Clinical trial NCT03442725
Conditions: Renal Impairment
Sponsor: Ipsen
Start date: 2018-02-09; Completion date: 2018-05-13
Enrollment: 16 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Renal excretion is a minor elimination route of telotristat etiprate. So this trial is intended to assess the drug behaviour in subjects with decreased renal function.

This is a staged study with Part B contingent upon the results of Part A. Part A will enrol a total of 16 subjects, eight with severely impaired renal function and eight healthy subjects. Part B with enrol a total of 16 subjects, eight subjects in each additional renal function group, i.e. mildly impaired renal function group and moderately impaired group.

Detailed description:

Arms: arm 1: Subjects will receive a single oral 250-mg tablet dose of Telotristat etiprate (Xermelo® 250 mg) on day 1 under fed conditions (i.e. between 15 minutes before and 1 hour after the meal or snack). arm 2: Subjects will receive a single oral 250-mg tablet dose of Telotristat etiprate (Xermelo® 250 mg) on day 1 under fed conditions (i.e. between 15 minutes before and 1 hour after the meal or snack). arm 3: Subjects will receive a single oral 250-mg tablet dose of Telotristat etiprate (Xermelo® 250 mg) on day 1 under fed conditions (i.e. between 15 minutes before and 1 hour after the meal or snack). arm 4: Subjects will receive a single oral 250-mg tablet dose of Telotristat etiprate (Xermelo® 250 mg) on day 1 under fed conditions (i.e. between 15 minutes before and 1 hour after the meal or snack).
Interventions: intervention 1: Telotristat etiprate
Intervention descriptions: intervention 1: Oral administration of 1 tablet of Xermelo® containing telotristat etiprate equivalent to 250 mg telotristat ethyl.

Protocol documents:
Prot_001.pdf: 





































































































































SAP_000.pdf: 
IPSEN GROUP 
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STATISTICAL ANALYSIS PLAN 
 
A PHASE I, OPEN-LABEL STUDY TO COMPARE THE PHARMACOKINETICS OF 
TELOTRISTAT ETHYL AND ITS METABOLITE IN SUBJECTS WITH IMPAIRED 
RENAL FUNCTION TO HEALTHY SUBJECTS WITH NORMAL RENAL FUNCTION 
AFTER A SINGLE DOSE OF TELOTRISTAT ETIPRATE 
 
 
 
PROTOCOL VERSION AND DATE: 
Version 2.0 – 20 December 2017 
 
 
 
 
Statistical Analysis Plan (SAP) Version 
Date 
Final Version 2.0 
04JUN2018 




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RESPONSIBILITY 
NAME, TITLE & OFFICE 
SIGNATURE 
DATE 
Study statistician 
 
Biostatistics Project Leader 
Biotrial Biometrics 
7-9 Rue Jean-Louis Bertrand 
35042 Rennes Cedex, France 
 
 
Pharmacokineticist 
 
Biotrial  
7-9 Rue Jean-Louis Bertrand 
35042 Rennes Cedex, France 
 
 
 
IMPORTANT: This completed record (with additional sheets, where required), confirms the 
above-mentioned Statistical Analysis Plan version became the Final Statistical Analysis Plan 
PPD
PPD




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TABLE OF CONTENTS 
1 
INFORMATION TAKEN FROM THE PROTOCOL ............................................. 10 
1.1 
Study objectives ............................................................................................................. 10 
1.1.1 
Primary objective ......................................................................................... 10 
1.1.2 
Secondary Study Objectives ........................................................................ 10 
1.2 
Study design ................................................................................................................... 10 
1.2.1 
Study population ......................................................................................... 11 
1.2.2 
Study duration ............................................................................................. 12 
1.3 
Methods and procedures .............................................................................................. 12 
1.3.1 
Subject identification and allocation to study treatment ........................... 12 
1.3.2 
Subjects assessments ................................................................................... 12 
1.3.2.1 
Efficacy assessments .................................................................................... 12 
1.3.2.2 
Pharmacokinetic assessments ...................................................................... 12 
1.3.2.3 
Safety assessments ....................................................................................... 13 
1.3.2.4 
Other Assessments ....................................................................................... 14 
1.3.2.5 
Withdrawal/discontinuation ......................................................................... 14 
1.3.3 
Schedule of assessments ............................................................................. 15 
1.3.4 
Planned sample size .................................................................................... 18 
2 
SUBJECT POPULATIONS (ANALYSIS SETS) ...................................................... 18 
2.1 
Efficacy .......................................................................................................................... 18 
2.2 
Safety .............................................................................................................................. 18 
2.3 
Pharmacokinetics .......................................................................................................... 18 
2.4 
Included population ...................................................................................................... 18 
2.5 
Screened population ..................................................................................................... 18 
2.6 
Primary population ....................................................................................................... 18 
3 
STATISTICAL METHODS ........................................................................................ 18 
3.1 
Statistical analysis strategy .......................................................................................... 18 
3.1.1 
Primary efficacy endpoint ........................................................................... 18 
3.1.2 
Secondary efficacy endpoint ....................................................................... 18 
3.1.3 
Pharmacokinetic endpoints ........................................................................ 19 
3.1.4 
Protein binding endpoints ........................................................................... 20 
3.1.5 
Safety endpoints .......................................................................................... 21 
3.1.6 
Multiplicity .................................................................................................. 21 
3.1.7 
Significance testing and estimation ............................................................ 21 
3.2 
Analysis methods ........................................................................................................... 21 
3.2.1 
Efficacy ........................................................................................................ 21 
3.2.2 
Pharmacokinetics ........................................................................................ 21 
3.2.2.1 
PK parameters calculation .......................................................................... 21 
3.2.2.2 
Descriptive statistics and listings ................................................................. 22 
3.2.2.3 
Graphical representations ........................................................................... 23 


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3.2.2.4 
Statistical analyses ....................................................................................... 23 
3.2.3 
Safety ........................................................................................................... 25 
3.2.3.1 
Adverse events .............................................................................................. 25 
3.2.3.2 
Laboratory data ........................................................................................... 26 
3.2.3.3 
Physical examination ................................................................................... 27 
3.2.3.4 
Vital signs ..................................................................................................... 27 
3.2.3.5 
ECG .............................................................................................................. 27 
3.2.3.6 
Pregnancy tests ............................................................................................ 28 
3.2.4 
Missing data and outliers ............................................................................ 28 
3.2.4.1 
Missing data ................................................................................................. 28 
3.2.4.2 
Missing or incomplete dates ........................................................................ 28 
3.2.4.3 
Outliers ........................................................................................................ 28 
3.2.5 
Subject disposition ....................................................................................... 29 
3.2.6 
Withdrawals ................................................................................................. 29 
3.2.7 
Demographic and baseline characteristics ................................................ 29 
3.2.8 
Medical and surgical history ...................................................................... 29 
3.2.9 
Subject compliance ..................................................................................... 30 
3.2.10 
Prior and concomitant medications ........................................................... 30 
3.2.11 
Prior and concomitant non-drug therapies ................................................ 30 
3.2.12 
Concomitant surgical procedures ............................................................... 30 
3.2.13 
Derived data ................................................................................................. 30 
3.2.14 
Rules and data formats ............................................................................... 30 
3.2.15 
Pooling of Centres ....................................................................................... 31 
3.2.16 
Interim analysis ........................................................................................... 31 
3.2.17 
Role of data review committee (DRC) ........................................................ 31 
3.2.18 
Covariates and analysis of subgroups ........................................................ 31 
4 
COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS . 32 
4.1 
Hardware ....................................................................................................................... 32 
4.2 
Software ......................................................................................................................... 32 
4.3 
Validation programs ..................................................................................................... 32 
4.4 
Restitution of the programs ......................................................................................... 32 
5 
CHANGES FROM PROTOCOL ................................................................................ 32 
6 
REFERENCES .............................................................................................................. 33 
7 
APPENDICES TO THE SAP TEMPLATE ............................................................... 34 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ȜZ: 
Terminal elimination rate constant 
Ae: 
Amount of unchanged drug excreted in urine 
AE: 
Adverse Event 
ALP: 
Alkaline phosphatase 
ALT: 
Alanine aminotransferase  
ANOVA: 
Analysis of Variance 
APTT: 
Activated Partial Thromboplastin Time 
AST: 
Aspartate aminotransferase  
ATC: 
Anatomic Therapeutic Class 
AUC: 
Area Under the (plasma concentration vs time) Curve 
AUC0-tlast: 
Area Under the plasma concentration-time Curve from time 0 
to time t corresponding to the last quantifiable concentration 
AUC0-tlastu: 
Area Under the plasma concentration-time Curve from time 0 
to time t corresponding to the last quantifiable unbound 
concentration 
AUC0-inf: 
Area Under the plasma concentration-time Curve from time 0 
to infinity 
AUC0-infu: 
Area Under the plasma concentration-time Curve unbound 
from time 0 to infinity 
BLQ: 
Below the Limit of Quantification 
BMI: 
Body Mass Index 
BP: 
Blood pressure 
bpm: 
Beats per minute 
CI: 
Confidence Interval 
Clast: 
Last quantifiable concentration 
CL/F: 
Apparent total clearance (from plasma) 
CLu/F: 
Apparent total clearance (from plasma) unbound 
Cmax: 
Observed maximal (peak) concentration 
Cmaxu: 
Observed maximal (peak) concentration unbound 
CRF: 
Case Report Form 
CRP: 
C reactive protein 
CS: 
Clinically significant 
CSR: 
Clinical Study Report 
CV: 
Coefficient of Variation 


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DRC: 
Data Review Committee 
ECG: 
Electrocardiogram 
eCRF: 
Electronic Case Report Form 
EMA: 
European Medicines Agency 
EOS: 
End Of Study 
FDA: 
Food and Drug Administration 
FSH: 
Follicle Stimulating Hormone 
fu: 
Unbound plasma fraction 
GFR 
Glomerular filtration rate 
GGT: 
Gamma-Glutamyl Transpeptidase  
HbA1C 
Glycated haemoglobin A1c 
HBsAg: 
Hepatitis B Surface Antigen 
HCV: 
Hepatitis C Virus 
HIV: 
Human Immunodeficiency Virus 
ICH: 
International Conference on Harmonisation 
IMP: 
Investigational Medicinal Product 
INR: 
International Normalised Ratio 
LC-MS/MS:  
Liquid chromatography-tandem mass spectrometry 
LOQ: 
Limit of Quantification 
LS: 
Least-Squares 
MCH: 
Mean Cell Haemoglobin 
MCHC: 
Mean Cell Haemoglobin Concentration 
MCV: 
Mean Corpuscular Volume 
MDRD 
Modification of Diet Renal Disease 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MR: 
Metabolitic ratios 
PDM: 
Pharmacokinetics Drug Metabolism 
PK: 
Pharmacokinetic(s) 
PTT 
Partial Thromboplastin Time 
QTcF: 
Corrected QT interval according to Fridericia’s formula 
RBC: 
Red Blood Cell(s) 
SAE: 
Serious Adverse Event 
SAP: 
Statistical Analysis Plan  
SAS®: 
Statistical Analysis System® 
SD: 
Standard Deviation 


