TELEHEART: Telotristat Ethyl in a Heart Biomarker Study
Phase: PHASE3
Conditions: Locally Advanced Neuroendocrine Neoplasm, Metastatic Neuroendocrine Neoplasm
Sponsor: M.D. Anderson Cancer Center

 
 
 
 
Cover Page for Clinical Trials.gov 
 
Document: 
Results Data Entry Form 2019-1205 
 
OƯicial Study Title: 
TELEHEART: Telotristat Ethyl in a Heart Biomarker Study 
 
NCT Number: 
NCT04810091 
 
Document Date: 
December 11, 2025 

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TELEHEART: Telotristat Ethyl in a Heart Biomarker Study 
 
 
 
 
 
 
 
 
 
 
 
PI: Cezar Iliescu, MD 
 
 
 
 
 
Department of Cardiology 
The University of Texas, MD Anderson 
 
 
 
 
 
 
 
 

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Table of Contents 
1.0 
TITLE OF PROPOSED PROJECT:  TELEHEART: Telotristat Ethyl in a Heart Biomarker Study .............. 4 
2.0 
Objectives .......................................................................................................................................... 5 
3.0 
Background ....................................................................................................................................... 7 
3.1 
Purpose ......................................................................................................................................... 7 
3.2 
Historical Experience ..................................................................................................................... 7 
3.3 
Carcinoid Syndrome leading to Carcinoid Heart Disease: The role of Serotonin ......................... 7 
3.4 
Biomarkers in Carcinoid Heart Disease and Carcinoid Syndrome ................................................ 8 
3.5 
Cardiac Imaging in Carcinoid Disease and Carcinoid Heart Disease ............................................. 9 
3.6 
Proposed Therapy with Telotristat Ethyl (XERMELO) ................................................................. 10 
4.0 
Background and Drug Information ................................................................................................. 11 
4.1 
Background ................................................................................................................................. 11 
4.2 
Preclinical Pharmacology Studies ............................................................................................... 11 
4.3 
Preclinical Toxicology Studies ..................................................................................................... 11 
4.4 
Clinical Studies of telotristat ethyl in Humans ............................................................................ 11 
4.5 
Rationale for telotristat ethyl (XERMELO) in patients with Carcinoid ........................................ 11 
4.6 
Drug Product ............................................................................................................................... 12 
4.6.1 
Identity ................................................................................................................................ 12 
4.6.2 
Drug Product Supply ........................................................................................................... 12 
4.6.3 
Storage ................................................................................................................................ 12 
5.0 
Patient Eligibility ............................................................................................................................. 13 
5.1 
Inclusions .................................................................................................................................... 13 
5.2 
Exclusions .................................................................................................................................... 14 
6.0 
Treatment Plan ............................................................................................................................... 16 
6.1 
General ........................................................................................................................................ 16 
6.2 
Treatment Plan ........................................................................................................................... 16 
6.2.1 
Screening Criteria and Randomization plan ........................................................................ 16 
6.2.2 
Study Overview ................................................................................................................... 16 
6.2.3 
Treatment Arms .................................................................................................................. 17 
6.3 
Dose of Modifications of telotristat ethyl ................................................................................... 17 
6.3.1 
Definitions ........................................................................................................................... 17 
6.3.2 
Dose Adjustments for adverse events related to the study drug ....................................... 17 
6.3.3 
Recommended management for the following AEs ........................................................... 18 

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6.4 
Treatment Compliance ............................................................................................................... 18 
6.5 
Missed Doses .............................................................................................................................. 19 
6.6 
Duration of Therapy .................................................................................................................... 19 
6.7 
Prohibited and Restricted Therapies During and Prior to the Study .......................................... 19 
7.0 
Baseline Evaluation ......................................................................................................................... 20 
8.0 
Evaluation during Study .................................................................................................................. 22 
8.14 
Call schedule during study .......................................................................................................... 24 
9.0 
Criteria for response/change .......................................................................................................... 26 
9.1 
Biochemical response/change .................................................................................................... 26 
9.2 
Echocardiographic response ....................................................................................................... 26 
9.3 
Functional response/change ....................................................................................................... 26 
10.0 
Criteria for Removal from the Study ............................................................................................... 27 
11.0 
Statistical Consideration ................................................................................................................. 28 
11.1 
Sample Size Justification ............................................................................................................. 28 
11.2 
Statistical Analysis Plan ............................................................................................................... 28 
11.3 
Toxicity Monitoring ..................................................................................................................... 29 
12.0 
Reporting Requirements ................................................................................................................. 30 
12.1 
Adverse Event Reporting ............................................................................................................ 30 
12.2 
Serious Adverse Event Reporting (SAE) ...................................................................................... 34 
12.3 
Investigator Communication with Supporting Company ............................................................ 36 
12.4 
Reporting of External SAEs .......................................................................................................... 36 
12.5 
Follow-up of Adverse Events ....................................................................................................... 36 
13.0 
Budget ................................................................................................ Error! Bookmark not defined. 
13.1 
Total Product Supply Requirements .............................................. Error! Bookmark not defined. 
13.2 
Budget Justification ........................................................................ Error! Bookmark not defined. 
13.2.1 
Personnel Costs ...................................................................... Error! Bookmark not defined. 
13.2.2 
Direct Costs ............................................................................ Error! Bookmark not defined. 
13.2.3 
Indirect Costs ......................................................................... Error! Bookmark not defined. 
13.3 
Alternative Funding ........................................................................ Error! Bookmark not defined. 
14.0 
Publication Plan .................................................................................. Error! Bookmark not defined. 
15.0 
Appendix ......................................................................................................................................... 37 
16.0 
References ...................................................................................................................................... 41 

Page 4 of 42 
 
1.0 
TITLE OF PROPOSED PROJECT: TELEHEART: Telotristat Ethyl in a Heart 
Biomarker Study 
 
 
TOTAL PROJECT DURATION: 56 months 
 
 
EXPECTED START DATE: estimated to be 1/1/2021 
 
 
EXPECTED FINISH DATE: estimated to be 8/31/2025  

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2.0 
Objectives 
 
The purpose of the study is to evaluate the effect of telotristat ethyl (XERMELO) + 
somatostatin analog (SSA) (Treatment arm) versus placebo + SSA (standard of care 
arm) in patients with carcinoid syndrome and carcinoid heart disease. The study will be 
conducted in agreement with Good Clinical Practice guidelines and the Declaration of 
Helsinki and be submitted for approval to the MD Anderson Cancer Center IRB before 
initiation. 
 
