An Observational Study to Evaluate the Real-world Experience of Patients Who Are Initiating Treatment With Telotristat Ethyl (XERMELO™)
Conditions: Carcinoid Syndrome
Sponsor: TerSera Therapeutics LLC

 
Title:   An Observational Study to Evaluate the Real-world Experience of Patients who 
are Initiating Treatment with Telotristat Ethyl (XERMELOTM) 
 
 
NCT Number: 03223428  
 
Protocol Approval Date:  06 January 2020  
 
Certain information within this protocol has been redacted (ie, Specific content is 
masked irreversibly from view with a black bar) to protect either personally 
identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
• Named persons or organizations associated with the study. 
 
• Proprietary information, such as scales or coding systems, which are 
considered confidential information under prior agreements with license 
holder. 
 
• Other information as needed to protect confidentiality of TerSera or 
partners, personal information, or to otherwise protect the integrity of the 
clinical study. 
 
The information contained in the following document is the property of TerSera 
Therapeutics LLC and should not be shared or used for any purpose other than for 
which it was provided. 
 
 

 
REGISTRY PROTOCOL 
Protocol Number: 
LX1606.1-401-CS 
LX1606.401 (Abbreviated number) 
Investigational Phase: 
4 
Protocol Title: 
An Observational Study to Evaluate the Real-world 
Experience of Patients who are Initiating Treatment with 
Telotristat Ethyl (XERMELO®) 
Study Name: 
Real-world Evidence Study EvaLuating PAtient-
Reported Outcomes with XERMELO (RELAX) 
 
 
Amendment 1 Date: 
06 January 2020 
Original Version Date: 
19 May 2017 
 
 
Sponsor: 
Lexicon Pharmaceuticals, Inc. 
 
 
Medical Director: 
  
EVP and CMO 
Lexicon Pharmaceuticals, Inc. 
 
 
SIGN

 
XERMELO Protocol No. LX1606.401 A1 
 
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Investigator Signature Page 
Protocol Number: 
LX1606.1-401-CS 
Protocol Title: 
An Observational Study to Evaluate the Real-world 
Experience of Patients who are Initiating Treatment with 
Telotristat Ethyl (XERMELO®) 
Amendment 1 Date: 
06 January 2020 
Original Version Date: 
19 May 2017 
Sponsor: 
Lexicon Pharmaceuticals, Inc. 
 
 
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 Council for 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 US Food and Drug Administration (FDA) or other 
applicable regulatory agencies, before they can be implemented, except where necessary to 
eliminate hazards to participants. 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
 
 
 
 
Principal Investigator’ Name (Print) 
 
 
 
 
Lexicon Executive Vice President and Chief Medical Officer 
(Signature) 
 
Date 
 
 
Lexicon Executive Vice President and Chief Medical Officer  
 
 
 
 

 
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1. 
Synopsis 
Name of Study Drug 
Telotristat ethyl (XERMELO®) 
Protocol Number 
LX1606.1-401-CS 
LX1606.401 (Abbreviated number) 
Protocol Title  
 
An Observational Study to Evaluate the Real-world Experience of 
Patients who are Initiating Treatment with Telotristat Ethyl 
(XERMELO) 
Primary Objective 
The primary objective of the study is to estimate the proportion of 
carcinoid syndrome (CS) patients who are satisfied with their overall 
symptom control, 6 months after initiating treatment with telotristat 
ethyl (XERMELO). 
Secondary Objective 
The following secondary objectives will be assessed 6 months after 
initiating treatment with telotristat ethyl (XERMELO): 
• 
To estimate the proportion of patients reporting satisfaction 
of CS- related diarrhea control  
• 
To estimate proportion of patients reporting satisfaction of 
CS- related flushing control 
• 
To estimate the proportion of patients reporting reduction in 
rescue somatostatin analog (SSA) use  
• 
To estimate the proportion of patients reporting reduction in 
the dose of long-acting SSA injection 
• 
To estimate the proportion of patients reporting reduction in 
the frequency of long-acting SSA injection 
• 
To estimate the proportion of patients reporting an overall 
improvement in CS control after initiating XERMELO based 
on patient global impression of change (PGIC) 
• 
To estimate the proportion of patients that had a reduction in 
work-related absenteeism, presenteeism, activity impairment, 
and overall productivity loss after initiating XERMELO 
based on Worker Productivity and Activity Impairment: 
Specific Health Problem v2.0 (WPAI- SHP) 
• 
To estimate the proportion of patients reporting weight gain 
Exploratory Objectives 
 
  
Phase of Development 
4 

 
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Methodology 
 
This observational, noninterventional, single-arm study will include 
patients with CS and who are initiating treatment with XERMELO. 
Patients will be asked to complete up to 7 web-based surveys 
including a Baseline assessment and then every 6 months for a total 
of up to 3 years. Each survey is anticipated to take no more than 20 
minutes on average. All assessments, except mortality, will be 
patient-reported; medical records will not routinely be requested or 
reviewed as part of this observational study unless required for 
safety reporting purposes. 
XERMELO prescription fill data will be collected directly from the 
specialty pharmacies, for all study patients that enter this study. 
Upon entering the study, patients will be asked to provide 
sociodemographic information, current medical history (specifically 
date of CS and neuroendocrine [NET] diagnosis, NET location, CS-
related hospitalization and/or ER visits, and NET-related surgery), 
height, weight, concomitant medications (specifically those related 
to SSA therapy, systemic therapy, and liver-directed therapy). In 
addition, patients will be asked to complete a work productivity and 
activity impairment (WPAI) assessment and describe satisfaction 
with CS, CS-related diarrhea and/or flushing prior to initiating 
treatment with XERMELO. 
Patients will complete a survey every 6 months, describing changes 
to previously reported data and/or new occurrence of pre-specified 
events.  
Data that may be collected at the 6 month time point includes 
changes in weight, concomitant medications (specifically those 
related to SSA therapy, systemic therapy, and liver-directed 
therapy), WPAI assessment, and satisfaction with CS, CS-related 
diarrhea and/or flushing following the initiation of treatment with 
XERMELO, as well as, new occurrence(s) of CS-related 
hospitalization and/or ER visit(s) will also be collected. 
Following the month 6 time point, long-term assessments are to 
include changes in weight, concomitant medications (specifically 
those related to SSA therapy, systemic therapy, and liver-directed 
therapy), as well as, new occurrence(s) of CS-related hospitalization 
and/or ER visit(s) will also be collected. 
Throughout the study information related to mortality will be 
collected through indirect sources. 
Number of Patients 
A minimum of 643 patients with CS who initiate treatment with 
XERMELO are expected to participate in this study.  
Patients 
Eligible patients are defined as adult patients (≥18 years) diagnosed 
with CS and initiating XERMELO as a new treatment. 