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SI: 
International System 
t1/2: 
Apparent terminal elimination half-life 
TEAE: 
Treatment Emergent Adverse Event 
TFLs:  
Tables, Figures and Listings  
TG: 
Triglycerides 
tlast: 
Time to last quantifiable concentration 
tmax: 
Time to maximum observed plasma concentration 
Vz/F: 
Apparent volume of distribution 
Vzu/F: 
Apparent volume of distribution (unbound) 
WBC: 
White Blood Cell 
WHO-DD: 
World Health Organisation – Drug Dictionary 
 


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1 
INFORMATION TAKEN FROM THE PROTOCOL 
1.1 
Study objectives 
1.1.1 
Primary objective 
The primary objective of the study is to compare the pharmacokinetics (PK) of 
telotristat ethyl and its active metabolite telotristat (LP-778902) following a single 
oral dose of 250 mg telotristat ethyl in subjects with renal impaired function versus 
the PK in healthy subjects with normal renal function. 
1.1.2 
Secondary Study Objectives 
The secondary objectives of the study are: 
 
to compare the safety and tolerability of a single oral dose of 250 mg 
telotristat ethyl in subjects with renal impaired function versus healthy 
subjects with normal renal function; 
 
to assess the effect of impaired renal function on protein binding of telotristat 
ethyl and its active metabolite telotristat (LP-778902); 
 
to evaluate the PK of the inactive metabolite LP-951757 following a single 
oral dose of 250 mg telotristat ethyl in subjects with renally impaired function 
and healthy subjects with normal renal function. 
1.2 
Study design  
This study is an open-label single dose staged study with Part B contingent upon the 
results of Part A. Part A will include two groups, a test group and a control group. 
The test group will include subjects with a Glomerular Filtration Rate (GFR) as low 
as possible i.e. < 20 mL/min, but not requiring dialysis (subjects with severely 
impaired renal function). If inclusion of such subjects is not possible, subjects with 
severely decreased renal function and a GFR between 15 and 29 ml/min (both 
inclusive) may be included. The test group will be compared to a control group of 
demographically-matched healthy subjects with normal renal function (i.e. with a 
GFR equal or above 90 mL/min). 
The PK and protein binding analysis of telotristat ethyl, its active metabolite 
telotristat (LP-778902) and the inactive metabolite LP-951757 will be assessed in 
eight subjects with severely decreased renal function and compared to those in eight 
demographically-matched subjects with normal renal function (GFR  90 mL/min) 
following single oral dose of 250 mg telotristat ethyl. If results of Part A show a 
substantial effect (set as 2-fold increase in total and unbound of either the maximal 
plasma concentration (Cmax) or plasma exposure (AUC) of the active metabolite 
telotristat (LP-77902)), the PK and protein binding analysis of telotristat ethyl, its 
active metabolite telotristat (LP-778902) and the inactive metabolite LP-951757 
will also be assessed in eight subjects with a mildly (GFR between 60 and 89 
mL/min, both inclusive) and eight subjects with a moderately (GFR between 30 and 
59 mL/min, both inclusive) decreased renal function (Part B) following single oral 
dose of 250 mg telotristat ethyl. Safety and tolerability of the single oral dose of 250 
mg telotristat ethyl will also be evaluated. 
Renal function will be classified based on estimated GFR as determined by the 
Modification of Diet in Renal Disease (MDRD) formula. 
After a maximum 28-day screening period (56 days for subjects with mildly and 
moderately impaired renal function), eligible subjects will begin their stay at the 
clinical unit on Day-1 (admission day). Subjects will receive a single oral dose of 
telotristat etiprate (as one tablet containing 250 mg telotristat ethyl) on Day 1. 


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Following safety assessments, subjects will be discharged from the clinical unit 
either on Day 2 or Day 4. In the first option (discharge on Day 2), subjects will 
return to the clinical unit for outpatient visits on Day 3 and Day 4 for PK blood 
sampling and supply of urine collected at home. In the second option (involving a 
stay up to Day 4), subjects will have safety assessments performed on Day 2 and 
will be discharged upon completion of PK blood samplings and urine collection on 
Day 4. All subjects will return to the clinical unit for an end of study (EOS) visit no 
less than seven days after dose administration (between Day 8 and Day 15). 
1.2.1 
Study population 
A total of 16 (up to 32) subjects are planned to be included in the study. This study 
has a staged approach such that the recruitment of subjects for Part B of the study is 
contingent upon the results of Part A, as follows: 
 
Part A: Total of 16 subjects - eight subjects (aiming for at least three males 
and three females) with severely impaired renal function (i.e. with GFR as 
low as possible i.e. < 20 mL/min) but not requiring dialysis. If inclusion of 
such subjects is not possible, subjects with severely decreased renal function 
(GFR between 15 and 29 mL/min, both inclusive), and eight healthy subjects 
demographically-matched for gender, age (± 10 years) and body mass index 
(BMI ± 20%). 
Healthy subjects will be included based on the characteristics of the severe 
renal impairment subject population according to a one-to-one matching 
procedure. For this purpose, individual recruitment of healthy subjects will 
start after each completed subject with severely impaired renal function. 
 
Part B: Total of 16 subjects - eight subjects (aiming for at least three males 
and three females) in each additional renal function group, i.e. mildly 
impaired renal function group and moderately impaired one. 
 
The renal function of the specific population with renal impairment will be assessed 
based on estimated GFR as determined by the Modification of Diet in Renal Disease 
(MDRD) formula as presented below: 
 
GFR (mL/min/1.73 m²) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 
if African/American) 
Scr: serum creatinine (mg/dL) - GFR reported normalised to 1.73 m² body surface 
area 
Or 
 
GFR (mL/min/1.73 m²) = 175 × (Scr × 0.0113)-1.154 × (Age)-0.203 × (0.742 if female) 
× (1.212 if African/American) 
Scr: serum creatinine (ȝmol/L) - GFR reported normalised to 1.73 m² body surface 
area 
 
Measured GFR using an exogenous substance are not readily available in routine 
clinical practice, and thus may not be an optimal endpoint for dosing 
recommendation. Besides, measuring GFR using exogenous marker is subject to 
diurnal variations of GFR and may not be more reliable than estimated GFR from 
prediction equations (e.g. MDRD and Cockcroft-Gault method). 
 


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Table 1 
Renal function groups  
Description 
GFR (mL/min) 
Normal renal function 
 90 
Mildly decreased renal function 
60 - < 90 
Moderately decreased renal function 
30 - < 60 
Severely decreased renal function 
< 30 not requiring dialysis 
End stage renal disease 
< 15 requiring dialysis 
 
1.2.2 
Study duration 
This study will consist of a maximum 28-day screening period (56 days for subjects 
with mildly and moderately impaired renal function), one day dosing, and a 
maximum of 15-day follow-up period. Subjects are expected to participate in this 
study for a minimum of 10 days and maximum of 71 days for the mild and moderate 
subjects. 
The overall study is anticipated to last approximately 12 months. 
The study will be considered to have started when the first subject has provided 
informed consent and will be considered to have ended after the last subject has 
completed the EOS/early discontinuation visit. 
1.3 
Methods and procedures 
1.3.1 
Subject identification and allocation to study treatment 
After informed consent is obtained, screened subjects will be allocated a study-
specific subject number which must comply with formatting specifications provided 
by the sponsor. All screened subjects must be identifiable throughout the study. The 
investigator will maintain a list of all subjects screened with subject numbers and 
names to enable records to be found at a later date if required. 
1.3.2 
Subjects assessments 
1.3.2.1 
Efficacy assessments 
There is no efficacy assessment in this study. 
1.3.2.2 
Pharmacokinetic assessments 
Plasma and urine concentrations of telotristat ethyl and its active metabolite 
telotristat 
(LP-778902) 
will 
be 
determined 
by 
validated 
liquid 
chromatography/tandem mass spectrometry (LC-MS/MS) methods. 
Plasma concentrations of telotristat ethyl inactive metabolite (LP-951757) will be 
determined by validated liquid chromatography/tandem mass spectrometry (LC-
MS/MS) methods. 
Pharmacokinetic blood samples will be collected predose (time 0) and up to 72 
hours postdose [at timepoints 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (day 2), 48 (day 3), 72 
(day 4) hours postdose; see Section 1.3.3]. 
Urine samples will be collected on day -1 (two 4-hours intervals predose), and up to 
72 hours postdose [0-4h, 4-8h, 8-12h, 12-24h, 24-48h (day 2), 48-72h (day 3) 
postdose urine collection intervals; see Section 1.3.3]. 
 
Protein binding 
Plasma protein binding will be assessed using equilibrium dialysis followed by LC-
MS/MS for determination of unbound drug concentrations. 


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Blood samples will be collected for protein binding of telotristat ethyl, its active 
metabolite telotristat (LP-778902) and the inactive metabolite (LP-951757) on day 1 
at 0.5, 1, 2 and 3 hours postdose (see Section 1.3.3). 
1.3.2.3 
Safety assessments 
The safety assessments are: 
 
Adverse events (AEs) monitored from the time that the subject gives 
informed consent and throughout the study, elicited by direct, non-leading 
questioning or by spontaneous reports; 
 
Clinical safety assessments: 
 
Physical examination assessed at screening, Day -1, Day 2 (in case of 
discharge), Day 4 and EOS/Early discontinuation visit; 
 
Vital signs measured at screening, Day -1, Day 2 (approximately 24 h 
postdose), Day 4 and EOS/ Early discontinuation visit, including 
supine blood pressures (BP) and heart rate and temperature at Day -1 
only; 
 
12-lead electrocardiograms (ECGs) measured at screening, Day -1, 
Day 2 (approximately 24 h postdose), Day 4 and EOS/ Early 
discontinuation visit, including sinus rhythm, RR interval, heart rate, 
PR interval, QRS interval, QT interval, corrected QT (QTc) calculated 
using Fridericia methodology as well as their clinical significance; 
 
Clinical laboratory tests measured at screening*, Day -1*, Day 2, Day 4 and 
EOS*/ Early discontinuation visit: 
 
Haematology: erythrocyte count (RBC), haematocrit, haemoglobin, 
mean 
cell 
haemoglobin 
(MCH), 
mean 
cell 
haemoglobin 
concentration (MCHC), mean cell volume (MCV), leukocyte count 
(WBC), absolute count of neutrophils, lymphocytes, monocytes, 
eosinophils and basophils and platelets count; 
 
Clinical chemistry: Alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), gamma-
glutamyl transferase (GGT), conjugated bilirubin, total bilirubin, 
total protein, albumin, creatinine, urea, glucose (fasting), glomerular 
filtration rate (GFR, for renal impaired only and only at screening 
and day-1), glycated haemoglobin A1c (HbA1C, for renal impaired 
only and only at screening and day-1), amylase, bicarbonate, C 
reactive protein (CRP), calcium, chloride, inorganic phosphate, 
potassium, sodium, total cholesterol, triglycerides (TG); 
 
Coagulation (only at flagged * visits): Activated partial 
thromboplastin 
time (aPTT) 
and 
international 
normalised 
ratio (INR); 
 
Urinalysis (dipstick): bilirubin, blood, leukocyte, nitrite, glucose, 
ketones, specific gravity, pH, proteins, urobilinogen; 
 
Urinalysis (quantitative results): Potassium, sodium, chloride, 
bicarbonates, urea and creatinine. 
 
Pregnancy tests at screening, Day -1 and EOS/ Early discontinuation visit 
(women of childbearing potential only). 


