence of treatment-emergent adverse events (TEAEs) 
• Changes from Baseline in clinical laboratory results, vital signs results, and ECG 
findings 
5. 
Investigational Plan 
5.1 
Overall Study Design 
The study will be conducted as a multicenter, open-label, long-term extension study to further 
evaluate long-term safety and tolerability of telotristat etiprate. 
Patients currently participating in any LX1606 Phase 2 CS study may enter into this 
extension study upon institutional or local approval of the protocol. Patients participating in a 
Phase 3 CS study may enter into this extension study at the Week 48 visit. All patients who 
enter into this extension study will be exempt from any follow-up visit required by the 
original study and will not experience an interruption in study drug due to the transition from 
the original protocol to LX1060.1-302-CS. 
Following confirmation of eligibility, patients will complete a series of visit assessments in 
order to establish Baseline symptoms. Patients will then continue on open-label LX1606 at 
the same dose level identified in the original study.  
Downward dose adjustment will be permitted during the study if evidence of intolerability 
emerges. Patients who experience intolerability at the 250 mg tid dose level must be 
discontinued from the study. Patients may return to the previous dosing at the discretion of 
the Investigator and in consultation with the Medical Monitor. 
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Upon completion or early withdrawal from treatment, all patients will be required to 
complete a 14-day Follow-up Period, during which no study drug will be administered.  
A Data Safety Monitoring Board (DSMB) will review safety data quarterly throughout the 
study.  
6. 
Study Population 
Adult patients who are currently participating in ongoing Phase 2 or Phase 3 telotristat 
etiprate CS clinical protocols will be enrolled into the study. Up to 100 patients are expected 
to enroll in this study. Approximately 70 sites worldwide will participate in the study. Patients 
may continue allowed medications as background therapy provided they remain on stable-
doses throughout the Treatment Period. 
6.1 
Inclusion Criteria 
Patients must meet all of the following criteria to be considered eligible to participate in the 
study: 
1. Ongoing participation in a Phase 2 (eg, LX1606.1-202-CS, LX1606.1-203-CS) or 
Phase 3 (eg, LX1606.1-301-CS, LX1606.1-303-CS) study  
2. Patients of childbearing potential must agree to use an adequate method of 
contraception (defined as having a failure rate of <1% per year) during the study and 
for 12 weeks after the Follow-up visit. Adequate methods of contraception for 
patients or partner include condoms with spermicide gel, diaphragm with spermicide 
gel, coil (intrauterine device), surgical sterilization, vasectomy, oral contraceptive pill, 
depot progesterone injections, progesterone implant, and abstinence during the study 
and for 12 weeks after the Follow-up Visit.  
a. Childbearing potential is defined as those who have not undergone surgical 
sterilization, or those who are not considered postmenopausal. Postmenopause 
is defined as absence of menstruation for at least 2 years. If necessary, follicle-
stimulating hormone (FSH) results >50 IU/L at Screening are confirmatory in 
the absence of a clear postmenopausal history. 
3. Ability and willingness to provide written informed consent prior to participation in 
any study-related procedure. 
6.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participating in the 
study:   
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1. Major protocol violations or tolerability concerns in a Phase 2 (eg, LX1606.1-202-CS, 
LX1606.1-203-CS) or Phase 3 (eg, LX1606.1-301-CS, LX1606.1-303-CS) study  
2. Positive pregnancy test 
3. Presence of any clinically significant findings at entry for medical history, laboratory 
values, or physical examination (relative to patient population) that, in the 
Investigator’s or Medical Monitor’s opinion, would compromise patient safety or the 
outcome of the study 
4. Patients who are currently committed to an institution by virtue of an order issued 
either by judicial or administrative authorities 
6.3 
Criteria for Stopping Treatment/Study Withdrawal 
A patient may also be discontinued from the study for the following medical or 
administrative reasons: 
• Withdrawal of consent by the patient or legal guardian 
• Noncompliance, including refusal of the study medication and/or failure to adhere to 
the study requirements as in the study protocol 
• Investigator decides that, in the interest of the patient, it is not medically acceptable to 
continue participation in the study 
• The Sponsor terminates the study (Section 6.4) 
• Pregnancy (Section 9.4.1) 
Note:  If a patients voluntarily withdraws or is discontinued from study treatment before 
completing the entire duration of the Treatment Period, they should be encouraged to 
continue clinic visits according to the study schedule.  
Patients who discontinue study treatment, and who are not willing to continue clinic visits 
(eg, withdrawal of consent) should be encouraged to complete End-of-Study (EOS) 
assessments as identified in Appendix A – Schedule of Events and agree to report any SAEs 
(Section 9.2) that occur within 30 days following the last dose of telotristat etiprate. 
The date the patient discontinues study treatment, the primary reason for study treatment 
discontinuation, study termination, and/or termination of participation (eg, withdrawal of 
consent), will be captured within the Case Report Form (CRF). 
When patients withdraw consent from study participation, it must be recorded on the CRF 
whether the withdrawal of consent applies to specific aspects of the study such as 
discontinuation of study treatment, participation in study visits, contact by study personnel, or 
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access to information about potential SAEs. If specific consent has not been withdrawn, study 
personnel should contact the patient (or a previously approved designee such as a caregiver, 
partner, or family member) at the scheduled Follow-up visit to inquire about health status. 
6.4 
Criteria for Termination of the Study 
If the Sponsor, Investigator, study monitor, DSMB, or regulatory officials discover conditions 
arising during the study that indicate that the patient safety and/or scientific value of the study 
and/or quality of the study drugs have been compromised, the study should be halted or the 
study center’s participation should be terminated. Conditions that may warrant termination of 
the study include, but are not limited to, the following: 
• The discovery of an unexpected, serious, or unacceptable risk to the patients enrolled in 
the study; 
• A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product for any reason; 
• Failure of the Investigator to enroll patients into the study at an acceptable rate; 
• Failure of the Investigator to comply with pertinent governing body regulations; 
• Submission of knowingly false information from the research facility to the Sponsor, 
study monitor, medical officer, or regulatory official; and, 
• Insufficient adherence to protocol requirements.  
Study termination and Follow-up would be performed in compliance with applicable 
governing body regulations. 
6.5 
Clinical Stopping Rules 
Criteria for individual patient withdrawal or study termination are summarized in Sections 
6.3 and 6.4, respectively. 
6.6 
Method of Assigning Patients to Treatment  
Patients will enter the study at the same dose level and regimen as identified in the prior 
Phase 2 or Phase 3 CS study. Randomization will not be used to assign patients to study 
treatments. 
6.7 
Blinding and Unblinding of Study Medication 
This is an open-label study.  
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6.8 
Replacement of Patients 
Patients who do not complete the study will not be replaced. 
7. 
Treatment 
7.1.1 
Telotristat Etiprate (LX1606) 
7.1.1.1 
Identity 
LX1606 hippurate is the salt form of the drug substance. LX1606 hippurate is a crystalline 
white to off-white to tan solid with a melting point of 147°C. LX1606 is insoluble in water 
within the pH range of 5 to 9 (≤2 mg/L). It undergoes hydrolysis under strongly basic or 
strongly acidic conditions. The solubility of LX1606 hippurate in water is about 22 mg/L at 
25°C. 
Study drug dosage form consists of white coated debossed oval tablets containing 250 mg 
LX1606. 
7.1.1.2 
Packaging, Labeling, and Storage 
Patients will receive 250 mg telotristat etiprate tablets packaged in 100 cc high density 
polyethylene bottles with child-resistant polypropylene screw caps and heat-induction seal 
liners.  
Telotristat etiprate should be stored between 15 to 25°C (59 to 77°F). 
7.2 
Prior and Concomitant Medications 
7.2.1 
Prior Medications 
All medications and other treatments taken by patients within 30 days prior to entry will be 
recorded on the CRF.  
7.2.2 
Concomitant Medications 
All concomitant medications taken by patients during the study will be recorded on the CRF. 
Treatment with prescription or over-the-counter (OTC) antidiarrheal therapy, bile acid 
sequestrants, or pancreatic enzyme is permitted; however, the use of these concomitant 
therapies should be associated with a documented history of disease (eg, fat malabsorption, 
bile acid malabsorption, or steatorrhea).  
The dosage(s) of all concomitant medication should remain stable. Should the need arise to 
modify/adjust a patient’s therapy the Medical Monitor should be contacted. The Investigator 
and Medical Monitor will make a determination if such a change would impact the safety of 
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the patient and the integrity of the study. The Medical Monitor will determine if the patient 
can continue in the study. 
7.2.3 
Prohibited Medications or Concomitant Therapy 
None 
7.3 
Administration of Study Medication 
All patients will be instructed to take the study medication with food. “With food” means 
taking telotristat etiprate tablets within 15 minutes before or within 1 hour after a meal or 
snack. Patients will be instructed to take study drug 3 times daily during waking hours, with 
doses spaced approximately 6 hours apart.  
Study medication and instructions will be dispensed to patients at each visit as described in 
the schedule of study procedures (Appendix A). 
7.3.1 
Treatment Compliance  
Patients will be asked to bring their unused or unopened study medication to each visit 
(Appendix A). At each visit and in the presence of the patient, study site personnel will count 
returned tablets and reconcile the counts against planned number of doses for that interval. 
Site personnel will clarify any discrepancy and record this information within the CRF.  
Patients must maintain at least 75% compliance in dosing to be deemed as compliant. In the 
event of a missed or vomited dose, patients will take their subsequent dose of study drug at 
the next scheduled time point, following the tid dosing regimen of approximately every 6 
hours. A dose outside of a 3 hour window should be considered missed. Missed or vomited 
doses will not be made up.  
7.4 
Dose Adjustment 
Downward dose adjustment of telotristat etiprate will be permitted if evidence of 
intolerability emerges. After a period at the lowered dose level, patients may resume the 
previous dosing level at the discretion of the Investigator after consultation with the Medical 
Monitor. Patients who experience intolerability at the 250 mg tid dose level must be 
discontinued from study treatment. Interruptions or delays in dosing throughout the entire 
study may be permitted after consultation with the Medical Monitor, at which time the patient 
will be reassessed for study continuation, dosage reduction, or discontinuation. 
8. 
Study Procedures 
A schedule of study assessments is provided in Appendix A. 
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8.1 
Restrictions during Study 
Patients should be advised to avoid food and drink containing grapefruit for 2-3 hours prior to 
and following dosing while participating in the study. 
8.2 
Description of Study Assessments 
8.2.1 
Efficacy Assessments 
Efficacy assessments include the patient reported QOL measures; EORTC QLQ-C30 
(Appendix D) & GI.NET21 (Appendix E) questionnaires and subjective global assessment of 
symptoms associated with CS. 
A description of the efficacy assessments is provided below. 
8.2.1.1 
EORTC QLQ-C30 & GI.NET21 
Patients will complete the questionnaires during each visit as indicated in Appendix A. 
8.2.1.2 
Subjective Global Assessment 
A subjective global assessment of symptoms associated with CS will be evaluated using 2 
methods at each visit.  
Patients will first be asked to respond to the following question:  “In the past 7 days, have 
you had adequate relief of your carcinoid syndrome bowel complaints such as diarrhea, 
urgent need to have a bowel movement, abdominal pain, or discomfort?”. 
Then patients will be asked the following question to assess global symptoms associated with 
CS on an 11-point scale: “Rate the severity of your overall carcinoid symptoms over the past 
7 days on a scale from 0-10, where 0 = no symptoms and 10 = worst symptoms ever 
experienced.” 
 
8.2.2 
Clinical Laboratory Assessment  
Clinical laboratory assessments will consist of hematology (complete blood count [CBC] 
with differential and platelet counts), blood chemistry (complete metabolic panel and liver 
function tests), and urinalysis. All laboratory tests will be performed by a central laboratory, 
with the exception of the urine pregnancy test, which will be performed by the study site with 
the provided laboratory kit.  
The incidence of clinically significant laboratory values, as well as clinically significant shifts 
in laboratory values, should be reported as an AE in the patient’s CRF (see also Section 9.1 
for reporting of AEs related to laboratory abnormalities). The Investigator will assess any 
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clinically significant values relevant to the patient population to determine if termination of 
the study drug is required. 
8.2.2.1 
Monitoring Hepatic Function 
Patients with clinically significant abnormalities in liver function tests should be excluded 
from participating; however, the patient’s clinical situation as a whole should be taken into 
account when evaluating hepatic transaminase elevations, which may represent a 
consequence of the underlying disease and/or therapeutic interventions. Patients with 
abnormalities in liver function test results, as defined below, should be further assessed by the 
Investigator and may have additional tests performed by the central laboratory as clinically 
indicated. The following describes the Sponsor’s recommended approach to evaluating these 
events. This approach is not meant to replace the Investigator’s clinical judgment.  
These guidelines apply to the following events: 
1) A new confirmed result (after Day 1 dosing) of ALT or AST >3 x ULN (in 
patients previously within normal range) 
OR 
2) A confirmed increase in transaminases above the patient’s previous Baseline to a 
degree that is significant in the clinical judgment of the Investigator and ALT or 
AST >3 x ULN (in patients with previous abnormal liver-test results) 
OR 
3) Any occurrence of an elevation of ALT or AST > 3 x ULN and total bilirubin >2 
x ULN (in any patient) 
For any such event, the Investigator should discuss the Follow-up approach with the Medical 
Monitor.  
The Sponsor’s recommended approach is as follows: 
1. Schedule the patient for a Follow-up visit within 3 days following the receipt of 
laboratory results to assess the patient and conduct further evaluation, to include the 
following: 
a. Obtain repeat testing of ALT, AST, total bilirubin, and ALP through the central 
laboratory. 
b. Reassess the patient through patient interview and physical examination to 
uncover new or emerging risk factors of liver injury including an increased use 
of alcohol, gallbladder disease, hemochromatosis, fatty liver, use of 
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hepatotoxic concomitant medications (including acetaminophen), occupational 
exposures, liver metastases, and other causes for potential clues as to the 
underlying etiology of the event. 
c. Continue to monitor the patient’s transaminases and total bilirubin regularly 
until the liver function test values return to Baseline levels.  
Additional recommendations include: 
• Consider referral to a hepatologist or gastroenterologist 
• Consider reimaging (eg, ultrasound, CT, or MRI) the liver and biliary tract 
• Consider additional laboratory testing as clinically indicated. Laboratory assays 
available to the Investigator for further workup are described in the laboratory manual 
Upon completion of hepatic assessment, the Investigator should review results with the 
Medical Monitor and assess continued study participation. 
8.2.3 
Pharmacodynamic Assessments 
8.2.3.1 
Plasma 5-HIAA 
Fasting blood samples (≥6 hours) for measurement of 5-HIAA in plasma will be collected 
and analyzed by a specialty laboratory. All sample processing information will be supplied by 
the laboratory in a separate document/study manual. Efforts should be made to schedule these 
visits in the morning, with instructions to the patient to arrive in a fasted state and not dose 
prior to the blood draw. 
8.2.4 
Safety Assessments 
In addition to the clinical laboratory assessments described in Section 8.2.2, monitoring of 
AEs is also considered a safety assessment and is described in detail in Section 9. Clinically 
significant changes compared with Baseline findings for these variables should be reported as 
AEs on the CRF. Clinically significant changes compared with Baseline values, which are 
determined to be AEs, should be followed until the event has resolved, the condition has 
stabilized, etiology of the event is determined to be not related to study drug, or the patient is 
lost to Follow-up. 
8.2.4.1 
Vital Sign Measurements 
Measurement of vital signs will include assessment of blood pressure, respiratory rate, pulse 
rate, and oral temperature. Vital sign measurements should not be conducted with the 
30 minutes immediately following any phlebotomy. 
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Efforts should be made to standardize blood pressure collection across all patients and visits. 
Patients should be seated for at least 5 minutes prior to collection. All measurements will be 
collected using dedicated equipment, supplied by the Sponsor, assessed on the same arm, and 
by the same technician where possible. 
Additional measurements may be obtained if clinically indicated. Vital sign measurements 
will be measured as indicated in Appendix A. 
8.2.4.2 
Physical Examinations 
Complete physical examinations will be performed as outlined in Appendix A. Complete 
physical examinations will include a minimum of a review of the patient’s general 
appearance, head, eyes, ears, nose, and throat (HEENT), neck, heart, lungs, abdomen, back 
and extremities, skin, and general neurological system.  
Symptom-oriented physical examinations will be performed at all other time points and as 
clinically indicated.  
In addition, weight will be captured during each physical examination. Efforts should be 
made to standardize weight collection across all patients and visits. Patients should be 
instructed to remove shoes and heavy clothing (eg, heavy coats, jackets) prior to 
measurement. For weight collection, an effort should be made to use the same scale 
throughout the study where possible. In instances where multiple scales may be used, efforts 
should be made to reset the scale to zero prior to collection of weight measurement. 
8.2.4.3 
Electrocardiograms 
Electrocardiograms (12-lead ECGs) will be performed as specified in Appendix A. 
8.2.4.4 
Adverse Events of Special Interest 
Monitoring of these events will be the responsibility of the DSMB. The process of data 
collection and assessment of the events will be detailed in a separate DSMB charter.  
Additional information will be collected if episodes of any of the following AEs of special 
interest occur. 
8.2.4.4.1 
Central Nervous System Events 
Central nervous system events of special interest may include any clinically significant 
changes in mood, physical affect, or exacerbation of preexisting CNS conditions (eg, 
depression, migraine headaches). 
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8.2.4.4.1.1 
Depression Detection 
Patients will be evaluated beginning at Day 1 (Baseline) and at each subsequent visit for 
indications of depression. During each visit the patient will first be asked to respond to the 
question “During the past month, have you often been bothered by feeling down, depressed, 
or hopeless?” Followed by “During the past month, have you often been bothered by little 
interest or pleasure in doing things?” A positive response prior to Day 1 dosing will be 
captured on the medical history CRF page. Positive responses following the first dose will be 
captured as an AE and will be followed as an AE of special interest.  
8.3 
Other Assessments 
8.3.1   Chromogranin A (CgA) 
Blood samples for measurement of chromogranin A (CgA) levels will be collected as 
indicated in Appendix A. 
8.3.2 
Disease Progression 
Data will also be collected on measures of disease progression as performed as standard of 
care (including, but not limited to: interpretation of clinical scans [eg, PET, CAT, MRI scans 
of tumor], Investigator assessment of disease status) while the patient is enrolled in the study.  
8.3.3 
Quality of Sleep Assessment 
Quality of sleep will also be evaluated beginning Day 1 (Baseline) and at each subsequent 
visit thereafter. Patients will be asked to respond to the following question “Since your last 
visit, how many times a night (on average) do you wake up due to your CS symptoms?” 
based on the following scale 0, 1, 2, 3, 4, >4.  
8.4  
Appropriateness of Assessments 
The assessments used in this study conform to the usual clinical and laboratory assessments 
of patients with CS participating in clinical trials and are typical of a Phase 3 study.  
8.4.1  
Blood Collection 
An attempt should be made to collect all samples as per the schedule outlined in Appendix A. 
Any portion of samples remaining after the required tests for this study have been completed 
will be destroyed. 
The estimated amount of blood scheduled for collection per patient, over the course of the 
study, may be found in Appendix B. 
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9. 
Safety Reporting 
Medical queries should be addressed to the medical monitor responsible for the region. 
Sites in North America: 
, MD 
  
INC Research 
 
 
Phone: 
 
 
 
Sites outside North America:  
, MD, PhD 
 
INC Research 
 
 
The Netherlands 
Phone: 
 
Mobile:
 
 
 
, MD, PhD 
Medical Monitor 
INC Research, LLC 
 
 
Czech Republic 
Phone: 
 
Fax: 
 
 
After-hours emergency medical coverage is available to site personnel should the regional 
Medical Monitor and regional backup Medical Monitor be unavailable. 
 
Sites in North America dial 1-877-462-0134. 
 
Sites outside North America dial the country prefix number plus 1-877-462-0134. Prefix 
numbers are determined by accessing the AT&T Direct on-line link 
http://www.usa.att.com/traveler/access_numbers/country/index.jsp. Note: These calls are not 
toll-free. 
9.1 
Adverse Events 
It is the responsibility of the Investigator to document all AEs that occur during the study. 
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Adverse event is defined as any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. 
Life-threatening adverse event or life-threatening suspected adverse reaction: An adverse 
event or suspected adverse reaction is considered "life-threatening" if, in the view of either 
the Investigator or Sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred 
in a more severe form, might have caused death. 
An AE includes any noxious, pathological, or unintended change in anatomical, 
physiological, or metabolic functions as indicated by physical signs or symptoms occurring in 
any phase of the clinical study whether or not considered related to the study medication. 
This definition includes an exacerbation of preexisting medical conditions or events, 
historical condition not present prior to study treatment, which reappear following study 
treatment, intercurrent illnesses, hypersensitivity reactions, drug interaction, or the significant 
worsening of the disease under investigation that is not recorded elsewhere in the CRF. 
Anticipated day-to-day fluctuations of pre-existing conditions that do not represent a 
clinically significant exacerbation or worsening need not be considered AEs. 
Any laboratory abnormality fulfilling the criteria for a SAE (Section 9.2) should be reported 
as such, in addition to being recorded as an AE. Any treatment-emergent abnormal laboratory 
result which is clinically significant, ie, meeting 1 or more of the following conditions, 
should be recorded as a single diagnosis AE: 
• Is considered to be an SAE, 
• Results in discontinuation from study treatment, or 
• Results in a requirement for a change in concomitant therapy (ie, addition of concomitant 
therapy) 
In the event of medically significant unexplained abnormal laboratory test values, the tests 
should be repeated and followed up until they have returned to the normal range and/or an 
adequate explanation of the abnormality is determined.  
TEAEs are defined as any AEs reported after the first dose of randomized treatment on 
Day 1. Adverse events reported after consent of a patient, but before administration of study 
medication, will be reported in the Medical History. 
AEs should not be solicited with leading questions that suggest specific signs or symptoms. 
Rather, AEs should be solicited by asking the patient a non-leading question such as: “Do you 
feel different in any way since receiving the dose or since the last assessment?” 
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The Investigator will evaluate all AEs with regard to the maximum intensity and relationship 
to study drug, as follows: 
• Maximum intensity  
Maximum intensity should be assigned using 1 of the following 3 severity grades: 
o 
Mild: aware of event but easily tolerated 
o 
Moderate: discomfort, enough to cause interference with usual activity 
o 
Severe: incapacitating: patient unable to work or perform usual activities 
• Relationship to study drug 
Not related:  
o 
Does not follow a reasonable temporal sequence from administration of the drug 
o 
Could be reasonably explained by other factors, including underlying disease, 
complications, concomitant drugs, or concurrent treatment. 
Possibly related:  
o 
That follows a reasonable temporal sequence from administration of the drug 
(including the course after withdrawal of the drug), or 
o 
For which the possibility of the study drug being the causative factor (eg, existence 
of similar reports attributed to the suspected drug and its analogues; reactions 
attributable to the pharmacological effect) could not be excluded, although other 
factors such as underlying disease, complications, concomitant drugs, or concurrent 
treatment are presumable. 
Probably related: 
o 
That follows a reasonable temporal sequence from administration of the drug 
(including the course after withdrawal of the drug), and 
o 
For which the possibility of factors other than the drug, such as underlying disease, 
complications, concomitant drugs, or concurrent treatment, could not be excluded as 
the cause. 
Definitely related: 
o 
Follows a clear temporal sequence from administration of the study drug. 
o 
Could not be possibly explained by the known characteristics of the patient’s 
clinical state, environmental or toxic factors, or other modes of therapy 
administered to the patient. 
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o 
Disappears or decreases on cessation or reduction in dose of the study drug. 
o 
Reappears or worsens when the study drug is re-administered. 
o 
Follows a response pattern known to be associated with administration of the study 
drug. 
The degree of certainty with which an AE is attributed to treatment with study medication (or 
alternative causes, eg, natural history of the underlying diseases, concomitant therapy, etc.) 
will be determined by how well the event can be understood in terms of known 
pharmacology of the study medication and/or reaction of similar nature being previously 
observed with the study medication or the class of study medication. 
All AEs should be followed for at least 30 days following the last dose of study drug or until 
the event has resolved, the condition has stabilized, or the patient is lost to Follow-up. For 
each patient for whom an AE was reported that did not resolve before the end of the reporting 
period, Follow-up information on the subsequent course of events must be submitted to the 
Sponsor. This requirement indicates that follow-up may be required for some AEs after the 
patient has completed his/her participation in the study 
9.2 
Serious Adverse Events (SAEs) 
An SAE is defined as any event that results in any of the following outcomes: 
1. Death 
2. A life-threatening adverse event; 
3. Inpatient hospitalization or prolonging of an existing hospitalization;  
4. A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; or 
5. A congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed above. 
Any SAE must be reported by telephone or facsimile within 24 hours of discovery of the 
event. Investigators should not wait to receive additional information to fully document the 
event before notifying the Sponsor of an SAE at: 
Sites in North America must report to: 
Safety Data Facsimile: 001 (832) 442-5917 
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Safety Hotline: 001 (877) 372-3597 
 
Email address (in case of fax failure): drugsafetyfax@lexpharma.com 
 
Sites outside North America must report to the country specific toll-free fax numbers 
identified below: 
Australia: 
 
Belgium: 
 
Brazil: 
 
France: 
 
Germany: 
 
Israel: 
 
Italy: 
 
Netherlands: 
 
Spain: 
 
Sweden: 
 
United Kingdom: 
 
 
Email Address (in case of fax failure):  
 
 
The telephone report should be followed by full written summary detailing relevant aspects 
of the SAE in question using the provided SAE report form. Where applicable, information 
from relevant hospital case records and autopsy reports should be obtained. The SAE should 
also be recorded on the AE page of the patient’s CRF. 
An SAE that occurs after completion of the study but, in the opinion of the Investigator, is 
related to the study medication, should be reported as described for an SAE. If an AE does 
not meet the regulatory definition of “serious” but is considered by the Investigator to be 
related to the study medication and of such clinical concern as to influence the overall 
assessment of safety, it must be reported as defined for an SAE. 
All patients (including discontinued patients) with a SAE must be followed until the event 
resolves or reaches a new Baseline, but for a minimum of 30 days after the last dose of study 
drug. 
9.3 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
The FDA and/or other applicable Regulatory Authorities and all participating Investigators 
will be notified by a written Investigational New Drug Application (IND) safety report and/or 
other applicable regulatory report (eg, SUSAR) of any suspected adverse reaction that is both 
serious and unexpected, no later than 15 calendar days from the “date learned” of the event. 
In addition, all applicable regulatory bodies will be notified within 7 calendar days of any 
unexpected fatal or life-threatening suspected adverse reaction.  
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An adverse reaction is defined as any untoward and unintended response to an investigational 
medicinal product (IMP) related to any dose administered. This definition also covers 
medication errors and uses outside what is foreseen in the protocol, including misuse and 
abuse of the product. The definition also implies a reasonable possibility of a causal 
relationship between the event and the IMP.  
An unexpected adverse reaction is any adverse drug event, which is not listed in the current 
Investigator’s Brochure or is not listed at the specificity or severity that has been observed. 
For example, (A) a single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (eg, angioedema, hepatic injury, Stevens-Johnson Syndrome); 
(B) 1 or more occurrences of an event that is not commonly associated with drug exposure, 
but is otherwise uncommon in the population exposed to the drug (eg, tendon rupture); (C) an 
aggregate analysis of specific events observed in a clinical trial (such as known consequences 
of the underlying disease or condition under investigation or other events that commonly 
occur in the study population independent of drug therapy) that indicates those events occur 
more frequently in the drug treatment group than in a concurrent or historical control group. 
An untoward and unintended response to a non-IMP is by definition not a SUSAR. 
9.4 
Precautions 
9.4.1 
Pregnancy 
Any patient (or patient’s partner) who becomes pregnant during the study should be followed 
through delivery or termination of the pregnancy. In addition, patients who become pregnant 
during the study must be discontinued from the study treatment immediately.  
In pregnancies that progress to term, any congenital abnormalities/birth defects in the 
offspring of a patient who received study medication should be reported as an SAE. The 
outcome of the pregnancy and the presence or absence of a congenital abnormality will be 
documented by completion of a Pregnancy Questionnaire and a Pregnancy Outcome Form in 
accordance with GCP and ICH guidelines and the Sponsor’s SOPs.  
Female patients should also notify the Investigator if they become pregnant within 30 days 
after last dose of study medication. Male patients should notify the Investigator if a female 
partner becomes pregnant within 30 days after last dose of study medication. The Sponsor 
must be notified of all pregnancies reported to the Investigator (see Section 9.2 for contact 
information). 
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10. 
Statistical Methodology 
10.1 
Determination of Sample Size 
No formal sample size calculation was made. The number of patients expected to participate 
in this study was calculated from estimated enrollment rates from other carcinoid cancer trials 
employed in the LX1606 clinical program. 
10.2 
Analysis Populations 
Per protocol: A Per Protocol population will consist of those patients that receive study 
treatment and have no major protocol violation that would interfere with the collection or 
interpretation of the efficacy data. The primary analyses of efficacy will be based on the 
safety population; the per-protocol population will be used in a supplemental manner.  
Safety: The safety population consists of all patients receiving any fraction of a dose of study 
drug during this study.  
10.3 
Study Endpoints 
10.3.1 
Efficacy Endpoints 
The primary efficacy endpoint is to evaluate the long-term safety and tolerability of orally 
administered telotristat etiprate. 
Secondary efficacy endpoint is to evaluate changes in patients’ QOL over multiple years of 
therapy.  
10.3.2 
Safety Endpoints 
Safety endpoints are as follows:  
• Incidence of TEAEs, suspected adverse reaction, AEs leading to discontinuation from the 
study, SAEs, and deaths 
• Actual and change from Baseline in clinical laboratory results  
• Actual and change from Baseline in vital signs results  
• Actual and change from Baseline in physical examinations 
• Actual and change from Baseline in ECG findings 
10.4 
Statistical Methods 
Descriptive analysis methods will be used to summarize the data. Continuous variables will 
be summarized by the N, mean, standard deviation, median, minimum, and maximum values. 
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Categorical variables will be summarized as counts and related percentages. Data tabulations 
will be categorized by the treatment received on Day 1 of this study and combined across all 
treated patients. All data will be listed. 
Primary analyses of the data will be based on the Safety population which includes all 
patients treated with any fraction of study drug during this study. Supportive analyses of the 
efficacy data will be made on a Per Protocol population. This dataset will include the Safety 
population, but limited to those patients that have at least one assessment post Day 1 and do 
not have any protocol violations that would interfere with collection or interpretation of the 
data. The Per Protocol analysis will be applied to the QOL measures, subjective global 
assessment, and plasma 5-HIAA values. 
Data will be summarized per study visit as the actual (raw) outcomes and change from 
Baseline scores, where applicable. Day 1 of this study will serve as the Baseline assessment. 
10.4.1 
Efficacy Analyses 
All efficacy and PD variables will be summarized descriptively and listed. 
Statistical tests and estimates of within patient effects for these measures will be derived from 
application of a mixed linear model with repeated measures. The model will be generalized to 
handle missing data and specific to the measurement properties of the dependent variable. 
There is no plan to impute data for missing observations for any variable. Non-parametric 
methods will be used to supplement the tests and estimates from the mixed linear model. 
Exploratory analyses of treatment group differences may be performed by use of propensity 
score models. The treatments groups will correspond to how patients were dosed on Day 1 of 
this study.  
10.4.2 
Safety Analyses 
Statistical analysis of the safety data will involve examination of the descriptive statistics and 
individual patient listings for any effects of study treatment on clinical tolerability and safety. 
Reporting of these data will be based on the Safety population. Summaries will be prepared 
by treatment group (corresponding to the LX1606 dose given on Day 1), pooled across all 
patients, and as needed, by study visit. All safety data will be listed. 
Treatment-emergent adverse event summaries will include the overall incidence (by system 
organ class and preferred term), events by maximum intensity, event by relationship to study 
treatment, events leading to discontinuation of study drug, and serious adverse events. 
Vital signs, ECG, and laboratory parameters (hematology, chemistry, and urinalysis) will be 
summarized descriptively at each time point. Actual and change from Baseline data will be 
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calculated and summarized. In addition, shift table analysis will be applied to the laboratory 
data and summarized. 
10.4.2.1 
Adverse Events 
All AEs will be coded and listed by body system and preferred term based on the Medical 
Dictionary for Regulatory Activities (MedDRA). Summaries using descriptive statistics will 
be provided for treatment-emergent AEs, drug-related AEs and AEs by intensity. Treatment-
emergent AEs are those events not present at Baseline, but occurring after the start of study 
drug, or if existing at Baseline, increasing in intensity after initiation study drug. Summaries 
made by intensity will select the event with the highest intensity when multiple occurrences 
of the same event are reported for the same patient. In a similar manner, summaries prepared 
by drug relationship will select the event with the greatest degree of relationship when a 
study reports multiple occurrences of the same event. On-study deaths will be reported for 
deaths occurring during the active phase of the treatment period and 30 days after stopping 
study drug. Also, deaths occurring outside the 30-day window, but secondary to an AE 
reported within the 30-day post treatment period, will be reported as well.  
Listings will be provided for deaths, SAEs, and discontinuations due to AEs. Additional 
summaries or listings of AEs may also be provided. 
10.4.2.2 
Clinical Laboratory Parameters 
Laboratory results will be reported in conventional units in all tables, figures, and listings. 
Laboratory results falling out of the normal range will be marked as high or low in the 
listings. Actual and changes from Baseline (Day 1) in clinical laboratory results will be 
summarized by using descriptive statistics. Summaries of shifts from Baseline to abnormal 
clinical laboratory results will also be provided. Actual and change from Baseline in 
chromogranin A levels will be summarized descriptively as well. 
10.4.2.3 
Vital Sign Measurements 
Actual and changes from Baseline (Day 1) in vital signs results will be summarized by using 
descriptive statistics. 
10.4.2.4 
Electrocardiograms 
Clinically significant changes in ECGs compared to Baseline, as determined by the 
Investigator, will be summarized by using descriptive statistics. Actual and change from 
Baseline (Day 1 predose values) to each time point in corrected QT interval (QTcF) will be 
summarized as well. 
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10.4.3 
Pharmacodynamic Analyses 
Analysis and summarization of the plasma 5-HIAA data are described in Section 10.4.1. 
10.4.4 
Baseline Characteristics and Other Summaries 
Treatment group differences will be summarized descriptively for demographic data, prior 
and concomitant medications, treatment compliance, and final disposition. Data collected 
from assessments of tumor status, when available, will be listed. 
Protocol deviations will provided as listings. 
10.4.5 
Interim Analysis 
An independent DSMB will be charged with reviewing interim safety data on a quarterly 
basis and reporting its recommendations to Lexicon Pharmaceuticals, Inc. Appropriate 
procedures will be detailed in a DSMB Charter that defines accessibility and disclosure of the 
interim study results. 
The study will be analyzed and reported in 2 phases. The first report will summarize data 
obtained from all patients providing information up to a specified data cut-off point. The 
second report will update the initial report by including data from the remaining portion of 
the study. The first reporting of the data may be taken as an interim analysis in terms of the 
procedural efforts needed to summarize these data, but it will not serve as a means to modify 
the analysis/study conduct.   
11. 
Study Management 
The Investigator is responsible for completing and maintaining adequate and accurate CRFs 
and source documentation. Source documentation constitutes original records, which may 
include: progress notes, medication administration records, laboratory reports, ECG tracings, 
and discharge summaries.  
All data on the CRF must be recorded in accordance with the CRF guidelines. If a correction 
is necessary, it should be made by the Investigator or a designated qualified individual as 
specified within the guideline. All CRFs should be completed in their entirety and stored in a 
secure location. The Investigator must sign the Investigator’s statement in each patient’s CRF 
indicating that the data reported are accurate. 
At the study site, clinical research associates will verify 100% of CRFs in their entirety 
against source documentation. Computer programmed edit checks will be run against the 
database to check for discrepancies and reasonableness of the data, and the safety database 
will be reconciled with the clinical database. All issues resulting from the computer generated 
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checks and the safety database reconciliation will be resolved according to standard data 
management practices in conjunction with the Sponsor, clinical study personnel, and the 
study Investigators. 
11.1 
Monitoring 
The Sponsor is responsible for ensuring the proper conduct of the study with regard to ethics, 
protocol adherence, site procedures, integrity of the data, and applicable laws and/or 
regulations. At regular intervals during the study and following completion of the study, the 
Sponsor’s study monitors will contact the study site via visits to the site, telephone calls, 
and/or letters in order to review study progress, CRF completion, and address any concerns 
or questions regarding the study conduct. During monitoring visits, the following aspects of 
study conduct will be carefully reviewed: informed consent of patients, patient recruitment, 
patient compliance with the study procedures, source data verification, drug accountability, 
use of concomitant therapy by patients, AE and SAE documentation and reporting, and 
quality of data. Records pertaining to these aspects are expected to be kept current. 
The Investigator must make study data accessible to the clinical monitor, to other authorized 
representatives of the Sponsor, and to regulatory inspectors 
11.2 
Audits and Inspections 
The Sponsor, regulatory authority, or IRB/ERC may visit the study site at any time during the 
study or after completion of the study to perform audits or inspections. The purpose of a 
Sponsor audit or regulatory inspection is to systematically and independently examine all 
study-related activities and documents to determine whether these activities were conducted 
according to the protocol, GCP, ICH guidelines, and any other applicable regulatory 
requirements. Investigators should contact the Sponsor immediately if contacted by a 
regulatory agency about an inspection at their site. 
11.3 
Amendments 
Any amendments to the protocol will be written and approved by the Sponsor. All 
amendments must be submitted to the IRB/ERC for approval prior to implementing the 
changes. In some instances, an amendment may require changes to the informed consent 
form, which also must be submitted for IRB/ERC approval prior to administration to patients. 
If any changes to the CRF are required, the Sponsor will issue supplemental or revised CRF 
pages. 
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11.4 
Record Keeping 
11.4.1 
Drug Accountability  
The Investigator must maintain accurate records of receipt of study drug, dispensing 
information (date, lot, and dose for each patient), and the prompt return or destruction of 
unused supplies. If the Investigator cannot account for all clinical supplies at the termination 
of the study, a written explanation must be provided.  
11.4.2 
Health Insurance Portability Accountability Act of 1996 and 
Subsequent Updates 
The Investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of patient health information, including, but not limited to, 
the Standards for Individually Identifiable Health Information, 45 Code of Federal 
Regulations (CFR) Parts 160 and 164 (the Health Insurance Portability Accountability Act of 
1996 [HIPAA] Privacy Regulation and any applicable updates). The Investigator shall ensure 
that study patients authorize the use and disclosure of protected health information in 
accordance with HIPAA Privacy Regulation and in a form satisfactory to the Sponsor. 
11.4.3 
Financial Disclosure 
The Investigator shall provide to the Sponsor sufficient accurate financial information to 
allow the Sponsor to submit complete and accurate financial certification or disclosure 
statements to the FDA and/or other applicable regulatory agencies. The Investigator shall 
promptly update this information if any relevant changes occur in the course of the study or 
for 1 year following completion of the study. 
11.4.4 
Access to Original Records 
It is an expectation of regulatory authorities that monitors, auditors, and representatives of 
national and international government regulatory agency bodies have access to original 
source documentation (see examples in Section 11) to ensure data integrity. “Original” in this 
context is defined as the first documentation of an observation and does not differentiate 
between hard copy and electronic records. 
11.4.5 
Retention of Study Documents 
According to 21 CFR Part 312.62 and ICH E6, study-related records must be retained for at 
least 2 years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region, or at least 
2 years have elapsed since the formal discontinuation of clinical development of the 
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investigational product. These documents should be retained for a longer period, however, if 
required by applicable regulatory requirements or by an agreement with the Sponsor. 
The Investigator must not destroy any study-related records without receiving approval from 
the Sponsor. The Investigator must notify the Sponsor in the event of accidental loss or 
destruction of any study records. If the Investigator leaves the institution where the study was 
conducted, the Sponsor must be contacted to arrange alternative record storage options. 
12. 
Administrative Structure of the Study 
The study will be monitored by Sponsor personnel or Sponsor representative. The following 
functions for this study will be performed by organizations designated by the Sponsor: data 
management and statistical analysis, including PD analysis and reporting.
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13. 
Appendix A – Schedule of Events 
Procedure 
Extension Period 
2 Week Follow-
up4 
Baseline Day 11 
Week 12 
Week 24 
Week 36 
Week 48/ EOS 
Tolerance (days) 
NA 
± 5 
± 5 
± 5 
± 5 
± 5 
Inclusion/Exclusion criteria 
X 
Medical history 
X 
Physical examination incl. weight 
X 
X3 
X
X
3 
3 
X 
X5 
Urine pregnancy test2 
X 
X 
X 
X 
X 
Serum pregnancy test2 
X 
Hematology, Blood chemistry 
X 
X 
X 
X 
X 
X5 
Urinalysis 
X 
X 
X5 
Chromogranin A 
X 
X 
Vital signs  
X 
X 
X 
X 
X 
X 
ECG 
X 
X 
X5 
Subjective Global Assessment 
X 
X 
X 
X 
X 
X 
EORTC QLQ-C30 and GI.NET21 
X 
X 
X 
Sleep and Depression Assessments 
X 
X 
X 
X 
X 
X 
Plasma 5-HIAA 
X 
X 
X 
X 
X 
X 
Dispensation of telotristat etiprate (LX1606) 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
1Eligibility will be determined at last visit of the original protocol; Day 1 will replace the next scheduled visit in the original protocol schedule. Visits should coincide with 
LAR injections for those patients receiving SSA therapy. 2Females of child-bearing potential only. 3Brief physical examination only (symptom-oriented, including weight). 
4Visit to be performed for subjects who withdraw early and will not return for a 2 week follow-up visit; In all other cases the EOS visit should be performed followed by the 
follow-up visit 2 weeks postdose. 5To be performed only if evaluation at Week 48/EOS is abnormal.   
 