 
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Number of Study Sites 
2 
Treatments 
250-mg XERMELO tablet administered as directed 
Route of Administration 
Oral 
Duration of Participation 
Up to 3 years 
Inclusion Criteria 
Patients must meet all of the following criteria to be considered 
eligible to participate in the study: 
1. Adult, ≥18 years of age at the time of informed consent  
2. A new, valid prescription for XERMELO  
3. Initiating XERMELO for the treatment of carcinoid 
syndrome  
4. Able and willing to provide informed consent prior to 
participation in the study 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded 
from participating in the study: 
1. Unable to understand and read English 
2. Unable to access the internet 
3. Prior exposure to XERMELO 
Statistical Methods 
The analysis population is comprised of all patients who provide 
consent, are enrolled into the study, and have data available for 1 or 
more of the primary and secondary endpoints. Descriptive statistics 
will be used to summarize the data. Continuous and ordinal variables 
will be summarized by n, mean, standard deviation, median, 
minimum, and maximum values. Categorical variables will be 
summarized by patient counts and related percentages.  
Confidence limits (CLs) corresponding to point estimates of the 
proportions or means corresponding to the study endpoints will be 2-
sided and calculated with 95% confidence coefficient. Statistical 
tests will be 2-sided and have an associated α-level=0.05.  
For the primary endpoint, the proportion of CS patients who are at 
least somewhat satisfied with their overall symptom control at 6 
months, a point estimate and the corresponding 95% CLs will be 
calculated based on the assumption of approximate normal 
distribution. Secondarily, a point estimate and corresponding 95% 
CLs will be calculated for the proportion of CS patients who are very 
satisfied with their overall symptom control at 6 months.  
All the secondary endpoints correspond to proportions and will be 
summarized through point estimates and 95% CLs, as described 
above for the primary endpoint. In addition, for the primary and 
secondary endpoints, the frequency distributions of the categorical 

 
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responses and summary statistics of the corresponding ordinal values 
of the categories will be presented. 
 
The incidences of at least 1 CS-related hospitalization, at least 1 CS-
related ER visit, and mortality Baseline will  
be calculated at each 6-month interval. Kaplan-Meier estimates of 
each time-to-event variable, including quartiles, medians, and their 
corresponding 95% CLs, will be presented. The association or 
relationship between the primary endpoint and each long-term health 
outcome will be evaluated through descriptive statistics and the use 
of statistical models, as appropriate. 
Assessments 
Assessments include the following measures: patient satisfaction 
with CS, CS-related diarrhea and/or flushing control; PGIC; rescue 
SSA use; long-acting SSA dose and frequency; weight; productivity 
(WPAI-SHP); incidence of CS-related hospitalization(s), incidence 
of CS-related ER visit(s), and incidence of mortality. 
 

 
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Table of Contents 
1. 
Synopsis ............................................................................................................................. 3 
2. 
List of Abbreviations and Definitions of Terms ................................................................ 9 
3. 
Introduction ...................................................................................................................... 10 
3.1 
Background on Telotristat Ethyl (XERMELO®) and Carcinoid Syndrome (CS) ..... 10 
3.2 
Rationale for Current Study ...................................................................................... 13 
4. 
Study Objectives .............................................................................................................. 13 
4.1 
Primary Objective ..................................................................................................... 13 
4.2 
 Secondary Objective ................................................................................................ 13 
4.3 
Exploratory Objective(s) ........................................................................................... 14 
5. 
Investigational Plan .......................................................................................................... 14 
5.1 
Overall Study Design ................................................................................................ 14 
5.1.1 
Survey Conduct .................................................................................................. 16 
6. 
Study Population .............................................................................................................. 17 
6.1 
Inclusion Criteria ....................................................................................................... 18 
6.2 
Exclusion Criteria ...................................................................................................... 18 
6.3 
Criteria for Stopping/Study Withdrawal ................................................................... 18 
6.4 
Criteria for Termination of the Study ........................................................................ 18 
7. 
Treatment ......................................................................................................................... 19 
7.1 
Telotristat Ethyl (XERMELO) .................................................................................. 19 
7.2 
Prior and Concomitant Medications .......................................................................... 19 
7.2.1 
Prior Medications ............................................................................................... 19 
7.2.2 
Concomitant Medications .................................................................................. 19 
7.3 
Prohibited Medications or Concomitant Therapy ..................................................... 19 
8. 
Study Procedures ............................................................................................................. 20 
8.1 
Restrictions during Study .......................................................................................... 20 
8.2 
Description of Study Assessments ............................................................................ 20 
8.2.1 
Assessments ....................................................................................................... 20 
8.2.2 
Other Assessments ............................................................................................. 21 
8.3 
Prescription Fill Data ................................................................................................ 22 
8.4 
Appropriateness of Assessments ............................................................................... 22 
9. 
Safety Reporting .............................................................................................................. 22 

 
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9.1 
Adverse Events .......................................................................................................... 22 
9.2  
Definition of an Adverse Event ................................................................................. 23 
9.3 
Assessment of Adverse Events ................................................................................. 23 
9.4  
Follow-up of Adverse Events .................................................................................... 24 
9.5 
Special Situations ...................................................................................................... 24 
9.5.1 
Pregnancy ........................................................................................................... 24 
10. 
Statistical Methodology ................................................................................................ 24 
10.1 
Determination of Sample Size ............................................................................... 24 
10.2 
Analysis Populations ............................................................................................. 25 
10.3 
Study Endpoints ..................................................................................................... 25 
10.3.1 Primary and Secondary Endpoints ..................................................................... 25 
10.3.2 Other Endpoints ................................................................................................. 26 
10.4 
Statistical Methods ................................................................................................ 26 
10.4.1 Analyses of Study Endpoints ............................................................................. 27 
10.4.2 Safety Analyses .................................................................................................. 28 
10.4.3 Baseline Characteristics and Other Summaries ................................................. 28 
10.4.4 Interim Analysis ................................................................................................. 28 
11. 
Study Management ....................................................................................................... 28 
11.1 
Monitoring ............................................................................................................. 29 
11.2 
Protocol Deviations ............................................................................................... 29 
11.3 
Audits and Inspections........................................................................................... 29 
11.4 
Amendments .......................................................................................................... 30 
11.5  
Record Keeping ..................................................................................................... 33 
11.5.1 Health Insurance Portability Accountability Act of 1996 and Subsequent 
Updates 33 
11.5.2 Access to Original Records ................................................................................ 34 
11.5.3 Retention of Study Documents .......................................................................... 34 
12. 
Administrative Structure of the Study .......................................................................... 34 
13. 
Appendix A – Schedule of Events ................................................................................ 35 
14. 
Appendix B – Ethical Standards ................................................................................... 36 
15. 
Appendix C – Investigator Obligations ........................................................................ 38 
16. 
Appendix D – Work Productivity and Activity Impairment Questionnaire: ................ 42 
17. 
References ..................................................................................................................... 44 

 
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2. 
List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
AE 
adverse event 
BM 
bowel movement 
CFR 
Code of Federal Regulations 
CL 
confidence limit 
CS 
carcinoid syndrome 
e-mail 
electronic mail 
ER 
emergency room 
ERC 
Ethics Review Committee 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GINA 
Genetic Information Nondiscrimination Act 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Council for Harmonisation 
ID 
Identification 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
INCA 
International Neuroendocrine Cancer Alliance 
LAR 
long-acting release 
NET 
neuroendocrine tumor 
NRI 
non-responder imputation 
PGIC 
Patient Global Impression of Change 
RTI 
Research Triangle Institute 
SAP 
Statistical Analysis Plan 
SSA 
somatostatin analog 
TPH 
tryptophan hydroxylase 
US 
United States 
u5-HIAA 
urinary 5-hydroxyindoleacetic acid 
WPAI-SHP 
Work Productivity and Activity Impairment – Specific Health 
Problem 
 
