Clinical trial NCT03286829
Conditions: Healthy Male Subjects
Sponsor: Saniona
Start date: 2017-12-18; Completion date: 2018-02-06
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A randomized, open-label, single-dose, parallel-arm, Phase 1 study to investigate the pharmacokinetic profile of a fixed-dose combination tablet of tesofensine and metoprolol (Tesomet) and co-administration of tesofensine plus commercial metoprolol in adult healthy subjects

Detailed description:
This is a randomized, open-label, parallel-arm study in 60 healthy male subjects who meet the inclusion and none of the exclusion criteria for the study. Each subject will participate in a screening period, a baseline period (the day preceding drug administration), and a single-dose treatment period with an on-site observation period of at least 48 hours after the dose.

Arms: arm 1: A Tesomet FDC tablet (20 mg immediate release \[IR\] metoprolol, 1 mg tesofensine, 80 mg extended release \[ER\] metoprolol) in fasted condition ("High" dose) arm 2: Treatment B (Test 2): A Tesomet FDC tablet (5 mg immediate IR metoprolol, 0.2 mg tesofensine, 20 mg ER metoprolol) in fasted condition. ("Low" dose) arm 3: 1 mg tesofensine (2 tablets of 0.5 mg), 25 mg commercial IR metoprolol (1 tablet of 25 mg), 75 mg commercial ER metoprolol (1 tablet of 25 mg ER metoprolol and 1 tablet of 50 mg ER metoprolol), fasted condition arm 4: A Tesomet FDC tablet (20 mg immediate IR metoprolol, 1 mg tesofensine, 80 mg ER metoprolol in fed condition ("High" dose)
Interventions: intervention 1: Tesomet "High dose" in fasted condition intervention 2: Tesomet "Low dose" in fasted condition intervention 3: Comperator 1 mg tesofensine, 25 mg commercial IR metoprolol, 75 mg commercial ER metoprolol, fasted condition. intervention 4: Tesomet "High dose" in fed condition
Intervention descriptions: intervention 1: To evaluate the PK profile and relative bioavailability of a single dose of the Tesomet fixed-dose combination (FDC) tablet and co-administration of tesofensine plus commercial metoprolol. intervention 2: To evaluate the PK profile and relative bioavailability of a single dose of the Tesomet fixed-dose combination (FDC) tablet and co-administration of tesofensine plus commercial metoprolol. intervention 3: To evaluate the PK profile and relative bioavailability of a single dose of the Tesomet fixed-dose combination (FDC) tablet and co-administration of tesofensine plus commercial metoprolol. intervention 4: To evaluate the PK profile and relative bioavailability of a single dose of the Tesomet fixed-dose combination (FDC) tablet and co-administration of tesofensine plus commercial metoprolol.

Protocol documents:
SAP_002.pdf: 
PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
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TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 1 of 35 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
TM003 
 
A Randomized, Open-label, Single-dose, Parallel-arm, Phase 1 Study to Investigate the 
Pharmacokinetic Profile of a Fixed-Dose Combination Tablet of Tesofensine and Metoprolol 
(Tesomet) and Co-Administration of Tesofensine Plus Commercial Metoprolol in Adult Healthy 
Subjects 
 
 
 
 
 
Version:  Final 1.0 
Date: 19/Jan/2018 
REVISION HISTORY 
Version 
Version Date 
Author 
Summary of Changes Made 
Draft 1.0 
29/Nov/2017 
Kees Duineveld 
New Document 
Draft 2.0 
13/Dec/2017 
Kees Duineveld 
Sponsor Comments processed 
Draft 3.0 
17/Jan/2018 
Kees Duineveld 
Sponsor Comments processed 
Final 1.0 
19/Jan/2018 
Kees Duineveld 
Finalized 
 
 






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TABLE OF CONTENTS 
REVISION HISTORY .................................................................................................................... 1 
SIGNATURE PAGE – SANIONA A/S ......................................................................................... 2 
SIGNATURE PAGE - PAREXEL ................................................................................................. 3 
TABLE OF CONTENTS ................................................................................................................ 4 
LIST OF TABLES .......................................................................................................................... 6 
ABBREVIATION AND ACRONYM LIST .................................................................................. 7 
STATISTICAL ANALYSIS PLAN ............................................................................................. 10 
1. 
STUDY OBJECTIVES.................................................................................................... 10 
1.1 
Primary Objective ............................................................................................... 10 
1.2 
Secondary Objective ........................................................................................... 10 
2. 
STUDY DESIGN ............................................................................................................ 10 
3. 
ENDPOINTS ................................................................................................................... 11 
3.1 
Pharmacokinetics Endpoints ............................................................................... 11 
3.2 
Safety Endpoints ................................................................................................. 12 
4. 
STUDY POPULATION .................................................................................................. 12 
5. 
STATISTICAL BASIS FOR SAMPLE SIZE ................................................................. 12 
6. 
RANDOMIZATION ....................................................................................................... 12 
7. 
STATISTICAL ANALYSIS CONVENTIONS .............................................................. 13 
7.1 
Analysis Variables .............................................................................................. 13 
7.1.1 
Demographic and Background Variables ........................................................13 
7.1.2 
Safety Variables ..............................................................................................14 
7.1.2.1 
Adverse Events ................................................................................14 
7.1.2.2 
Clinical Laboratory Tests .................................................................15 
7.1.2.3 
Vital Signs ........................................................................................15 
7.1.2.4 
Electrocardiograms ..........................................................................16 
7.1.2.5 
Physical Examination .......................................................................16 
7.1.2.6 
Concomitant Medication ..................................................................16 
7.1.3 
Pharmacokinetic Variables ..............................................................................16 
7.1.3.1 
Pharmacokinetic Parameter Calculation Methods ...........................17 
7.2 
Analysis Populations .......................................................................................... 18 
7.2.1 
Randomized Set ...............................................................................................18 
7.2.2 
Safety Population ............................................................................................19 
7.2.3 
Pharmacokinetic Population ............................................................................19 
7.3 
Statistical Analysis Methods .............................................................................. 19 
7.3.1 
Listings and Descriptive Statistics ..................................................................19 


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7.3.2 
Rounding and Decimal Places .........................................................................20 
7.3.3 
Software ..........................................................................................................21 
7.3.4 
Missing Data ...................................................................................................21 
7.3.5 
Interim Analysis ..............................................................................................21 
7.3.6 
Disposition ......................................................................................................21 
7.3.7 
Protocol Deviations .........................................................................................21 
7.3.8 
Demographic Data ...........................................................................................22 
7.3.9 
Concomitant Medication .................................................................................22 
7.3.10 
Exposure to the Investigational Medicinal Product .........................................22 
7.3.11 
Pharmacokinetic Concentrations and Variables ..............................................22 
7.3.11.1 Exploratory Model for Relative Bioavailability ..............................23 
7.3.11.2 Handling of Values Below the Limit of Quantification in 
Concentration Summaries and Listings ...........................................23 
7.3.12 
Safety Analysis ................................................................................................24 
7.3.12.1 Adverse Events ................................................................................24 
7.3.12.2 Clinical Safety Laboratory Tests (hematology, biochemistry and 
urinalysis) .........................................................................................24 
7.3.12.3 Vital Signs ........................................................................................25 
7.3.12.4 Twelve-Lead Electrocardiogram ......................................................25 
7.3.12.5 Physical Examination .......................................................................26 
8. 
REFERENCES ................................................................................................................ 27 
9. 
TABLES AND LISTINGS TO BE INCLUDED IN SECTION 14 OF THE CLINICAL 
STUDY REPORT ............................................................................................................ 28 
10. 
FIGURES ......................................................................................................................... 31 
11. 
LISTINGS TO BE INCLUDED IN SECTION 16 OF THE CLINICAL STUDY REPORT
 ......................................................................................................................................... 32 
12. 
DOCUMENTATION OF STATISTICAL METHODS.................................................. 34 
13. 
APPENDIX 1: SCHEDULE OF ASSESSMENTS ......................................................... 35 
 
 
 


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LIST OF TABLES 
Table 1 
Pharmacokinetic Parameters after Single Dose Administration .............................. 17 
 
 
 


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ABBREVIATION AND ACRONYM LIST  
Abbreviation / Acronym 
Definition / Expansion 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
Anti-HBc 
Hepatitis B core antibody 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
AUC 
Area under the concentration-time curve 
AUC0-48 
AUC from time zero to 48 hours 
BLQ 
Below the lower limit of quantification 
BMI 
Body Mass Index 
Bpm 
Beats per minute 
CPK 
Creatine phosphokinase 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
Cmax 
Maximum observed concentration 
CS 
Clinically significant 
CV 
Coefficient of variation 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
ER 
Extended Release 
FDC 
Fixed-dose combination 
gCV 
Geometric CV 
GGT 
Gamma glutamyl transferase 
gMean 
Geometric Mean 
Hb 
Hemoglobin 
HBsAg 
Hepatitis B surface antigen 
HCT 
Hematocrit 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 


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Abbreviation / Acronym 
Definition / Expansion 
HR 
Heart rate 
IMP 
Investigational Medicinal Product 
IR 
Immediate release 
LDH 
Albumin Lactate dehydrogenase 
LLOQ 
Lower limit of quantification 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
Not clinically significant 
NK 
Not known 
NS 
No Sample 
PK 
Pharmacokinetic 
PT 
Preferred Term 
QTc 
QT interval corrected for HR 
QTcB 
QT interval corrected for heart rate using Bazett’s correction 
QTcF 
QT interval corrected for heart rate using Fridericia’s correction 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation  
SOC 
System Organ Class 
TSH 
Thyroid-stimulating hormone 
t½ 
Apparent terminal elimination half-life  
TEAE 
Treatment-emergent adverse event 
TFL 
Tables, Listings and Figures 
tmax 
Time corresponding to occurrence of Cmax 
WHO-DD 
World Health Organisation - Drug Dictionary 
WBC 
White blood cell 
λz 
Terminal elimination rate constant 


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Statistical Analysis Plan 
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STATISTICAL ANALYSIS PLAN 
The Statistical Analysis Plan (SAP) details the statistical methodology to be used in analyzing study 
data and outlines the statistical programming specifications for the Tables, Listings and Figures (TLFs). 
It describes the variables and populations, anticipated data transformations and manipulations and other 
details of the analyses not provided in the Clinical Study Protocol (CSP). 
The analyses described are based on the final CSP 1.0, dated, 15/Sep/2017.  
The SAP will be finalized prior to database lock and describes the statistical analysis as it is foreseen 
when the study is being planned. If circumstances should arise during the study rendering this analysis 
inappropriate, or if improved methods of analysis should arise, updates to the analyses may be made. 
Any deviations from the SAP after database lock, reasons for such deviations and all alternative or 
additional statistical analyses that may be performed, will be described in a SAP Addendum. 
1. 
STUDY OBJECTIVES 
1.1 
Primary Objective 
 To evaluate the pharmacokinetic (PK) profile and relative bioavailability of a single dose of the 
Tesomet fixed-dose combination (FDC) tablet and co-administration of tesofensine plus 
commercial metoprolol 
1.2 
Secondary Objective 
 To evaluate the PK profile and relative bioavailability of a single dose of the Tesomet FDC 
tablet in fed state 
 To evaluate the PK profile of a single dose of the high and low dose of the Tesomet FDC tablet 
 To evaluate overall safety and tolerability of the Tesomet FDC tablet and co-administration of 
tesofensine plus commercial metoprolol in adult healthy volunteers 
2. 
STUDY DESIGN 
This is a randomized, open-label, parallel-arm study in 60 healthy male subjects who meet the 
inclusion and none of the exclusion criteria for the study. Each subject will participate in a screening 
period, a baseline period (the day preceding drug administration), a single-dose treatment period with 


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an on-site observation period of at least 48 hours after the dose and an end-of-study (EoS) safety 
evaluation 7 days after dosing over the phone.  
Subjects will be admitted to the study center at least 24 hours prior to dosing. Each subject will then be 
randomized to one of the 4 treatment groups and receive one of the following treatments: 
 Treatment A (Test 1): A Tesomet FDC tablet (20 mg immediate release [IR] metoprolol, 1 mg 
tesofensine, 80 mg extended release [ER] metoprolol) in fasted condition (“High” dose) 
 Treatment B (Test 2): A Tesomet FDC tablet (5 mg IR metoprolol, 0.2 mg tesofensine, 20 mg 
ER metoprolol) in fasted condition (“Low” dose) 
 Treatment C (Comparator): 1 mg tesofensine (2 tablets of 0.5 mg), 25 mg commercial IR 
metoprolol (1 tablet of 25 mg), 75 mg commercial ER metoprolol (1 ER tablet of 25 mg and 1 
ER tablet of 50 mg), fasted condition 
 Treatment D (Test 3): A Tesomet FDC tablet (20 mg IR metoprolol, 1 mg tesofensine, 80 mg 
[ER] metoprolol in fed condition (“High” dose) 
3. 
ENDPOINTS 
3.1 
Pharmacokinetics Endpoints 
The following PK parameters for tesofensine and metoprolol will be determined after dosing for all 4 
treatments, as appropriate: 
 Cmax: Maximum tesofensine and metoprolol concentrations determined directly from the 
concentration-time profile 
 AUC0-48: Area under the concentration-time curve (AUC) from pre-dose (time 0) to 48 hours 
postdose calculated using the linear-log trapezoidal rule 
 Tmax: Time of maximum tesofensine and metoprolol concentrations determined directly from 
the concentration-time profile 
 λz: The terminal elimination rate constant determined by selection of at least 3 data points on 
the terminal phase of the concentration-time curves 
 t½: Terminal elimination half-life calculated as: ln2/λz 


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3.2 
Safety Endpoints 
The following safety variables will be recorded at regular intervals during the study: 
 Vital signs supine blood pressure (BP), pulse, body temperature and respiratory rate) 
 Twelve-lead Electrocardiogram (ECG): Heart Rate (HR), PR interval, QRS interval, RR 
interval, QT interval and QT interval corrected for HR (QTc) (Bazett’s correction [QTcB] and 
Fridericia’s correction [QTcF]) 
 Clinical laboratory tests (hematology, clinical chemistry and urinalysis) 
 Adverse event assessments 
 Concomitant medication assessments 
 Physical examinations 
4. 
STUDY POPULATION 
The study population will consist of 60 healthy male subjects. 
Detailed lists of inclusion and exclusion criteria are shown in Sections 4.2 and 4.3 of the CSP. 
5. 
STATISTICAL BASIS FOR SAMPLE SIZE 
Formal sample size calculations were not performed. The number of subjects was chosen based on 
literature and experience from similar studies and is considered sufficient to meet the study objectives. 
No formal statistical test will be performed. Only descriptive statistics for PK and safety data by 
treatment group will be presented. The sample size chosen is therefore judged reasonable to gain 
knowledge regarding key parameters in each of the treatment groups. 
6. 
RANDOMIZATION 
A total of 60 subjects is planned for enrollment in the clinical study (N=15 will be randomly assigned 
to one of the 4 treatment groups). Withdrawn subjects may be replaced after mutual agreement between 
Principal Investigator and Sponsor. 


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Prior to dosing on Day 1, subjects will be assigned a randomization number in accordance with the 
randomization code generated by PAREXEL International. The randomization code will include 3-digit 
subject numbers starting with 101.  
If subjects withdraw prematurely from the study and are replaced under the direction of the Sponsor, 
then a replacement randomization number will be assigned. A replacement randomization code will be 
generated such that replacement subjects are assigned to the same treatment as the discontinued 
subjects. The replacement randomization code will differ only in randomization numbers, which will 
be 4-digit numbers starting with a leading 1 followed by the digits from the randomization number of 
the replaced subject. For example, if Subject 102 withdraws and is replaced, then the randomization 
number for the replacement subject will be 1102. 
7. 
STATISTICAL ANALYSIS CONVENTIONS 
7.1 
Analysis Variables 
7.1.1 
Demographic and Background Variables 
The following demographic and anthropometric information will be recorded: 
 Date of informed consent 
 Medical history (including previous and current medical conditions and medications) 
 History of blood or plasma donation 
 Drug, alcohol, caffeine (or other stimulating beverages) and smoking history 
 Special diet (vegetarian) 
 Age (years) 
 Gender 
 Ethnic origin (Hispanic/Latino or not Hispanic/not Latino) 
 Race (White, Black, Asian, Native Hawaiian or other Pacific Islands, American Indian or 
Alaska Native, Asian-Japanese, Asian-Korean, Other) 
 Height, without shoes (cm) 


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 Body weight (kg) 
 Body mass index (BMI) (kg/m2) 
All medical history will be coded using Version 20.1 of the Medical Dictionary for Regulatory 
Activities (MedDRA). 
7.1.2 
Safety Variables 
7.1.2.1 
Adverse Events 
An Adverse Event (AE) is defined as any untoward medical occurrence in a subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) product. 
All AEs will be coded using Version 20.1 of MedDRA. 
Other untoward events occurring in the framework of a clinical study will be recorded as AEs, e.g., 
those occurring during treatment-free periods (including Screening or post-treatment follow-up 
periods), in association with study-related procedures and assessments. 
Concomitant illnesses, which existed prior to entry into the clinical study, will not be considered AEs 
unless they worsen during the treatment period. Pre-existing conditions will be recorded as part of the 
subject’s medical history. 
Any AE which started or increased in severity after first dosing of investigational medicinal product 
(IMP) is considered a treatment emergent AE (TEAE). 
Any AEs with incomplete start and end dates/times will be treated as follows: 
 Adverse events with unknown start and/or end times (but where the date is known) will be 
imputed with a time of 00:00 h for the tabulations but will be shown as NK:NK in the listings 
(where NK = Not Known). 
o An AE that started or increased in severity on first dosing day of IMP with unknown 
start time will be considered a TEAE unless the end time is known and is before dosing 
time of the IMP 


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 Adverse events with completely unknown start dates will be considered as treatment-emergent 
for the tabulations and will be shown as NK in the listings. 
7.1.2.2 
Clinical Laboratory Tests 
The following safety laboratory parameters will be measured according to the schedule in Appendix 1: 
 Clinical 
Chemistry: 
Alanine 
aminotransferase 
(ALT), 
Glucose, 
Albumin 
Lactate 
dehydrogenase (LDH), Alkaline phosphatase (ALP), Phosphorus, Aspartate aminotransferase 
(AST), Potassium, Blood urea nitrogen (BUN), Sodium, Calcium, Total bilirubin, Chloride, 
Total protein, Cholesterol, Triglycerides, Creatinine, Thyroid-stimulating hormone (TSH), 
Creatine phosphokinase (CPK), Uric acid, Gamma glutamyl transferase (GGT) 
 Hematology: White blood cell (WBC) count, Neutrophils (percentage and absolute count), Red 
blood cell (RBC) count, Lymphocytes (percentage and absolute count), Hemoglobin (Hb), 
Monocytes (percentage and absolute count), Hematocrit (HCT), Eosinophils (percentage and 
absolute count), Mean corpuscular volume (MCV), Basophils (percentage and absolute count), 
Mean corpuscular hemoglobin (MCH), Platelet count, Mean corpuscular hemoglobin 
concentration (MCHC), RBC distribution width  
 Urinalysis: Bilirubin, Blood, Glucose, pH, specific gravity, Ketones, Protein, Leukocytes, 
Urobilinogen, Nitrite  
 Viral Serology: Hepatitis B core antibody (anti-HBc), Human immunodeficiency virus (HIV), 
Hepatitis B surface antigen (HBsAg), (Types 1 and 2) antibodies, Hepatitis A virus antibodies 
(immunoglobulin M), Hepatitis C virus antibody (anti-HCV) 
 Drugs of abuse: Amphetamines, Cocaine, Barbiturates, Opiates, Benzodiazepines, 
Phencyclidine, Cannabinoids, Cotinine, Ethanol 
7.1.2.3 
Vital Signs 
The following vital signs measurements will be obtained according to the schedule in Appendix 1: 
 Systolic blood pressure (SBP) [mmHg] 
 Diastolic blood pressure (DBP) [mmHg] 
 Pulse rate [bpm] 


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 Body temperature (oral) [°C] 
 Respiratory rate [breaths per minute] 
7.1.2.4 
Electrocardiograms  
The following ECG parameters will be recorded according to the schedule in Appendix 1: 
 RR-interval [msec] 
 PR (PQ)-interval [msec] 
 QRS-interval [msec] 
 QT-interval [msec] 
 QT-interval corrected using the Bazett correction formula (QTcB) [msec] 
 QT-interval corrected using the Fridericia correction formula (QTcF) [msec] 
 Heart rate (HR) (beats per minute [bpm]) 
The ECG will be evaluated by the Investigator as ‘Normal’, ‘Abnormal, NCS (Not clinically 
significant)’ or ‘Abnormal, CS (clinically significant)’. 
7.1.2.5 
Physical Examination 
The physical examination will be performed according to the schedule in Appendix 1. 
7.1.2.6 
Concomitant Medication 
Concomitant medication will be coded using the World Health Organisation-Drug Dictionary (WHO-
DD) (Version Jun2017) and will be classified by Anatomical Therapeutic Chemical (ATC) categories 
up to level 2. 
7.1.3 
Pharmacokinetic Variables 
Blood sampling for PK will be performed according to the schedule in Appendix 1. 
Unless otherwise stated, derivation of pharmacokinetic (PK) parameters will be the responsibility of 
Early Phase, Quantitative Clinical Development (QCD), PAREXEL International.  The following PK 


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parameters will be determined for tesofensine and metoprolol in plasma following single dose 
administration as appropriate: 
Table 1 
Pharmacokinetic Parameters after Single Dose Administration 
Parameter 
Definition 
Cmax 
Maximum observed concentration 
Tmax 
Time corresponding to occurrence of Cmax 
t½ 
Apparent terminal elimination half life 
λz 
Terminal elimination rate constant 
AUC0-48 
AUC from time zero to 48 hours 
λz lower 
First time point for λz calculation 
λz upper 
Last time point for λz calculation 
7.1.3.1 
Pharmacokinetic Parameter Calculation Methods 
PK parameters will be calculated by non-compartmental analysis methods from the concentration-time 
data using WinNonlin Professional (Version 6.3 or later) following these guidelines: 
 Actual sampling times relative to dosing rather than nominal times will be used in the 
calculation of all derived PK parameters. 
 There will be no imputation of missing data.  
 All below the limit of quantification (BLQ) values pre-dose and in the absorption phase prior to 
the first quantifiable concentration will be substituted by zeros. Thereafter BLQ values between 
evaluable concentrations will be substituted as missing, before the calculation of the PK 
variables. Terminal BLQ values will be disregarded. 
PK parameters will be estimated according to the following guidelines: 
 Cmax will be obtained directly from the concentration-time data. 
 Tmax is the time at which Cmax is observed. 
 λz will be estimated at terminal phase by linear regression after log-transformation of the 
concentrations: 


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o Only those data points that are judged to describe the terminal log-linear decline will be 
used in the regression; the first and last time points used in the calculation of λz will be 
listed.  
o A minimum number of three data points in the terminal phase will be used in calculating λz 
with the line of regression starting at any post-Cmax data point (Cmax should not be part of the 
regression slope). 
o The adjusted correlation coefficient (R2 adjusted) in general should be greater than 0.90. 
Any value less than 0.90 may be used at the PK Scientist’s best knowledge and judgment. 
(R2 adjusted is the Goodness of fit statistic for the terminal elimination phase, adjusted for 
the number of points used in the estimation of λz). 
o An appropriate number of decimal places should be used for λz to enable the reported value 
of t½ to be calculated. 
 t½ will be calculated as ln2/λZ. 
 AUC is calculated as follows: 
o The linear trapezoidal method will be employed for all incremental trapezoids arising 
from increasing concentrations and the logarithmic trapezoidal method will be used for 
those arising from decreasing concentrations. 
o AUC0-48=
48
 
0
)
( dt
t
C
. 
 For concentration-time profiles where the last quantifiable concentration occurs 
prior to 48h, extrapolation to 48 hours will be accomplished for the calculation 
of AUC0-48. 
7.2 
Analysis Populations 
7.2.1 
Randomized Set 
The Randomized Set will consist of all subjects who have been randomized 


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7.2.2 
Safety Population 
The Safety Population will consist of all randomized subjects who received at least one dose of study 
drug. Subjects will be included in analyses according to the dose and study drug received. 
7.2.3 
Pharmacokinetic Population 
All randomized subjects with at least one quantifiable tesofensine or metoprolol concentration. 
Subjects will be included in the analysis according to the dose and study drug received. 
Data may be excluded from PK analysis (concentrations listed only) if any of the following criteria are 
fulfilled: 
 Concomitant medication, which could render the plasma concentration-time profile unreliable  
 Subject vomits within 2 x the reported median tmax of the treatment in which the subject is 
analyzed for the analyte. 
 Subject has moderate or severe diarrhea within 2 x the reported median tmax for the analyte. 
 Major protocol deviations which could affect the concentration profile 
Any data excluded will be discussed in the Clinical Study Report (CSR).  
7.3 
Statistical Analysis Methods 
7.3.1 
Listings and Descriptive Statistics 
All original and derived parameters as well as population characteristics will be listed and described 
using summary statistics. Frequency counts (number of subjects [n] and percentages) will be made for 
each qualitative variable. Descriptive statistics (n, mean, standard deviation [SD], median, minimum 
and maximum) will be calculated for each quantitative variable (unless otherwise stated). All listings 
will include repeated and unscheduled measurements. 
The following rules will apply to any repeated measurements: 
 If the repeated measurement occurs prior to the first dose of study drug then the last obtained 
value of any repeated measurement will be used in the descriptive statistics. 