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Safety
Hematology
2
6
12
Blood chemistry
6
6
36
Other
CgA
2
2
4
Serum Pregnancy
2
1
2
Pharmacodynamic Plasma 5-HIAA
4
6
24
78
*Maximum number of samples is indicated
Total 
Assessment
Sample volume (mL)
Number of samples*
Estimated total volume (mL)
 
14. 
Appendix B – Amount of Blood to be Collected from Each Patient 
 
 
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15. 
Appendix C – EORTC QLQ-C30 
 
 
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16. 
Appendix D – EORTC QLQ - GI.NET21 
 
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17. 
Appendix E – Ethical Standards 
Ethics and Regulatory Considerations 
This study will be conducted according to GCP, 21 CFR Part 50, (Protection of Human 
Subjects), 21 CFR Part 56 (Institutional Review Boards), International Conference on 
Harmonisation Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance, the 
Nuremberg Code, and the Declaration of Helsinki.  
General Instructions 
The FDA regulates studies of drugs, biologics, and medical devices. Consequently, these 
studies are subject to GCP regulations and guidance issued by the FDA and are included in, 
but not limited to, the following parts of the CFR and guideline document: 
• 21 CFR Part 11 – Electronic Records 
• 21 CFR Part 50 – Protection of Human Subjects 
• 21 CFR Part 54 – Financial Disclosure 
• 21 CFR Part 56 – Institutional Review Boards 
• 21 CFR Part 312 – Investigational New Drug Application 
• Current FDA Guideline for the Monitoring of Clinical Investigations 
• Current Guidance for Institutional Review Boards and Clinical Investigators 
• ICH E6 – Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance  
Studies conducted in the European Union are also regulated by Volume 10 of the publications 
“The rules governing medicinal products in the European Union”. 
Copies of these materials are available from the Sponsor upon request. The purpose of these 
regulations and legal obligations is to define the standards and principles for the proper 
conduct of clinical trials that have been developed by the medical, scientific, and regulatory 
communities. They are not intended to impede or restrict clinical research.  
The ethical standards defined within GCP are intended to ensure that: 
• human subjects are provided with an adequate understanding of the possible risks of their 
participation in the study, and that they have a free choice to participate or not; 
• the study is conducted with diligence and in conformance with the protocol in such a way 
as to insure the integrity of the findings; 
• the potential benefits of the research justify the risks. 
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Lexicon Pharmaceuticals, Inc. is the Sponsor of the IND. The Sponsor is responsible for the 
following: 
• selecting qualified Investigators, 
• providing Investigators with the information they need to properly conduct an 
investigation, 
• ensuring proper monitoring of the investigation, 
• ensuring that the study is conducted according to the general investigational plan and 
protocols contained in the IND, 
• maintaining the IND, and  
• ensuring that regulatory authorities and all participating Investigators are properly 
informed of significant new information regarding adverse effects or risks associated with 
the drug being studied 
• ensuring the study is conducted in accordance to FDA and ICH guidelines and all 
applicable regulations 
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18. 
Appendix F – Investigator Obligations 
Per Title 21 of the US Government Code of Federal Regulations (21 CFR) Parts 50 and 56 
and ICH E6, the study protocol and the final version of the subject informed consent form 
will be approved by the IRB/ERC before enrollment of any subjects. The opinion of the 
IRB/ERC will be dated and given in writing. A copy of the letter of approval from the 
IRB/ERC and a copy of the approved informed consent form will be received by the Sponsor 
prior to shipment of study medication supplies to the Investigator. 
The Investigator will ensure that the IRB/ERC will be promptly informed of all changes in 
the research activity and of all unanticipated problems including risk to subjects. The 
Investigator will also ensure that no changes will be made to the protocol without IRB/ERC 
approval. 
As a part of the IRB/ERC requirement for continuing review of approved research, the 
Investigator will be responsible for submitting periodic progress reports to the IRB/ERC at 
intervals appropriate to the degree of subject risk involved, but no less than once per year. 
Written informed consent must be given freely and obtained from every subject prior to 
clinical trial participation. The rights, safety, and well-being of the trial subjects are the most 
important considerations and should prevail over interests of science and society. 
As described in GCP guidelines, study personnel involved in conducting this trial will be 
qualified by education, training, and experience to perform their respective task(s). Study 
personnel will not include individuals against whom sanctions have been invoked after 
scientific misconduct or fraud (eg, loss of medical licensure, debarment). Quality assurance 
systems and procedures will be implemented to assure the quality of every aspect of the 
study. 
Principal Investigators must provide Lexicon with a fully executed Form FDA 1572 
(statement of Investigator) and all updates on a new fully executed Form FDA 1572. 
Principal Investigators must provide Lexicon with his/her own curriculum vitae and current 
curriculum vitae for each sub-Investigator listed on Form FDA 1572. 
Protection of Human Subjects (21 CFR Part 50 and ICH E6)  
Informed consent must be obtained from every subject before entry into a clinical study. It 
must be given freely and not under duress. Consent must be documented by use of an 
IRB/ERC-approved consent form and signed by the subject or the subject’s legally authorized 
representative. The US Department of Health and Human Services suggests that when minors 
are involved, a parent or guardian should sign the consent form. If the minor is an adolescent, 
his signature should also be included. Non-English-speaking subjects must be presented with 
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a consent form written in a language that they understand. A copy of the signed consent form 
must be given to the subject signing it. Another copy must be kept in the Investigator’s files 
and made available to regulatory authority representatives upon request. If, for any reason, 
subject risk is increased as the study progresses, a revised, IRB/ERC-approved consent form 
must be signed by the subject. Before the study begins, a sample of the consent form must be 
provided to the Sponsor for review. The FDA and/or other applicable regulatory agencies 
may reject otherwise scientifically valid studies if proper informed consent has not been 
obtained from all subjects. 
Only in the case of a life-threatening incident may an investigational product be used without 
prior signed consent. In such an emergency situation, separate certifications must be written 
both by a physician not participating in the study and by the Investigator. The certifications, 
along with the protocol and informed consent, must be sent to the IRB/ERC within 5 working 
days. In this situation, the Investigator may not administer any subsequent product to that 
subject until informed consent and IRB/ERC approval are obtained. 
Informed Consent 
Written informed consent must be obtained from each subject prior to entry in the study. One 
copy of the signed informed consent document will be given to the subject, and another will 
be retained by the Investigator. Additionally, the subject must be allowed adequate time to 
consider the potential risks and benefits associated with his/her participation in the study.  
In situations where the subject is not legally competent to provide consent (ie, mentally 
incapacitated), written consent must be obtained from a parent, legal guardian, or legal 
representative. In these situations, the consent must be signed and dated by a witness. 
The informed consent document must have been reviewed and approved by the Sponsor and 
by the Investigator’s IRB/ERC prior to the initiation of the study. The document must contain 
the 8 basic elements of informed consent and may contain the 6 additional elements 
described in 21 CFR Part 50. Every consent form must include the following 8 elements: 
• A statement that the study involves research, an explanation of the purpose of the research 
and the expected duration of the subject’s participation, a description of the procedures to 
be followed, and identification of any procedures that are experimental 
• A description of any reasonably foreseeable risks or discomforts to the subject 
• A description of any benefits to the subject or to others that may reasonably be expected 
from the research 
• A disclosure of appropriate alternative procedures or course of treatment, if any, that 
might be advantageous to the subject 
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• A statement describing the extent, if any, to which confidentiality of records identifying 
the subject will be maintained and noting the possibility that the FDA and/or other 
applicable regulatory authority representatives may inspect the records 
• An explanation as to whether any compensation or medical treatments are available if 
injury occurs for research involving more than minimal risk. The explanation should 
involve a description of the compensation or treatment available, or a statement 
describing where further information may be obtained 
• An explanation of whom to contact for answers to pertinent questions about the research 
and the subject’s rights and whom to contact in the event of a research related injury 
• A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the subject is otherwise entitled, and that the subject 
may discontinue participation at any time without penalty or loss of benefits to which the 
subject is otherwise entitled. 
When appropriate, 1 or more of the following elements of information shall also be included 
in the consent form: 
• A statement that the particular treatment or procedure may involve risks to the subject (or 
to the embryo or fetus, if the subject is or may become pregnant) which are currently 
unforeseeable 
• Anticipated circumstances under which the subject’s participation may be terminated by 
the Investigator without regard to the subject’s consent 
• Any additional costs the subject may incur from participation in the research 
• The consequences of a subject’s decision to withdraw from the research and procedures 
for orderly termination of participation by the subject 
• A statement that significant new findings developed during the course of the research that 
may relate to the subject’s willingness to continue participation will be provided to the 
subject 
• The approximate number of subjects involved in the study 
The Declaration of Helsinki includes further details regarding the specific requirements for 
informed consent.  
Nothing in these regulations is intended to limit the authority of a physician to provide 
emergency medical care to the extent the physician is permitted to do so under applicable 
federal, state, or local laws. 
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The informed consent requirements in these regulations are not intended to preempt any 
applicable federal, state, or local laws that require additional information to be disclosed in 
order that informed consent be legally effective. Some states, such as California and Oregon, 
require further action on the Investigator’s part concerning subject consent. 
Study Documentation 
IRB/ERC Review/Approval 
The protocol and informed consent for this study, including advertisements used to recruit 
subjects, must be reviewed and approved by an appropriate IRB/ERC prior to enrollment of 
subjects in the study. It is the responsibility of the Investigator to assure that all aspects of the 
ethical review are conducted in accordance with the current Declaration of Helsinki, ICH, 
GCP, and/or local laws, whichever provide the greatest level of protection. A letter 
documenting the IRB/ERC approval which specifically identifies the study/protocol and a list 
of the committee members must be received by the Sponsor prior to initiation of the study. 
Amendments to the protocol will be subject to the same requirements as the original protocol. 
A progress report with a request for re-evaluation and re-approval will be submitted by the 
Investigator to the IRB/ERC at intervals required by the IRB/ERC, and not less than 
annually. A copy of the report will be sent to the Sponsor.  
When the Sponsor provides the Investigator with a Safety Report, the Investigator must 
promptly forward a copy to the IRB/ERC. 
After completion or termination of the study, the Investigator will submit a final report to the 
IRB/ERC and to the Sponsor, if required. This report should include: deviations from the 
protocol, the number and types of subjects evaluated, the number of subjects who 
discontinued (with reasons), results of the study, if known, and significant AEs, including 
deaths. 
Study Files 
The Investigator is required to maintain complete and accurate study documentation in 
compliance with current Good Clinical Practice standards and all applicable federal, state, 
and local laws, rules, and regulations related to the conduct of a clinical study. Study 
documents include, but are not limited to, the Investigator’s Brochure, drug accountability 
records, Sponsor/Investigator correspondence, IRB/ERC correspondence, protocol and 
amendments, information regarding monitoring activities, subject exclusion records, CRFs, 
and data queries. 
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Confidentiality 
The anonymity of subjects must be maintained. Patients will be identified by their initials and 
an assigned subject number on CRFs and other documents submitted to the clinical monitor. 
Documents that will be submitted to the clinical monitor and that identify the subject (eg, the 
signed informed consent document) must be maintained in strict confidence by the Principal 
Investigator, except to the extent necessary to allow auditing by regulatory authorities, the 
clinical monitor, or Sponsor personnel. 
All information regarding the nature of the proposed investigation provided by the Sponsor to 
the Investigator (with the exception of information required by law or regulations to be 
disclosed to the IRB/ERC, the subject, or the regulatory authority) must be kept in confidence 
by the Investigator. 
Drug Accountability 
The Investigator or designee is responsible for accountability of the investigational product at 
the site. The Investigator or designee must maintain records of the product’s delivery to the 
site, inventory at the site, use by each subject, and return to the Sponsor or alternative 
disposition of any unused product. These records must include dates, quantities, 
batch/serial/lot numbers, and expiration dates (if applicable). 
The Investigator should ensure that the investigational product is used only in accordance 
with the protocol 
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19. 
References 
1. 
Bhattacharyya S, Toumpanakis C, Chilkunda D, Caplin ME, Davar J. Risk factors for 
the development and progression of carcinoid heart disease. Am J Cardiol. 2011 Apr 
15;107(8):1221-6. Epub 2011 Feb 4. 
2. 
Møller JE, Connolly HM, Rubin J, Seward JB, Modesto K, Pellikka PA. Factors 
associated with progression of carcinoid heart disease. N Engl J Med. 2003 Mar 
13;348(11):1005-15. 
3. 
Druce M, Rockall A, Grossman AB. Fibrosis and carcinoid syndrome: from causation to 
future therapy. Nat Rev Endocrinol. 2009 May;5(5):276-83. Review. 
4. 
DePonti F. Pharmacology of serotonin: what a clinician should know. Gut. 2004; 
53:1520 35. 
5. 
Cote F, et al. Disruption of the nonneuronal tph 1 gene demonstrates the importance of 
peripheral serotonin in cardiac function. Proc Natl Acad Sci. 2003 Nov 
11;100(23):13525-30. 
6. 
De Vries H, et al. Diagnostic, surgical, and medical aspect of the midgut carcinoids. 
Cancer Treat Rev. 2002; 28:11-25. 
7. 
Sandostatin LAR® depot product label. Revised August, 2008. Accessed at: 
http://www.pharma.us.novartis.com/product/pi/pdf/sandostatin_lar.pdf  
8. 
Investigator Brochure LX1606, Lexicon Pharmaceuticals, Inc.  
9. 
Dmitrienko A, Tamhane A, Wiens B. General multistage gatekeeping procedures. 
Biometrical Journal. 2008; 50:667-77 
 
 
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CLINICAL STUDY PROTOCOL 
Protocol Number: 
LX1606.1-302-CS 
LX1606.302 (Abbreviated number) 
EudraCT Number 
2013-002596-18 
Investigational Phase: 
3 
Protocol Title: 
A Multicenter, Long-term Extension Study to Further 
Evaluate the Safety and Tolerability of Telotristat Etiprate 
(LX1606) 
Study Name: 
TELEPATH (Telotristat Etiprate – Expanded Treatment 
for Patients with Carcinoid Syndrome) 
Amendment 1 Date: 
30 December 2014 (France only) 
Original Version Date: 
14 June 2013 
Sponsor: 
Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Place 
The Woodlands, TX 77381-1160 
Telephone: 001 (281) 863-3000 
Safety Hotline: 001 (877) 372-3597 
Safety Data Facsimile: 001 (832) 442-5917 
 
 
 
 
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1. 
Synopsis 
Name of Study Drug 
Telotristat etiprate 
Protocol Number 
LX1606.1-302-CS 
LX1606.302 (Abbreviated number) 
Protocol Title  
 
A Multicenter, Long-term Extension Study to Further Evaluate the 
Safety and Tolerability of Telotristat Etiprate (LX1606) 
Primary Objective 
The primary objective of this study is to evaluate the long-term 
safety and tolerability of orally administered telotristat etiprate   
Secondary Objective 
To evaluate long-term changes in patients’ quality of life (QOL)  
Phase of Development 
3 
Methodology 
 
The study will be conducted as a multicenter, open-label, long-term 
extension study to further evaluate long-term safety and tolerability 
of telotristat etiprate. 
Patients currently participating in any LX1606 Phase 2 carcinoid 
syndrome (CS) study may enter into this extension study upon 
institutional or local approval of the protocol. Patients participating 
in a Phase 3 CS study may enter into this extension study at the 
Week 48 visit. All patients who enter into this extension study will 
be exempt from any follow-up visit required by the original study 
and will not experience an interruption in study drug due to the 
transition from the original study to LX1060.1-302-CS. 
Following confirmation of eligibility, patients will complete a series 
of visit assessments in order to establish Baseline symptoms. 
Patients will then continue on open-label study drug at the same dose 
level and regimen as identified in their original study.  
Downward dose adjustment will be permitted during the study if 
evidence of intolerability emerges. Patients who experience 
intolerability at the 250 mg tid dose level must be discontinued from 
the study. Patients may return to the previous dosing at the discretion 
of the Investigator and in consultation with the Medical Monitor. 
Upon completion or early withdrawal from treatment, all patients 
will be required to complete a 14-day Follow-up Period, during 
which no study drug will be administered.  
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A Data Safety Monitoring Board (DSMB) will review safety data 
quarterly throughout the study.  
Number of Patients 
Up to 100 patients are expected to participate in this study.  
Patients 
Eligible patients are defined as those that are currently participating 
in a Phase 2 or Phase 3 telotristat etiprate carcinoid syndrome study. 
Number of Study Sites 
Approximately 70 sites 
Treatments 
Telotristat etiprate, 250 mg  tablet, administered at the same dose 
level and regimen identified in the patient’s original study 
Route of Administration 
Oral 
Duration of Participation 
Up to 50 weeks including Treatment and Follow-up 
Inclusion Criteria 
Patients must meet all of the following criteria to be considered 
eligible to participate in the study: 
1. Ongoing participation in a Phase 2 (eg, LX1606.1-202-CS, 
LX1606.1-203-CS) or Phase 3 (eg, LX1606.1-301-CS, 
LX1606.1-303-CS) study 
2. Patients of childbearing potential must agree to use an adequate 
method of contraception (defined as having a failure rate of <1% 
per year) during the study and for 12 weeks after the Follow-up 
visit. Adequate methods of contraception for patients or partner 
include condoms with spermicide gel, diaphragm with 
spermicide gel, coil (intrauterine device), surgical sterilization, 
vasectomy, oral contraceptive pill, depot progesterone injections, 
progesterone implant, and abstinence during the study and for 12 
weeks after the Follow-up Visit. 
a. Childbearing potential is defined as those who have not 
undergone surgical sterilization, or those who are not 
considered postmenopausal. Postmenopause is defined as 
absence of menstruation for at least 2 years. If necessary, 
follicle-stimulating hormone (FSH) results >50 IU/L at entry 
are confirmatory in the absence of a clear postmenopausal 
history. 
3. Ability and willingness to provide written informed consent 
prior to participation in any study-related procedure 
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Exclusion Criteria 
Patients who meet any of the following criteria will be excluded 
from participating in the study:   
1. Major protocol violations or tolerability concerns in a Phase 2 
(eg, LX1606.1-202-CS, LX1606.1-203-CS) or Phase 3 (eg, 
LX1606.1-301-CS, LX1606.1-303-CS) study 
2. Positive pregnancy test 
3. Presence of any clinically significant findings at entry for 
medical history, laboratory values, or physical examination 
(relative to patient population) that, in the Investigator’s or 
Medical Monitor’s opinion, would compromise patient safety or 
the outcome of the study 
4. Patients who are currently committed to an institution by virtue 
of an order issued either by judicial or administrative authorities 
Statistical Methods 
Descriptive analysis methods will be used to summarize the data. 
Continuous variables will be summarized by the N, mean, standard 
deviation, median, minimum, and maximum values. Categorical 
variables will be summarized as counts and related percentages. Data 
tabulations will be categorized by the treatment received on Day 1 of 
this study and combined across all treated patients. Primary analyses 
of the data will be based on the Safety population which includes all 
patients treated on Day 1 of this study. Supportive analyses of the 
efficacy data will be made on a Per Protocol population.  
Data will be summarized per study visit as the actual (raw) outcomes 
and change from Baseline scores, where applicable. Day 1 of this 
study will serve as the Baseline assessment.  
Study Assessments 
Safety 
Safety assessments include monitoring of adverse events, clinical 
laboratory tests, vital signs measurements, 12-lead ECG, and 
physical examinations 
Efficacy 
Efficacy assessments will include patient reported quality of life 
measures as captured in the European Organization for Research and 
Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-
C30 and the module specific for gastrointestinal symptoms of 
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carcinoid neuroendocrine tumors (GI.NET21) and subjective global 
assessment of symptoms associated with CS 
Pharmacodynamics 
Pharmacodynamic (PD) assessments include determination of 5-
HIAA levels in plasma 
Efficacy Data Analysis 
 
All efficacy and PD variables will be summarized descriptively and 
listed. 
Statistical tests and estimates of within patient effects for the 
efficacy and PD measures will be derived from application of a 
mixed linear model with repeated measures. The form of the model 
will be specific to measurement properties of the dependent variable. 
Non-parametric methods will be used to supplement the tests and 
estimates from the mixed linear model. 
Exploratory analyses of treatment group differences may be 
performed by use of propensity score models. The treatments groups 
will correspond to patients’ LX1606 dose level on Day 1 of this 
study.  
Safety Data Analysis 
 
Statistical analysis of the safety data will involve examination of the 
descriptive statistics and individual patient listings for any effects of 
study treatment on clinical tolerability and safety. Reporting of these 
data will be based on the Safety population. Summaries will be 
prepared by treatment group, and as needed, by study visit. 
Treatment-emergent adverse event summaries will include the 
overall incidence (by system organ class and preferred term), events 
by maximum intensity, event by relationship to study treatment, 
events leading to discontinuation of study drug, and serious adverse 
events. 
Vital signs, ECG, and laboratory parameters (hematology, chemistry, 
and urinalysis) will be summarized descriptively at each time point. 
Actual and change from Baseline data will be calculated and 
summarized. In addition, shift table analysis will be applied to the 
laboratory data. 
 