 
Primary Objective: 
 
1. To estimate the percent change in NT-proBNP at 6 month visit from baseline 
after initiation of study drug in each arm and to compare the percent change 
between the two study arms. 
Secondary Objectives: 
 
1. To evaluate the change in functional capacity from baseline at 3 and 6 month 
visits as assessed by a 6 minute walk test (6MWT) in each arm 
2. To evaluate changes in echocardiographic parameters (CVHD score, global 
longitudinal myocardial strain assessment of the Left and right ventricle/TAPSE) 
from baseline to 3 and 6 month visits in each arm 
a. Carcinoid Valvular Heart Disease (CVHD) score is determined by 1) 
tricuspid valve appearance, 2) tricuspid regurgitation severity by either 
spectral pulsed wave or color Doppler flow mapping; 3) pulmonary 
stenosis severity by spectral pulsed or continuous wave Doppler, and 4) 
pulmonary insufficiency severity by color Doppler. (Denney et al. JACC 
1998) 
b. Global longitudinal myocardial strain assessment will be conducted using 
GE Vivid echocardiography machines in all studies. Significant change 
will be defined as a change in global longitudinal strain by 15%. 
c. TAPSE will be defined as normal (≥ 1.6cm) or abnormal (< 1.6cm) 

Page 6 of 42 
 
3. To evaluate the change from baseline to 3 and 6 month visits in Plasma 5- 
hydroxyindoleacetic Acid (5-HIAA) levels in each arm. 5-HIAA is a standard test 
used in clinical practice to assess neuroendocrine tumor (NET) activity. 
4. To evaluate the change from baseline to 3 and 6 month visits in high sensitivity 
troponin T in each arm 
5. To evaluate the change from baseline to 3 and 6 month visits in health related 
quality of life with using the MD Anderson Symptom Inventory (MDASI) in each 
arm 
6. To evaluate compliance of medications 
 
Primary endpoint: The percent change in NT-proBNP at 6 month visit from baseline 
 
 
Secondary Endpoints: 
 
1. The change in 6MWT from baseline at 3 and 6 months 
2. The change in CVHD score from baseline at 3 and 6 months , change (significant 
change or non-significant change) in global longitudinal myocardial strain 
assessment of the left and right ventricle from baseline at 3 and 6 months, change 
(normal or abnormal) in TAPSE from baseline at 3 and 6 months 
3. The change in plasma 5-HIAA levels from baseline at 3 and 6 months 
4. The change in high sensitivity troponin T from baseline at 3 and 6 months 
5. The change in quality of life questionnaire (using MD Anderson Symptom Inventory 
(MDASI)) from baseline at 3 and 6 months 
6. The proportion of patients maintaining at least 70% compliance 

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3.0 
Background 
 
 
3.1 
Purpose 
The basic hypothesis of our therapeutic programs in patients with carcinoid syndrome 
and carcinoid heart disease is to achieve meaningful and lasting symptom-improvement 
and look for responses to therapies that are associate with improved survival and 
favorable prognosis. 
 
 
3.2 
Historical Experience 
Our group has a keen interest in the prevention, detection, and treatment of patients with 
carcinoid syndrome and those who develop carcinoid heart disease. Being part of MD 
Anderson Cancer Center, we have the unique advantage of having a robust GI medical 
oncology group and cardiology group that interact together and care for a significant 
number of patients with carcinoid syndrome and carcinoid heart disease. Most of these 
patients are treated with somatostatin analogs (SSA) therapy, but a significant portion 
have uncontrolled symptoms or develop carcinoid heart disease where medical therapy 
is limited and morbidity and mortality is extremely high. 
 
 
3.3 
Carcinoid Syndrome leading to Carcinoid Heart Disease: The role of 
Serotonin 
 
Carcinoid tumors are rare neuroendocrine tumors (NETs) that can arise from 
enterochromaffin cells throughout the body. Some NETs are malignant and arise most 
commonly in the lung, rectum, and ileum (1). These malignant NETs metastasize to 
produce carcinoid syndrome. Patients with carcinoid syndrome present with vasomotor 
changes, diarrhea, hypotension, bronchospasm, and with carcinoid heart disease. 
A large portion of patients with carcinoid syndrome are thought to develop carcinoid 
heart disease. In fact, carcinoid heart disease is the initial presentation of carcinoid 
syndrome in up to 20% of patients and occurs in more than 50% percent of these 
patients (2, 3). 

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Carcinoid heart disease is a result of plaque-like deposits of fibrous tissue composed of 
smooth muscle cells, myofibroblasts, extracellular matrix, and an overlying endothelial 
layer. These fibrous deposits affect cardiac valves. This leads to stenosis and/or 
regurgitation of the valve, with regurgitation being more common.  Patients with 
carcinoid heart disease present with symptoms in the fifth to seventh decades of life (13- 
15). Because the clinical manifestations of this disease are subtle early in its course, 
diagnosis of carcinoid heart disease requires a high suspicion. In fact, in one study 37% 
of patients had no clinical signs of cardiac abnormalities by physical exam and 27% of 
patients with moderate to severe tricuspid regurgitation were in New York Heart 
Association class 1 (13). There is also a significant time lag from onset of symptoms to 
the diagnosis of this disease, ranging from 2 to 5 years before diagnosis is confirmed. 
Patients usually present with fatigue and dyspnea. In those with disease progression, 
right-sided heart failure occurs with edema, ascites, and dyspnea (16-18) 
It is believed that alterations in the metabolism of serotonin, its associated receptors, 
and a transporter gene are involved in the mechanisms of serotonin-induced carcinoid 
heart disease (4, 5). Furthermore, indirect evidence of higher serotonin levels in patients 
with known carcinoid heart disease than in patients without carcinoid heart disease 
points to a role for high serotonin levels as a likely contributor to the development of 
carcinoid heart disease (6-8). More recently, researchers have implicated roles for 
serotonin and 5-hydroxytryptamine receptors in the development of valve disease. The 
activation of 5-hydroxytryptamine 2B receptors via expression of the tyrosine kinase 
SRC and mediation by transforming growth factor B1 promotes myofibroblast deposition 
and infiltration and activation of valvular interstitial cells, leading to fibrosis of the valves 
(5, 9-12). 
 
 
3.4 
Biomarkers in Carcinoid Heart Disease and Carcinoid Syndrome 
 
 
While clinical signs maybe difficult to assess the role of the cardiac biomarkers has been 
studied and utilized in both patient with carcinoid heart disease and carcinoid syndrome. 
Patients with normal NT-proBNP levels have a better survival when they have carcinoid 
syndrome irrespective of whether or not they have carcinoid heart disease (17). 
Furthermore, NT-pro-BNP and 5-HIAA levels are independently associated with 

Page 9 of 42 
 
symptom status and mortality in patients with metastatic NETs and carcinoid heart 
disease (26). 
Patients with carcinoid heart disease in general have elevated NT-proBNP levels 
(Median 1,149 pg/ml vs 101 pg/ml) (18) highlighting the prognostic implications of this 
cardiac biomarker. Lastly, an NT-proBNP level cutoff of 260 pg/ml provides a high 
sensitivity (92%) and specificity (91%) to detect carcinoid heart disease (18). In fact this 
NT-ProBNP levels cutoff is being advocated in the Carcinoid Heart Disease expert 
statement for the screening and investigation of carcinoid heart disease (19). 
As serotonin levels are implicated in both carcinoid syndrome and carcinoid heart 
disease, urinary 5-HIAA levels are also associated with the disease. In fact, a Urinary 5- 
HIAA level of >300 μmol/24 hours is associated with a 2.74-fold increase of the 
development and progression of carcinoid heart disease (20). 
Furthermore, a novel echocardiographic technique, myocardial strain analysis, has some 
promising applications in patients with carcinoid disease. In a study using the RV free 
wall strain and tricuspid annular plane systolic excursion (TAPSE), it has been 
demonstrated that RV function is reduced in patients with intestinal carcinoid disease 
independent of obvious valvular involvement. This finding, in addition to the fact that 
patients with and without carcinoid heart disease showed slightly but significantly 
reduced LV global strain compared with healthy individuals, would suggest that that 
intestinal carcinoid disease may affect cardiac function before valvular involvement (25) 
and perhaps the possible role of serotonin in this process. 
 