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1.3.2.4 
Other Assessments 
 
Demographics (country, sex, race, ethnicity, age) at screening; 
 
Eligibility criteria at screening and day -1; 
 
Medical or surgical history, including ongoing medical history at screening 
and Day -1; 
 
Body height at screening, body weight and BMI at screening and Day-1 and 
EOS/ Early discontinuation; 
 
Urine drug of abuse tests (cannabis and metabolites, cocaine, amphetamines, 
opiates, methamphetamines, barbiturates, benzodiazepines) at screening and 
Day-1; 
 
Alcohol breath test at screening and Day-1; 
 
Tobacco, caffeine and alcohol use at screening; 
 
Serology at screening only: Hepatitis B surface antigen, Hepatitis C (HCV 
ribonucleic acid) and Human immunodeficiency virus (HIV); 
 
Endocrine (FSH) (if applicable) at screening; 
 
Postmenopausal status at screening; 
 
Prior and concomitant medications, prior and concomitant non-drug therapies 
and concomitant surgical procedures; 
 
For renal impaired subjects only: renal function classification at screening. 
1.3.2.5 
Withdrawal/discontinuation 
In accordance with the declaration of Helsinki and the applicable country’s 
acceptance, each subject is free to withdraw from the study at any time, for any 
reason (e.g. lost to follow-up, withdrawal of consent, AE). 
The investigator can withdraw a subject from the study at any time for any reason 
(e.g. protocol deviation, noncompliance with the protocol conditions, lack of 
cooperation, in the event of concurrent illness, AE, or other reasons concerning the 
health or well-being of the subject). 
The reason for and date of withdrawal from the study must be recorded in the CRF. 
If withdrawal is based on subject’s decision every attempt will be made to 
determine: 
 
The reason for withdrawal, 
 
Whether the subject also decides to withdraw his consent for the sponsor to 
collect and use the data collected up to the withdrawal point. 
Data collected prior to subject withdrawal may be kept in study records and shared 
with the sponsor for further analyses unless the subject formally specifies his 
decision to withdraw consent for using data already collected. 
If the reason for withdrawal is an AE or a clinically significant laboratory test 
abnormality, monitoring will continue until the event has resolved or stabilised, 
until the subject is referred to the care of a local health care professional, or until a 
determination of a cause unrelated to the study drug or study procedure is made. 
The specific AE(s) or test result(s) must be recorded in the CRF. 
Should a subject drop out or be withdrawn from the study after study drug 
administration and before normal study completion, all efforts will be made to 
complete the follow-up end-of-study assessments and report the observations up to 
the time of withdrawal as thoroughly as possible. A complete final evaluation at the 
time of the subject’s withdrawal should be made whenever possible. 


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Any subject who drops out or is discontinued from the study before normal study 
completion may be replaced at the discretion of the sponsor. Replacement subjects 
will receive the same schedule and treatment as the subject they replace. 
All cases of discontinuation will be discussed between the investigator and the 
sponsor. 
1.3.3 
Schedule of assessments 
Here are the schedules of assessments extracted from the protocol:


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Table 2 
Study schedule of assessments 
 
 


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Table 3 
Study schedule of assessments (Continued) 
 
 


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1.3.4 
Planned sample size 
No prospective calculations of statistical power are made. The sample size (eight 
subjects per group) is selected to provide information on PK following single oral 
dose of telotristat etiprate. Safety and tolerability will be evaluated as secondary 
parameters. 
These number of subjects per group are mentioned in the Food and Drug 
Administration (FDA) and European Medicines Agency (EMA) guidelines. Based 
on previous data from subjects treated with a single dose of 250 mg (53% 
coefficient of variation), eight subjects per group will provide 84% power to detect a 
2-fold difference in AUC0-inf between the renal impaired group and the control 
group with normal renal function. 
Subjects who withdraw from the study or do not complete the study may be 
replaced as deemed necessary after agreement between the sponsor or its 
representative and investigator. 
2 
SUBJECT POPULATIONS (ANALYSIS SETS) 
2.1 
Efficacy 
There is no efficacy assessment in this study. 
2.2 
Safety 
The safety population is all subjects who received the single oral dose of study 
drug. 
2.3 
Pharmacokinetics 
The pharmacokinetics valid population is all subjects who received the single oral 
dose and have no major protocol deviations affecting the PK variables and for 
whom the renal function group is assessable and who have a sufficient number of 
plasma concentrations to estimate the main PK parameters. 
2.4 
Included population 
The included population is all screened subjects who are included in the study. 
2.5 
Screened population 
The screened population is all subjects screened i.e. who signed the informed 
consent. 
2.6 
Primary population 
The analyses of safety data will be performed based on the safety population. The 
analyses of PK will be performed on the PK population. 
3 
STATISTICAL METHODS 
3.1 
Statistical analysis strategy 
The statistical analyses will be performed in accordance with ICH E9 guideline and 
will be based on the pooled data from the individual study sites, unless otherwise 
stated. 
Statistical analyses described in this document will be performed by Biotrial 
Biometrics, Rennes, France. 
3.1.1 
Primary efficacy endpoint 
There is no efficacy assessment in this study. 
3.1.2 
Secondary efficacy endpoint 
There is no efficacy assessment in this study. 


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3.1.3 
Pharmacokinetic endpoints 
The following PK plasma parameters for total telotristat ethyl, its active metabolite 
telotristat (LP-778902) and its inactive metabolite (LP-951757) will be derived by 
non-compartmental analysis of the plasma concentration-time profiles on Day 1 
(pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours post-dose), Day 2 (24 h), Day 3 (48 h) and 
Day 4 (72 h): 
 
Cmax: Maximum observed plasma drug concentration 
 
tmax: Time to maximum observed plasma concentration 
 
AUC0-inf: Area under the plasma concentration-time curve from time 0 to 
infinity calculated as follows:  
AUC0-inf = AUC0-tlast + Clast/Ȝz, 
with Clast as the last quantifiable concentration 
 
AUC0-tlast: Area under the plasma concentration-time curve from 0 to time t 
corresponding to the last quantifiable concentration 
 
t1/2: Apparent terminal elimination half-life calculated as follows: 
t1/2 = Ln(2)/Ȝz 
 
Ȝz: Apparent first order terminal elimination rate constant 
 
CL/F: Apparent total clearance from plasma 
 
Vz/F: Apparent volume of distribution 
 
fu: Unbound plasma fraction, there will be 4 replicates by timepoint. 
For Cmax and AUC, the following active metabolite/parent (i.e telotristat ethyl) and 
active metabolite (LP-778902)/[active metabolite+ telotristat ethyl] ratios 
(normalized and not normalized) will also be calculated: 
 
MRCmax = (Cmax LP-778902)/ (Cmax telotristat ethyl) 
 
MRCmaxNorm = (Cmax LP-778902/Molecular weight(MW)LP-778902)/ (Cmax 
telotristat ethyl/MWtelotristat ethyl) 
 
MRAUC0-inf = (AUC0-inf LP-778902)/ (AUC0-inf telotristat ethyl) 
 
MRAUC0-infNorm = (AUC0-inf LP-778902/MWLP-778902)/ (AUC0-inf telotristat 
ethyl/MWtelotristat ethyl) 
 
MRAUC0-tlast = (AUC0-tlast LP-778902)/ (AUC0-tlast telotristat ethyl) 
 
MRAUC0-tlastNorm = (AUC0-tlast LP-778902/MWLP-778902)/ (AUC0-tlast telotristat 
ethyl/MWtelotristat ethyl) 
 
MRCmaxTotal = (Cmax LP-778902)/ (Cmax LP-778902 + Cmax telotristat ethyl) 
 
MRCmaxTotalNorm = (Cmax LP-778902/MWLP-778902)/ (Cmax LP-778902/MWLP-
778902 + Cmax telotristat ethyl/MWtelotristat ethyl) 
 
MRAUC0-infTotal = (AUC0-inf LP-778902)/ (AUC0-inf LP-778902 + AUC0-inf 
telotristat ethyl) 
 
MRAUC0-infTotalNorm = (AUC0-inf LP-778902/MWLP-778902)/ (AUC0-inf LP-
778902/MWLP-778902 + AUC0-inf telotristat ethyl/MWtelotristat ethyl 
 
MRAUC0-tlastTotal = (AUC0-tlast LP-778902)/ (AUC0-tlast LP-778902 + AUC0-tlast 
telotristat ethyl) 
 
MRAUC0-tlastTotalNorm = (AUC0-tlast LP-778902/MWLP-778902)/ (AUC0-tlast LP-
778902/MWLP-778902 + AUC0-tlast telotristat ethyl/MWtelotristat ethyl) 


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For the calculation of metabolic ratios (MR) for AUC0-tlast, tlast for telotristat ethyl 
could be different from tlast for its active metabolite telotristat (LP-778902). 
 
The amount of unchanged telotristat ethyl and its active metabolite telotristat (LP-
778902) excreted in urine (Ae) will also be determined (where possible). 
 
3.1.4 
Protein binding endpoints 
The unbound concentrations for telotristat ethyl, its active metabolite telotristat (LP-
778902) and its inactive metabolite (LP-951757) will be derived at each time point 
available as follows : Cu = CTotal*mean(fu), where mean(fu) represents the mean of 
the unbound fractions by timepoint. 
 
The following PK parameters for unbound telotristat ethyl and its active metabolite 
telotristat (LP-778902) will be calculated using the unbound fraction Fu (defined for 
each subject as the mean over all time points of the mean of fu): 
 
Cmaxu: Maximum plasma concentration calculated by: Cmaxu=Cmax*Fu 
 
AUC0-infu: Area under the concentration-time curve unbound from 0 to 
infinity calculated by: AUC0-infu=AUC0-inf*Fu 
 
AUC0-tlastu: AUC from 0 to the last quantifiable unbound concentration 
calculated by: AUC0-tlastu=AUC0-tlast*Fu 
 
CLu/F: Apparent total clearance from plasma calculated by: CLu/F=CL/F*Fu 
 
Vzu/F: Apparent volume of distribution calculated by: Vzu/F=Vz/F*Fu. 
For Cmaxu and AUCu, the following MR (normalized and not normalized) will also 
be calculated: 
 
MRCmaxu = (Cmaxu LP-778902)/ (Cmaxu telotristat ethyl) 
 
MRCmaxuNorm = (Cmaxu LP-778902/Molecular weight(MW)LP-778902)/ (Cmaxu 
telotristat ethyl/MWtelotristat ethyl) 
 
MRAUC0-infu = (AUC0-infu LP-778902)/ (AUC0-infu telotristat ethyl) 
 
MRAUC0-infuNorm = (AUC0-infu LP-778902/MWLP-778902)/ (AUC0-infu telotristat 
ethyl/MWtelotristat ethyl) 
 
MRAUC0-tlastu = (AUC0-tlastu LP-778902)/ (AUC0-tlastu telotristat ethyl) 
 
MRAUC0-tlastuNorm 
= 
(AUC0-tlastu 
LP-778902/MWLP-778902)/ 
(AUC0-tlastu 
telotristat ethyl/MWtelotristat ethyl) 
 
MRCmaxuTotal = (Cmaxu LP-778902)/ (Cmaxu LP-778902 + Cmaxu telotristat ethyl) 
 
MRCmaxuTotalNorm = (Cmaxu LP-778902/MWLP-778902)/ (Cmaxu LP-778902/MWLP-
778902 + Cmax telotristat ethyl/MWtelotristat ethyl) 
 
MRAUC0-infuTotal = (AUC0-infu LP-778902)/ (AUC0-infu LP-778902 + AUC0-infu 
telotristat ethyl) 
 