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 If the repeated measurement occurs after the first dose of study drug then the original value of 
any repeated measurements will be used in the descriptive statistics. 
 All descriptive statistics will be presented by treatment (dose). The baseline for all 
measurements (where applicable) will be the last pre-dose measurement. 
7.3.2 
Rounding and Decimal Places 
 The following rules will be followed with regard to the number of decimal places and 
presentation of data in the tables and listings of safety data: 
1. All data will be listed according to the number of decimal places presented in the source 
data 
2. Mean and median will be tabulated to one more decimal place than the source data 
3. Minimum and maximum values will be tabulated to the same number of decimal places 
as the source data 
4. Standard deviation will be tabulated to two more decimal places than the source data 
5. Coefficient of variation (CV)%, if applicable, will be presented to one decimal place 
6. Percentages will be displayed to two decimal places. 
 The following rules will be followed with regards to the number of decimal places and 
presentation of data in the tables and listings of PK concentration data: 
1. The individual concentrations will be reported to the same precision as the source data 
(for example, if the source data is presented to five significant digits, the individual 
values will be presented to five significant digits) 
2. The mean, SD, geometric mean (gMean), geometric SD and median will be tabulated to 
one more significant digit compared to the source data.  
3. Minimum and maximum values will be tabulated to the same precision as the source 
data. 
4. Geometric CV% will be presented to one decimal place. 
 The following rules will be followed with regards to the number of decimal places and 
presentation of data in the tables and listings of PK parameters: 
1. Individual PK parameters will be presented to three significant digits, with the exception 
of tmax, which will be presented to two decimal places. In addition, parameters directly 
derived from source data (e.g. Cmax) shall be reported with the same precision as the 
source data  


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2. The mean, gMean, median and SD values will be reported to one more significant digit 
than the source data, except for CV% which will be presented to one decimal place. For 
tmax, the median, minimum and maximum will be presented to two decimal places  
7.3.3 
Software 
All statistical analyses will be performed using Statistical Analysis Software (SAS®) Version 9.3 or 
later. The PK analysis will be performed using WinNonlin Professional Software Version 6.3. 
7.3.4 
Missing Data 
There will be no imputation of missing data.  
7.3.5 
Interim Analysis 
Not applicable. 
7.3.6 
Disposition 
Subject disposition will be listed. The number and percentage of subjects entering and completing the 
clinical study will be presented by treatment. 
Subjects excluded from the safety and PK analysis sets and data excluded from the PK analysis will be 
listed including the reason for exclusion. Subject disposition will be summarized by treatment and will 
include the following information: number of subjects randomized, dosed and in PK analysis set, 
number and percentage of subjects completing the study and the number and percentage of subjects 
who were withdrawn (including reasons for withdrawal). Disposition data will be presented based on 
all subjects randomized. 
Subject discontinuations will be listed including the date of study exit, duration of treatment and reason 
for discontinuation. A listing of informed consent response will also be presented. 
A randomization listing will be presented and include the following: each subject’s randomization 
number and the treatment to which the subject has been randomized 
7.3.7 
Protocol Deviations 
All protocol deviations will be recorded by the Investigator and will be listed by subject. All protocol 
deviations will be discussed between PAREXEL (physician, Data Manager, Biostatistician, PK 


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Scientist/Analyst) and also the Sponsor during the data review meeting before database lock in order to 
determine whether these may warrant exclusion of a subject from the statistical analyses. 
7.3.8 
Demographic Data 
All demographic data will be presented using the safety population. Demographic characteristics will 
be summarized by treatment and for all subjects using both the safety population and the PK 
population. 
7.3.9 
Concomitant Medication 
Prior medications are those that started and stopped prior to the first dose of investigational medicinal 
product (IMP). Concomitant medications are those taken after first dosing (including medications that 
started prior to dosing and continued after). 
Prior and concomitant medication will be listed by subject and will include the following information: 
reported name, WHO-DD Preferred Term (PT), ATC code, the route of administration, dose, 
frequency, start date/time, duration and indication. 
7.3.10 
Exposure to the Investigational Medicinal Product 
A listing of drug administration will be created and will include the date and time of administration, 
consumption of breakfast and for treatment D the time of breakfast. 
7.3.11 
Pharmacokinetic Concentrations and Variables 
The analysis of the PK data will be based on the PK population. 
Concentrations below the lower limit of quantification (LLOQ) will be indicated by BLQ in the 
listings.  
Pharmacokinetic concentration data will be listed by subject including actual sampling times relative to 
dosing. Plasma concentrations will be summarized by analyte and treatment and timepoint. The 
following descriptive statistics will be presented for plasma concentrations obtained at each nominal 
time point: n, arithmetic mean, SD, coefficient of variation (CV%), geometric mean, geometric SD, 
geometric CV% (calculated as: gCV%=SQRT(es²-1)*100; where s is the standard deviation of the log-
transformed values), median, minimum and maximum values. 


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Pharmacokinetic parameters will be listed by subject and summarized by treatment. Descriptive 
statistics for calculated PK parameters will include: n, arithmetic mean, SD, CV%, geometric mean, 
median, minimum and maximum values. For tmax, only median, minimum and maximum values will be 
presented. Additional summary by will be provided using dose normalized Cmax and AUC0-48. For the 
dose normalized summary, the parameters for treatment B will multiplied with a factor 4 for metoprolol 
and with a factor 5 for tesofensine. No descriptive statistics will be determined when fewer than three 
individual PK parameters are available. 
Individual plasma concentration versus actual times will be plotted for each analyte in linear and semi-
logarithmic scale. Mean plasma concentrations versus nominal times will also be presented in linear 
and semi-logarithmic scale by analyte, SD will be added in the plot for the linear scale. All treatments 
will be overlaid on the same plot. 
7.3.11.1 
Exploratory Model for Relative Bioavailability 
Relative bioavailability will be estimated for tesofensine and metoprolol by the ratios of the gMeans 
(test/comparator [T/C]) for AUC0-48 and Cmax. Comparator will be treatment C. Additionally, their two-
sided 90% CIs will be provided. 
The statistical model will be a one way analysis of variance (ANOVA) on the logarithmic scale 
including fixed effects for treatment. For each endpoint, the difference between the expected means for 
log(T)-log(C) will be estimated by the difference in the corresponding adjusted means (Least Squares 
Means). CIs will be calculated based on the residual error from ANOVA. The differences between the 
test and reference product and the CIs will be back-transformed to the original scale, resulting in point 
estimates of the T/C gMean ratios and 90% CIs. 
7.3.11.2 
Handling of Values Below the Limit of Quantification in Concentration Summaries and 
Listings 
Handling of values BLQ in listings and for the calculation of descriptive statistics at each time point: 
All concentrations BLQ or missing data will be labeled as such in the concentration data listings. 
Missing samples will be reported as no sample ("NS") and excluded from analysis.  
Values that are BLQ will be substituted with zero for the calculation of descriptive statistics of 
concentration by time point.  


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Graphical presentation: 
Any BLQ values prior to the last quantifiable concentration will be plotted at zero for individual 
linear/linear graphs and excluded from log/linear graphs. All BLQ values after the last quantifiable 
concentration will be excluded from individual linear/linear and log/linear graphs.  
For graphs of arithmetic means all BLQ mean concentrations will follow the rules of summary 
statistics.  Graphs of geometric means include only time points with minimum concentration greater 
than zero. Any arithmetic mean that is BLQ will be excluded from log/linear presentation of arithmetic 
means.  
7.3.12 
Safety Analysis 
The analysis of the safety variables will be based on the safety population. 
7.3.12.1 
Adverse Events 
The following listings will be produced: 
 All pre-treatment AEs and TEAEs. 
 Withdrawals due to AEs (if applicable). 
 SAEs (if applicable). 
The following information will be included in the listings: AE number, reported term, System Organ 
Class (SOC), PT, start and end date/time, intensity, causality, action taken, outcome, classified as 
serious and treatment emergence. 
Numbers of TEAEs will be summarized by treatment (including category any treatment), SOC, PT, and 
also by treatment, SOC, PT and severity and also by treatment (including category any treatment), 
SOC, PT and causality to treatment. In addition serious TEAES will be summarized by treatment, SOC 
and PT. 
7.3.12.2 
Clinical Safety Laboratory Tests (hematology, biochemistry and urinalysis) 
Laboratory values (hematology, biochemistry and urinalysis) will be listed by subject and study time 
point including changes from baseline (with the exception of urinalysis). The baseline for the 
laboratory values will be the last observation prior to dosing, these are expected to be the results 
obtained on Day -1. 


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All values outside the clinical reference ranges will be flagged in the data listings. The abnormal values 
will be flagged with ‘L’ for values below the lower limit of the clinical reference range and ‘H’ for 
values above the upper limit of the clinical reference range and included in the listings. The 
Investigator will assess whether the values outside the clinical reference range are clinically significant 
and these will be reported as abnormal NCS or abnormal CS. Clinically significant laboratory values 
will be recorded by the Investigator as AEs. 
Descriptive statistics (for non-categorical data including hematology and biochemistry) will be 
presented by treatment for both individual values (N, mean, SD, median, minimum, maximum) and 
changes from baseline. 
Shift tables of laboratory range classification from baseline to Day 2 will be presented for clinical 
chemistry, hematology and urinalysis laboratory parameters. 
7.3.12.3 
Vital Signs 
Vital signs data will be listed by subject including changes from baseline. The baseline for the vital 
signs measurements will be the last observation prior to dosing, these are expected to be the pre-dose 
measurements on Day 1. 
Descriptive statistics (n, mean, SD, median, minimum, maximum) for absolute values and changes 
from baseline will be presented by treatment. 
Spaghetti plots of SBP, DBP, pulse rate and respiratory rate will be presented by treatment, using time 
points Day -1 to Day 3, both inclusive. 
7.3.12.4 
Twelve-Lead Electrocardiogram 
All ECG parameters obtained from the ECG measurement will be listed by subject for each treatment 
and time point including changes from baseline. The baseline for the ECG measurements will be the 
last observation prior to dosing, this is expected to be the pre-dose measurement obtained on Day 1. 
Descriptive statistics (n, mean, SD, median, minimum, maximum) for absolute values and changes 
from baseline will be presented by treatment. 
Spaghetti plots of QTcF, QTcB and HR will be presented by treatment, using time points Day -1 to 
Day 3, both inclusive. 


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A categorical QTc analysis will be performed. QTcF and QTcB will be summarized in four categories: 
≤450ms, interval >450ms and ≤480 ms, interval >480 ms and ≤500 ms, >500 ms. Change from 
baselines will be summarized in three categories, ≤30 ms, interval >30 ms and ≤60 ms, >60 ms. 
7.3.12.5 
Physical Examination 
The abnormal results of the physical examination will be listed by subject and time-point. 
 
 


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8. 
REFERENCES 
1. SAS® Version 9.2 of the SAS System for Personal Computers. Copyright ©2002-2003. SAS 
Institute Inc. SAS and all other SAS Institute Inc. product or service names are registered 
trademarks or trademarks of SAS Institute Inc., Cary, NC, USA. 
2. WinNonlin Professional Software Version 6.3. http://www.pharsight.com 
 
 


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9. 
TABLES AND LISTINGS TO BE INCLUDED IN SECTION 14 OF THE 
CLINICAL STUDY REPORT 
Subject Disposition 
Table 14.1.1 
Subject Analysis Sets (Randomized Population) 
Table 14.1.2 
Subject Disposition by Treatment (Randomized Population) 
 
 
Baseline and Demographic Data 
Table 14.1.3 
Subject Demographics (Safety Population) 
Table 14.1.4 
Subject Demographics (Pharmacokinetic Population) 
 
 
Pharmacokinetic Data 
Table 14.2.1 
Summary of Tesofensine Plasma Concentrations (unit) versus Nominal 
Sampling Times by Treatment (Pharmacokinetic Population) 
Table 14.2.2 
Summary of Metoprolol Plasma Concentrations (unit) versus Nominal Sampling 
Times by Treatment (Pharmacokinetic Population) 
Table 14.2.3 
Summary 
of 
Tesofensine 
Pharmacokinetic 
Parameters 
by 
Treatment 
(Pharmacokinetic Population) 
Table 14.2.4 
Summary 
of 
Metoprolol 
Pharmacokinetic 
Parameters 
by 
Treatment 
(Pharmacokinetic Population) 
Table 14.2.5 
Summary of Dose Normalized Tesofensine Pharmacokinetic Parameters by 
Treatment (Pharmacokinetic Population) 
Table 14.2.6 
Summary of Dose Normalized Metoprolol Pharmacokinetic Parameters by 
Treatment (Pharmacokinetic Population) 
Table 14.2.7 
Statistical Analysis of Pharmacokinetic Parameters of Tesofensine in Plasma 


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(Pharmacokinetic Population) 
Table 14.2.8 
Statistical Analysis of Pharmacokinetic Parameters of Metoprolol in Plasma 
(Pharmacokinetic Population) 
 
 
Safety Data 
 
Table 14.3.1.1 
Summary of Treatment Emergent Adverse Events (Safety Population) 
Table 14.3.1.2 
Treatment Emergent Adverse Events by Treatment, System Organ Class and 
Preferred Term (Safety Population) 
Table 14.3.1.3 
Treatment Emergent Adverse Events by Treatment, System Organ Class, 
Preferred Term and Causality (Safety Population) 
Table 14.3.1.4 
Treatment Emergent Adverse Events by Treatment, System Organ Class, 
Preferred Term and Severity (Safety Population) 
Listing 14.3.2.1 
Serious Adverse Events (Safety Population) 
Listing 14.3.2.2 
Adverse Events Leading to Withdrawal (Safety Population) 
Listing 14.3.4.1 
Abnormal Clinical Chemistry Values (Safety Population) 
Listing 14.3.4.2 
Abnormal Hematology Values (Safety Population) 
Listing 14.3.4.3 
Abnormal Urinalysis Values (Safety Population) 
Table 14.3.5.1 
Clinical Chemistry (Safety Population) 
Table 14.3.5.2 
Hematology (Safety Population) 
Table 14.3.5.3 
Clinical Chemistry Shift Table (Safety Population) 
Table 14.3.5.4 
Hematology Shift Table (Safety Population) 
Table 14.3.6.1 
Vital Signs (Safety Population) 
Table 14.3.6.2 
Electrocardiograms (Safety Population) 


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Table 14.3.6.3 
Categorical Analysis Electrocardiograms (Safety Population) 
 
 
 


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10. 
FIGURES 
Figure 14.2.1 
Subject Profiles for Tesofensine Plasma Concentration Time Data (Linear Scale) 
(Pharmacokinetic Population) 
Figure 14.2.2 
Subject Profiles for Metoprolol Plasma Concentration Time Data (Linear Scale) 
(Pharmacokinetic Population) 
Figure 14.2.3 
Subject Profiles for Tesofensine Plasma Concentration Time Data (Semi-logarithmic 
Scale) (Pharmacokinetic Population) 
Figure 14.2.4 
Subject Profiles for Metoprolol Plasma Concentration Time Data (Semi-logarithmic 
Scale) (Pharmacokinetic Population) 
Figure 14.2.5 
Mean (± Standard Deviation) Profiles for Tesofensine Plasma Concentration Time Data 
(Linear Scale) (Pharmacokinetic Population) 
Figure 14.2.6 
Mean (± Standard Deviation) Profiles for Metropolol Plasma Concentration Time Data 
(Linear Scale) (Pharmacokinetic Population) 
Figure 14.2.7 
Mean Profiles for Tesofensine Plasma Concentration Time Data (Semi-logarithmic 
Scale) (Pharmacokinetic Population) 
Figure 14.2.8 
Mean Profiles for Metoprolol Plasma Concentration Time Data (Semi-logarithmic 
Scale) (Pharmacokinetic Population) 
Figure 14.3.1 
Spaghetti Plots of Vital Signs (Safety Population) 
Figure 14.3.2 
Spaghetti Plots of ECG Parameters (Safety Population) 


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11. 
LISTINGS TO BE INCLUDED IN SECTION 16 OF THE CLINICAL 
STUDY REPORT 
Subject Disposition 
Listing 16.2.1.1 
Withdrawals from the Study (Randomized Set) 
Listing 16.2.1.2 
Informed Consent (Randomized Set) 
Listing 16.2.1.3 
Study Visits (Safety Population) 
Listing 16.2.1.4 
Failed Inclusion and Exclusion Criteria (Safety Population) 
Listing 16.2.2 
Protocol Deviations (Safety Population) 
Listing 16.2.3 
Assignment to Analysis Populations (Randomized Set) 
 
 
Baseline and Demographic Data 
Listing 16.2.4.1 
Subject Demographics (Safety Population) 
Listing 16.2.4.2 
Medical History (Safety Population) 
Listing 16.2.4.3 
Subject Habits (Safety Population) 
Listing 16.2.4.4 
History of Blood or Plasma Donation(Safety Population)  
 
 
Concomitant Medication 
Listing 16.2.4.5 
Prior and Concomitant Medication (Safety Population) 
 
 
Exposure 
Listing 16.2.5.1 
Exposure to Investigational Medicinal Product (Safety Population) 


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Listing 16.2.5.2 
Individual Blood Sampling Times and Concentrations (Safety Population) 
 
 
Pharmacokinetic Data 
Listing 16.2.6.1 
Pharmacokinetic Parameters of Tesofensine (Pharmacokinetic Population) 
Listing 16.2.6.2 
Pharmacokinetic Parameters of Metoprolol (Pharmacokinetic Population) 
 
 
Safety Variables 
Listing 16.2.7 
Adverse Events (Safety Population) 
Listing 16.2.8.1 
Clinical Chemistry (Safety Population) 
Listing 16.2.8.2 
Hematology (Safety Population) 
Listing 16.2.8.3 
Urinalysis (Safety Population) 
Listing 16.2.8.4 
Serology (Safety Population) 
Listing 16.2.8.5 
Drugs of Abuse (Safety Population) 
Listing 16.2.9.1 
Vital Signs (Safety Population) 
Listing 16.2.9.2 
Electrocardiogram Parameters (Safety Population) 
Listing 16.2.9.3 
Abnormal Physical Examinations 
 
 


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12. 
DOCUMENTATION OF STATISTICAL METHODS 
Appendix 16.1.9.1: WinNonlin outputs 
Appendix 16.1.9.2: Statistical Analysis of Pharmacokinetic Parameters of Tesofensine in Plasma 
(Pharmacokinetic Population)  
Appendix 16.1.9.3: Statistical Analysis of Pharmacokinetic Parameters of Metropolol in Plasma 
(Pharmacokinetic Population)  
 
 


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13. 
APPENDIX 1: SCHEDULE OF ASSESSMENTS 
Evaluation 
Screening 
 
Treatment 
Period 
 
 
Safety FU 
Phone call 
 
Day -30 to 
Day -2 
Admission 
Day -1 
Baseline / 
Day 1 
Day 2 
Discharge 
Day 3 
Day 8 
Admission 
 
X 
 
 
 
 
In-house staya 
 
X 
X 
X 
X 
 
Ambulatory visits 
X 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
Physical examination  
X 
X 
 
 
X 
 
Height and body weight, BMI 
X 
 
 
 
 
 
Viral serology 
X 
 
 
 
 
 
Supine blood pressure and pulseb 
X 
X 
X 
X 
X 
 
Body temperature, respiratory ratec 
X 
X 
Xd 
X 
X 
 
Clinical laboratory tests (clinical 
chemistry, hematology and 
urinalysis) 
X 
X 
 
X 
 
 
Urine drug screen, cotinine and 
alcohol test 
X 
X 
 
 
 
 
12-lead ECGd 
X 
X 
X 
X 
X 
 
Randomization 
 
 
X 
 
 
 
Study drug administratione 
 
 
X 
 
 
 
Blood sampling for PKf 
 
 
X 
X 
X 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
AE monitoring 
X 
X 
X 
X 
X 
X 
Discharge 
 
 
 
 
X 
 
AE = adverse event; BMI = Body Mass Index; ECG = electrocardiogram; FU = Follow-up; PK = pharmacokinetics 
a Subjects will be admitted in the morning of Day -1 and will leave the study center on Day 3 after completion of all study-
related assessments. 
b  At Screening and on Day -1. On Day 1 at pre-dose and 1, 2, 4, 8, 12 and 16 hours post-dose, on Day 2 at 24, 30 and 36 
hours post-dose and on Day 3 at 48 hours post-dose. 
c Once daily, on in-house days in the morning. 
d At Screening and on Day -1. On Day 1 at pre-dose and 1, 6 and 12 hours post-dose, on Day 2 at 24 hours post-dose and on 
Day 3 at 48 hours post-dose. 
e In Treatment Groups A, B and C, dosing will be performed after an overnight fast of at least 10 hours before dosing and 
subjects will fast until 4 hours post-dose. At 4 hours after dosing a light standardized meal will be served. 
In Treatment D, subjects will be required to eat an FDA standardized high-fat breakfast within a period of 30 minutes 
before dosing. The Investigator or a designee will administer the treatment to the subjects 30 minutes after start of the 
breakfast and within 5 minutes of completing the meal. 
The Investigator or a designee will administer the appropriate treatment with 240 mL water to the subjects as per 
randomization schedule. If more water is needed for the intake of the 5 tablets in Group C, up to further 200 mL water 
may be taken. 
f Blood sampling at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 30, 36 and 48 hours post-dose. 