 
3.5 
Cardiac Imaging in Carcinoid Disease and Carcinoid Heart Disease 
 
 
Echocardiography has been the mainstay of evaluation of patients with carcinoid heart 
disease and is in fact recommend as a screening and investigational tool (19). 
Furthermore, a novel echocardiographic technique, known as myocardial strain analysis 
has some promising applications in patients with carcinoid disease. In a study using the 
RV free wall strain and tricuspid annular plane systolic excursion (TAPSE), it has been 
demonstrated that RV function is reduced in patients with intestinal carcinoid disease 
independent of obvious valvular involvement. This finding, in addition to the fact that 
patients with and without carcinoid heart disease showed slightly but significantly 

Page 10 of 42 
 
reduced LV global strain compared with healthy individuals, would suggest that that 
intestinal carcinoid disease may affect cardiac function before valvular involvement (25) 
and perhaps the possible role of serotonin in this process. 
 
 
3.6 
Proposed Therapy with Telotristat Ethyl (XERMELO) 
 
 
In this trial, we propose to use of telotristat ethyl in patients with carcinoid syndrome and 
carcinoid heart disease. We know that 5-HIAA and serotonin are implicated in both 
carcinoid syndrome and carcinoid heart disease. We know that telotristat ethyl works 
with SSA therapy to reduce hormone overproduction and control carcinoid syndrome 
diarrhea. We also know that the cardiac biomarker NT-proBNP provides prognostic 
information in these patients. In this study we propose that by using telotristat ethyl in 
conjunction with a SSA versus SSA alone, that telotristat ethyl will have a positive effect 
on hormone production and will demonstrate biochemical response in patients with 
known carcinoid syndrome and/or carcinoid heart disease. 

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4.0 
Background and Drug Information 
 
4.1 
Background 
Telotristat etiprate is the United States Adopted Name (USAN) for the hippurate salt of 
telotristat ethyl, the ethyl ester prodrug of LP-778902. In vivo, telotristat etiprate 
dissociates to form telotristat ethyl which is rapidly converted through the activity of 
carboxylesterase 1and 2 to its active metabolite LP-778902. Telotristat ethyl 
(XERMELO) is a novel, oral, small-molecule tryptophan hydroxylase (TPH) inhibitor that 
has a high molecular weight and acidic moieties, which inhibits it from crossing the 
blood-brain barrier. Telotristat ethyl has been shown to lower serotonin (5-HT) levels 
system by inhibiting TPH. Through inhibition of TPH, Telotristat ethyl reduces the 
production of peripheral 5-HT and the frequency of CS diarrhea and has been FDA 
approved for the treatment of carcinoid syndrome diarrhea. Two studies in patients with 
carcinoid syndrome suggested that telotristat etiprate, the hippurate salt of telotristat 
ethyl, reduced bowel movement (BM) frequency and decreased urinary 5-HIAA without 
overt CNS adverse effects (27,28). Although the name “telotristat etiprate” was 
previously granted by the United States Adopted Names Council and has been used in 
the literature, recent guidance from the US Food and Drug Administration recommends 
using the name of the neutral form (telotristat ethyl) rather than the name of the salt for 
drug products. 
 
4.2 
Preclinical Pharmacology Studies 
Please refer to TerSera Therapeutics investigative brochure (IB) for details. Information 
in this proposal was derived from IB. 
 
 
4.3 
Preclinical Toxicology Studies 
Please refer to TerSera Therapeutics investigative brochure (IB) for details. 
 
 
4.4 
Clinical Studies of telotristat ethyl in Humans 
Please refer to TerSera Therapeutics investigative brochure (IB) for details 
 
 
 
4.5 
Rationale for telotristat ethyl (XERMELO) in patients with Carcinoid 

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Telotristat ethyl is indicated for the treatment of diarrhea in combination with SSA 
therapy in adults with inadequately controlled diarrhea on SSA therapy. This is thought 
to occur through the mediation of 5-HT. 5-HT is also implicated in the development of 
many of the signs and symptoms of carcinoid syndrome and carcinoid heart disease. A 
treatment which could further reduce 5-HT production may prove to be of immense 
clinical benefit. By adding a TPH inhibitor that can lower serotonin levels, telotristat ethyl 
could be of clinical benefit. One way to assess the potential of this clinical benefit is to 
look at the effect of telotristat ethyl on biomarkers such as NT-proBNP which have been 
associated with worsening cardiac prognosis. Furthermore, echocardiographic 
parameters and functional capacity changes can be clinically assessed. 
 
 
4.6 
Drug Product 
4.6.1 Identity 
Telotristat ethyl 250 mg and 500-mg tablets are white to off-white, coated, 
and oval. Placebo pills will be identical in size, shape, and color. 
 
4.6.2 
Drug Product Supply 
Tablets will be supplied by TerSera Therapeutics and will include 
TELOTRISTAT ETHYL 250 mg tablets. 
PLACEBO MATCHING 250 mg tablets. 
 
 
4.6.3 Storage 
 
 
Telotristat ethyl should be stored at 25°C (77°F); excursions are 
permitted 15°C to 30°C (59°F to 86°F). 

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5.0 
Patient Eligibility 
 
5.1 
Inclusions 
5.1.1 
Patients who are ≥18 years old will be eligible for the study. 
5.1.2 Histopathologically-confirmed, metastatic neuroendocrine tumor and/or 
locally/regionally advanced neuroendocrine tumor 
5.1.3 Documented history of carcinoid syndrome based on clinical parameters 
5.1.4 Currently receiving stable-dose somatostatin analog (SSA) therapy defined 
as ≥2 months 
5.1.4.1  dose of long-acting release (LAR) or depot SSA therapy and on 
at least: 
5.1.4.1.1 
Octreotide LAR at 30 mg every 4 weeks 
5.1.4.1.2 
Lanreotide Depot at 120 mg every 4 weeks 
5.1.4.1.3 
Patients who cannot tolerate SSA therapy at a level 
indicated above will be allowed to enter at their highest 
tolerated dose 
5.1.5 Ability and willingness to provide written informed consent 
5.1.6 Patients of childbearing potential must agree to use an adequate method of 
contraception during the study and for 30 days after the last dose of 
telotristat ethyl. 
5.1.6.1 a. Childbearing potential is defined as those who have not 
undergone surgical sterilization (eg. documented hysterectomy, 
tubal ligation, or bilateral salpingo-oophorectomy) or those who 
are not considered postmenopausal (defined as 12 months of 
spontaneous amenorrhea). 
5.1.6.2 b. Adequate methods of contraception, defined as having a failure 
rate of <1% per year, for patients or their partner include the 
following: condom with spermicidal gel, diaphragm with 
spermicidal gel, intrauterine device, surgical sterilization, 
vasectomy, oral contraceptive pill, depo-progesterone injections, 
progesterone implant (ie, Implanon®), patch (Ortho Evra®), 
NuvaRing®, and abstinence. If a patient is not sexually active but 
becomes active, he or his partner should use medically accepted 
forms of contraception. 
5.1.7 ECOG 0-2 