 

 
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3. 
Introduction 
3.1 
Background on Telotristat Ethyl (XERMELO®) and Carcinoid Syndrome 
(CS) 
Well differentiated neuroendocrine tumor (NET), formerly known as carcinoid tumor, is a 
relatively rare tumor type that arises from cells of the neuroendocrine system (Kulke, 2011; 
Turaga, 2011; Yao 2008).  
Carcinoid syndrome (CS) occurs when well differentiated NETs secrete large amounts of 
serotonin and other vasoactive products into the systemic circulation. By one estimate, CS 
develops in approximately 10% of adult patients with well differentiated NET and, with a 
few exceptions, only manifests itself in the presence of liver metastasis (Tomassetti, 2001). 
By another estimate, approximately 8% to 35% of patients with NET have associated CS, 
with tumors of the small intestine carrying the highest risk (Rorstad, 2005). Classically, 
symptoms associated with CS include flushing, diarrhea, wheezing, abdominal pain, and 
valvular heart disease, although, a variety of other symptoms can occur. Roughly 75% of 
patients with CS experience diarrhea, which can occur either with or without other 
manifestations of the syndrome, and has perhaps the most direct impact on activities of daily 
living (Moertel, 1987).  
Valvular heart disease has been associated with high serotonin levels (as measured by its 
metabolite, urinary 5-hydroxyindoleacetic acid [u5-HIAA]). Due to the slow growing nature 
of NETs and the prolonged course of disease, about 50% of patients with CS will eventually 
develop heart disease. Usually only metastatic NETs result in pathological changes to the 
heart as a result of the hypersecretion of vasoactive substances; in these cases, the 
development of cardiac pathology heralds a more precipitous decline in clinical course (Fox,  
2004; Gustafsson, 2008; Turaga, 2011).  
In epidemiological studies, high levels of u5-HIAA in patients with NETs have been 
associated with poor survival. van der Horst Schrivers, et al prospectively studied 76 patients 
with midgut well differentiated NETs (van der Horst Schrivers, 2007). Urine collected over a 
24 hour period every 3 months was tested for u5 HIAA levels. Patients with high u5-HIAA 
levels (>20 mmol/mol creatinine) had a median survival of 33 months compared with 90 
months for patients with a moderately high level (≤20 mmol/mol creatinine) (hazard 
ratio=3.33; 95% confidence limit [CL]: 1.66 6.66; p=0.001) (Turaga, 2011).  
Morbidity Associated with Carcinoid Syndrome 
For the patient with CS, severe diarrhea can lead to weight loss, electrolyte imbalance, 
malnutrition, and anxiety often resulting in social isolation. In a study of health-related 

 
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quality of life (QOL) using the European Organisation for Research and Treatment of Cancer 
(EORTC) Quality of Life Questionnaire (QLQ) C30 (version 3.0), patients with CS in 
Sweden reported a lower health-related QOL than the Swedish general population. A 
majority of patients reported higher levels of emotional distress, fatigue, and diarrhea, as well 
as worries about their prognosis, their families, and medical examinations (Fröjd, 2007). 
Issues with flushing, an intense reddening of the skin, produce considerable discomfort and 
impair social function. A higher bowel movement (BM) frequency is strongly associated with 
more reports of fatigue, sleep disturbance, anxiety, depression, pain, and worsening social 
and physical function. In a cross-sectional survey, undesirable associations were observed 
between a high number of BMs/day and domains including physical function, anxiety, 
depression, fatigue, pain impact, sleep disturbance, and social role, suggesting that a 
reduction in BMs could lead to a much better quality of  life (Beaumont, 2012; Turaga, 
2011).  
The burden of symptoms associated with CS has been recently described in a global survey 
of 1,928 patients with NET (International Neuroendocrine Cancer Alliance [INCA], 2014; 
Turaga, 2011). According to the president of the INCA, the survey “...confirms for us the 
devastating impact this rare cancer can have on patients’ lives”. Diarrhea and flushing were 
prominent issues for patients in the survey. The majority of patients (92%) reported a lifestyle 
change as a result of their neuroendocrine cancer and 60% reported a negative effect on their 
emotional health. Patients commonly reported that their cancer led them to stop or to cut back 
on physical activity (49%) or on social life (43%). 
Available Treatment Options 
Somatostatin analogs (SSAs), like lanreotide and octreotide, are the cornerstone of therapy 
for the relief of CS and tumor stasis. Somatostatin analogs inhibit the release of serotonin by 
NETs and have become first line therapy for CS providing the most efficient treatment for the 
control of flushing, diarrhea, and other symptoms (Modlin, 2010).  
Common side effects of SSAs are back pain, fatigue, headache, abdominal pain, nausea, and 
dizziness. Other side effects identified include biliary tract abnormalities (jaundice, 
gallstones, sludge, and dilatation), hyper- or hypoglycemia, hypothyroidism, and cardiac 
changes (sinus bradycardia, conduction abnormalities, and arrhythmias) (Novartis 
Pharmaceuticals Corp., Sandostatin® LAR Depot package insert, 2016).  
Recently, results from the PROMID and CLARINET studies demonstrated the 
antiproliferative effects of octreotide and lanreotide autogel® (Caplin, 2014; Rinke, 2009). 

 
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Therefore, use of SSAs to reduce tumor proliferation has become increasingly common in the 
treatment paradigm for many patients with NET with or without symptoms.  
In a substantial number of NET patients with CS, a tachyphylaxis to SSA treatment may 
occur as soon as 1 week and as long as 12.5 months after starting therapy (Garland, 2003; 
Moertel, 1987), possibly due to desensitization of the SSAs’ effect on the somatostatin 
receptors (Hofland, 2003). This desensitization to SSAs may be overcome in some patients 
by increasing the dosage of SSA above the approved label; however, the efficacy and safety 
of higher doses is not yet established (Broder, 2015). Significant tumor progression might 
also contribute to the decrease in efficacy of SSAs over time. 
Patients whose symptoms are generally controlled using long-acting SSA therapy may 
require supplemental doses of short acting SSA therapy when symptoms become 
exacerbated. Results of a 93 patient study with octreotide indicate approximately 35% to 40% 
of the patients who received the long-acting release (LAR) Depot formulation still require 
supplemental subcutaneous (rescue) therapy to control exacerbation of CS symptoms. After 6 
months of treatment with octreotide, the number of patients requiring “rescue” doses 
increased to approximately 50% to 70% of patients. When a patient’s response to SSA 
therapy declines, it is accepted practice to continue SSA therapy while initiating additional 
treatments, including additional prescribed and over the counter medications (Oberg, 2004).  
Surgical debulking of tumors, radiation, various liver directed therapies, and chemotherapy 
may be attempted as a way of addressing overall tumor burden and reducing associated 
serotonin production (Kulke, 1999; Kulke, 2011; Öberg, 2012; Turaga, 2011).  
Scientific Background for Development of XERMELO 
Given the established role of serotonin in CS, inhibiting activity of tryptophan hydroxylase 
(TPH), the rate limiting enzyme responsible for the production of serotonin, should 
ameliorate symptoms and could perhaps avoid longer term disease sequelae.  
XERMELO is a tryptophan hydroxylase inhibitor indicated for the treatment of carcinoid 
syndrome diarrhea in combination with SSA therapy in adults inadequately controlled by 
SSA therapy. Through inhibition of tryptophan hydroxylase, XERMELO reduces the 
production of peripheral serotonin, and the frequency of carcinoid syndrome diarrhea 
(Lexicon Pharmaceuticals, Inc., XERMELO™ package insert, 2017).  