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Table of Contents 
1. 
Synopsis ......................................................................................................................... 3 
2. 
List of Abbreviations and Definitions of Terms ........................................................... 10 
3. 
Introduction .................................................................................................................. 12 
3.1 
Background on Telotristat Etiprate (LX1606) and Disease .......................... 12 
3.2 
Clinical Trials of Telotristat Etiprate (LX1606) in Humans ......................... 13 
3.2.1 
 Phase 1 Studies ............................................................................................ 13 
3.2.2 
 Phase 2 Studies ............................................................................................ 15 
3.3 
Rationale for Current Study .......................................................................... 17 
3.3.1 
Rationale for Selection of Dose ..................................................... 17 
3.3.2 
Benefit/Risk Assessment ................................................................ 17 
3.4 
Rationale for Study Design and Control Groups .......................................... 18 
4. 
Study Objectives .......................................................................................................... 19 
4.1 
Efficacy Objectives ....................................................................................... 19 
4.1.1 
Primary Objective .......................................................................... 19 
4.1.2 
Secondary Objective(s) .................................................................. 19 
4.2 
Safety Objectives .......................................................................................... 19 
5. 
Investigational Plan ...................................................................................................... 19 
5.1 
Overall Study Design .................................................................................... 19 
6. 
Study Population .......................................................................................................... 20 
6.1 
Inclusion Criteria .......................................................................................... 20 
6.2 
Exclusion Criteria ......................................................................................... 20 
6.3 
Criteria for Stopping Treatment/Study Withdrawal ...................................... 21 
6.4 
Criteria for Termination of the Study ............................................................ 22 
6.5 
Clinical Stopping Rules ................................................................................ 22 
6.6 
Method of Assigning Patients to Treatment .................................................. 22 
6.7 
Blinding and Unblinding of Study Medication ............................................. 22 
6.8 
Replacement of Patients ................................................................................ 23 
7. 
Treatment ..................................................................................................................... 23 
7.1.1 
Telotristat Etiprate (LX1606) ......................................................... 23 
7.1.1.1 
Identity ......................................................................... 23 
7.1.1.2 
Packaging, Labeling, and Storage ................................ 23 
7.2 
Prior and Concomitant Medications ............................................................. 23 
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7.2.1 
Prior Medications ........................................................................... 23 
7.2.2 
Concomitant Medications .............................................................. 23 
7.2.3 
Prohibited Medications or Concomitant Therapy .......................... 24 
7.3 
Administration of Study Medication ............................................................ 24 
7.3.1 
Treatment Compliance ................................................................... 24 
7.4 
Dose Adjustment ........................................................................................... 24 
8. 
Study Procedures ......................................................................................................... 24 
8.1 
Restrictions during Study .............................................................................. 25 
8.2 
Description of Study Assessments ................................................................ 25 
8.2.1 
Efficacy Assessments ..................................................................... 25 
8.2.1.1 
EORTC QLQ-C30 & GI.NET21 ................................. 25 
8.2.1.2 
Subjective Global Assessment ..................................... 25 
8.2.2 
Clinical Laboratory Assessment .................................................... 25 
8.2.2.1 
Monitoring Hepatic Function ....................................... 26 
8.2.3 
Pharmacodynamic Assessments..................................................... 27 
8.2.3.1 
Plasma 5-HIAA ............................................................ 27 
8.2.4 
Safety Assessments ........................................................................ 27 
8.2.4.1 
Vital Sign Measurements ............................................. 27 
8.2.4.2 
Physical Examinations ................................................. 28 
8.2.4.3 
Electrocardiograms ...................................................... 28 
8.2.4.4 
Adverse Events of Special Interest .............................. 28 
8.2.4.4.1 
Central Nervous System Events ........... 28 
8.2.4.4.1.1 
Depression Detection ......................................................................... 29 
8.3 
Other Assessments ........................................................................................ 29 
8.3.1   
Chromogranin A (CgA)................................................................................. 29 
8.3.2 
Disease Progression ...................................................................................... 29 
8.3.3 
Quality of Sleep Assessment ......................................................................... 29 
8.4  
Appropriateness of Assessments ................................................................... 29 
8.4.1  
Blood Collection ............................................................................ 29 
9. 
Safety Reporting .......................................................................................................... 30 
9.1 
Adverse Events ............................................................................................. 30 
9.2 
Serious Adverse Events (SAEs) .................................................................... 33 
9.3 
Suspected Unexpected Serious Adverse Reactions (SUSARs) .................... 34 
9.4 
Precautions .................................................................................................... 35 
9.4.1 
Pregnancy ....................................................................................... 35 
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10. 
Statistical Methodology ............................................................................................... 36 
10.1 
Determination of Sample Size ...................................................................... 36 
10.2 
Analysis Populations ..................................................................................... 36 
10.3 
Study Endpoints ............................................................................................ 36 
10.3.1 
Efficacy Endpoints ......................................................................... 36 
10.3.2 
Safety Endpoints ............................................................................ 36 
10.4 
Statistical Methods ........................................................................................ 36 
10.4.1 
Efficacy Analyses ........................................................................... 37 
10.4.2 
Safety Analyses .............................................................................. 37 
10.4.2.1 
Adverse Events ............................................................ 38 
10.4.2.2 
Clinical Laboratory Parameters ................................... 38 
10.4.2.3 
Vital Sign Measurements ............................................. 38 
10.4.2.4 
Electrocardiograms ...................................................... 38 
10.4.3 
Pharmacodynamic Analyses .......................................................... 39 
10.4.4 
Baseline Characteristics and Other Summaries ............................. 39 
10.4.5 
Interim Analysis ............................................................................. 39 
11. 
Study Management ...................................................................................................... 39 
11.1 
Monitoring .................................................................................................... 40 
11.2 
Audits and Inspections .................................................................................. 40 
11.3 
Amendments ................................................................................................. 40 
11.4 
Record Keeping ............................................................................................ 41 
11.4.1 
Drug Accountability ....................................................................... 41 
11.4.2 
Health Insurance Portability Accountability Act of 1996 and 
Subsequent Updates ....................................................................... 41 
11.4.3 
Financial Disclosure ....................................................................... 41 
11.4.4 
Access to Original Records ............................................................ 41 
11.4.5 
Retention of Study Documents ...................................................... 41 
12. 
Administrative Structure of the Study ......................................................................... 42 
13. 
Appendix A – Schedule of Events ............................................................................... 43 
14. 
Appendix B – Amount of Blood to be Collected from Each Patient ........................... 44 
15. 
Appendix C – EORTC QLQ-C30 ................................................................................ 45 
16. 
Appendix D – EORTC QLQ - GI.NET21 ................................................................... 47 
17. 
Appendix E – Ethical Standards .................................................................................. 48 
18. 
Appendix F – Investigator Obligations ........................................................................ 50 
19. 
Appendix G – Guidance on the Selection of Patients .................................................. 55 
20. 
Appendix H - Guidance on the Use of Pro-serotonergic Drugs as Concomitant 
Medications .................................................................................................................. 56 
21. 
References .................................................................................................................... 57 
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2. 
List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
5-HIAA 
5-hydroxyindoleacetic acid 
5-HT 
serotonin 
AE 
adverse event 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
ALP 
alkaline phosphatase 
AST 
aspartate transaminase 
bid 
twice daily 
BM 
bowel movements 
BMI 
body mass index 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CgA 
chromogranin A 
CNS 
central nervous system 
CRF 
case report form 
CRO 
contract research organization 
CS 
carcinoid syndrome 
CT 
computed tomography 
DSMB 
Data Safety Monitoring Board 
EC 
enterochromaffin 
ECG 
electrocardiogram 
ERC 
Ethic Review Committee 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HEENT 
head, eyes, ears, nose, and throat 
Hgb 
hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
IBD 
inflammatory bowel disease 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
Continued on the next page 
 
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Abbreviation 
Definition 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IMP 
Investigational Medicinal Product 
IWRS 
interactive web response system 
LAR 
long-acting release 
LS 
least square 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCP 
multiple comparison procedure 
MRI 
magnetic resonance imaging 
NET 
neuroendocrine tumor 
NRS 
numeric rating scale 
OOR 
out-of-range 
OTC 
over-the-counter 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
qd 
once daily 
SAE 
serious adverse event 
SBS 
short bowel syndrome 
SOP 
standard operating procedure 
SSA 
somatostatin analog 
SUSAR 
suspected unexpected serious adverse reactions 
TEAE 
treatment-emergent adverse events 
tid 
3 times daily 
TPH 
tryptophan hydroxylase 
ULN 
upper limit of the normal reference range 
WRS 
Wilcoxon rank sum 
 
Definitions of Terms  
Term 
Definition 
LP-778902 
active moiety of LX1606 
LX1606 
ethyl-ester prodrug of the active moiety LP-778902; a serotonin 
synthesis inhibitor being developed by Lexicon Pharmaceuticals, Inc. 
QTcF 
corrected QT interval using Fredericia’s formula 
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Protocol No. LX1606.302 
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3. 
Introduction 
3.1 
Background on Telotristat Etiprate (LX1606) and Disease 
Serotonin (5-HT) plays a critical role in regulating several major physiological processes of 
the gastrointestinal tract, including aspects of secretion, motility, inflammation and sensation. 
Enterochromaffin (EC) cells release 5-HT when the intestinal wall is stimulated by 
intraluminal pressure or chemicals. Through multiple classes of receptors, 5-HT is believed to 
initiate directly, or facilitate, peristaltic and secretory reflexes. 5-HT is also reportedly 
involved in the pathophysiology of various types of functional gastrointestinal (GI) disorders, 
valvular heart disease, and may play a role in the pathophysiology of inflammatory bowel 
disease (IBD).  
Carcinoid tumors are mostly derived from EC cells of the midgut, and often produce and 
release large amounts of 5-HT. Such excess of 5-HT is believed to be responsible for the 
severe diarrhea and eventual valvular heart damage and mesenteric fibrosis in patients with 
carcinoid syndrome (CS).1-3 Inhibition of tryptophan hydroxylase (TPH) activity in carcinoid 
tumors should lead to a reduction of peripheral 5-HT in afflicted patients and thus an 
amelioration of the pathophysiology and symptomology of CS. A peripheral TPH inhibitor, 
such as telotristat etiprate, should alleviate the symptoms due to excess 5-HT in carcinoid 
patients without central nervous system (CNS)-related adverse events (AEs). 
Approximately 90% of the body's 5-HT is found in the EC cells of the GI tract, with the 
remainder distributed between the platelets and CNS.4 TPH catalyzes the biopterin-dependent 
monooxygenation of tryptophan to 5-hydroxytryptophan, which is subsequently 
decarboxylated to form 5-HT. Expression of TPH is limited to a few specialized tissues:  
raphe neurons, pinealocytes, mast cells, mononuclear leukocytes, beta cells of the islets of 
Langerhans, and intestinal and pancreatic EC cells.5 Two isoforms of the enzyme exist, TPH1 
and TPH2. TPH1 is exclusively located in the EC cells of the GI tract and pineal gland and is 
the rate limiting enzyme responsible for the majority of systemic 5-HT production and is also 
responsible for 5-HT synthesis in carcinoid tumors. TPH2 is located in the central and enteric 
nervous systems and is the rate-limiting enzyme in the production of neuronal 5-HT. 
The oral TPH inhibitor, telotristat etiprate, represents a novel approach to potentially lessen 
the pathophysiology of CS by reducing 5-HT levels via inhibition of TPH. Telotristat etiprate 
was designed specifically as a prodrug in order to gain greater systemic exposure, opening 
the potential application for indications in which hyperserotonemia is thought to contribute to 
the disorder, such as CS. Preclinical pharmacology studies of telotristat etiprate were 
designed to evaluate the compound’s mechanism of action and effects in vivo. Telotristat 
etiprate is the ethyl-ester prodrug of the active moiety LP-778902. Telotristat etiprate was 
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designed as a prodrug in order to enhance peripheral exposure without crossing the blood-
brain barrier. In vivo, telotristat etiprate is readily converted through esterase activity to its 
corresponding acid, LP-778902. LP-778902 has an in vitro potency of 0.028 μM on purified 
human TPH1 enzyme and 0.032 μM on purified human TPH2 enzyme. Therefore, telotristat 
etiprate is a robust inhibitor of TPH both in vitro and in vivo and has been shown in Phase 2 
studies to provide clinical benefit to patients with carcinoid tumors and associated CS.  
Telotristat etiprate is being developed to manage GI symptoms and possibly other symptoms 
associated with CS. Currently, the standard of care for patients with CS is symptom 
management using somatostatin analogs (SSA), which are available in both short- and long-
acting release (LAR) formulations. Somatostatin analogs such as octreotide are indicated for 
the control of flushing, diarrhea, and other symptoms associated with CS. Common side 
effects of the long-acting depot form of the drug are pain at the site of the injection, reported 
in as many as 30 to 50% of carcinoid patients at the 20 and 30 mg dose levels, and less 
commonly, stomach cramps, nausea, vomiting, headaches, dizziness, and fatigue.6 Other side 
effects identified in the product labeling include biliary tract abnormalities (gallstones, 
sludge, and dilatation), hypothyroidism, dietary fat malabsorption, and hyper or 
hypoglycemia.7 In addition to the morbidity associated with parenterally administered agents, 
tachyphylaxis will occur in the majority of patients, resulting in recurrent symptoms. 
There are currently no specific oral treatments indicated for the management of symptoms 
associated with CS. As a result of the morbidity associated with SSAs and the associated 
tachyphylaxis, there is an unmet medical need to provide symptom management and modify 
the pathophysiology of patients with metastatic CS. Inhibition of the excessive 5-HT 
produced by these tumors with an orally delivered agent such as telotristat etiprate could 
provide significant benefit as an additional treatment option for patients and clinicians.  
3.2 
Clinical Trials of Telotristat Etiprate (LX1606) in Humans 
Telotristat etiprate has been studied in single/multiple doses in Phase 1 studies, approximately 
109 healthy volunteers participated in Phase 1 trials with 88 subjects receiving telotristat 
etiprate and 21 subjects receiving placebo. In addition, 37 patients with CS have received 
telotristat etiprate during the clinical development program in Phase 2.  An additional 59 
patients with ulcerative colitis have been enrolled into an ongoing Phase 2 study to evaluate 
telotristat etiprate versus placebo in patients with ulcerative colitis experiencing active flares. 
3.2.1 
 Phase 1 Studies 
LX1606.1-101-NRM utilized telotristat etiprate as a single oral dose and was noted to be safe 
and well tolerated up to doses of 1,000 mg. At doses of ≥1,000 mg, an increase in GI AEs 
was observed, which were assessed as at least possibly related to study drug. These AEs led 
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to a decision not to escalate the dose beyond 1,500 mg. No serious adverse events (SAEs) or 
deaths were reported and no patient discontinued due to an AE. Twenty-three patients 
experienced at least 1 AE. The majority of the AEs were assessed as mild. The most common 
AEs were diarrhea and nausea. Random out-of-range laboratory values at various time points 
in several patients occurred without any apparent trend. There were no other clinically 
significant vital signs, laboratory or physical examination findings.  
LX1606.1-102-NRM utilized telotristat etiprate as multiple oral doses over 14 days and was 
tolerated up to the maximum dose assessed, 500 mg tid; 1,500 mg total dose daily. Most AEs 
were mild, the most common being nausea and headache; all resolved. Most AEs were at 
least possibly related to study treatment. Four AEs required treatment with concomitant 
medication, 3 AEs of constipation and 1 of headache. No deaths or SAEs were reported. One 
patient was discontinued due to an AE of abnormal liver function. There were no apparent 
trends or clinically significant findings observed upon review of vital signs and 
electrocardiogram (ECG) data. There were no clinically significant abnormal physical 
examination findings. 
Overall, in LX1606.1-102-NRM, treatment with telotristat etiprate was associated with mild 
elevations, generally ≤2x the upper limit of normal (ULN), in alanine transaminase (ALT) 
and aspartate transaminase (AST), with elevations in values observed earlier in the higher 
dose cohorts. Results were assessed as clinically significant for only 1 patient, in Cohort 4, 
who was withdrawn on Day 10. The trend was most pronounced in Cohort 5, in which 5 out 
of 6 patients who received telotristat etiprate had increases in ALT values which were above 
normal range and 4 patients had increases in AST values which were above normal range at 
Day 14. Mean increases in ALT and AST appeared earlier in the study for Cohorts 4 and 5 
than in the other cohorts, and were noted for all cohorts by Day 12. All patients had normal 
ALT and AST values at Baseline and most elevated transaminases returned to normal range 
within 48 hours after the last dose of study drug. No changes in alkaline phosphatase (ALP) 
or total bilirubin were observed in any patient. 
LX1606.1-103-NRM evaluated 2 oral formulations of telotristat etiprate in an open-label 
crossover study. Each formulation was given as a single oral dose followed by a 5-day 
washout and then patients were given a single oral dose of the second formulation. During 
this study, there were no deaths or SAEs reported and no AEs lead to discontinuation. The 
most commonly reported AE was diarrhea. No clinically significant observations or changes 
in other safety parameters (eg, clinical laboratory evaluations, vital signs, physical 
examinations, ECGs, and AEs) were identified in the patient population during the study 
conduct. 
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3.2.2 
 Phase 2 Studies 
LX1606.1-202-CS was a randomized, double-blind, placebo-controlled, multiple ascending 
dose study conducted in 2 parts in order to evaluate a total of 23 patients at a dose range of 
450 to 1500 mg given as 150, 250, 350, or 500 mg tid (telotristat etiprate or matching 
placebo) on a background therapy of octreotide. In Part 1, 16 patients were randomly 
assigned 3:1 into 4 sequential cohorts. Each cohort evaluated 1 of the following daily doses 
given as 150, 250, 350, or 500 mg tid over a course of 4 weeks. During the study, all patients 
continued on a stable-dose background therapy of octreotide. In Part 2, an additional 7 
patients were randomly assigned 3:1 in order to evaluate 500 mg tid, the highest tolerated 
dose as determined in Part 1. Upon completion of the initial 4-week portion, eligible patients 
had the option to continue into an open-label Extension Period. 
There was 1 treatment emergent SAE assessed as possibly related to study drug which 
occurred in the 350 mg tid dose group. The patient had a history of nausea and vomiting and 
was hospitalized for exacerbation of these conditions.  
Telotristat etiprate was generally well tolerated with no evidence of dose-limiting tolerability. 
Adverse events were mostly mild to moderate and with similar frequencies between 
treatment groups and placebo. No significant changes in vital signs, ECG, or physical exam 
findings were noted after administration of telotristat etiprate at any dose level. The most 
common AEs were GI-related and reported as diarrhea, nausea, and abdominal pain, 
respectively. The modest elevations in transaminases seen in the Phase 1 multiple ascending 
dose study (LX1606.1-102-NRM) were not apparent in this 4-week study in patients with CS.  
Patients that received telotristat etiprate achieved a clinical response (28%) defined as at least 
a 30% reduction in bowel movements (BMs) for at least 2 weeks; a biochemical response 
(56%) defined as at least a 50% reduction or normalization of urinary 5-hydroxyindoleacetic 
acid (5-HIAA); and reported adequate relief at Week 4 (46%) while no placebo patients 
experienced clinical response, biochemical response, or adequate relief. 
LX1606.1-203 was an open-label, serial ascending, multiple dose, individual titration study 
that evaluated the same dose ranges as the LX1606.1-202-CS study in a total of 15 patients. 
Patients were serially escalated to the next dose level every 2 weeks until a maximally 
tolerated dose or 500 mg tid was reached. Once a dose had been determined, the patient 
would remain on the dose for an additional 4 weeks. Patients then had the option to continue 
into an Extension Period.  
Telotristat etiprate was generally safe and well-tolerated in subjects with CS in the 
LX1606.1-203 study. Most AEs were mild to moderate in severity and assessed as unrelated 
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to study drug. Events in the Gastrointestinal Disorders SOC were common, as is anticipated 
with the underlying illness. 
Statistically significant reductions from Baseline in the mean number of BMs/day were 
observed in this study throughout the entire dose-escalation and stable-dose phases, as were 
improvements in stool form. Telotristat etiprate produced an improvement in global 
assessment of GI symptoms associated with CS in the majority of subjects (12 of 15 subjects, 
80%) across the 12-week period. The global assessment of GI symptoms was based on the 
following question, “In the past 7 days, have you had adequate relief of your carcinoid 
syndrome bowel complaints such as diarrhea, urgent need to have a BM, abdominal pain or 
discomfort?” In addition, subjects experienced statistically significant decreases in the mean 
daily number of cutaneous flushing episodes. 
Thirteen subjects (86.7%) experienced a complete biochemical response (defined as a ≥50% 
reduction from Baseline in u5-HIAA levels at 1 or more time points). Consistent with the 
proposed mechanism of action for telotristat etiprate, a complete biochemical response 
correlated closely with measures of clinical response, such as number of bowel movements 
per day. 
Detailed information regarding the completed clinical studies can be found in the Investigator 
Brochure.8 
3.2.3   
Ongoing Studies 
The open-label extension portions in LX1606.1-202-CS and LX1606.1-203-CS remain 
ongoing. 
LX1606.1-204-UC is currently evaluating patients with active flares of ulcerative colitis. 
Doses under evaluation are 500 mg once daily (qd) and 500 mg tid vs. placebo; 59 patients 
have been enrolled for an 8-week treatment period.  
LX1606.1-301-CS is intended to evaluate patients who are currently on a background of SSA 
therapy and still experiencing breakthrough symptoms such as an increased frequency of 
BMs ≥ 4 per day on average: (1) the efficacy of telotristat etiprate on reducing the number of 
BMs; (2) the efficacy of telotristat etiprate on a number of clinically relevant secondary 
endpoints; and, (3) the safety of telotristat etiprate over the 12-week double-blind portion 
(Treatment Period) of the study. Upon completion of the Treatment Period, patients will 
continue into a 36-week open-label Extension Period (Extension Period).  
LX1606.1-303-CS is intended to evaluate patients with carcinoid syndrome whose primary 
symptoms are not GI related and may be naïve to SSA therapy: (1) the safety of telotristat 
etiprate over the 12-week double-blind portion (Treatment Period) of the study; (2) percent 
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(%) change  from Baseline in 24-hour u5-HIAA levels at Week 12; (3) the effects of 
telotristat etiprate on a number of clinically relevant secondary endpoints. Upon completion 
of the Treatment Period, patients will continue into a 36-week open-label Extension Period. 
3.3 
Rationale for Current Study 
3.3.1 
Rationale for Selection of Dose 
The dose levels of telotristat etiprate selected for this study are consistent with prior clinical 
study experience and based upon clinical safety and pharmacodynamic (PD) data from 2 
Phase 2 multiple ascending-dose studies in patients with symptomatic CS (LX1606.1-202-CS 
and LX1606.1-203-CS).  
Based upon observations noted in Section 3.2, it is anticipated that the doses to be utilized in 
this protocol will be safe and well tolerated and may provide clinical benefit to patients with 
CS. 
3.3.2 
Benefit/Risk Assessment 
Clinical experience with telotristat etiprate (treated subjects) consists of completed single and 
multiple ascending dose studies in 88 normal subjects (36 in single dose studies and 52 in the 
multiple dose study), two Phase 2 studies (37 patients with symptomatic CS) and 2 ongoing 
Phase 3 studies in patients with symptomatic CS. 
In healthy volunteer studies, single doses up to 1000 mg were found to be generally well 
tolerated, while at the 1500 mg dose level GI-related adverse events increased. A similar 
adverse event profile was observed after multiple dose administration over 14 days with GI 
events predominating. Mild, dose-dependent increases in hepatic transaminase levels (≤2 x 
ULN) were observed with increased frequency in relation to dose, with 1 subject requiring 
withdrawal from therapy at the 500 mg bid dose level. Most subjects that were observed to 
have increased transaminase levels did not exceed >2 x ULN. No abnormalities in total 
bilirubin were observed at any dose level. GI events have been the most commonly observed 
events to date. The adverse event profile in normal subjects may differ significantly from 
what is observed in patients with hyperserotonemia. All adverse events resolved without 
sequelae. In addition, there were no significant changes in vital signs or ECG. No physical 
examination abnormalities were noted in studies to date. There were no serious adverse 
events reported in healthy volunteers. 
In patients with CS, dose escalations have proceeded up to and including 500 mg tid. To date, 
there has been no evidence of dose-limiting intolerability. Dose levels have been generally 
well tolerated with no evidence to suggest elevations in hepatic transaminase levels. Based 
upon observations from preclinical and clinical studies conducted to date, it is anticipated that 
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orally administered telotristat etiprate will be well tolerated at dose levels required to 
influence peripheral 5-HT production in patients with symptomatic CS. Potential adverse 
events primarily involve the GI tract, and could include alterations in gut motility, nausea, 
vomiting, diarrhea, constipation, abdominal bloating, and/or pain. Regular and ongoing 
clinical and laboratory assessments should detect any of these events, and depending on the 
type of event, further dose adjustment or discontinuation from the trial would occur. Although 
CNS effects are not anticipated at dose levels planned for evaluation, standard adverse event 
questioning and/or physical examination should reveal any subtle CNS findings. As 
elevations in hepatic transaminase levels were observed with multiple dosing in normal 
subjects, monitoring clinical laboratory tests of hepatic function will be incorporated into 
clinical trials conducted in CS patients. 
Treatment has the potential to improve several signs and symptoms of CS. The Phase 2 
clinical trial results indicated that treatment may lead to improvements in BM frequency, 
stool consistency, urgency, abdominal pain, diarrhea, flushing, and reductions in 5-HIAA. 
These potential benefits relate to a unique mechanism of action. Symptomatic improvement 
may lead to a better quality of life (QOL) for patients with few treatment options available, 
and a reduction in serotonin may help reduce the risk of carcinoid heart disease. Overall the 
benefit/risk profile of telotristat etiprate is expected to be favorable for participation in this 
clinical study. 
3.4 
Rationale for Study Design and Control Groups 
Currently, no approved therapy exists for the treatment of symptoms driven by underlying 
serotonin pathophysiology of CS in patients whose disease is refractory to SSA therapy or for 
those patients who are unable to tolerate SSA therapy or who are unwilling to take SSA 
therapy. 
This study will allow for continued access to telotristat etiprate after patients have completed 
the required study visits in ongoing Phase 2 and Phase 3 studies. Continuation of CS patients 
into this study will allow for the collection of additional long-term safety and efficacy data, 
while providing access to patients who may be receiving benefit. The treatment duration is 
supported by results of chronic toxicology studies (6-month rat and 9-month dog) and the 
current safety profile from completed and ongoing clinical trials. 
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4. 
Study Objectives 
4.1 
Efficacy Objectives 
4.1.1 
Primary Objective 
The primary objective of the study is to evaluate the long-term safety and tolerability of 
orally administered telotristat etiprate. 
4.1.2 
Secondary Objective(s) 
The secondary objective of this study is to evaluate changes in patients’ QOL. 
4.2 
Safety Objectives 
Evaluation of overall safety will be assessed as: 
 Incidence of treatment-emergent adverse events (TEAEs) 
 Changes from Baseline in clinical laboratory results, vital signs results, and ECG 
findings 
5. 
Investigational Plan 
5.1 
Overall Study Design 
The study will be conducted as a multicenter, open-label, long-term extension study to further 
evaluate long-term safety and tolerability of telotristat etiprate. 
Patients currently participating in any LX1606 Phase 2 CS study may enter into this 
extension study upon institutional or local approval of the protocol. Patients participating in a 
Phase 3 CS study may enter into this extension study at the Week 48 visit. All patients who 
enter into this extension study will be exempt from any follow-up visit required by the 
original study and will not experience an interruption in study drug due to the transition from 
the original protocol to LX1060.1-302-CS. 
Following confirmation of eligibility, patients will complete a series of visit assessments in 
order to establish Baseline symptoms. Patients will then continue on open-label LX1606 at 
the same dose level identified in the original study.  
Downward dose adjustment will be permitted during the study if evidence of intolerability 
emerges. Patients who experience intolerability at the 250 mg tid dose level must be 
discontinued from the study. Patients may return to the previous dosing at the discretion of 
the Investigator and in consultation with the Medical Monitor. 
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Upon completion or early withdrawal from treatment, all patients will be required to 
complete a 14-day Follow-up Period, during which no study drug will be administered.  
A Data Safety Monitoring Board (DSMB) will review safety data quarterly throughout the 
study.  
6. 
Study Population 
Adult patients who are currently participating in ongoing Phase 2 or Phase 3 telotristat 
etiprate CS clinical protocols will be enrolled into the study. Up to 100 patients are expected 
to enroll in this study. Approximately 70 sites worldwide will participate in the study. Patients 
may continue allowed medications as background therapy provided they remain on stable-
doses throughout the Treatment Period. 
6.1 
Inclusion Criteria 
Patients must meet all of the following criteria to be considered eligible to participate in the 
study: 
1. Ongoing participation in a Phase 2 (eg, LX1606.1-202-CS, LX1606.1-203-CS) or 
Phase 3 (eg, LX1606.1-301-CS, LX1606.1-303-CS) study  
2. Patients of childbearing potential must agree to use an adequate method of 
contraception (defined as having a failure rate of <1% per year) during the study and 
for 12 weeks after the Follow-up visit. Adequate methods of contraception for 
patients or partner include condoms with spermicide gel, diaphragm with spermicide 
gel, coil (intrauterine device), surgical sterilization, vasectomy, oral contraceptive pill, 
depot progesterone injections, progesterone implant, and abstinence during the study 
and for 12 weeks after the Follow-up Visit.  
a. Childbearing potential is defined as those who have not undergone surgical 
sterilization, or those who are not considered postmenopausal. Postmenopause 
is defined as absence of menstruation for at least 2 years. If necessary, follicle-
stimulating hormone (FSH) results >50 IU/L at Screening are confirmatory in 
the absence of a clear postmenopausal history. 
3. Ability and willingness to provide written informed consent prior to participation in 
any study-related procedure. 
6.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participating in the 
study:   
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1. Major protocol violations or tolerability concerns in a Phase 2 (eg, LX1606.1-202-CS, 
LX1606.1-203-CS) or Phase 3 (eg, LX1606.1-301-CS, LX1606.1-303-CS) study  
2. Positive pregnancy test 
3. Presence of any clinically significant findings at entry for medical history, laboratory 
values, or physical examination (relative to patient population) that, in the 
Investigator’s or Medical Monitor’s opinion, would compromise patient safety or the 
outcome of the study 
4. Patients who are currently committed to an institution by virtue of an order issued 
either by judicial or administrative authorities 
6.3 
Criteria for Stopping Treatment/Study Withdrawal 
A patient may also be discontinued from the study for the following medical or 
administrative reasons: 
 Withdrawal of consent by the patient or legal guardian 
 Noncompliance, including refusal of the study medication and/or failure to adhere to 
the study requirements as in the study protocol 
 Investigator decides that, in the interest of the patient, it is not medically acceptable to 
continue participation in the study 
 The Sponsor terminates the study (Section 6.4) 
 Pregnancy (Section 9.4.1) 
Note:  If a patients voluntarily withdraws or is discontinued from study treatment before 
completing the entire duration of the Treatment Period, they should be encouraged to 
continue clinic visits according to the study schedule.  
Patients who discontinue study treatment, and who are not willing to continue clinic visits 
(eg, withdrawal of consent) should be encouraged to complete End-of-Study (EOS) 
assessments as identified in Appendix A – Schedule of Events and agree to report any SAEs 
(Section 9.2) that occur within 30 days following the last dose of telotristat etiprate. 
The date the patient discontinues study treatment, the primary reason for study treatment 
discontinuation, study termination, and/or termination of participation (eg, withdrawal of 
consent), will be captured within the Case Report Form (CRF). 
When patients withdraw consent from study participation, it must be recorded on the CRF 
whether the withdrawal of consent applies to specific aspects of the study such as 
discontinuation of study treatment, participation in study visits, contact by study personnel, or 
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access to information about potential SAEs. If specific consent has not been withdrawn, study 
personnel should contact the patient (or a previously approved designee such as a caregiver, 
partner, or family member) at the scheduled Follow-up visit to inquire about health status. 
6.4 
Criteria for Termination of the Study 
If the Sponsor, Investigator, study monitor, DSMB, or regulatory officials discover conditions 
arising during the study that indicate that the patient safety and/or scientific value of the study 
and/or quality of the study drugs have been compromised, the study should be halted or the 
study center’s participation should be terminated. Conditions that may warrant termination of 
the study include, but are not limited to, the following: 
 The discovery of an unexpected, serious, or unacceptable risk to the patients enrolled in 
the study; 
 A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product for any reason; 
 Failure of the Investigator to enroll patients into the study at an acceptable rate; 
 Failure of the Investigator to comply with pertinent governing body regulations; 
 Submission of knowingly false information from the research facility to the Sponsor, 
study monitor, medical officer, or regulatory official; and, 
 Insufficient adherence to protocol requirements.  
Study termination and Follow-up would be performed in compliance with applicable 
governing body regulations. 
6.5 
Clinical Stopping Rules 
Criteria for individual patient withdrawal or study termination are summarized in Sections 
6.3 and 6.4, respectively. 
6.6 
Method of Assigning Patients to Treatment  
Patients will enter the study at the same dose level and regimen as identified in the prior 
Phase 2 or Phase 3 CS study. Randomization will not be used to assign patients to study 
treatments. 
6.7 
Blinding and Unblinding of Study Medication 
This is an open-label study.  
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6.8 
Replacement of Patients 
Patients who do not complete the study will not be replaced. 
7. 
Treatment 
7.1.1 
Telotristat Etiprate (LX1606) 
7.1.1.1 
Identity 
LX1606 hippurate is the salt form of the drug substance. LX1606 hippurate is a crystalline 
white to off-white to tan solid with a melting point of 147°C. LX1606 is insoluble in water 
within the pH range of 5 to 9 (≤2 mg/L). It undergoes hydrolysis under strongly basic or 
strongly acidic conditions. The solubility of LX1606 hippurate in water is about 22 mg/L at 
25°C. 
Study drug dosage form consists of white coated debossed oval tablets containing 250 mg 
LX1606. 
7.1.1.2 
Packaging, Labeling, and Storage 
Patients will receive 250 mg telotristat etiprate tablets packaged in 100 cc high density 
polyethylene bottles with child-resistant polypropylene screw caps and heat-induction seal 
liners.  
Telotristat etiprate should be stored between 15 to 25°C (59 to 77°F). 
7.2 
Prior and Concomitant Medications 
7.2.1 
Prior Medications 
All medications and other treatments taken by patients within 30 days prior to entry will be 
recorded on the CRF.  
7.2.2 
Concomitant Medications 
All concomitant medications taken by patients during the study will be recorded on the CRF. 
Treatment with prescription or over-the-counter (OTC) antidiarrheal therapy, bile acid 
sequestrants, or pancreatic enzyme is permitted; however, the use of these concomitant 
therapies should be associated with a documented history of disease (eg, fat malabsorption, 
bile acid malabsorption, or steatorrhea).  
The dosage(s) of all concomitant medication should remain stable. Should the need arise to 
modify/adjust a patient’s therapy the Medical Monitor should be contacted. The Investigator 
and Medical Monitor will make a determination if such a change would impact the safety of 
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the patient and the integrity of the study. The Medical Monitor will determine if the patient 
can continue in the study. 
7.2.3 
Prohibited Medications or Concomitant Therapy 
None 
7.3 
Administration of Study Medication 
All patients will be instructed to take the study medication with food. “With food” means 
taking telotristat etiprate tablets within 15 minutes before or within 1 hour after a meal or 
snack. Patients will be instructed to take study drug 3 times daily during waking hours, with 
doses spaced approximately 6 hours apart.  
Study medication and instructions will be dispensed to patients at each visit as described in 
the schedule of study procedures (Appendix A). 
7.3.1 
Treatment Compliance  
Patients will be asked to bring their unused or unopened study medication to each visit 
(Appendix A). At each visit and in the presence of the patient, study site personnel will count 
returned tablets and reconcile the counts against planned number of doses for that interval. 
Site personnel will clarify any discrepancy and record this information within the CRF.  
Patients must maintain at least 75% compliance in dosing to be deemed as compliant. In the 
event of a missed or vomited dose, patients will take their subsequent dose of study drug at 
the next scheduled time point, following the tid dosing regimen of approximately every 6 
hours. A dose outside of a 3 hour window should be considered missed. Missed or vomited 
doses will not be made up.  
7.4 
Dose Adjustment 
Downward dose adjustment of telotristat etiprate will be permitted if evidence of 
intolerability emerges. After a period at the lowered dose level, patients may resume the 
previous dosing level at the discretion of the Investigator after consultation with the Medical 
Monitor. Patients who experience intolerability at the 250 mg tid dose level must be 
discontinued from study treatment. Interruptions or delays in dosing throughout the entire 
study may be permitted after consultation with the Medical Monitor, at which time the patient 
will be reassessed for study continuation, dosage reduction, or discontinuation. 
8. 
Study Procedures 
A schedule of study assessments is provided in Appendix A. 
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8.1 
Restrictions during Study 
Patients should be advised to avoid food and drink containing grapefruit for 2-3 hours prior to 
and following dosing while participating in the study. 
8.2 
Description of Study Assessments 
8.2.1 
Efficacy Assessments 
Efficacy assessments include the patient reported QOL measures; EORTC QLQ-C30 
(Appendix D) & GI.NET21 (Appendix E) questionnaires and subjective global assessment of 
symptoms associated with CS. 
A description of the efficacy assessments is provided below. 
8.2.1.1 
EORTC QLQ-C30 & GI.NET21 
Patients will complete the questionnaires during each visit as indicated in Appendix A. 
8.2.1.2 
Subjective Global Assessment 
A subjective global assessment of symptoms associated with CS will be evaluated using 2 
methods at each visit.  
Patients will first be asked to respond to the following question:  “In the past 7 days, have 
you had adequate relief of your carcinoid syndrome bowel complaints such as diarrhea, 
urgent need to have a bowel movement, abdominal pain, or discomfort?”. 
Then patients will be asked the following question to assess global symptoms associated with 
CS on an 11-point scale: “Rate the severity of your overall carcinoid symptoms over the past 
7 days on a scale from 0-10, where 0 = no symptoms and 10 = worst symptoms ever 
experienced.” 
 