Page 14 of 42 
 
5.2 
Exclusions 
5.2.1 
Prior telotirstat exposure in the last 3 months 
5.2.2 History of active treatment for malignancy, other than neuroendocrine tumor 
(malignancies that in the opinion of the Investigator are considered cured, 
may participate) 
5.2.3 Treatment with any tumor directed therapy, including interferon, 
chemotherapy, mechanistic target of rapamycin (mTOR) inhibitors <4 
weeks prior to screening, or hepatic embolization, radiotherapy, peptide 
receptor radionuclide therapy, and/or tumor debulking <12 weeks prior to 
screening 
5.2.4 History of short bowel syndrome or other known causes of diarrhea 
unrelated to carcinoid syndrome 
5.2.5 Clinically significant (as per primary investigators judgement) cardiac 
arrhythmia, bradycardia, tachycardia that would compromise patient safety 
or the outcome of the study 
5.2.6 estimated glomerular filtration rate eGFR < 30ml/min 
5.2.7 Hepatic laboratory values of aspartate transaminase (AST) or alanine 
aminotransferase (ALT): 
5.2.7.1 a. >5 x upper limit of normal (ULN) if patient has documented 
history of hepatic metastases; or 
5.2.7.2 b. >2.5 x ULN if no liver metastases are present 
5.2.8 Pregnant or lactating patients 
5.2.9 Patients receiving everolimus due to poor response to SSA 
5.2.10 Life expectancy < 6 months 
5.2.11 Any other clinically significant laboratory abnormality that would 
compromise patient safety or the outcome of the study as per primary 
investigators judgement 
5.2.12 Any clinically significant and/or uncontrolled cardiac-related abnormality 
that would compromise patient safety or the outcome of the study including 
as per primary investigators judgement, but not limited to: 
5.2.12.1 
Arrhythmia causing hemodynamic compromise 
5.2.12.2 
Symptomatic severe valvular disease 
5.2.12.3 
Symptomatic congestive heart failure classified by New 
York Heart Association (NYHA) Class IV 

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5.2.12.4 
Evidence of ischemia on ECG with chest pain 
5.2.12.5 
Unstable angina pectoris 
5.2.13 Current complaints of persistent constipation or history of chronic 
constipation, bowel obstruction or fecaloma within the past 6 months 
5.2.14 Investigator assessment of known history and/or uncontrolled hepatitis B 
surface antigen (HBsAg), hepatitis C antibody (HCV Ab), or human 
immunodeficiency virus (HIV)-1 or HIV-2 
5.2.15 History of substance or alcohol abuse (Diagnostic and Statistical Manual of 
Mental Disorders 5th edition [DSM-V] Criteria for Substance-Related 
Disorders) within the past 2 years 
5.2.16 History of galactose intolerance, deficiency of Lapp lactase, or glucose- 
galactose malabsorption 
5.2.17 Receipt of any investigational agent or study treatment (other treatment nor 
approved by FDA for carcinoid syndrome or carcinoid heart disease) within 
the past 30 days 
5.2.18 Existence of any surgical or medical condition that, in the judgment of the 
Investigator, might compromise patient safety or the outcome of the study 
5.2.19 Presence of any clinically significant findings (relative to the patient 
population) during review of medical history or upon PE that, in the 
Investigator’s opinion, would compromise patient safety or the outcome of 
the study (eg, psychiatric illness/social situations that would limit 
compliance with study requirements) 
5.2.20 Unable or unwilling to communicate or cooperate with the Investigator for 
any reason 

Page 16 of 42 
 
6.0 
Treatment Plan 
 
6.1 
General 
All patients should be registered with the Data Management Office Prometheus 
system. 
 
 
6.2 
Treatment Plan 
Patients who present to the MD Anderson Cancer Center and have a confirmed 
diagnosis of carcinoid syndrome and/or carcinoid heart disease based on clinical, 
imaging, and/or expert physician diagnosis would be eligible for enrollment in the 
trial (see above for eligibility criteria). Patients will be referred directly from 
oncology clinic and/or by electronic medical record screening by the research 
team to determine eligibility. Patients would then be enrolled into one of 2 arms 
of the clinical trial in a stratified randomized, double-blinded fashion into a 
treatment arm (XERMELO + SSA) versus a placebo standard treatment arm 
(PLACEBO + SSA). A maximum of 79 participants will be recruited to participate 
in the study for 6 months. 
6.2.1 Screening Criteria and Randomization plan 
Written, Electronic, or Virtual informed consent will be obtained from all 
patients before beginning any study related screening procedures. The 
collection of adverse events will begin after patient has received his first 
dose of treatment. Participants will be allocated to one of two treatment 
arms by stratified block randomization method, considering age group 
(≤60 years vs. >60 years) and disease status (with vs. without Carcinoid 
heart disease) as stratifying factors using Clinical trial conduct website 
(https://biostatistics.mdanderson.org/ClinicalTrialConduct). 
 
6.2.2 Study Overview 
Study Type: 
Prospective Clinical Trial 
Enrollment: 
79 participants 
Allocation: 
Randomized 1: 1 
Intervention Model Description: Participants were randomized to one of 
two treatment arms by stratified randomization method. Those who were 
randomized to treatment arm would 
receive telotristat ethyl 500 mg po TID + SSA and those who were 
randomized to placebo arm would receive placebo + SSA 
Blinding: Double (Participant and Investigators) 

Page 17 of 42 
 
Primary Purpose: Treatment and disease progression 
6.2.3 Treatment Arms 
Treatment Arm: A 
Experimental: 500 mg Telotristat Ethyl (2 tablets of 250 mg) TID with 
meals + SSA Patients who are currently on stable-dose somatostatin 
analog (SSA) 
therapy (octreotide or lanreotide for 2 months) are randomized to receive 
one 500 mg telotristat ethyl tablet administered three times daily for 6 
months in the treatment period. 
Placebo/Standard Treatment Arm: B 
Placebo: Placebo-matching telotristat ethyl tablet TID with meals + SSA 
Patients who are currently on stable-dose somatostatin analog (SSA) 
therapy (octreotide or lanreotide for 2 months) are randomized to receive 
one placebo-matching 500 mg telotristat ethyl tablet administered three 
times daily for 6 months in the treatment period 
 
 
6.3 
Dose of Modifications of telotristat ethyl 
6.3.1 Definitions 
6.3.1.1 Interruption: temporary stoppage of telotristat ethyl but then 
resuming the treatment(s) within 3 weeks 
6.3.1.2  Discontinuation: premature withdrawal from telotristat ethyl 
defined as a dose interruption lasting for >3 weeks 
6.3.2 Dose Adjustments for adverse events related to the study drug 
Adverse Events will be graded as follows (NCI CTCAE version 5.0) 
 
Grade 1 No change in dose 
Grade 2 Hold until ≤Grade 1. Resume at same dose level. 
Grade 3 Hold until ≤Grade 1. Resume at 1 dose level lower (250 mg tid). 
Grade 4 Hold and contact the Primary Investigator 
 
Dose can also be adjusted or discontinued per PI’s discretion for 
patients’ safety. 
*Patients unable to tolerate 250 mg tid should be discontinued from 
telotristat ethyl. **Constipation and abdominal pain dose adjustment is 
different (see below) 

Page 18 of 42 
 
6.3.3 Recommended management for the following AEs: 
6.3.3.1 Nausea and/or vomiting: treatment with antiemetics 
6.3.3.2 Diarrhea: treat underlying cause and/or with antidiarrheal 
6.3.3.3 Gastrointestinal toxicity 
6.3.3.3.1 
Monitor concomitant medication usage 
6.3.3.3.2 
Constipation (Grade 1 and above): initiate treatment as 
clinically indicated; examples of therapies include: 
laxatives, enemas, suppositories, psyllium hydration, 
over-the-counter (OTC) agents 
6.3.3.3.3 
Abdominal pain (Grade 1 and above): initiate treatment 
as clinically indicated; examples of therapies) include: 
analgesics, anti-gas/bloating agents 
6.3.3.3.4 
Hold telotristat ethyl for Grade 2 constipation or 
abdominal pain until ≤Grade 1. 
6.3.3.3.5 
Discontinue telotristat ethyl for Grade 3 constipation or 
abdominal pain*(please not this is different than above 
table) 
6.3.3.4 Suicidal ideation: discontinue telotristat ethyl 
 
 
6.4 
Treatment Compliance 
Patients will be asked to bring their unused or unopened bottles of telotristat ethyl 
to each visit. Patients will be allowed to ship their unused and/or unopened 
bottles of telotristat ethyl back to PI at MDAnderson if traveling is 
impossible/restricted.  At each visit study site personnel will count returned 
tablets and reconcile the counts against planned number of doses for that 
interval. All dosages prescribed and dispensed to the patient, dose 
modification(s), and missed dose(s), including planned dose interruptions during 
the study must be recorded. Site personnel are to clarify any discrepancy and 
record this information. 
 