 
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3.2 
Rationale for Current Study 
This observational study will capture patient experience with XERMELO in a real-world 
setting. XERMELO is the first orally available drug to be indicated for the treatment of CS 
diarrhea.  
The clinical development program provided experience in more than 200 patients with CS 
and demonstrated statistically significant reductions in daily BM frequency, as well as an 
acceptable safety and tolerability profile. Data from 2 clinical studies, TELESTAR and 
TELECAST, support that the mechanism of action for XERMELO holds an important role in 
the treatment of CS. By reducing the production of peripheral serotonin, XERMELO is able 
to significantly reduce the frequency of CS diarrhea.  
Patient satisfaction with XERMELO was not thoroughly studied in the clinical program and 
is not readily available in medical records. Results of a 35-patient interview sub-study 
conducted in TELESTAR after 12 weeks of blinded treatment indicated that nearly all 
patients reporting reductions in BM frequency during the Double-blind Treatment Period 
described them as meaningful, allowing them to better enjoy life and participate more in 
social and physical activities. Among interview participants (n=33) answering the question 
about satisfaction with the ability of the blinded study drug to treat CS, 50% of patients 
(12/24) on active treatment reported “very satisfied” while 0 patients in the placebo group 
reported the same term. The Sponsor assumes that satisfied patients will continue 
XERMELO to avoid the complications of CS, leading to better long-term outcomes (Lexicon 
Pharmaceuticals, Inc., Clinical Study Report, 2017).  
Real-world experience with pharmaceutical products may only be evaluated once the product 
is available within the marketplace. In capturing patient experience, this study will also assess 
the patient journey though medical diagnosis of NET and treatment for CS in the clinical 
setting. 
4. 
Study Objectives 
4.1 
Primary Objective 
The primary objective of the study is to estimate the proportion of CS patients who are 
satisfied with their overall symptom control, 6 months after initiating treatment with 
telotristat ethyl (XERMELO).  
4.2 
 Secondary Objective 
The following secondary objectives will be assessed 6 months after initiating treatment with 
telotristat ethyl (XERMELO): 

 
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• 
To estimate the proportion of patients reporting satisfaction of CS-related diarrhea 
control  
• 
To estimate proportion of patients reporting satisfaction of CS- related flushing 
control 
• 
To estimate the proportion of patients reporting reduction in rescue SSA use  
• 
To estimate the proportion of patients reporting reduction in the dose of long-acting 
SSA injection 
• 
To estimate the proportion of patients reporting reduction in the frequency of long-
acting SSA injection 
• 
To estimate the proportion of patients reporting an overall improvement in CS control 
after initiating XERMELO based on patient global impression of change (PGIC) 
• 
To estimate the proportion of patients that had reduction in in work-related 
absenteeism, presenteeism, activity impairment, and overall productivity loss after 
initiating XERMELO based on Worker Productivity and Activity Impairment: 
Specific Health Problem v2.0 (WPAI- SHP) 
• 
To estimate the proportion of patients reporting weight gain 
4.3 
Exploratory Objective(s) 
 
 
  
5. 
Investigational Plan 
5.1 
Overall Study Design 
In this study, the 2 specialty pharmacies, tasked with distributing XERMELO to patients, will 
be responsible for the identification and recruitment of patients. All eligible patients initiating 
treatment with XERMELO will be invited to participate in this study.  
Individuals assigned by the specialty pharmacies (the ‘site staff’) will be responsible for 
describing the study to patients. An initial verbal consent will be obtained to collect personal 
contact information and to share it with the 
and/or Research Triangle Institute 
(RTI) (collectively, the ‘study team’) for the purpose of providing additional information 
about the study, collecting informed consent, and managing access and/or support for the 
web-based survey.  

 
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The specialty pharmacies will send contact information to the study team, for patients who 
express interest in participation, via an approved method of communication noting the 
patient’s unique specialty pharmacy identification (ID) number, first name, phone number, 
electronic mail (e-mail) address, and preferred time of contact (eg, morning, mid-day, 
evening). For patients who do not provide consent for further contact, the specialty 
pharmacies will be asked to provide aggregate data to the study team including patient(s) age, 
sex, geographic region, insurance type, reason for refusal to participate, and total number of 
patients who refused to provide consent. 
As this study will be completed via an online survey and patients are to complete the 
enrollment process independently, electronic consent will be utilized for this study. 
Enrollment will be self-directed through a unique survey link sent directly to the patient’s e-
mail address. Each patient receiving an invitation to the survey will be assigned a numerical 
patient ID code; the patient ID will be assigned by the study team, based on a subject ID log 
at each specialty pharmacy. If successful enrollment is not logged within 30 days of the initial 
survey e-mail invitation or within 14 days of the subsequent survey e-mail invitations, the 
study team will make up to 3 attempts to contact the patient via e-mail and/or telephone to 
complete the enrollment process for study participation. The enrollment process and Baseline 
survey may be completed anytime within the 30-day window, at a time convenient for the 
patient.   
If the study team is unsuccessful in reaching the patient, the patient will be considered lost-
to-follow up and the study team will update the enrollment status as appropriate. 
Upon completion of the electronic consent and successful enrollment, the patient will be 
prompted to complete an online survey at Baseline, then every 6 months for a period of up to 
3 years. All surveys will be completed online, at the patient’s convenience, and in accordance 
with Appendix A. The study team will provide technical support and reminder prompts, as 
described above, throughout the duration of participation.  
At any time after Baseline, if the study team is unable to reach a patient after 3 attempts and 
the patient does not complete the survey within the prespecified window, the patient will be 
considered lost-to-follow up and the study team will disable the patient’s unique study link as 
appropriate. Awareness by the specialty pharmacy of any change in the patient’s status (ie, 
withdrawal of consent, treatment discontinuation) must be communicated to the study team. 
Should the specialty pharmacy communicate a patient’s status change during the 3-year 
Follow-up Period, the study team will disable the patient’s unique study link upon 
notification and no further survey invitations or reminders will be triggered.  