8.2.2 
Clinical Laboratory Assessment  
Clinical laboratory assessments will consist of hematology (complete blood count [CBC] 
with differential and platelet counts), blood chemistry (complete metabolic panel and liver 
function tests), and urinalysis. All laboratory tests will be performed by a central laboratory, 
with the exception of the urine pregnancy test, which will be performed by the study site with 
the provided laboratory kit.  
The incidence of clinically significant laboratory values, as well as clinically significant shifts 
in laboratory values, should be reported as an AE in the patient’s CRF (see also Section 9.1 
for reporting of AEs related to laboratory abnormalities). The Investigator will assess any 
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clinically significant values relevant to the patient population to determine if termination of 
the study drug is required. 
8.2.2.1 
Monitoring Hepatic Function 
Patients with clinically significant abnormalities in liver function tests should be excluded 
from participating; however, the patient’s clinical situation as a whole should be taken into 
account when evaluating hepatic transaminase elevations, which may represent a 
consequence of the underlying disease and/or therapeutic interventions. Patients with 
abnormalities in liver function test results, as defined below, should be further assessed by the 
Investigator and may have additional tests performed by the central laboratory as clinically 
indicated. The following describes the Sponsor’s recommended approach to evaluating these 
events. This approach is not meant to replace the Investigator’s clinical judgment.  
These guidelines apply to the following events: 
1) A new confirmed result (after Day 1 dosing) of ALT or AST >3 x ULN (in 
patients previously within normal range) 
OR 
2) A confirmed increase in transaminases above the patient’s previous Baseline to a 
degree that is significant in the clinical judgment of the Investigator and ALT or 
AST >3 x ULN (in patients with previous abnormal liver-test results) 
OR 
3) Any occurrence of an elevation of ALT or AST > 3 x ULN and total bilirubin >2 
x ULN (in any patient) 
For any such event, the Investigator should discuss the Follow-up approach with the Medical 
Monitor.  
The Sponsor’s recommended approach is as follows: 
1. Schedule the patient for a Follow-up visit within 3 days following the receipt of 
laboratory results to assess the patient and conduct further evaluation, to include the 
following: 
a. Obtain repeat testing of ALT, AST, total bilirubin, and ALP through the central 
laboratory. 
b. Reassess the patient through patient interview and physical examination to 
uncover new or emerging risk factors of liver injury including an increased use 
of alcohol, gallbladder disease, hemochromatosis, fatty liver, use of 
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hepatotoxic concomitant medications (including acetaminophen), occupational 
exposures, liver metastases, and other causes for potential clues as to the 
underlying etiology of the event. 
c. Continue to monitor the patient’s transaminases and total bilirubin regularly 
until the liver function test values return to Baseline levels.  
Additional recommendations include: 
 Consider referral to a hepatologist or gastroenterologist 
 Consider reimaging (eg, ultrasound, CT, or MRI) the liver and biliary tract 
 Consider additional laboratory testing as clinically indicated. Laboratory assays 
available to the Investigator for further workup are described in the laboratory manual 
Upon completion of hepatic assessment, the Investigator should review results with the 
Medical Monitor and assess continued study participation. 
8.2.3 
Pharmacodynamic Assessments 
8.2.3.1 
Plasma 5-HIAA 
Fasting blood samples (≥6 hours) for measurement of 5-HIAA in plasma will be collected 
and analyzed by a specialty laboratory. All sample processing information will be supplied by 
the laboratory in a separate document/study manual. Efforts should be made to schedule these 
visits in the morning, with instructions to the patient to arrive in a fasted state and not dose 
prior to the blood draw. 
8.2.4 
Safety Assessments 
In addition to the clinical laboratory assessments described in Section 8.2.2, monitoring of 
AEs is also considered a safety assessment and is described in detail in Section 9. Clinically 
significant changes compared with Baseline findings for these variables should be reported as 
AEs on the CRF. Clinically significant changes compared with Baseline values, which are 
determined to be AEs, should be followed until the event has resolved, the condition has 
stabilized, etiology of the event is determined to be not related to study drug, or the patient is 
lost to Follow-up. 
8.2.4.1 
Vital Sign Measurements 
Measurement of vital signs will include assessment of blood pressure, respiratory rate, pulse 
rate, and oral temperature. Vital sign measurements should not be conducted with the 
30 minutes immediately following any phlebotomy. 
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Efforts should be made to standardize blood pressure collection across all patients and visits. 
Patients should be seated for at least 5 minutes prior to collection. All measurements will be 
collected using dedicated equipment, supplied by the Sponsor, assessed on the same arm, and 
by the same technician where possible. 
Additional measurements may be obtained if clinically indicated. Vital sign measurements 
will be measured as indicated in Appendix A. 
8.2.4.2 
Physical Examinations 
Complete physical examinations will be performed as outlined in Appendix A. Complete 
physical examinations will include a minimum of a review of the patient’s general 
appearance, head, eyes, ears, nose, and throat (HEENT), neck, heart, lungs, abdomen, back 
and extremities, skin, and general neurological system.  
Symptom-oriented physical examinations will be performed at all other time points and as 
clinically indicated.  
In addition, weight will be captured during each physical examination. Efforts should be 
made to standardize weight collection across all patients and visits. Patients should be 
instructed to remove shoes and heavy clothing (eg, heavy coats, jackets) prior to 
measurement. For weight collection, an effort should be made to use the same scale 
throughout the study where possible. In instances where multiple scales may be used, efforts 
should be made to reset the scale to zero prior to collection of weight measurement. 
8.2.4.3 
Electrocardiograms 
Electrocardiograms (12-lead ECGs) will be performed as specified in Appendix A. 
8.2.4.4 
Adverse Events of Special Interest 
Monitoring of these events will be the responsibility of the DSMB. The process of data 
collection and assessment of the events will be detailed in a separate DSMB charter.  
Additional information will be collected if episodes of any of the following AEs of special 
interest occur. 
8.2.4.4.1 
Central Nervous System Events 
Central nervous system events of special interest may include any clinically significant 
changes in mood, physical affect, or exacerbation of preexisting CNS conditions (eg, 
depression, migraine headaches). 
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8.2.4.4.1.1 
Depression Detection 
Patients will be evaluated beginning at Day 1 (Baseline) and at each subsequent visit for 
indications of depression. During each visit the patient will first be asked to respond to the 
question “During the past month, have you often been bothered by feeling down, depressed, 
or hopeless?” Followed by “During the past month, have you often been bothered by little 
interest or pleasure in doing things?” A positive response prior to Day 1 dosing will be 
captured on the medical history CRF page. Positive responses following the first dose will be 
captured as an AE and will be followed as an AE of special interest.  
8.3 
Other Assessments 
8.3.1   Chromogranin A (CgA) 
Blood samples for measurement of chromogranin A (CgA) levels will be collected as 
indicated in Appendix A. 
8.3.2 
Disease Progression 
Data will also be collected on measures of disease progression as performed as standard of 
care (including, but not limited to: interpretation of clinical scans [eg, PET, CAT, MRI scans 
of tumor], Investigator assessment of disease status) while the patient is enrolled in the study.  
8.3.3 
Quality of Sleep Assessment 
Quality of sleep will also be evaluated beginning Day 1 (Baseline) and at each subsequent 
visit thereafter. Patients will be asked to respond to the following question “Since your last 
visit, how many times a night (on average) do you wake up due to your CS symptoms?” 
based on the following scale 0, 1, 2, 3, 4, >4.  
8.4  
Appropriateness of Assessments 
The assessments used in this study conform to the usual clinical and laboratory assessments 
of patients with CS participating in clinical trials and are typical of a Phase 3 study.  
8.4.1  
Blood Collection 
An attempt should be made to collect all samples as per the schedule outlined in Appendix A. 
Any portion of samples remaining after the required tests for this study have been completed 
will be destroyed. 
The estimated amount of blood scheduled for collection per patient, over the course of the 
study, may be found in Appendix B. 
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9. 
Safety Reporting 
Medical queries should be addressed to the medical monitor responsible for the region. 
Sites in North America: 
, MD 
  
INC Research 
 
 
Phone: 
 
 
 
Sites outside North America:  
 MD, PhD 
 
INC Research 
 
 
The Netherlands 
Phone: 
 
Mobile: 
 
 
 
, MD, PhD 
Medical Monitor 
INC Research, LLC 
 
 
Czech Republic 
Phone: 
 
Fax: 
 
 
After-hours emergency medical coverage is available to site personnel should the regional 
Medical Monitor and regional backup Medical Monitor be unavailable. 
 
Sites in North America dial 1-877-462-0134. 
 
Sites outside North America dial the country prefix number plus 1-877-462-0134. Prefix 
numbers are determined by accessing the AT&T Direct on-line link 
http://www.usa.att.com/traveler/access_numbers/country/index.jsp. Note: These calls are not 
toll-free. 
9.1 
Adverse Events 
It is the responsibility of the Investigator to document all AEs that occur during the study. 
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Adverse event is defined as any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. 
Life-threatening adverse event or life-threatening suspected adverse reaction: An adverse 
event or suspected adverse reaction is considered "life-threatening" if, in the view of either 
the Investigator or Sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred 
in a more severe form, might have caused death. 
An AE includes any noxious, pathological, or unintended change in anatomical, 
physiological, or metabolic functions as indicated by physical signs or symptoms occurring in 
any phase of the clinical study whether or not considered related to the study medication. 
This definition includes an exacerbation of preexisting medical conditions or events, 
historical condition not present prior to study treatment, which reappear following study 
treatment, intercurrent illnesses, hypersensitivity reactions, drug interaction, or the significant 
worsening of the disease under investigation that is not recorded elsewhere in the CRF. 
Anticipated day-to-day fluctuations of pre-existing conditions that do not represent a 
clinically significant exacerbation or worsening need not be considered AEs. 
Any laboratory abnormality fulfilling the criteria for a SAE (Section 9.2) should be reported 
as such, in addition to being recorded as an AE. Any treatment-emergent abnormal laboratory 
result which is clinically significant, ie, meeting 1 or more of the following conditions, 
should be recorded as a single diagnosis AE: 
 Is considered to be an SAE, 
 Results in discontinuation from study treatment, or 
 Results in a requirement for a change in concomitant therapy (ie, addition of concomitant 
therapy) 
In the event of medically significant unexplained abnormal laboratory test values, the tests 
should be repeated and followed up until they have returned to the normal range and/or an 
adequate explanation of the abnormality is determined.  
TEAEs are defined as any AEs reported after the first dose of randomized treatment on 
Day 1. Adverse events reported after consent of a patient, but before administration of study 
medication, will be reported in the Medical History. 
AEs should not be solicited with leading questions that suggest specific signs or symptoms. 
Rather, AEs should be solicited by asking the patient a non-leading question such as: “Do you 
feel different in any way since receiving the dose or since the last assessment?” 
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The Investigator will evaluate all AEs with regard to the maximum intensity and relationship 
to study drug, as follows: 
 Maximum intensity  
Maximum intensity should be assigned using 1 of the following 3 severity grades: 
o 
Mild: aware of event but easily tolerated 
o 
Moderate: discomfort, enough to cause interference with usual activity 
o 
Severe: incapacitating: patient unable to work or perform usual activities 
 Relationship to study drug 
Not related:  
o 
Does not follow a reasonable temporal sequence from administration of the drug 
o 
Could be reasonably explained by other factors, including underlying disease, 
complications, concomitant drugs, or concurrent treatment. 
Possibly related:  
o 
That follows a reasonable temporal sequence from administration of the drug 
(including the course after withdrawal of the drug), or 
o 
For which the possibility of the study drug being the causative factor (eg, existence 
of similar reports attributed to the suspected drug and its analogues; reactions 
attributable to the pharmacological effect) could not be excluded, although other 
factors such as underlying disease, complications, concomitant drugs, or concurrent 
treatment are presumable. 
Probably related: 
o 
That follows a reasonable temporal sequence from administration of the drug 
(including the course after withdrawal of the drug), and 
o 
For which the possibility of factors other than the drug, such as underlying disease, 
complications, concomitant drugs, or concurrent treatment, could not be excluded as 
the cause. 
Definitely related: 
o 
Follows a clear temporal sequence from administration of the study drug. 
o 
Could not be possibly explained by the known characteristics of the patient’s 
clinical state, environmental or toxic factors, or other modes of therapy 
administered to the patient. 
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o 
Disappears or decreases on cessation or reduction in dose of the study drug. 
o 
Reappears or worsens when the study drug is re-administered. 
o 
Follows a response pattern known to be associated with administration of the study 
drug. 
The degree of certainty with which an AE is attributed to treatment with study medication (or 
alternative causes, eg, natural history of the underlying diseases, concomitant therapy, etc.) 
will be determined by how well the event can be understood in terms of known 
pharmacology of the study medication and/or reaction of similar nature being previously 
observed with the study medication or the class of study medication. 
All AEs should be followed for at least 30 days following the last dose of study drug or until 
the event has resolved, the condition has stabilized, or the patient is lost to Follow-up. For 
each patient for whom an AE was reported that did not resolve before the end of the reporting 
period, Follow-up information on the subsequent course of events must be submitted to the 
Sponsor. This requirement indicates that follow-up may be required for some AEs after the 
patient has completed his/her participation in the study 
9.2 
Serious Adverse Events (SAEs) 
An SAE is defined as any event that results in any of the following outcomes: 
1. Death 
2. A life-threatening adverse event; 
3. Inpatient hospitalization or prolonging of an existing hospitalization;  
4. A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; or 
5. A congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed above. 
Any SAE must be reported by telephone or facsimile within 24 hours of discovery of the 
event. Investigators should not wait to receive additional information to fully document the 
event before notifying the Sponsor of an SAE at: 
Sites in North America must report to: 
Safety Data Facsimile: 001 (832) 442-5917 
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Safety Hotline: 001 (877) 372-3597 
 
Email address (in case of fax failure): drugsafetyfax@lexpharma.com 
 
Sites outside North America must report to the country specific toll-free fax numbers 
identified below: 
Australia: 
 
Belgium: 
 
Brazil: 
 
France: 
 
Germany: 
 
Israel: 
 
Italy: 
 
Netherlands: 
 
Spain: 
 
Sweden:
 
United Kingdom: 
 
 
Email Address (in case of fax failure):  
 
 
The telephone report should be followed by full written summary detailing relevant aspects 
of the SAE in question using the provided SAE report form. Where applicable, information 
from relevant hospital case records and autopsy reports should be obtained. The SAE should 
also be recorded on the AE page of the patient’s CRF. 
An SAE that occurs after completion of the study but, in the opinion of the Investigator, is 
related to the study medication, should be reported as described for an SAE. If an AE does 
not meet the regulatory definition of “serious” but is considered by the Investigator to be 
related to the study medication and of such clinical concern as to influence the overall 
assessment of safety, it must be reported as defined for an SAE. 
All patients (including discontinued patients) with a SAE must be followed until the event 
resolves or reaches a new Baseline, but for a minimum of 30 days after the last dose of study 
drug. 
9.3 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
The FDA and/or other applicable Regulatory Authorities and all participating Investigators 
will be notified by a written Investigational New Drug Application (IND) safety report and/or 
other applicable regulatory report (eg, SUSAR) of any suspected adverse reaction that is both 
serious and unexpected, no later than 15 calendar days from the “date learned” of the event. 
In addition, all applicable regulatory bodies will be notified within 7 calendar days of any 
unexpected fatal or life-threatening suspected adverse reaction.  
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An adverse reaction is defined as any untoward and unintended response to an investigational 
medicinal product (IMP) related to any dose administered. This definition also covers 
medication errors and uses outside what is foreseen in the protocol, including misuse and 
abuse of the product. The definition also implies a reasonable possibility of a causal 
relationship between the event and the IMP.  
An unexpected adverse reaction is any adverse drug event, which is not listed in the current 
Investigator’s Brochure or is not listed at the specificity or severity that has been observed. 
For example, (A) a single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (eg, angioedema, hepatic injury, Stevens-Johnson Syndrome); 
(B) 1 or more occurrences of an event that is not commonly associated with drug exposure, 
but is otherwise uncommon in the population exposed to the drug (eg, tendon rupture); (C) an 
aggregate analysis of specific events observed in a clinical trial (such as known consequences 
of the underlying disease or condition under investigation or other events that commonly 
occur in the study population independent of drug therapy) that indicates those events occur 
more frequently in the drug treatment group than in a concurrent or historical control group. 
An untoward and unintended response to a non-IMP is by definition not a SUSAR. 
9.4 
Precautions 
9.4.1 
Pregnancy 
Any patient (or patient’s partner) who becomes pregnant during the study should be followed 
through delivery or termination of the pregnancy. In addition, patients who become pregnant 
during the study must be discontinued from the study treatment immediately.  
In pregnancies that progress to term, any congenital abnormalities/birth defects in the 
offspring of a patient who received study medication should be reported as an SAE. The 
outcome of the pregnancy and the presence or absence of a congenital abnormality will be 
documented by completion of a Pregnancy Questionnaire and a Pregnancy Outcome Form in 
accordance with GCP and ICH guidelines and the Sponsor’s SOPs.  
Female patients should also notify the Investigator if they become pregnant within 30 days 
after last dose of study medication. Male patients should notify the Investigator if a female 
partner becomes pregnant within 30 days after last dose of study medication. The Sponsor 
must be notified of all pregnancies reported to the Investigator (see Section 9.2 for contact 
information). 
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10. 
Statistical Methodology 
10.1 
Determination of Sample Size 
No formal sample size calculation was made. The number of patients expected to participate 
in this study was calculated from estimated enrollment rates from other carcinoid cancer trials 
employed in the LX1606 clinical program. 
10.2 
Analysis Populations 
Per protocol: A Per Protocol population will consist of those patients that receive study 
treatment and have no major protocol violation that would interfere with the collection or 
interpretation of the efficacy data. The primary analyses of efficacy will be based on the 
safety population; the per-protocol population will be used in a supplemental manner.  
Safety: The safety population consists of all patients receiving any fraction of a dose of study 
drug during this study.  
10.3 
Study Endpoints 
10.3.1 
Efficacy Endpoints 
The primary efficacy endpoint is to evaluate the long-term safety and tolerability of orally 
administered telotristat etiprate. 
Secondary efficacy endpoint is to evaluate changes in patients’ QOL over multiple years of 
therapy.  
10.3.2 
Safety Endpoints 
Safety endpoints are as follows:  
 Incidence of TEAEs, suspected adverse reaction, AEs leading to discontinuation from the 
study, SAEs, and deaths 
 Actual and change from Baseline in clinical laboratory results  
 Actual and change from Baseline in vital signs results  
 Actual and change from Baseline in physical examinations 
 Actual and change from Baseline in ECG findings 
10.4 
Statistical Methods 
Descriptive analysis methods will be used to summarize the data. Continuous variables will 
be summarized by the N, mean, standard deviation, median, minimum, and maximum values. 
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Categorical variables will be summarized as counts and related percentages. Data tabulations 
will be categorized by the treatment received on Day 1 of this study and combined across all 
treated patients. All data will be listed. 
Primary analyses of the data will be based on the Safety population which includes all 
patients treated with any fraction of study drug during this study. Supportive analyses of the 
efficacy data will be made on a Per Protocol population. This dataset will include the Safety 
population, but limited to those patients that have at least one assessment post Day 1 and do 
not have any protocol violations that would interfere with collection or interpretation of the 
data. The Per Protocol analysis will be applied to the QOL measures, subjective global 
assessment, and plasma 5-HIAA values. 
Data will be summarized per study visit as the actual (raw) outcomes and change from 
Baseline scores, where applicable. Day 1 of this study will serve as the Baseline assessment. 
10.4.1 
Efficacy Analyses 
All efficacy and PD variables will be summarized descriptively and listed. 
Statistical tests and estimates of within patient effects for these measures will be derived from 
application of a mixed linear model with repeated measures. The model will be generalized to 
handle missing data and specific to the measurement properties of the dependent variable. 
There is no plan to impute data for missing observations for any variable. Non-parametric 
methods will be used to supplement the tests and estimates from the mixed linear model. 
Exploratory analyses of treatment group differences may be performed by use of propensity 
score models. The treatments groups will correspond to how patients were dosed on Day 1 of 
this study.  
10.4.2 
Safety Analyses 
Statistical analysis of the safety data will involve examination of the descriptive statistics and 
individual patient listings for any effects of study treatment on clinical tolerability and safety. 
Reporting of these data will be based on the Safety population. Summaries will be prepared 
by treatment group (corresponding to the LX1606 dose given on Day 1), pooled across all 
patients, and as needed, by study visit. All safety data will be listed. 
Treatment-emergent adverse event summaries will include the overall incidence (by system 
organ class and preferred term), events by maximum intensity, event by relationship to study 
treatment, events leading to discontinuation of study drug, and serious adverse events. 
Vital signs, ECG, and laboratory parameters (hematology, chemistry, and urinalysis) will be 
summarized descriptively at each time point. Actual and change from Baseline data will be 
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calculated and summarized. In addition, shift table analysis will be applied to the laboratory 
data and summarized. 
10.4.2.1 
Adverse Events 
All AEs will be coded and listed by body system and preferred term based on the Medical 
Dictionary for Regulatory Activities (MedDRA). Summaries using descriptive statistics will 
be provided for treatment-emergent AEs, drug-related AEs and AEs by intensity. Treatment-
emergent AEs are those events not present at Baseline, but occurring after the start of study 
drug, or if existing at Baseline, increasing in intensity after initiation study drug. Summaries 
made by intensity will select the event with the highest intensity when multiple occurrences 
of the same event are reported for the same patient. In a similar manner, summaries prepared 
by drug relationship will select the event with the greatest degree of relationship when a 
study reports multiple occurrences of the same event. On-study deaths will be reported for 
deaths occurring during the active phase of the treatment period and 30 days after stopping 
study drug. Also, deaths occurring outside the 30-day window, but secondary to an AE 
reported within the 30-day post treatment period, will be reported as well.  
Listings will be provided for deaths, SAEs, and discontinuations due to AEs. Additional 
summaries or listings of AEs may also be provided. 
10.4.2.2 
Clinical Laboratory Parameters 
Laboratory results will be reported in conventional units in all tables, figures, and listings. 
Laboratory results falling out of the normal range will be marked as high or low in the 
listings. Actual and changes from Baseline (Day 1) in clinical laboratory results will be 
summarized by using descriptive statistics. Summaries of shifts from Baseline to abnormal 
clinical laboratory results will also be provided. Actual and change from Baseline in 
chromogranin A levels will be summarized descriptively as well. 
10.4.2.3 
Vital Sign Measurements 
Actual and changes from Baseline (Day 1) in vital signs results will be summarized by using 
descriptive statistics. 
10.4.2.4 
Electrocardiograms 
Clinically significant changes in ECGs compared to Baseline, as determined by the 
Investigator, will be summarized by using descriptive statistics. Actual and change from 
Baseline (Day 1 predose values) to each time point in corrected QT interval (QTcF) will be 
summarized as well. 
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10.4.3 
Pharmacodynamic Analyses 
Analysis and summarization of the plasma 5-HIAA data are described in Section 10.4.1. 
10.4.4 
Baseline Characteristics and Other Summaries 
Treatment group differences will be summarized descriptively for demographic data, prior 
and concomitant medications, treatment compliance, and final disposition. Data collected 
from assessments of tumor status, when available, will be listed. 
Protocol deviations will provided as listings. 
10.4.5 
Interim Analysis 
An independent DSMB will be charged with reviewing interim safety data on a quarterly 
basis and reporting its recommendations to Lexicon Pharmaceuticals, Inc. Appropriate 
procedures will be detailed in a DSMB Charter that defines accessibility and disclosure of the 
interim study results. 
The study will be analyzed and reported in 2 phases. The first report will summarize data 
obtained from all patients providing information up to a specified data cut-off point. The 
second report will update the initial report by including data from the remaining portion of 
the study. The first reporting of the data may be taken as an interim analysis in terms of the 
procedural efforts needed to summarize these data, but it will not serve as a means to modify 
the analysis/study conduct.   
11. 
Study Management 
The Investigator is responsible for completing and maintaining adequate and accurate CRFs 
and source documentation. Source documentation constitutes original records, which may 
include: progress notes, medication administration records, laboratory reports, ECG tracings, 
and discharge summaries.  
All data on the CRF must be recorded in accordance with the CRF guidelines. If a correction 
is necessary, it should be made by the Investigator or a designated qualified individual as 
specified within the guideline. All CRFs should be completed in their entirety and stored in a 
secure location. The Investigator must sign the Investigator’s statement in each patient’s CRF 
indicating that the data reported are accurate. 
At the study site, clinical research associates will verify 100% of CRFs in their entirety 
against source documentation. Computer programmed edit checks will be run against the 
database to check for discrepancies and reasonableness of the data, and the safety database 
will be reconciled with the clinical database. All issues resulting from the computer generated 
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checks and the safety database reconciliation will be resolved according to standard data 
management practices in conjunction with the Sponsor, clinical study personnel, and the 
study Investigators. 
11.1 
Monitoring 
The Sponsor is responsible for ensuring the proper conduct of the study with regard to ethics, 
protocol adherence, site procedures, integrity of the data, and applicable laws and/or 
regulations. At regular intervals during the study and following completion of the study, the 
Sponsor’s study monitors will contact the study site via visits to the site, telephone calls, 
and/or letters in order to review study progress, CRF completion, and address any concerns 
or questions regarding the study conduct. During monitoring visits, the following aspects of 
study conduct will be carefully reviewed: informed consent of patients, patient recruitment, 
patient compliance with the study procedures, source data verification, drug accountability, 
use of concomitant therapy by patients, AE and SAE documentation and reporting, and 
quality of data. Records pertaining to these aspects are expected to be kept current. 
The Investigator must make study data accessible to the clinical monitor, to other authorized 
representatives of the Sponsor, and to regulatory inspectors 
11.2 
Audits and Inspections 
The Sponsor, regulatory authority, or IRB/ERC may visit the study site at any time during the 
study or after completion of the study to perform audits or inspections. The purpose of a 
Sponsor audit or regulatory inspection is to systematically and independently examine all 
study-related activities and documents to determine whether these activities were conducted 
according to the protocol, GCP, ICH guidelines, and any other applicable regulatory 
requirements. Investigators should contact the Sponsor immediately if contacted by a 
regulatory agency about an inspection at their site. 
11.3 
Amendments 
Any amendments to the protocol will be written and approved by the Sponsor. All 
amendments must be submitted to the IRB/ERC for approval prior to implementing the 
changes. In some instances, an amendment may require changes to the informed consent 
form, which also must be submitted for IRB/ERC approval prior to administration to patients. 
If any changes to the CRF are required, the Sponsor will issue supplemental or revised CRF 
pages. 
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11.4 
Record Keeping 
11.4.1 
Drug Accountability  
The Investigator must maintain accurate records of receipt of study drug, dispensing 
information (date, lot, and dose for each patient), and the prompt return or destruction of 
unused supplies. If the Investigator cannot account for all clinical supplies at the termination 
of the study, a written explanation must be provided.  
11.4.2 
Health Insurance Portability Accountability Act of 1996 and 
Subsequent Updates 
The Investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of patient health information, including, but not limited to, 
the Standards for Individually Identifiable Health Information, 45 Code of Federal 
Regulations (CFR) Parts 160 and 164 (the Health Insurance Portability Accountability Act of 
1996 [HIPAA] Privacy Regulation and any applicable updates). The Investigator shall ensure 
that study patients authorize the use and disclosure of protected health information in 
accordance with HIPAA Privacy Regulation and in a form satisfactory to the Sponsor. 
11.4.3 
Financial Disclosure 
The Investigator shall provide to the Sponsor sufficient accurate financial information to 
allow the Sponsor to submit complete and accurate financial certification or disclosure 
statements to the FDA and/or other applicable regulatory agencies. The Investigator shall 
promptly update this information if any relevant changes occur in the course of the study or 
for 1 year following completion of the study. 
11.4.4 
Access to Original Records 
It is an expectation of regulatory authorities that monitors, auditors, and representatives of 
national and international government regulatory agency bodies have access to original 
source documentation (see examples in Section 11) to ensure data integrity. “Original” in this 
context is defined as the first documentation of an observation and does not differentiate 
between hard copy and electronic records. 
11.4.5 
Retention of Study Documents 
According to 21 CFR Part 312.62 and ICH E6, study-related records must be retained for at 
least 2 years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region, or at least 
2 years have elapsed since the formal discontinuation of clinical development of the 
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investigational product. These documents should be retained for a longer period, however, if 
required by applicable regulatory requirements or by an agreement with the Sponsor. 
The Investigator must not destroy any study-related records without receiving approval from 
the Sponsor. The Investigator must notify the Sponsor in the event of accidental loss or 
destruction of any study records. If the Investigator leaves the institution where the study was 
conducted, the Sponsor must be contacted to arrange alternative record storage options. 
12. 
Administrative Structure of the Study 
The study will be monitored by Sponsor personnel or Sponsor representative. The following 
functions for this study will be performed by organizations designated by the Sponsor: data 
management and statistical analysis, including PD analysis and reporting.
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13. 
Appendix A – Schedule of Events 
Procedure 
Extension Period 
2 Week Follow-
up4 
Baseline Day 11 
Week 12 
Week 24 
Week 36 
Week 48/ EOS 
Tolerance (days) 
NA 
± 5 
± 5 
± 5 
± 5 
± 5 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Physical examination incl. weight 
X 
X3 
X3 
X3 
X 
X5 
Urine pregnancy test2 
X 
X 
X 
X 
 
X 
Serum pregnancy test2 
 
 
 
 
X 
 
Hematology, Blood chemistry 
X 
X 
X 
X 
X 
X5 
Urinalysis 
X 
 
 
 
X 
X5 
Chromogranin A 
X 
 
 
 
X 
 
Vital signs  
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
X 
X5 
Subjective Global Assessment 
X 
X 
X 
X 
X 
X 
EORTC QLQ-C30 and GI.NET21 
X 
 
X 
 
X 
 
Sleep and Depression Assessments 
X 
X 
X 
X 
X 
X 
Plasma 5-HIAA 
X 
X 
X 
X 
X 
X 
Dispensation of telotristat etiprate (LX1606) 
X 
X 
X 
X 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
1Eligibility will be determined at last visit of the original protocol; Day 1 will replace the next scheduled visit in the original protocol schedule. Visits should coincide with 
LAR injections for those patients receiving SSA therapy. 2Females of child-bearing potential only. 3Brief physical examination only (symptom-oriented, including weight). 
4Visit to be performed for subjects who withdraw early and will not return for a 2 week follow-up visit; In all other cases the EOS visit should be performed followed by the 
follow-up visit 2 weeks postdose. 5To be performed only if evaluation at Week 48/EOS is abnormal.   
 