Patients must maintain at least 70% compliance at clinical visits (3 month interval 
including allowed window; see section 8 for details) in dosing to be deemed as 
compliant. 

Page 19 of 42 
 
6.5 
Missed Doses 
In the event of a missed or vomited telotristat ethyl dose, patients will take their 
subsequent dose at the next scheduled time point, following the tid dosing 
regimen of approximately every 6 hours. A dose outside of a 3-hour window for 
telotristat ethyl should be considered missed. Missed or vomited doses will not 
be made up. 
 
 
6.6 
Duration of Therapy 
The total duration of therapy with the study drug telotristat ethyl will be 6 months 
as part of the clinical trial assessment. 
6.7 
Prohibited and Restricted Therapies During and Prior to the Study 
Treatment with any tumor directed therapy, including interferon, chemotherapy, 
mechanistic target of rapamycin (mTOR) inhibitors <4 weeks prior to screening, 
or hepatic embolization, radiotherapy, radiolabeled SSA, and/or tumor debulking 
<12 weeks prior to screening. Patients receiving everolimus due to poor 
response to SSA 

Page 20 of 42 
 
7.0 
Baseline Evaluation 
 
7.1 
Obtain Informed Consent (telemedicine technology and language assistant may 
be used). We will follow the Office of Clinical Research Standard Operating 
Procedure (SOP) for informed consent process. During this process, the 
iConsent feature within EPIC will be utilized. The consent process can be 
completed either in-person or remote. 
 
7.2 
Complete history and physical examination including vital signs, NYHA 
classification, and ECOG (telemedicine technology and language assistant may 
be used) 
 
7.3 
CBC with differential, Liver panel (to include AST, ALT, bilirubin, albumin), basic 
metabolic panel (Sodium, potassium, bicarbonate, chloride, BUN, creatinine, 
glucose) within 6 weeks (**-asterisk- labs and tests maybe done 3 weeks prior or 
up to 3 weeks after clinical baseline/follow-up date) 
 
7.4 
ECG within 6 weeks** 
 
 
7.5 
Serum Pregnancy test for females of childbearing age within 1 week 
 
 
7.6 
MD Anderson Symptom Inventory MDASI module (in Appendix) within 6 weeks 
(telemedicine technology and language assistant may be used)** 
 
7.7 
Echocardiography with a 2D transthoracic echocardiography (2D TTE), 3- 
dimensional echocardiography (3D TTE), and myocardial strain of the left and 
right ventricle within 6 weeks** 
 
7.8 
Plasma 5-HIAA collection within 6weeks** (it will be kept frozen in Cryogene lab 
and will be transferred to Frontage Lab for analysis. More information is included in 
the lab manual.) 
 
 
7.9 
Cardiac biomarkers to include: N-terminal pro B-type natriuretic peptide (NT- 
proBNP) and high sensitivity troponin T (HS-troponin T) within 6 weeks** 
 
7.10 
6 minute walk test (6MWT) (in Appendix) where distance is recorded in meters 
within 6 weeks** 
 

Page 21 of 42 
 
7.11 
Assessment for Depression: Validated 2 question case finding instrument: (1) 
“During the past month, have you often been bothered by feeling down, 

Page 22 of 42 
 
depressed, or hopeless?” and (2) “During the past month, have you often been 
bothered by little interest or pleasure in doing things? (telemedicine technology 
and language assistant may be used) 
 
** labs and tests maybe done 3 weeks prior or up to 3 weeks after clinical 
baseline/follow-up date (this is defined as acceptable time window) 
***Above labs and tests from other institutions can be used in lieu of labs done at 
clinical research site*** 

Page 23 of 42 
 
 
 
 
 
 
 
8.0 
Evaluation during Study 
 
8.1 
Complete history and physical examination done at 3 and 6 months as part of 
clinical follow-up. (telemedicine technology and language assistant may be used) 
**A window of 3 weeks before or after for these visits will be acceptable to 
accommodate for patient convenience. 
 
8.2 
CBC with differential, Liver panel (to include AST, ALT, bilirubin, albumin), basic 
metabolic panel (Sodium, potassium, bicarbonate, chloride, BUN, creatinine, 
glucose) done at 3 and 6 month (**-asterisk- labs and tests maybe done 3 weeks 
prior or up to 3 weeks after clinical follow-up date ) 
 
8.3 
ECG done at 3 and 6 months within 6 weeks of clinical visit** 
 
 
8.4 
Pregnancy test for females of childbearing age within one week 
 
 
8.5 
MDASI done at 3 and 6 months (telemedicine technology and language assistant 
may be used;can be done within 6 weeks of clinical follow-up) 
 
8.6 
Echocardiography with a 2D transthoracic echocardiography (2D TTE), 3- 
dimensional echocardiography (3D TTE), and myocardial strain of the left and 
right ventricle to be done at 3 and 6 months for those patients with carcinoid 
heart disease and with carcinoid syndrome and high suspicion of carcinoid heart 
disease (CHD group), such as those with clinical features or increased NT- 
proBNP (> 260) mg/ml and/or 5-HIAA levels (24 hr urine 5-HIAA > 100 mg). (**- 
asterisk- labs and tests maybe done 3 weeks prior or up to 3 weeks after clinical 
follow-up date 
 
8.7 
Echocardiography will be done at 6 months in patients with carcinoid syndrome 
(CS group) who do not have high suspicion for carcinoid heart disease 

Page 24 of 42 
 
8.8 
Plasma 5-HIAA collection at 3 and 6 months (**-asterisk- labs and tests maybe 
done 3 weeks prior or up to 3 weeks after clinical follow-up date) (it will be kept 
frozen in Cryogene lab and will be transferred to Frontage Lab for analysis. 
More information is included in the lab manual.) 
 