ICF_001.pdf: 
Participant Information  
PAREXEL Clinical Trial 236073 
Saniona Clinical Trial TM003 
Version date: 
18 September 2017 
Page 1 of 19 
Version No.: 
1.0 
The Ethics Committee gave its favorable opinion on ### 
Version No.: 
1.0 
The Ethics Committee gave its favorable opinion on ### 
Version date:  18 September 2017  
English Translation of the German Original 
Participant Information for the PAREXEL Clinical Trial 236073 
EudraCT No.:  2017-003339-13 
A Randomized, Open-label, Single-dose, Parallel-arm, Phase 1 Study to Investigate the 
Pharmacokinetic Profile of a Fixed-Dose Combination Tablet of Tesofensine and 
Metoprolol (Tesomet) and Co-Administration of Tesofensine Plus Commercial 
Metoprolol in Adult Healthy Subjects 
 
 
Investigator: 
Dr. med. Astrid Breitschaft 
Investigator’s Deputy: 
Dr. Tommaso Fadini 
 
Sponsor: 
Saniona A/S  
 
Baltorpvej 154 
 
DK-2750 Ballerup 
 
Denmark 
 
Phone: +45 70 705-225 
 
 
Institute 
Early Phase Clinical Unit - Berlin 
 
PAREXEL International GmbH 
Participant Services after  
start of the trial: 
Early Phase Clinical Unit - Berlin 
 
PAREXEL International GmbH 
 
(On the premises of DRK Kliniken Berlin 
 
 
Westend) 
 
Haus 31 
 
Spandauer Damm 130 
 
Eingang Fürstenbrunner Weg 
 
14050 Berlin 
 
Phone: 030 30685–5100 (reception) 
 
Fax: 030 30685–7018 
 


Participant Information  
PAREXEL Clinical Trial 236073 
Saniona Clinical Trial TM003 
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18 September 2017 
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Table of Content 
1.	  
PREFACE ............................................................................................................. 3	  
2.	  
INTRODUCTION ................................................................................................... 3	  
3.	  
AIM OF THE CLINICAL TRIAL AND OVERVIEW ................................................ 4	  
4.	  
RISKS OF THE INVESTIGATIONAL MEDICINAL PRODUCTS .......................... 5	  
5.	  
RISKS OF THE CLINICAL TRIAL ......................................................................... 7	  
6.	  
CONDITIONS FOR PARTICIPATION ................................................................... 8	  
7.	  
HANDLING OF SAMPLES AND DATA OBTAINED FROM THE SAMPLES ....... 9	  
8.	  
CONDUCT OF THE CLINICAL TRIAL ................................................................ 10	  
9.	  
BEHAVIOR OF PARTICIPANTS DURING THE CLINICAL TRIAL ..................... 12	  
10.	  
MEDICAL CARE ................................................................................................. 13	  
11.	  
PROTECTION OF PERSONAL DATA ................................................................ 15	  
12.	  
INSURANCE ....................................................................................................... 16	  
13.	  
ETHICAL AND LEGAL REGULATIONS ............................................................. 16	  
14.	  
EXPENSE ALLOWANCE .................................................................................... 16	  
15.	  
HIV- AND HEPATITIS-EXAMINATION ............................................................... 18	  
16.	  
CLINICAL TRIAL OVERVIEW ............................................................................. 19	  
 
 


Participant Information  
PAREXEL Clinical Trial 236073 
Saniona Clinical Trial TM003 
Version date: 
18 September 2017 
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1. 
Preface 
We thank you for your interest and your possible participation in this clinical trial. 
This clinical trial is ethically justifiable only if it delivers evaluable results.  If you decide to 
participate in this clinical trial, you must strictly adhere to the required behavior patterns.  An 
infringement of the rules may endanger your health and can interfere with the results of the 
clinical trial concerning the investigational medicinal product. 
PAREXEL International GmbH is a contract research organization, which will conduct this 
clinical trial at the request of Saniona and will be paid for it by Saniona. 
This clinical trial is an investigation which involves research. 
The information and the materials that are given to you in relation to the clinical trial are 
confidential information belonging to the Sponsor Saniona and should be kept private.   
However, you can discuss this information in confidence with your doctor or friends and 
family to decide whether to take part in this clinical trial and in discussing your healthcare. 
This clinical trial will be registered in the European Clinical Trials Database (EudraCT).  The 
sponsor of this clinical trial is also obliged to post the results of this clinical trial after its 
completion in EudraCT. A subset of data could be available to the public via the European 
Union Clinical Trials Register.  The public data will not contain information that can identify 
you.  At most, the Clinical Trial Register will include a summary of the results as well as 
possibly a description of the clinical trial. 
A description of this clinical trial will be available on https://CinicalTrials.gov/, as required by 
U.S. Law.  This Web site will not include information that can identify you.  At most, the 
website will include a summary of the results.  You can search this Web site at any time. 
Please read this Participant Information carefully.  If you have further questions 
concerning this Participant Information, please refer them to our investigators who will be 
pleased to explain. 
2. 
Introduction 
The investigational medicinal product Tesomet is under development by Saniona for the 
treatment of a variety of conditions, for which a weight reducing effect is relevant to the 
treatment, such as obesity, type 2 diabetes and Prader-Willi Syndrome (an inborn disorder, 
which commonly causes obesity in children and adults). 
Tesomet is a combination tablet, containing tesofensine and metoprolol.  Tesofensine was 
originally under development as a treatment for Parkinson’s and Alzheimer’s disease.  
During a clinical trial, a significant weight loss was noticed in overweight participants, despite 
the fact that the subjects did not attempted to lose weight.  It was therefore further developed 
for the treatment of obesity.  Metoprolol has been approved in Germany and other countries 
for the treatment of heart conditions and high blood pressure. 
The results obtained from previous clinical trials indicate that tesofensine is generally well 
tolerated.  A slight increase in blood pressure (1 to 5 mmHg) and heart rate (8 beats per 
minute) has, however, been observed after being administered alone.  As even a slight 
increase in blood pressure and heart rate may constitute an unacceptable safety risk after a 
while, tesofensine will be administered together with metoprolol, which mitigates these side 
effects.  Metoprolol blocks certain beta receptors in the body (beta1-selective beta receptor 
blocker) and through this leads to a slowing down of the heartbeat and a decrease in blood 
pressure. 
Tesofensin and metoprolol have thus far been administered together, but in two separate 
tablets, in two clinical trials.  The investigational medicinal product Tesomet is a tablet that 
contains both substances in a fixed dose combination.  In this clinical trial the so-called 
“bioavailability” of Tesomet will be compared to that of a simultaneous administration of 


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Saniona Clinical Trial TM003 
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tesofensine and metoprolol. The bioavailability indicates the amount of study drug that is 
available to the body after it reaches the blood circulation. 
Tesofensine and metoprolol are being administered as a single combination tablet for the 
first time in this clinical trial. 
Please be aware that this clinical trial has the purpose to investigate particular characteristics 
of an investigational medicinal product.  Therefore, you will not have any benefit for your 
health if you chose to participate in this clinical trial. 
3. 
Aim of the Clinical Trial and Overview 
The main aim of this clinical trial is to investigate the bioavailability of a single dose of the 
fixed dose combination Tesomet tablet and a single dose of simultaneous administration of 
tesofensine together with commercial metoprolol.  Therefore, it will be compared how much 
tesofensine and how much metoprolol is in your body over a certain period of time 
(pharmacokinetics).  For this reason, blood samples will be collected at planned intervals 
after the single doses to measure the concentration of tesofensine and metoprolol. 
It will also be investigated, how much a meal consumed before administration affects the 
amount of both substances that is taken up into the blood compared to a dose given under 
fasting conditions.  Additionally, the pharmacokinetics of Tesomet will be investigated after a 
single administration of a higher dose and of a lower dose.  Again for this reason, blood 
samples will be collected at planned intervals after the dose of Tesomet to measure its 
concentration. 
Additionally, the safety and tolerability of a single dose of Tesomet as well as of the 
simultaneous dose of tesofensine and metoprolol will be investigated.  The safety and the 
tolerability will be investigated by regularly assessing the vital signs (blood pressure, pulse, 
body temperature and respiratory rate) and the cardiac function (electrocardiogram [ECG]), 
by performing physical examinations and by questioning for adverse events.  In addition, 
blood and urine samples will be collected for the determination of the safety parameters. 
A total of 60 healthy male participants will participate in this clinical trial.  The participants will 
be divided into 4 groups of 15 participants each.  Each group will be assigned to one of the 
following treatments: 
 
 
 
 
Treatment 
Amount of 
tesofensine 
Amount of 
immediate 
release 
metoprolol 
Amount of 
extended 
release 
metoprolol 
Fasting 
condition or 
after meal 
Group 1 
1 Tesomet tablet 
(„higher Dose“) 
1 mg 
20 mg 
80 mg 
Fasting 
Group 2 
1 Tesomet tablet 
(„lower Dose “) 
0,2 mg 
5 mg 
20 mg 
Fasting 
Group 3 
Tesofensine and 
metoprolol 
tablets  
1 mg 
(2 tablets) 
25 mg 
(1 tablet) 
75 mg 
(2 tablets) 
Fasting 
Group 4 
1 Tesomet tablet 
(„higher Dose“) 
1 mg 
20 mg 
80 mg 
After meal 
 
It will be randomly determined, which of the possible treatments you will receive; it will be like 
drawing a lot.  The possibility that you are assigned to a specific group will be 25% or 1:4. 


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PAREXEL Clinical Trial 236073 
Saniona Clinical Trial TM003 
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This is an open-label trial.  Therefore, both you and the Investigator will know which 
treatment you are receiving.   
The total duration of the clinical trial for each participant is up to 38 days (including the 
screening period). 
It cannot be excluded that health impairment or disturbances in your well-being might occur 
during the clinical trial.  It is necessary that you comply with the instructions given in this 
Participant Information and with the instructions given by the investigators.  Please contact 
the Investigator or the trial staff directly if any symptoms occur. 
4. 
Risks of the Investigational Medicinal Products 
The evaluation of side effects is based on the following frequencies: 
Very common  more than 1 out of 10 patients 
Common 
less than 1 out of 10 but more than 1 out of 100 patients 
Uncommon 
less than 1 out of 100 but more than 1 out of 1,000 patients 
Rare 
less than 1 out of 1,000 but more than 1 out of 10,000 patients 
Very rare 
less than 1 out of 10,000 patients, including single cases 
Not known 
frequency cannot be estimated based on available data  
 
Risks of Tesofensine 
To date, 25 clinical trials with tesofensine have been completed, with 289 healthy 
participants, 167 obese patients and 849 patients with Parkinson’s and Alzheimer’s disease.  
The following adverse events were observed in the clinical trials: 
Very common: 
- 
Headache, insomnia, dizziness, sleepiness, loss of appetite, lack of energy, dry 
mouth, attention disturbances, cold-like symptoms, diarrhea, constipation. 
Common: 
- 
Nausea, vomiting, fast pulse, muscle spasms, sweating, palpitations, vertigo, blurry 
vision, flatulence, abdominal pain or discomfort, tooth pain, fatigue. 
Rare: 
- 
Altered state of consciousness, sensory disturbance. Agitation and persecutory 
delusion were found in a subject that received multiple doses of 4 mg tesofensine per 
day. 
 
To date, tesofensine and metoprolol have been administered together in 2 clinical trials to a 
total of 42 participants (12 healthy participants and 30 overweight or obese type 2 diabetes 
patients).  The most common adverse events from the trials with 30 type 2 diabetes patients 
were: 
Nausea 
(7 
participants), 
excessive 
sweating 
(6 
participants), 
headache 
(5 participants), dry mouth (4 participants), impaired emptying of stomach, fatigue, muscle 
spasms, dizziness and restlessness (3 participants each). 
 
Risks of Metoprolol 
Extended release metoprolol (Metoprolol-ratiopharm® Succinat Retardtabletten) 
Like all medicines, this medication may have side effects, although not everybody gets them. 
Very common: 
- 
Significant decrease in blood pressure, especially when standing up, very rarely with 
a loss of consciousness 
- 
Tiredness. 


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Saniona Clinical Trial TM003 
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Common: 
- 
Decreased heartrate (bradycardia), impaired balance (very rarely with a loss of 
consciousness), irregular heartbeat or palpitations 
- 
Dizziness, headache 
- 
Shortness of breath under physical strain 
- 
Nausea, stomach pain, diarrhea, constipation 
- 
Cold hands and feet. 
Uncommon 
- 
Temporary worsening of complaints related to a heart muscle insufficiency, a specific 
form of heart arrhythmia (Grade 1 AV-block), pain around the heart 
- 
Abnormal sensations such as tingling (paresthesia) 
- 
Spasm of the airways 
- 
Vomiting 
- 
Skin alterations, psoriasis-like skin rash 
- 
Increased sweating 
- 
Muscle spasm 
- 
Weight gain 
- 
Fluid trapped in tissue (edema) 
- 
Depression, difficulty concentrating, lightheadedness or insomnia 
Rare: 
- 
Functional heart complaints, such as irregular heartbeat or racing heart, certain heart 
arrhythmias (impaired conductivity) 
- 
Impaired vision, dry or agitated eyes, conjunctivitis 
- 
Common cold 
- 
Dry mouth 
- 
Hair loss 
- 
Worsening of diabetes 
- 
Abnormal values in liver function tests 
- 
Impotence and other sexual disorders, hardening of the connective tissue in the 
cavernous body of the penis (induratio penis plastica) 
- 
Nervousness, anxiety 
Very rare: 
- 
Decrease in blood platelets (thrombocytopenia), decrease in white blood cells 
(leukopenia) 
- 
Tinnitus, hearing disturbance 
- 
Taste disorder 
- 
Light sensitivity, Worsening of psoriasis, emerging psoriasis, psoriasis-like skin 
alterations 
- 
Joint pain, muscle weakness 
- 
Tissue death (necrosis) in patients with severe blood flow impairment in the arms 
and/or legs before treatment, increased complaints of intermittent blood flow 
problems in the legs (intermittent claudication) or blood vessel spasms in the toes 
and fingers (Raynaud syndrome) 
- 
Liver inflammation 
- 
Forgetfulness or memory difficulties, confusion, hallucinations, personality changes 
(e. g. mood changes)  


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PAREXEL Clinical Trial 236073 
Saniona Clinical Trial TM003 
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Immediate release metoprolol (Egilok metoprolol tartrate) 
The following side effects may occur during the treatment: Tiredness, headache, feeling 
unwell, abdominal pain, diarrhea or constipation, dizziness, sleeplessness, cold feeling in the 
extremities, excessive sweating, blurred vision, shortness of breath. 
 
For the documentation of possibly occurring side effects, affected body parts may be 
photographed. The photos are stored in pseudonymised (encoded) form, which means that 
your personal identification attributes (such as name, birthday, address) will be replaced by a 
number. 
The Investigator will explain all important points about the investigational medicinal products 
Tesomet and tesofensine to you during the information meeting.  In addition, together with 
this Participant Information you will receive the package leaflet of metoprolol immediate 
release tablet (Egilok) and metoprolol extended release tablets (Metoprolol-ratiopharm® 
Succinat Retardtabletten). 
Serious adverse reactions and hospitalization: 
Although all possible precautions are taken to prevent serious adverse reactions (side 
effects), such events cannot be completely excluded. It might be necessary that during a 
possible treatment at the hospital medical information from the clinical trial at PAREXEL is 
shared with the treating clinician so that he/she can provide the appropriate therapeutic 
measures. Similarly, it is necessary to make the data collected during the medical treatment 
accessible the Investigator at PAREXEL, in order to transfer insights about the safety of the 
investigational medicinal product.  The exchange of this information is not possible without 
your prior written consent. 
Clear criteria are defined for this clinical trial, which lead to stopping of the clinical trial in a 
single participant as well as the whole clinical trial.  These criteria may comprise abnormal 
laboratory values, defined adverse events or clinically relevant ECG recordings, as judged by 
the Investigator. 
You will be informed immediately if during the course of this clinical trial any new findings 
from this clinical trial or other clinical trial, including animal experiments, become known 
about the investigational medicinal products Tesomet or tesofensine and metoprolol, which 
could influence your decision to further participate in this clinical trial.  Subsequently, you 
decide anew about your participation.  You will be informed immediately in case of any 
changes or additions to the protocol of the clinical trial, as applicable, and you will receive an 
updated Participant Information and will then decide again on your consent to participation. 
In this clinical trial the current formulation of the investigational medicinal product is 
administered in humans for the first time.  Therefore, you should also be aware that adverse 
events other than those mentioned may occur.  Clinical trials with new investigational 
medicinal products generally bear the risk that you may experience adverse events that are 
currently unknown and unforeseeable. 
5. 
Risks of the Clinical Trial 
During the regular course of the entire clinical trial, no more than 144 ml of blood will be 
drawn.  This blood amount may increase accordingly by unanticipated control blood samples 
for safety monitoring and by repeated examinations at the Screening Visit or on days 
immediately before the administration of the investigational medicinal product.  For 
comparison:  at a single blood donation, up to 500 ml of blood are drawn. 
 
To take a single blood sample, a disposable needle will be used.  To take multiple blood 
samples, an intravenous cannula will be inserted, to avoid repeated puncturing of the vein 


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with a disposable needle.  An intravenous cannula is a short thin plastic tube, which will be 
inserted through a steel cannula into a forearm vein or a cubital vein (bend of the arm) by the 
Investigator or qualified trial staff and will remain there for the respective blood-sampling day 
or until the next morning.  Puncturing a vein with a disposable needle or a cannula does not 
generally entail any risks.  In rare cases, bleeding into the surrounding tissue (bruising), and 
very rarely inflammation of the vein or thrombosis (formation of blood clots) may occur.  In 
rare cases a nerve may be hit, which may cause pain and temporary tingling in the arm. 
The further examinations, such as ECG recordings, measurements of blood pressure, pulse, 
body temperature and respiratory rate are of no health risk to you.   
In case any changes occur in your well-being, in laboratory values or other findings, which 
indicate an impairment of your health, we are obliged to undertake all necessary medical 
measures to restore your initial condition or to monitor your findings until they have 
normalized again. 
6. 
Conditions for Participation 
To participate in this clinical trial you must fulfill several criteria.  Your Investigator will assess 
your eligibility for participation in this clinical trial from the examinations at the Screening 
Visit.  In any case, the responsible Investigator will inform you about the results of the 
examinations and the possible need for any further clarification.   
The examinations at the Screening Visit can only take place after you have signed the written 
Informed Consent Form attached to this Participant Information.  You will sign the Informed 
Consent Form after you have clarified all aspects of the clinical trial that are of interest to you 
from this Participant Information and by additional verbal explanations by the Investigator. 
Prior to the information meeting, you will be, in accordance with the law, handed the 
confirmation of insurance, the Participant Information, as well as the Informed Consent Form. 
You may only be enrolled in the clinical trial after you have fulfilled all requirements assessed 
during the Screening Visit, and also there are no concerns immediately before the (first) 
administration of the investigational medicinal product.  If you are not enrolled in the clinical 
trial after the Screening Visit or immediately before the (first) administration, you cannot put 
forward any claim from your consent for participation. 
• 
Your participation in this clinical trial is voluntary.  You have the right to withdraw 
your consent to participate in this clinical trial at any time.  If you decide not to 
participate in the clinical trial, you may do so without giving any reason.  No new 
information will be collected after you have withdrawn from the clinical trial. 
• 
Withdrawing from participation in this clinical trial or a premature termination of 
the clinical trial has no detrimental effects for you. 
• 
You are asked to report to the Investigator your withdrawal from participation in 
the clinical trial immediately.  You can withdraw from the clinical trial without 
giving any reason.  We would appreciate, though, if you would tell us if you 
withdraw your consent due to an adverse event or any other reason (e.g. illness). 
• 
Your withdrawal from the clinical trial by the Investigator or the Sponsor must be 
justified.  These may include, in addition to medical reasons, also deliberate 
infringements of the rules of the house or misbehavior during the clinical trial, 
which may endanger your safety or the evaluability of collected data.  Regardless 
of the reasons for the withdrawal, you will be asked to attend a Follow-up Visit for 
an examination, for your own health benefit. 
• 
You have the right to access your data through the Investigator and to have them 
corrected in case of errors. 
• 
After administration of Tesomet or tesofensine and metorpolol a mouth and hand 
check will be performed.  You will be asked to open the mouth and stick the tongue 
out after you have swallowed the tablets.  The Investigator will examine the mouth 


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with a light source.  You will be asked to lift the tongue and then move it from side 
to side so that the Investigator can examine the areas.   
• 
You must have private or statutory health insurance of unlimited duration.  If you 
hold private health insurance you are advised to check with the insurance 
company before you agree to take part in this clinical trial, as your coverage may 
be affected. 
The following circumstances may lead to withdrawal from the clinical trial or to the 
termination of the clinical trial: 
• 
Occurrence of adverse events, which, in the interest of your health, do not allow the 
clinical trial to proceed; 
• 
Protocol deviations that imply a health risk or jeopardize the clinical trial in a relevant 
way; 
• 
Your own wish; 
• 
New results become known, including from this clinical trial that indicate unacceptable 
risks for the participants of this clinical trial. 
7. 
Handling of Samples and Data Obtained from the Samples 
Blood samples collected during the course of this clinical trial will be sent to external 
laboratories for further processing.  Your samples will be handled only in encoded form (refer 
to Section 11:  Protection of Personal Data).  Sponsor Saniona and third parties that 
cooperate with Sponsor Saniona will investigate your samples only for the purposes 
specified in this clinical trial  Blood and urine samples, which are investigated by PAREXEL, 
or third parties that cooperate with PAREXEL, for safety laboratory tests will be handled also 
only in encoded form (refer to Section 11:  Protection of Personal Data).  No genetic 
investigations will be performed with these samples. 
Certain values cannot individually independently be measured with some of the technical 
devices used for the determination of safety laboratory values in blood and urine samples. 
Therefore, it may happen that in some cases values are issued by the device, which are not 
necessary for the clinical trial and hence, are in addition to the required values. The external 
safety laboratory responsible for the blood test will neither provide these additional values to 
the Investigator nor to the Sponsor.  Should the urinalysis conducted at the PAREXEL-
Laboratory show abnormal results in the unintended values, then these will be send to the 
Investigator for assessment. 
Your samples will be sent to the below listed laboratories for storage or analysis, but may 
also be sent to third parties.  You will not receive an additional notification if there is a change 
of laboratories during the trial or if your samples will be sent to third parties.  The laboratories 
listed below and the Sponsor Saniona remain responsible to ensure that all institutions 
adhere to the appropriate standards regarding the handling of the samples and data 
protection. 
Laboratories assigned to the different assessments are: 
• 
Safety laboratory for blood:  synlab pharma institute, Turmstraße 21, 10559 Berlin. 
• 
Safety laboratory for urinalysis:  PAREXEL International GmbH, EP Labor, 
Spandauer Damm 130, 14050 Berlin. 
• 
Blood for concentration measurement of tesofensine and metoprolol:  Envigo CRS 
Limited, Woolley Road, Alconbury, Huntingdon, Cambridgeshire PE28 4HS, United 
Kingdom 
If you decide later on not to participate in the clinical trial, you have the right to request the 
destruction of your samples.  For this purpose please contact the Investigator.  The Sponsor 
is the single owner of all data and inventions, which result from the investigation of these 
samples, so long as the rights of the donor of the sample are not affected.  Results obtained 
from samples that were collected prior to the time of withdrawal of consent may still be used 
further under specific conditions (refer to Section 11:  Protection of Personal Data).  The 


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Sponsor or third parties will destroy your samples after the end of the clinical trial; data 
obtained from these samples must be stored for at least 10 years according to applicable law 
(refer to Section 11:  Protection of Personal Data).  In case of commercial use of any product 
which is a result of this clinical trial, the Sponsor is the single owner of this product and you 
do not have the right to participate in the financial profit.  PAREXEL stores personal data for 
a period of 15 years. 
8. 
Conduct of the Clinical Trial 
The clinical trial consists of an ambulatory Screening Visit, a treatment period of 3 days and 
a Safety Follow-up phone call.  The total duration of the clinical trial for each participant is up 
to 38 days. 
Screening Visit 
After giving your written consent for participation in the clinical trial, within a period of 30 to 2 
days before the start of the clinical trial you will take part in the Screening Visit, where your 
eligibility for participation will be assessed. 
Your personal data such as age, weight, height, body mass index, sex and medical history 
will be assessed and the following assessments and procedures will be performed: 
• 
Physical examination 
• 
Measurement of blood pressure, pulse, body temperature and respiratory rate 
• 
ECG recording 
• 
Blood samples will be taken for safety laboratory, including HIV and hepatitis test 
(serology) 
• 
Collection of a urine sample for safety laboratory test, for drugs of abuse (illegal 
drugs), nicotine and alcohol 
• 
Recording of complaints and concomitant medication. 
After this the Investigator will assess your eligibility for this clinical trial. 
 
Treatment period 
You will come to the institute on Day –1 in the morning and will remain there until the 
morning of Day 3. 
In addition, the following assessments will be performed: 
Day –1: 
• 
Physical examination 
• 
Measurement of blood pressure, pulse, body temperature and respiratory rate 
• 
Test for drugs of abuse, nicotine and alcohol, from a urine sample 
• 
Blood sampling and collection of a urine sample for the safety laboratory before 
dosing 
• 
ECG recording 
• 
Complaints and concomitant medications will be recorded. 
 
Day 1: 
Participants of Groups 1, 2 and 3 must not eat and drink anything except for water from 
10 hours before the administration of Tesomet or tesofensine and metoprolol until 4 hours 
afterwards.  From 1 hour before until 1 hour after the administration the participants must not 
drink anything except for the water for swallowing the tablets.  Four (4) hours after dosing the 
participants will receive lunch – a breakfast will not be served.  
Participants of Group 4 will be served a high-fat breakfast approximately 30 minutes before 
dosing of Tesomet, which they are required to eat within a period of 30 minutes.  The 


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breakfast consists of 2 scrambled eggs fried in butter, 2 strips of bacon, 2 slices of toast with 
butter, 120 g of fried potatoes and 240 ml of whole milk.  The participants may not eat and 
drink anything except for water until 4 hours after their breakfast.  From 1 hour before until 
1 hour after the administration the participants must not drink anything except for the water 
for swallowing the tablets and the 240 ml milk as part of the breakfast. 
On this day you will be allocated to a certain treatment sequence.  In the morning of Day 1 
you will receive a dosing of Tesomet or tesofensine and metoprolol, which must be taken 
together with 240 ml of water.  Following dosing you will be required to sit upright on the 
edge of your bed for 20 minutes and must not lie down during this time.  You will be required 
to sit or walk upright for the first 2 hours following dose administration with the exception of 
supine rest period prior to certain measurements.  You will receive standardized meals at set 
times during your stay at the institute. 
The following assessments and procedures will be performed: 
• 
Measurement of blood pressure and pulse pre-dose and 1, 2, 4, 8, 12 and 16 hours 
post-dose 
• 
Measurement of body temperature and respiratory rate in the morning 
• 
ECG recording pre-dose and 1, 6 and 12 hours post-dose 
• 
Blood sampling for determination of the concentration of tesofensine and metoprolol 
pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 20 hours post-dose 
• 
Complaints and additional intake of medications will be recorded. 
 