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14. 
Appendix B – Amount of Blood to be Collected from Each Patient 
Safety
Hematology
2
6
12
Blood chemistry
6
6
36
Other
CgA
2
2
4
Serum Pregnancy
2
1
2
Pharmacodynamic Plasma 5-HIAA
4
6
24
78
*Maximum number of samples is indicated
Total 
Assessment
Sample volume (mL)
Number of samples*
Estimated total volume (mL)
 
 
 
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15. 
Appendix C – EORTC QLQ-C30 
 
 
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16. 
Appendix D – EORTC QLQ - GI.NET21 
 
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17. 
Appendix E – Ethical Standards 
Ethics and Regulatory Considerations 
This study will be conducted according to GCP, 21 CFR Part 50, (Protection of Human 
Subjects), 21 CFR Part 56 (Institutional Review Boards), International Conference on 
Harmonisation Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance, the 
Nuremberg Code, and the Declaration of Helsinki.  
General Instructions 
The FDA regulates studies of drugs, biologics, and medical devices. Consequently, these 
studies are subject to GCP regulations and guidance issued by the FDA and are included in, 
but not limited to, the following parts of the CFR and guideline document: 
 21 CFR Part 11 – Electronic Records 
 21 CFR Part 50 – Protection of Human Subjects 
 21 CFR Part 54 – Financial Disclosure 
 21 CFR Part 56 – Institutional Review Boards 
 21 CFR Part 312 – Investigational New Drug Application 
 Current FDA Guideline for the Monitoring of Clinical Investigations 
 Current Guidance for Institutional Review Boards and Clinical Investigators 
 ICH E6 – Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance  
Studies conducted in the European Union are also regulated by Volume 10 of the publications 
“The rules governing medicinal products in the European Union”. 
Copies of these materials are available from the Sponsor upon request. The purpose of these 
regulations and legal obligations is to define the standards and principles for the proper 
conduct of clinical trials that have been developed by the medical, scientific, and regulatory 
communities. They are not intended to impede or restrict clinical research.  
The ethical standards defined within GCP are intended to ensure that: 
 human subjects are provided with an adequate understanding of the possible risks of their 
participation in the study, and that they have a free choice to participate or not; 
 the study is conducted with diligence and in conformance with the protocol in such a way 
as to insure the integrity of the findings; 
 the potential benefits of the research justify the risks. 
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Lexicon Pharmaceuticals, Inc. is the Sponsor of the IND. The Sponsor is responsible for the 
following: 
 selecting qualified Investigators, 
 providing Investigators with the information they need to properly conduct an 
investigation, 
 ensuring proper monitoring of the investigation, 
 ensuring that the study is conducted according to the general investigational plan and 
protocols contained in the IND, 
 maintaining the IND, and  
 ensuring that regulatory authorities and all participating Investigators are properly 
informed of significant new information regarding adverse effects or risks associated with 
the drug being studied 
 ensuring the study is conducted in accordance to FDA and ICH guidelines and all 
applicable regulations 
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18. 
Appendix F – Investigator Obligations 
Per Title 21 of the US Government Code of Federal Regulations (21 CFR) Parts 50 and 56 
and ICH E6, the study protocol and the final version of the subject informed consent form 
will be approved by the IRB/ERC before enrollment of any subjects. The opinion of the 
IRB/ERC will be dated and given in writing. A copy of the letter of approval from the 
IRB/ERC and a copy of the approved informed consent form will be received by the Sponsor 
prior to shipment of study medication supplies to the Investigator. 
The Investigator will ensure that the IRB/ERC will be promptly informed of all changes in 
the research activity and of all unanticipated problems including risk to subjects. The 
Investigator will also ensure that no changes will be made to the protocol without IRB/ERC 
approval. 
As a part of the IRB/ERC requirement for continuing review of approved research, the 
Investigator will be responsible for submitting periodic progress reports to the IRB/ERC at 
intervals appropriate to the degree of subject risk involved, but no less than once per year. 
Written informed consent must be given freely and obtained from every subject prior to 
clinical trial participation. The rights, safety, and well-being of the trial subjects are the most 
important considerations and should prevail over interests of science and society. 
As described in GCP guidelines, study personnel involved in conducting this trial will be 
qualified by education, training, and experience to perform their respective task(s). Study 
personnel will not include individuals against whom sanctions have been invoked after 
scientific misconduct or fraud (eg, loss of medical licensure, debarment). Quality assurance 
systems and procedures will be implemented to assure the quality of every aspect of the 
study. 
Principal Investigators must provide Lexicon with a fully executed Form FDA 1572 
(statement of Investigator) and all updates on a new fully executed Form FDA 1572. 
Principal Investigators must provide Lexicon with his/her own curriculum vitae and current 
curriculum vitae for each sub-Investigator listed on Form FDA 1572. 
Protection of Human Subjects (21 CFR Part 50 and ICH E6)  
Informed consent must be obtained from every subject before entry into a clinical study. It 
must be given freely and not under duress. Consent must be documented by use of an 
IRB/ERC-approved consent form and signed by the subject or the subject’s legally authorized 
representative. The US Department of Health and Human Services suggests that when minors 
are involved, a parent or guardian should sign the consent form. If the minor is an adolescent, 
his signature should also be included. Non-English-speaking subjects must be presented with 
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a consent form written in a language that they understand. A copy of the signed consent form 
must be given to the subject signing it. Another copy must be kept in the Investigator’s files 
and made available to regulatory authority representatives upon request. If, for any reason, 
subject risk is increased as the study progresses, a revised, IRB/ERC-approved consent form 
must be signed by the subject. Before the study begins, a sample of the consent form must be 
provided to the Sponsor for review. The FDA and/or other applicable regulatory agencies 
may reject otherwise scientifically valid studies if proper informed consent has not been 
obtained from all subjects. 
Only in the case of a life-threatening incident may an investigational product be used without 
prior signed consent. In such an emergency situation, separate certifications must be written 
both by a physician not participating in the study and by the Investigator. The certifications, 
along with the protocol and informed consent, must be sent to the IRB/ERC within 5 working 
days. In this situation, the Investigator may not administer any subsequent product to that 
subject until informed consent and IRB/ERC approval are obtained. 
Informed Consent 
Written informed consent must be obtained from each subject prior to entry in the study. One 
copy of the signed informed consent document will be given to the subject, and another will 
be retained by the Investigator. Additionally, the subject must be allowed adequate time to 
consider the potential risks and benefits associated with his/her participation in the study.  
In situations where the subject is not legally competent to provide consent (ie, mentally 
incapacitated), written consent must be obtained from a parent, legal guardian, or legal 
representative. In these situations, the consent must be signed and dated by a witness. 
The informed consent document must have been reviewed and approved by the Sponsor and 
by the Investigator’s IRB/ERC prior to the initiation of the study. The document must contain 
the 8 basic elements of informed consent and may contain the 6 additional elements 
described in 21 CFR Part 50. Every consent form must include the following 8 elements: 
 A statement that the study involves research, an explanation of the purpose of the research 
and the expected duration of the subject’s participation, a description of the procedures to 
be followed, and identification of any procedures that are experimental 
 A description of any reasonably foreseeable risks or discomforts to the subject 
 A description of any benefits to the subject or to others that may reasonably be expected 
from the research 
 A disclosure of appropriate alternative procedures or course of treatment, if any, that 
might be advantageous to the subject 
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 A statement describing the extent, if any, to which confidentiality of records identifying 
the subject will be maintained and noting the possibility that the FDA and/or other 
applicable regulatory authority representatives may inspect the records 
 An explanation as to whether any compensation or medical treatments are available if 
injury occurs for research involving more than minimal risk. The explanation should 
involve a description of the compensation or treatment available, or a statement 
describing where further information may be obtained 
 An explanation of whom to contact for answers to pertinent questions about the research 
and the subject’s rights and whom to contact in the event of a research related injury 
 A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the subject is otherwise entitled, and that the subject 
may discontinue participation at any time without penalty or loss of benefits to which the 
subject is otherwise entitled. 
When appropriate, 1 or more of the following elements of information shall also be included 
in the consent form: 
 A statement that the particular treatment or procedure may involve risks to the subject (or 
to the embryo or fetus, if the subject is or may become pregnant) which are currently 
unforeseeable 
 Anticipated circumstances under which the subject’s participation may be terminated by 
the Investigator without regard to the subject’s consent 
 Any additional costs the subject may incur from participation in the research 
 The consequences of a subject’s decision to withdraw from the research and procedures 
for orderly termination of participation by the subject 
 A statement that significant new findings developed during the course of the research that 
may relate to the subject’s willingness to continue participation will be provided to the 
subject 
 The approximate number of subjects involved in the study 
The Declaration of Helsinki includes further details regarding the specific requirements for 
informed consent.  
Nothing in these regulations is intended to limit the authority of a physician to provide 
emergency medical care to the extent the physician is permitted to do so under applicable 
federal, state, or local laws. 
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The informed consent requirements in these regulations are not intended to preempt any 
applicable federal, state, or local laws that require additional information to be disclosed in 
order that informed consent be legally effective. Some states, such as California and Oregon, 
require further action on the Investigator’s part concerning subject consent. 
Study Documentation 
IRB/ERC Review/Approval 
The protocol and informed consent for this study, including advertisements used to recruit 
subjects, must be reviewed and approved by an appropriate IRB/ERC prior to enrollment of 
subjects in the study. It is the responsibility of the Investigator to assure that all aspects of the 
ethical review are conducted in accordance with the current Declaration of Helsinki, ICH, 
GCP, and/or local laws, whichever provide the greatest level of protection. A letter 
documenting the IRB/ERC approval which specifically identifies the study/protocol and a list 
of the committee members must be received by the Sponsor prior to initiation of the study. 
Amendments to the protocol will be subject to the same requirements as the original protocol. 
A progress report with a request for re-evaluation and re-approval will be submitted by the 
Investigator to the IRB/ERC at intervals required by the IRB/ERC, and not less than 
annually. A copy of the report will be sent to the Sponsor.  
When the Sponsor provides the Investigator with a Safety Report, the Investigator must 
promptly forward a copy to the IRB/ERC. 
After completion or termination of the study, the Investigator will submit a final report to the 
IRB/ERC and to the Sponsor, if required. This report should include: deviations from the 
protocol, the number and types of subjects evaluated, the number of subjects who 
discontinued (with reasons), results of the study, if known, and significant AEs, including 
deaths. 
Study Files 
The Investigator is required to maintain complete and accurate study documentation in 
compliance with current Good Clinical Practice standards and all applicable federal, state, 
and local laws, rules, and regulations related to the conduct of a clinical study. Study 
documents include, but are not limited to, the Investigator’s Brochure, drug accountability 
records, Sponsor/Investigator correspondence, IRB/ERC correspondence, protocol and 
amendments, information regarding monitoring activities, subject exclusion records, CRFs, 
and data queries. 
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Confidentiality 
The anonymity of subjects must be maintained. Patients will be identified by their initials and 
an assigned subject number on CRFs and other documents submitted to the clinical monitor. 
Documents that will be submitted to the clinical monitor and that identify the subject (eg, the 
signed informed consent document) must be maintained in strict confidence by the Principal 
Investigator, except to the extent necessary to allow auditing by regulatory authorities, the 
clinical monitor, or Sponsor personnel. 
All information regarding the nature of the proposed investigation provided by the Sponsor to 
the Investigator (with the exception of information required by law or regulations to be 
disclosed to the IRB/ERC, the subject, or the regulatory authority) must be kept in confidence 
by the Investigator. 
Drug Accountability 
The Investigator or designee is responsible for accountability of the investigational product at 
the site. The Investigator or designee must maintain records of the product’s delivery to the 
site, inventory at the site, use by each subject, and return to the Sponsor or alternative 
disposition of any unused product. These records must include dates, quantities, 
batch/serial/lot numbers, and expiration dates (if applicable). 
The Investigator should ensure that the investigational product is used only in accordance 
with the protocol 
 
 
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19. 
Appendix G – Guidance on the Selection of Patients  
This long-term study in France is intended for patients who experience clinical benefit in 
their prior experience with telotristat etiprate, either in study LX1606.1-301-CS or 
LX1606.303.1-303-CS. 
Clinical benefit should be present for subjects to meet entry criteria #3 described in section 
6.1 of the protocol: ability and willingness to provide written consent prior to participation in 
any study-related procedure.  
In this study population, clinical benefit may be represented by any of the following:  
 Reduction in bowel movement frequency, or 
 A positive response on the subjective global assessment of adequate relief, or  
 A reduction in urinary 5-HIAA either in study LX1606.1-301-CS or LX1606.1-303-
CS. 
Reduction in bowel movement frequency: a reduction of at least 30% in bowel movement 
frequency from baseline to the end of study LX1606.1-301-CS or LX1606.303.1-303-CS 
may represent clinical benefit. In patients with carcinoid syndrome, benefits of this 
magnitude have been associated with improvements in patient-reported outcomes. 
A positive response on the subjective global assessment of adequate relief: An answer of 
“yes” to the question “In the past 7 days, have you had adequate relief of your carcinoid 
syndrome bowel complaints such as diarrhea, urgent need to have a bowel movement, 
abdominal pain, or discomfort?” at the time of completing participation in LX1606.1-301-CS 
or LX1606.303.1-303-CS is a clinical benefit. 
A reduction in urinary 5-HIAA either in study LX1606.1-301-CS or LX1606.1-303-CS: 
Normalization of urinary 5-HIAA or a reduction of at least 50% in urinary 5-HIAA is a 
clinical benefit for patients at risk of the development of new or progressive carcinoid heart 
disease. 
In addition to the absence of the above signs of benefit, a lack of clinical benefit may reflect 
itself in one of the criteria for stopping treatment or study withdrawal (section 6.3 of the 
protocol): withdrawal of consent, refusal of the study medication, or an investigator decision 
that it is not medically acceptable to continue participation in the study. 
 
 
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20. 
Appendix H - Guidance on the Use of Pro-serotonergic Drugs as 
Concomitant Medications 
Serotonin-synthesis reuptake inhibitors (SSRis) are associated with serotonin syndrome, and 
patients with carcinoid syndrome may be at higher risk of this complication.  
There is some experience with the use of SSRis with telotristat etiprate. In study LX1606.1-
202-CS there were 8 patients on SSRis at baseline, and one patient had an SSRi added during 
the study. There were no reports of serotonin syndrome. However, since the experience was 
relatively limited, caution should be given to the use of SSRis as a concomitant medication in 
study LX1606.1-302-CS. 
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21. 
References 
1. 
Bhattacharyya S, Toumpanakis C, Chilkunda D, Caplin ME, Davar J. Risk factors for 
the development and progression of carcinoid heart disease. Am J Cardiol. 2011 Apr 
15;107(8):1221-6. Epub 2011 Feb 4. 
2. 
Møller JE, Connolly HM, Rubin J, Seward JB, Modesto K, Pellikka PA. Factors 
associated with progression of carcinoid heart disease. N Engl J Med. 2003 Mar 
13;348(11):1005-15. 
3. 
Druce M, Rockall A, Grossman AB. Fibrosis and carcinoid syndrome: from causation to 
future therapy. Nat Rev Endocrinol. 2009 May;5(5):276-83. Review. 
4. 
DePonti F. Pharmacology of serotonin: what a clinician should know. Gut. 2004; 
53:1520 35. 
5. 
Cote F, et al. Disruption of the nonneuronal tph 1 gene demonstrates the importance of 
peripheral serotonin in cardiac function. Proc Natl Acad Sci. 2003 Nov 
11;100(23):13525-30. 
6. 
De Vries H, et al. Diagnostic, surgical, and medical aspect of the midgut carcinoids. 
Cancer Treat Rev. 2002; 28:11-25. 
7. 
Sandostatin LAR® depot product label. Revised August, 2008. Accessed at: 
http://www.pharma.us.novartis.com/product/pi/pdf/sandostatin_lar.pdf  
8. 
Investigator Brochure LX1606, Lexicon Pharmaceuticals, Inc.  
9. 
Dmitrienko A, Tamhane A, Wiens B. General multistage gatekeeping procedures. 
Biometrical Journal. 2008; 50:667-77 
 
 
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Lexicon Pharmaceuticals, Inc.                             
Protocol No.  LX1606.302  
 
 
 
 
CLINICAL PROTOCOL ADDENDUM 
STUDY LX1606.302 
 
 
A Multicenter, Long-term Extension Study to Further Evaluate the Safety and 
Tolerability of Telotristat Etiprate (LX1606) 
 
PROTOCOL NO.: 
LX1606.1-302-CS 
LX1606.302 (Abbreviated number) 
 
 
EudraCT Number: 
2013-002596-18 
 
 
INVESTIGATIONAL PHASE: 
3 
 
 
 
SPONSOR: 
Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Place 
The Woodlands, TX 77381 
Telephone: from USA (281) 863 3000 
 
International sites dial +1 281 863 3000 
Safety Data Facsimile: +1 832 442 5917 
ADDENDUM DATE: 
13 April 2015 (the Netherlands only) 
PROTOCOL AMENDMENT 1 DATE: 
31 January 2014 
ORIGINAL VERSION DATE: 
14 June 2013 
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Protocol No.  LX1606.302  
 
CONFIDENTIAL 
Page 2 
13 April 2015 
 
 
Addendum 
 
Rationale 
 
A source of confusion has been identified in the clinical study protocol relating to terminology 
that is inconsistently used to identify primary objectives and endpoints versus secondary 
objectives and endpoints.  Specifically, the term “efficacy” has been used in relation to primary 
parameters that pertain solely to safety and tolerability.  This addendum is designed to both 
clarify the primary and secondary study parameters and describe the plan for correcting the 
errant language in an upcoming protocol amendment.   
 
 
1. Primary Objective and Secondary Objective –Synopsis – page 3: This is to clarify that 
study objectives are as described in the Synopsis of Amendment 1, dated 31 January 
2014, and summarized below: 
 
Primary Objective: 
To evaluate the long-term safety and tolerability of orally 
administered telotristat etiprate. 
Secondary Objective: 
To evaluate long-term changes in patients’ quality of life 
(QOL). 
 
 
2. An amendment to the clinical study protocol is planned in the near future.  Revisions 
will include corrections to the errant language that unintentionally associates the term 
“efficacy” with the primary objectives of the protocol.  At minimum, the necessary 
corrections identified in the following comparative table will be made: 
 
 
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       Protocol No.  LX1606.302  
 
 
CONFIDENTIAL 
Page 3 
13 April 2015 
Section 
Current Version 31 January 2014 
with Proposed Revisions in Track 
Change Mode 
Proposed Protocol Amendment 
New Wording 
Section 4./ 
Study Objectives 
(page 19) 
4. Study Objectives 
4. 1 Efficacy Objectives 
4.1.1 Primary Objective 
The primary objective of the study is 
to evaluate the long-term safety and 
tolerability of orally administered 
telotristat etiprate. 
4.1.2 Secondary Objective(s) 
The secondary objective of this 
study is to evaluate changes in 
patients’ QOL. 
4.23 Safety Objectives 
Evaluation of overall safety will be 
assessed as: 
 Incidence of treatment-emergent 
adverse events (TEAEs) 
 Changes from Baseline in clinical 
laboratory results, vital signs 
results, and ECG findings 
4. Study Objectives 
4.1 Primary Objective 
The primary objective of the study is 
to evaluate the long-term safety and 
tolerability of orally administered 
telotristat etiprate. 
4.2 Secondary Objective(s) 
The secondary objective of this 
study is to evaluate changes in 
patients’ QOL. 
4.3 Safety Objectives 
Evaluation of overall safety will be 
assessed as: 
 Incidence of treatment-emergent 
adverse events (TEAEs) 
 Changes from Baseline in clinical 
laboratory results, vital signs 
results, and ECG findings 
Section 10.3.1/ 
Efficacy Endpoints 
(page 36) 
10.3.1 Efficacy Primary and 
Secondary Endpoints 
The primary efficacy endpoint is to 
evaluate the long-term safety and 
tolerability of orally administered 
telotristat etiprate. 
Secondary efficacy endpoint is to 
evaluate changes in patients’ QOL 
over multiple years of therapy. 
10.3.1 Primary and Secondary 
Endpoints 
The primary endpoint is to evaluate 
the long-term safety and tolerability 
of orally administered telotristat 
etiprate. 
Secondary endpoint is to evaluate 
changes in patients’ QOL over 
multiple years of therapy. 
added text / deleted text 
 
 
Lexicon Pharmaceuticals, Inc.
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The Woodlands, TX 77381-1160
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Page 1 of 14 
 
 
CLINICAL PROTOCOL AMENDMENT 1  
STUDY LX1606.302 
 
 
A Multicenter, Long-term Extension Study to Further Evaluate the Safety and 
Tolerability of Telotristat Etiprate (LX1606) 
 
 
PROTOCOL NO.: 
LX1606.1-302-CS 
LX1606.302 (Abbreviated number) 
 
 
EudraCT Number: 
2013-002596-18 
 
 
INVESTIGATIONAL PHASE: 
3 
 
 
SPONSOR: 
Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Place 
The Woodlands, TX 77381-1160 
Telephone: 001 (281) 863-3000 
Safety Hotline: 001 (877) 372-3597 
Safety Data Facsimile: 001 (832) 442-5917 
 
 
 
PROTOCOL AMENDMENT 1 DATE: 
31 January 2014 
ORIGINAL VERSION DATE: 
14 June 2013 
 
 
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Amendment Changes 
 
Rationale 
 
A protocol amendment is proposed to clarify that (1) the frequency of the Data Safety 
Monitoring Board (DSMB) meetings; (2) patients who are currently committed to an institution 
by virtue of an order issued either by judicial or administrative authorities are excluded from 
participation; (3) patients may transition into the study at the same dose level as the original 
protocol; (4) pregnancy tests will be conducted at each visit (5) both food and drink containing 
grapefruit should be avoided; (6) mobile research services will not be used for this study; and (7) 
interim analysis will be performed for this study. 
In addition, the study name has been modified to remove ‘symptoms’. As noted in the protocol 
the secondary objective of the long-term study is to evaluate long-term changes in patients’ 
quality of life (QOL).   
Modifications have also been made to: (1) revise the number of patients expected to participate;  
(2) include Depression and Sleep Assessments at each visit; (3) revise the definition of AE/SAE 
to be consistent with current regulatory guideline; (4) capture weight with each physical 
examination; (5) update Schedule of Events to reflect new assessments; (6) include contact 
information for the reporting SAEs in Israel and Brazil; (7) reflect current guidance documents 
will be used to conduct the trial. 
The following administrative changes have also been made: 
• The Lexicon safety hotline has been added to the Sponsor contact information 
• Minor formatting, capitalization, and punctuation have been corrected 
• List of Abbreviations and Definition of Terms has been updated to reflect additional 
abbreviations as necessary 
• Due to the insertion of new sections, renumbering has occurred as appropriate  
• Table of contents has been updated as appropriate 
In response to these changes, the following sections have been revised as follows (changes are 
indicated in italics):  
1. CLINICAL STUDY PROTOCOL – Study Name, page 1 – The term ‘Symptoms’ 
has been removed to be consistent with the secondary objective of study. To evaluate 
long-term changes in patients’ overall quality of life (QOL). The revised Study 
Name now reads: 
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Page 3 of 14 
“TELEPATH (Telotristat Etiprate – Expanded Treatment for Patients with Carcinoid 
Syndrome)” 
2.  SYNOPSIS – Methodology, pages 3-4, and INVESTIGATIONAL PLAN – Overall 
Study Design, Section 5.1, page 19 – This section was modified to clarify that 
patients will continue on open-label study drug at the same dose level identified in 
“their” specific original study. In addition, Data Safety Monitoring Board review 
will occur quarterly throughout the study.  The revised section now reads: 
“The study will be conducted as a multicenter, open-label, long-term extension study to further 
evaluate long-term safety and tolerability of telotristat etiprate. 
Patients currently participating in any LX1606 Phase 2 CS study may enter into this extension 
study upon institutional or local approval of the protocol. Patients participating in a Phase 3 CS 
study may enter into this extension study at the Week 48 visit. All patients who enter into this 
extension study will be exempt from any follow-up visit required by the original study and will 
not experience an interruption in study drug due to the transition from the original protocol to 
LX1060.1-302-CS. 
Following confirmation of eligibility, patients will complete a series of visit assessments in order 
to establish Baseline symptoms. Patients will then continue on open-label LX1606 at the same 
dose level identified in their original study.  
Downward dose adjustment will be permitted during the study if evidence of intolerability 
emerges. Patients who experience intolerability at the 250 mg tid dose level must be discontinued 
from the study. Patients may return to the previous dosing at the discretion of the Investigator 
and in consultation with the Medical Monitor. 
Upon completion or early withdrawal from treatment, all patients will be required to complete a 
14-day Follow-up Period, during which no study drug will be administered. 
A Data Safety Monitoring Board (DSMB) will review safety data quarterly throughout the study.” 
3. SYNOPSIS – Number of Patients, page 4, and STUDY POPULATION, Section 6, 
page 19, 2nd sentence – The number of patients expected to participate has been 
modified. The revised section now reads: 
“Up to 100 patients are expected to participate in this study.” 
4. SYNOPSIS – Treatments, page 4 – This section has been modified to clarify that 250 
mg telotristat tablets will be administered at the same dose level and regimen 
identified in the patient’s original study. The revised section now reads: 
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“Telotristat etiprate, 250 mg tablet, administered at the same dose level and regimen identified in 
the patient’s original study.” 
5. SYNOPSIS – Exclusion Criteria, page 5, and STUDY POPULATION – Exclusion 
Criteria, Section 6.2, page 20 – This section have been modified to add Exclusion 
Criterion #4. The added text reads: 
“Patients who are currently committed to an institution by virtue of an order issued either by 
judicial or administrative authorities.” 
6. INTRODUCTION – Background on Telotristat Etiprate (LX1606) and Disease, 
Section 3.1, pages 12-13, Paragraph #4 – This paragraph was modified to clarify 
that the discussion referenced the human TPH2 enzyme.  The revised paragraph 
now reads: 
“The oral TPH inhibitor, telotristat etiprate, represents a novel approach to potentially lessen the 
pathophysiology of CS by reducing 5-HT levels via inhibition of TPH. Telotristat etiprate was 
designed specifically as a prodrug in order to gain greater systemic exposure, opening the 
potential application for indications in which hyperserotonemia is thought to contribute to the 
disorder, such as CS. Preclinical pharmacology studies of telotristat etiprate were designed to 
evaluate the compound’s mechanism of action and effects in vivo. Telotristat etiprate is the 
ethyl-ester prodrug of the active moiety LP-778902. Telotristat etiprate was designed as a 
prodrug in order to enhance peripheral exposure without crossing the blood-brain barrier. In 
vivo, telotristat etiprate is readily converted through esterase activity to its corresponding acid, 
LP-778902. LP-778902 has an in vitro potency of 0.028 μM on purified human TPH1 enzyme 
and 0.032 μM on purified human TPH2 enzyme. Therefore, telotristat etiprate is a robust 
inhibitor of TPH both in vitro and in vivo and has been shown in Phase 2 studies to provide 
clinical benefit to patients with carcinoid tumors and associated CS.”  
7. INTRODUCTION – Clinical Trials of Telotristat Etiprate (LX1606) in Humans, 
Section 3.2, page 13, 1st paragraph – This paragraph has been modified to reflect the 
most current data in reference to the ulcerative colitis study.  The revised paragraph 
now reads: 
“Telotristat etiprate has been studied in single/multiple doses in Phase 1 studies, approximately 
109 healthy volunteers participated in Phase 1 trials with 88 subjects receiving telotristat etiprate 
and 21 subjects receiving placebo. In addition, 37 patients with CS have received telotristat 
etiprate during the clinical development program in Phase 2.  An additional 59 patients with 
ulcerative colitis have been enrolled into an ongoing Phase 2 study to evaluate telotristat etiprate 
versus placebo in patients with ulcerative colitis experiencing active flares.” 
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8800 Technology Forest Pl.
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8. INTRODUCTION – Clinical Trials of Telotristat Etiprate (LX1606) in Humans, 
Section 3.2, pages 13-16 – Section headings for Phase 1 Studies, Phase 2 Studies, and 
Ongoing Studies have been inserted to provide a clear delineation between the 
phases of study. Sections 3.2.1 Phase 1 Studies, Section 3.2.2 Phase 2 Studies, and 
Section 3.2.2 Ongoing Studies have been inserted as appropriate. Section 3.2.3 
Ongoing Studies has been modified to reflect current status of all ongoing studies.  
The revised Ongoing Studies section now reads: 
 “The open-label extension portion in LX1606.1-202-CS and LX1606.1-203-CS remains ongoing. 
LX1606.1-204-UC is currently evaluating patients with active flares of ulcerative colitis. Doses 
under evaluation are 500 mg once daily (qd) and 500 mg tid vs. placebo; 59 patients have been 
enrolled for an 8-week treatment period.  
LX1606.1-301-CS is intended to evaluate patients who are currently on a background of SSA 
therapy and still experiencing breakthrough symptoms such as an increased frequency of BMs ≥ 
4 per day on average: (1) the efficacy of telotristat etiprate on reducing the number of BMs; (2) 
the efficacy of telotristat etiprate on a number of clinically relevant secondary endpoints; and, (3) 
the safety of telotristat etiprate over the 12-week double-blind portion (Treatment Period) of the 
study. Upon completion of the Treatment Period, patients will continue into a 36-week open-
label Extension Period (Extension Period).  
LX1606.1-303-CS is intended to evaluate patients with carcinoid syndrome whose primary 
symptoms are not GI related and may be naïve to SSA therapy: (1) the safety of telotristat 
etiprate over the 12-week double-blind portion (Treatment Period) of the study; (2) % change 
from Baseline in 24-hr u5-HIAA levels at Week 12; (3) the effects of telotristat etiprate on a 
number of clinically relevant secondary endpoints. Upon completion of the Treatment Period, 
patients will continue into a 36-week open-label Extension Period.”    
9. INTRODUCTION – Rationale for Selection of Dose, Section 3.3.1, pages 16-17 – 
This section was modified to clarify that dose levels evaluated are consistent with 
prior clinical experience.  The revised section now reads: 
“The dose levels of telotristat etiprate selected for this study are consistent with prior clinical 
study experience and based upon clinical safety and pharmacodynamic (PD) data from 2 Phase 2 
multiple ascending-dose studies in patients with symptomatic CS (LX1606.1-202-CS and 
LX1606.1-203-CS).  
Based upon observations noted in Section 3.2, it is anticipated that the doses to be utilized in this 
protocol will be safe and well tolerated and may provide clinical benefit to patients with CS.” 
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10. INTRODUCTION – Benefit/Risk Assessment, Section 3.3.2, pages 17-18, Paragraph
#5 – This section has been modified to clarify that a reduction in serotonin may help
reduce the risk of carcinoid heart disease.  The revised paragraph now reads:
“Treatment has the potential to improve several signs and symptoms of CS. The Phase 2 clinical 
trial results indicated that treatment may lead to improvements in BM frequency, stool 
consistency, urgency, abdominal pain, diarrhea, flushing, and reductions in 5-HIAA. These 
potential benefits relate to a unique mechanism of action. Symptomatic improvement may lead to 
a better quality of life (QOL) for patients with few treatment options available, and a reduction 
in serotonin may help reduce the risk of carcinoid heart disease. Overall the benefit/risk profile 
of telotristat etiprate is expected to be favorable for participation in this clinical study.”  
11. STUDY POPULATION – Criteria for Stopping Treatment/Study Withdrawal,
Section 6.3, page 21 – This section was modified to clarify patient responsibilities
following voluntary withdrawal from the study.  The revised section now reads:
“A patient may also be discontinued from the study for the following medical or administrative 
reasons: 
•
Withdrawal of consent by the patient or legal guardian
•
Noncompliance, including refusal of the study medication and/or failure to adhere to the
study requirements as in the study protocol
•
Investigator decides that, in the interest of the patient, it is not medically acceptable to
continue participation in the study
•
The Sponsor terminates the study (Section 6.4)
•
Pregnancy (Section 9.4.1)
Note:  If a patient voluntarily withdraws or is discontinued from study treatment before 
completing the entire duration of the Treatment Period, they should be encouraged to continue 
clinic visits according to the study schedule.  
Patients who discontinue study treatment, and who are not willing to continue clinic visits (eg, 
withdrawal of consent) should be encouraged to complete End-of-Study (EOS) assessments as 
identified in Appendix A – Schedule of Events and agree to report any SAEs (Section 9.2) 
that occur within 30 days following the last dose of telotristat etiprate. 
The date the patient discontinues study treatment, the primary reason for study treatment 
discontinuation, study termination, and/or termination of participation (eg, withdrawal of 
consent), will be captured within the Case Report Form (CRF). 
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When patients withdraw consent from study participation, it must be recorded on the CRF 
whether the withdrawal of consent applies to specific aspects of the study such as discontinuation 
of study treatment, participation in study visits, contact by study personnel, or access to 
information about potential SAEs. If specific consent has not been withdrawn, study personnel 
should contact the patient (or a previously approved designee such as a caregiver, partner, or 
family member) at the scheduled Follow-up visit to inquire about health status.”  
12. TREATMENT – Dose Adjustment, Section 7.4, page 24 – This section was revised to
clarify dose adjustment during the study. The revised section now reads:
“Downward dose adjustment of telotristat etiprate will be permitted if evidence of intolerability 
emerges. After a period at the lowered dose level, patients may resume the previous dosing level 
at the discretion of the Investigator after consultation with the Medical Monitor. Patients who 
experience intolerability at the 250 mg tid dose level must be discontinued from study treatment. 
Interruptions or delays in dosing throughout the entire study may be permitted after consultation 
with the Medical Monitor, at which time the patient will be reassessed for study continuation, 
dosage reduction, or discontinuation.” 
13. STUDY PROCEDURES, Section 8, page 24 – This section has been modified to
remove the reference to study visits being performed by a mobile research service
outside of the investigational site.  No mobile research services will be utilized for
this protocol. The revised section now reads:
“A schedule of study assessments is provided in Appendix A.” 
14. STUDY PROCEDURES – Restrictions during Study, Section 8.1, page 24 – This
section has been modified to clarify that food and drink containing grapefruit
should be avoided. The revised section now reads:
“Patients should be advised to avoid food and drink containing grapefruit for 2-3 hours prior to 
and following dosing while participating in the study.” 
15. STUDY PROCEDURES – Efficacy Assessments, Section 8.2.1, page 25 – This
section was modified to indicate the EORTC QLQ-C30 and GI.NET21 and the
subjective global assessment are quality of life measure.  The revised section now
reads:
“Efficacy assessments include the patient reported QOL measures; EORTC QLQ-C30 (Appendix 
D) & GI.NET21 (Appendix E) questionnaires and subjective global assessment of symptoms
associated with CS. 
A description of the efficacy assessments is provided below.” 
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16. STUDY PROCEDURES – Depression Detection, Section 8.2.4.4.1.1, pages 28 – This
section has been inserted to include parameters for depression detection at each visit
during the Treatment Period. The new section reads:
“Patients will be evaluated beginning at Day 1 (Baseline) and at each subsequent visit for 
indications of depression. During each visit the patient will first be asked to respond to the 
question “During the past month, have you often been bothered by feeling down, depressed, or 
hopeless?” Followed by “During the past month, have you often been bothered by little interest 
or pleasure in doing things?” A positive response prior to Day 1 dosing will be captured on the 
medical history CRF page. Positive responses following the first dose will be captured as an AE 
and will be followed as an AE of special interest.”  
17. STUDY PROCEDURES – Quality of Sleep Assessment, Section 8.3.3, pages 29 –
This section has been inserted to include parameters for the assessment of the
quality of sleep at each visit during the Treatment Period. The new section reads:
“Quality of sleep will also be evaluated beginning Day 1 (Baseline) and at each subsequent visit 
thereafter. Patients will be asked to respond to the following question “Since your last visit, how 
many times a night (on average) do you wake up due to your CS symptoms?” based on the 
following scale 0, 1, 2, 3, 4, >4.”  
18. SAFETY REPORTING – Adverse Events, Section 9.1, pages 30-32, Paragraphs #1-
4 – These paragraphs were modified to revise the language in order to be consistent
with the current regulatory definitions of Adverse Events.  The revised section now
reads:
“It is the responsibility of the Investigator to document all AEs that occur during the study. 
Adverse event is defined as any untoward medical occurrence associated with the use of a drug 
in humans, whether or not considered drug related. 
Life-threatening adverse event or life-threatening suspected adverse reaction: An adverse event 
or suspected adverse reaction is considered "life-threatening" if, in the view of either the 
Investigator or Sponsor, its occurrence places the patient or subject at immediate risk of death. It 
does not include an adverse event or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death. 
An AE includes any noxious, pathological, or unintended change in anatomical, physiological, or 
metabolic functions as indicated by physical signs or symptoms occurring in any phase of the 
clinical study whether or not considered related to the study medication. This definition includes 
an exacerbation of preexisting medical conditions or events, historical condition not present prior 
to study treatment, which reappear following study treatment, intercurrent illnesses, 
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hypersensitivity reactions, drug interaction, or the significant worsening of the disease under 
investigation that is not recorded elsewhere in the CRF. Anticipated day-to-day fluctuations of 
pre-existing conditions that do not represent a clinically significant exacerbation or worsening 
need not be considered AEs.” 
19. SAFETY REPORTING – Serious Adverse Events (SAEs), Section 9.2, pages 32-34 –
This section has been modified to revise the language in order to be consistent with
the current regulatory definitions of Serious Adverse Events and to include contact
information for Israel and Brazil.  The revised section now reads:
“An SAE is defined as any event that results in any of the following outcomes: 
1. Death
2. A life-threatening adverse event;
3. Inpatient hospitalization or prolonging of an existing hospitalization;
4. A persistent or significant incapacity or substantial disruption of the ability to conduct
normal life functions; or
5. A congenital anomaly/birth defect.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of 
the outcomes listed above. 
Any SAE must be reported by telephone or facsimile within 24 hours of discovery of the event. 
Investigators should not wait to receive additional information to fully document the event 
before notifying the Sponsor of an SAE at: 
Sites in North America must report to: 
Safety Data Facsimile: 001 (832) 442-5917 
Safety Hotline: 001 (877) 372-3597 
Email address (in case of fax failure): drugsafetyfax@lexpharma.com 
Sites outside North America must report to the country specific toll-free fax numbers identified 
below: 
Australia: 
 
