A Double-Blind, Randomized, Placebo-Controlled, Multiple-Dose, Multi-Center Safety and Efficacy Study of Co-Administration of Tesofensine/Metoprolol for 12 Weeks in Adult and Adolescent Patients With Prader-Willi Syndrome (PWS), Followed by Two Open Label 12 Weeks Extension Periods for Adolescent Patients
Phase: PHASE2
Conditions: Confirmed Genetic Diagnosis of Prader-Willi Syndrome
Sponsor: Saniona

 
 
 
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CLINICAL STUDY PROTOCOL 
 
 
A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, 
MULTIPLE-DOSE, MULTI-CENTER SAFETY AND EFFICACY STUDY OF 
CO-ADMINISTRATION OF TESOFENSINE/METOPROLOL IN SUBJECTS 
WITH PRADER-WILLI SYNDROME  
“SECOND 12 WEEKS OPEN LABEL EXTENSION” 
 
  
 
Sponsor:  
 
 
Saniona, A/S 
 
 
 
Baltorpvej 154 
 
 
 
DK2750 Ballerup 
 
 
 
Denmark 
 
 
 
 
 
Protocol number: 
TM002 
EudraCT number: 
2016-003694-18 
 
 
 
 
 
 
 
 
 
 
 
The information contained in this document is provided in confidence. It is understood that 
this information will not be disclosed to others without prior agreement with Saniona A/S, 
according to the statement in the clinical study protocol, and in accordance with the 
confidentiality agreement. 
The information contained in this document is provided in confidence. It is understood that 
this information will not be disclosed to others without prior agreement with Saniona A/S, 
according to the statement in the clinical study protocol, and in accordance with the 
confidentiality agreement. 

 
 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS  
 
Study Title 
A double-blind, randomized, placebo-controlled, multiple-dose, 
multi-centre safety and efficacy study of co-administration of 
tesofensine/metoprolol in subjects with Prader-Willi syndrome 
(PWS) “Second 12 weeks open label extension” 
Study Sponsor 
Saniona, A/S 
Baltorpvej 154 
DK2750 Ballerup 
Denmark 
Study Phase 
2a 
Number of sites 
2 sites; one in Czech Republic and one in Hungary  
Number of subjects 
Subjects who completed the first open label phase (12 weeks) 
will be invited to participate in the second open label 12 weeks 
extension phase. 
• A subject’s participation in the second 12 weeks open 
label extension (OLE) study will be based on the 
Investigators’ judgment on whether or not it is safe for 
the subject to continue in the extension study. 
Study design 
Two-centre, multiple-dose clinical study. The second open 
label 12 weeks extension study will be initiated immediately 
during the Visit 17 (Day 180) of the first OLE part (12 weeks), 
which will then become the baseline visit of the second OLE, 
and study medication will be administered, without 
interruption, for another 90 days.  
• Previously approved part: Step 2 – 5-15 children with 
PWS. Study medication (0.125/25 mg) was 
administered for ninety one (91) days (+2 days after the 
final assessments with half-dose of metoprolol in those 
who did not continue in the OLE) and first OLE where 
all eligible patients have been receiving 0.125/25 mg). 
  
• Second open label extension: All subjects who 
completed the first OLE and are deemed eligible by the 
Investigators will be invited to participate in the second 
OLE for another 12 weeks followed by a final visit one 
month after the last dose of the study medication for a 
safety review and PK sampling. 
 
Those patients who refuse to participate in the second OLE, or 
are not deemed eligible by the Investigators, will complete the 
final visit (Visit 18) 1 month after the last dose in the first OLE 

 
 
 
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is taken (Visit 17). 
Study timelines 
Q2 2019 – Q3 2019 
Study treatment and 
Dosing schedule 
In the second OLE all subjects deemed eligible by the PI will 
receive tesofensine 0.125 mg (0.25 mg every second day)  + 
metoprolol ER 25 mg (Metoprolol Orion 25mg) administered 
once a day, in the morning with a meal. Those patients who 
tolerated the 0.125/25 mg tesofensine/metoprolol dose well in 
the first OLE will receive 0.25 mg of tesofensine with 25 mg of 
metoprolol ER.   
  
In case a patient, in the opinion of the PI, experiences an 
adverse event that by the PI is suspected to be potentially 
related to an undesirable drug concentration of the 
investigational medication, the investigators at each site, based 
on their discretion, can extend the period between dosages of 
the IMP or implement a drug holiday, or reduce the dose (those 
on 0.25 mg of tesofensine) in order to optimally manage the 
wellbeing and safety of the patient. Each of these cases should 
be discussed in advance with the Sponsor’s medical monitor. 
Each tablet will be formulated separately; a currently available 
commercial formulation of extended-release metoprolol will be 
used. 
Study objectives  
  
Primary objective: 
• To examine the effect of co-administration of 
tesofensine/metoprolol on body weight in subjects with 
PWS in an open labeled extension study 
Secondary objectives: 
• To establish pharmacokinetic profile of tesofensine and 
metoprolol in subjects with PWS  
• To examine the change in hyperphagia-related behavior 
in subjects with PWS by use of the Hyperphagia 
Questionnaire for Clinical Trials (HQ-CT) 
• To examine the effect of co-administration of 
tesofensine/metoprolol on glycaemic control and lipid 
profile in subjects with PWS 
• To examine the effect of co-administration of 
tesofensine/metoprolol on HR and BP in   subjects with 
PWS 
• To examine the effects of co-administration of 
tesofensine/metoprolol 
on 
body 
composition 
in  
subjects with PWS 
• To evaluate overall safety and tolerability of co-
administration 
of 
the 
tesofensine/metoprolol 
in  
subjects with PWS 
Study population 
(inclusion/exclusion 
All male and female pediatric subjects with confirmed 
diagnosis of PWS who completed the double blind phase (12 

 
 
 
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criteria) 
weeks) and the first OLE, will be invited to participate in the 
second open label 12 weeks extension phase, if deemed eligible 
by the Investigators. 
 