Day 2: 
• 
Measurement of blood pressure and pulse 24, 30 and 36 hours post-dose 
• 
Measurement of body temperature and respiratory rate in the morning 
• 
Blood sampling and collection of a urine sample for the safety laboratory 
• 
ECG recording 24 hours after dosing 
• 
Blood sampling for determination of the concentration of tesofensine and metoprolol 
24, 30 and 36 hours after dosing 
• 
Complaints and additional intake of medications will be recorded. 
 
Day 3: 
• 
Physical examination 
• 
Measurement of blood pressure and pulse 48 hours after dosing 
• 
Measurement of body temperature and respiratory rate in the morning 
• 
ECG recording 48 hours after dosing 
• 
Blood sampling for determination of the concentration of tesofensine and metoprolol 
48 hours after dosing 
• 
Complaints and additional intake of medications will be recorded. 
If you are in good health and if there are no safety concerns, as judged by the Investigator, 
you will be discharged from the institute after all assessments have been completed on 
Day 3.  
 
Safety Follow-up phone call (Day 8): 
Seven (7) days after dosing of Tesomet or tesofensine and metoprolol you will receive a 
phone call and you will be asked for complaints and additional drugs you might have taken. 
 


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Saniona Clinical Trial TM003 
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18 September 2017 
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Please refer to the table at the end of this Participant Information for details of the clinical trial 
course and please contact your Investigator at any time if you wish more detailed 
explanations about this.  Please note that PAREXEL reserves the right to perform additional 
alcohol urine tests, nicotine tests (cotinine test) or tests for drugs of abuse without advance 
notice during the clinical trial.  A positive result in one of these tests may lead to your 
exclusion from the clinical trial. 
9. 
Behavior of Participants during the Clinical Trial 
• 
Please come to the unit at Screening in a fasted state.  
• 
Please do not consume poppy-seed containing food (e.g. poppy-seed cake) up to 3 days 
before the Screening Visit and up to 3 days before Day -1 because this can lead to a 
positive result of your urine test for drugs of abuse. 
• 
Please do not consume alcohol containing beverages within 48 hours before the 
Screening Visit and from 48 hours before Day -1 until you are discharged from the 
institute.   
• 
Please abstain from caffeine-containing food and beverages (chocolate, coffee, tea, cola, 
cocoa, mate, guarana, energy drinks) from 48 hours before Day -1 until you are 
discharged from the institute. 
• 
Only non-smokers may participate in this clinical trial.  You are not allowed to smoke/use 
cigarettes or similar products containing nicotine during the preceding 6 months and are 
not allowed to do this during the trial.  Please also avoid passive smoking as it may lead 
to a positive cotinine (=metabolite of nicotine) test in your urine. 
• 
Please abstain from strenuous physical activities (including sporting events) for 48 hours 
before Day -1 until discharge.  After discharge, mild physical activity can be resumed.  
• 
In order to enable proper functioning of the ECG electrodes and a correct and failure-free 
ECG recording, participants may be shaved on the affected areas.  Participants must 
disrobe from the waist up in order to ensure correct ECG recording.  
• 
Please note that you are not allowed to remove equipment attached to you (i.e. ECG) 
without being instructed by the trial staff. 
• 
During your in-house stay you will receive standardized meals and standardized 
beverages.  You are asked to finish these meals completely since different food amounts 
can influence the results of the clinical trial.  You are not allowed to consume additional 
food. 
• 
You will receive an emergency card confirming that you are participating in a clinical trial 
with a new investigational medicinal product.  The address of the clinical trial institute and 
an emergency telephone number are given in this card.  Please carry this card with you 
during the entire duration of the clinical trial, especially when you are not at the clinical 
trial institute. 
• 
Under no circumstances should you have participated in another clinical trial within the 
last 3 months before the clinical trial	  or (in more than 3 clinical studies within 12 months) 
and during the entire clinical trial!  Otherwise, you might seriously damage your health, 
since it is not foreseeable what kind of interactions might occur between the 
investigational medicinal products in the different clinical trials. 
• 
You should not have donated one or more units (≥450 mL) of blood or had any significant 
blood loss within 60 days before clinic admission on Day -1, or have donated plasma 
within 7 days before clinic admission on Day -1 and you must not donate blood or plasma 
during the participation in the clinical trial.  You may not donate any blood within 
3 months after discharge from the institute 
• 
CONCOMITANT MEDICATIONS (i.e. prescription or over the counter drugs, including 
natural and herbal remedies [including St. John’s Wort], vitamins and dietary 
supplements), must not be taken within 2 weeks prior to the administration of the 
investigational medicinal product and until the Safety Follow-up phone call.  The 
occasional intake of paracetamol (not more than 2 g daily) or other non-steroidal anti-
inflammatory drugs (NSAIDs, such as Aspirin [acetylsalicylic acid] or Ibuprofen) is 


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permitted if agreed by the Investigator.  You must inform the Investigator of a medical 
treatment beforehand.  Emergencies are an exemption. 
• 
Should an illness occur or a medical treatment is required, the responsible Investigator 
will decide whether you may continue to participate in the clinical trial. 
• 
DRUGS OF ABUSE:  Under no circumstances are you allowed to take drugs of abuse for 
the duration of the clinical trial.  This could lead to unpredictable risks, which can 
seriously damage your health. 
• 
During your stay at the institute you must rest from 23:00 until 06:00. 
• 
We would like to inform you that all corridors and the dining room of the institute are 
under video surveillance. 
• 
Access to the toilet area is controlled by an electronic chip card system. 
• 
You are not allowed to bring food or beverages with you.  Please note that PAREXEL 
staff may check your bags, rucksacks etc. at admission.  If there is reasonable ground for 
suspicion your personal belongings may also be checked at unannounced time points 
during your in-house stay at the institute. 
• 
You can meet your visitors in a designated room only between 12:00 and 19:00.  Visitors 
will be asked to leave their bags in lockers at the reception. 
• 
Should you have difficulty in keeping an appointment at the institute, please report this in 
advance, if possible, in order not to endanger the regular course of this clinical trial. 
• 
IN-HOUSE STAYS:  You are explicitly instructed that you are not allowed to leave the 
institute during in-house stays for insurance reasons.  Visiting the park of the institute is 
allowed only if you are accompanied by PAREXEL staff. 
• 
TRANSPORT TO/FROM THE INSTITUTE:  Please use public transport when coming to 
and when returning from our trial institute.  Please note that your ability to participate in 
road traffic and your capacity of reaction time may be impaired temporarily even after you 
have left the trial institute. 
• 
We would like to ask you not to bring any valuable articles for your in-house stay; 
PAREXEL is not liable for any lost property. 
You must always follow the instructions of the Investigator and staff and always adhere to 
PAREXEL rules of the house. 
10. 
Medical Care 
A physician-on-call service will be available for the entire duration of the clinical trial.  You 
can contact one of our investigators by telephone should any adverse events occur or if you 
wish to do so for any other reason. 
On weekdays, your responsible Investigator or one of his or her deputies will be present in 
the trial institute between 08:00 and 17:00 and can be contacted under the following phone 
numbers: 
Phone:  030 30685–4254 (Dr. med. Astrid Breitschaft) 
or 
030 30685–4225 (Dr. Tommaso Fadini) 
After 17:00 and on Saturdays, Sundays and on public holidays the following phone number is 
available: 
Phone:  030 30685–347 
(Responsible Employee on Duty at PAREXEL) 
You will be immediately connected with the Investigator on duty. 
Should you have questions concerning your participation in this clinical trial, the course of 
this clinical trial or your rights as a participant in a clinical trial, please contact the following 
phone number from your admission day to the institute: 


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Saniona Clinical Trial TM003 
Version date: 
18 September 2017 
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Phone:  030 30685–5100 
You should also inform your general practitioner about your participation in a clinical trial. 
Furthermore, you can contact the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM 
– Federal Institute for Drugs and Medicinal Products) to obtain information about the conduct 
of a clinical trial.  The contact address is: 
Bundesinstitut für Arzneimittel und Medizinprodukte 
Fachgruppe Klinische Prüfung / Inspektionen 
Kurt-Georg-Kiesinger-Allee 3 
53175 Bonn 
Phone: 
0228 207-43 18 
Fax: 
0228 207-43 55 
 


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Saniona Clinical Trial TM003 
Version date: 
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11. 
Protection of Personal Data  
During the clinical trial medical findings and personal information (as age, gender, race and 
ethnical origin) will be collected from you through the Investigator and written down in the 
institute in your personal file or stored electronically. 
All employees of the companies Saniona and PAREXEL International GmbH, Berlin, involved 
in the above mentioned clinical trial, are subject to professional secrecy.  The employees of 
Competent Authorities are officially obliged to discretion.  This guarantees that your personal 
data will be handled absolutely confidentially and will not be available to the public, i.e. your 
name will not appear in any report and in any publication.  Important data for the clinical trial 
will be additionally stored, transferred and evaluated in a pseudonymous manner. 
The procedure of pseudonymisation (encoding) of your data means that your personal 
identification attributes (such as name, birthday, address) will be replaced by a number.  The 
data are protected against unauthorized access.  The Investigator creates and files a 
decoding list, which helps to reassign the pseudonymised data to your person, to an allowed 
extent and as appropriate.  A decoding only takes place in compliance with the requirements 
regulated by law. 
Without your consent to the processing of your data you cannot participate in the 
clinical trial mentioned above. 
Personal data collected from you and stored in the course of the above mentioned 
clinical trial will be, if required, held available for viewing by the Competent Authority 
or representatives of the Sponsor to verify the proper conduct of the clinical trial. 
Where required, your data will be transferred in a pseudonymous manner 
a) to the Sponsor or to an agency commissioned by it for the purpose of scientific 
evaluation or publication, 
b) in case an application for marketing authorization is filed, to the applicant and the 
concerned higher authority, 
c) in case of adverse events of the investigational medicinal product to the Sponsor, 
to the responsible Ethics Committee and the concerned Higher Federal Authority 
which then transfers them to the European Database, 
d) to companies in European and non-European foreign countries which are affiliates 
of the Sponsor and, if necessary, from these companies to the responsible foreign 
competent authorities.  
The consent to the processing of your data is irrevocable.  In case of withdrawal of 
your consent to participate in the above mentioned clinical trial, the data stored up to 
this point may be used further, if required, to 
1. determine the effects of the investigational medicinal product, 
2. ensure that legitimate interests of the concerned person are not compromised, 
3. comply with the requirement to provide complete marketing authorization 
documents. 
In addition, PAREXEL International GmbH sometimes receives requests by job centers, 
employment agencies, social welfare authorities, and other authorities (e. g. tax office) with 
regard to the expense allowance paid to you.  In such a case, PAREXEL International GmbH 
will provide data about the expense allowance paid to you in the course of this trial to the 
requesting authority. 
The Sponsor will archive all of your data for at least 10 years after completion or 
discontinuation of the clinical trial.  Personal data are archived at PAREXEL for 15 years.  
You may request the disclosure of your data, provided this is technically not impossible as a 
result of a deletion of identifying attributes and keywords for decoding that has been made in 


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the meantime.  In this case please contact the Investigator or the Sponsor.  Inaccurately 
processed data concerning you will be corrected on your request. 
12. 
Insurance 
For this clinical trial an insurance policy has been taken out as defined in § 40 para. 1 
sentence 3 No. 8 and paragraph 3 of the German Pharmaceuticals Act (Arzneimittelgesetz, 
AMG).  This insurance covers damage to the health of the participants, which occurs during 
the conduct of the clinical trial.  In case a person dies, the body or the health of the 
participant is harmed during the conduct of the clinical trial; insurance coverage will also take 
over liability, if no other party will assume responsibility. 
The insurance does not apply to already existing damage to the health and its worsening, 
which would have occurred or persisted also without your participation in this clinical trial.  
Genetic damage, i.e. changes of the genetic material (genome), of the chromosomes, of the 
genes or of single nucleotides, is also excluded from the insurance coverage.  However, 
insurance coverage will be provided in case organic health damage of the insurant with 
effects on the clinical picture (phenotype) is the consequence. 
The insurance coverage is only guaranteed, if you have not violated the instructions of the 
Investigator and the conditions in the Participant Information.  In particular, you are obliged: 
• 
not to undergo any other medical treatment – except in an emergency – unless it is in 
agreement with the Investigator 
• 
to notify the insurer (the insurance company) immediately about any damage to your 
health, which could have occurred as a consequence of the clinical trial 
Please inform the Investigator immediately about possible emergency treatments.  
The “General Insurance Conditions for Clinical Studies” and the confirmation of insurance 
coverage will be handed out to you. 
PAREXEL has taken out the insurance policy for this clinical trial with the ‘Allianz 
Versicherungs-AG’, P.O. Box 10900 Berlin, Phone:  040.69469-33406, Fax:  0800.440 01 01 
(Policy No. AS-0243360732) to the amount of EURO 500,000 per participant, which is the 
legally obligatory minimal amount.  Accordingly, you are insured up to a maximum of 
EURO 500,000 in case of health damage, death or permanent occupational disability. 
13. 
Ethical and Legal Regulations 
This clinical trial will be conducted in accordance with the German Pharmaceuticals Act and 
the German Guidelines on the implementation of Good Clinical Practice (GCP-Guidelines – 
GCP-V) – according to the directives of the European Community, the Declaration of Helsinki 
for biomedical research in humans (revised version of 1996) and the International Council for 
Harmonisation.  The clinical trial protocol as well as the Participant Information and the 
Informed Consent Form have been submitted to the Ethics Committee of the Land Berlin and 
to the Competent Authority (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM) for 
the required reasoned opinion and authorization, respectively.  The clinical trial will be 
conducted only if these agencies raised no reservations against it. 
This information is part of the Informed Consent for the participation in the clinical trial with 
the investigational medicinal product specified in Section 2.  You also will be informed by an 
Investigator or a member of the investigator group, who are physicians, about the clinical trial 
in an information meeting.  If you have any further questions, please discuss them with the 
responsible Investigator or the Investigator Dr. med. Astrid Breitschaft. 
14. 
Expense Allowance 
For the participation in this clinical trial each participant will receive an expense allowance.  It 
consists of a partial installment for the clinical trial course and a second installment payable 
at the end of the clinical trial (i.e. after the Safety Follow-up phone call and possible control 


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examinations).  A claim for the entire amount of the expense allowance is only possible if you 
have participated in all planned examinations, including the examinations at the Safety 
Follow-up phone call and have also fulfilled the conditions for trial participation during the 
clinical trial. 
The check for the first installment of the expense allowance will be issued at the earliest on 
the day of the Safety Follow-up phone call or later, if necessary, only on presenting a valid 
official identity card.  No interim payments will be made.   
You will receive the second installment of the expense allowance after the Investigator has 
assessed all findings and no further control examinations are necessary (i.e. within one week 
after Safety Follow-up phone call or a control examination, respectively).  In case of changes 
to your medical results compared to screening, PAREXEL is obliged to monitor these 
changes even after the follow-up until they have returned to their initial level or, where 
necessary, to take appropriate medical measures.  Therefore, should it be necessary to 
perform additional control examinations / additional visits prescribed by a doctor, you will 
receive an expense allowance of EURO 20 for each additional visit to the trial institute (this 
does not apply for screening). 
In the event of an infringement of the duties detailed in this Participant Information (in 
particular concerning the intake of other medicines, alcohol or drugs of abuse), you 
will relinquish your rights to an expense allowance, if the respective data cannot be 
used for evaluation.  Deliberate infringements of the rules of the house or serious 
misbehavior may lead to your withdrawal from the clinical trial, followed by the 
cancellation of the second installment of your expense allowance. 
Once again, we would like to emphasize the fact that the clinical trial course and the planned 
number of single examinations to be performed are described according to current status.  It 
is possible that shortly before the start of the clinical trial or during the clinical trial the number 
of single examinations may be increased or reduced based upon new scientific evidence or 
requirements, which could result in changes to the expense allowance.  You will be informed 
of any substantial changes, which are to be notified to the Ethics Committee. 
For the sake of completeness, we would also like to point out that we do not make any 
deductions for tax or social security contributions, because no contract of employment 
between you and PAREXEL exists.  Expense allowances are generally subject to income 
tax.  Tax needs not to be paid only if the entire annual income, including the expense 
allowance, does not exceed the tax exemption limit specified in the tax scale. 
If the clinical trial is terminated prematurely, either as a whole or for single participants, or if 
single trial days are canceled, the participants will receive a proportional amount of the 
expense allowance. 
You will receive EURO 30 for the participation in the screening.  This amount covers 
additional visits, for example for controls of blood and/or urine during the entire screening 
period.  This sum is only paid out separately if you are not suitable for the clinical trial; 
otherwise it is included in the first instalment (see below). 
If you are invited to the admission but receive no medication, you will receive an amount of 
up to EURO 150 (depending on the time spent). 
You will not receive a separate reimbursement of your travel expenses; these are covered by 
the expense allowance. 
Please claim the check immediately after you have received it.  If you have not collected or 
claimed the checks your entitlement to the expense allowance expires 6 months after the 
Safety Follow-up phone call.   
The first installment of the expense allowance is EURO 480, the second installment is 
EURO 192.  Thus, the total amount of the expense allowance is EURO 672, if you complete 
the entire clinical trial course. 


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15. 
HIV- and Hepatitis-Examination 
With the participation in this clinical trial you will be asked to give your consent to blood 
examinations for a HIV test, Hepatitis B test, Hepatitis A test and Hepatitis C test during the 
Screening Visit.  The following precautions will be taken to protect the anonymity of your test 
results: 
Your blood sample will be labeled in a pseudonymous manner as described in Section 11, 
i.e. the laboratory staff doing the test cannot connect your blood sample with your name.  
The laboratory will transfer the results of the examination electronically to that part of the 
internal database system at PAREXEL, to which only authorized persons have access, who 
are obliged to confidentiality (according to §13 of the Bundesdatenschutzgesetz, German 
Data Protection Law).  The Investigator or a medical designee will inform you about the 
finding in a confidential, personal conversation. 
A positive result of the HIV test will be reported anonymously according to the German 
„Infektionsschutzgesetz” §7 (3), i.e. without giving your name, to the Robert Koch Institute 
(Berlin).  The reporting of a positive result to third parties indicating your name is not possible 
without your written consent. 
We want to point out explicitly the following:  Your participation in the clinical trial is only 
possible in case of a negative result of the HIV test.  In no case should you draw 
consequences from the inclusion in a clinical trial regarding your sexual behavior, e.g. 
refraining from protective measures just because you assume that your test result is 
negative. 
A positive test result from the Hepatitis B, Hepatitis A or the Hepatitis C test will be reported 
according to the German „Infektionsschutzgesetz” §7 (1) by name to the responsible health 
authority (“Gesundheitsamt”). 
Only a newly acquired infection will be reported, for example, a known chronic Hepatitis C 
disease is exempted from this. 
Your participation in the clinical trial is only possible in case of a negative result from the 
Hepatitis B-, Hepatitis A- and the Hepatitis C-tests. 
Should you have further questions about this, please contact the responsible Investigator at 
PAREXEL, an independent medical examiner or a competent outreach clinic. 
 

Prot_000.pdf: 
Saniona A/S 
Clinical Study Protocol 
TM003 
CONFIDENTIAL 
 
Final 1.0 
Page 1 of 63 
15 September 2017 
 
Clinical Study Protocol 
A Randomized, Open-label, Single-dose, Parallel-arm, Phase 1 
Study to Investigate the Pharmacokinetic Profile of a Fixed-Dose 
Combination Tablet of Tesofensine and Metoprolol (Tesomet) and 
Co-Administration of Tesofensine Plus Commercial Metoprolol in 
Adult Healthy Subjects 
 
Sponsor: 
Saniona A/S 
Baltorpvej 154 
DK-2750 Ballerup 
Denmark 
Contract Research Organization: 
PAREXEL International GmbH 
Early Phase Clinical Unit 
Klinikum Westend, Haus 31 
Spandauer Damm 130 
14050 Berlin, Germany 
Principal Investigator: 
Dr. med. Astrid Breitschaft 
PAREXEL Study Number: 
236073 
Sponsor Study Number: 
TM003 
EudraCT Number:  
2017-003339-13 
IMP Name: 
Tesofensine, metoprolol 
Development Phase: 
Phase 1, pharmacokinetics, relative bioavailability 
Version (Date) of Final Protocol: 
Final 1.0 (15 September 2017) 
 
This clinical study will be conducted in accordance with the International Council for Harmonisation Tripartite 
Guideline for Good Clinical Practice (GCP) (E6), the Declaration of Helsinki (Version 1996), the protocol and with 
other applicable regulatory requirements. 
Confidentiality Statement 
This document contains confidential information of Saniona A/S.  Do not copy or distribute without written 
permission from the Sponsor. 






Saniona A/S 
Clinical Study Protocol 
TM003 
CONFIDENTIAL 
 
Final 1.0 
Page 4 of 63 
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LIST OF STUDY STAFF 
Sponsor 
Saniona A/S 
Baltorpvej 154 
DK-2750 Ballerup 
Telephone number: +45 70 705 225 
Email: rdv@saniona.com 
 
Principal Investigator 
Dr. med. Astrid Breitschaft 
PAREXEL International GmbH 
Early Phase Clinical Unit Berlin 
Klinikum Westend, Haus 31 
Spandauer Damm 130 
14050 Berlin 
Germany 
Telephone number: +49 (0)30 30685 4254 
Email: Astrid.Breitschaft@parexel.com 
 
Contract Research Organization 
PAREXEL International GmbH 
Early Phase Clinical Unit Berlin 
Klinikum Westend, Haus 31 
Spandauer Damm 130 
14050 Berlin 
Germany 
Telephone number: +49 (0)30 30685 0 
Fax number: +49 (0)30 30685 7017 
 
Adverse Event Reporting 
PAREXEL International GmbH 
Medical Services Department Germany, Berlin 
Fax number: +49 30 315118 7777 
Email: Medical_Berlin@parexel.com 
 
Bioanalytical Laboratory 
Envigo CRS Limited 
Woolley Road  
Alconbury  
Huntingdon  
Cambridgeshire 
PE28 4HS 
Untited Kingdom 
Contact Person: Lynn Laugher 
Telephone number: +44 (0) 1480 892 030 
Fax number: +44 (0) 1480 892 362 
 
 
 


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Clinical Study Protocol 
TM003 
CONFIDENTIAL 
 
Final 1.0 
Page 5 of 63 
15 September 2017 
 
PROTOCOL SYNOPSIS 
Protocol Title 
A randomized, open-label, single-dose, parallel-arm, Phase 1 study to 
investigate the pharmacokinetic profile of a fixed-dose combination tablet of 
tesofensine and metoprolol (Tesomet) and co-administration of tesofensine 
plus commercial metoprolol in adult healthy subjects 
Study Numbers 
PAREXEL Study No.: 236073 
Sponsor Protocol No.: TM003 
Development Phase 
Phase 1, pharmacokinetics (PK), relative bioavailability 
Sponsor 
Saniona A/S 
Principal Investigator 
Dr. med. Astrid Breitschaft 
Study Center 
PAREXEL International GmbH 
Early Phase Clinical Unit Berlin 
Klinikum Westend, Haus 31 
Spandauer Damm 130 
14050 Berlin 
The study will be conducted at a single center (PAREXEL International 
GmbH, Early Phase Clinical Unit Berlin). 
Study Objectives 
Primary objective 
To evaluate the PK profile and relative bioavailability of a single dose of the 
Tesomet fixed-dose combination (FDC) tablet and co-administration of 
tesofensine plus commercial metoprolol. 
Secondary objectives 
• 
To evaluate the PK profile and relative bioavailability of a single dose of 
the Tesomet FDC tablet in fed state 
• 
To evaluate the PK profile of a single dose of the high and low dose of the 
Tesomet FDC tablet  
• 
To evaluate overall safety and tolerability of the Tesomet FDC tablet and 
co-administration of tesofensine plus commercial metoprolol in adult healthy 
volunteers 
Study Design 
This is a randomized, open-label, parallel-arm study in 60 healthy male 
subjects who meet the inclusion and none of the exclusion criteria for the 
study.  Each subject will participate in a screening period, a baseline period 
(the day preceding drug administration), and a single-dose treatment period 
with an on-site observation period of at least 48 hours after the dose.  
Subjects will be admitted to the study center at least 24 hours prior to dosing. 
Each subject will then be randomized to one of the 4 treatment groups and 
receive one of the following treatments: 
Treatment A (Test 1): A Tesomet FDC tablet (20 mg immediate release [IR] 
metoprolol, 1 mg tesofensine, 80 mg extended release [ER] metoprolol) in 
fasted condition (“High” dose) 
Treatment B (Test 2): A Tesomet FDC tablet (5 mg IR metoprolol, 0.2 mg 
tesofensine, 20 mg ER metoprolol) in fasted condition (“Low” dose) 
Treatment C (Comparator): 1 mg tesofensine (2 tablets of 0.5 mg), 25 mg 
commercial IR metoprolol (1 tablet of 25 mg), 75 mg commercial ER 
metoprolol (1 ER tablet of 25 mg and 1 ER tablet of 50 mg), fasted condition 
Treatment D (Test 3): A Tesomet FDC tablet (20 mg IR metoprolol, 1 mg 
tesofensine, 80 mg ER metoprolol in fed condition (“High” dose) 