Belgium: 
 
Brazil: 
 
France: 
 
Germany:
 
Israel: 
 
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Page 10 of 14 
Italy: 
 
Netherlands:
 
Spain: 
 
Sweden: 
 
United Kingdom: 
 
 
Email Address (in case of fax failure):  
 
 
The telephone report should be followed by full written summary detailing relevant aspects of 
the SAE in question using the provided SAE report form. Where applicable, information from 
relevant hospital case records and autopsy reports should be obtained. The SAE should also be 
recorded on the AE page of the patient’s CRF. 
An SAE that occurs after completion of the study but, in the opinion of the Investigator, is 
related to the study medication, should be reported as described for an SAE. If an AE does not 
meet the regulatory definition of “serious” but is considered by the Investigator to be related to 
the study medication and of such clinical concern as to influence the overall assessment of safety, 
it must be reported as defined for an SAE. 
All patients (including discontinued patients) with a SAE must be followed until the event 
resolves or reaches a new Baseline, but for a minimum of 30 days after the last dose of study 
drug.” 
20. SAFETY REPORTING – Pregnancy, Section 9.4.1, pages 34-35, 1st Paragraph – 
This paragraph was modified to clarify that should a patient become pregnant 
during the study, they must be discontinued immediately from the study treatment.  
The revised section now reads: 
“Any patient (or patient’s partner) who becomes pregnant during the study should be followed 
through delivery or termination of the pregnancy. In addition, patients who become pregnant 
during the study must be discontinued from the study treatment immediately.”   
21. STATISTICAL METHODOLOGY – Interim Analysis, Section 10.4.5, page 38 – 
This section was modified to clarify the frequency of DSMB meetings and provide 
information regarding how the study will be reported.  The revised section now 
reads: 
“An independent DSMB will be charged with reviewing interim safety data on a quarterly basis 
and reporting its recommendations to Lexicon Pharmaceuticals, Inc. Appropriate procedures will 
be detailed in a DSMB Charter that defines accessibility and disclosure of the interim study 
results. 
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The study will be analyzed and reported in 2 phases. The first report will summarize data 
obtained from all patients providing information up to a specified data cut-off point. The second 
report will update the initial report by including data from the remaining portion of the study. 
The first reporting of the data may be taken as an interim analysis in terms of the procedural 
efforts needed to summarize these data, but it will not serve as a means to modify the 
analysis/study conduct.”   
22. Study Management – Health Insurance Portability Accountability Act of 1996 and 
Subsequent Updates, Section 11.4.2, page 40 – This section and its title have been 
modified to clarify that all updates to HIPAA are applicable.  The revised section 
now reads: 
“The Investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of patient health information, including, but not limited to, the 
Standards for Individually Identifiable Health Information, 45 Code of Federal Regulations 
(CFR) Parts 160 and 164 (the Health Insurance Portability Accountability Act of 1996 [HIPAA] 
Privacy Regulation and any applicable updates). The Investigator shall ensure that study patients 
authorize the use and disclosure of protected health information in accordance with HIPAA 
Privacy Regulation and in a form satisfactory to the Sponsor.” 
23. APPENDIX A – Schedule of Events, Section 13, page 42 – The Schedule of Events 
has been updated to reflect the following changes: 
• Include weight with all Physical Examinations, including brief, symptom oriented 
examinations 
• Remove references to visits conducted by mobile research services (MRS) 
• Add urine pregnancy test to be conducted for females of child-bearing potential at Weeks 12, 
24, and 36 
• Add Sleep and Depression Assessments to be captured at every visit, including the Follow-up 
visit 
Changes are indicated by highlighted cells in ‘Revised Appendix A – Schedule of Events’ table 
below. 
 
 
 
 
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Revised Appendix A – Schedule of Events  
Procedure 
Extension Period 
2 Week Follow-
up4 
Baseline Day 11 
Week 12 
Week 24 
Week 36 
Week 48/ EOS 
Tolerance (days) 
NA 
± 5 
± 5 
± 5 
± 5 
± 5 
Inclusion/Exclusion criteria 
X 
Medical history 
X 
Physical examination incl. weight 
X 
X3 
X3 
X3 
X 
X5 
Urine pregnancy test2 
X 
X 
X 
X 
X 
Serum pregnancy test2 
X 
Hematology, Blood chemistry 
X 
X 
X 
X 
X 
X5 
Urinalysis 
X 
X 
X5 
Chromogranin A 
X 
X 
Vital signs  
X 
X 
X 
X 
X 
X 
ECG 
X 
X 
X5 
Subjective Global Assessment 
X 
X 
X 
X 
X 
X 
EORTC QLQ-C30 & GI.NET21 
X 
X 
X 
Sleep and Depression Assessments 
X 
X 
X 
X 
X 
X 
Plasma 5-HIAA 
X 
X 
X 
X 
X 
X 
Dispensation of LX1606 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
1Eligibility will be determined at last visit of the original protocol; Day 1 will replace the next scheduled visit in the original protocol schedule. Visits should coincide with 
LAR injections for those patients receiving SSA therapy. 2Females of child-bearing potential only. 3Brief physical examination only (symptom-oriented, including weight). 
4Visit to be performed for subjects who withdraw early and will not return for a 2 week follow-up visit; In all other cases the EOS visit should be performed followed by the 
follow-up visit 2 weeks postdose. 5To be performed only if evaluation at Week 48/EOS is abnormal.   
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Protocol No.  LX1606.302 A1 
 
31 January 2014 
CONFIDENTIAL 
 
 
 
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24. Appendix E – Ethical Standards, Section 17, General Instructions, pages 47-48 – 
This section has been modified to reflect that current guidance documents will be 
used for the conduct of this study. The revised General Instructions now read:  
“General Instructions 
The FDA regulates studies of drugs, biologics, and medical devices. Consequently, these studies 
are subject to GCP regulations and guidance issued by the FDA and are included in, but not 
limited to, the following parts of the CFR and guideline document: 
• 21 CFR Part 11 – Electronic Records 
• 21 CFR Part 50 – Protection of Human Subjects 
• 21 CFR Part 54 – Financial Disclosure 
• 21 CFR Part 56 – Institutional Review Boards 
• 21 CFR Part 312 – Investigational New Drug Application 
• Current FDA Guideline for the Monitoring of Clinical Investigations 
• Current Guidance for Institutional Review Boards and Clinical Investigators 
• ICH E6 – Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance  
Studies conducted in the European Union are also regulated by Volume 10 of the publications 
“The rules governing medicinal products in the European Union”. 
Copies of these materials are available from the Sponsor upon request. The purpose of these 
regulations and legal obligations is to define the standards and principles for the proper conduct 
of clinical trials that have been developed by the medical, scientific, and regulatory communities. 
They are not intended to impede or restrict clinical research.  
The ethical standards defined within GCP are intended to ensure that: 
• human subjects are provided with an adequate understanding of the possible risks of their 
participation in the study, and that they have a free choice to participate or not; 
• the study is conducted with diligence and in conformance with the protocol in such a way as 
to insure the integrity of the findings; 
• the potential benefits of the research justify the risks. 
Lexicon Pharmaceuticals, Inc. is the Sponsor of the IND. The Sponsor is responsible for the 
following: 
• selecting qualified Investigators, 
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• providing Investigators with the information they need to properly conduct an investigation, 
• ensuring proper monitoring of the investigation, 
• ensuring that the study is conducted according to the general investigational plan and 
protocols contained in the IND, 
• maintaining the IND, and  
• ensuring that regulatory authorities and all participating Investigators are properly informed 
of significant new information regarding adverse effects or risks associated with the drug 
being studied 
• ensuring the study is conducted in accordance to FDA and ICH guidelines and all applicable 
regulations” 
 
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CLINICAL STUDY PROTOCOL 
Protocol Number: 
LX1606.1-302-CS 
LX1606.302 (Abbreviated number) 
EudraCT Number 
2013-002596-18 
Investigational Phase: 
3 
Protocol Title: 
A Multicenter, Long-term Extension Study to Further 
Evaluate the Safety and Tolerability of Telotristat Etiprate 
(LX1606) 
Study Name: 
TELEPATH (Telotristat Etiprate – Expanded Treatment 
for Patients with Carcinoid Syndrome Symptoms) 
Original Version Date: 
14 June 2013 
Sponsor: 
Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Place 
The Woodlands, TX 77381-1160 
Telephone: 001 (281) 863-3000 
Safety Data Facsimile: 001 (832) 442-5917 
 
 
 
 
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1. 
Synopsis 
Name of Study Drug 
Telotristat etiprate 
Protocol Number 
LX1606.1-302-CS 
LX1606.302 (Abbreviated number) 
Protocol Title  
 
A Multicenter, Long-term Extension Study to Further Evaluate the 
Safety and Tolerability of Telotristat Etiprate (LX1606) 
Primary Objective 
The primary objective of this study is to evaluate the long-term 
safety and tolerability of orally administered telotristat etiprate  
Secondary Objective 
To evaluate long-term changes in patients’ quality of life (QOL)  
Phase of Development 
3 
Methodology 
 
The study will be conducted as a multicenter, open-label, long-term 
extension study to further evaluate long-term safety and tolerability 
of telotristat etiprate. 
Patients currently participating in any LX1606 Phase 2 carcinoid 
syndrome (CS) study may enter into this extension study upon 
institutional or local approval of the protocol. Patients participating 
in a Phase 3 CS study may enter into this extension study at the 
Week 48 visit. All patients who enter into this extension study will 
be exempt from any follow-up visit required by the original study 
and will not experience an interruption in study drug due to the 
transition from the original study to LX1060.1-302-CS. 
Following confirmation of eligibility, patients may enter into the 
study at a dose level of 250 mg or 500 mg telotristat etiprate given 3 
times daily (tid). Upon entering, these patients will complete a series 
of visit assessments in order to establish Baseline symptoms. 
Patients will then continue on open-label study drug at the same dose 
level and regimen as identified in the previous study.  
Downward dose adjustment from 500 mg to 250 mg tid will be 
permitted during the study if evidence of intolerability emerges. 
Patients who experience intolerability at the 250 mg tid dose level 
must be discontinued from the study. Patients may return to 500 mg 
tid dosing at the discretion of the Investigator and in consultation 
with the Medical Monitor. 
Upon completion or early withdrawal from treatment, all patients 
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will be required to complete a 14-day Follow-up Period, during 
which no study drug will be administered.  
Number of Patients 
Up to 160 patients are expected to participate in this study.  
Patients 
Eligible patients are defined as those that are currently participating 
in a Phase 2 or Phase 3 telotristat etiprate carcinoid syndrome study. 
Number of Study Sites 
Approximately 70 sites 
Treatments 
Telotristat etiprate tablets administered as 250 mg (1 x 250 mg) tid 
or 500 mg (2 x 250 mg) tid 
Route of Administration 
Oral 
Duration of Participation 
Up to 50 weeks including Treatment and Follow-up 
Inclusion Criteria 
Patients must meet all of the following criteria to be considered 
eligible to participate in the study: 
1. Ongoing participation in a Phase 2 (eg, LX1606.1-202-CS, 
LX1606.1-203-CS) or Phase 3 (eg, LX1606.1-301-CS, 
LX1606.1-303-CS) study 
2. Patients of childbearing potential must agree to use an adequate 
method of contraception (defined as having a failure rate of <1% 
per year) during the study and for 12 weeks after the Follow-up 
visit. Adequate methods of contraception for patients or partner 
include condoms with spermicide gel, diaphragm with 
spermicide gel, coil (intrauterine device), surgical sterilization, 
vasectomy, oral contraceptive pill, depot progesterone injections, 
progesterone implant, and abstinence during the study and for 12 
weeks after the Follow-up Visit. 
a. Childbearing potential is defined as those who have not 
undergone surgical sterilization, or those who are not 
considered postmenopausal. Postmenopause is defined as 
absence of menstruation for at least 2 years. If necessary, 
follicle-stimulating hormone (FSH) results >50 IU/L at entry 
are confirmatory in the absence of a clear postmenopausal 
history. 
3. Ability and willingness to provide written informed consent 
prior to participation in any study-related procedure 
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Exclusion Criteria 
Patients who meet any of the following criteria will be excluded 
from participating in the study:   
1. Major protocol violations or tolerability concerns in a Phase 2 
(eg, LX1606.1-202-CS, LX1606.1-203-CS) or Phase 3 (eg, 
LX1606.1-301-CS, LX1606.1-303-CS) study 
2. Positive pregnancy test 
3. Presence of any clinically significant findings at entry for 
medical history, laboratory values, or physical examination 
(relative to patient population) that, in the Investigator’s or 
Medical Monitor’s opinion, would compromise patient safety or 
the outcome of the study 
Statistical Methods 
Descriptive analysis methods will be used to summarize the data. 
Continuous variables will be summarized by the N, mean, standard 
deviation, median, minimum, and maximum values. Categorical 
variables will be summarized as counts and related percentages. Data 
tabulations will be categorized by the treatment received on Day 1 of 
this study and combined across all treated patients. Primary analyses 
of the data will be based on the Safety population which includes all 
patients treated on Day 1 of this study. Supportive analyses of the 
efficacy data will be made on a Per Protocol population.  
Data will be summarized per study visit as the actual (raw) outcomes 
and change from Baseline scores, where applicable. Day 1 of this 
study will serve as the Baseline assessment.  
Study Assessments 
Safety 
Safety assessments include monitoring of adverse events, clinical 
laboratory tests, vital signs measurements, 12-lead ECG, and 
physical examinations 
Efficacy 
Efficacy assessments will include patient reported quality of life 
measures as captured in the European Organization for Research and 
Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-
C30 and the module specific for gastrointestinal symptoms of 
carcinoid neuroendocrine tumors (GI.NET21) and subjective global 
assessment of symptoms associated with CS 
 
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Pharmacodynamics 
Pharmacodynamic (PD) assessments include determination of 5-
HIAA levels in plasma 
Efficacy Data Analysis 
 
All efficacy and PD variables will be summarized descriptively and 
listed. 
Statistical tests and estimates of within patient effects for the efficacy 
and PD measures will be derived from application of a mixed linear 
model with repeated measures. The form of the model will be 
specific to measurement properties of the dependent variable. Non-
parametric methods will be used to supplement the tests and 
estimates from the mixed linear model. 
Exploratory analyses of treatment group differences may be 
performed by use of propensity score models. The treatments groups 
will correspond to patients’ LX1606 dose level on Day 1 of this 
study.  
Safety Data Analysis 
 
Statistical analysis of the safety data will involve examination of the 
descriptive statistics and individual patient listings for any effects of 
study treatment on clinical tolerability and safety. Reporting of these 
data will be based on the Safety population. Summaries will be 
prepared by treatment group, and as needed, by study visit. 
Treatment-emergent adverse event summaries will include the 
overall incidence (by system organ class and preferred term), events 
by maximum intensity, event by relationship to study treatment, 
events leading to discontinuation of study drug, and serious adverse 
events. 
Vital signs, ECG, and laboratory parameters (hematology, chemistry, 
and urinalysis) will be summarized descriptively at each time point. 
Actual and change from Baseline data will be calculated and 
summarized. In addition, shift table analysis will be applied to the 
laboratory data. 
 
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Table of Contents 
1. 
Synopsis ......................................................................................................................... 3 
2. 
List of Abbreviations and Definitions of Terms ........................................................... 10 
 
Definitions of Terms .................................................................................................... 11 
3. 
Introduction .................................................................................................................. 12 
3.1 
Background on Telotristat Etiprate (LX1606) and Disease .......................... 12 
3.2 
Clinical Trials of Telotristat Etiprate (LX1606) in Humans ......................... 13 
3.2.1 
Ongoing Studies ............................................................................. 16 
3.3 
Rationale for Current Study .......................................................................... 16 
3.3.1 
Rationale for Selection of Dose ..................................................... 16 
3.3.2 
Benefit/Risk Assessment ................................................................ 17 
3.4 
Rationale for Study Design and Control Groups .......................................... 18 
4. 
Study Objectives .......................................................................................................... 18 
4.1 
Efficacy Objectives ....................................................................................... 18 
4.1.1 
Primary Objective .......................................................................... 18 
4.1.2 
Secondary Objective(s) .................................................................. 18 
4.2 
Safety Objectives .......................................................................................... 19 
5. 
Investigational Plan ...................................................................................................... 19 
5.1 
Overall Study Design .................................................................................... 19 
6. 
Study Population .......................................................................................................... 19 
6.1 
Inclusion Criteria .......................................................................................... 20 
6.2 
Exclusion Criteria ......................................................................................... 20 
6.3 
Criteria for Stopping Treatment/Study Withdrawal ...................................... 21 
6.4 
Criteria for Termination of the Study ............................................................ 21 
6.5 
Clinical Stopping Rules ................................................................................ 22 
6.6 
Method of Assigning Patients to Treatment .................................................. 22 
6.7 
Blinding and Unblinding of Study Medication ............................................. 22 
6.8 
Replacement of Patients ................................................................................ 22 
7. 
Treatment ..................................................................................................................... 22 
7.1.1 
Telotristat Etiprate (LX1606) ......................................................... 22 
7.1.1.1 
Identity ......................................................................... 22 
7.1.1.2 
Packaging, Labeling, and Storage ................................ 23 
7.2 
Prior and Concomitant Medications ............................................................. 23 
7.2.1 
Prior Medications ........................................................................... 23 
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7.2.2 
Concomitant Medications .............................................................. 23 
7.2.3 
Prohibited Medications or Concomitant Therapy .......................... 23 
7.3 
Administration of Study Medication ............................................................ 23 
7.3.1 
Treatment Compliance ................................................................... 24 
7.4 
Dose Adjustment ........................................................................................... 24 
8. 
Study Procedures ......................................................................................................... 24 
8.1 
Restrictions during Study .............................................................................. 24 
8.2 
Description of Study Assessments ................................................................ 25 
8.2.1 
Efficacy Assessments ..................................................................... 25 
8.2.1.1 
EORTC QLQ-C30 & GI.NET21 ................................. 25 
8.2.1.2 
Subjective Global Assessment ..................................... 25 
8.2.2 
Clinical Laboratory Assessment .................................................... 25 
8.2.2.1 
Monitoring Hepatic Function ....................................... 26 
8.2.3 
Pharmacodynamic Assessments..................................................... 27 
8.2.3.1 
Plasma 5-HIAA ............................................................ 27 
8.2.4 
Safety Assessments ........................................................................ 27 
8.2.4.1 
Vital Sign Measurements ............................................. 27 
8.2.4.2 
Physical Examinations ................................................. 28 
8.2.4.3 
Electrocardiograms ...................................................... 28 
8.2.4.4 
Adverse Events of Special Interest .............................. 28 
8.2.4.4.1 
Central Nervous System Events ........... 28 
8.3 
Other Assessments ........................................................................................ 29 
8.4 
Appropriateness of Assessments ................................................................... 29 
8.4.1 
Blood Collection ............................................................................ 29 
9. 
Safety Reporting .......................................................................................................... 29 
9.1 
Adverse Events ............................................................................................. 30 
9.2 
Serious Adverse Events (SAEs) .................................................................... 32 
9.3 
Suspected Unexpected Serious Adverse Reactions (SUSARs) .................... 34 
9.4 
Precautions .................................................................................................... 34 
9.4.1 
Pregnancy ....................................................................................... 34 
10. 
Statistical Methodology ............................................................................................... 35 
10.1 
Determination of Sample Size ...................................................................... 35 
10.2 
Analysis Populations ..................................................................................... 35 
10.3 
Study Endpoints ............................................................................................ 35 
10.3.1 
Efficacy Endpoints ......................................................................... 35 
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10.3.2 
Safety Endpoints ............................................................................ 35 
10.4 
Statistical Methods ........................................................................................ 36 
10.4.1 
Efficacy Analyses ........................................................................... 36 
10.4.2 
Safety Analyses .............................................................................. 37 
10.4.2.1 
Adverse Events ............................................................ 37 
10.4.2.2 
Clinical Laboratory Parameters ................................... 37 
10.4.2.3 
Vital Sign Measurements ............................................. 38 
10.4.2.4 
Electrocardiograms ...................................................... 38 
10.4.3 
Pharmacodynamic Analyses .......................................................... 38 
10.4.4 
Baseline Characteristics and Other Summaries ............................. 38 
10.4.5 
Interim Analysis ............................................................................. 38 
11. 
Study Management ...................................................................................................... 38 
11.1 
Monitoring .................................................................................................... 39 
11.2 
Audits and Inspections .................................................................................. 39 
11.3 
Amendments ................................................................................................. 39 
11.4 
Record Keeping ............................................................................................ 40 
11.4.1 
Drug Accountability ....................................................................... 40 
11.4.2 
Health Insurance Portability Accountability Act of 1996 .............. 40 
11.4.3 
Financial Disclosure ....................................................................... 40 
11.4.4 
Access to Original Records ............................................................ 40 
11.4.5 
Retention of Study Documents ...................................................... 40 
12. 
Administrative Structure of the Study ......................................................................... 41 
13. 
Appendix A – Schedule of Events ............................................................................... 42 
14. 
Appendix B – Amount of Blood to be Collected from Each Patient ........................... 43 
15. 
Appendix C – EORTC QLQ-C30 ................................................................................ 44 
16. 
Appendix D – EORTC QLQ - GI.NET21 ................................................................... 46 
17. 
Appendix E – Ethical Standards .................................................................................. 47 
18. 
Appendix F – Investigator Obligations ........................................................................ 49 
19. 
References .................................................................................................................... 54 
 
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2. 
List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
5-HIAA 
5-hydroxyindoleacetic acid 
5-HT 
serotonin 
AE 
adverse event 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
ALP 
alkaline phosphatase 
AST 
aspartate transaminase 
bid 
twice daily 
BM 
bowel movements 
BMI 
body mass index 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CgA 
chromogranin A 
CNS 
central nervous system 
CRF 
case report form 
CRO 
contract research organization 
CS 
carcinoid syndrome 
CT 
computed tomography 
DSMB 
Data Safety Monitoring Board 
EC 
enterochromaffin 
ECG 
electrocardiogram 
ERC 
Ethic Review Committee 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HEENT 
head, eyes, ears, nose, and throat 
Hgb 
hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
IBD 
Inflammatory Bowel Disease 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
Continued on the next page 
 
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Abbreviation 
Definition 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IMP 
Investigational Medicinal Product 
IWRS 
interactive web response system 
LAR 
long-acting release 
LS 
least square 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCP 
multiple comparison procedure 
MRI 
magnetic resonance imaging 
NET 
neuroendocrine tumor 
NRS 
numeric rating scale 
OOR 
out-of-range 
OTC 
over-the-counter 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
qd 
once daily 
SAE 
serious adverse event 
SBS 
short bowel syndrome 
SOP 
standard operating procedure 
SSA 
somatostatin analog 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TEAE 
treatment-emergent adverse events 
tid 
3 times daily 
TPH 
tryptophan hydroxylase 
ULN 
upper limit of the normal reference range 
WRS 
Wilcoxon rank sum 
 
Definitions of Terms  
Term 
Definition 
LP-778902 
Active moiety of LX1606 
LX1606 
Ethyl-ester prodrug of the active moiety LP-778902; a serotonin 
synthesis inhibitor being developed by Lexicon Pharmaceuticals, Inc. 
QTcF 
corrected QT interval using Frederica’s formula 
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3. 
Introduction 
3.1 
Background on Telotristat Etiprate (LX1606) and Disease 
Serotonin (5-HT) plays a critical role in regulating several major physiological processes of 
the gastrointestinal tract, including aspects of secretion, motility, inflammation and sensation. 
Enterochromaffin (EC) cells release 5-HT when the intestinal wall is stimulated by 
intraluminal pressure or chemicals. Through multiple classes of receptors, 5-HT is believed to 
initiate directly, or facilitate, peristaltic and secretory reflexes. 5-HT is also reportedly 
involved in the pathophysiology of various types of functional gastrointestinal (GI) disorders, 
valvular heart disease and may play a role in the pathophysiology of inflammatory bowel 
disease (IBD).  
Carcinoid tumors are mostly derived from EC cells of the midgut, and often produce and 
release large amounts of 5-HT. Such excess of 5-HT is believed to be responsible for the 
severe diarrhea and eventual valvular heart damage and mesenteric fibrosis in patients with 
carcinoid syndrome (CS).1-3 Inhibition of tryptophan hydroxylase (TPH) activity in carcinoid 
tumors should lead to a reduction of peripheral 5-HT in afflicted patients and thus an 
amelioration of the pathophysiology and symptomology of CS. A peripheral TPH inhibitor, 
such as telotristat etiprate, should alleviate the symptoms due to excess 5-HT in carcinoid 
patients without central nervous system (CNS)-related adverse events (AEs). 
Approximately 90% of the body's 5-HT is found in the EC cells of the GI tract, with the 
remainder distributed between the platelets and CNS.4 TPH catalyzes the biopterin-dependent 
monooxygenation of tryptophan to 5-hydroxytryptophan, which is subsequently 
decarboxylated to form 5-HT. Expression of TPH is limited to a few specialized tissues:  
raphe neurons, pinealocytes, mast cells, mononuclear leukocytes, beta cells of the islets of 
Langerhans, and intestinal and pancreatic EC cells.5 Two isoforms of the enzyme exist, TPH1 
and TPH2. TPH1 is exclusively located in the EC cells of the GI tract and pineal gland and is 
the rate limiting enzyme responsible for the majority of systemic 5-HT production and is also 
responsible for 5-HT synthesis in carcinoid tumors. TPH2 is located in the central and enteric 
nervous systems and is the rate-limiting enzyme in the production of neuronal 5-HT. 
The oral TPH inhibitor, telotristat etiprate, represents a novel approach to potentially lessen 
the pathophysiology of CS by reducing 5-HT levels via inhibition of TPH. Telotristat etiprate 
was designed specifically as a prodrug in order to gain greater systemic exposure, opening 
the potential application for indications in which hyperserotonemia is thought to contribute to 
the disorder, such as CS. Preclinical pharmacology studies of telotristat etiprate were 
designed to evaluate the compound’s mechanism of action and effects in vivo. Telotristat 
etiprate is the ethyl-ester prodrug of the active moiety LP-778902. Telotristat etiprate was 
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designed as a prodrug in order to enhance peripheral exposure without crossing the blood-
brain barrier. In vivo, telotristat etiprate is readily converted through esterase activity to its 
corresponding acid, LP-778902. LP-778902 has an in vitro potency of 0.028 μM on purified 
human TPH1 enzyme and 0.032 μM on purified TPH2 enzyme. Therefore, telotristat etiprate 
is a robust inhibitor of TPH both in vitro and in vivo and has been shown in Phase 2 studies 
to provide clinical benefit to patients with carcinoid tumors and associated CS.  
Telotristat etiprate is being developed to manage GI symptoms and possibly other symptoms 
associated with CS. Currently, the standard of care for patients with CS is symptom 
management using somatostatin analogs (SSA), which are available in both short- and long-
acting release (LAR) formulations. Somatostatin analogs such as octreotide are indicated for 
the control of flushing, diarrhea, and other symptoms associated with CS. Common side 
effects of the long-acting depot form of the drug are pain at the site of the injection, reported 
in as many as 30 to 50% of carcinoid patients at the 20 and 30 mg doses, and less commonly, 
stomach cramps, nausea, vomiting, headaches, dizziness, and fatigue.6 Other side effects 
identified in the product labeling include biliary tract abnormalities (gallstones, sludge, and 
dilatation), hypothyroidism, dietary fat malabsorption, and hyper or hypoglycemia.7 In 
addition to the morbidity associated with parenterally administered agents, tachyphylaxis will 
occur in the majority of patients, resulting in recurrent symptoms. 
There are currently no specific oral treatments indicated for the management of symptoms 
associated with CS. As a result of the morbidity associated with SSAs and the associated 
tachyphylaxis, there is an unmet medical need to provide symptom management and modify 
the pathophysiology of patients with metastatic CS. Inhibition of the excessive 5-HT 
produced by these tumors with an orally delivered agent such as telotristat etiprate could 
provide significant benefit as an additional treatment option for patients and clinicians.  
3.2 
Clinical Trials of Telotristat Etiprate (LX1606) in Humans 
Telotristat etiprate has been studied in single/multiple doses in Phase 1 studies, approximately 
109 healthy volunteers participated in Phase 1 trials with 88 subjects receiving telotristat 
etiprate and 21 subjects placebo. In addition, 37 CS patients have received telotristat etiprate 
during the clinical development program in Phase 2. To date, an additional 56 ulcerative 
colitis patients have been enrolled into an ongoing Phase 2 study to evaluate telotristat 
etiprate versus placebo in ulcerative colitis patients experiencing active flare. 
LX1606.1-101-NRM utilized telotristat etiprate as a single oral dose and was noted to be safe 
and well tolerated up to doses of 1,000 mg. At doses of ≥1,000 mg, an increase in GI AEs 
was observed, which were assessed as at least possibly related to study drug. These AEs led 
to a decision not to escalate the dose beyond 1,500 mg. No serious adverse events (SAEs) or 
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deaths were reported and no patient discontinued due to an AE. Twenty-three patients 
experienced at least 1 AE. The majority of the AEs were assessed as mild. The most common 
AEs were diarrhea and nausea. Random out-of-range laboratory values at various time points 
in several patients occurred without any apparent trend. There were no other clinically 
significant vital signs, laboratory or physical examination findings.  
LX1606.1-102-NRM utilized telotristat etiprate as multiple oral doses over 14 days and was 
tolerated up to the maximum dose assessed, 500 mg tid; 1,500 mg total dose daily. Most AEs 
were mild, the most common being nausea and headache; all resolved. Most AEs were at 
least possibly related to study treatment. Four AEs required treatment with concomitant 
medication, 3 AEs of constipation and 1 of headache. No deaths or SAEs were reported. One 
patient was discontinued due to an AE of abnormal liver function. There were no apparent 
trends or clinically significant findings observed upon review of vital signs and 
electrocardiogram (ECG) data. There were no clinically significant abnormal physical 
examination findings. 
Overall, in LX1606.1-102-NRM, treatment with telotristat etiprate was associated with mild 
elevations, generally ≤2x the upper limit of normal (ULN), in alanine transaminase (ALT) 
and aspartate transaminase (AST), with elevations in values observed earlier in the higher 
dose cohorts. Results were assessed as clinically significant for only 1 patient, in Cohort 4, 
who was withdrawn on Day 10. The trend was most pronounced in Cohort 5, in which 5 out 
of 6 patients who received telotristat etiprate had increases in ALT values which were above 
normal range and 4 patients had increases in AST values which were above normal range at 
Day 14. Mean increases in ALT and AST appeared earlier in the study for Cohorts 4 and 5 
than in the other cohorts, and were noted for all cohorts by Day 12. All patients had normal 
ALT and AST values at Baseline and most elevated transaminases returned to normal range 
within 48 hours after the last dose of study drug. No changes in alkaline phosphatase (ALP) 
or total bilirubin were observed in any patient. 
LX1606.1-103-NRM evaluated 2 oral formulations of telotristat etiprate in an open-label 
crossover study. Each formulation was given as a single oral dose followed by a 5-day 
washout and then patients were given a single oral dose of the second formulation. During 
this study, there were no deaths or SAEs reported and no AEs lead to discontinuation. The 
most commonly reported AE was diarrhea. No clinically significant observations or changes 
in other safety parameters (eg, clinical laboratory evaluations, vital signs, physical 
examinations, ECGs, and AEs) were identified in the patient population during the study 
conduct. 
LX1606.1-202-CS was a randomized, double-blind, placebo-controlled, multiple ascending 
dose study conducted in 2 parts in order to evaluate a total of 23 patients at a dose range of 
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450 to 1500 mg given as 150, 250, 350, or 500 mg tid (telotristat etiprate or matching 
placebo) on a background therapy of octreotide. In Part 1, 16 patients were randomly 
assigned 3:1 into 4 sequential cohorts. Each cohort evaluated 1 of the following daily doses 
given as 150, 250, 350, or 500 mg tid over a course of 4 weeks. During the study all patients 
continued on a stable-dose background therapy of octreotide. In Part 2, an additional 7 
patients were randomly assigned 3:1 in order to evaluate 500 mg tid, the highest tolerated 
dose as determined in Part 1. Upon completion of the initial 4-week portion, eligible patients 
had the option to continue into an open-label Extension Period. 
There was 1 treatment emergent SAE assessed as possibly related to study drug which 
occurred in the 350 mg tid dose group. The patient had a history of nausea and vomiting and 
was hospitalized for exacerbation of these conditions.  
Telotristat etiprate was generally well tolerated with no evidence of dose-limiting tolerability. 
Adverse events were mostly mild to moderate and with similar frequencies between 
treatment groups and placebo. No significant changes in vital signs, ECG, or physical exam 
findings were noted after administration of telotristat etiprate at any dose level. The most 
common AEs were GI-related and reported as diarrhea, nausea, and abdominal pain, 
respectively. The modest elevations in transaminases seen in the Phase 1 multiple ascending 
dose study were not apparent in this 4-week study in patients with CS.  
Patients that received telotristat etiprate achieved a clinical response (28%) defined as at least 
a 30% reduction in bowel movements (BMs) for at least 2 weeks; a biochemical response 
(56%) at least 50% reduction or normalization of urinary 5-hydroxyindoleacetic acid (5-
HIAA); and reported adequate relief at Week 4 (46%) while no placebo patients experienced 
clinical response, biochemical response, or adequate relief. 
LX1606.1-203 was an open-label, serial ascending, multiple dose, individual titration study 
that evaluated the same dose ranges as the 1606.1-202-CS study in a total of 15 patients. 
Patients were serially escalated to the next dose level every 2 weeks until a maximally 
tolerated dose or 500 mg tid was reached. Once a dose had been determined, the patient 
would remain on the dose for an additional 4 weeks. Patients then had the option to continue 
into an Extension Period.  
Telotristat etiprate was generally safe and well-tolerated in subjects with CS in the 
LX1606.1-203 study. Most AEs were mild to moderate in severity and assessed as unrelated 
to study drug. Events in the Gastrointestinal Disorders SOC were common, as is anticipated 
with the underlying illness. 
Statistically significant reductions from Baseline in the mean number of BMs/day were 
observed in this study throughout the entire dose-escalation and stable-dose phases, as were 
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associated improvements in stool form. Telotristat etiprate produced an improvement in 
global assessment of GI symptoms associated with CS in the majority of subjects (12 of 15 
subjects, 80%) across the 12-week period. The global assessment of GI symptoms was based 
on the following question, “In the past 7 days, have you had adequate relief of your carcinoid 
syndrome bowel complaints such as diarrhea, urgent need to have a BM, abdominal pain or 
discomfort?” In addition, subjects experienced statistically significant decreases in the mean 
daily number of cutaneous flushing episodes. 
Thirteen subjects (86.7%) experienced a complete biochemical response (defined as a ≥50% 
reduction from Baseline in u5-HIAA levels at 1 or more time points). Consistent with the 
proposed mechanism of action for telotristat etiprate, a complete biochemical response 
correlated closely with measures of clinical response, such as numbers of bowel movements 
per day. 
Detailed information regarding the completed clinical studies can be found in the Investigator 
Brochure.8  
3.2.1 
Ongoing Studies 
LX1606.1-204-UC is currently evaluating patients with active flares of ulcerative colitis. 
Doses under evaluation are 500 mg once daily (qd) and 500 mg tid vs. placebo; 60 patients 
are expected to enroll for an 8-week treatment period.  
LX1606.1-301-CS is intended to evaluate (1) the efficacy of telotristat etiprate on reducing 
the number of BMs; (2) the efficacy of telotristat etiprate on a number of clinically relevant 
secondary endpoints; and, (3) the safety of telotristat etiprate over the 12-week double-blind 
portion (Treatment Period) of the study. Upon completion of the Treatment Period, patients 
will continue into a 36-week open-label Extension Period (Extension Period).  
LX1606.1-303-CS is intended to evaluate (1) the safety of telotristat etiprate over the 12-
week double-blind portion (Treatment Period) of the study and (2) the effects of telotristat 
etiprate on a number of clinically relevant secondary endpoints. Upon completion of the 
Treatment Period, patients will continue into a 36-week open-label Extension Period. 
 