MRAUC0-infuTotalNorm = (AUC0-infu LP-778902/MWLP-778902)/ (AUC0-infu LP-
778902/MWLP-778902 + AUC0-infu telotristat ethyl/MWtelotristat ethyl 
 
MRAUC0-tlastuTotal = (AUC0-tlastu LP-778902)/ (AUC0-tlastu LP-778902 + AUC0-
tlastu telotristat ethyl) 
 
MRAUC0-tlastuTotalNorm = (AUC0-tlastu LP-778902/MWLP-778902)/ (AUC0-tlastu LP-
778902/MWLP-778902 + AUC0-tlastu telotristat ethyl/MWtelotristat ethyl) 


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3.1.5 
Safety endpoints 
The safety endpoints are: 
 
AEs; 
 
Clinical safety endpoints: physical examination, vital signs, 12-lead ECGs; 
 
Clinical laboratory tests: haematology, coagulation, biochemistry, urinalysis; 
 
Pregnancy tests at screening, Day -1 and EOS/ Early discontinuation visit. 
3.1.6 
Multiplicity 
A multiplicity correction will be used in the statistical analysis to compare renal 
impaired function groups to the healthy group. A Bonferroni procedure will be used 
to keep the overall type 1 error equals to 10%. For each test, the statistical level of 
significance will be 10% divided by the number of hypotheses tested. 
3.1.7 
Significance testing and estimation 
A 90% confidence interval (CI) will be calculated for the geometric least square 
mean ratios from the analysis of the variance (ANOVA) on the log transformed 
Cmax, AUC0-inf and AUC0-tlast to illustrate the difference between renal impaired 
group versus the control group with normal renal function. If the data permitted, 
90% CI will also be calculated for PK parameters of the unbound fractions. 
Moreover, 90% CI of the median difference for tmax will be produced using Hodges-
Lehmann estimation. 
The statistical analysis of safety is only descriptive therefore no formal statistical 
significance testing will be performed. 
3.2 
Analysis methods 
3.2.1 
Efficacy 
Not applicable. 
3.2.2 
Pharmacokinetics 
The PK analysis will be performed by a non-compartmental approach using 
Phoenix£ WinNonLin£ version 7.0 (Pharsight) and will be performed on the PK 
population. 
3.2.2.1 
PK parameters calculation 
The Ipsen PDM (Pharmacokinetics Drug Metabolism) instructions (version dated 
20JUN2014) for PK parameters calculation will be followed. 
The following rules will be used: 
 
Actual sampling times will be used for deriving PK parameters. 
 
If an entire concentration-time profile is below the limit of quantification 
(BLQ), the profile will be excluded from the PK analysis 
 
For plasma concentrations: all BLQ values occurring before Cmax will be 
replaced by 0, the first BLQ concentration after Cmax will be replaced by 
LOQ/2 and the following BLQ concentrations after Cmax will be treated as 
missing. 
 
A non-BLQ data after 2 BLQ data or a BLQ data between 2 measurable 
concentrations will be treated as missing. 
 
If the pre-dose concentration is  5% of the Cmax value for a particular subject, 
that subject’s data without baseline correction can be included in all PK and 
statistical analysis. If the pre-dose value is > 5% of Cmax, descriptive statistics 
will be reported with and without the specific concerned subject(s). 


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 
If the percentage of extrapolated part of AUC0-inf exceeds 20% of AUC0-inf, the 
value of AUC0-inf is not reported. 
 
All estimations of Ȝz will be determined using at least the three last measurable 
concentration data (excluding the Cmax) and over a time interval equal to at 
least 2 times the estimated elimination half-life (t1/2). Moreover, only those data 
points judged to describe the terminal log-linear decline resulting in an 
adjusted coefficient of determination value > 0.7 will be used in the regression. 
If at least one of these 3 conditions is not fulfilled Ȝz will be flagged. If Ȝz is 
flagged, the derived parameters (t1/2, AUC0-inf…) are flagged accordingly. 
 
The AUC will be estimated using lin/log trapezoidal rule with at least 4 
measurable concentrations including at least 3 consecutive time points. 
 
AUC of a subject should represent more than 5% of the geometric mean AUC 
for each renal function group. If not, the subject is considered to have a very 
low plasma concentration and is not included in the calculation of descriptive 
statistics. However, concentrations for that subject will be reported in the 
appendix of the report. 
 
If the conditions on PK parameters detailed above are not fulfilled, unreliable 
PK parameters will be flagged in listings and excluded from the analysis. 
Following oral administration of telotristat etiprate, absorption of telotristat ethyl 
was rapid and it was almost completely converted to the active metabolite telotristat 
(LP-778902). Therefore, as reported in the previous studies, some PK parameters 
for telotristat ethyl may not be calculated due to the telotristat ethyl concentrations 
being under the Limit of Quantification (LOQ). 
 
No quantitative exposure data are available yet on the inactive metabolite (LP-
951757) after oral administration of telotristat etiprate in humans. From the mass-
balance study in humans, around 10% of the inactive metabolite (LP-951757) are 
retrieved in plasma from the initial amount of telotristat etiprate. Therefore, some 
LP-951757 concentrations may be under the LLOQ, making the estimation of the 
corresponding PK parameters difficult. 
3.2.2.2 
Descriptive statistics and listings 
Descriptive summaries for each renal function group (arithmetic means, Standard 
Deviation (SD), Coefficient of Variation (CV%), geometric mean, geometric CV%, 
median, minimum, maximum, n and missing) of the plasma concentrations are 
calculated only if at least 2/3 of the data are above LOQ. If not, only minimum and 
maximum are reported. 
For descriptive statistics on concentration data, the following rules will be followed: 
For BLQ concentrations before Cmax: 
 
If at least 2/3 of values are either BLQ values replaceable by zero and/or 
numeric values: statistics will be calculated considering replaceable and 
numeric values. 
 
If more than 1/3 of values are BLQ values not replaceable by zero (i.e. 
subjects for whom all values are BLQ): mean (SD) will not be calculated and 
considered as BLQ. Minimum (BLQ) and maximum value will be presented. 
 
For BLQ concentrations after Cmax: 
 
If at least 2/3 of values are not BLQ: statistics will be calculated with BLQ 
values replaced by the numerical value (LOQ/2). 


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 
If more than 1/3 of values are BLQ: mean (SD) will not be calculated and 
considered as BLQ. Minimum (BLQ) and maximum value will be presented. 
 
Descriptive summaries (arithmetic mean, SD, CV%, geometric mean, geometric 
CV%, median, minimum, maximum, n and missing) of the PK parameters will be 
presented by renal function group. Only median, [Min-Max] and n will be reported 
for tmax. 
 
The descriptive statistics on the PK parameters will be calculated only if at least 2/3 
of the data are well determined. Otherwise only minimum and maximum values will 
be reported. 
 
All concentrations below LOQ or missing data will be labelled as such in the 
concentration data listings. 
In case of outliers, two analyses will be performed: one considering the outliers and 
one excluding the outliers. 
All listings will be sorted by renal function group, subject and measurement time. 
 
3.2.2.3 
Graphical representations 
The following rules for plasma concentration versus time graphic representation will 
be used: 
 
No graphic representation will be made if all values are BLQ. 
 
BLQ values occurring before Cmax will be replaced by “0”. 
 
The first BLQ concentration after Cmax will be replaced by LOQ/2 and the 
following BLQ concentrations after Cmax will be treated as missing. 
Nominal times are to be used to display the concentration plots. 
The graphic representation of PK parameters will be made only if at least 2/3 of the 
data are well determined. 
3.2.2.4 
Statistical analyses 
3.2.2.4.1 Plasma pharmacokinetics 
For each of the 3 analytes, listings with plasma concentrations (including PK blood 
sampling dates and times), plasma PK parameters and metabolic ratios will be 
provided by renal function group and subject. 
Descriptive statistics on plasma concentrations of telotristat ethyl, its active 
metabolite telotristat (LP-778902) and its inactive metabolite (LP-951757) will be 
computed for each renal function group, overall and by gender. 
The individual plasma concentration-time profiles of telotristat ethyl, its active 
metabolite telotristat (LP-778902) and its inactive metabolite (LP-951757) will be 
presented graphically on linear and log/linear coordinates for each renal function 
group in a separated graph, using different colors for males and females. Graph of 
arithmetic mean (±SD) on linear and log/linear coordinates will be presented with 
all renal function groups on the same graph and also for each renal function group 
by gender. All graphs will be presented on scales 0-24 h and 0-72 h. 
 
Descriptive statistics on PK parameters and metabolic ratios for telotristat ethyl, its 
active metabolite telotristat (LP-778902) and its inactive metabolite (LP-951757) 
will be computed for each renal function group, overall and by gender. 


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Scatter plots and box-whisker plots will be presented for the comparison of Cmax, 
AUC0-tlast and AUC0-inf of renal function groups versus healthy control group, 
overall and by gender. 
Additionally, for each of the 3 analytes, a linear-linear plot will be performed for 
Cmax, AUC0-inf and AUC0-tlast, with individual PK parameters (y-axis) versus the 
respective individual estimated GFR value at baseline (x-axis). All subjects will be 
on the same graph. 
 
An ANOVA will be performed separately for each renal impaired function group on 
the natural log-transformed Cmax, AUC0-tlast and AUC0-inf for both telotristat ethyl 
and its active metabolite with renal function group as a fixed term. Geometric mean 
ratios and corresponding 90% CI for each renal impaired group (Test) versus the 
healthy control group (Reference) will be computed using the following sample 
SAS code: 
proc mixed data=ADPP; 
where=(<Renal function group> in (Healthy Severe) 
/* (Healthy Moderate) (Healthy Mild) */); 
model log(AVAL) = <Renal function group>; 
lsmeans <Renal function group> / cl alpha=0.10/<nb of hypotheses>; 
estimate "Renal impaired / Healthy" <Renal function group> -1 1 / cl 
alpha=0.10/<nb of hypotheses>; 
run; 
 
The resulting least-squares (LS) means, difference in LS means between two groups 
(test minus reference), and corresponding 90% CIs will be exponentiated. The 
exponentiation of the difference in LS means will yield the estimated ratio of the PK 
parameter for a renal impaired function group relative to healthy subjects. These 
ratios will be expressed as a percentage relative to the reference group (test [mild, 
moderate, or severe renal impaired groups] versus reference [healthy group]). 
For each test, a Bonferroni correction will be applied to adjust the statistical level of 
significance in order to keep the overall type 1 error equals to 0.10 (see section 3.1.6 
for details). 
No analysis will be performed if more than 1/3 of the values are not determined. 
In case of exclusion of subjects in the severe renal impaired function group or in the 
healthy group, a sensitivity ANOVA will be performed with the included subjects 
and only including their matching subjects. 
 