 
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Information regarding a patient’s initial prescription and refill(s) will also be collected from 
the specialty pharmacies for all enrolled patients.  
5.1.1 
Survey Conduct 
An electronic consent and survey questionnaire approved by an Institutional Review Board 
(IRB) will be used by RTI to program the online survey for the purpose of standardizing 
responses among patients.  
Each patient will complete up to 7 web-based surveys over the duration of the study. Each 
survey is anticipated to take no more than 20 minutes on average.  
All assessments, except mortality, will be patient-reported; medical records will not routinely 
be requested or reviewed as part of this observational study unless required for safety 
reporting purposes. As patient recall over time may be limited, partial responses as in the case 
of dates of onset, and/or estimates of numerical information will be accepted. 
Participation in the study is contingent on continued use of XERMELO. Each survey will 
establish ongoing treatment with XERMELO and continued consent to study participation 
prior to subsequent data collection.  
The initial survey is intended to gather Baseline information, which may include: 
• 
Sociodemographics (age, year of birth, sex, race, ethnicity, education, geographic 
region) 
• 
Current medical history as it relates to CS, NET burden, NET location, and related 
conditions 
o Location of NET 
o Date of diagnosis; CS and NET 
o CS-related hospitalization(s)  
o CS-related ER visit(s) 
o NET-related surgery (eg, tumor debulking, lysis of adhesions) 
• 
Satisfaction with CS, CS-related diarrhea and/or flushing control prior to starting 
XERMELO, where applicable 
• 
Height and weight 
• 
Concomitant medication as it relates to the following: 
o Long-acting SSA therapy  

 
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o Use of rescue medication - short-acting SSA 
o Systemic tumor-directed therapy 
o Liver-directed therapy (eg, chemoembolization) 
• 
WPAI-SHP 
The initial survey should be completed no later than 30 days, and subsequent surveys should 
be completed no later than 14 days, after the unique survey link has been provided to the 
patient via e-mail. Patients will be asked to complete a survey every 6 months for up to 3 
years. The following patient-reported data may be collected as described in Appendix A:  
• 
Satisfaction with CS, CS-related diarrhea and/or flushing control after initiating 
XERMELO, where applicable 
• 
PGIC 
• 
Concomitant medication as it relates to the following: 
o Change in use of rescue medication - short-acting SSA 
o Change in long-acting SSA therapy  
o Systemic tumor-directed therapy 
o Liver-directed therapy (eg, chemoembolization) 
• 
Change in weight 
• 
WPAI-SHP 
• 
Incidence of CS-related hospitalization(s)  
• 
Incidence of CS-related ER visit(s) 
The incidence of mortality will be tracked indirectly based upon information received by RTI 
through secondary sources of information (eg, available pharmacy records). 
6. 
Study Population 
This observational, noninterventional, single-arm study will include patients with CS and 
who are initiating treatment with XERMELO.  
The recruitment period was anticipated to be approximately 18 months from first patient 
enrolled; however, due to slow enrollment, the recruitment period has been extended to 6 
months before data collection end. Each patient will be followed for up to 3 years; the last 
patient enrolled will be eligible to complete a Baseline survey and the first 6 month survey. 

 
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6.1 
Inclusion Criteria 
Patients must meet all of the following criteria to be considered eligible to participate in the 
study: 
1. Adult, ≥18 years of age at the time of informed consent 
2. A new, valid prescription for XERMELO  
3. Initiating XERMELO for the treatment of carcinoid syndrome  
4. Able and willing to provide informed consent prior to participation in the study 
6.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participating in the 
study: 
1. Unable to understand and read English 
2. Unable to access the internet 
3. Prior exposure to XERMELO 
6.3 
Criteria for Stopping/Study Withdrawal 
Study participation will continue for up to 3 years or until 
• 
withdrawal of consent by the patient or legal guardian 
• 
the patient is lost-to-follow-up 
• 
death 
• 
data collection ends 
A patient may also be discontinued from the study for the following medical or 
administrative reasons: 
• 
Noncompliance, including failure to adhere to the study requirements  
• 
The Sponsor terminates the study 
One missed survey completion in the period of 1 year will automatically withdraw the patient 
from the study, unless otherwise indicated the patient will be categorized as lost-to-follow up. 
6.4 
Criteria for Termination of the Study 
If the Sponsor or regulatory officials discover conditions arising during the study that indicate 
that the study should be halted or that a specialty pharmacy's participation in the study should 

 
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be terminated, action may be taken at the discretion of the Sponsor. 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 evaluation of the product 
• 
Failure to enroll patients into the study at an acceptable rate 
• 
Failure to comply with pertinent Food and Drug Administration (FDA) regulations 
• 
Submission of knowingly false information to the Sponsor, or the FDA 
• 
Insufficient adherence to protocol requirements  
Study termination and follow up would be performed in compliance with the conditions set 
forth in the following sections of the Code of Federal Regulations: 21 CFR 312.50 and 21 
CFR 312.56. 
7. 
Treatment 
7.1 
Telotristat Ethyl (XERMELO) 
Treatment with XERMELO 250-mg tablets is a requirement of this study. However, 
XERMELO will not be supplied to participants of this study. XERMELO is available by 
prescription and patients are expected to take XERMELO as directed by the prescribing 
physician. 
7.2 
Prior and Concomitant Medications 
7.2.1 
Prior Medications 
Information relating to SSA therapy, systemic tumor-directed therapy, and/or liver-directed 
therapy intended to treat NET, CS, individual symptoms, and/or related conditions taken by 
patients within 1 month of enrolling into the study will be collected. 
7.2.2 
Concomitant Medications 
Information relating to SSA therapy, systemic tumor-directed therapy, and/or liver-directed 
therapy intended to treat NET, CS, individual symptoms, and/or related conditions taken by 
patients during the study will be collected. 
7.3 
Prohibited Medications or Concomitant Therapy 
None  

 
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8. 
Study Procedures 
A schedule of study assessments is provided in Appendix A.  
8.1 
Restrictions during Study 
None  
8.2 
Description of Study Assessments 
8.2.1 
Assessments 
Assessments will include the following: satisfaction with CS control, CS-related diarrhea 
control and/or flushing control, PGIC, change in use of short-acting SSA as rescue 
medication, change in long-acting SSA dose or frequency, change in weight, incidence of 
CS-related hospitalization(s), incidence of CS-related ER visit(s), incidence of mortality, and 
WPAI-SHP.  
All responses will be collected electronically via a web-based survey in accordance with 
Appendix A. 
A description of the study assessments is provided below.  
8.2.1.1 
Satisfaction with Overall Carcinoid Syndrome Control, Carcinoid 
Syndrome-related Diarrhea Control, Carcinoid Syndrome-related 
Flushing Control 
Patient satisfaction with treatment prior to initiating XERMELO and satisfaction at the month 
6 interval will be assessed. 
8.2.1.2 
Rescue Short-Acting Somatostatin Analogs (SSAs) and Long-acting 
SSAs 
Beginning with the month 6 survey, patients will be asked to describe changes (ie, frequency, 
dosage) in the use of short and long-acting SSA therapy, where applicable, since initiating 
XERMELO.  
8.2.1.3 
Patient Global Impression of Change (PGIC) 
At the month 6 survey, patients will be asked to describe change in overall status since the 
start of treatment with XERMELO. 