 
8.9 
Cardiac biomarkers to include: N-terminal pro B-type natriuretic peptide (NT- 
proBNP) and high sensitivity troponin T (HS-troponin T) at 3 and 6 months (**- 
asterisk- labs and tests maybe done 3 weeks prior or up to 3 weeks after clinical 
baseline/follow-up date ) 
 
8.10 
6 minute walk test (6MWT) where distance is recorded in meters at 3 and 6 
months (**-asterisk- labs and tests maybe done 3 weeks prior or up to 3 weeks 
after clinical follow-up date ) 
 
8.11 
Assessment for Depression at 3 and 6 month (**following window above) clinical 
follow-up: Validated 2 question case finding instrument: (1) “During the past 
month, have you often been bothered by feeling down, depressed, or hopeless?” 
and (2) “During the past month, have you often been bothered by little interest or 
pleasure in doing things? (telemedicine technology and language assistant may 
be used) 
 
8.12 
Data on hospitalization, death, routine clinical data, and routine imaging data 
(such as CT scan, MRI, PET, and echocardiography) will be collected and 
explored with correlation with study interventions 
 
8.13 
Study schedule (table) 
 
 
Baseline 
3 Months** 
6 Months** 
Clinical /Virtual Clinic Follow-up 
X 
X 
X 
CBC with Diff 
Basic Metabolic Panel (BMP) 
LFTs 
X 
X 
X 
ECG 
X 
X 
X 

Page 25 of 42 
 
 
Pregnancy Test ^ 
(for females of childbearing age) 
X 
X 
X 
Echocardiography 
(CHD group ) 
X 
X 
X 
Echocardiography (CS group) 
X 
X 
Plasma collection for 5-HIAA 
X 
X 
X 
NT-proBNP 
X 
X 
X 
Hs-troponin T 
X 
X 
X 
6 minute walk test 
X 
X 
X 
MDASI 
X 
X 
X 
Depression Assessment 
X 
X 
X 
 
 
(**-asterisk- labs and tests maybe done 3 weeks prior or up to 3 weeks after clinical 
baseline/follow-up date. ^- pregnancy test will be within one week of visit) 
 
 
8.14 
Call schedule during study 
Patients will be called by Research team once a week for the first month after 
baseline and monthly afterwards except for the months with clinical visit (3 
month visit, 6 month visit) to assess for potential toxicities, adverse events, 
treatment compliance, and answer patient questions. 
*Research Phone Calls have a time window of +/- 1 business day to account for 
institutional holidays and subject availability. 
*Patients with adverse events noted on the call will be called every week until the 
adverse events resolve. 
*If a dosage change is made after the first month the patient will be called the 
following week for assessment. 
 
Research Call 
Clinical Visit 
Week 0 (Baseline) 
X 
Week 1 
X 

Page 26 of 42 
 
 
Week 2 
X 
Week 3 
X 
Week 4 
X 
Week 8 
X 
Week 12 (3 months) 
X 
Week 16 
X 
Week 20 
X 
Week 24 (6 months) 
X 

Page 27 of 42 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.0 
Criteria for response/change 
 
9.1 
Biochemical response/change. 
9.1.1 5-HIAA levels- response will be defined as a reduction in plasma5-HIAA of 
30% 
9.1.2 Change in NT-ProBNP 
9.1.3 Change in HS-troponin T 
9.2 
Echocardiographic response 
9.2.1 Echocardiographic scoring system for CVHD- response will be defined as a 
change in CVHD score of 10% 
9.2.2 Myocardia strain assessment- response will be defined as a change in 
global longitudinal strain by 15% 
9.3 
Functional response/change 
9.3.1 Change in 6MWT by 50 meters would considered significant 

Page 28 of 42 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.0 
Criteria for Removal from the Study 
 
10.1 
Patient request/consent withdrawal 
10.2 
Noncompliance, including failure to adhere to the study requirements as in the 
study protocol, and/or lost to follow-up 
10.3 
Investigator decides that, in the interest of the patient, it is not medically 
acceptable to continue participation in the study 
10.4 
Pregnancy 
10.5 
Patient is unable to tolerate telotristat ethyl following dosage reduction to 250 mg 
tid 
10.6 
Patient experiences: 
10.6.1 Unresolved Grade 3 constipation as graded by the NCI CTCAE v5.0; 
10.6.2 Development of severe, persistent, or worsening abdominal pain 
10.6.3 Grade 4 toxicity 
10.6.4 Suicidal ideation 
10.6.5 Death 

Page 29 of 42 
 
11.0 
Statistical Consideration 
 
 
11.1 
Sample Size Justification 
Primary endpoint is the percent change in NT-proBNP at 6 months from baseline, which 
is defined as the absolute change divided by the baseline value multiplied by 100. A total 
sample size of 60 (30 in each group) will be enrolled, accounting for ~13% drop out rate 
to have 52 subjects with a primary endpoint. Enrolled participants who were dropped out 
of study will be replaced with additional participants if more than 13% participants were 
dropped out of the study. A sample size of 30 in each group produces a 95% confidence 
interval equal to the sample mean change in NT-proBNP plus or minus 10 when the 
estimated standard deviation is 25, accounting for ~13% drop out rate. There is no 
preliminary data and there are no similar studies to obtain preliminary estimates for the 
percent change in NT-proBNP in any of 2 arms. 
Therefore, the sample size calculation was performed based on an effect size of 0.8, 
which is considered as large. Group sample sizes of 30 and 30 achieve 80% power to 
detect a standard effect size of 0.8 (for example, mean percent difference of 20 when 
the standard deviation of 25) with a significance level (alpha) of 0.05 using a two-sided 
two-sample t-test, accounting for ~13% drop out rate. PASS 2005 (Hintze, J. (2004). 
NCSS and PASS. Number Cruncher Statistical Systems. Kaysville, Utah. 
www.ncss.com) was used for the sample size calculation. The caveat is that if the true 
effect size is smaller than the effect used in power calculation then the calculated 
sample size will not be enough to achieve 80% power. In case the study turns to be not 
significant but promising in this setting, these data can be used as preliminary estimates 
to design a bigger trial. 
 
After enrolling 60 subjects, we evaluated the observed drop-out rate. Three subjects 
were not randomized yet. Six-month follow-up was not reached for 13 subjects. Sixteen 
subjects were dropped out of the study (withdrawn prior to randomization (n=6), 
randomized but withdrawn prior to receiving study treatment (n=4), and randomized, 
treated, but withdrawn prior to 6-month follow-up (n=6)). Drop-out rate among those 
who were enrolled, excluding those not reaching 6-month follow-up and those not 
randomized yet, is 36% (16/44). Since the drop-out rate is higher than 13%, we will 
enroll additional subjects to replace those who dropped out of the study.  
 
Among those who received the study drug, 28 subjects have completed 6-month follow-
up; 13 subjects were not reached 6-month follow-up yet; 6 subjects were withdrawn 
prior to 6-month follow-up. 6-month follow-up completion rate among those who 
received the study drug and reached 6-month follow-up visit is 82% (28/34). At this rate, 
we expect that 10 of 13 not reaching 6-month will complete 6-month follow-up. To have 
52 subjects with a primary endpoint, we still need 14 (i.e., 52-38) additional subjects 
with a primary endpoint.  
 
Applying the drop-out rate of 36%, we may need to enroll 19 additional subjects in 
addition to 3 subjects who were not randomized yet. As we enroll additional subjects in 
the study, we will monitor the number of subjects who complete 6-month follow-up with 
a primary endpoint. Our goal is to have 52 subjects with a primary endpoint. We will 
stop enrolling additional subjects once the number of subjects who complete 6-month 
follow-up with a primary endpoint reaches 52. 
 