For tmax, an estimate of the median difference and 90% CI of the median difference 
will be provided using Hodges-Lehmann estimation, based on Walsh averages, 
using the following SAS code: 
proc npar1way hl alpha=0.1 data= ADPP; 
where <Renal function group> in (Severe Healthy) and  
PARAMCD=’TMAX’; 
class <Renal function group>; 
var AVAL; 
exact hl; 
run; 


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The Wilcoxon-Mann-Whitney test will be used to test for the difference in tmax 
between healthy subjects and each renal function group. 
3.2.2.4.2 Urine pharmacokinetics 
Listings with urine concentrations (including PK urine sampling dates and times), 
and urine PK parameters will be provided by renal function group and subject. 
Descriptive statistics on urine concentrations and urine PK parameter (Ae) of 
telotristat ethyl and its active metabolite telotristat (LP-778902) will be computed 
for each renal function group, overall and by gender. 
Individual urine cumulative recovered amount versus time profiles of telotristat 
ethyl and its active metabolite telotristat (LP-778902) will be presented graphically 
for each renal impaired function group with all subjects on the same graph. 
The graph of arithmetic mean + SD over time will be provided for urine 
concentration of telotristat ethyl and its active metabolite telotristat (LP-778902) 
with all renal function groups on the same graph, as well as for urine cumulative 
recovered amount (Ae), overall and by gender. 
 
3.2.2.4.3 Protein binding 
Listings with unbound plasma concentrations (including unbound plasma fraction 
and PK blood sampling dates and times), unbound plasma PK parameters and 
metabolic ratios will be provided by renal function group and subject. 
Descriptive statistics on plasma unbound concentrations of telotristat ethyl, its 
active metabolite telotristat (LP-778902) and its inactive metabolite (LP-951757) 
will be computed for each renal function group, overall and by gender. 
 
Descriptive statistics on unbound PK parameters (including unbound fractions) and 
metabolic ratios for telotristat ethyl, its active metabolite telotristat (LP-778902) and 
its inactive metabolite (LP-951757) will be computed for each renal function group, 
overall and by gender. 
Scatter plots and box-whisker plots will be presented for the comparison of Cmaxu, 
AUC0-tlastu, AUC0-infu and unbound fractions of renal function groups versus healthy 
control group, overall and by gender. 
 
If the data permitted, same ANOVA as above will be performed separately for each 
renal impaired function group on the natural log-transformed Cmaxu, AUC0-tlastu, 
AUC0-infu and unbound fractions (fu; no log-transformed) for both telotristat ethyl 
and its active metabolite with renal function group as a fixed term. The same SAS 
code as the previous analysis will be used. Sensitivity analysis will also be 
conducted, the same method as described above will be used. 
 
3.2.3 
Safety 
All safety data will be included in the data listings and summary tables will be based 
on the safety population. 
3.2.3.1 
Adverse events 
AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) with the current version at Ipsen coding department at the time of 
database lock. 


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Listings will be presented and sorted by renal impaired function group, subject, start 
date-time, primary system organ class, preferred term and reported term for all AEs 
recorded during the study. 
Listings of all AEs, serious adverse events (SAE), AEs leading to withdrawal and 
listing of deaths will also be presented. 
Treatment Emergent Adverse Events (TEAE) will be flagged (*) in the listing of 
AEs and will be summarised. 
A TEAE is defined as any AE that occurs during the active phase of the study (from 
the time of the subject giving informed consent until the EOS/early withdrawal) if: 
 
it was not present prior to administration of IMP, or 
 
it was present prior to administration of IMP but the intensity increased after 
administration of IMP. 
An overall summary table of all AEs will be presented. 
TEAEs will be summarised by renal function group with the number and percentage 
of subjects with AEs classified by primary system organ class and preferred term. 
The number of occurrences of a TEAE will also be presented. 
In addition, summary tables will also be presented for SAEs, serious TEAEs, 
TEAEs by decreasing frequency, TEAEs by maximum intensity, TEAEs by most 
serious causality and TEAEs leading to premature study withdrawal. 
In case of missing intensity, the intensity will be considered as severe and in case of 
missing causality, the causality will be considered as related. 
In the event of multiple reports of the same preferred term being reported by the 
same subject, the maximum intensity (severe > missing> moderate > mild) and the 
most serious causality (related > not related) will be chosen. 
3.2.3.2 
Laboratory data 
3.2.3.2.1 Standardisation 
As in this study several laboratories are involved in the assessment of biological 
samples, a standardisation method will be used in order to take into account the 
differences between the reference ranges of these laboratories. 
The laboratory which analyses the majority of the samples will be used as the 
reference laboratory. 
 
In a general way, standardised values will be assessed using the following formula: 


L
U
L
LRef
URef
LRef
St
X
X
X
X
X
X
X
X




 
 where 
X = measured value 
XL = lower limit value for the laboratory of the measured value 
XU = upper limit value for the laboratory of the measured value 
XLRef = lower limit value for the laboratory chosen as a reference 
XURef = upper limit value for the laboratory chosen as a reference 
 
If a standardised value is negative it will be replaced by 0. 
 
Standardised values will be used for the quantitative analyses, initial values will be 
used for qualitative analyses. 


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3.2.3.2.2 Laboratory data 
Laboratory data will be displayed in International System (SI) units and a separate 
listing of normal ranges for SI units will be provided (by gender and age where 
relevant). 
Laboratory data (haematology, biochemistry, coagulation and urinalysis) will be 
listed in SI units and abnormal values will be flagged (High [H], Low [L], clinically 
significant [CS]) where applicable. Any unscheduled laboratory assessments will be 
flagged [U] in the listings. 
In addition, a listing will be presented of all values for a subject with at least a 
clinically significant abnormal laboratory value. 
The baseline will be defined as the last available (and reliable if applicable) 
assessment collected prior to IMP administration. 
For haematology, biochemistry and coagulation, summary statistics will be 
presented by renal function group at each scheduled assessment for standardised 
values and changes from baseline. For haematology and biochemistry, shift tables 
from baseline to each applicable post baseline visit will be presented using the 
number and percentage of subjects with low, normal or high values. 
For continuous urinalysis, summary statistics will be presented by renal function 
group at each scheduled assessment for standardised values and changes from 
baseline. 
For categorical urinalysis (absent/trace/positive) frequency tables, by renal function 
group, will be presented at each scheduled assessment. 
Subject plots over time representing all subjects on the same graph will also be 
presented for creatinine. Normal ranges will also be displayed. 
3.2.3.3 
Physical examination 
A listing with the date of test will be provided by renal function group, subject and 
date. 
3.2.3.4 
Vital signs 
Vital signs will be listed at each assessment by renal function group and subject. 
Any unscheduled vital signs will be flagged [U] in the listing. 
The baseline will be defined as the last available (and reliable if applicable) 
assessment collected prior to IMP administration. 
Summary statistics by renal function group will be presented at each scheduled 
assessment for actual values and changes from baseline of supine BP, heart rate and 
weight. 
Shift tables will be presented of the number and percentage of subjects with low, 
normal or high values. 
Summary statistics by renal function group will also be presented for body 
temperature at Day-1. 
3.2.3.5 
ECG 
ECG results will be listed at each assessment by renal function group and subject. 
Any unscheduled ECG will be flagged [U] in the listings. 
The baseline will be defined as the last available (and reliable if applicable) 
assessment collected prior to IMP administration. 
For continuous ECG parameters (HR, RR, PR, QRS, QT and QTcF), summary 
statistics by renal function group will be presented at each scheduled assessment for 
actual values and changes from baseline. Shift tables will also be presented using 
the number and percentage of subjects with low, normal or high values. 


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For interpretation of clinical significance (within normal limits / abnormal, not 
clinically significant / abnormal, clinically significant / not evaluable), a frequency 
table will be presented, by renal function group, at each post-dose assessment. 
3.2.3.6 
Pregnancy tests 
A listing with the date of examination, the status of the examination (performed/not 
performed) and the result (positive/negative) will be provided by renal function 
group, subject and examination date. 
3.2.4 
Missing data and outliers 
3.2.4.1 
Missing data 
No missing value will be replaced. 
If a value required a retest, the last reliable non-missing value will be taken into 
account if measured before the administration of IMP; and the first non-missing 
reliable value for post-baseline assessments. An assessment will be considered 
reliable if it is performed without any technical problem and if the result is within 
the range of plausible values. 
Any repeat or additional assessments performed will be included in the individual 
subject data listings. 
If there is a significant number of missing values for a subject (or if there is 
confirmed data appearing spurious), a decision will be made following consultation 
with the sponsor regarding the handling of these data in summaries, prior to 
database lock and will be documented in the minutes of the data review meeting. 
3.2.4.2 
Missing or incomplete dates 
In all listings, missing or incomplete dates should be left as they have been 
recorded. However, for calculation / sorting / assignation based on dates, the 
following methods will be used: 
(1) 
The most conservative approach will be systematically considered (i.e. if the 
onset date of an AE is missing / incomplete, it is assumed to have occurred 
during the study treatment phase (e.g. a TEAE for AEs) except if the partial 
onset date or other data [stop date, …] indicates differently). 
(2) 
A missing/incomplete date of medical history or disease diagnosis will be 
assumed to have occurred before any study treatment. 
(3) 
If a partial date and the associated information do not allow to state about the 
assignation to a group / category, all the possible groups / categories will be 
considered (e.g. a medication with partial start and stop dates could be 
considered as prior and concomitant treatment). 
(4) 
Where this is possible, the derivations based on a partial date will be 
presented as superior inequalities (e.g. for an AE started in FEB2004 after the 
administration performed on 31JAN2004, the days since last dose will be 
“ 2”, similarly the duration of ongoing AEs or medication will be “ xx” 
according to the start and last visit dates). 
3.2.4.3 
Outliers 
Any outlier which is implausible will be excluded from the analysis and will be 
documented in the minutes of the data review or in a note-to-file. For other 
identified outliers, the impact should be assessed by performing the statistical 
analysis with the actual values and at least one other analysis eliminating or 
reducing the outlier effect. 
 


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3.2.5 
Subject disposition 
A listing of screen failures and a listing of subject disposition will also be presented 
on the screened population. 
The number and percentage of subjects screened and included in each analysis 
population will be presented by renal function group and overall for the screened 
population. 
A listing of the inclusion and exclusion criteria will be provided by renal function 
group and subject as well as listings of subjects with inclusion or exclusion criteria 
not respected. Subject eligibility will also be listed. 
The reasons for subject exclusions from each population will also be tabulated and 
listed by renal function group on the included population. 
A summary table will present the extent of subject duration in the study for each 
renal function group. The definition of the length of study duration is calculated 
from the date of administration to the last study visit. 
A listing of dates of assessments and their study duration will be presented by 
subject for each renal function group. The number and percentage of subjects at 
each planned visit during the study will be presented, by renal function group for the 
Safety population. 
3.2.6 
Withdrawals 
Discontinued subjects will be listed with their reasons for withdrawal and a 
summary table of the number and percentage of subjects who withdrew from the 
study and the reasons for withdrawal will be presented by renal function group for 
the included population. 
3.2.7 
Demographic and baseline characteristics 
The baseline will be defined as the last available (and reliable if applicable) 
assessment collected prior to IMP administration. 
All demographic (sex, ethnicity, race) and baseline characteristics (age, height, body 
weight and BMI at baseline) as well as the substance use (tobacco, caffeine and 
alcohol) will be listed by renal function group and subject. 
Summary statistics will be provided for demographic and baseline characteristics as 
well as the substance use, by renal function group on the Safety population. 
The results of urine drug of abuse tests, alcohol breath test, serology, 
postmenopausal status and FSH (if applicable) will only be provided in the 
demographics data listings. 
Number and percentages of subjects in each renal function classification will be 
tabulated by renal function group and renal classification will also be listed with the 
eGFR results by renal function group on the safety population. 
3.2.8 
Medical and surgical history 
Medical and surgical history will be coded using MedDRA current version at Ipsen 
coding department at the time of database lock. 
Listings will present the primary system organ class, the preferred term and the 
reported term. The listings will be sorted by renal function group, subject, start date, 
primary system organ class, preferred term and reported term. 
A frequency table of the number and percentage of subjects will be provided for all 
medical and surgical history by primary system organ class and preferred term for 
each renal function group and overall for the Safety population. 