 
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8.2.1.4 
Work Productivity and Activity Impairment – Specific Health 
Problem (WPAI-SHP) 
At Baseline and at month 6, patients will complete the WPAI-SHP questionnaire. The WPAI-
SHP has 6 items and yields 4 types of scores: (1) Absenteeism (work time missed); (2) 
Presenteeism (impairment at work / reduced on-the-job effectiveness); (3) Work productivity 
loss (overall work impairment / absenteeism plus presenteeism); and, (4) Activity 
impairment. WPAI-SHP outcomes are expressed as impairment percentages, with higher 
numbers indicating greater impairment and less productivity (ie, worse outcomes). 
8.2.1.5 
Change in Weight 
Beginning with the month 6 survey, patients will be asked to describe perceived changes in 
weight, where applicable.  
8.2.1.6 
Incidence of CS-related Hospitalizations and Emergency Room (ER) 
Visit 
The incidence of CS- related hospitalization and/or ER visits will be collected at Baseline and 
at each of the subsequent time points. Patients will be asked to provide additional 
information, including but not limited to the date(s), reason for each CS-related 
hospitalization or ER visit, action taken, outcome, dosage, and dose regimen of XERMELO.  
8.2.1.7 
Incidence of Mortality 
The incidence of mortality will be tracked indirectly based upon information received by 
RTI. 
8.2.2 
Other Assessments 
Additional information will include sociodemographic information, current medical history, 
height, weight, prior and concomitant medications, and prescription fill data. 
8.2.2.1 
 Sociodemographics 
Age, year of birth, sex, race, ethnicity, education, geographic region, and insurance type will 
be collected for all enrolled patients.  
Aggregate demographic information (eg, age, sex, geographic region, insurance type) for all 
patients invited to participate but chose to opt-out will be provided by the specialty 
pharmacies in a de-identified format.  
8.2.2.2 
Height and Weight 
Patient reported height and weight will be captured at Baseline. 

 
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8.2.2.3 
Current Medical History 
Patient-reported dates and diagnosis will be captured for all ongoing medical conditions 
related to CS, NET burden, and related conditions: 
• 
Location of NET 
• 
Date of diagnosis; CS and NET 
• 
NET-related surgery (eg, tumor debulking, lysis of adhesions) 
8.2.2.4 
Prior and Concomitant Medications 
Patients will be asked to provide information on the following taken within 1 month of study 
enrollment: 
• 
Long-acting SSA therapy 
• 
Use of rescue medication – short-acting SSA 
• 
Systemic tumor-directed therapy 
• 
Liver-directed therapy (eg, chemoembolization) 
Patients will be asked to provide an update on therapy usage every 6 months. 
8.3 
Prescription Fill Data 
Information regarding a patient’s initial prescription fill and subsequent refill(s) will be 
collected. 
8.4 
Appropriateness of Assessments 
The assessments used in this study conform to accepted standards for observational studies. 
9. 
Safety Reporting 
9.1 
Adverse Events 
This is an observational, noninterventional study assessing patients initiating treatment of 
XERMELO via web-based surveys. Given the indirect contact with patients, adverse event 
(AE) collection will be limited by the questions included in the survey.  
Explorative objectives of CS-related hospitalizations and CS-related ER visits will be 
reported as AEs.  All information will be captured as part of the web-based survey and will 
be reported to Sponsor using a format agreed by the Sponsor and RTI. Information related to 
these events will be patient reported, unless the event is designated by the Sponsor as 
requiring additional follow-up as described in Section 9.4. 

 
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The AEs will be forwarded by the study team to the Sponsor within 24 hours of the 
completion of a survey using the following e-mail address. 
E-mail address (in case of fax failure):
 
Patient mortality will be collected outside of this study as part of routine practice at the 
specialty pharmacies and will be received by the Sponsor on an ongoing basis as spontaneous 
reports and reported as such. These data will be reported in this study only as the study 
endpoint.  
In case where an AE is received outside of the web-based surveys by the study team, an AE 
Report form will be completed and sent to the Sponsor at the above e-mail address within 24 
hours of the study team’s awareness of the AE. 
Exposure (either maternal or paternal) to XERMELO during pregnancy, received either 
through or outside the web-based surveys, will be reported following the same process as that 
for the AEs, and additional information will be collected following the process described in 
Section 9.5.1. 
9.2  
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  
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. Anticipated day-to-day fluctuations of 
preexisting conditions that do not represent a clinically significant exacerbation or worsening 
need not be considered AEs. 
Medication error, overdose, misuse/abuse, and off-label use should also be reported and 
followed according to the same timeline and process as those for AEs. 
9.3 
Assessment of Adverse Events 
The Sponsor will be responsible for assessing AEs collected for seriousness, expectedness, 
and causality using standard definitions and categories for safety reporting purpose. 

 
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9.4  
Follow-up of Adverse Events 
For events designated by the Sponsor as requiring additional information, consent will be 
obtained from the patient for additional contact and access to medical records as applicable. 
The follow-up action will be directed by the Sponsor and carried out by the study team and/or 
site staff. All actions will be in accordance with local and/or federal reporting requirements.  
9.5 
Special Situations 
9.5.1 
Pregnancy 
Exposure of an embryo or infant to study medication during pregnancy or lactation (ie, in 
utero through either maternal exposure or transmission via semen following paternal 
exposure, or after birth via breast milk) should be reported and followed for the outcome of 
the pregnancy and/or development of the child, following the same timeline and process as 
those for AEs; see Section 9.1 for contact information. 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 Good Clinical 
Practice (GCP) and International Council for Harmonisation (ICH) guidelines and the 
Sponsor’s SOPs. Patients should report if they become pregnant or father a child within 30 
days after last dose of XERMELO.  
10. 
Statistical Methodology 
10.1 
Determination of Sample Size 
The sample size was derived by satisfying design assumptions for the primary study endpoint 
of proportion of CS patients who are satisfied with their overall symptom control, 6 months 
after initiating treatment with telotristat ethyl (XERMELO). Of specific interest is the 
proportion of patients with CS who are at least somewhat satisfied with their control of CS at 
6 months, defined as those patients with a response of either “very satisfied” or “somewhat 
satisfied”. 
 where 
 
 
Two-sided 95% confidence limits 
(CLs) will be calculated for this proportion using normal approximation. 
 
 
 
 
 
 
hen a minimum of N=643 patients with CS, 

 
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who initiate treatment with XERMELO, should be entered into the study. Table 10.1-1 shows 
precision estimates with the expected 95% confidence intervals (CIs) assuming various 
combinations of sample size. 
Table 10.1-1: Expected 95% Confidence Intervals 
Sample 
size 
Estimated 
proportion 
Sides 
on 
CI 
LCL 
(Exact) 
UCL 
(Exact) 
Width of 
exact 
interval 
LCL 
(Wald) 
UCL 
(Wald) 
Width of 
Wald 
interval 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.2 
Analysis Populations 
The analysis population is comprised of all patients who provide consent, are enrolled into 
the study, and have data available for 1 or more of the primary and secondary endpoints. 
10.3 
Study Endpoints 
10.3.1 
Primary and Secondary Endpoints 
The primary study endpoint is the proportion of CS patients who are satisfied with their 
overall symptom control, 6 months after initiation of treatment with telotristat ethyl 
(XERMELO).  
Secondary endpoints include the following outcomes, assessed at 6 months among patients 
with CS after initiation of treatment with telotristat ethyl (XERMELO): 
• 
Proportion of patients reporting satisfaction of CS-related diarrhea control  
• 
Proportion of patients reporting satisfaction of CS-related flushing control 