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Final 1.0 
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Subjects assigned to Treatments A, B and C will be required to remain fasted 
from at least 10 hours before dosing and until 4 hours post-dose.  At 4 hours 
after dosing a light standardized meal will be served.  The Investigator or a 
designee will administer the appropriate treatment with 240 mL water to the 
subjects as per randomization schedule.  Subjects assigned to Treatment D will 
be required to eat a Food and Drug Administration (FDA) standardized high-
fat breakfast within a period of 30 minutes before dosing. 
The Investigator or a designee will administer the treatment to the subjects 30 
minutes after start of the breakfast and within 5 minutes of completing the 
meal. 
For each of the treatment groups, blood samples will be collected pre-dose and 
at designated time points post dosing.  Subjects will be discharged after the 
48 hours post-dose assessments have been completed.  The end-of-study (EoS) 
safety evaluation will be performed 7 days (i.e., on Day 8) after dosing over the 
phone.  Subjects will be asked regarding adverse events (AE), and concomitant 
medications. 
The total duration for each subject will be up to 38 days, including Screening. 
Investigational Medicinal 
Products 
• 
Tesomet “high” dose: An FDC tablet with 20 mg IR metoprolol, 1 mg 
tesofensine, 80 mg ER metoprolol, single oral dose, Treatment Group A 
and D only 
• 
Tesomet “low” dose: An FDC tablet with 5 mg IR metoprolol, 0.2 mg 
tesofensine, 20 mg ER metoprolol, single oral dose, Treatment Group B 
only 
• 
Tesofensine, film-coated tablet, 0.5 mg, single oral dose of 2 tablets, 
Treatment Group C only 
• 
Metoprolol, 25 mg IR tablet, single oral dose, Treatment Group C only 
Egilok 25 mg - EGIS Pharmaceuticals PLC (Hungary) 
• 
Metoprolol, 25 mg ER tablet, single oral dose of 1 tablet, Treatment 
Group C only 
 
Metoprolol-ratiopharm® Succinat 23,75 mg Retardtabletten – ratiopharm 
GmbH (Germany) (corresponding to 25 mg metoprolol tartrate) 
• 
Metoprolol, 50 mg ER tablet, single oral dose of 1 tablet, Treatment 
Group C only 
 
Metoprolol-ratiopharm® Succinat 47,5 mg Retardtabletten - ratiopharm 
GmbH (Germany) (corresponding to 50 mg metoprolol tartrate)  
Number of Subjects 
A total of 60 subjects is planned for enrollment.  The subjects will be randomly 
assigned to one of the 4 treatment groups with 15 subjects per group. 
Study Population 
Inclusion Criteria 
Subjects who meet the following criteria will be considered eligible to 
participate in the clinical study: 
1. Subject voluntarily agrees to participate in this study and signs an 
Independent Ethics Committee (IEC)-approved informed consent prior to 
performing any of the Screening Visit procedures. 
2. Males between 18 to 55 years of age, inclusive, at the Screening Visit. 
3. Nonsmokers (or other nicotine use) as determined by history (no nicotine 
use over the past 6 months) and by urine cotinine concentration (< 500 ng/mL) 
at the Screening Visit and admission. 
4. Body mass index (BMI) between 18.5 and 30.0 kg/m2, inclusive, at the 
Screening Visit. 
5. Healthy, determined by pre-study medical evaluation (medical history, 
physical examination, vital signs, 12-lead ECG and clinical laboratory 


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Clinical Study Protocol 
TM003 
CONFIDENTIAL 
 
Final 1.0 
Page 7 of 63 
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evaluations). 
Exclusion Criteria 
Subjects who meet one or more of the following criteria will not be considered 
eligible to participate in the clinical study: 
1. Subject has history or evidence of any clinically significant cardiovascular, 
gastrointestinal, 
endocrinologic, 
hematologic, 
hepatic, 
immunologic, 
metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, 
and/or other major disease or malignancy as judged by the Investigator. 
2. Subject has any disorder that would interfere with the absorption, 
distribution, metabolism or excretion of drugs. 
3. Subject 
has 
a 
clinically 
significant 
abnormality 
following 
the 
Investigator’s review of the physical examination, ECG and clinical study 
protocol-defined clinical laboratory tests at Screening or admission to the 
clinical unit or has any concurrent disease or condition that, in the opinion of 
the Investigator, would make the subject unsuitable for participation in the 
clinical study.  One re-test is allowed, if (a) test result(s) is outside the limits. 
4. Subject has a pulse < 50 or > 90 bpm; systolic blood pressure (SBP) < 90 
mmHg or > 140 mmHg; diastolic blood pressure (DBP) < 50 mmHg or > 
90 mmHg at the Screening Visit or admission.  One re-test is allowed, if (a) 
test result(s) is outside these limits. 
5. Subject has a corrected QT interval using Fridericia’s formula (QTcF) 
interval > 450 msec at Screening.  If the mean QTcF exceeds the limits above, 
an additional ECG may be taken.  If this also gives an abnormal result, the 
subject will be excluded. 
6. Subject has positive test for Hepatitis B surface antigen (HBsAg), or 
Hepatitis B core antibody (indicative of active Hepatitis B), Hepatitis A virus 
antibodies (immunoglobulin M), Hepatitis C virus (HCV) antibodies or human 
immunodeficiency virus (HIV) 1 and/or -2 antibodies. 
7. Use of any prescribed or non-prescribed drugs (including vitamins, natural 
and herbal remedies, e.g., St. John’s Wort) in the 2 weeks prior to study drug 
administration, except for the occasional use of paracetamol (up to 2 g/day) or 
other non-steroidal anti-inflammatory drugs (NSAIDs). 
8. Subject has history of alcohol and/or illicit drug abuse within 2 years of 
entry. 
9. Subject has positive urine drug test (e.g., cocaine, amphetamines, 
barbiturates, opiates, benzodiazepines, cannabinoids) or alcohol test at the 
Screening Visit or admission.  
10. History of drinking more than 21 units of alcohol per week (1 unit = 10 g 
pure alcohol = 250 mL of beer [5%] or 35 mL of spirits [35%] or 100 mL of 
wine [12%]) within 3 months prior to admission to the clinical unit. 
11. Subject is unwilling to avoid consumption of coffee and caffeine-
containing beverages within 48 hours prior to admission until discharge from 
the clinical site. 
12. Subject is unwilling to avoid use of alcohol or alcohol-containing foods, 
medications or beverages, within 48 hours prior to admission until discharge 
from the clinical site. 
13. Any significant blood loss, donated one unit (450 mL) of blood or more, 
or received a transfusion of any blood or blood products within 60 days, or 
donated plasma within 7 days prior to the admission to the clinical unit. 
14. Participation in any clinical study within 3 months prior to the expected 
date of investigational medicinal product (IMP) administration, provided that 
the clinical study did not entail a biological compound with a long t1/2 or 


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participation in more than 3 clinical studies within 12 months. 
15. History of any clinically significant cardiac arrhythmia. 
16. History of bulimia or anorexia nervosa. 
17. Use of any agent used for weight loss within the last 3 months. 
18. More than 5% weight loss within the last 3 months. 
19. Hypo- or hyperthyroidism. 
20. Subject is unwilling to abstain from vigorous exercise from 48 hours prior 
to admission until discharge. 
21. Subject has a history of hypersensitivity to the study drugs or any of the 
excipients or to medicinal products with similar chemical structures. 
22. Subject has lactose intolerance. 
23. Subject is unable to understand and communicate in German language or 
to understand the protocol requirements, instructions and study-related 
restrictions, the nature, scope and possible consequences of the clinical study 
or is unlikely to comply with the study requirements; e.g., uncooperative 
attitude and improbability of completing the clinical study. 
24. Subject has previously been enrolled in this clinical study. 
25. Vulnerable subjects defined as individuals whose willingness to volunteer 
in a clinical study may be unduly influenced by the expectation, whether 
justified or not, of benefits associated with participation, or of a retaliatory 
response from senior members of a hierarchy in case of refusal to participate 
(e.g., persons in detention, minors and those incapable of giving consent). 
26. Subject is the Investigator or any Sub-Investigator, research assistant, 
pharmacist, study coordinator, other staff or relative thereof directly involved 
in the conduct of the study or employee of the Sponsor or PAREXEL.  
Criteria for Evaluation 
Pharmacokinetics Endpoints 
 
The following PK parameters for tesofensine and metoprolol will be 
determined after dosing for all 4 treatments, as appropriate: 
• 
Cmax: Maximum tesofensine and metoprolol concentrations determined 
directly from the concentration-time profile 
• 
AUC0-48: Area under the concentration-time curve from pre-dose (time 0) 
to 48 hours post-dose calculated using the linear-log trapezoidal rule 
• 
Tmax: Time of maximum tesofensine and metoprolol concentrations 
determined directly from the concentration-time profile 
• 
λz: The terminal elimination rate constant determined by selection of at 
least 3 data points on the terminal phase of the concentration-time curves 
• 
t½: Terminal elimination half-life calculated as: ln2/λz 
 
Safety Endpoints 
The following safety variables will be recorded at regular intervals during the 
study: 
• 
Vital signs (supine blood pressure [BP], pulse, body temperature and 
respiratory rate) 
• 
Twelve-lead electrocardiogram (ECG) 
• 
Clinical laboratory tests (hematology, clinical chemistry and urinalysis) 
• 
Adverse event assessments 
• 
Concomitant medication assessments 
• 
Physical examinations 


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Statistical Methods 
Sample Size Considerations 
Formal sample size calculations were not performed.  The number of subjects 
was chosen based on literature and experience from similar studies and is 
considered sufficient to meet the study objectives.  No formal statistical test 
will be performed.  Only descriptive statistics for PK and safety data by 
treatment group will be presented.  The sample size chosen is therefore judged 
reasonable to gain knowledge regarding key parameters in each of the 
treatment groups. 
Data Presentation/Descriptive Statistics 
All demographic, safety and PK data will be listed and summarized in tabular 
format by descriptive statistics as appropriate.  Only descriptive statistics will 
be applied and presented by treatment group.  No imputation of missing data 
will be performed but for PK the trapezoidal method will handle missing data 
by interpolation over a single time point where PK is missing.  Summary 
statistics of the PK parameters, e.g., AUC0-48, Cmax, Tmax, t½, etc. will be 
presented by treatment and dose-normalized when relevant.  Pharmacokinetics 
data may also be displayed graphically as appropriate. A statistical analysis 
plan (SAP) will be issued as a separate document, providing detailed methods 
for the analyses. 
 


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TABLE OF CONTENTS 
SIGNATURE PAGE ...................................................................................................................... 2 
SIGNATURE PAGE ...................................................................................................................... 3 
LIST OF STUDY STAFF ............................................................................................................... 4 
PROTOCOL SYNOPSIS ............................................................................................................... 5 
TABLE OF CONTENTS .............................................................................................................. 10 
List of Tables ............................................................................................................................. 13 
List of Figures ........................................................................................................................... 14 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................. 15 
1. 
INTRODUCTION ................................................................................................................. 18 
1.1. 
Pharmacokinetics ........................................................................................................... 19 
1.1.1. 
Tesofensine ............................................................................................................. 19 
1.1.2. 
Metoprolol............................................................................................................... 20 
1.1.3. 
Tesomet (Co-administration of Tesofensine and Metoprolol)................................ 21 
1.2. 
Rationale for the Clinical Study ..................................................................................... 21 
1.2.1. 
Safety in Previous Clinical Studies with Tesofensine ............................................ 21 
1.2.2. 
Safety of Metoprolol ............................................................................................... 23 
1.2.3. 
Safety of Tesomet (Co-administration of Tesofensine and Metoprolol) ................ 23 
1.3. 
Risk-benefit Assessment ................................................................................................ 23 
2. 
STUDY OBJECTIVES ......................................................................................................... 25 
2.1. 
Primary Objective .......................................................................................................... 25 
2.2. 
Secondary Objectives ..................................................................................................... 25 
3. 
OVERALL DESIGN AND PLAN OF THE STUDY........................................................... 26 
3.1. 
Overview ........................................................................................................................ 26 
3.2. 
Endpoints ........................................................................................................................ 28 
3.2.1. 
Pharmacokinetics Endpoints ................................................................................... 28 
3.2.2. 
Safety Endpoints ..................................................................................................... 28 


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3.3. 
Justification of the Study Design ................................................................................... 28 
3.4. 
Stopping Criteria for the Clinical Study ......................................................................... 29 
4. 
STUDY POPULATION ........................................................................................................ 31 
4.1. 
Number of Subjects ........................................................................................................ 31 
4.2. 
Inclusion Criteria ............................................................................................................ 31 
4.3. 
Exclusion Criteria ........................................................................................................... 31 
4.4. 
Subject Withdrawal and Replacement ........................................................................... 33 
4.5. 
Termination of the Clinical Study .................................................................................. 35 
5. 
INVESTIGATIONAL MEDICINAL PRODUCT ................................................................ 36 
5.1. 
Identity of the Investigational Medicinal Products ........................................................ 36 
5.2. 
Dose Rationale Including Time of Dosing ..................................................................... 36 
5.3. 
Supply, Packaging, Labeling and Storage ...................................................................... 37 
5.4. 
Drug Accountability, Dispensing and Destruction ........................................................ 37 
5.5. 
Subject Identification and Randomization ..................................................................... 38 
5.5.1. 
Screening Numbers ................................................................................................. 38 
5.5.2. 
Randomization Numbers ........................................................................................ 38 
5.6. 
Administration of Investigational Medicinal Products .................................................. 38 
5.7. 
Compliance..................................................................................................................... 39 
5.8. 
Blinding and Breaking the Blind .................................................................................... 39 
5.9. 
Prior and Concomitant Medications ............................................................................... 39 
5.10. 
Treatment of Overdose ............................................................................................... 39 
6. 
MEASUREMENTS AND METHODS OF ASSESSMENT ................................................ 40 
6.1. 
Medical History, Demographic and Other Baseline Information .................................. 40 
6.2. 
Safety Variables ............................................................................................................. 41 
6.2.1. 
Adverse Events ....................................................................................................... 41 
6.2.2. 
Clinical Laboratory Assessments ............................................................................ 45 
6.2.3. 
Vital Signs ............................................................................................................... 47 
6.2.4. 
Standard 12-lead Electrocardiograms ..................................................................... 47 


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6.2.5. 
Physical Examinations ............................................................................................ 47 
6.3. 
Pharmacokinetics Variables ........................................................................................... 48 
6.3.1. 
Blood Sample Collection ........................................................................................ 48 
6.4. 
Total Amount of Blood .................................................................................................. 48 
7. 
STUDY CONDUCT.............................................................................................................. 49 
7.1. 
Schedule of Assessments ............................................................................................... 49 
7.2. 
Order of Assessments ..................................................................................................... 51 
7.3. 
Early Termination .......................................................................................................... 51 
7.4. 
End-of-Study .................................................................................................................. 51 
7.5. 
Restrictions ..................................................................................................................... 51 
7.5.1. 
Dietary and Fluid Restrictions ................................................................................ 51 
7.5.2. 
Other Restrictions ................................................................................................... 52 
8. 
STATISTICAL METHODS.................................................................................................. 53 
8.1. 
Study Population ............................................................................................................ 53 
8.1.1. 
Analysis Populations ............................................................................................... 53 
8.2. 
General Considerations .................................................................................................. 53 
8.3. 
Protocol Deviations ........................................................................................................ 53 
8.4. 
Subject Disposition ........................................................................................................ 53 
8.5. 
Demographic and Anthropometric Information and Baseline Characteristics .............. 54 
8.6. 
Prior and Concomitant Medication and Drug Administration ....................................... 54 
8.7. 
Exposure ......................................................................................................................... 54 
8.8. 
Safety Analyses .............................................................................................................. 55 
8.8.1. 
Adverse Events ....................................................................................................... 55 
8.8.2. 
Clinical Laboratory Tests ........................................................................................ 55 
8.8.3. 
Vital Signs ............................................................................................................... 55 
8.8.4. 
Standard 12-lead Electrocardiogram ....................................................................... 55 
8.8.5. 
Physical Examination.............................................................................................. 55 
8.9. 
Pharmacokinetic Analyses ............................................................................................. 56 


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8.10. 
Interim Analyses ......................................................................................................... 56 
8.11. 
Determination of Sample Size .................................................................................... 56 
9. 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS ................................................ 57 
9.1. 
Data Quality Assurance .................................................................................................. 57 
9.1.1. 
Data Collection ....................................................................................................... 57 
9.1.2. 
Data Management ................................................................................................... 58 
9.2. 
Access to Source Data/Documents ................................................................................ 58 
9.3. 
Archiving Study Documents .......................................................................................... 59 
9.4. 
Good Clinical Practice ................................................................................................... 59 
9.5. 
Informed Consent ........................................................................................................... 59 
9.6. 
Protocol Approval and Amendment(s) .......................................................................... 60 
9.7. 
Insurance and Indemnity ................................................................................................ 60 
9.8. 
Confidentiality Data Protection ...................................................................................... 61 
9.9. 
Publication Policy .......................................................................................................... 61 
10. 
REFERENCE LIST ........................................................................................................... 62 
11. 
APPENDICES ................................................................................................................... 63 
11.1. 
Appendix 1 - List of Prohibited Medication ............................................................... 63 
 
 
List of Tables 
Table 1 
Identity of Investigational Products ............................................................................ 36 
Table 2 
Assessment of Relationship of Adverse Events to Investigational Product ............... 43 
Table 3 
Clinical Laboratory Assessments ............................................................................... 46 
Table 4 
Approximate Total Amount of Blood for Each Subject ............................................. 48 
Table 5 
Schedule of Assessments ............................................................................................ 50 
 
 


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List of Figures 
Figure 1 
Study Flow Chart ........................................................................................................ 27 
Figure 2 
Study Overview .......................................................................................................... 27 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
AUC0-48 
Area under the concentration-time curve from pre-dose (time 0) 
until 48 hours post-dose 
BMI 
Body mass index 
BP 
Blood pressure 
bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CL/F 
Total body clearance 
Cmax 
Maximum plasma concentration 
CPK 
Creatine phosphokinase 
CSR 
Clinical study report 
CV 
Cardiovascular 
CYP 
Cytochrome P450 
DAT 
Dementia of Alzheimer type 
DBP 
Diastolic blood pressure 
DDI 
Drug-drug interaction 
DMP 
Data management plan 
ECG 
Electrocardiogram 
EoS 
End-of-study 
ER 
Extended release 
eSDR 
Electronic source data report 
FDA 
Food and Drug Administration 
FDC 
Fixed-dose combination 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
Hb 
Hemoglobin 


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Abbreviation 
Definition 
HBsAg 
Hepatitis B surface antigen 
HCT 
Hematocrit 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
i.v. 
Intravenous 
IB 
Investigator’s Brochure 
ICD 
Informed consent document 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
IR 
Immediate release 
LDH 
Lactate dehydrogenase 
MAO 
Monoamine oxidase 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
NSAID 
Non-steroidal anti-inflammatory drug 
OTC 
Over-the-counter 
PD 
Parkinson’s disease 
PK 
Pharmacokinetic(s) 
PT 
Preferred Term 
QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected for heart rate using Bazett’s correction 
QTcF 
QT interval corrected for heart rate using Fridericia’s correction 
RA 
Regulatory authority 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SMP 
Safety management plan 
SNRI 
Serotonin and norepinephrine reuptake inhibitor 


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Abbreviation 
Definition 
SOC 
System organ class 
SOP 
Standard operating procedure 
SPC 
Summary of Product Characteristics 
SSRI 
Selective serotonin reuptake inhibitor 
t½ 
Terminal elimination half-life 
T2DM 
Type 2 diabetes mellitus 
TEAE 
Treatment emergent adverse event 
Tmax 
Time of maximum plasma concentration 
TSH 
Thyroid-stimulating hormone 
TZD 
Thiazolidinediones 
ULN 
Upper limit of normal 
USA 
United States of America 
WBC 
White blood cell 
WHO-DD 
World Health Organization Drug Dictionary 
λz 
The terminal elimination rate constant 


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1. 
INTRODUCTION 
Tesomet is a fixed-dose combination (FDC) product with 2 active ingredients – tesofensine 
(NS2330) – a serotonin, norepinephrine and dopamine reuptake inhibitor and metoprolol – a 
β1-(cardio-selective) selective adrenoceptor-blocking agent. 
Tesofensine was initially noted to cause a marked weight loss in overweight patients with 
Parkinson’s disease (PD) and dementia of Alzheimer type (DAT), even though no attempts to 
promote weight control was included in the study.  The weight reducing effect was confirmed in 
a subsequent Phase 2 clinical study in obese subjects (TIPO-1), exceeding benchmarks set by the 
regulatory agencies for approval of weight loss agents [1].  Although tesofensine was generally 
well tolerated in these studies, an increase of blood pressure (BP) of 1–5 mmHg and an increase 
of heart rate (HR) up to 8 beats per minute (bpm) were observed in patients dosed with 0.25 to 
1.0 mg of tesofensine once daily.  
Historically, cardiovascular (CV) safety and the need for a favorable CV safety profile has been 
a critical requirement and hurdle for approval in the area of endocrine and metabolic, thus, it has 
been concluded that any increase in HR and/or BP constitutes an unacceptable safety risk and 
significantly impact the overall benefit/risk profile of tesofensine.  Consequently, it has been 
decided by Saniona not to develop tesofensine as a stand-alone therapy.  Instead, tesofensine has 
been combined with the beta-blocker metoprolol in order to mitigate the increase in BP and HR 
and ensure a favorable risk/benefit profile for the combination product Tesomet.  
To date, co-administration of tesofensine and metoprolol to human has been investigated in 2 
completed clinical studies.  First, a Phase 1 drug-drug interaction study (Q-21125) where a single 
dose of metoprolol was added to tesofensine administered for 14 days to study pharmacokinetics 
(PK) of both when administered together.  Second, a Phase 2 study in obese and overweight 
patients with type 2 diabetes mellitus (T2DM) (TM001) designed to provide the proof-of-
concept data that addition of metoprolol mitigates the tesofensine-induced increase in HR and 
BP.  In both studies, the drugs were generally well tolerated and the collected data have provided 
solid base for future investigation of Tesomet for various indications.  Currently, there is an 
ongoing Phase 2 study in patients with Prader-Willi syndrome (TM002). 
In addition, the clinical development program of Tesomet draws heavily on a substantial body of 
data available for tesofensine, for which - despite not being approved or developed as a 
stand-alone agent - there is a complete pre-clinical efficacy and safety data package available and 
has been to date studied in more than 1300 subjects.  Also, metoprolol was approved in the 


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United States of America (USA) in 1978 and has since become one of the most widely used 
drugs ever with millions of patient-years of safety data available. 
Given the mechanism of action, available pre-clinical and clinical data, it is anticipated that 
Tesomet could be developed for a variety of indications such as treatment of obesity, T2DM, 
pre-diabetes, Prader-Willi syndrome, binge eating disorder, etc.  For more information please see 
the Tesomet Investigator’s Brochure (IB) [2]. 
1.1. 
Pharmacokinetics 
1.1.1. 
Tesofensine 
In man the clearance after oral administration was low (total body clearance [CL/F] 30 to 
40 mL/min) and tesofensine was shown to have a long half-life (t1/2) of about 9 days (220 hours).  
In all species including man the volume of distribution exceeded the total volume of body water, 
indicating that tesofensine was extensively distributed into the tissues.  The protein binding was 
about 91%. 
Tesofensine was mainly metabolized to the N-desmethyl-metabolite (NS2360), which was the 
only metabolite found in human plasma.  NS2360 was shown to have a longer half-life than 
tesofensine, i.e., approximately 16 days (374 hours) in man and have an exposure of 31 to 34% 
of the parent compound at steady state.  In vivo data indicated that NS2360 was responsible for 
approximately 6% of the activity.  Similarly to animals, the kidney seems to play only a minor 
role in the clearance of tesofensine in man (about 15 to 20%). 
The PK profile in man was linear after single and multiple doses over all doses tested.  No 
relevant differences in the PK of healthy elderly subjects, patients with mild DAT or PD were 
observed.  Similarly, no differences were observed between Japanese and Caucasians or between 
recreational drug abusers and non-abusers.  No relevant changes of the PK in subjects with mild 
renal impairment were observed, but an increase in exposure (of about 30%) occurred in subjects 
with moderate and severe renal impairment.  Steady state plasma concentrations in the target 
population (obese patients) did not differ significantly from that in healthy volunteers.  The 
relative bioavailability of tesofensine was not significantly affected by food intake.  Based on 
cross-study comparison with intravenous (i.v.) data the absolute bioavailability after oral 
administration was estimated to be > 90%.  Investigation of cytochrome P450 2D6 (CYP2D6) 
and CYP3A4 interaction in man did not indicate clinically relevant PK interactions. 
For further details refer to the IB of tesofensine [3]. 