3.3 
Rationale for Current Study 
3.3.1 
Rationale for Selection of Dose 
Two dose levels of telotristat etiprate (250 mg and 500 mg tid) were selected for this study 
based upon clinical safety and pharmacodynamic (PD) data from 2 Phase 2 multiple 
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ascending-dose studies in patients with symptomatic CS (LX1606.1-202-CS and LX1606.1-
203-CS).  
Based upon observations noted in Section 3.2, it is anticipated that the doses to be utilized in 
this protocol will be safe and well tolerated and may provide clinical benefit to patients with 
CS. 
3.3.2 
Benefit/Risk Assessment 
Clinical experience with telotristat etiprate (treated subjects) consists of completed single and 
multiple ascending dose studies in 88 normal subjects (36 in single dose studies and 52 in the 
multiple dose study), two Phase 2 studies (37 patients with symptomatic CS) and 2 ongoing 
Phase 3 studies in patients with symptomatic CS. 
In healthy volunteer studies, single doses up to 1000 mg were found to be generally well 
tolerated, while at the 1500 mg dose level GI-related adverse events increased. A similar 
adverse event profile was observed after multiple dose administration over 14 days with GI 
events predominating. Mild, dose-dependent increases in hepatic transaminase levels (≤2 x 
ULN) were observed with increased frequency in relation to dose, with 1 subject requiring 
withdrawal from therapy at the 500 mg bid dose level. Most subjects that were observed to 
have increased transaminase levels did not exceed >2 times upper limits of normal. No 
abnormalities in total bilirubin were observed at any dose level. GI events have been the most 
commonly observed events to date. The adverse event profile in normal subjects may differ 
significantly from what is observed in patients with hyperserotonemia. All adverse events 
resolved without sequelae. In addition, there were no significant changes in vital signs or 
ECG. No physical examination abnormalities were noted in studies to date. There were no 
serious adverse events reported in healthy volunteers. 
In patients with CS, dose escalations have proceeded up to and including 500 mg tid. To date, 
there has been no evidence of dose-limiting intolerability. Dose levels have been generally 
well tolerated with no evidence to suggest elevations in hepatic transaminase levels. 
Discontinuations that have occurred to date have not been dose-dependent and include lack of 
effect (n=1, 350 mg tid) and a serious adverse event of nausea/vomiting (n=1, 350 mg tid). 
Based upon observations from preclinical and clinical studies conducted to date, it is 
anticipated that orally administered telotristat etiprate will be well tolerated at dose levels 
required to influence peripheral 5-HT production in patients with symptomatic CS. Potential 
adverse events primarily involve the GI tract, and could include alterations in gut motility, 
nausea, vomiting, diarrhea, constipation, abdominal bloating, and/or pain. Regular and 
ongoing clinical and laboratory assessments should detect any of these events, and depending 
on the type of event, further dose adjustment or discontinuation from the trial would occur. 
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Although CNS effects are not anticipated at dose levels planned for evaluation, standard 
adverse event questioning and/or physical examination should reveal any subtle CNS 
findings. As elevations in hepatic transaminase levels were observed with multiple dosing in 
normal subjects, monitoring clinical laboratory tests of hepatic function will be incorporated 
into clinical trials conducted in CS patients. 
Treatment has the potential to improve several signs and symptoms of CS. The Phase 2 
clinical trial results indicated that treatment may lead to improvements in bowel movement 
frequency, stool consistency, urgency, abdominal pain, diarrhea, flushing, and reductions in 5-
HIAA. These potential benefits relate to a unique mechanism of action. Symptomatic 
improvement may lead to a better quality of life (QOL) for patients with few treatment 
options available, and 5-HIAA reduction may help reduce the risk of carcinoid heart disease. 
Overall the benefit/risk profile of telotristat etiprate is expected to be favorable for 
participation in this clinical study. 
3.4 
Rationale for Study Design and Control Groups 
Currently, no approved therapy exists for the treatment of symptoms driven by underlying 
serotonin pathophysiology of CS in patients whose disease is refractory to SSA therapy or for 
those patients who are unable to tolerate SSA therapy or who are unwilling to take SSA 
therapy. 
This study will allow for continued access to telotristat etiprate after patients have completed 
the required study visits in ongoing Phase 2 and Phase 3 studies. Continuation of CS patients 
into this study will allow for the collection of additional long-term safety and efficacy data, 
while providing access to patients who may be receiving benefit. The treatment duration is 
supported by results of chronic toxicology studies (6-month rat and 9-month dog) and the 
current safety profile from completed and ongoing clinical trials. 
4. 
Study Objectives 
4.1 
Efficacy Objectives 
4.1.1 
Primary Objective 
The primary objective of the study is to evaluate the long-term safety and tolerability of 
orally administered telotristat etiprate. 
4.1.2 
Secondary Objective(s) 
The secondary objective of this study is to evaluate changes in patients’ QOL. 
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4.2 
Safety Objectives 
Evaluation of overall safety will be assessed as: 
 Incidence of treatment-emergent adverse events (TEAEs) 
 Changes from Baseline in clinical laboratory results, vital signs results, and ECG 
findings 
5. 
Investigational Plan 
5.1 
Overall Study Design 
The study will be conducted as a multicenter, open-label, long-term extension study to further 
evaluate long-term safety and tolerability of telotristat etiprate. 
Patients currently participating in any LX1606 Phase 2 CS study may enter into this 
extension study upon institutional or local approval of the protocol. Patients participating in a 
Phase 3 CS study may enter into this extension study at the Week 48 visit. All patients who 
enter into this extension study will be exempt from any follow-up visit required by the 
original study and will not experience an interruption in study drug due to the transition from 
the original protocol to LX1060.1-302-CS. 
Following confirmation of eligibility, patients may enter into the study at a dose level of 
250 mg or 500 mg telotristat etiprate given 3 times daily (tid). Upon entering, these patients 
will complete a series of visit assessments in order to establish Baseline symptoms. Patients 
will then continue on open-label LX1606 at the same dose level identified in the previous 
study.  
Downward dose adjustment from 500 mg to 250 mg tid will be permitted during the study if 
evidence of intolerability emerges. Patients who experience intolerability at the 250 mg tid 
dose level must be discontinued from the study. Patients may return to 500 mg tid dosing at 
the discretion of the Investigator and in consultation with the Medical Monitor. 
Upon completion or early withdrawal from treatment, all patients will be required to 
complete a 14-day Follow-up Period, during which no study drug will be administered.  
A Data Safety Monitoring Board (DSMB) will review safety data throughout the study.  
6. 
Study Population 
Adult patients who are currently participating in ongoing Phase 2 or Phase 3 telotristat 
etiprate CS clinical protocols will be enrolled into the study. Up to 160 patients are expected 
to enroll in this study. Approximately 70 sites worldwide will participate in the study. Patients 
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may continue allowed medications as background therapy provided they remain on stable-
doses throughout the Treatment Period. 
6.1 
Inclusion Criteria 
Patients must meet all of the following criteria to be considered eligible to participate in the 
study: 
1. Ongoing participation in a Phase 2 (eg, LX1606.1-202-CS, LX1606.1-203-CS) or 
Phase 3 (eg, LX1606.1-301-CS, LX1606.1-303-CS) study  
2. Patients of childbearing potential must agree to use an adequate method of 
contraception (defined as having a failure rate of <1% per year) during the study and 
for 12 weeks after the Follow-up visit. Adequate methods of contraception for 
patients or partner include condoms with spermicide gel, diaphragm with spermicide 
gel, coil (intrauterine device), surgical sterilization, vasectomy, oral contraceptive pill, 
depot progesterone injections, progesterone implant, and abstinence during the study 
and for 12 weeks after the Follow-up Visit.  
a. Childbearing potential is defined as those who have not undergone surgical 
sterilization, or those who are not considered postmenopausal. Postmenopause 
is defined as absence of menstruation for at least 2 years. If necessary, follicle-
stimulating hormone (FSH) results >50 IU/L at Screening are confirmatory in 
the absence of a clear postmenopausal history. 
3. Ability and willingness to provide written informed consent prior to participation in 
any study-related procedure. 
6.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participating in the 
study:   
1. Major protocol violations or tolerability concerns in a Phase 2 (eg, LX1606.1-202-CS, 
LX1606.1-203-CS) or Phase 3 (eg, LX1606.1-301-CS, LX1606.1-303-CS) study  
2. Positive pregnancy test 
3. Presence of any clinically significant findings at entry for medical history, laboratory 
values, or physical examination (relative to patient population) that, in the 
Investigator’s or Medical Monitor’s opinion, would compromise patient safety or the 
outcome of the study 
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6.3 
Criteria for Stopping Treatment/Study Withdrawal 
A patient may also be discontinued from the study for the following medical or 
administrative reasons: 
 Withdrawal of consent by the patient or legal guardian 
 Noncompliance, including refusal of the study medication and/or failure to adhere to 
the study requirements as in the study protocol 
 Investigator decides that, in the interest of the patient, it is not medically acceptable to 
continue participation in the study 
 The Sponsor terminates the study (Section 6.4) 
 Pregnancy (Section 9.4.1) 
Note: Patients who are discontinued from study treatment before completing the entire 
duration of the Treatment Period should continue clinic visits according to the study 
schedule; this includes the reporting of any AEs, including SAEs (Section 9.2).  
Patients who discontinue study treatment, and who are not willing to continue clinic visits 
(eg, withdrawal of consent) should be encouraged to complete End-of-Study (EOS) 
assessments as identified in Appendix A – Schedule of Events. 
The date the patient discontinues study treatment, the primary reason for study treatment 
discontinuation, study termination, and/or termination of participation (eg, withdrawal of 
consent), will be captured within the Case Report Form (CRF). 
When patients withdraw consent from study participation, it must be recorded on the CRF 
whether the withdrawal of consent applies to specific aspects of the study such as 
discontinuation of study treatment, participation in study visits, contact by study personnel, or 
access to information about potential SAEs. If specific consent has not been withdrawn, study 
personnel should contact the patient (or a previously approved designee such as a caregiver, 
partner, or family member) at the scheduled Follow-up visit to inquire about health status. 
6.4 
Criteria for Termination of the Study 
If the Sponsor, Investigator, study monitor, DSMB, or regulatory officials discover conditions 
arising during the study that indicate that the patient safety and/or scientific value of the study 
and/or quality of the study drugs have been compromised, the study should be halted or the 
study center’s participation should be terminated. Conditions that may warrant termination of 
the study include, but are not limited to, the following: 
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 The discovery of an unexpected, serious, or unacceptable risk to the patients enrolled in 
the study; 
 A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product for any reason; 
 Failure of the Investigator to enroll patients into the study at an acceptable rate; 
 Failure of the Investigator to comply with pertinent governing body regulations; 
 Submission of knowingly false information from the research facility to the Sponsor, 
study monitor, medical officer, or regulatory official; and, 
 Insufficient adherence to protocol requirements.  
Study termination and Follow-up would be performed in compliance with applicable 
governing body regulations. 
6.5 
Clinical Stopping Rules 
Criteria for individual patient withdrawal or study termination are summarized in Sections 
6.3 and 6.4, respectively. 
6.6 
Method of Assigning Patients to Treatment  
Patients will enter the study at the same dose level and regimen as identified in the prior 
Phase 2 or Phase 3 CS study. Randomization will not be used to assign patients to study 
treatments. 
6.7 
Blinding and Unblinding of Study Medication 
This is an open-label study.  
6.8 
Replacement of Patients 
Patients who do not complete the study will not be replaced. 
7. 
Treatment 
7.1.1 
Telotristat Etiprate (LX1606) 
7.1.1.1 
Identity 
LX1606 hippurate is the salt form of the drug substance. LX1606 hippurate is a crystalline 
white to off-white to tan solid with a melting point of 147°C. LX1606 is insoluble in water 
within the pH range of 5 to 9 (≤2 mg/L). It undergoes hydrolysis under strongly basic or 
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strongly acidic conditions. The solubility of LX1606 hippurate in water is about 22 mg/L at 
25°C. 
Study drug dosage form consists of white coated debossed oval tablets containing 250 mg 
LX1606. 
7.1.1.2 
Packaging, Labeling, and Storage 
Patients will receive 250 mg telotristat etiprate tablets packaged in 100 cc high density 
polyethylene bottles with child-resistant polypropylene screw caps and heat-induction seal 
liners.  
Telotristat etiprate should be stored between 15 to 25°C (59 to 77°F). 
7.2 
Prior and Concomitant Medications 
7.2.1 
Prior Medications 
All medications and other treatments taken by patients within 30 days prior to entry will be 
recorded on the CRF.  
7.2.2 
Concomitant Medications 
All concomitant medications taken by patients during the study will be recorded on the CRF. 
Treatment with prescription or over-the-counter (OTC) antidiarrheal therapy, bile acid 
sequestrants, or pancreatic enzyme is permitted; however, the use of these concomitant 
therapies should be associated with a documented history of disease (eg, fat malabsorption, 
bile acid malabsorption, or steatorrhea).  
The dose(s) of all concomitant medication should remain stable. Should the need arise to 
modify/adjust a patient’s therapy the Medical Monitor should be contacted. The Investigator 
and Medical Monitor will make a determination if such a change would impact the safety of 
the patient and the integrity of the study. The Medical Monitor will determine if the patient 
can continue in the study. 
7.2.3 
Prohibited Medications or Concomitant Therapy 
None 
7.3 
Administration of Study Medication 
All patients will be instructed to take the study medication with food. “With food” means 
taking telotristat etiprate tablets within 15 minutes before or within 1 hour after a meal or 
snack. Patients will be instructed to take study drug 3 times daily during waking hours, with 
doses spaced approximately 6 hours apart.  
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Study medication and instructions will be dispensed to patients at each visit as described in 
the schedule of study procedures (Appendix A). 
7.3.1 
Treatment Compliance  
Patients will be asked to bring their unused or unopened study medication to each visit 
(Appendix A). At each visit and in the presence of the patient, study site personnel will count 
returned tablets and reconcile the counts against planned number of doses for that interval. 
Site personnel will clarify any discrepancy and record this information within the CRF.  
Patients must maintain at least 75% compliance in dosing to be deemed as compliant. In the 
event of a missed or vomited dose, patients will take their subsequent dose of study drug at 
the next scheduled time point, following the tid dosing regimen of approximately every 6 
hours. A dose outside of a 3 hour window should be considered missed. Missed or vomited 
doses will not be made up.  
7.4 
Dose Adjustment 
Downward dose adjustment of telotristat etiprate, from 500 mg to 250 mg tid, will be 
permitted if evidence of intolerability emerges. Patients who experience intolerability at the 
250 mg tid dose level must be discontinued from the study. After a period at the 250 mg dose 
level, patients may resume 500 mg tid dosing at the discretion of the Investigator after 
consultation with the Medical Monitor. Interruptions or delays in dosing throughout the entire 
study may be permitted after consultation with the Medical Monitor, at which time the patient 
will be reassessed for study continuation, dose reduction, or discontinuation. 
8. 
Study Procedures 
A schedule of study assessments is provided in Appendix A. 
Select study visits may be performed outside of the investigative site (eg, in home visit) by a 
mobile research service at the discretion of the Investigator and Sponsor. Visits eligible for 
this service are identified in the schedule of study assessments in Appendix A. 
8.1 
Restrictions during Study 
Patients should be advised to avoid grapefruit juice for 2-3 hours prior to and following 
dosing while participating in the study. 
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8.2 
Description of Study Assessments 
8.2.1 
Efficacy Assessments 
Efficacy assessments include the patient reported measures EORTC QLQ-C30 (Appendix D) 
& GI.NET21 (Appendix E) and subjective global assessment of symptoms associated with 
CS. 
A description of the efficacy assessments is provided below. 
8.2.1.1 
EORTC QLQ-C30 & GI.NET21 
Patients will complete the questionnaires during each visit as indicated in Appendix A. 
8.2.1.2 
Subjective Global Assessment 
A subjective global assessment of symptoms associated with CS will be evaluated using 2 
methods at each visit.  
Patients will first be asked to respond to the following question:  “In the past 7 days, have 
you had adequate relief of your carcinoid syndrome bowel complaints such as diarrhea, 
urgent need to have a bowel movement, abdominal pain, or discomfort?”. 
Then patients will be asked the following question to assess global symptoms associated with 
CS on an 11-point scale: “Rate the severity of your overall carcinoid symptoms over the past 
7 days on a scale from 0-10, where 0=no symptoms and 10 = worst symptoms ever 
experienced.” 
8.2.2 
Clinical Laboratory Assessment  
Clinical laboratory assessments will consist of hematology (complete blood count [CBC] 
with differential and platelet counts), blood chemistry (complete metabolic panel and liver 
function tests), and urinalysis. All laboratory tests will be performed by a central laboratory, 
with the exception of the urine pregnancy test, which will be performed by the study site with 
the provided laboratory kit.  
The incidence of clinically significant laboratory values, as well as clinically significant shifts 
in laboratory values, should be reported as an AE in the patient’s CRF (see also Section 9.1 
for reporting of AEs related to laboratory abnormalities). The Investigator will assess any 
clinically significant values relevant to the patient population to determine if termination of 
the study drug is required. 
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8.2.2.1 
Monitoring Hepatic Function 
Patients with clinically significant abnormalities in liver function tests should be excluded 
from participating; however, the patient’s clinical situation as a whole should be taken into 
account when evaluating hepatic transaminase elevations, which may represent a 
consequence of the underlying disease and/or therapeutic interventions. Patients with 
abnormalities in liver function test results, as defined below, should be further assessed by the 
Investigator and may have additional tests performed by the central laboratory as clinically 
indicated. The following describes the Sponsor’s recommended approach to evaluating these 
events. This approach is not meant to replace the Investigator’s clinical judgment.  
These guidelines apply to the following events: 
1) A new confirmed result (after Day 1 dosing) of ALT or AST >3x ULN (in 
patients previously within normal range) 
OR 
2) A confirmed increase in transaminases above the patient’s previous baseline to a 
degree that is significant in the clinical judgment of the Investigator and ALT or 
AST >3x ULN (in patients with previous abnormal liver-test results) 
OR 
3) Any occurrence of an elevation of ALT or AST > 3x ULN and total bilirubin >2x 
ULN (in any patient) 
For any such event, the Investigator should discuss the Follow-up approach with the Medical 
Monitor.  
The Sponsor’s recommended approach is as follows: 
1. Schedule the patient for a Follow-up visit within 3 days following the receipt of 
laboratory results to assess the patient and conduct further evaluation, to include the 
following: 
a. Obtain repeat testing of ALT, AST, total bilirubin, and ALP through the central 
laboratory. 
b. Reassess the patient through patient interview and physical examination to 
uncover new or emerging risk factors of liver injury including an increased use 
of alcohol, gallbladder disease, hemochromatosis, fatty liver, use of 
hepatotoxic concomitant medications (including acetaminophen), occupational 
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exposures, liver metastases, and other causes for potential clues as to the 
underlying etiology of the event. 
c. Continue to monitor the patient’s transaminases and total bilirubin regularly 
until the liver function test values return to Baseline levels.  
Additional recommendations include: 
 Consider referral to a hepatologist or gastroenterologist 
 Consider reimaging (eg, ultrasound, CT, or MRI) the liver and biliary tract 
 Consider additional laboratory testing as clinically indicated. Laboratory assays 
available to the Investigator for further workup are described in the laboratory manual 
Upon completion of hepatic assessment, the Investigator should review results with the 
Medical Monitor and assess continued study participation. 
8.2.3 
Pharmacodynamic Assessments 
8.2.3.1 
Plasma 5-HIAA 
Fasting blood samples (of at least 6 hours) for measurement of 5-HIAA in plasma will be 
collected and analyzed by a specialty laboratory. All sample processing information will be 
supplied by the laboratory in a separate document/study manual. Efforts should be made to 
schedule these visits in the morning, with instructions to the patient to arrive in a fasted state 
and not dose prior to the blood draw. 
8.2.4 
Safety Assessments 
In addition to the clinical laboratory assessments described in Section 8.2.2, monitoring of 
AEs is also considered a safety assessment and is described in detail in Section 9. Clinically 
significant changes compared with Baseline findings for these variables should be reported as 
AEs on the CRF. Clinically significant changes compared with Baseline values, which are 
determined to be AEs, should be followed until the event has resolved, the condition has 
stabilized, etiology of the event is determined to be not related to study drug, or the patient is 
lost to Follow-up. 
8.2.4.1 
Vital Sign Measurements 
Measurement of vital signs will include assessment of blood pressure, respiratory rate, pulse 
rate, and oral temperature. Vital sign measurements should not be conducted with the 
30 minutes immediately following any phlebotomy. 
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Efforts should be made to standardize blood pressure collection across all patients and visits. 
Patients should be seated for at least 5 minutes prior to collection. All measurements will be 
collected using dedicated equipment, supplied by the Sponsor, assessed on the same arm, and 
by the same technician where possible. 
Additional measurements may be obtained if clinically indicated. Vital sign measurements 
will be measured as indicated in Appendix A. 
8.2.4.2 
Physical Examinations 
Complete physical examinations will be performed as outlined in Appendix A. Complete 
physical examinations will include a minimum of a review of the patient’s general 
appearance, head, eyes, ears, nose, and throat (HEENT), neck, heart, lungs, abdomen, back 
and extremities, skin, and general neurological system.  
Symptom-oriented physical examinations will be performed at all other time points and as 
clinically indicated.  
In addition, weight will be captured during each physical examination. Efforts should be 
made to standardize weight collection across all patients and visits. Patients should be 
instructed to remove shoes and heavy clothing (eg, heavy coats, jackets) prior to 
measurement. For weight collection, an effort should be made to use the same scale 
throughout the study where possible. In instances where multiple scales may be used, efforts 
should be made to reset the scale to zero prior to collection of weight measurement. 
8.2.4.3 
Electrocardiograms 
Electrocardiograms (12-lead ECGs) will be performed as specified in Appendix A. 
8.2.4.4 
Adverse Events of Special Interest 
Monitoring of these events will be the responsibility of the DSMB. The process of data 
collection and assessment of the events will be detailed in a separate DSMB charter.  
Additional information will be collected if episodes of any of the following AEs of special 
interest occur. 
8.2.4.4.1 
Central Nervous System Events 
Central nervous system events of special interest may include any clinically significant 
changes in mood, physical affect, or exacerbation of preexisting CNS conditions (eg, 
depression, migraine headaches). 
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8.3 
Other Assessments 
Blood samples for measurement of chromogranin A (CgA) levels will be collected as 
indicated in Appendix A. 
Data will also be collected on measures of disease progression as performed as standard of 
care (including, but not limited to: interpretation of clinical scans [eg, PET, CAT, MRI scans 
of tumor], Investigator assessment of disease status) while the patient is enrolled in the study.  
8.4 
Appropriateness of Assessments 
The assessments used in this study conform to the usual clinical and laboratory assessments 
of patients with CS participating in clinical trials and are typical of a Phase 3 study.  
8.4.1 
Blood Collection 
An attempt should be made to collect all samples as per the schedule outlined in Appendix A. 
Any portion of samples remaining after the required tests for this study have been completed 
will be destroyed. 
The estimated amount of blood scheduled for collection per patient, over the course of the 
study, may be found in Appendix B. 
9. 
Safety Reporting 
Medical queries should be addressed to the medical monitor responsible for the region. 
Sites in North America: 
, MD 
  
INC Research 
 
 
Phone: 
 
 
 
Sites outside North America:  
, MD, PhD 
 
INC Research 
 
The Netherlands 
Phone: 
 
Mobile: 
 
 
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 MD, PhD 
Medical Monitor 
INC Research, LLC 
 
 
Czech Republic 
Phone: 
 
Fax: 
 
 
After-hours emergency medical coverage is available to site personnel should the regional 
Medical Monitor and regional backup Medical Monitor be unavailable. 
 
Sites in North America dial 1-877-462-0134. 
 
Sites outside North America dial the country prefix number plus 1-877-462-0134. Prefix 
numbers are determined by accessing the AT&T Direct on-line link 
http://www.usa.att.com/traveler/access_numbers/country/index.jsp. Note:  these calls are not 
toll-free. 
9.1 
Adverse Events 
It is the responsibility of the Investigator to document all AEs that occur during the study. 
An AE includes any noxious, pathological, or unintended change in anatomical, 
physiological, or metabolic functions as indicated by physical signs or symptoms occurring in 
any phase of the clinical study whether or not associated with the study medication and 
whether or not considered related to the study medication. This definition includes an 
exacerbation of preexisting medical conditions or events, historical condition not present 
prior to study treatment, which reappear following study treatment, intercurrent illnesses, 
hypersensitivity reactions, drug interaction, or the significant worsening of the disease under 
investigation that is not recorded elsewhere in the CRF. Anticipated day-to-day fluctuations 
of pre-existing conditions that do not represent a clinically significant exacerbation or 
worsening need not be considered AEs. 
Any laboratory abnormality fulfilling the criteria for a SAE (Section 9.2) should be reported 
as such, in addition to being recorded as an AE. Any treatment-emergent abnormal laboratory 
result which is clinically significant, ie, meeting 1 or more of the following conditions, 
should be recorded as a single diagnosis AE: 
 Is considered to be an SAE, 
 Results in discontinuation from study treatment, or 
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 Results in a requirement for a change in concomitant therapy (ie, addition of concomitant 
therapy) 
In the event of medically significant unexplained abnormal laboratory test values, the tests 
should be repeated and followed up until they have returned to the normal range and/or an 
adequate explanation of the abnormality is determined.  
TEAEs are defined as any AEs reported after the first dose of randomized treatment on 
Day 1. Adverse events reported after consent of a patient, but before administration of study 
medication, will be reported in the Medical History. 
AEs should not be solicited with leading questions that suggest specific signs or symptoms. 
Rather, AEs should be solicited by asking the patient a non-leading question such as: “Do you 
feel different in any way since receiving the dose or since the last assessment?” 
The Investigator will evaluate all AEs with regard to the maximum intensity and relationship 
to study drug, as follows: 
 Maximum intensity  
Maximum intensity should be assigned using 1 of the following 3 severity grades: 
o 
Mild: aware of event but easily tolerated 
o 
Moderate: discomfort, enough to cause interference with usual activity 
o 
Severe: incapacitating: patient unable to work or perform usual activities 
 Relationship to study drug 
Not related:  
o 
Does not follow a reasonable temporal sequence from administration of the drug 
o 
Could be reasonably explained by other factors, including underlying disease, 
complications, concomitant drugs, or concurrent treatment. 
Possibly related:  
o 
That follows a reasonable temporal sequence from administration of the drug 
(including the course after withdrawal of the drug), or 
o 
For which the possibility of the study drug being the causative factor (eg, existence 
of similar reports attributed to the suspected drug and its analogues; reactions 
attributable to the pharmacological effect) could not be excluded, although other 
factors such as underlying disease, complications, concomitant drugs, or concurrent 
treatment are presumable. 
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Probably related: 
o 
That follows a reasonable temporal sequence from administration of the drug 
(including the course after withdrawal of the drug), and 
o 
For which the possibility of factors other than the drug, such as underlying disease, 
complications, concomitant drugs, or concurrent treatment, could not be excluded as 
the cause. 
Definitely related: 
o 
Follows a clear temporal sequence from administration of the study drug. 
o 
Could not be possibly explained by the known characteristics of the patient’s 
clinical state, environmental or toxic factors, or other modes of therapy 
administered to the patient. 
o 
Disappears or decreases on cessation or reduction in dose of the study drug. 
o 
Reappears or worsens when the study drug is re-administered. 
o 
Follows a response pattern known to be associated with administration of the study 
drug. 
The degree of certainty with which an AE is attributed to treatment with study medication (or 
alternative causes, eg, natural history of the underlying diseases, concomitant therapy, etc.) 
will be determined by how well the event can be understood in terms of known 
pharmacology of the study medication and/or reaction of similar nature being previously 
observed with the study medication or the class of study medication. 
All AEs should be followed for at least 30 days following the last dose of study drug or until 
the event has resolved, the condition has stabilized, or the patient is lost to follow-up. For 
each patient for whom an AE was reported that did not resolve before the end of the reporting 
period, follow-up information on the subsequent course of events must be submitted to the 
Sponsor. This requirement indicates that follow-up may be required for some AEs after the 
patient has completed his/her participation in the study 
9.2 
Serious Adverse Events (SAEs) 
An SAE is defined as any event that results in any of the following outcomes: 
1. Death 
2. Life-threatening situation, defined as one in which a patient is at immediate risk, in the 
Investigator’s opinion, of death from the reaction as it occurs. This does not include an 
event that might have caused death if it had occurred in a more severe form; 
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3. Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; 
4. Inpatient hospitalization or prolonging of an inpatient hospitalization;  
5. Congenital anomaly/birth defect in the offspring of a patient who received study 
medication; or 
6. Medical or surgical intervention that is necessary to prevent 1 of the outcomes listed in 
this definition 
Any SAE must be reported by telephone or facsimile within 24 hours of discovery of the 
event. Investigators should not wait to receive additional information to fully document the 
event before notifying the Sponsor of an SAE at: 
Sites in North America must report to: 
Safety Data Facsimile: 001 (832) 442-5917 
Safety Hotline: 001 (877) 372-3597 
 
Email address (in case of fax failure): drugsafetyfax@lexpharma.com 
 
Sites outside North America must report to the country specific toll-free fax numbers 
identified below: 
Australia: 
 
Belgium: 
 
France: 
 
Germany: 
 
Italy: 
 
Netherlands: 
 
Spain: 
 
Sweden:
 
United Kingdom:
 
 
Email Address (in case of fax failure):  
 