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3.2.9 
Subject compliance 
All treatment administration information will be listed by renal function group and 
subject. 
Protocol deviations, defined prior to database lock, will be listed by renal function 
group and subject. Protocol deviations which exclude a subject from the PK 
population will be flagged. Additionally, major protocol deviations will be 
summarised on the included population. 
3.2.10 
Prior and concomitant medications 
Concomitant medications will be coded using WHO-DD with the current version at 
Ipsen coding department at the time of database lock. The therapeutic class will 
correspond to the second level of Anatomic Therapeutic Class (ATC) code, which 
corresponds to the first 3 digits. 
The date and time of baseline (study day 1) will be used as the cut-off date for the 
definition of prior and concomitant medications. A medication that started before 
study day 1 and is continuing at time of day 1 will be considered as both, prior and 
concomitant. Prior, concomitant and both prior and concomitant medications will be 
flagged P, C and PC respectively, in all listings. 
Listings will be presented for the therapeutic class, preferred name and reported 
name. The listings will be sorted by renal function group, subject, chronological 
start date, therapeutic class, preferred name and reported name. 
Frequency tables of the number and percentage of subjects with at least one 
concomitant medication will be provided by therapeutic class and preferred name 
for each renal function group and overall. 
3.2.11 
Prior and concomitant non-drug therapies 
Prior and concomitant non-drug therapies will be coded using MedDRA Dictionary 
with the current version at Ipsen coding department at the time of database lock.  
Prior and concomitant non-drug therapies will be listed by renal function group, 
subject, chronological start date, primary system organ class, preferred term, and 
reported term. 
3.2.12 
Concomitant surgical procedures 
Concomitant surgical procedures will be coded using MedDRA Dictionary with the 
current version at Ipsen coding department at the time of database lock. 
Concomitant surgical procedures will be listed by renal function group, subject, 
chronological start date, primary system organ class, preferred term, and reported 
term.  
3.2.13 
Derived data 
The derived data are variables which are calculated from the raw data in the eCRF 
and not included in the database and will be included in the listings (see Appendix 
1). 
3.2.14 
Rules and data formats 
Data will be presented using an appropriate number of decimal places (i.e. the 
number of decimal places used does not imply undue precision). Raw data will be 
presented with the number of decimal places collected, and derived data will be 
presented to an appropriate number of decimal places. The appropriate number of 
decimal places will be determined by general practice, mathematical rationale or 
scientific rationale (e.g. age should be presented in whole numbers). For plasma 


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concentrations and PK parameters, all values will be reported with 3 significant 
digits for numbers < 1000, otherwise values will not be rounded. 
For summary statistics, the following will be presented: n, missing, arithmetic mean, 
standard deviation, median and the range (minimum, maximum). Geometric mean, 
CV% and geometric CV% will also be presented for plasma concentrations and PK 
parameters (where applicable). 
Mean, median and standard deviation values will be reported with one decimal 
place greater than the raw/derived data that they summarise. Minimum and 
maximum values will be reported with the same precision as the raw data. For 
plasma concentrations and PK parameters, all statistics will be reported with 3 
significant digits for numbers < 1000, otherwise values will not be rounded. 
CV% and ratio will be presented with one decimal place. 
Percentages will be reported with 1 decimal place and 0% will not be presented. 
Percentages will be calculated using a denominator of all subjects in a specified 
population and by renal function group. The denominator will be specified in a 
footnote to the tables for clarification if necessary. 
All values below or above a limit of detection (e.g. < 0.1 or > 100) will be listed as 
such. For each safety parameter for which it is possible to have values below or 
above LOQ, the rule to be used in the statistical tables is to replace values below or 
above a limit of quantification by LOQ. Rules for BLQ plasma concentrations are 
detailed in section 3.2.2.1. 
All text fields must be left justified and numeric or numeric with some text 
specification (e.g. not done, unknown, < 4.5, …) must be decimal justified. Dates 
will be presented in the format [yyyy-mmm-dd] and times in the format [hh:mm]. 
3.2.15 
Pooling of Centres 
It is not planned to perform a subgroup analysis on individual or groups of centres. 
3.2.16 
Interim analysis 
There will be an interim analysis of PK and safety data following the completion of 
subjects with severely impaired renal function and demographically-matched 
healthy subjects with normal renal function (Part A) to determine whether subjects 
with mildly, and moderately impaired renal function (Part B) will be enrolled in the 
study. 
3.2.17 
Role of data review committee (DRC) 
Decision to include (or not) subjects with mildly impaired renal function and 
subjects with moderately impaired renal function will be made by a committee 
(comprising at least the co-ordinating principal investigator and the sponsor’s 
medical monitor), and will be based on the PK evaluation of the Part A subjects and 
the observation of a 2-fold increase in total and unbound fraction of either the 
maximal plasma concentration (Cmax) or plasma exposure (AUC) of the active 
metabolite telotristat. 
Decision will not be based on the PK evaluation of the telotristat ethyl since it is 
rapidly converted to its active metabolite, but also because its PK profile might not 
be fully characterised because of anticipated low (or below limit of quantification) 
plasma concentrations. 
3.2.18 
Covariates and analysis of subgroups 
Descriptive statistics and graphs for plasma and urine concentrations and plasma PK 
parameters of telotristat ethyl, its active metabolite telotristat (LP-778902) and its 
inactive metabolite (LP-951757) as well as Ae will be also performed by gender. 


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4 
COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS 
4.1 
Hardware 
The statistical analysis will be performed using PC on a Windows 7 Professionnel 
operating system. 
4.2 
Software 
Pharmacokinetic data will be analysed using Phoenix£ WinNonLin£ version 7.0 
(Pharsight). 
All TFLs will be produced and statistical analysis performed using SAS version 9.4 
[2]. All outputs will be in Microsoft Word Format. 
4.3 
Validation programs 
Biotrial Biometrics will provide a validation plan to Ipsen identifying the methods 
of validation. 
The study statistician is responsible for reviewing each output associated with the 
deliverable product. Program logs are checked by the statistical programmer for 
logical, syntax and fatal errors. The checks in SAS includes, but is not limited to, all 
ERRORS, 
WARNINGS, 
BY-VALUE 
merge 
messages, 
NOTES, 
and 
UNINITIALIZED variables. Program logs are also reviewed for accurate and 
consistent variable and observation counts following each procedure and data step. 
The study statistician is responsible for checking and reviewing the work produced 
using whatever method he/she feels is appropriate (e.g. SAS code review, hand 
calculation, etc.) to reassure of the quality of the output. 
Outputs are reviewed for typographical errors, misspellings and nonsensical values 
or results and to check the consistency with the statistical analysis plan. Outputs are 
cross-checked against each other for accuracy and consistency. For statistical tables, 
listings, appendix listings, and figures, this procedure includes comparison of 
subject group numbers, counts of subjects at each observation point, and 
consistency of results for variables between outputs. 
Findings of the quality control reviews are communicated to the party responsible 
for making necessary changes. The programs will be retested after modifications. 
After final review, and when no further change is required to produce the 
deliverable, the statistical programmer and the study statistician have to complete 
and sign the quality control and statistical analysis results follow-up’s validation 
checklist, to indicate that they have successfully performed all of their 
responsibilities. Copies of the internal quality control forms produced for the 
validation process will be provided to the sponsor to support the validation. 
4.4 
Restitution of the programs 
All programs (including macros and analysis datasets) producing the tables, listings 
and statistical outputs along with associated logs should be given to the sponsor 
when the TFLs and statistical analyses have been finalised. 
5 
CHANGES FROM PROTOCOL 
Compared to the final protocol dated 20 December 2017, the included population 
was added in the SAP. 
In section 1.3.2.2, the method of determination of the inactive metabolite (LP-
951757) plasma concentrations was precised based on Clarification N°1 to the 
protocol version 2.0 signed 27 February 2018. 
No other change was stated at the time of finalisation of the SAP. 
 


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6 
REFERENCES 
1. International Conference on Harmonisation (ICH) E9 and Federal register Vol. 63, 
No. 179 (September 1998). 
2. SAS, Version 9.4. SAS Institute Inc., Cary, NC, USA, 2012. 


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7 
APPENDICES TO THE SAP TEMPLATE 
Appendix 1: Derived Data 
 
The following derived data will be calculated: 
(1) 
Study day 
Study day will be defined as ‘-1’ for the day prior to IMP administration and as ‘1’ 
for the day of IMP administration (i.e. day 0 does not exist). 
(2) 
Study duration 
Study duration (days) will be calculated as (last visit attended - date of IMP 
administration) + 1. 
(3) 
Baseline 
Baseline will be derived as the last available (and reliable if applicable) assessment 
before IMP administration. 
(4) 
Changes from baseline 
Changes from baseline will be calculated as the difference from baseline (e.g. 
assessment at the visit – assessment at baseline). 
(5) 
Therapeutic Class 
The therapeutic class will correspond to the first 3 digits of the ATC code. The 
decoding of the therapeutic class will be done from the WHO-DD (current version 
at the time of database lock). 
(6) 
Prior and concomitant flags 
The date and time of baseline (study day 1) is used as the cut-off date for the 
definition of prior and concomitant medications. A medication started before study 
day 1 and continuing at time of Day 1 is considered as both, prior and concomitant. 
Prior, concomitant and both prior and concomitant will be coded as P, C and PC 
respectively. 
(7) 
Prior and concomitant medication duration 
If the start and end dates of the medication are identical then “<1” day will be 
presented with the duration in hh:mm recorded in the eCRF if it is available. If times 
are available, the duration of concomitant treatments will be calculated as (end 
date/time - start date/time). If at least one time is missing, the duration of 
concomitant treatments will be calculated as (end date - start date) + 1. If the 
recorded end date is continuing at the end of the study then the end date will be 
listed as “ongoing” and the duration will be approximated as “(last attended visit 
date – start date) + 1” day(s). If the start date or the end date are partial, the duration 
will be presented as an inequality “xx” day(s) [i.e. 2 where start date=31JAN2004 
and end date=FEB2004 or start date=JAN2004 and end date=01FEB2004] but if 
both are partial or one is missing the duration will not be presented. 
(8) 
Medical and surgical history duration 
The duration of medical and surgical history will be calculated as (end date – start 
date) + 1. If the recorded end date is CONT. (for continuing), the end date will be 
listed as “ongoing” and the duration will be approximated as “ (screening visit date 
– start date)+1” day(s). If the start date or the end date are partial, the duration will 
be presented as an inequality “ xx”day(s) (i.e. 2 where start date=31JAN2004 and 
end date=FEB2004 or start date=JAN2004 and end date=01FEB2004) but if both 
are partial or one is missing the duration will not be presented. 