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1.1.2. 
Metoprolol 
Adults: In man, absorption of metoprolol is rapid and complete.  Plasma levels following oral 
administration of conventional metoprolol tablets, however, approximate 50% of levels 
following intravenous administration, indicating about 50% first-pass metabolism.  Metoprolol 
crosses the blood-brain barrier and has been reported in the cerebrospinal fluid in a concentration 
78% of the simultaneous plasma concentration.  
Plasma levels achieved are highly variable after oral administration.  Only a small fraction of the 
drug (about 12%) is bound to human serum albumin.  Metoprolol is a racemic mixture of R- and 
S-enantiomers, and is primarily metabolized by CYP2D6.  When administered orally, it exhibits 
stereoselective metabolism that is dependent on oxidation phenotype.  Elimination is mainly by 
biotransformation in the liver, and the plasma t1/2 ranges from approximately 3 to 7 hours.  Less 
than 5% of an oral dose of metoprolol is recovered unchanged in the urine; the rest is excreted by 
the kidneys as metabolites that appear to have no beta-blocking activity.  
Following intravenous administration of metoprolol, the urinary recovery of unchanged drug is 
approximately 10%.  The systemic availability and half-life of metoprolol in patients with renal 
failure do not differ to a clinically significant degree from those in normal subjects. 
Consequently, no reduction in metoprolol succinate dosage is usually needed in patients with 
chronic renal failure. 
Metoprolol is metabolized predominantly by CYP2D6, an enzyme that is absent in about 8% of 
Caucasians (poor metabolizers) and about 2% of most other populations.  CYP2D6 can be 
inhibited by a number of drugs.  Poor metabolizers and extensive metabolizers who 
concomitantly use CYP2D6 inhibiting drugs will have increased (several-fold) metoprolol blood 
levels, decreasing metoprolol's cardioselectivity [4, 5, 6].  
In comparison to conventional metoprolol, the plasma metoprolol levels following 
administration of MetoHEXAL® 100 mg (metoprolol succinate extended release [ER] tablets) 
are characterized by lower peaks, longer time to peak and significantly lower peak to trough 
variation.  The peak plasma levels following once-daily administration of MetoHEXAL average 
one-fourth to one-half the peak plasma levels obtained following a corresponding dose of 
conventional metoprolol, administered once daily or in divided doses.  At steady state the 
average bioavailability of metoprolol following administration of MetoHEXAL, across the 
dosage range of 50 to 400 mg once daily, was 77% relative to the corresponding single or 
divided doses of conventional metoprolol.  Nevertheless, over the 24-hour dosing interval, 
β1-blockade is comparable and dose-related (see Section Clinical Pharmacology of IB [2]).  The 


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bioavailability of metoprolol shows a dose-related, although not directly proportional, increase 
with dose and is not significantly affected by food following MetoHEXAL administration. 
1.1.3. 
Tesomet (Co-administration of Tesofensine and Metoprolol) 
PK data when tesofensine and metoprolol were co-administered chronically are available from 
the study TM001.  Tesofensine, its N-desmethyl-metabolite (NS2360) and metoprolol 
concentrations in plasma were measured pre-dose at baseline and at the end of treatment.  The 
tesofensine PK results obtained in this study are in line with the PK data obtained in the study 
TIPO-1 where tesofensine was administered in similar population of patients for 24 weeks.  The 
exposures of metoprolol are also in line with those previously published. 
For further details refer to the IB [2] and Summaries of Product Characteristics (SPCs) of 
metoprolol immediate release (IR) and ER tablets [4, 5, 6]. 
1.2. 
Rationale for the Clinical Study 
It has been decided to develop combination tablets with tesofensine and metoprolol, with 
metoprolol mitigating the increases in BP and HR caused by tesofensine.  In this study, the 
release characteristics of the multi-layer tablet will be investigated in an exploratory manner.  
The PK profiles will be compared to those of mono-components administered to a parallel group.  
1.2.1. 
Safety in Previous Clinical Studies with Tesofensine 
Sixteen Phase 1 studies with 339 healthy volunteers have been completed, with 289 subjects 
being exposed to tesofensine.  Tesofensine was well tolerated up to and including single oral 
doses of 6.75 mg.  Multiple daily doses up to 1.0 mg and loading doses up to 2.0 mg in Phase 1 
studies were considered to be well tolerated.  In all single and multiple dose Phase 1 studies in 
healthy volunteers, including a study with intravenous infusion up to 1.2 mg in volunteers, no 
clinically significant changes in vital signs, electrocardiogram (ECG) or laboratory parameters 
were observed, and no serious adverse events (SAEs) occurred. 
Seven Phase 2 studies have been completed in patients with neurodegenerative diseases and one 
Phase 2 study in patients with obesity.  Three 4-week studies used forced-titration and included 
62 patients (60 to 80 years) with possible DAT and 9 patients with advanced PD.  A total of 53 
of them were exposed to tesofensine.  Tesofensine was well tolerated at all doses, i.e., daily 
doses up to 2.0 mg for the first 3 days (loading doses) followed by daily doses up to 1.0 mg for 
up to 25 consecutive days.  In 4 dose finding studies of 14 weeks’ duration, 1036 DAT and PD 
patients were included and 796 of them were exposed to doses of 0.125-1.0 mg of tesofensine.  


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In obese patients, one dose ranging study of 24 weeks’ duration was conducted including 
203 obese patients, with 151 of them exposed to 0.25 to 1.0 mg tesofensine.  The most frequent 
adverse events (AEs) in these studies were insomnia, dry mouth, dizziness, and constipation.  
These events were dose-dependent and categorized as expected for drugs belonging to same 
pharmacological class. 
In conclusion, tesofensine has shown a robust, dose-dependent effect on weight loss in the target 
population of obese patients and a benign safety profile in toxicological and clinical studies 
compatible with its pharmacological profile.  The emerging efficacy and safety profile of 
tesofensine from the studies in obese patients has identified a clinically relevant, safe and well 
tolerated dose range of 0.25 mg up to 6.75 mg. 
Tesofensine has been evaluated in approximately 170 subjects in studies examining the 
metabolic and weight loss effects in overweight and obese patients and in approximately 
800 patients in other indications. 
Based on the pharmacological profile it can be assumed that tesofensine causes dopaminergic 
side effects such as insomnia, agitation, hallucinations, psychoses including delusion, paranoid 
ideation and depression. 
The AEs which were commonly reported in all investigated populations were insomnia, dry 
mouth, dizziness, and constipation, which also expressed dose-dependency.  In obese patients the 
most frequent AEs were dry mouth, headache, nasopharyngitis, nausea, influenza, insomnia, 
diarrhea, constipation, and back pain.  Psychiatric side effects were more frequently reported in 
the elderly population (patients with PD or DAT).  Psychotic events, such as hallucinations, were 
also observed in this elderly population, mostly with high doses (> 0.75 mg/day). 
Undesired effects which have been observed up to now comprise: 
• Very frequently (> 10%): headache, insomnia, dizziness, somnolence, loss of appetite, lack 
of energy, dry mouth, attention disturbances, cold-like symptoms, diarrhea, constipation 
• Frequently (< 10%): nausea, vomiting, fast pulse, muscle spasms, sweating, palpitations, 
vertigo, blurry vision, flatulence, abdominal pain or discomfort, tooth pain, fatigue 
• Rarely (< 0.1%): altered state of consciousness, sensory disturbance, agitation and 
persecutory delusion were found in a subject with high doses of tesofensine 


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Overdose 
Clinical experience with tesofensine in overdose is limited.  Exaggerated dopaminergic action 
should be anticipated with risk of psychotic behavior, cardiac symptoms (tachycardia, 
palpitations, atrial extrasystolia), orthostatic hypotension, and gastrointestinal symptoms (nausea, 
emesis, diarrhea). 
For further details refer to the IB [3]). 
1.2.2. 
Safety of Metoprolol 
Metoprolol is a selective β1 receptor blocker, used in the treatment of, e.g., hypertension, angina 
pectoris, acute myocardial infarction, supraventricular tachycardia, ventricular tachycardia, 
congestive heart failure and prevention of migraine headaches.  
Metoprolol is available as IR and ER tablets and as solution for i.v. injection. 
For further details refer to the SPC of the different metoprolol formulations [4, 5, 6].  
1.2.3. 
Safety of Tesomet (Co-administration of Tesofensine and Metoprolol) 
To date, Tesomet (as co-administration of tesofensine tablet and metoprolol tablet) has been 
administered to humans in 2 completed clinical studies.  Firstly, a Phase 1 drug-drug interaction 
(DDI) study (Q-21125) where a single dose of metoprolol was added to tesofensine administered 
for 2 weeks to study PK of both drugs when administered together. Secondly, a 90 days Phase 2 
study in obese and overweight patients with T2DM (TM001) designed to provide the proof-of-
concept data that addition of metoprolol mitigates the tesofensine-induced increase in HR and 
BP.  In both studies, the co-administration of the drugs was generally well tolerated.  No new or 
unexpected safety findings have been observed in the study compared to previous studies with 
tesofensine alone.  Currently, there is an ongoing Phase 2 study in patients with Prader-Willi 
syndrome (TM002). 
1.3. 
Risk-benefit Assessment 
For details regarding safety data of Tesomet and tesofensine tablets refer to the IBs [2, 3].  For 
details regarding safety data of metoprolol refer to SPCs of metoprolol IR and ER tablets 
[4, 5, 6]. 
There will be no direct health benefit for healthy subjects from receipt of the study drug.  The 
protocol has been designed to minimize the risk to research participants.  Subjects will be 


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monitored to detect AEs during the study and followed appropriately to ensure resolution of 
AEs. 
Tesofensine and metoprolol have been co-administered in a previous clinical study and were 
well tolerated.  Steady state levels of tesofensine had no major influence on the PK of metoprolol 
(Study Q-21125).  No additional risks are expected by the co-administration compared to those 
known for single dosing of tesofensine and metoprolol alone. 


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2. 
STUDY OBJECTIVES 
The objectives of this study are as follows: 
2.1. 
Primary Objective 
• To evaluate the PK profile and relative bioavailability of a single dose of the Tesomet FDC 
tablet and co-administration of tesofensine plus commercial metoprolol 
2.2. 
Secondary Objectives 
• To evaluate the PK profile and relative bioavailability of a single dose of the Tesomet FDC 
tablet  in fed state 
• To evaluate the PK profile of a single dose of the high and low dose of the Tesomet FDC 
tablet  
• To evaluate overall safety and tolerability of the Tesomet FDC tablet and co-administration 
of tesofensine plus commercial metoprolol in adult healthy volunteers 


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3. 
OVERALL DESIGN AND PLAN OF THE STUDY 
3.1. 
Overview 
This is a randomized, open-label, parallel-arm study in 60 healthy male subjects who meet the 
inclusion and none of the exclusion criteria for the study.  Each subject will participate in a 
screening period, a baseline period (the day preceding drug administration), and a single-dose 
treatment period with an on-site observation period of at least 48 hours after the dose.  A study 
flow chart is provided in Figure 1. 
Subjects will be admitted to the study center at least 24 hours prior to dosing. Each subject will 
then be randomized to one of the 4 treatment groups and receive one of the following treatments: 
• Treatment A (Test 1): A Tesomet FDC tablet (20 mg IR metoprolol, 1 mg tesofensine, 
80 mg ER metoprolol) in fasted condition (“High” dose) 
• Treatment B (Test 2): A Tesomet FDC tablet (5 mg IR metoprolol, 0.2 mg tesofensine, 20 
mg ER metoprolol) in fasted condition (“Low” dose) 
• Treatment C (Comparator): 1 mg tesofensine (2 tablets of 0.5 mg), 25 mg commercial IR 
metoprolol (1 tablet of 25 mg), 75 mg commercial ER metoprolol (1 ER tablet of 25 mg and 
1  ER tablet of 50 mg), fasted condition 
• Treatment D (Test 3): A Tesomet FDC tablet  (20 mg IR metoprolol, 1 mg tesofensine, 80 
mg [ER] metoprolol in fed condition (“High” dose) 
An overview is provided in Figure 2. Subjects assigned to Treatments A, B and C will be 
required to remain fasted from at least 10 hours before dosing and until 4 hours post-dose.  At 
4 hours after dosing a light standardized meal will be served.  The Investigator or a designee will 
administer the appropriate treatment with 240 mL water to the subjects as per randomization 
schedule.  Subjects assigned to Treatment D will be required to eat a Food and Drug 
Administration (FDA) standardized high-fat breakfast within a period of 30 minutes before 
dosing.  The Investigator or a designee will administer the treatment to the subjects 30 minutes 
after start of the breakfast and within 5 minutes of completing the meal. 
For each of the treatment groups, blood samples will be collected pre-dose and at designated 
time points post dosing.  Subjects will be discharged after the 48 hours post-dose assessments 
have been completed.  The end-of-study (EoS) safety evaluation will be performed 7 days (i.e., 
on Day 8) after dosing over the phone.  Subjects will be asked regarding AEs, and concomitant 
medications.  The total duration for each subject will be up to 38 days, including Screening. 


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Figure 1 
Study Flow Chart 
Screening 
Treatment Period 
Follow-up Phone Call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed  
Consent 
Admission 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
 
 
 
 
 
DOSING 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day -30 to -2 
 
Day -1 
Day 1 
 
Day 3 
 
Day 8 
 
 
Figure 2 
Study Overview 
 
ER = extended release; IR = immediate release 
 
Please refer to Table 5 for a detailed list of procedures performed on each study day and visit. 


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3.2. 
Endpoints 
3.2.1. 
Pharmacokinetics Endpoints 
The following PK parameters for tesofensine and metoprolol will be determined after dosing for 
all 4 treatments, as appropriate: 
• Cmax: Maximum tesofensine and metoprolol concentrations determined directly from the 
concentration-time profile 
• AUC0-48: Area under the concentration-time curve from pre-dose (time 0) to 48 hours post-
dose calculated using the linear-log trapezoidal rule 
• Tmax: Time of maximum tesofensine and metoprolol concentrations determined directly from 
the concentration-time profile 
• λz: The terminal elimination rate constant determined by selection of at least 3 data points on 
the terminal phase of the concentration-time curves 
• t½: Terminal elimination half-life calculated as: ln2/λz 
3.2.2. 
Safety Endpoints 
The following safety variables will be recorded at regular intervals during the study: 
• Vital signs (supine BP, pulse, body temperature and respiratory rate) 
• Twelve-lead ECG: HR PR interval, QRS interval, RR interval, QT interval and QT interval 
corrected for HR (QTc) (Bazett’s correction [QTcB] and Fridericia’s correction [QTcF]) 
• Clinical laboratory tests (hematology, clinical chemistry and urinalysis) 
• Adverse event assessments 
• Concomitant medication assessments 
• Physical examinations 
3.3. 
Justification of the Study Design 
The safety assessments included in the study are accepted measures for ensuring safety of 
subjects during a clinical study. 
The PK sampling schedule is considered appropriate given the information available and the 
goals of this study.  This study evaluates the PK profiles of tesofensine and metoprolol 
administered orally as single doses in fasted and fed condition.  The design is considered 


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appropriate to meet the exploratory (i.e., non-confirmatory) objectives of the study.  Safety and 
PK of tesofensine have already been evaluated in many other studies and, therefore, it is not 
considered necessary to investigate the PK profile of tesofensine until a full half-life period or a 
multiple thereof has been completed, which would mean blood sampling for PK for at least 
10 days.  The proposed sampling period was deemed satisfactory given the exploratory nature of 
this study and because: 
• Metoprolol’s plasma profile is fully covered within 48 hours sampling - both as IR and 
ER formulation. 
• Tesofensine’s plasma distribution phase into the elimination phase has a duration of 
approximately 24 hours, i.e., within 48 hours the known (and established) elimination 
phase constant has been reached meaning that the rest of the plasma profile can be 
simulated and predicted.  This means that there is no real scientific rationale for 
performing more sampling.  If one would like to add more sampling points then this 
should be done in an a) outpatient basis (subjects to come to the unit for blood sampling) 
and b) sampling every 5 to 7 days to ensure an array of data points making the estimated 
area under the curve (AUC) more qualified than just one final sampling point.  
Due to the very long half-life of tesofensine of about 9 days, a cross-over approach with intra-
individual comparison of the PK profiles of 2 or more treatments is not considered feasible, 
because the wash-out period would have to be too long.  Therefore, a parallel-group design was 
chosen.  
The rationale for dose selection is discussed in Section 5.2. 
3.4. 
Stopping Criteria for the Clinical Study 
Based on safety criteria, the study will be stopped in case of any of the following: 
• Adverse event stopping criteria: 
−  More than 25% of subjects experience a severe AE of related  causality 
− Any SAE of related causality 


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Based on safety criteria, the study will be stopped, if 2 or more subjects in a treatment group 
experience the same stopping criterion of the following: 
• Vital signs stopping criteria: 
− Symptomatic hypotension (systolic blood pressure [SBP] < 85 mmHg).  If 
symptomatic hypotension is observed during the study, then a minimum of 2 repeat 
BP measurements should be obtained over a brief period.  The mean of the 3 SBP 
measurements will be used to determine stopping criteria. 
− Tachycardia defined as HR > 120  bpm lasting longer than 30 minutes or with 
impaired consciousness. 
• Electrocardiogram stopping criteria: 
− QTcB or QTcF interval > 500 msec or increase of QTc interval > 60 msec compared 
to baseline (If a prolonged QTc interval is observed during the study, then a minimum 
of 2 repeat ECGs should be obtained over a brief period.  The mean of the 3 ECGs 
will be used to determine stopping criteria.) 
• Clinical laboratory stopping criteria: 
− Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≥ 3 times 
the upper limit of normal (ULN)  
with 
bilirubin ≥ 2 times the ULN 
− Creatine phosphokinase (CPK) ≥ 3 times the ULN (that cannot be attributed to causes 
other than the study drug; i.e., vigorous exercise) 


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4. 
STUDY POPULATION 
The study population will consist of healthy male volunteers.  Subjects must be able to provide 
written informed consent and meet all the inclusion criteria and none of the exclusion criteria. 
4.1. 
Number of Subjects 
A total of 60 subjects is planned for enrollment in the clinical study (N=15 will be randomly 
assigned to one of the 4 treatment treatment groups) according to the inclusion/exclusion criteria. 
4.2. 
Inclusion Criteria 
Subjects who meet the following criteria will be considered eligible to participate in the clinical 
study: 
1. Subject voluntarily agrees to participate in this study and signs an Independent Ethics 
Committee (IEC)-approved informed consent prior to performing any of the Screening Visit 
procedures. 
2. Males between 18 to 55 years of age, inclusive, at the Screening Visit. 
3. Nonsmokers (or other nicotine use) as determined by history (no nicotine use over the past 
6 months) and by urine cotinine concentration (< 500 ng/mL) at the Screening Visit and 
admission. 
4. Body mass index (BMI) between 18.5 and 30.0 kg/m2, inclusive, at the Screening Visit. 
5. Healthy, determined by pre-study medical evaluation (medical history, physical examination, 
vital signs, 12-lead ECG and clinical laboratory evaluations). 
4.3. 
Exclusion Criteria 
Subjects who meet one or more of the following criteria will not be considered eligible to 
participate in the clinical study: 
1. Subject has history or evidence of any clinically significant cardiovascular, gastrointestinal, 
endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, 
neurologic, dermatologic, psychiatric, renal, and/or other major disease or malignancy as 
judged by the Investigator. 
2. Subject has any disorder that would interfere with the absorption, distribution, metabolism or 
excretion of drugs. 


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3. Subject has a clinically significant abnormality following the Investigator’s review of the 
physical examination, ECG and clinical study protocol-defined clinical laboratory tests at 
Screening or admission to the clinical unit or has any concurrent disease or condition that, in 
the opinion of the Investigator, would make the subject unsuitable for participation in the 
clinical study.  One re-test is allowed, if (a) test result(s) is outside the limits. 
4. Subject has a pulse < 50 or > 90 bpm; SBP < 90 mmHg or > 140 mmHg; diastolic blood 
pressure (DBP) < 50 mmHg or > 90 mmHg at the Screening Visit or admission.  One re-test 
is allowed, if (a) test result(s) is outside these limits. 
5. Subject has a corrected QTcF interval > 450 msec at Screening.  If the mean QTcF exceeds 
the limits above, an additional ECG may be taken.  If this also gives an abnormal result, the 
subject will be excluded. 
6. Subject has positive test for Hepatitis B surface antigen (HBsAg), or Hepatitis B core 
antibody 
(indicative 
of 
active 
Hepatitis 
B), 
Hepatitis 
A 
virus 
antibodies 
(immunoglobulin M), Hepatitis C virus (HCV) antibodies or human immunodeficiency virus 
(HIV)-1 and/or -2 antibodies. 
7. Use of any prescribed or non-prescribed drugs (including vitamins, natural and herbal 
remedies, e.g., St. John’s Wort) in the 2 weeks prior to study drug administration, except for 
the occasional use of paracetamol (up to 2 g/day) or other non-steroidal anti-inflammatory 
drugs (NSAIDs). 
8. Subject has history of alcohol and/or illicit drug abuse within 2 years of entry. 
9. Subject has positive urine drug test (e.g., cocaine, amphetamines, barbiturates, opiates, 
benzodiazepines, cannabinoids) or alcohol test at the Screening Visit or admission.  
10. History of drinking more than 21 units of alcohol per week (1 unit = 10 g pure alcohol = 
250 mL of beer [5%] or 35 mL of spirits [35%] or 100 mL of wine [12%]) within 3 months 
prior to admission to the clinical unit. 
11. Subject is unwilling to avoid consumption of coffee and caffeine-containing beverages 
within 48 hours prior to admission until discharge from the clinical site. 
12. Subject is unwilling to avoid use of alcohol or alcohol-containing foods, medications or 
beverages, within 48 hours prior to admission until discharge from the clinical site. 
13. Any significant blood loss, donated one unit (450 mL) of blood or more, or received a 
transfusion of any blood or blood products within 60 days, or donated plasma within 7 days 
prior to the admission to the clinical unit. 