 
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• 
Proportion of patients reporting reduction in rescue SSA use  
• 
Proportion of patients reporting reduction in the dose of long-acting SSA injection 
• 
Proportion of patients reporting reduction in the frequency of long-acting SSA 
injection  
• 
Proportion of patients reporting an overall improvement in CS control after initiating 
XERMELO based on PGIC 
• 
Proportion of patients that had improvement reduction in work-related absenteeism, 
presenteeism activity impairment, and overall productivity loss after initiating 
XERMELO based on WPAI- SHP 
• 
Proportion of patients reporting weight gain 
10.3.2 
Other Endpoints 
Other endpoints include incidence of CS-related hospitalizations, incidence of CS-related ER 
visits, and incidence of mortality at 6-month intervals for up to 3 years after initiation of 
treatment with XERMELO. 
10.4 
Statistical Methods 
Descriptive statistics will be used to summarize the data. Continuous and ordinal variables 
will be summarized by n, mean, standard deviation, median, minimum, and maximum values. 
Categorical variables will be summarized by patient counts and related percentages. 
Summaries will be by study time point, as applicable.  
Confidence limits corresponding to point estimates of the proportions or means 
corresponding to the study endpoints will be 2-sided and calculated with 95% confidence 
coefficient. Statistical tests will be 2-sided and have an associated α-level=0.05. As there is 
no specified hierarchy for the statistical tests and a potentially large number of tests may be 
performed without adjustments for multiplicity, the p-values from these tests will be 
considered descriptive rather than inferential. 
All data will be provided in by-patient listings. 
A more detailed description of the analysis and reporting of data will be provided in a 
Statistical Analysis Plan (SAP). An overview of the main analysis strategy is provided in the 
following sections. 

 
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10.4.1 
Analyses of Study Endpoints 
For the primary endpoint, the proportion of CS patients who are at least somewhat satisfied 
with their overall symptom control at 6 months, a point estimate and the corresponding 95% 
CLs will be calculated. Secondarily, a point estimate and corresponding 95% CLs will be 
calculated for the proportion of CS patients who are very satisfied with their overall symptom 
control at 6 months. The 95% CLs will be unadjusted and based on the assumption of 
approximate normal distribution. Missing data will not be imputed in the main analysis of the 
primary endpoint. As a sensitivity analysis, a patient with a missing response at 6 months will 
be imputed as a non-responder. This approach corresponds to non-responder imputation.  
In addition to the point estimates and 95% CLs for the primary endpoint, the frequency 
distribution of the categorical responses, on a 5-point Likert scale, to patient satisfaction with 
overall symptom control at 6 months will be presented. The patient satisfaction measure will 
also be summarized as an ordinal variable with a value of 1 corresponding to “very 
dissatisfied” up to 5 corresponding to “very satisfied”. 
All the secondary endpoints correspond to proportions and will be summarized through point 
estimates and 95% CLs, as described above for the primary endpoint. Frequency distributions 
of the categorical responses and summary statistics of the corresponding ordinal values of the 
categories will be presented. The handling of patients with a response of “not applicable” to 
patient satisfaction with CS-related diarrhea control or patient satisfaction with CS-related 
flushing control in the analysis will be described in the SAP. 
The 4 WPAI-SHP scores at Baseline and month 6 will be summarized, as well as the change 
from Baseline to month 6.  
The incidences of at least 1 CS-related hospitalization, at least 1 CS-related ER visit, and 
mortality after Baseline will be calculated at each 6-month interval. Kaplan-Meier estimates 
of each time-to-event variable, including quartiles, medians, and their corresponding 95% 
CLs, will be presented. The association or relationship between the primary endpoint and 
each long-term health outcome will be evaluated through descriptive statistics and the use of 
statistical models, as appropriate. Any statistical models that will be used and the 
appropriateness and/or limitations of their use will be described in the SAP. 
For any other study endpoints assessed at 12 months and thereafter, descriptive statistics will 
be presented and 95% CLs will be calculated.  
Subgroup analyses of study endpoints based on categories of sociodemographics or clinical 
characteristics of patients may be performed, but will serve as exploratory assessments only. 

 
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10.4.2 
Safety Analyses 
10.4.2.1 
Adverse Events 
Since AEs will not be actively solicited during the study, there are no planned 
summaries of AEs. Descriptions of AEs in the study report will be based on a medical 
review of the data reported in the AE Reporting forms. 
10.4.3 
Baseline Characteristics and Other Summaries 
Sociodemographics and clinical characteristics of patients collected at Baseline will be 
summarized through descriptive statistics. 
10.4.3.1 
Protocol Deviations 
Protocol deviations will be listed in the study report. 
10.4.4 
Interim Analysis 
The study may be analyzed and reported in multiple phases. Analyses will be conducted 
yearly upon the anniversary of the first patient’s initial survey completed for the purposes of 
summarizing available data.  
In addition, an analysis will be performed after the last patient completes the Baseline 
assessments in order to assess the baseline burden of patients initiating XERMELO. A 
primary endpoint analysis will be performed after the last patient completes the online survey 
at 6 months and will include the analysis of the data corresponding to the primary and 
secondary endpoints at 6 months.  
Since the study is an observational, noninterventional, single-arm study, no statistical 
adjustments will be made to the results of any of the interim or final analysis. The reporting 
of data in multiple phases while the study is still ongoing may be taken as an interim analysis 
in terms of procedural efforts needed to summarize these data, but it will not serve as a means 
to modify the study conduct. 
11. 
Study Management 
The study will be conducted as described in Section 5. The study team will be responsible for 
maintaining adequate documentation as provided by the specialty pharmacies.  
Issues resulting from data reconciliation will be resolved according to standard data 
management practices in conjunction with the Sponsor and the study team. As survey data is 
patient-reported, no changes to the data will occur.  

 
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11.1 
Monitoring 
The Sponsor is responsible for ensuring the proper conduct of the study with regard to ethics, 
protocol adherence, operating 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 will contact the study team via visits, telephone calls, and/or letters in order to 
review study progress and address any concerns or questions regarding the study conduct. 
During these monitoring activities, the following aspects of study conduct will be carefully 
reviewed: informed consent of patients, patient recruitment, patient compliance with the 
study procedures, and AE documentation and reporting. Records pertaining to these aspects 
are expected to be kept current. 
All parties must make study data accessible to the Sponsor, to other authorized 
representatives of the Sponsor, and to regulatory inspectors 
11.2 
Protocol Deviations 
A protocol deviation is any noncompliance with the protocol, GCP, or other procedural 
requirements. The noncompliance may be either on the part of the participant, site staff, or 
the study team. As a result of deviations, corrective actions are to be developed and 
implemented promptly. 
It is the responsibility of the study team and/or site staff to use continuous vigilance to 
identify and report deviations within 3 working days of identification, or within 5 working 
days of the scheduled protocol-required activity. All deviations must be addressed in study 
source documents, and reported to the Sponsor. Protocol deviations must be sent to the local 
IRB as per their guidelines. All parties are responsible for knowing and adhering to their 
applicable IRB requirements. Further details about the handling of protocol deviations will be 
included in the study plans. 
11.3 
Audits and Inspections 
The Sponsor, regulatory authority, or IRB may visit the study team and/or the specialty 
pharmacies 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. 