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(9) 
AE duration 
If the start and end dates of the AE are identical then “<1” day will be presented 
with the duration in hh:mm recorded in the eCRF if it is available. If times are 
available, the duration will be calculated as (end date/time – start date/time) and 
presented in days hh:mm. If at least one time is missing and if the duration is greater 
than 24 hours then it will be calculated as (end date - start date) + 1 and presented in 
days. If the recorded end date is continuing at the end of the study, the end date will 
be listed as “ongoing” and the duration will be approximated as “(last attended 
visit date – start date) + 1” day(s). If the start date or the end date are partial the 
duration will be presented as a superior inequality “xx” day(s) [i.e. 2 where start 
date=31JAN2004 and end date=FEB2004 or start date=JAN2004 and end 
date=01FEB2004]. 
(10) Unbound concentration 
For each subject and at each protein binding timepoint, the mean of the replicates of 
the unbound fractions (fu1, fu2, fu3 and fu4) will be derived. The unbound 
concentrations at time t for telotristat ethyl, its active metabolite telotristat (LP-
778902) and its inactive metabolite (LP-951757) will be derived as follows: Ctu = Ct* 
mean(fu1, fu2, fu3, fu4). 


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Appendix 2: List of TFLs 
 
Listings index 
 
16.1.7 Randomisation Scheme and Codes 
Not applicable 
16.2 SUBJECT DATA LISTINGS 
16.2.1 Discontinued subjects 
Listing 16.2.1.1: 
Subject Disposition – Screened Population 
Listing 16.2.1.2: 
Subject Disposition – Study Withdrawals – Included 
Population 
Listing 16.2.1.3.1: Inclusion Criteria Assessments 
Listing 16.2.1.3.2: Inclusion Criteria not respected– Included Population 
Listing 16.2.1.4.1: Exclusion Criteria Assessments 
Listing 16.2.1.4.2: Exclusion Criteria not respected– Included Population 
Listing 16.2.1.5: 
Screen failures– Screened Population 
Listing 16.2.1.6: 
Assessments Dates – Included Population 
16.2.2 Protocol deviations 
Listing 16.2.2.1: 
Subject Eligibility for the Study – Included Population 
Listing 16.2.2.2: 
Protocol Deviations – Included Population 
Listing 16.2.2.3: 
Reasons for Exclusion from the Populations – Included 
Population 
16.2.3 Subjects excluded from the efficacy analysis 
Not applicable 
16.2.4 Demographic data 
Listing 16.2.4.1: 
Demographics and Baseline Characteristics – Safety 
Population 
Listing 16.2.4.2: 
Alcohol screen – Safety Population 
Listing 16.2.4.3: 
Urine Drug of Abuse Tests – Safety Population 
Listing 16.2.4.4: 
Substance Use – Safety Population 
Listing 16.2.4.5: 
Serology – Safety Population 
Listing 16.2.4.6: 
Postmenopausal Status – Safety Population 
Listing 16.2.4.7: 
FSH – Safety Population 
Listing 16.2.4.8: 
Renal Function Classification – Safety Population 
Listing 16.2.4.9.1: Medical and Surgical History – Reported Terms and 
Associated MedDRA Terms – Safety Population 
Listing 16.2.4.9.2: Medical and Surgical History – Safety Population 
Listing 16.2.4.10.1: Prior and Concomitant Medications – WHO-DD Names – 
Safety Population 
Listing 16.2.4.10.2: Prior and Concomitant Medications – Safety Population 
Listing 16.2.4.11.1: Prior and Concomitant Non-Drug Therapies – Reported 
Terms and Associated MedDRA Terms – Safety Population 


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Listing 16.2.4.11.2: Prior and Concomitant Non-Drug Therapies – Safety  
 
 
Population 
Listing 16.2.4.12.1: Concomitant Surgical Procedures – Reported Terms and 
Associated MedDRA Terms – Safety Population 
Listing 16.2.4.12.2: Concomitant Surgical Procedures – Safety Population 
16.2.5 Compliance and drug concentration data 
Listing 16.2.5.1: 
Study Treatment Administration – Safety Population 
Listing 16.2.5.2: 
Study Duration – Safety Population 
Listing 16.2.5.3.1: Telotristat Ethyl – Plasma Concentrations – Included 
Population 
Listing 16.2.5.3.2: LP-778902 – Plasma Concentrations – Included Population 
Listing 16.2.5.3.3: LP-951757 – Plasma Concentrations – Included Population 
Figure 16.2.5.4.1: Telotristat Ethyl – Individual Plasma Concentration Time 
Curves – Pharmacokinetic Population 
Figure 16.2.5.4.2: LP-778902 – Individual Plasma Concentration Time Curves 
– Pharmacokinetic Population 
Figure 16.2.5.4.3: LP-951757 – Individual Plasma Concentration Time Curves 
– Pharmacokinetic Population 
Listing 16.2.5.5.1: Telotristat Ethyl – Plasma Pharmacokinetic Parameters – 
Pharmacokinetic Population 
Listing 16.2.5.5.2: LP-778902 
– 
Plasma 
Pharmacokinetic 
Parameters 
– 
Pharmacokinetic Population 
Listing 16.2.5.5.3: LP-951757 
– 
Plasma 
Pharmacokinetic 
Parameters 
– 
Pharmacokinetic Population 
Listing 16.2.5.5.4: Metabolic Ratios – Pharmacokinetic Population 
Listing 16.2.5.6.1: Telotristat Ethyl – Urine Concentrations – Included 
Population 
Listing 16.2.5.6.2: LP-778902 – Urine Concentrations – Included Population 
Figure 16.2.5.7.1: Telotristat Ethyl - Individual urine cumulative recovered 
amount versus time profiles – Pharmacokinetic Population 
Figure 16.2.5.7.2: LP-778902 - Individual urine cumulative recovered amount 
versus time profiles – Pharmacokinetic Population 
Listing 16.2.5.8.1: Telotristat Ethyl – Urine Pharmacokinetic Parameters – 
Pharmacokinetic Population 
Listing 16.2.5.8.2: LP-778902 
– 
Urine 
Pharmacokinetic 
Parameters 
– 
Pharmacokinetic Population 
Listing 16.2.5.9.1: Telotristat Ethyl – Unbound Plasma Concentrations – 
Included Population 
Listing 16.2.5.9.2: LP-778902 – Unbound Plasma Concentrations – Included 
Population 
Listing 16.2.5.9.3: LP-951757 – Unbound Plasma Concentrations – Included 
Population 
Listing 16.2.5.10.1: Telotristat Ethyl – Unbound Pharmacokinetic Parameters – 
Pharmacokinetic Population 


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Listing 16.2.5.10.2: LP-778902 – Unbound Pharmacokinetic Parameters – 
Pharmacokinetic Population 
Listing 16.2.5.10.3: LP-951757 – Unbound Pharmacokinetic Parameters – 
Included Population 
Listing 16.2.5.10.4: Metabolic Ratios for Unbound Pharmacokinetic Parameters – 
Pharmacokinetic Population 
16.2.6 Pharmacodynamic data 
Not applicable 
16.2.7 Adverse event listings 
Listing 16.2.7.1: 
Adverse Events Key Information 
Listing 16.2.7.2: 
All Adverse Events – Safety Population 
Listing 16.2.7.3: 
Serious Adverse Events – Safety Population 
Listing 16.2.7.4: 
Adverse Events Leading to Withdrawal – Safety Population 
Listing 16.2.7.5: 
Deaths – Safety Population 
16.2.8 Listing of individual laboratory measurements by subject 
Listing 16.2.8.1: 
Normal Ranges for SI Units 
Listing 16.2.8.2: 
Haematology (SI Units) [Raw Data and Changes from 
Baseline] – Safety Population 
Listing 16.2.8.3: 
Biochemistry (SI Units) [Raw Data and Changes from 
Baseline] – Safety Population 
Listing 16.2.8.4: 
Coagulation (SI Units) [Raw Data and Changes from 
Baseline] – Safety Population 
Listing 16.2.8.5: 
Urinalysis (SI Units) [Raw Data and Changes from Baseline] 
– Safety Population 
Listing 16.2.8.6: 
Pregnancy Test – Safety Population 
16.2.9 Listing of other safety data 
Listing 16.2.9.1: 
Assessment of Physical Examination – Safety Population 
Listing 16.2.9.2: 
Vital Signs [Raw Data and Changes from Baseline] – Safety 
Population 
Listing 16.2.9.3: 
12-lead ECG [Raw Data and Changes from Baseline] – 
Safety Population 
 
Tables index 
 
14. TABLES, FIGURES AND GRAPHS REFERRED TO BUT NOT 
INCLUDED IN THE TEXT 
14.1 DEMOGRAPHIC DATA 
Table 
14.1.1: 
Subjects Populations - Screened Population 
Table 
14.1.2: 
Subjects Disposition - Screened Population 
Table 
14.1.3.1: 
Major Protocol Deviations – Included Population 
Table 
14.1.3.2: 
Reasons for Exclusion from the Populations – Included 
Population 
Table 
14.1.4: 
Subjects Disposition by Visit – Safety Population 
Table 
14.1.5: 
Study Duration – Safety Population 


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Table 
14.1.6: 
Demographics and Baseline Characteristics – Safety 
Population 
Table 
14.1.7: 
Substance Use – Safety Population 
Table 
14.1.8: 
Renal Function Classification – Safety Population 
Table 
14.1.9: 
Medical and Surgical History – Safety Population 
Table 
14.1.10: 
Concomitant Medications – Safety Population 
 
14.2 PHARMACOKINETIC DATA 
14.2.1 PLASMA PHARMACOKINETIC DATA 
Table 
14.2.1.1.1: Telotristat Ethyl Plasma Concentrations (unit) (Summary 
Statistics) – Pharmacokinetic Population 
Table 
14.2.1.1.2: LP-778902 
Plasma 
Concentrations 
(unit) 
(Summary 
Statistics) – Pharmacokinetic Population 
Table 
14.2.1.1.3: LP-951757 
Plasma 
Concentrations 
(unit) 
(Summary 
Statistics) – Pharmacokinetic Population 
Figure 14.2.1.2.1: Graphs of Plasma Concentrations Arithmetic Means (±SD) 
over Time for Telotristat Ethyl – Pharmacokinetic Population 
Figure 14.2.1.2.2: Graphs of Plasma Concentrations Arithmetic Means (±SD) 
over Time for LP-778902 – Pharmacokinetic Population 
Figure 14.2.1.2.3: Graphs of Plasma Concentrations Arithmetic Means (±SD) 
over Time for LP-951757 – Pharmacokinetic Population 
Table 
14.2.1.3.1: Telotristat 
Ethyl 
Plasma 
Pharmacokinetic 
Parameters 
(Summary Statistics) – Pharmacokinetic Population 
Table 
14.2.1.3.2: LP-778902 Plasma Pharmacokinetic Parameters (Summary 
Statistics) – Pharmacokinetic Population 
Table 
14.2.1.3.3: LP-951757 Plasma Pharmacokinetic Parameters (Summary 
Statistics) – Pharmacokinetic Population 
Table 
14.2.1.3.4: Metabolic Ratios (Summary Statistics) – Pharmacokinetic 
Population 
Figure 14.2.1.4.1: Scatter Plots of Cmax, AUC0-tlast and AUC0-inf for Telotristat 
Ethyl – Pharmacokinetic Population 
Figure 14.2.1.4.2: Scatter Plots of Cmax, AUC0-tlast and AUC0-inf for LP-778902 – 
Pharmacokinetic Population 
Figure 14.2.1.4.3: Scatter Plots of Cmax, AUC0-tlast and AUC0-inf for LP-951757 – 
Pharmacokinetic Population 
Figure 14.2.1.5.1: Box-Whisker Plots of Cmax, AUC0-tlast and AUC0-inf for 
Telotristat Ethyl – Pharmacokinetic Population 
Figure 14.2.1.5.2: Box-Whisker Plots of Cmax, AUC0-tlast and AUC0-inf for LP-
778902 – Pharmacokinetic Population 
Figure 14.2.1.5.3: Box-Whisker Plots of Cmax, AUC0-tlast and AUC0-inf for LP-
951757 – Pharmacokinetic Population 
Figure 14.2.1.6.1: Plots of Cmax, AUC0-tlast and AUC0-inf versus individual eGFR 
values for Telotristat Ethyl – Pharmacokinetic Population 
Figure 14.2.1.6.2: Plots of Cmax, AUC0-tlast and AUC0-inf versus individual eGFR 
values for LP-778902 – Pharmacokinetic Population 