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14. Participation in any clinical study within 3 months prior to the expected date of 
investigational medicinal product (IMP) administration, provided that the clinical study did 
not entail a biological compound with a long t1/2 or participation in more than 3 clinical 
studies within 12 months. 
15. History of any clinically significant cardiac arrhythmia. 
16. History of bulimia or anorexia nervosa. 
17. Use of any agent used for weight loss within the last 3 months. 
18.  More than 5% weight loss within the last 3 months. 
19. Hypo- or hyperthyroidism. 
20. Subject is unwilling to abstain from vigorous exercise from 48 hours prior to admission until 
discharge. 
21. Subject has a history of hypersensitivity to the study drugs or any of the excipients or to 
medicinal products with similar chemical structures. 
22. Subject has lactose intolerance. 
23. Subject is unable to understand and communicate in German language or to understand the 
protocol requirements, instructions and study-related restrictions, the nature, scope and 
possible consequences of the clinical study or is unlikely to comply with the study 
requirements; e.g., uncooperative attitude and improbability of completing the clinical study. 
24. Subject has previously been enrolled in this clinical study. 
25. Vulnerable subjects defined as individuals whose willingness to volunteer in a clinical study 
may be unduly influenced by the expectation, whether justified or not, of benefits associated 
with participation, or of a retaliatory response from senior members of a hierarchy in case of 
refusal to participate (e.g., persons in detention, minors and those incapable of giving 
consent). 
26. Subject is the Investigator or any Sub-Investigator, research assistant, pharmacist, study 
coordinator, other staff or relative thereof directly involved in the conduct of the study or 
employee of the Sponsor or PAREXEL. 
4.4. 
Subject Withdrawal and Replacement 
The Sponsor reserves the right to request the withdrawal of a subject due to protocol deviation, 
administrative or any other valid and ethical reason.  If an Investigator judges a subject to be at 


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medical risk by complying with the protocol, he or she may discontinue the participation of the 
subject.  The circumstances surrounding the decision must be discussed with the Sponsor and 
recorded in the subject’s source documents and electronic source data report (eSDR). 
For this study with single dosing safety related individual withdrawal criteria are not applicable, 
as no further doses will be given.  Therefore, mainly withdrawal criteria are applicable that limit 
the validity of the data: 
• Incompliance with required procedures 
• Intake of not-allowed medication 
• Study procedures pose a medical risk to the subject 
Subject participation may be terminated prior to completing the study and the reason recorded as 
follows: 
1. Adverse event 
2. Protocol violation 
3. Loss to follow-up 
4. Subject withdrew consent at own request 
5. Other 
While subjects are encouraged to complete all study evaluations, they may withdraw from the 
study at any time and for any reason.  Reasonable effort will be made to determine why any 
subject withdraws from the study prematurely.  All subjects who withdraw from the study with 
an ongoing AE must be followed until the event is resolved or deemed stable.  If a subject 
withdraws prematurely after dosing, all data to be collected prior to discharge from the clinical 
site should be collected at the time of premature discontinuation or at the scheduled discharge 
(see also Section 7.3). 
A genuine effort must be made to determine the reason(s) why a subject fails to return for the 
necessary visits (if needed) or is discontinued from the study.  If the subject is unreachable by 
telephone, a registered letter, at the minimum, should be sent to the subject requesting him to 
contact the clinic. 
Enrollment will continue until a total of 60 subjects are randomized.  Withdrawn subjects may be 
replaced after mutual agreement between Principal Investigator and Sponsor. 


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4.5. 
Termination of the Clinical Study 
If the Principal Investigator or the Sponsor becomes aware of conditions or events that suggest a 
possible hazard to subjects if the clinical study continues, then the clinical study will be 
terminated after appropriate consultation among the involved parties.  The clinical study may be 
terminated at the Sponsor’s discretion also in the absence of such a finding. 
Conditions that may warrant termination of the clinical study include, but are not limited to: 
• The discovery of an unexpected, relevant or unacceptable risk to the subjects enrolled in the 
clinical study; 
• Failure to enroll subjects at the required rate; 
• A decision of the Sponsor to suspend or discontinue development of the study drug. 
Should the study be terminated and/or the site closed for whatever reason, all documentation 
pertaining to the study and study drugs must be returned to the Sponsor.  Any actions of 
PAREXEL required for assessing or maintaining subject safety will continue as required, despite 
termination of the study by the Sponsor. 
Study-specific stopping criteria are listed in Section 3.4. 
For definition of EoS refer to Section 7.4. 


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5. 
INVESTIGATIONAL MEDICINAL PRODUCT 
5.1. 
Identity of the Investigational Medicinal Products 
The products that will be used in this study are outlined in Table 1. 
Table 1 
Identity of Investigational Products 
Drug Name 
Formulation 
Strength 
Route 
Manufacturer 
Tesomet “high” dose 
Tablet 
20 mg IR metoprolol 
1 mg tesofensine 
80 mg ER metoprolol 
Oral 
Sponsor 
Tesomet “low” dose 
Tablet 
5 mg IR metoprolol 
0.2 mg tesofensine 
20 mg ER metoprolol 
Oral 
Sponsor 
Tesofensine 
Film-coated tablet 
0.5 mg tesofensine 
Oral 
Sponsor 
Egilok 25 mg 
IR tablet 
25 mg metoprolol 
Oral 
EGIS Pharmaceuticals 
PLC (Hungary) 
Metoprolol-ratiopharm® 
Succinat 23,75 mg 
Retardtabletten1 
ER tablet 
25 mg metoprolol 
Oral 
ratiopharm GmbH 
(Germany) 
Metoprolol-ratiopharm® 
Succinat 47,5 mg 
Retardtabletten2 
ER tablet 
50 mg metoprolol 
Oral 
ratiopharm GmbH 
(Germany) 
ER = extended release; IR = immediate release 
1 
corresponding to 25 mg metoprolol tartrate 
2 
corresponding to 50 mg metoprolol tartrate 
5.2. 
Dose Rationale Including Time of Dosing 
The doses of tesofensine selected for this study are based on the previous clinical experience, 
particularly the tesofensine-alone study TIPO-1 (0.25 to 1.0 mg of tesofensine once daily for up 
to 24 weeks) as well as the recently completed Phase 2 study with Tesomet TM001 (0.5 mg of 
tesofensine co-administered with 100 mg of metoprolol ER for 12 weeks).  In addition, 
tesofensine alone was administered to more than 1300 patients at doses up to 1.0 mg for up to 
48 weeks.  Tesofensine was well tolerated up to and including single oral doses of 6.75 mg.  
Based on the available data it is anticipated that the highest clinical dose of tesofensine co-
administered with metoprolol might be 1.0 mg once daily.  On the other side of the dose range, 
doses < 0.2 mg of tesofensine are unlikely to produce clinically meaningful efficacy.  For more 
information please see the Tesomet IB [2]. 
The doses of metoprolol selected for this study are based on the study TM001 mentioned above 
and also the vast amount of clinical experience with metoprolol and its SPCs [4, 5, 6].  From the 
results of TM001, it seems that the required doses of metoprolol to be used in Tesomet are 


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≤100 mg ER.  On the low side, metoprolol ER is usually prescribed as 50 mg once daily, but it is 
possible that for the low end of tesofensine dose range 25 mg of metoprolol may be enough.  For 
more information please the Tesomet IB [2] and metoprolol SPCs [4, 5, 6]. 
It is important to note that the doses for both compounds proposed for administration in this 
study have been extensively studied and have a solid tolerability and safety track record. 
5.3. 
Supply, Packaging, Labeling and Storage 
Investigational medicinal products will be supplied by Saniona A/S or a third party contracted by 
PAREXEL.  Investigational medicinal products will be packaged and labeled according to 
applicable local and regulatory requirements. 
All supplies of study drugs must be stored in accordance with the manufacturer’s instructions.  
The study drugs will be stored in a securely locked area, accessible to authorized persons only, 
until needed for dosing. 
5.4. 
Drug Accountability, Dispensing and Destruction 
The Investigator or designee is responsible for maintaining accurate accountability records of the 
study drugs throughout the clinical study.  The drug accountability log includes information such 
as, random number, amount dispensed and amount returned to the pharmacy (if any).  Products 
returned to the pharmacy will be stored under the same conditions as products not yet dispensed.  
The returned products should be marked as ‘returned’ and kept separate from the products not 
yet dispensed. 
All dispensing and accountability records will be available for Sponsor review.  When the Study 
Monitor visits PAREXEL, he/she will reconcile the drug accountability log with the products 
stored in the contract pharmacy.  
The pharmacist (or designee under the direction of the pharmacist) will prepare the IMPs for 
each subject according to the randomization list and will ship the IMPs to the site.  
After receiving Sponsor approval in writing, PAREXEL is responsible for returning all unused or 
partially used study drugs to the Sponsor or designated third party or for preparing the study 
drugs for destruction via incineration by the contract pharmacy. 


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5.5. 
Subject Identification and Randomization 
5.5.1. 
Screening Numbers 
Subjects will be assigned a RunIn number after the subject has signed the informed consent 
document (ICD). A subject who was screened for the study on a previous occasion but who was 
not enrolled may be re-screened for eligibility again. The re-screened subject will then be 
assigned a new RunIn number after signing a new informed consent form.  
5.5.2. 
Randomization Numbers 
Prior to dosing on Day 1, subjects will be assigned a randomization number in accordance with 
the randomization code generated by PAREXEL International.  The randomization code will 
include 3-digit subject numbers starting with 101. 
Once a randomization number has been allocated to one subject, it may not be assigned to 
another subject.  If subjects withdraw prematurely from the study and are replaced under the 
direction of the Sponsor, then a replacement randomization number will be assigned.  A 
replacement randomization code will be generated such that replacement subjects are assigned to 
the same treatment as the discontinued subjects.  The replacement randomization code will differ 
only in randomization numbers, which will be 4-digit numbers starting with a leading 1.  For 
example, if Subject 202 withdraws and is replaced, then the randomization number for the 
replacement subject will be 1202. 
5.6. 
Administration of Investigational Medicinal Products 
Subjects assigned to Treatments A, B and C will be required to remain fasted from at least 
10 hours before dosing.  At 4 hours after dosing a light standardized meal will be served.  The 
Investigator or a designee will administer the appropriate treatment with 240 mL water to the 
subjects as per randomization schedule.  If more water is needed for the intake of the 5 tablets in 
Group C, up to further 200 mL water may be taken.  All IMPs should be swallowed whole with 
water. 
For subjects assigned to Treatment D, dosing will be performed in fed state as detailed in 
Section 3.1.  All IMPs should be swallowed whole with water. 
A mouth check will be performed to ensure the entire dose was swallowed by the subject.  
Subjects must remain in an upright position for at least 2 hours after dosing.  Subjects should not 
drink anything within 1 hour before and after dosing (except for water with IMP administration 


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and high-fat breakfast for Treatment D).  Subjects must remain fasting from food and drink other 
than water for at least 4 hours after dosing. 
5.7. 
Compliance 
Dosing will be performed by trained, qualified personnel designated by the Investigator.  The 
date and time of dosing will be documented.  For Treatment Group D, the date and time of 
breakfast will also be documented.  Comments will be recorded if there are any deviations from 
the planned dosing procedures. 
5.8. 
Blinding and Breaking the Blind 
Not applicable in this open-label study.  
5.9. 
Prior and Concomitant Medications 
Any medicinal product, prescribed or over-the-counter (OTC), including herbal and other 
nontraditional remedies, is considered a concomitant medication.  Prior and concomitant 
medication use will be recorded for the 30 days prior to the Screening Visit until the Safety 
Follow-up phone call.  Prior and concomitant medication use is not permitted from 2 weeks 
before Day 1 until discharge (occasional use of paracetamol up to 2 g/day or other NSAIDs is 
permitted).  However, concomitant medication use may be warranted for the treatment of AEs, a 
list of prohibited medication is provided in Appendix 11.1, with emergencies being the 
exemption. 
5.10. Treatment of Overdose 
Overdose is very unlikely to occur in this single-dose study.  Standard symptomatic support 
measures should be used in the case of excessive pharmacological effects or overdose.  No 
antidotes are available.  At intoxication, symptomatic treatment with dopamine D2-receptor 
antagonist haloperidol should be considered. 
An overdose of tesofensine is defined in this study as 6 times of single dose and metoprolol as 4 
times of a daily dose with or without occurrence of clinical symptoms.  If a subject or any 
unintended other person not part of the study has an accidental or intentional overdose of the 
IMP, even if the consequences are not serious, the overdose must be reported to the Sponsor 
immediately (within 24 hours).  The procedure for reporting SAEs should be followed. 


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6. 
MEASUREMENTS AND METHODS OF ASSESSMENT 
For timing of assessments, refer to the Schedule of Assessments (Table 5). 
A Safety management plan (SMP) will be signed between the Sponsor and PAREXEL. 
6.1. 
Medical History, Demographic and Other Baseline Information 
The medical history comprises: 
• General medical history 
• Medication history 
The following demographic information will be recorded: 
• Age 
• Gender 
• Ethnic origin (Hispanic/Latino or not Hispanic/not Latino) 
• Race (White, Black, Asian, Native Hawaiian or other Pacific Islands, American Indian or 
Alaska Native, Asian-Japanese, Asian-Korean, Other) 
• Height, without shoes (cm) 
• Body weight, without shoes (kg) 
• BMI (kg/m2) 
Other baseline characteristics will be recorded as follows: 
• History of drug abuse 
• History of alcohol abuse 
• Smoking history 
• History of caffeine use (or other stimulating beverages) 
• Special diet (vegetarian) 
• History of blood or plasma donation 


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6.2. 
Safety Variables 
6.2.1. 
Adverse Events 
Adverse event reporting will begin for each subject from the date the ICD is signed and will 
continue until the Safety Follow-up phone call. 
6.2.1.1. 
Definitions 
6.2.1.1.1. 
Definition of Adverse Event 
Any untoward medical occurrence in a subject administered a pharmaceutical product and which 
does not necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
Other untoward events occurring in the framework of a clinical study will be recorded as AEs, 
e.g., those occurring during treatment-free periods (including Screening or post-treatment 
follow-up periods), in association with study-related procedures and assessments.  
Concomitant illnesses, which existed prior to entry into the clinical study, will not be considered 
AEs unless they worsen during the treatment period.  Pre-existing conditions will be recorded as 
part of the subject’s medical history. 
6.2.1.1.2. 
Definition of Serious Adverse Event 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening; this means that the subject was at risk of death at the time of the event; it 
does not mean that the event hypothetically might have caused death if it were more severe 
• Requires inpatient hospitalization or prolongation in existing hospitalization 
• Results in persistent or significant disability/incapacity or substantial disruption of the ability 
to conduct normal life functions 
• Is a congenital anomaly/birth defect, or 
• Is another important medical event (see below) 


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Important medical events that do not result in death, are not life-threatening or do not require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or in a physician’s office, blood dyscrasias 
or seizures that do not result in inpatient hospitalization, and the development of drug 
dependency or drug abuse. 
A distinction should be drawn between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria above.  For example, a mild degree of 
gastrointestinal bleeding requiring an overnight hospitalization for monitoring purposes would be 
considered an SAE, but is not necessarily severe.  Similarly, an AE that is severe in intensity is 
not necessarily an SAE.  For example, alopecia may be assessed as severe in intensity but would 
not be considered an SAE. 
Medical and scientific judgment should be exercised in deciding if an AE is serious and if 
expedited reporting is appropriate. 
6.2.1.2. 
Recording of Adverse Events 
Adverse events should be collected and recorded for each subject from the date the ICD is signed 
until the end of their participation in the study, i.e., the subject has discontinued or completed the 
study. 
Adverse events may be volunteered spontaneously by the subject, or discovered by the study 
staff during physical examinations or by asking an open, non-leading question such as ‘How 
have you been feeling since you were last asked?’ All AEs and any required remedial action will 
be recorded. The nature of AE, date (and time, if known) of AE onset, date (and time, if known) 
of AE outcome to date, severity and action taken of the AE will be documented together with the 
Investigator’s assessment of the seriousness of the AE and causal relationship to study drug 
and/or study procedure. 
All AEs should be recorded individually unless, in the opinion of the Investigator, the AEs 
constitute components of a recognized condition, disease or syndrome.  In the latter case, the 
condition, disease or syndrome should be named rather than each individual symptom.  The AEs 
will subsequently be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 


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6.2.1.3. 
Assessment of Adverse Events 
Each AE will be assessed by the Investigator with regard to the categories discussed in the 
following sections. 
6.2.1.3.1. 
Intensity 
The Principal Investigator or designee will assess all AEs for severity in accordance with the 
following standard ratings. 
• Mild: Ordinarily transient symptoms, does not influence performance of subject’s daily 
activities.  Treatment is not ordinarily indicated. 
• Moderate: Marked symptoms, sufficient to make the subject uncomfortable.  Moderate 
influence on performance of subject’s daily activities.  Treatment may be necessary. 
• Severe: Symptoms cause considerable discomfort. Substantial influence on subject’s daily 
activities.  May be unable to continue in the study and treatment may be necessary. 
When changes in the intensity of an AE occur, the maximum intensity for the event will be 
noted. 
6.2.1.3.2. 
Causality 
The Investigator will assess the causality/relationship between the study drugs (overall 
relationship to IMP) and the AE.  One of the categories described in Table 2 should be selected 
based on medical judgment, considering the definitions below and all contributing factors. 
Table 2 
Assessment of Relationship of Adverse Events to Investigational Product 
Related 
A clinical event, including laboratory test abnormality, occurs in a plausible time 
relationship to treatment administration, and which concurrent disease or other drugs or 
chemicals cannot explain. 
Not related 
A clinical event, including laboratory test abnormality, with little or no temporal relationship 
with treatment administration or confirmed other cause (e.g., other medical condition).   
 
6.2.1.3.3. 
Seriousness 
Severity is a measure of intensity whereas seriousness is defined by the criteria in 
Section 6.2.1.1.2. 


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6.2.1.4. 
Reporting of Serious Adverse Events 
The Investigator will review each SAE and evaluate the intensity and the causal relationship of 
the event to study drug.  All SAEs will be recorded from signing of the ICD until the EoS, i.e., 
the Safety Follow-up phone call.  Serious AEs occurring after the EoS and coming to the 
attention of the Investigator must be reported only if there is (in the opinion of the Investigator) 
reasonable causal relationship with the study drug. 
An SAE Report Form has to be completed and sent by email to: 
Berlin_Medical@parexel.com 
The Investigator is responsible for providing notification to the Sponsor of any SAE, whether 
deemed IMP-related or not, that a subject experiences during their participation in study within 
24 hours of becoming aware of the event. 
As a minimum requirement, the initial notification should provide the following information: 
• Study number 
• Subject number 
• Sex 
• Year of birth 
• Name of Principal Investigator and full clinical site address 
• Details of SAE 
• Criterion for classification as ‘serious’ 
• Study drug name, or code and treatment start date 
• Date of SAE onset 
• Causality assessment (if sufficient information is available to make this classification) 
The Sponsor will request clarification of omitted or discrepant information from the initial 
notification.  The Principal Investigator or an authorized delegate is responsible for sending the 
requested information to the Sponsor within 24 hours of the Sponsor’s request. 
Initial reports of SAEs must be followed later with detailed descriptions, including clear 
photocopies of other documents as necessary (e.g., hospital reports, consultant reports, autopsy 
reports), with the subject’s personal identifiers removed.  All relevant information obtained by 


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the Principal Investigator through review of these documents will be recorded and sent to the 
Sponsor within 24 hours of receipt of the information.  If a new SAE Report Form is sent, then 
the Investigator must sign and date the form.  The Sponsor may also request additional 
information on the SAE, which the Principal Investigator or an authorized delegate must send to 
the Sponsor within 24 hours of the request. 
6.2.1.5. 
Follow-up of Adverse Events 
All AEs experienced by a subject, irrespective of the suspected causality, will be monitored until 
the event has resolved, until any abnormal laboratory values have returned to baseline or 
stabilized at a level acceptable to the Principal Investigator, until there is a satisfactory 
explanation for the changes observed or until the subject is lost to follow-up. 
6.2.2. 
Clinical Laboratory Assessments 
Samples for clinical laboratory assessments will be collected at the time points detailed in the 
Schedule of Assessments (Table 5). 
Clinical laboratory tests will be performed by the laboratories mentioned in the List of Study 
Staff of this clinical study protocol.  Samples will be collected in appropriate tubes and handled 
according to standard procedures of the applicable laboratory. 
Clinical laboratory variables will be determined as outlined in Table 3. 


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Table 3 
Clinical Laboratory Assessments 
Hematology 
White blood cell (WBC) count 
Neutrophils (percentage and absolute count) 
Red blood cell (RBC) count 
Lymphocytes (percentage and absolute count)  
Hemoglobin (Hb) 
Monocytes (percentage and absolute count)  
Hematocrit (HCT) 
Eosinophils (percentage and absolute count)  
Mean corpuscular volume (MCV) 
Basophils (percentage and absolute count)  
Mean corpuscular hemoglobin (MCH) 
Platelet count 
Mean corpuscular hemoglobin concentration (MCHC) 
RBC distribution width  
Clinical Chemistry 
Alanine aminotransferase (ALT) 
Glucose 
Albumin 
Lactate dehydrogenase (LDH) 
Alkaline phosphatase (ALP) 
Phosphorus 
Aspartate aminotransferase (AST) 
Potassium 
Blood urea nitrogen (BUN) 
Sodium 
Calcium 
Total bilirubin 
Chloride 
Total protein 
Cholesterol 
Triglycerides 
Creatinine 
Thyroid-stimulating hormone (TSH) 
Creatine phosphokinase (CPK) 
Uric acid 
Gamma glutamyl transferase (GGT) 
 
Urinalysis 
Bilirubin 
Blood 
Glucose 
pH and specific gravity 
Ketones 
Protein 
Leukocytes 
Urobilinogen 
Nitrite 
 
Upon a positive urine test from leucocytes, blood or protein, the Investigator may require further urine analysis, such 
as flow cytometry. Results of additional urine analyses will be included in the database. 
If the flow cytometry examination shows a different result than the urine stix, it will be checked by microscopy, 
(e.g., leukocytes, erythrocytes, casts in urine will be analyzed). 
Viral Serology 
Hepatitis B core antibody (anti-HBc) 
Human immunodeficiency virus (HIV)  
(Types 1 and 2) antibodies 
Hepatitis B surface antigen (HBsAg) 
Hepatitis A virus antibodies (immunoglobulin M) 
Hepatitis C virus antibody (anti-HCV) 
Urine Drug Screening and Cotinine Test 
Amphetamines 
Cocaine 
Barbiturates 
Opiates 
Benzodiazepines 
Phencyclidine 
Cannabinoids 
Cotinine 
Urinary creatinine (to exclude dilution effect) 
 
Any value outside the normal range will be flagged for the attention of the Principal Investigator 
or designee at the site.  The Principal Investigator or designee will indicate whether or not the 


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value is of clinical significance.  If the result of any test (or repeat test, if done) from the samples 
taken during the screening period is indicated as clinically significant, the subject will not be 
allowed into the study.  Additional testing during the study may be done if medically indicated.  
If a clinically significant abnormality is found in the samples taken after dosing, during the 
study, and/or at discharge, it should be recorded as an AE and the subject will be followed until 
the test(s) has (have) normalized or stabilized, at the discretion of the Principal Investigator. 
6.2.3. 
Vital Signs 
Vital signs will be assessed at the time points detailed in the Schedule of Assessments (Table 5).  
The following vital signs will be measured with an appropriate cuff always at the same arm: 
• Blood pressure (systolic and diastolic [mmHg]) 
• Pulse (bpm) 
In addition, body temperature (°C) and respiratory rate (breaths per minute) will be measured.  
Recordings will be made after the subject has been supine and at rest ≥ 5 minutes. 
6.2.4. 
Standard 12-lead Electrocardiograms 
Standard safety 12-lead ECGs will be performed at the time points detailed in the Schedule of 
Assessments (Table 5). 
The12-lead ECGs will be performed after the subject has been resting supine for ≥ 5 minutes.  
The ECG will include all 12 standard leads and a Lead II rhythm strip on the bottom of the 
tracing.  The ECG will be recorded at a paper speed of 25 mm/sec.  The following ECG 
parameters will be collected: HR, PR interval, QRS interval, RR interval, QT interval and QTc 
interval (QTcB and QTcF). 
All ECGs must be evaluated by a qualified physician for the presence of abnormalities. 
6.2.5. 
Physical Examinations 
Physical examinations will be performed at the time points detailed in the Schedule of 
Assessments (Table 5). 
Physical examination: 
An assessment of general appearance and a review of systems (dermatologic, head, eyes, ears, 
nose, mouth/throat/neck, thyroid, lymph nodes, respiratory, cardiovascular, gastrointestinal, 
extremities, musculoskeletal), including orientating neurologic examination. 


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Other evaluations may be performed as deemed necessary by the Investigator.  This will be 
commented upon in the clinical study report (CSR), if performed. 
6.3. 
Pharmacokinetics Variables 
6.3.1. 
Blood Sample Collection 
Blood for the analysis of tesofensine and metoprolol will be collected at the time points detailed 
in the Schedule of Assessments (Table 5).  Analysis of tesofensine’s active metabolite will not be 
performed. 
Blood sample collection, processing and shipping details will be outlined in a separate laboratory 
manual.  In brief, blood will be processed and plasma analyzed using validated assays. 
6.4. 
Total Amount of Blood 
Each subject will have less than 500 mL of blood collected over the course of the entire study 
(from the Screening Visit to discharge, but not including repeat or additional tests ordered by the 
Investigator), which presents no undue risk to the subjects (see Table 4). 
Table 4 
Approximate Total Amount of Blood for Each Subject 
Assessment 
Sample Volume 
(mL) 
Number of Samples 
Total Blood Volume 
(mL) 
Pharmacokinetics 
7.5 
15 
112.5 
Hematology and clinical chemistry1 
10.2 
3 
30.6 
Total Blood Volume2 per Subject 
143.1 
1 
Viral serology will be performed on the sample collected for hematology and clinical chemistry at Screening, as 
applicable.   
2 
Excluding repeat laboratory investigations. 
 