If needed, we will evaluate the observed drop-out rate and re-estimate the number of 

Page 30 of 42 
 
additional subjects to enroll to have 52 subjects with a primary endpoint after enrolling 
19 additional subjects, 
 
11.2 
Statistical Analysis Plan 
 
 
We will analyze two analysis sets, including modified intention-to-treat and per 
protocol analysis sets. Modified intention-to-treat analysis set will include all 
patients who were randomized and started a study treatment, regardless of whether 
they received treatment as planned. Per protocol analysis set will include all 
patients who received treatment as planned. 
Patient baseline characteristics and outcome variables (primary endpoint and 
secondary endpoints (absolute changes and percent changes for continuous endpoints)) 
will be summarized by study arm, using mean (standard deviation (SD)) or median (inter 
quartile range (IQR)) for continuous variables and frequency (%) for categorical 
variables. Repeatedly measured variables will be summarized using descriptive statistics 
by study arm and by time point (baseline, 3 months, and 6 months). The mean percent 

Page 31 of 42 
 
change in NT-proBNP at 6 months from baseline will be estimated in each arm along 
with the standard deviation. The mean percent change in NT-proBNP will be compared 
between 2 arms by two-sample t-test. Linear regression model will be used to compare 
the 2 arms in the mean percent change, adjusting for stratification factors. Those without 
3-months or 6-months NT-proBNP may be imputed, using last observation carried 
forward method or other methods. 
Compliance is defined as the total number of medications taken divided by the total 
number of medications provided during 6 month treatment period. The proportion of 
patients maintaining at least 70% compliance will be estimated in each arm. Proportion 
of patients experiencing each type of side effects will be estimated in each arm along 
with 95% confidence interval (CI). The change from baseline to 3 months and the 
change from baseline to 6 months in variables described in secondary objectives will be 
compared within each arm by paired t-test or Wilcoxon signed-rank test for continuous 
variables and Mantel-Haenszel test for categorical variables. Generalized linear mixed 
effects models will be used to compare two arms in repeatedly measured outcomes over 
time. P-values less than 0.05 will indicate statistical significances. SAS 9.4 (Cary, NC) 
and other relevant software will be used for statistical analysis. 
 
 
 
 
11.3 
Toxicity Monitoring 
 
 
Telotristat is an FDA approved drug for management of diarrhea in patients with 
carcinoid syndrome in patients who are on SSAs. The FDA approved dose is 250 mg to 
be taken by mouth with meals three times daily. In this study we will also be using 
telotristat in patients with carcinoid syndrome but with a dose of 500mg three times daily. 
Both dosing regimens (250mg TID and 500 mg TID) were used in the phase 3 
TELESTAR trial along with a companion phase 3 trial, TELECAST, which assessed the 
safety and efficacy of telotristat ethyl in patients with carcinoid syndrome during a 12- 
week double-blind treatment period followed by a 36-week open-label extension 
(OLE). The overall incidence of treatment related adverse events was similar among all 
groups. During a 12 week period, 5 patients (19.2%) in the placebo group experienced a 
serious adverse event (SAE), whereas only 1 patient (4.0%) and 3 patients (12.0%) 
experienced a SAE in the telotristat ethyl 250 mg and telotristat ethyl 500 mg groups. 

Page 32 of 42 
 
Given the safety and efficacy of this FDA approved drug has been established we will 
not be conducting toxicity monitoring (Pavel et al. doi: 10.1530/ERC-17-0455). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12.0 
Reporting Requirements 
 
Data and safety monitoring will be conducted by MD Anderson Cancer Center DSMB. 
12.1 
Adverse Event Reporting 

Page 33 of 42 
 
These guidelines serve to bring the Department of Cardiology in compliance with the 
institutional policy on Reporting of Serious Adverse Events-definition of expected AE-“ 
All clinical protocols should include a list of the expected and anticipated events or 
hospitalizations relating to the study treatment” and Guideline for Good Clinical Practice 
4.11.1 
 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after the first protocol intervention, even if the event is not 
considered to be related to study treatment. Medical conditions/diseases present before 
starting study therapy are only considered adverse events if they worsen after starting 
study treatment. Abnormal laboratory values or test results constitute adverse events 
only if they induce clinical signs or symptoms, are considered clinically significant, or 
require therapy. 
 
 
Adverse event is any untoward medical occurrence that may present during treatment 
with a pharmaceutical product but which does not necessarily have a causal relationship 
with this treatment. 
 
Adverse drug reaction is a response to a drug which is noxious and unintended and 
which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of 
disease or for the modification of physiologic function. 
 
Assessing causal connections between agents and disease is fundamental to the 
understanding of adverse drug reactions. In general, a drug may be considered a 
contributory cause of an adverse event if, had the drug not been administered, 1) the 
event would not have happened at all, 2) the event would have occurred later than it 
actually did, or 3) the event would have been less severe. 
 
For each AE, the Investigator will assess the causal relationship between each of the 
study drugs and the AE using their clinical expertise and judgment according to the most 
appropriate description as follows: 

Page 34 of 42 
 
• Not related: The AE does not follow a reasonable temporal relationship to 
administration of the study drug, or an alternative etiology (eg, underlying disease, 
complications, concomitant drugs, or concurrent treatment) is more likely 
• Unlikely related: The AE has an improbable temporal relationship to administration of 
the study drug, or an alternative etiology (eg, underlying disease, complications, 
concomitant drugs, or concurrent treatment) is more likely 
• Possibly related: The AE follows a reasonable temporal relationship to administration 
of the study drug (including the course after withdrawal of the drug), and an alternative 
etiology (eg, underlying disease, complications, concomitant drugs, or concurrent 
treatment) is equally or less likely 
• Probably related: The AE follows a reasonable temporal relationship to administration 
of the study drug (including the course after withdrawal of the drug), and an alternative 
etiology (eg, underlying disease, complications, concomitant drugs, or concurrent 
treatment) is unlikely 
• Definitely related: The AE follows a plausible temporal relationship to administration of 
the study drug (including the course after withdrawal of the drug) and alternative etiology 
(eg, underlying disease, complications, concomitant drugs, or concurrent treatment) can 
be ruled out. Positive rechallenge (ie, reappearance or worsening of the AE after study 
drug is reintroduced) or a response pattern known to be associated with administration 
of the study drug provides further evidence of a definitive causality assessment. 
 
Adverse Events (AEs) will be evaluated according to CTC version 5 in each protocol. 
AEs will be documented in an AE log. Prometheus will be used to enter data for this 
protocol. The Investigator or physician designee is responsible for verifying and 
providing source documentation for all adverse events and assigning the attribution for 
each event for all subjects enrolled on the trial. 
 
Severity of the adverse events (AEs) -The severity of the adverse events (AEs) will be 
graded according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) V.05. Events not included in the NCI CTCAE will be 
scored as follows: 
General grading: 
• 
Grade 1: Mild: discomfort present with no disruption of daily activity, no treatment 
required beyond prophylaxis. 

Page 35 of 42 
 
• 
Grade 2: Moderate: discomfort present with some disruption of daily activity, 
require treatment. 
• 
Grade 3: Severe: discomfort that interrupts normal daily activity, not responding 
to first line treatment. 
• 
Grade 4: Life Threatening: discomfort that represents immediate risk of death 
 
 
Recommended Adverse Event Recording Guidelines 
 
 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase II 
 
Unlikely 
Phase I 
Phase I 
Phase I 
Phase II 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Possible 
Phase I 
Phase II 
 
Probable 
Phase I 
Phase II 
 
Definitive 
Phase I 
Phase II 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
 
 
Expected events during carcinoid syndrome and carcinoid heart disease therapy are: 
a. Nausea 
b. Headache 
c. Edema 
d. Flatulence 
e. Pyrexia 
f. 
Decreased appetite 
g. Fatigue 
h. Flushing 
i. 
Diarrhea 
j. 
Constipation 
k. Abdominal pain 
l. 
electrolyte abnormalities (sodium, potassium, CO2, magnesium) 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 