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Figure 14.2.1.6.3: Plots of Cmax, AUC0-tlast and AUC0- inf versus individual eGFR 
values for LP-951757 – Pharmacokinetic Population 
Table 
14.2.1.7.1.1: Comparison of Cmax, AUC0-tlast and AUC0-inf for Telotristat 
Ethyl between each Renal Impairment Group and Healthy 
Control Group (ANOVA) – Pharmacokinetic Population 
Table 
14.2.1.7.1.2: Comparison of Cmax, AUC0-tlast and AUC0-inf for Telotristat 
Ethyl between each Renal Impairment Group and Healthy 
Control 
Group 
(ANOVA) 
– 
Sensitivity 
analysis 
– 
Pharmacokinetic Population 
Table 
14.2.1.7.2.1: Comparison of Cmax, AUC0-tlast and AUC0-inf  for LP-778902 
between each Renal Impairment Group and Healthy Control 
Group (ANOVA) – Pharmacokinetic Population 
Table 
14.2.1.7.2.2: Comparison of Cmax, AUC0-tlast and AUC0-inf for LP-778902 
between each Renal Impairment Group and Healthy Control 
Group (ANOVA) - Sensitivity analysis – Pharmacokinetic 
Population 
Table 
14.2.1.8.1: Comparison of tmax for Telotristat Ethyl between each Renal 
Impairment Group and Healthy Control Group (Hodges-
Lehmann Estimation) – Pharmacokinetic Population 
Table 
14.2.1.8.2: Comparison of tmax for LP-778902 between each Renal 
Impairment Group and Healthy Control Group (Hodges-
Lehmann Estimation) – Pharmacokinetic Population 
14.2.2 URINE PHARMACOKINETIC DATA 
Table 
14.2.2.1.1: Telotristat Ethyl Urine Concentrations (unit) (Summary 
Statistics) – Pharmacokinetic Population 
Table 
14.2.2.1.2: LP-778902 Urine Concentrations (unit) (Summary Statistics) 
– Pharmacokinetic Population 
Figure 14.2.2.2.1: Telotristat Ethyl – Graphs of Urine Concentrations 
Arithmetic Means (+SD) – Pharmacokinetic Population 
Figure 14.2.2.2.2: LP-778902 - Graphs of Urine Concentrations Arithmetic 
Means (+SD) – Pharmacokinetic Population 
Table 
14.2.2.3.1: Telotristat Ethyl Urine PK parameters (Summary Statistics) – 
Pharmacokinetic Population 
Table 
14.2.2.3.2: LP-778902 Urine PK parameters (Summary Statistics) – 
Pharmacokinetic Population 
Figure 14.2.2.4.1: Telotristat Ethyl – Graphs of Cumulative Recovered Amount-
Time Curves Arithmetic Means (+SD) – Pharmacokinetic 
Population 
Figure 14.2.2.4.2: LP-778902 - Graphs of Cumulative Recovered Amount-Time 
Curves 
Arithmetic 
Means 
(+SD) 
– 
Pharmacokinetic 
Population 
14.2.3 DERIVED UNBOUND PHARMACOKINETIC DATA 
Table 
14.2.3.1.1: Telotristat Ethyl Unbound Plasma Concentrations (unit) 
(Summary Statistics) – Pharmacokinetic Population 
Table 
14.2.3.1.2: LP-778902 
Unbound 
Plasma 
Concentrations 
(unit) 
(Summary Statistics) – Pharmacokinetic Population 


IPSEN GROUP 
D-FR-01017-002 
 
SAP Final Version 2.0: 04 June 2018 
41/43 
CONFIDENTIAL 
 
Table 
14.2.3.1.3: LP-951757 
Unbound 
Plasma 
Concentrations 
(unit) 
(Summary Statistics) – Pharmacokinetic Population 
Table 
14.2.3.2.1: Telotristat Ethyl Unbound Pharmacokinetic Parameters and 
Unbound Fractions (Summary Statistics) – Pharmacokinetic 
Population 
Table 
14.2.3.2.2: LP-778902 Unbound Pharmacokinetic Parameters and 
Unbound Fractions  (Summary Statistics) – Pharmacokinetic 
Population 
Table 
14.2.3.2.3: LP-951757 Unbound Pharmacokinetic Parameters and 
Unbound Fractions (Summary Statistics) – Pharmacokinetic 
Population 
Table 
14.2.3.2.4: Metabolic Ratios for Unbound Pharmacokinetic Parameters 
(Summary Statistics) – Pharmacokinetic Population 
Figure 14.2.3.3.1: Scatter Plots of Cmaxu, AUC0-tlastu, AUC0-infu and unbound 
fractions for Telotristat Ethyl – Pharmacokinetic Population 
Figure 14.2.3.3.2: Scatter Plots of Cmaxu, AUC0-tlastu, AUC0-infu and unbound 
fractions for LP-778902 – Pharmacokinetic Population 
Figure 14.2.3.3.3: Scatter Plots of Cmaxu, AUC0-tlastu, AUC0-infu and unbound 
fractions for LP-951757 – Pharmacokinetic Population 
Figure 14.2.3.4.1: Box-Whisker Plots of Cmaxu, AUC0-tlastu, AUC0-infu and 
unbound fractions for Telotristat Ethyl – Pharmacokinetic 
Population 
Figure 14.2.3.4.2: Box-Whisker Plots of Cmaxu, AUC0-tlastu, AUC0-infu and 
unbound fractions for LP-778902 – Pharmacokinetic 
Population 
Figure 14.2.3.4.3: Box-Whisker Plots of Cmaxu, AUC0-tlastu, AUC0-infu and 
unbound fractions for LP-951757 – Pharmacokinetic 
Population 
Table 
14.2.3.5.1.1: Comparison of Cmaxu, AUC0-tlastu, AUC0-infu and unbound 
fractions 
for 
Telotristat 
Ethyl 
between 
each 
Renal 
Impairment Group and Healthy Control Group (ANOVA) – 
Pharmacokinetic Population 
Table 
14.2.3.5.1.2: Comparison of Cmaxu, AUC0-tlastu, AUC0-infu and unbound 
fractions 
for 
Telotristat 
Ethyl 
between 
each 
Renal 
Impairment Group and Healthy Control Group (ANOVA) – 
Sensitivity analysis – Pharmacokinetic Population 
Table 
14.2.3.5.2.1: Comparison of Cmaxu, AUC0-tlastu, AUC0-infu and unbound 
fractions for LP-778902 between each Renal Impairment 
Group 
and 
Healthy 
Control 
Group 
(ANOVA) 
– 
Pharmacokinetic Population 
Table 
14.2.3.5.2.2: Comparison of Cmaxu, AUC0-tlastu, AUC0-infu and unbound 
fractions for LP-778902 between each Renal Impairment 
Group and Healthy Control Group (ANOVA) - Sensitivity 
analysis – Pharmacokinetic Population 
14.3 SAFETY DATA 
14.3.1 Displays of adverse events 
Table 
14.3.1.1: 
Overall Summary of Adverse Events – Safety Population 


IPSEN GROUP 
D-FR-01017-002 
 
SAP Final Version 2.0: 04 June 2018 
42/43 
CONFIDENTIAL 
 
Table 
14.3.1.2: 
Number (%) of Subjects Reporting Treatment Emergent 
Adverse Events by Primary System Organ Class and 
Preferred Term – Safety Population 
Table 
14.3.1.3: 
Number (%) of Subjects Reporting Serious Adverse Events 
by Primary System Organ Class and Preferred Term – Safety 
Population 
Table 
14.3.1.4: 
Number (%) of Subjects Reporting Serious Treatment 
Emergent Adverse Events by Primary System Organ Class 
and Preferred Term – Safety Population 
Table 
14.3.1.5: 
Number (%) of Subjects Reporting Treatment Emergent 
Adverse Events Leading to Withdrawal by Primary System 
Organ Class and Preferred Term – Safety Population 
Table 
14.3.1.6:  
Number (%) of Subjects Reporting Treatment Emergent 
Adverse Events by Decreasing Frequency of Preferred Term 
– Safety Population  
Table 
14.3.1.7: 
Number (%) of Subjects Reporting Treatment Emergent 
Adverse Events by Maximum Intensity – Safety Population 
Table 
14.3.1.8: 
Number (%) of Subjects Reporting Treatment Emergent 
Adverse Events by Most Serious Causality – Safety 
Population 
14.3.2 Listings of deaths, other serious and significant adverse events 
Not applicable 
 
14.3.3 Narratives of deaths, other serious and certain other significant adverse 
events 
Not applicable 
14.3.4 Abnormal laboratory value listing 
Listing 14.3.4.1:  
Haematology (SI Units): Abnormal Clinically Significant 
Values – Safety Population 
Listing 14.3.4.2:  
Biochemistry (SI Units): Abnormal Clinically Significant 
Values – Safety Population 
Listing 14.3.4.3:  
Coagulation (SI Units): Abnormal Clinically Significant 
Values – Safety Population 
Listing 14.3.4.4:  
Urinalysis (SI Units): Abnormal Clinically Significant Values 
– Safety Population 
14.3.5 Laboratory measurements 
Table 
14.3.5.1.1: Haematology (Summary Statistics on Raw Data with 
Changes from Baseline) – Safety Population 
Table 
14.3.5.1.2: Haematology (Shift Tables) – Safety Population 
Table 
14.3.5.2.1: Biochemistry (Summary Statistics on Raw Data with 
Changes from Baseline) – Safety Population 
Table 
14.3.5.2.2: Biochemistry (Shift Tables) – Safety Population 
Figure 14.3.5.2.3: Biochemistry (Subject Plots over Time) – Safety Population 
Table 
14.3.5.3: 
Coagulation (Summary Statistics on Raw Data with Changes 
from Baseline) – Safety Population 


IPSEN GROUP 
D-FR-01017-002 
 
SAP Final Version 2.0: 04 June 2018 
43/43 
CONFIDENTIAL 
 
Table 
14.3.5.4.1: Urinalysis – Quantitative Parameters (Summary Statistics on 
Raw Data with Changes from Baseline) – Safety Population 
Table 
14.3.5.4.2: Urinalysis – Qualitative Parameters (Frequency Tables) – 
Safety Population 
14.3.6 Other safety data 
Table 
14.3.6.1.1: Vital Signs (Summary Statistics on Raw Data with Changes 
from Baseline) – Safety Population 
Table 
14.3.6.1.2: Vital Signs (Shift Tables) – Safety Population 
Table 
14.3.6.2.1: ECG (Summary Statistics on Raw Data with Changes from 
Baseline) – Safety Population 
Table 
14.3.6.2.2: ECG (Shift Tables) – Safety Population 
Table 
14.3.6.2.3: ECG (Interpretation of Clinical Significance) – Safety 
Population