 
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11.4 
Amendments 
Any amendments to the protocol will be written and approved by the Sponsor. All 
amendments must be submitted to the IRB 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 approval prior to administration to patients. Table 11.4-1 
summarizes the IRB submissions and approvals for the study to date. 

 
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Table 11.4-1: IRB Submissions and Approvals 
Submission 
Number 
Summary of Changes 
Date of 
Approval 
1 
Full study implementation 
07 June 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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11.5  
Record Keeping 
11.5.1 
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 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. 
The Department of Health and Human Services updated a final rule to modify HIPAA. The 
new rule has been in effect since 26 Mar 2013, and strengthens the privacy and security 
protection for individual’s health information; modify the rule for Breach Notification for 
Unsecured Protected Health Information (Breach Notification Rule) under the HITECH Act 
to address public comment received on the interim final rule; modify the HIPAA Privacy 
Rule to strengthen the privacy protections for genetic information by implementing section 
105 of Title I of the Genetic Information Nondiscrimination Act of 2008 (GINA); and make 
certain other modifications to the HIPAA Privacy, Security, Breach Notification, and 
Enforcement Rules (the HIPAA Rules) to improve their workability and effectiveness and to 
increase flexibility for and decrease burden on the regulated entities.  

 
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The full text of the rule can be found at: 
https://www.federalregister.gov/documents/2013/01/25/2013-01073/modifications-to-the-
hipaa-privacy-security-enforcement-and-breach-notification-rules-under-the 
11.5.2 
Access to Original Records 
It is an expectation of regulatory authorities that the Sponsor, 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. 
11.5.3 
Retention of Study Documents 
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: 
recruiting, data collection, data management, statistical analysis, and reporting. 

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13.
Appendix A – Schedule of Events
Baseline 
Follow-up Period 
Day 1 
6 months 
12 months 
18 months 
24 months 
30 months 
36 months 
Tolerance (days) 
+30
±14 
±14 
±14 
±14 
±14 
±14 
Informed consent 
X 
Review and assess entry criteria (Section 6.1 and 
Section 6.2) 
X 
Sociodemographics (Section 8.2.2.1) 
X 
Height and weight (Section 8.2.2.2) 
X 
Change in weight (Section8.2.1.5) 
X 
X 
X 
X 
X 
X 
Medical history: (Section 8.2.2.3) 
X 
•
Location of NET
X 
•
Date of diagnosis; CS/NET
X 
•
CS-related hospitalization and/or ER
visit
X 
•
NET-related surgery
X 
Satisfaction with CS control (Section 8.2.1.1) 0 
X 
X 
Satisfaction with CS-related diarrhea control 
(Section 8.2.1.1)
X 
X 
Satisfaction with CS-related flushing control 
(Section 8.2.1.1) 
X 
X 
Patient Global Impression of Change (PGIC) 
Section 8.2.1.3  
X 
Work Productivity and Activity Impairment – 
Specific Health Problem instrument (WPAI-SHP) 
Section 8.2.1.4 
X 
X 
Patient-reported CS-related hospitalization and 
emergency room visit (Section 8.2.1.6) 
X 
X 
X 
X 
X 
X 
X 
Review of Concomitant Medications: (Section 
8.2.2.4)  
X 
X 
X 
X 
X 
X 
X 
•
Rescue short-acting somatostatin
analogs (SSAs)
X 
X 
X 
X 
X 
X 
X 
•
Long-acting SSAs
X 
X 
X 
X 
X 
X 
X 
•
Systemic tumor-directed therapy
X 
X 
X 
X 
X 
X 
X 
•
Liver-directed therapy
X 
X 
X 
X 
X 
X 
X 

 
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14. 
Appendix B – 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(s); including 
updates or revisions: 
• 
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  
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, the Sponsor is responsible for the following: 

 
XERMELO Protocol No. LX1606.401 
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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, 
• 
ensuring that FDA and all participating Investigators are properly informed of significant 
new information regarding adverse effects or risks associated with the drug being studied. 

 
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15. 
Appendix C – Investigator Obligations 
Per Title 21 of the US Government Code of Federal Regulations (21 CFR) Parts 50 and 56, 
the study protocol and the final version of the patient informed consent form will be approved 
by the IRB/ERC before enrollment of any patients. The opinion of the IRB/ERC will be 
dated and given in writing.  
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 patients. 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 patient risk involved, but no less than once per year. 
Informed consent must be given freely and obtained from every patient prior to participation. 
The rights, safety, and well being of the participants 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 the Sponsor with their own curriculum vitae. 
Informed Consent 
Informed consent must be obtained from every patient before entry into this study. It must be 
given freely and not under duress. The participant must be allowed adequate time to consider 
the potential risks and benefits associated with their participation in the study.  
Consent must be documented by use of an IRB/ERC-approved method and in a manner 
consistent with the IRB/ERC approval expectations.  If, for any reason, patient risk is 
increased as the study progresses, the new information must be presented to the patient.  
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: 

 
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• 
A statement that the study involves research, an explanation of the purpose of the 
research and the expected duration of the patient’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 patient 
• 
A description of any benefits to the patient 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 patient 
• 
A statement describing the extent, if any, to which confidentiality of records identifying 
the patient will be maintained and noting the possibility that the FDA and 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 patient’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 patient is otherwise entitled, and that the patient 
may discontinue participation at any time without penalty or loss of benefits to which the 
patient 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 patient (or 
to the embryo or fetus, if the patient is or may become pregnant) which are currently 
unforeseeable 
• 
Anticipated circumstances under which the patient’s participation may be terminated by 
the Investigator without regard to the patient’s consent 
• 
Any additional costs the patient may incur from participation in the research 
• 
The consequences of a patient’s decision to withdraw from the research and procedures 
for orderly termination of participation by the patient 

 
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• 
A statement that significant new findings developed during the course of the research that 
may relate to the patient’s willingness to continue participation will be provided to the 
patient 
• 
The approximate number of patients 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. 
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 patient consent. 
Study Documentation 
The protocol and informed consent for this study, including advertisements used to recruit 
participants, must be reviewed and approved by an appropriate IRB/ERC prior to enrollment 
of participants 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 reevaluation and reapproval 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 may include: deviations from the 
protocol, the number and types of participants evaluated, the number of participants who 
discontinued (with reasons), results of the study, if known, and significant AEs, including 
deaths. 
 

 
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Study Files 
The Investigator is required to maintain complete and accurate study documentation in 
compliance with current GCP 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, Sponsor/Investigator correspondence, IRB/ERC correspondence, protocol and 
amendments, information regarding monitoring activities, patient records, and data queries. 
Confidentiality 
The anonymity of participating patients must be maintained. Patients will be identified by 
their year of birth and an assigned patient number on documents submitted to the Sponsor. 
Documents that may be submitted to the Sponsor and that identify the patient must be 
maintained in strict confidence, except to the extent necessary to allow auditing by the FDA 
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 patient, or the FDA) must be kept in confidence by the 
Investigator. 
 
 

 
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16. 
Appendix D
 
 
 
 
 
                   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
   
 
 
 
 
 
 
                                                  
 
 
 
 
 
 

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6)
 
   
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
                                                  
 
 
 
 
 

 
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17. 
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