Page 36 of 42 
 
m. chemistry abnormalities (LDH, phosphorus, calcium, BUN, protein, albumin, uric 
acid, alkaline phosphatase, glucose) 
n. coagulation abnormalities 
o. bone, joint, or muscle pain 
p. liver function test abnormalities associated with infection or disease progression 
q. disease progression 
r. volume overload 
s. signs and symptoms of heart failure 
t. 
arrhythmias such as atrial fibrillation, atrial flutter, and supraventricular 
tachycardia 
u. development of depression - **patients with depression and suicidal ideation will 
be referred immediately to psychiatry services as per institutional guidelines ** 
 
12.2 
Serious Adverse Event Reporting (SAE) 
 
 
An adverse event or suspected adverse (possible, probable, and definite AE) 
reaction is considered “serious” if, in the view of either the investigator or the 
sponsor, it results in any of the following outcomes: 
• 
Death 
• 
A life-threatening adverse drug experience – any adverse experience that 
places the patient, in the view of the initial reporter, at immediate risk of death 
from the adverse experience as it occurred. It does not include an adverse 
experience that, had it occurred in a more severe form, might have caused 
death. 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions. 
• 
A congenital anomaly/birth defect 
 
 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. Examples of such medical events include 

Page 37 of 42 
 
allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 
312.32). 
 
• 
Important medical events as defined above, may also be considered 
serious adverse events. Any important medical event can and should be reported 
as an SAE if deemed appropriate by the Principal Investigator 
 
• 
All events occurring during the conduct of a protocol and meeting the 
definition of a SAE must be reported to the IRB in accordance with the 
timeframes and procedures outlined in “University of Texas M. D. Anderson 
Cancer Center Institutional Review Board Policy on Reporting Serious Adverse 
Events”. Unless stated otherwise in the protocol, all prompt SAEs, unexpected 
and related, must be reported to the IRB (within 10 working days of knowledge of 
the event). 
• 
The MDACC “Internal SAE Report Form for Prompt Reporting” will be 
used for reporting 
. • 
Elective admissions or admissions for transfusions will not be considered 
an SAE. 
• 
Serious adverse events will be captured from the time the patient take his 
first treatment drug dose until 30 days after the last dose of drug. Serious 
adverse events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of the event has 
stabilized, or there has been acceptable resolution of the event. 
 
• 
Additionally, any serious adverse events that are reported to the 
treatment team that occur after the 30 day time period that are related to the 
study treatment must be reported to the IRB. This may include the development 
of a secondary malignancy. 
 
• 
 Primary investigator and research team may become unblinded to the study 
arms if it is deemed a medical necessity required for patient treatment or 
safety. 

Page 38 of 42 
 
 
 
Reporting to FDA: 
 
 
It is the responsibility of the PI and the research team to ensure serious adverse 
events are reported according to the Code of Federal Regulations, Good Clinical 
Practices, the protocol guidelines, the sponsor’s guidelines, and Institutional 
Review Board policy. 
 
12.3 
Investigator Communication with Supporting Company 
All SAEs, regardless of causal relationship to study drug, and pregnancies must 
be reported to the TerSera Therapeutics within 72 hours of investigational site 
awareness of the event. Investigators should not wait for complete information on 
an event before notifying the TerSera Therapeutics of an SAE. 
Investigational site personnel must use the approved method of notification per 
the TerSera Therapeutics to report these events. 
If paper report forms are used, the form(s) should be sent to: 
Safety Data Facsimile: (832) 442-5462 or 
Email address (in case of fax failure): Medicalinformation@tersera.com 
In case of failure of/lack of access to eCRF, email, or fax, the event should be 
reported to the TerSera Medical Information Call Center within one business day 
of awareness: (844) 334-4035 
If an SAE is reported via telephone, the telephone report should be followed by a 
written report using a reporting method described above (ie, completion of eCRF 
of paper form). 
 
12.4 
Reporting of External SAEs 
The MDACC institutional policy for reporting of external SAEs will be followed. 
 
 
12.5 
Follow-up of Adverse Events 
All AEs should be followed until the event has resolved, the condition has 
stabilized, the patient is lost to follow-up, or at least 30 days following the last 
dose of any study drug. Final known outcome must be reported whenever 
possible. Medically significant abnormal laboratory test results should be 

Page 39 of 42 
 
repeated and followed until the test results have returned to the normal range or 
Baseline value, and/or an adequate explanation of the abnormality is determined 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13.0 
Appendix 

Page 40 of 42 
 
 
 

Page 41 of 42 
 
 
 

Page 42 of 42 
 
 
 
TIME   
 
 
Date:  
 
MRN:   
 
 
Patient Name:  
 
Sex: M / F 
 
Ord. Physician:  
Ord. #  
 
Resting 
Heart Rate 
Oxygen saturation 
Borg Scale Dyspnea 
Borg Scale Fatigue 
Blood Pressure Systolic 
Blood Pressure Diastolic 
Supplemental Oxygen 
During Test 
Highest Heart Rate 
Lowest Oxygen Saturation 
Borg Scale Dyspnea 
Borg Scale Fatigue 
Blood Pressure Systolic 
Blood Pressure Diastolic 
Number of Pauses 
Duration of Test 
Six Minute Walk Distance 
Post Test 
Oxygen Saturation Post Test 
LAPS 
**Please note below information will be entered electronically using the tablet** 

Page 43 of 42 
 
14.0 
References 
 
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2. 
Pellikka PA, Tajik AJ, Khandheria BK et al. Carcinoid heart disease. Clinical and 
echocardiographic spectrum in 74 patients. Circulation 1993;87:1188-96. 
3. 
Lundin L, Norheim I, Landelius J, Oberg K, Theodorsson-Norheim E. Carcinoid heart 
disease: relationship of circulating vasoactive substances to ultrasound-detectable 
cardiac abnormalities. Circulation 1988;77:264-9. 
4. 
Chaowalit N, Connolly HM, Schaff HV, Webb MJ, Pellikka PA. Carcinoid heart disease 
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5. 
Roth BL. Drugs and valvular heart disease. N Engl J Med 2007;356:6-9. 
6. 
Denney WD, Kemp WE, Jr., Anthony LB, Oates JA, Byrd BF, 3rd. Echocardiographic 
and biochemical evaluation of the development and progression of carcinoid heart 
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7. 
Robiolio PA, Rigolin VH, Wilson JS et al. Carcinoid heart disease. Correlation of high 
serotonin levels with valvular abnormalities detected by cardiac catheterization and 
echocardiography. Circulation 1995;92:790-5. 
8. 
Simula DV, Edwards WD, Tazelaar HD, Connolly HM, Schaff HV. Surgical pathology of 
carcinoid heart disease: a study of 139 valves from 75 patients spanning 20 years. Mayo 
Clinic proceedings 2002;77:139-47. 
9. 
Castillo JG, Silvay G, Solis J. Current concepts in diagnosis and perioperative 
management of carcinoid heart disease. Seminars in cardiothoracic and vascular 
anesthesia 2013;17:212-23. 
10. 
Etienne N, Schaerlinger B, Jaffre F, Maroteaux L. [The 5-HT2B receptor: a main cardio- 
pulmonary target of serotonin]. Journal de la Societe de biologie 2004;198:22-9. 
11. 
Hutcheson JD, Setola V, Roth BL, Merryman WD. Serotonin receptors and heart valve 
disease--it was meant 2B. Pharmacology & therapeutics 2011;132:146-57. 
12. 
Li B, Zhang S, Zhang H et al. Fluoxetine-mediated 5-HT2B receptor stimulation in 
astrocytes causes EGF receptor transactivation and ERK phosphorylation. 
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