 
The telephone report should be followed by full written summary detailing relevant aspects 
of the SAE in question using the provided SAE report form. Where applicable, information 
from relevant hospital case records and autopsy reports should be obtained. The SAE should 
also be recorded on the AE page of the patient’s CRF. 
An SAE that occurs after completion of the study but, in the opinion of the Investigator, is 
related to the study medication, should be reported as described for an SAE. If an AE does 
not meet the regulatory definition of “serious” but is considered by the Investigator to be 
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related to the study medication and of such clinical concern as to influence the overall 
assessment of safety, it must be reported as defined for an SAE. 
All patients (including discontinued patients) with a SAE must be followed until the event 
resolves or reaches a new baseline, but for a minimum of 30 days after the last dose of study 
drug. 
9.3 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
The FDA and/or other applicable Regulatory Authorities and all participating Investigators 
will be notified by a written Investigational New Drug Application (IND) safety report and/or 
other applicable regulatory report (eg, SUSAR) of any suspected adverse reaction that is both 
serious and unexpected, no later than 15 calendar days from the “date learned” of the event. 
In addition, all applicable regulatory bodies will be notified within 7 calendar days of any 
unexpected fatal or life-threatening suspected adverse reaction.  
An adverse reaction is defined as any untoward and unintended response to an investigational 
medicinal product (IMP) related to any dose administered. This definition also covers 
medication errors and uses outside what is foreseen in the protocol, including misuse and 
abuse of the product. The definition also implies a reasonable possibility of a causal 
relationship between the event and the IMP.  
An unexpected adverse reaction is any adverse drug event, which is not listed in the current 
Investigator’s Brochure or is not listed at the specificity or severity that has been observed. 
For example, (A) a single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (eg, angioedema, hepatic injury, Stevens-Johnson Syndrome); 
(B) 1 or more occurrences of an event that is not commonly associated with drug exposure, 
but is otherwise uncommon in the population exposed to the drug (eg, tendon rupture); (C) an 
aggregate analysis of specific events observed in a clinical trial (such as known consequences 
of the underlying disease or condition under investigation or other events that commonly 
occur in the study population independent of drug therapy) that indicates those events occur 
more frequently in the drug treatment group than in a concurrent or historical control group.
An untoward and unintended response to a non-IMP is by definition not a SUSAR. 
9.4 
Precautions 
9.4.1 
Pregnancy 
Any patient (or patient’s partner) who becomes pregnant during the study should be followed 
through delivery or termination of the pregnancy. In addition, patients who become pregnant 
during the study must be discontinued from the study immediately.  
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In pregnancies that progress to term, any congenital abnormalities/birth defects in the 
offspring of a patient who received study medication should be reported as an SAE. The 
outcome of the pregnancy and the presence or absence of a congenital abnormality will be 
documented by completion of a Pregnancy Questionnaire and a Pregnancy Outcome Form in 
accordance with GCP and ICH guidelines and the Sponsor’s SOPs.  
Female patients should also notify the Investigator if they become pregnant within 30 days 
after last dose of study medication. Male patients should notify the Investigator if a female 
partner becomes pregnant within 30 days after last dose of study medication. The Sponsor 
must be notified of all pregnancies reported to the Investigator (see Section 9.2 for contact 
information). 
10. 
Statistical Methodology 
10.1 
Determination of Sample Size 
No formal sample size calculation was made. The number of patients expected to participate 
in this study was calculated from estimated enrollment rates from other carcinoid cancer trials 
employed in the LX1606 clinical program. 
10.2 
Analysis Populations 
Per protocol: A Per Protocol population will consist of those patients that receive study 
treatment and have no major protocol violation that would interfere with the collection or 
interpretation of the efficacy data. The primary analyses of efficacy will be based on the 
safety population; the per-protocol population will be used in a supplemental manner.  
Safety: The safety population consists of all patients receiving any fraction of a dose of study 
drug during this study.  
10.3 
Study Endpoints 
10.3.1 
Efficacy Endpoints 
The primary efficacy endpoint is to evaluate the long-term safety and tolerability of orally 
administered telotristat etiprate. 
Secondary efficacy endpoint is to evaluate changes in patients’ QOL over multiple years of 
therapy.  
10.3.2 
Safety Endpoints 
Safety endpoints are as follows:  
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 Incidence of TEAEs, suspected adverse reaction, AEs leading to discontinuation from the 
study, SAEs, and deaths 
 Actual and change from Baseline in clinical laboratory results  
 Actual and change from Baseline in vital signs results  
 Actual and change from Baseline in physical examinations 
 Actual and change from Baseline in ECG findings 
10.4 
Statistical Methods 
Descriptive analysis methods will be used to summarize the data. Continuous variables will 
be summarized by the N, mean, standard deviation, median, minimum, and maximum values. 
Categorical variables will be summarized as counts and related percentages. Data tabulations 
will be categorized by the treatment received on Day 1 of this study and combined across all 
treated patients. All data will be listed. 
Primary analyses of the data will be based on the Safety population which includes all 
patients treated with any fraction of study drug during this study. Supportive analyses of the 
efficacy data will be made on a Per Protocol population. This dataset will include the Safety 
population, but limited to those patients that have at least one assessment post Day 1 and do 
not have any protocol violations that would interfere with collection or interpretation of the 
data. The Per Protocol analysis will be applied to the QOL measures, subjective global 
assessment, and plasma 5-HIAA values. 
Data will be summarized per study visit as the actual (raw) outcomes and change from 
Baseline scores, where applicable. Day 1 of this study will serve as the Baseline assessment. 
10.4.1 
Efficacy Analyses 
All efficacy and PD variables will be summarized descriptively and listed. 
Statistical tests and estimates of within patient effects for these measures will be derived from 
application of a mixed linear model with repeated measures. The model will be generalized to 
handle missing data and specific to the measurement properties of the dependent variable. 
There is no plan to impute data for missing observations for any variable. Non-parametric 
methods will be used to supplement the tests and estimates from the mixed linear model. 
Exploratory analyses of treatment group differences may be performed by use of propensity 
score models. The treatments groups will correspond to how patients were dosed on Day 1 of 
this study.  
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10.4.2 
Safety Analyses 
Statistical analysis of the safety data will involve examination of the descriptive statistics and 
individual patient listings for any effects of study treatment on clinical tolerability and safety. 
Reporting of these data will be based on the Safety population. Summaries will be prepared 
by treatment group (corresponding to the LX1606 dose given on Day 1), pooled across all 
patients, and as needed, by study visit. All safety data will be listed. 
Treatment-emergent adverse event summaries will include the overall incidence (by system 
organ class and preferred term), events by maximum intensity, event by relationship to study 
treatment, events leading to discontinuation of study drug, and serious adverse events. 
Vital signs, ECG, and laboratory parameters (hematology, chemistry, and urinalysis) will be 
summarized descriptively at each time point. Actual and change from Baseline data will be 
calculated and summarized. In addition, shift table analysis will be applied to the laboratory 
data and summarized. 
10.4.2.1 
Adverse Events 
All AEs will be coded and listed by body system and preferred term based on the Medical 
Dictionary for Regulatory Activities (MedDRA). Summaries using descriptive statistics will 
be provided for treatment-emergent AEs, drug-related AEs and AEs by intensity. Treatment-
emergent AEs are those events not present at Baseline, but occurring after the start of study 
drug, or if existing at Baseline, increasing in intensity after initiation study drug. Summaries 
made by intensity will select the event with the highest intensity when multiple occurrences 
of the same event are reported for the same patient. In a similar manner, summaries prepared 
by drug relationship will select the event with the greatest degree of relationship when a 
study reports multiple occurrences of the same event. On-study deaths will be reported for 
deaths occurring during the active phase of the treatment period and 30 days after stopping 
study drug. Also, deaths occurring outside the 30-day window, but secondary to an AE 
reported within the 30-day post treatment period, will be reported as well.  
Listings will be provided for deaths, SAEs, and discontinuations due to AEs. Additional 
summaries or listings of AEs may also be provided. 
10.4.2.2 
Clinical Laboratory Parameters 
Laboratory results will be reported in conventional units in all tables, figures, and listings. 
Laboratory results falling out of the normal range will be marked as high or low in the 
listings. Actual and changes from Baseline (Day 1) in clinical laboratory results will be 
summarized by using descriptive statistics. Summaries of shifts from Baseline to abnormal 
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clinical laboratory results will also be provided. Actual and change from Baseline in 
chromogranin A levels will be summarized descriptively as well. 
10.4.2.3 
Vital Sign Measurements 
Actual and changes from Baseline (Day 1) in vital signs results will be summarized by using 
descriptive statistics. 
10.4.2.4 
Electrocardiograms 
Clinically significant changes in ECGs compared to Baseline, as determined by the 
Investigator, will be summarized by using descriptive statistics. Actual and change from 
Baseline (Day 1 predose values) to each time point in corrected QT interval (QTcF) will be 
summarized as well. 
10.4.3 
Pharmacodynamic Analyses 
Analysis and summarization of the plasma 5-HIAA data are described in Section 10.4.1. 
10.4.4 
Baseline Characteristics and Other Summaries 
Treatment group differences will be summarized descriptively for demographic data, prior 
and concomitant medications, treatment compliance, and final disposition. Data collected 
from assessments of tumor status, when available, will be listed. 
Protocol deviations will provided as listings. 
10.4.5 
Interim Analysis 
An independent DSMB will be charged with reviewing interim safety data and reporting its 
recommendations to Lexicon Pharmaceuticals, Inc. Appropriate procedures will be detailed 
in a DSMB Charter that defines accessibility and disclosure of the interim study results. 
11. 
Study Management 
The Investigator is responsible for completing and maintaining adequate and accurate CRFs 
and source documentation. Source documentation constitutes original records, which may 
include: progress notes, medication administration records, laboratory reports, ECG tracings, 
and discharge summaries.  
All data on the CRF must be recorded in accordance with the CRF guidelines. If a correction 
is necessary, it should be made by the Investigator or a designated qualified individual as 
specified within the guideline. All CRFs should be completed in their entirety and stored in a 
secure location. The Investigator must sign the Investigator’s statement in each patient’s CRF 
indicating that the data reported are accurate. 
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At the study site, clinical research associates will verify 100% of CRFs in their entirety 
against source documentation. Computer programmed edit checks will be run against the 
database to check for discrepancies and reasonableness of the data, and the safety database 
will be reconciled with the clinical database. All issues resulting from the computer generated 
checks and the safety database reconciliation will be resolved according to standard data 
management practices in conjunction with the Sponsor, clinical study personnel, and the 
study Investigators. 
11.1 
Monitoring 
The Sponsor is responsible for ensuring the proper conduct of the study with regard to ethics, 
protocol adherence, site procedures, integrity of the data, and applicable laws and/or 
regulations. At regular intervals during the study and following completion of the study, the 
Sponsor’s study monitors will contact the study site via visits to the site, telephone calls, 
and/or letters in order to review study progress, CRF completion, and address any concerns 
or questions regarding the study conduct. During monitoring visits, the following aspects of 
study conduct will be carefully reviewed: informed consent of patients, patient recruitment, 
patient compliance with the study procedures, source data verification, drug accountability, 
use of concomitant therapy by patients, AE and SAE documentation and reporting, and 
quality of data. Records pertaining to these aspects are expected to be kept current. 
The Investigator must make study data accessible to the clinical monitor, to other authorized 
representatives of the Sponsor, and to regulatory inspectors 
11.2 
Audits and Inspections 
The Sponsor, regulatory authority, or IRB/ERC may visit the study site at any time during the 
study or after completion of the study to perform audits or inspections. The purpose of a 
Sponsor audit or regulatory inspection is to systematically and independently examine all 
study-related activities and documents to determine whether these activities were conducted 
according to the protocol, GCP, ICH guidelines, and any other applicable regulatory 
requirements. Investigators should contact the Sponsor immediately if contacted by a 
regulatory agency about an inspection at their site. 
11.3 
Amendments 
Any amendments to the protocol will be written and approved by the Sponsor. All 
amendments must be submitted to the IRB/ERC for approval prior to implementing the 
changes. In some instances, an amendment may require changes to the informed consent 
form, which also must be submitted for IRB/ERC approval prior to administration to patients. 
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If any changes to the CRF are required, the Sponsor will issue supplemental or revised CRF 
pages. 
11.4 
Record Keeping 
11.4.1 
Drug Accountability  
The Investigator must maintain accurate records of receipt of study drug, dispensing 
information (date, lot, and dose for each patient), and the prompt return or destruction of 
unused supplies. If the Investigator cannot account for all clinical supplies at the termination 
of the study, a written explanation must be provided.  
11.4.2 
Health Insurance Portability Accountability Act of 1996 
The Investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of patient health information, including, but not limited to, 
the Standards for Individually Identifiable Health Information, 45 Code of Federal 
Regulations (CFR) Parts 160 and 164 (the Health Insurance Portability Accountability Act of 
1996 [HIPAA] Privacy Regulation). The Investigator shall ensure that study patients 
authorize the use and disclosure of protected health information in accordance with HIPAA 
Privacy Regulation and in a form satisfactory to the Sponsor. 
11.4.3 
Financial Disclosure 
The Investigator shall provide to the Sponsor sufficient accurate financial information to 
allow the Sponsor to submit complete and accurate financial certification or disclosure 
statements to the FDA and/or other applicable regulatory agencies. The Investigator shall 
promptly update this information if any relevant changes occur in the course of the study or 
for 1 year following completion of the study. 
11.4.4 
Access to Original Records 
It is an expectation of regulatory authorities that monitors, auditors, and representatives of 
national and international government regulatory agency bodies have access to original 
source documentation (see examples in Section 11) to ensure data integrity. “Original” in this 
context is defined as the first documentation of an observation and does not differentiate 
between hard copy and electronic records. 
11.4.5 
Retention of Study Documents 
According to 21 CFR Part 312.62 and ICH E6, study-related records must be retained for at 
least 2 years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region, or at least 
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2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. These documents should be retained for a longer period, however, if 
required by applicable regulatory requirements or by an agreement with the Sponsor. 
The Investigator must not destroy any study-related records without receiving approval from 
the Sponsor. The Investigator must notify the Sponsor in the event of accidental loss or 
destruction of any study records. If the Investigator leaves the institution where the study was 
conducted, the Sponsor must be contacted to arrange alternative record storage options. 
12. 
Administrative Structure of the Study 
The study will be monitored by Sponsor personnel or Sponsor representative. The following 
functions for this study will be performed by organizations designated by the Sponsor: data 
management and statistical analysis, including PD analysis and reporting.
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8800 Technology Forest Pl. 
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Protocol No. LX1606.302 
13. 
Appendix A – Schedule of Events 
Baseline Day 
11
Week 122
Week 24
Week 362
Week 48/ EOS
Tolerance (days)
NA
± 5
± 5
± 5
± 5
± 5
Inclusion/Exclusion criteria
X
Medical history
X
Physical examination
X
X4
X4
X4
X
X6
Urine pregnancy test3
X
X
Serum pregnancy test3
X
 
Hematology, Blood chemistry
X
X
X
X
X
X6
Urinalysis
X
X
X6
Chromogranin A
X
X
Vital signs
X
X
X
X
X
X
ECG
X
X
X6
Subjective Global Assessment
X
X
X
X
X
X
EORTC QLQ-C30 & GI.NET21
X
X
X
Plasma 5-HIAA
X
X
X
X
X
X
Dispensation of LX1606
X
X7
X
X7
 
Concomitant medications
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
Procedure
Extension Period
2 Week Follow-
up5
1Eligibility will be determined at last visit of the original protocol, Day 1 will replace the next scheduled visit in the original protocol 
schedule. Visits should coincide with LAR injections for those patients receiving SSA therapy. 2Visits eligible to be conducted by 
mobile research service (MRS) at the discretion of the Investigator, MRS visits must be setup in advance, confirmed, and drug 
dispensation adjusted accordingly. 3Females of child-bearing potential only. 4Brief physical examination only (symptom-oriented) 
5Visit to be performed for subjects who withdraw early and will not return for a 2 week follow-up visit; In all other cases the EOS 
visit should be performed followed by the follow-up visit 2 weeks postdose. 6To be performed only if evaluation at Week 48/EOS is 
abnormal. 7If visit is conducted by MRS drug dispensation will not occur. Study drug dispensation will only occur during visits to 
Investigator study site. 
 
14 June 2013 
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8800 Technology Forest Pl. 
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Safety
Hematology
2
6
12
Blood chemistry
6
6
36
Other
CgA
2
2
4
Serum Pregnancy
2
1
2
Pharmacodynamic Plasma 5-HIAA
4
6
24
78
*Maximum number of samples is indicated
Total 
Assessment
Sample volume (mL)
Number of samples*
Estimated total volume (mL)
 
14. 
Appendix B – Amount of Blood to be Collected from Each Patient 
 
 
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8800 Technology Forest Pl. 
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15. 
Appendix C – EORTC QLQ-C30 
 
 
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16. 
Appendix D – EORTC QLQ - GI.NET21 
 
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17. 
Appendix E – Ethical Standards 
Ethics and Regulatory Considerations 
This study will be conducted according to GCP, 21 CFR Part 50, (Protection of Human 
Subjects), 21 CFR Part 56 (Institutional Review Boards), International Conference on 
Harmonisation Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance, the 
Nuremberg Code, and the Declaration of Helsinki.  
General Instructions 
The FDA regulates studies of drugs, biologics, and medical devices. Consequently, these 
studies are subject to GCP regulations and guidance issued by the FDA and are included in, 
but not limited to, the following parts of the CFR and guideline document: 
 21 CFR Part 11 – Electronic Records 
 21 CFR Part 50 – Protection of Human Subjects 
 21 CFR Part 54 – Financial Disclosure 
 21 CFR Part 56 – Institutional Review Boards 
 21 CFR Part 312 – Investigational New Drug Application 
 FDA Guideline for the Monitoring of Clinical Investigations, January 1988 
 FDA Information Sheets – Guidance for Institutional Review Boards and Clinical 
Investigators, 1998 Update 
 ICH E6 – Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance  
Studies conducted in the European Union are also regulated by Volume 10 of the publications 
“The rules governing medicinal products in the European Union”. 
Copies of these materials are available from the Sponsor upon request. The purpose of these 
regulations and legal obligations is to define the standards and principles for the proper 
conduct of clinical trials that have been developed by the medical, scientific, and regulatory 
communities. They are not intended to impede or restrict clinical research.  
The ethical standards defined within GCP are intended to ensure that: 
 human subjects are provided with an adequate understanding of the possible risks of their 
participation in the study, and that they have a free choice to participate or not; 
 the study is conducted with diligence and in conformance with the protocol in such a way 
as to insure the integrity of the findings; 
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8800 Technology Forest Pl. 
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 the potential benefits of the research justify the risks. 
Lexicon Pharmaceuticals, Inc. is the Sponsor of the IND. The Sponsor is responsible for the 
following: 
 selecting qualified Investigators, 
 providing Investigators with the information they need to properly conduct an 
investigation, 
 ensuring proper monitoring of the investigation, 
 ensuring that the study is conducted according to the general investigational plan and 
protocols contained in the IND, 
 maintaining the IND, and  
 ensuring that regulatory authorities and all participating Investigators are properly 
informed of significant new information regarding adverse effects or risks associated with 
the drug being studied 
 ensuring the study is conducted in accordance to FDA and ICH guidelines and all 
applicable regulations 
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8800 Technology Forest Pl. 
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18. 
Appendix F – Investigator Obligations 
Per Title 21 of the US Government Code of Federal Regulations (21 CFR) Parts 50 and 56 
and ICH E6, the study protocol and the final version of the subject informed consent form 
will be approved by the IRB/ERC before enrollment of any subjects. The opinion of the 
IRB/ERC will be dated and given in writing. A copy of the letter of approval from the 
IRB/ERC and a copy of the approved informed consent form will be received by the Sponsor 
prior to shipment of study medication supplies to the Investigator. 
The Investigator will ensure that the IRB/ERC will be promptly informed of all changes in 
the research activity and of all unanticipated problems including risk to subjects. The 
Investigator will also ensure that no changes will be made to the protocol without IRB/ERC 
approval. 
As a part of the IRB/ERC requirement for continuing review of approved research, the 
Investigator will be responsible for submitting periodic progress reports to the IRB/ERC at 
intervals appropriate to the degree of subject risk involved, but no less than once per year. 
Written informed consent must be given freely and obtained from every subject prior to 
clinical trial participation. The rights, safety, and well being of the trial subjects are the most 
important considerations and should prevail over interests of science and society. 
As described in GCP guidelines, study personnel involved in conducting this trial will be 
qualified by education, training, and experience to perform their respective task(s). Study 
personnel will not include individuals against whom sanctions have been invoked after 
scientific misconduct or fraud (eg, loss of medical licensure, debarment). Quality assurance 
systems and procedures will be implemented to assure the quality of every aspect of the 
study. 
Principal Investigators must provide Lexicon with a fully executed Form FDA 1572 
(statement of Investigator) and all updates on a new fully executed Form FDA 1572. 
Principal Investigators must provide Lexicon with his/her own curriculum vitae and current 
curriculum vitae for each sub-Investigator listed on Form FDA 1572. 
Protection of Human Subjects (21 CFR Part 50 and ICH E6)  
Informed consent must be obtained from every subject before entry into a clinical study. It 
must be given freely and not under duress. Consent must be documented by use of an 
IRB/ERC-approved consent form and signed by the subject or the subject’s legally authorized 
representative. The US Department of Health and Human Services suggests that when minors 
are involved, a parent or guardian should sign the consent form. If the minor is an adolescent, 
his signature should also be included. Non-English-speaking subjects must be presented with 
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a consent form written in a language that they understand. A copy of the signed consent form 
must be given to the subject signing it. Another copy must be kept in the Investigator’s files 
and made available to regulatory authority representatives upon request. If, for any reason, 
subject risk is increased as the study progresses, a revised, IRB/ERC-approved consent form 
must be signed by the subject. Before the study begins, a sample of the consent form must be 
provided to the Sponsor for review. The FDA and/or other applicable regulatory agencies 
may reject otherwise scientifically valid studies if proper informed consent has not been 
obtained from all subjects. 
Only in the case of a life-threatening incident may an investigational product be used without 
prior signed consent. In such an emergency situation, separate certifications must be written 
both by a physician not participating in the study and by the Investigator. The certifications, 
along with the protocol and informed consent, must be sent to the IRB/ERC within 5 working 
days. In this situation, the Investigator may not administer any subsequent product to that 
subject until informed consent and IRB/ERC approval are obtained. 
Informed Consent 
Written informed consent must be obtained from each subject prior to entry in the study. One 
copy of the signed informed consent document will be given to the subject, and another will 
be retained by the Investigator. Additionally, the subject must be allowed adequate time to 
consider the potential risks and benefits associated with his/her participation in the study.  
In situations where the subject is not legally competent to provide consent (ie, mentally 
incapacitated), written consent must be obtained from a parent, legal guardian, or legal 
representative. In these situations, the consent must be signed and dated by a witness. 
The informed consent document must have been reviewed and approved by the Sponsor and 
by the Investigator’s IRB/ERC prior to the initiation of the study. The document must contain 
the 8 basic elements of informed consent and may contain the 6 additional elements 
described in 21 CFR Part 50. Every consent form must include the following 8 elements: 
 A statement that the study involves research, an explanation of the purpose of the research 
and the expected duration of the subject’s participation, a description of the procedures to 
be followed, and identification of any procedures that are experimental 
 A description of any reasonably foreseeable risks or discomforts to the subject 
 A description of any benefits to the subject or to others that may reasonably be expected 
from the research 
 A disclosure of appropriate alternative procedures or course of treatment, if any, that 
might be advantageous to the subject 
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8800 Technology Forest Pl. 
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 A statement describing the extent, if any, to which confidentiality of records identifying 
the subject will be maintained and noting the possibility that the FDA and/or other 
applicable regulatory authority representatives may inspect the records 
 An explanation as to whether any compensation or medical treatments are available if 
injury occurs for research involving more than minimal risk. The explanation should 
involve a description of the compensation or treatment available, or a statement 
describing where further information may be obtained 
 An explanation of whom to contact for answers to pertinent questions about the research 
and the subject’s rights and whom to contact in the event of a research related injury 
 A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the subject is otherwise entitled, and that the subject 
may discontinue participation at any time without penalty or loss of benefits to which the 
subject is otherwise entitled. 
When appropriate, 1 or more of the following elements of information shall also be included 
in the consent form: 
 A statement that the particular treatment or procedure may involve risks to the subject (or 
to the embryo or fetus, if the subject is or may become pregnant) which are currently 
unforeseeable 
 Anticipated circumstances under which the subject’s participation may be terminated by 
the Investigator without regard to the subject’s consent 
 Any additional costs the subject may incur from participation in the research 
 The consequences of a subject’s decision to withdraw from the research and procedures 
for orderly termination of participation by the subject 
 A statement that significant new findings developed during the course of the research that 
may relate to the subject’s willingness to continue participation will be provided to the 
subject 
 The approximate number of subjects involved in the study 
The Declaration of Helsinki includes further details regarding the specific requirements for 
informed consent.  
Nothing in these regulations is intended to limit the authority of a physician to provide 
emergency medical care to the extent the physician is permitted to do so under applicable 
federal, state, or local laws. 
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8800 Technology Forest Pl. 
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The informed consent requirements in these regulations are not intended to preempt any 
applicable federal, state, or local laws that require additional information to be disclosed in 
order that informed consent be legally effective. Some states, such as California and Oregon, 
require further action on the Investigator’s part concerning subject consent. 
Study Documentation 
IRB/ERC Review/Approval 
The protocol and informed consent for this study, including advertisements used to recruit 
subjects, must be reviewed and approved by an appropriate IRB/ERC prior to enrollment of 
subjects in the study. It is the responsibility of the Investigator to assure that all aspects of the 
ethical review are conducted in accordance with the current Declaration of Helsinki, ICH, 
GCP, and/or local laws, whichever provide the greatest level of protection. A letter 
documenting the IRB/ERC approval which specifically identifies the study/protocol and a list 
of the committee members must be received by the Sponsor prior to initiation of the study. 
Amendments to the protocol will be subject to the same requirements as the original protocol. 
A progress report with a request for re-evaluation and re-approval will be submitted by the 
Investigator to the IRB/ERC at intervals required by the IRB/ERC, and not less than 
annually. A copy of the report will be sent to the Sponsor.  
When the Sponsor provides the Investigator with a Safety Report, the Investigator must 
promptly forward a copy to the IRB/ERC. 
After completion or termination of the study, the Investigator will submit a final report to the 
IRB/ERC and to the Sponsor, if required. This report should include: deviations from the 
protocol, the number and types of subjects evaluated, the number of subjects who 
discontinued (with reasons), results of the study, if known, and significant AEs, including 
deaths. 
Study Files 
The Investigator is required to maintain complete and accurate study documentation in 
compliance with current Good Clinical Practice standards and all applicable federal, state, 
and local laws, rules, and regulations related to the conduct of a clinical study. Study 
documents include, but are not limited to, the Investigator’s Brochure, drug accountability 
records, Sponsor/Investigator correspondence, IRB/ERC correspondence, protocol and 
amendments, information regarding monitoring activities, subject exclusion records, CRFs, 
and data queries. 
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8800 Technology Forest Pl. 
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Confidentiality 
The anonymity of subjects must be maintained. Patients will be identified by their initials and 
an assigned subject number on CRFs and other documents submitted to the clinical monitor. 
Documents that will be submitted to the clinical monitor and that identify the subject (eg, the 
signed informed consent document) must be maintained in strict confidence by the Principal 
Investigator, except to the extent necessary to allow auditing by regulatory authorities, the 
clinical monitor, or Sponsor personnel. 
All information regarding the nature of the proposed investigation provided by the Sponsor to 
the Investigator (with the exception of information required by law or regulations to be 
disclosed to the IRB/ERC, the subject, or the regulatory authority) must be kept in confidence 
by the Investigator. 
Drug Accountability 
The Investigator or designee is responsible for accountability of the investigational product at 
the site. The Investigator or designee must maintain records of the product’s delivery to the 
site, inventory at the site, use by each subject, and return to the Sponsor or alternative 
disposition of any unused product. These records must include dates, quantities, 
batch/serial/lot numbers, and expiration dates (if applicable). 
The Investigator should ensure that the investigational product is used only in accordance 
with the protocol 
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8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
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19. 
References 
1. 
Bhattacharyya S, Toumpanakis C, Chilkunda D, Caplin ME, Davar J. Risk factors for 
the development and progression of carcinoid heart disease. Am J Cardiol. 2011 Apr 
15;107(8):1221-6. Epub 2011 Feb 4. 
2. 
Møller JE, Connolly HM, Rubin J, Seward JB, Modesto K, Pellikka PA. Factors 
associated with progression of carcinoid heart disease. N Engl J Med. 2003 Mar 
13;348(11):1005-15. 
3. 
Druce M, Rockall A, Grossman AB. Fibrosis and carcinoid syndrome: from causation to 
future therapy. Nat Rev Endocrinol. 2009 May;5(5):276-83. Review. 
4. 
DePonti F. Pharmacology of serotonin: what a clinician should know. Gut. 2004; 
53:1520 35. 
5. 
Cote F, et al. Disruption of the nonneuronal tph 1 gene demonstrates the importance of 
peripheral serotonin in cardiac function. Proc Natl Acad Sci. 2003 Nov 
11;100(23):13525-30. 
6. 
De Vries H, et al. Diagnostic, surgical, and medical aspect of the midgut carcinoids. 
Cancer Treat Rev. 2002; 28:11-25. 
7. 
Sandostatin LAR® depot product label. Revised August, 2008. Accessed at: 
http://www.pharma.us.novartis.com/product/pi/pdf/sandostatin_lar.pdf  
8. 
Investigator Brochure LX1606, Lexicon Pharmaceuticals, Inc.  
9. 
Dmitrienko A, Tamhane A, Wiens B. General multistage gatekeeping procedures. 
Biometrical Journal. 2008; 50:667-77 
 
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8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
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SAP_001.pdf: 
 
Official Title: 
A Multicenter, Long-term Extension Study to Further Evaluate the 
Safety and Tolerability of Telotristat Etiprate (LX1606)   
NCT Number: 
NCT02026063 
Document Date: 
SAP Amendment/Version 1: 24 November 2014 
 
 


16.1.9
Documentation of statistical methods 
Statistical Analysis Plan Amendment 1 dated 24Nov2014*
Note to File dated 03Nov2015: Calculation of Extent of Exposure for Open Label Studies 
Revised Note to File dated 03Nov2015: Calculation of Extent of Exposure for Open Label 
Studies 
Note to File dated 23Nov2015: Handling of the Week 84/End of Study (EOS) Efficacy Data 
in the Statistical Analysis for Patients who Discontinued from the Study Prior to Week 84 
Note to File dated 23Nov2015: Race Information for Patient 
from 
LX1606.302 
Note to File dated 30Nov2015: Baseline Data for 302
Note to File dated 05Feb2016: Subject Numbers from Phase II Studies
Note to File dated 05Feb2016: Correcting Error in SAP Regarding Scoring Algorithm for
GI.NET21 Scales and Single Items
* Excludes SAP attachments 1-3, which were for review purposes only.
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8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
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8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
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8800 Technology Forest Pl. 
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CONFIDENTIAL 
FINAL 24 February 2016
Page 3
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 4
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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CONFIDENTIAL 
FINAL 24 February 2016
Page 5
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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8800 Technology Forest Pl. 
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CONFIDENTIAL 
FINAL 24 February 2016
Page 6
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 7
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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CONFIDENTIAL 
FINAL 24 February 2016
Page 8
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 9
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 10
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 11
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 12
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 13
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 14
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 15
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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Baseline Day 
11
Week 12
Week 24
Week 36
Week 48
Week 60
Week 72
Week 84 /
EOS
Tolerance (days)
NA
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
Inclusion/Exclusion criteria
X
Medical history
X
Physical examination incl. weight
X
X3
X3
X3
X
X3
X3
X
 X5
Urine pregnancy test2
X
X
X
X
X
X
X
X
X
Hematology, Blood chemistry
X
X
X
X
X
X
X
X
 X5
Urinalysis
X
X
X
 X5
Chromogranin A
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
ECG
X
X
X
 X5
Subjective Global Assessment
X
X
X
X
X
X
X
X
X
EORTC QLQ-C30 & GI.NET21
X
X
X
X
X
Sleep and Depression Assessment
X
X
X
X
X
X
X
X
X
Plasma 5-HIAA
X
X
X
X
X
X
X
X
X
Dispensation of LX1606
X
X
X
X
X
X
X
 
Concomitant medications
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
Procedure
Extension Period
2-Week 
Follow-up4
1Eligibility will be determined at last visit of the original protocol; Day 1 will replace the next scheduled visit in the original protocol schedule. Visits 
should coincide with LAR injections for those patients receiving SSA therapy. 2Females of child-bearing potential only. 3Brief physical examination only 
(symptom-oriented, including weight). 4Visit to be performed for subjects who withdraw early and will not return for a 2-week follow-up visit; in all other 
cases the EOS visit should be performed followed by the follow-up visit 2 weeks postdose. 5To be performed only if evaluation at Week 84/EOS is 
abnormal. 

Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 16
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 17
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 18
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 19
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 20
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 21
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 22
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 23
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 24
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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8800 Technology Forest Pl. 
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CONFIDENTIAL 
FINAL 24 February 2016
Page 25
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 26
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 27
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 28
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 29
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 30
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 31
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 32
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 33
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 34
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 35
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 36
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 37
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 38
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 39
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 40
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 41
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


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Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 42
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 43
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 44
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 45
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 46
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 47
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 48
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 49
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 50
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS


Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Pl. 
The Woodlands, TX 77381-1160
CONFIDENTIAL 
FINAL 24 February 2016
Page 51
INTERIM CLINICAL STUDY REPORT 
LX1606.1-302-CS