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7. 
STUDY CONDUCT 
7.1. 
Schedule of Assessments 
The study consists of a Screening Visit (Day –30 to Day –2, admission (Day –1), an in-house 
dosing, safety and PK visit (Day 1 to Day 3) and a Safety Follow-up phone call on Day 8.  
Therefore, the maximal study duration for an individual subject will be up to 38 days. 
Please see (Table 5) for the Schedule of Assessments. 


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Table 5 
Schedule of Assessments 
Evaluation 
Screening 
 
Treatment 
Period 
 
 
Safety FU 
Phone 
Call 
 
Day -30 to 
Day -2 
Admission 
Day -1 
Baseline/ 
Day 1 
Day 2 
Discharge 
Day 3 
Day 8 
Admission 
 
X 
 
 
 
 
In-house staya 
 
X 
X 
X 
X 
 
Ambulatory visits 
X 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
Physical examination  
X 
X 
 
 
X 
 
Height and body weight, BMI 
X 
 
 
 
 
 
Viral serology 
X 
 
 
 
 
 
Supine blood pressure and pulseb 
X 
X 
X 
X 
X 
 
Body temperature, respiratory ratec 
X 
X 
X 
X 
X 
 
Clinical laboratory tests (clinical 
chemistry, hematology and 
urinalysis) 
X 
X 
 
X 
 
 
Urine drug screen, cotinine and 
alcohol test 
X 
X 
 
 
 
 
12-lead ECGd 
X 
X 
X 
X 
X 
 
Randomization 
 
 
X 
 
 
 
Study drug administratione 
 
 
X 
 
 
 
Blood sampling for PKf 
 
 
X 
X 
X 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
AE monitoring 
X 
X 
X 
X 
X 
X 
Discharge 
 
 
 
 
X 
 
AE = adverse event; BMI = Body Mass Index; ECG = electrocardiogram; FU = Follow-up; PK = pharmacokinetics 
a 
Subjects will be admitted in the morning of Day -1 and will leave the study center on Day 3 after completion of 
all study-related assessments. 
b 
At Screening and on Day -1.  On Day 1 at pre-dose and 1, 2, 4, 8, 12 and 16 hours post-dose, on Day 2 at 24, 30 
and 36 hours post-dose and on Day 3 at 48 hours post-dose. 
c 
Once daily, on in-house days in the morning. 
d 
At Screening and on Day -1.  On Day 1 at pre-dose and 1, 6 and 12 hours post-dose, on Day 2 at 24 hours post-
dose and on Day 3 at 48 hours post-dose. 
e 
In Treatment Groups A, B and C, dosing will be performed after an overnight fast of at least 10 hours before 
dosing and subjects will fast until 4 hours post-dose.  At 4 hours after dosing a light standardized meal will be 
served.   
In Treatment D, subjects will be required to eat an FDA standardized high-fat breakfast within a period of 
30 minutes before dosing. The Investigator or a designee will administer the treatment to the subjects 
30 minutes after start of the breakfast and within 5 minutes of completing the meal.  
The Investigator or a designee will administer the appropriate treatment with 240 mL water to the subjects as 
per randomization schedule. If more water is needed for the intake of the 5 tablets in Group C, up to further 
200 mL water may be taken. 
f 
Blood sampling at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 30, 36 and 48 hours post-dose. 


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7.2. 
Order of Assessments 
The following priority order will be in effect when more than one assessment is required at a 
pre-dose (except for Screening and Day -1) and post-dose time point, with PK blood sampling 
being performed nearest to the specified time: 
1. 12-lead ECG 
2. Vital signs 
3. PK blood sampling 
4. Blood sampling for safety assessments 
7.3. 
Early Termination 
If a subject withdraws prematurely after dosing, all data normally collected at discharge from the 
clinical site should be collected at the time of premature discontinuation or at the scheduled 
discharge.  If deemed necessary by the Principal Investigator, the subject will be asked to return 
for a follow-up visit. 
7.4. 
End-of-Study 
End-of-study (EoS) is defined as completion of the final follow-up phone call.  For those 
subjects that withdraw prematurely, EoS is defined as the time of the subject’s last data 
collection. 
7.5. 
Restrictions 
7.5.1. 
Dietary and Fluid Restrictions 
Caffeine: 
Xanthine containing products (coffee, tea, chocolate, cola, energy drinks) are 
prohibited from 48 hours before admission until discharge. 
Alcohol: 
Alcohol use is prohibited 48 hours prior to the Screening Visit.  Alcohol use is 
prohibited from 48 hours prior to admission until discharge from the clinical site. 
Meals: 
No outside food or drink is permitted at the clinical site.  All meals and snacks 
will be provided.  Subjects will receive standard meals and snacks at regimented 
times during confinement. 
Beverages: 
Subjects should not drink anything within 1 hour before and after dosing (except 
for water with IMP administration and high-fat breakfast for Treatment D). 


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Fasting: 
Dosing in Treatment Groups A, B and C will take place after a minimum 10-hour 
overnight fast.  Fasting restrictions will continue (no food or drink other than 
water) for at least 4 hours post-dose. 
Fed: 
For subjects assigned to the fed treatment (Treatment Group D), subjects must 
consume a high-fat content meal that consists of the following: 2 scrambled eggs 
fried in butter, 2 strips of bacon, 2 slices of toast with butter, 120 g of fried 
potatoes and 240 mL of whole milk.  This high-fat meal contains the equivalent of 
approximately 125 protein calories, 255 carbohydrate calories and 605 fat 
calories.  Subjects should not eat or drink other than water for at least 4 hours 
post-dose. 
7.5.2. 
Other Restrictions 
Nicotine: 
Smoking and other nicotine containing products are prohibited.  The study must 
enroll nonsmoking subjects. 
Activity: 
Strenuous activity is prohibited from 48 hours prior to admission until discharge.  
After discharge, mild physical activity can be resumed.  Following IMP 
administration subjects will be required to sit upright on the edge of their beds for 
20 minutes and must not lie down during this time.  Subjects will remain 
ambulatory or seated upright for at least 2 hours following dose administration 
with the exception of supine rest period prior to measurements.  However, 
subjects may be placed in an appropriate position or permitted to lie down on their 
right side should AEs occur at any time (e.g., lightheadedness associated with a 
blood draw). 
Medications: Use of prescription, herbal, OTC medication(s) or dietary supplements is 
prohibited within the 2 weeks prior to study Day 1 until the Safety Follow-up 
phone call.  Concomitant medication use is permitted if indicated by the 
Investigator for treatment of an AE.  Occasional use of paracetamol (up to 
2 g/day) or other NSAIDs is permitted.  A list of prohibited medication is 
provided in Appendix 11.1. 
Blood donation: Donation of one unit (450 mL) of blood or more is prohibited during the study 
and until 3 months after discharge. 


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8. 
STATISTICAL METHODS 
Before database lock, a statistical analysis plan (SAP) will be issued as a separate document, 
providing detailed methods for the analyses outlined below.  Any deviations from the planned 
analyses will be described in an SAP addendum and described and justified in the CSR. 
8.1. 
Study Population 
8.1.1. 
Analysis Populations 
Safety population: All randomized subjects who received at least one dose of study drug.  
Subjects will be included in the analysis according to the dose and study drug received. 
PK population: All randomized subjects with at least one quantifiable tesofensine or metoprolol 
concentration.  Subjects will be included in the analysis according to the dose and study drug 
received. 
8.2. 
General Considerations 
Continuous data will be summarized by treatment group using descriptive statistics (number, 
mean, standard deviation [SD], minimum, median and maximum).  Categorical data will be 
summarized by treatment group using frequency tables (number and percentage). 
8.3. 
Protocol Deviations 
Important protocol deviations will be listed by subject. 
Protocol deviations will be handled in accordance with PAREXEL standard operating 
procedures (SOPs). 
8.4. 
Subject Disposition 
The number and percentage of subjects entering and completing the clinical study will be 
presented by treatment. 
Subjects excluded from the safety and PK analysis sets and data excluded from the PK analysis 
sets will be listed including the reason for exclusion.  Subject disposition will be summarized and 
will include the following information: number of subjects randomized and dosed, number and 
percentage of subjects completing the study and the number and percentage of subjects who were 
withdrawn (including reasons for withdrawal).  Disposition data will be presented based on all 
subjects randomized. 


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Subject discontinuations will be listed including the date of study exit, duration of treatment and 
reason for discontinuation.  A listing of informed consent response will also be presented. 
A randomization listing will be presented and include the following: each subject’s 
randomization number and the treatment to which the subject has been randomized. 
8.5. 
Demographic and Anthropometric Information and Baseline Characteristics 
Demographic and anthropometric variables (age, gender, ethnicity, race, height, weight and 
BMI) will be listed by subject.  Demographic characteristics (age, gender, ethnicity and race) and 
anthropometric characteristics (height, weight and BMI) will be summarized by treatment and 
for all subjects in the safety analysis set.  The denominator for percentages will be the number of 
subjects in the safety analysis set for each treatment or for all subjects as applicable. 
Medical history data will be listed by subject including visit, description of the 
disease/procedure, MedDRA system organ class (SOC), MedDRA preferred term (PT), start 
date, and stop date (or ongoing, if applicable). 
8.6. 
Prior and Concomitant Medication and Drug Administration 
Prior medications are those that started and stopped prior to the first dose of IMP.  Concomitant 
medications are those taken after first dosing (including medications that started prior to dosing 
and continued after). 
Prior and concomitant medication will be listed by subject and will include the following 
information: reported name, PT, the route of administration, dose, frequency, start date/time, 
duration and indication. 
Prior and concomitant medication will be coded according to the World Health Organization 
Drug Dictionary (WHO-DD) latest version. 
Drug administration dates and times will be listed for each subject. 
8.7. 
Exposure 
A listing of drug administration will be created and will include the date and time of 
administration. 


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8.8. 
Safety Analyses 
8.8.1. 
Adverse Events 
All AEs will be listed.  The number and percent of subjects experiencing a treatment emergent 
AE (TEAE) will be tabulated by treatment for each SOC and PT.  The TEAEs will also be 
tabulated according to intensity and causality. 
Serious AEs will be listed separately. 
8.8.2. 
Clinical Laboratory Tests 
Individual data listings of laboratory results will be presented for each subject.  Flags will be 
attached to values outside of the laboratory’s reference limits along with the Investigator’s 
assessment.  Clinically significant laboratory test abnormalities that were considered AEs by the 
Investigator will be presented in the AE listings. 
Clinical laboratory tests (observed values) will be summarized descriptively in tabular format.  
Shift tables will be presented for select laboratory parameters. 
8.8.3. 
Vital Signs 
Individual data listings of vital signs (observed and change from baseline) will be presented for 
each subject.  Individual clinically significant vital signs findings that were considered AEs by 
the Principal Investigator will be presented in the AE listings. 
Observed values as well as change from baseline data will be summarized descriptively in 
tabular format.  Graphical displays over time may be presented for individual and summarized 
data. 
8.8.4. 
Standard 12-lead Electrocardiogram 
Standard 12-lead ECG data (observed and change from baseline) will be listed for each subject 
and time point.  Observed values will be summarized descriptively in tabular format.  Change 
from baseline will be summarized descriptively for QTc data.  A categorical QTc analysis will 
also be performed.  Graphical displays over time may be presented for individual and 
summarized data. 
8.8.5. 
Physical Examination 
Abnormal physical examination findings will be listed. 


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8.9. 
Pharmacokinetic Analyses 
The individual subject concentration-time data will be listed and displayed graphically on the 
linear and log scales by analyte, treatment and overall, as applicable.  The concentration-time 
data will be summarized descriptively by analyte, treatment and overall in tabular and graphical 
formats (linear and log scales).  The non-compartmental PK parameters listed in Section 3.2.1 
will be calculated using WinNonlin version 6.3 or later.  The PK parameter data will be listed 
and summarized descriptively by analyte and treatment in tabular format. 
If needed, selected individual vital signs and ECG parameters may be plotted against 
concentration data of tesofensine and/or metoprolol. 
An SAP will be issued as a separate document, providing detailed methods for the analyses. 
8.10. Interim Analyses 
No formal interim analysis will be performed. 
8.11. Determination of Sample Size 
Formal sample size calculations were not performed.  The number of subjects was chosen based 
on literature and experience from similar studies and is considered sufficient to meet the study 
objectives.  No formal statistical test will be performed.  Only descriptive statistics for PK and 
safety data by treatment group will be presented.  The sample size chosen is therefore judged 
reasonable to gain knowledge regarding key parameters in each of the treatment groups. 


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9. 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS 
9.1. 
Data Quality Assurance 
The Sponsor will supervise a study initiation visit to verify the qualifications of the Principal 
Investigator, inspect the facilities and inform the Principal Investigator of responsibilities and 
procedures for ensuring adequate and correct documentation. 
The Principal Investigator must prepare and maintain adequate and accurate records of all 
observations and other data pertinent to the clinical study for each study participant.  Frequent 
communication between the clinical site and the Sponsor is essential to ensure that the safety of 
the study is monitored adequately.  The Principal Investigator will make all appropriate safety 
assessments on an ongoing basis.   
All aspects of the study will be carefully monitored with respect to Good Clinical Practice (GCP) 
and SOPs for compliance with applicable government regulations.  The Study Monitor will be an 
authorized individual designated by the Sponsor.  The Study Monitor will have access to all 
records necessary to ensure integrity of the data and will periodically review the progress of the 
study with the Principal Investigator. 
9.1.1. 
Data Collection 
PAREXEL’s ClinBase™ system (a Clinical Study Management System for source data capture 
and process control) will be utilised in this study.  Data from ClinBase™ can be exported 
to/prepared as an eSDR in PDF format.  The eSDR will follow the same design as the empty 
eSDR that is used for the database setup approval. 
PAREXEL ClinBase™ designer will design ClinBase™ to be completed for each subject who 
enters the study.  The entries will be checked by trained personnel.  Errors or inconsistencies will 
be corrected.  Any changes or corrections to ClinBase™ will be dated, initialled and explained 
(if necessary).  An explanation for the omission of any required data will appear on the 
appropriate page.  The Investigator will sign the completed ClinBase™, thereby taking 
responsibility for the accuracy of the data in the entire ClinBase™.  The Investigator will retain 
records of the changes and corrections.  
Source data will be defined as such in the Source Document Agreement.  The clinical unit’s 
ClinBase™ system will be used to capture certain safety data - this will be indicated on the 
Source Document Agreement. 


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Paper-based data will be subject to data entry in ClinBase™.  For electronic source data, no data 
entry will be performed. 
The responsible Study Monitor will check data at the monitoring visits to the clinical unit.  The 
Investigator will ensure that the data collected are accurate, complete and legible. 
All clinical work conducted under this clinical study protocol is subjected to GCP regulations. 
This includes an inspection by the Sponsor and Competent Authority representatives at any time.  
The Investigator will agree to the inspection of study-related records by Competent Authority 
representatives and the audits of the Sponsor or third parties named by the Sponsor. 
9.1.2. 
Data Management 
Data management of all data documented will be performed under the responsibility of the Head 
of the Department of Data Management, PAREXEL Early Phase and in accordance with the 
SOPs for data management. 
The Data management plan (DMP) will be provided to the Sponsor describing the work and data 
flow within this clinical study. Versions for the computer systems, coding and reconciliation of 
data will be defined in the DMP.  The DMP will be sent to the Sponsor for review and approval. 
The DMP must be finalized in accordance with PAREXEL SOP. 
9.2. 
Access to Source Data/Documents 
PAREXEL will use an electronic data capture system to manage data collection during this 
study.  The electronic data capture system (ClinBaseTM) is a software tool designed to ensure 
quality assurance and facilitate data capture during clinical studys.  Through a system regulated 
workflow that includes barcode scanning and interfaces to medical equipment to avoid manual 
data entry, study operations performance is controlled and captured in real time.  The system is 
fully Code of Federal Regulations (CFR) 21 part 11 compliant. 
The Principal Investigator will ensure the accuracy, completeness and timeliness of the data 
reported to the Sponsor.  Data collection processes and procedures will be reviewed and 
validated to ensure completeness, accuracy, reliability and consistency.  A complete audit trail 
will be maintained of all data changes.  The Principal Investigator or designee will cooperate 
with the Sponsor’s representative(s) for the periodic review of study documents to ensure the 
accuracy and completeness of the data capture system at each scheduled monitoring visit. 


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Electronic consistency checks and manual review will be used to identify any errors or 
inconsistencies in the data.  This information will be provided to the respective study sites by 
means of electronic or manual queries. 
The Principal Investigator or designee will prepare and maintain adequate and accurate study 
documents (e.g., medical records, ECGs, AE and concomitant medication reporting, raw data 
collection forms, etc.) designed to record all observations and other pertinent data for each 
subject receiving study drug. 
The Principal Investigator will allow Sponsor representatives, contract designees, authorized 
regulatory authority inspectors and the IEC to have direct access to all documents pertaining to 
the study. 
9.3. 
Archiving Study Documents 
According to International Council for Harmonisation (ICH) guidelines, essential documents 
should be retained for a minimum of 2 years after the last approval of a marketing application in 
an ICH region and until there are no pending or contemplated marketing applications in an ICH 
region or at least 2 years have elapsed since the formal discontinuation of clinical development 
of the study drug.  However, these documents should be retained for a longer period if required 
by the applicable legal requirements. 
9.4. 
Good Clinical Practice 
The procedures set out in this clinical study protocol are designed to ensure that the Sponsor and 
the Principal Investigator abide by the principles of the ICH guidelines on GCP.  The clinical 
study also will be carried out in keeping with national and local legal requirements and with 
ethical principles that have their origins in the Declaration of Helsinki (Version 1996). 
9.5. 
Informed Consent 
Before each subject is enrolled in the clinical study, written informed consent will be obtained 
from the subject according to the regulatory and legal requirements of the participating country.  
As part of this procedure, the Principal Investigator must explain orally and in writing the nature, 
duration and purpose of the study and the action of the drug in such a manner that the subject is 
aware of the potential risks, inconveniences or AEs that may occur.  The subject should be 
informed that he is free to withdraw from the study at any time.  He will receive all information 
that is required by federal regulations and ICH guidelines.  The Principal Investigator or 


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designee will provide the Sponsor with a copy of the IEC-approved ICD prior to the start of the 
study. 
The ICD must be signed and dated; one copy will be handed to the subject, and the Principal 
Investigator will retain a copy as part of the clinical study records.  The Principal Investigator 
will not undertake any investigation specifically required for the clinical study until written 
consent has been obtained.  The terms of the consent and when it was obtained must also be 
documented. 
If a protocol amendment is required, then the ICD may need to be revised to reflect the changes 
to the protocol.  If the ICD is revised, it must be reviewed and approved by the responsible IEC, 
and signed by all subjects subsequently enrolled in the clinical study as well as those currently 
enrolled in the clinical study. 
9.6. 
Protocol Approval and Amendment(s) 
Before the start of the clinical study, the clinical study protocol and other relevant documents 
will be approved by the RA (regulatory authority) and IEC, in accordance with local legal 
requirements.  The Sponsor must ensure that all ethical and legal requirements have been met 
before the first subject is enrolled in the clinical study. 
This protocol is to be followed exactly.  To alter the protocol, amendments must be written, 
which must be released by the responsible staff and receive RA and IEC approval prior to 
implementation (as appropriate).  
Administrative changes may be made without the need for a formal amendment, but will also be 
mentioned in the integrated CSR.  All amendments will be distributed to all study protocol 
recipients, with appropriate instructions. 
9.7. 
Insurance and Indemnity 
Every subject participating in the study is insured in accordance with local law against injuries to 
health, which may occur during the clinical study.  Any injury to health, which might have 
occurred as a result of participating in the study, must be reported by the subject to the 
Investigator without delay.  In all cases the Investigator is obliged to make a report to the 
Sponsor and the insurer.  The Investigator is responsible for dispensing the study medication 
according to this protocol, and for its secure storage and safe handling throughout the study.  
Additional insurance details will be provided in the Insurance Policy.  The subject insurance will 
be arranged by PAREXEL. 


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9.8. 
Confidentiality Data Protection 
All clinical study findings and documents will be regarded as confidential.  Study documents 
(protocols, IBs and other material) will be stored appropriately to ensure their confidentiality.  
The Principal Investigator and members of his/her research team (including the IEC) must not 
disclose such information without prior written approval from the Sponsor, except to the extent 
necessary to obtain informed consent from subjects who wish to participate in the study or to 
comply with regulatory requirements. 
The anonymity of participating subjects must be maintained.  Subjects will be specified on study 
documents by their randomization number, year of birth, not by name.  Documents that identify 
the subject (e.g., the signed ICD) must be maintained in confidence by the Principal Investigator. 
9.9. 
Publication Policy 
By signing the clinical study protocol, the Principal Investigator agrees with the use of results of 
the clinical study for the purposes of national and international registration, publication and 
information for medical and pharmaceutical professionals.  If necessary, the regulatory 
authorities will be notified of the Principal Investigator’s name, address, qualifications and extent 
of involvement. 
A Principal Investigator shall not publish any data (poster, abstract, paper, etc.) without 
obtaining prior written permission from the Sponsor. 
PAREXEL will prepare a CSR after the completion of the study. The Sponsor representative will 
sign the final study report intended to be submitted to regulatory authorities. 
The results of this study may be published or presented at scientific meetings.  The Sponsor will 
be responsible for publication of all the data generated in this study.   


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10. 
REFERENCE LIST 
1. Colman E. Food and Drug Administration’s Obesity Drug Guidance Document: A Short 
History. Circulation 2012;125(17):2156-2164 
2. Investigator's Brochure of Tesomet. Version 1.0, Final, 11 September 2017 
3. Investigator's Brochure of Tesofensine. Version 13, Final, 15 November 2016 
4. SPC of metoprolol 25 mg IR tablets.  Egilok 25 mg, EGIS Pharmaceuticals PLC (Hungary), 
SPC dated 23.1.2017 
5. SPC of metoprolol 25 mg ER tablets.  Metoprolol-ratiopharm® Succinat 23,75 mg 
Retardtabletten, ratiopharm GmbH (Germany), SPC dated October 2013 
6. SPC of metoprolol 50 mg ER tablets.  Metoprolol-ratiopharm® Succinat 47,5 mg 
Retardtabletten, ratiopharm GmbH (Germany), SPC dated October 2013 
 
 


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11. 
APPENDICES 
11.1. Appendix 1 - List of Prohibited Medication 
Drug Class 
Episodic 
Use 
Chronic 
Use 
Comment 
Antiarrhythmic (Amiodarone, quinidine) 
N 
N 
Strong inhibitor of CYP2D6 
Antiretroviral (Ritonavir) 
N 
N 
Strong inhibitor of CYP2D6 
Anorectic agents 
N 
N 
Antiandrogens (abiraterone, cyproterone acetate, 
finasteride) 
N 
N 
Antihistamines 
Y 
N 
Topical antihistamines – always approved 
Antiepileptic drugs 
N 
N 
Antidepressant drugs 
N 
N 
Anti-anxiety drugs 
N 
N 
Anti-Parkinsonian drugs  
N 
N 
Anti-Dementia drugs donepezil and galantamin 
N 
N 
Antifungal (terbinafine) 
N 
N 
Moderate inhibitor of  CYP2D6 
Muscarinreceptor blocker darifenacin 
N 
N 
Moderate inhibitor of  CYP2D6 
Barbiturates 
N 
N 
Benzodiazepines 
N 
N 
Beta- blockers 
N 
N 
Per protocol 
Buproprion (non-SSRI antidepressant) 
N 
N 
Strong inhibitor of  CYP2D6 
Calcium channel blockers 
N 
N 
Per protocol 
Carbonic anhydrase inhibitors (e.g., 
acetazolamide, dichlorphenamide, dorzolamide, 
methazolamide) 
N 
N 
Cinacalcet (calcimimetic) 
N 
N 
Strong inhibitor of  CYP2D6 
Dopamine reuptake inhibitors (e.g., bupropion) 
N 
N 
Glucocorticoids 
Y 
N 
Hypnotic sedative (glutethimide) 
N 
N 
Strong inducer of  CYP2D6 
H2-receptor antagonist (cimetidine) 
N 
N 
Weak inhibitor of  CYP2D6 
Immunosuppressives 
N 
N 
Insulin and/or other injectable anti-diabetic 
medications, or thiazolidinediones (TZDs) 
N 
N 
Per protocol 
Lithium 
N 
N 
Monoamine oxidase (MAO) inhibitors 
N 
N 
Opioids, cannabinidiols 
N 
N 
Oral hypoglycemic 
- 
- 
Per protocol 
Orlistat 
N 
N 
Phenothiazines 
N 
N 
Selective serotonin reuptake inhibitors (SSRIs) 
N 
N 
Serotonin and norepinephrine reuptake inhibitors 
(SNRIs) 
N 
N