If subject/parents decide to not participate in OLE, subject will 
finish the study based by completing the study as described 
previously. 
Study procedures 
Subjects who have completed the first OLE will continue in the 
second open label extension, starting on Visit 17 (Day 180) for 
another 12 weeks.   
Study procedures in the second OLE are the same as during the 
first OLE.  
Subjects will be invited for the monthly visits (30 days ± 3 
days) to the site for safety evaluations, and some additional 
efficacy assessments and PK (see the schedule of events for 
details). (Visit 18 Day 210; Visit 19 Day 240) 
Between the on-site visits one phone call follow up will be 
performed once per month. 
 
On Day 270 (Visit 20) the subjects will be given two days of 
half dose of metoprolol to take at home in order to gradually 
reduce the dose of metoprolol and avoid potential undesirable 
fluctuation in blood pressure. 
On Day 300 (Visit 21) the subjects will be invited for the final 
safety check, BP/HR assessment and PK sampling (30 days 
after last dose), which will conclude their participation in the 
study.   
 
Subjects who exceed predefined values of HbA1c (>10%), FPG 
>11.0 mmol/l) or BP>160/100 mmHg will be treated at the 
discretion of the investigator per established guidelines to 
improve the subjects glycaemic/BP control while remaining in 
the study. 
Assessments conducted during each visit are described in the 
schedule of events.  
Statistics 
The primary endpoint (percent change in body weight) will be 
summarized with mean estimate, standard deviation, range and 
95% confidence interval for the mean. Impact of treatment 
allocation in the double-blind part will be checked graphically. 
Safety analyses will include all participants who took at least 
one dose of IMP and efficacy analyses all treated participants 

 
 
 
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with post-dose data recorded (full analysis set). Continuous 
data will be summarized using non-missing counts, mean, 
standard deviation, median, minimum, maximum and, if 
appropriate, 95% confidence interval for the mean. Categorical 
data will be summarized using counts and percentages. 
Adverse events will be coded according to MedDRA. The 
number and percentage of subjects experiencing adverse events 
in each treatment group will be tabulated by MedDRA system 
organ class and preferred term.  
	  
Sample size estimate, power calculation: 
As this is an exploratory study, no formal sample size or power 
calculation was performed. Eligible patients are restricted to the 
completers from the first OLE. 
 

 
 
 
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INVESTIGATOR STATEMENT 
 
 
TM002: A double-blind, randomized, placebo-controlled, multiple-dose, two-centre 
safety and efficacy study of co-administration of tesofensine/metoprolol in subjects with 
Prader-Willi syndrome “Second 12 weeks open label extension”. 
I understand that this Clinical Study Protocol contains information that is confidential and 
proprietary to Saniona A/S. I hereby declare, that I will keep all information obtained from my 
participation in this Clinical Study confidential unless otherwise agreed in writing. 
 
I have read the Clinical Study Protocol and I understand the information. With my signature, I 
agree to conduct this Study in accordance with the protocol, ICH-GCP guidelines, Declaration 
of Helsinki and with all applicable local law and regulatory requirements.  
 
I will discuss the contents of this Clinical Study Protocol to all those authorized study staff, 
which will assist me in conducting this study in order to ensure that they are fully informed 
about the Investigational Medicinal Product and the course of the Study. 
 
If required, I will also provide necessary protocol information to the responsible Ethics 
Committee and/or to the Regulatory Authorities under the following condition: the contents of 
this Clinical Study Protocol will not be used in any other clinical study and may not be 
disclosed to any other person or entity without prior written permission of Saniona A/S. 
 
Any supplemental information that may be added to this document is also confidential and 
proprietary to Saniona A/S and must be kept in confidence in the same manner as the contents 
of this Clinical Study Protocol. 
 
____________________________________________________________________ 
 
Principle Investigator 
Signature: 
Date: 
 
 

 
 
 
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SIGNATURE PAGE 
 
 
TM002: A double-blind, randomized, placebo-controlled, multiple-dose, two-centre 
safety and efficacy study of co-administration of tesofensine/metoprolol in subjects with 
Prader-Willi syndrome “Second 12 weeks open label extension”. 
We hereby declare that this Clinical Study Protocol was prepared scientifically accurately and 
in full compliance with the current regulatory guidelines. 
 
With our signatures, we agree to conduct the Study in accordance with the protocol, ICH-
GCP guidelines, Declaration of Helsinki and with all applicable local law and regulatory 
requirements. Moreover, we will keep all information obtained in this Study confidential 
unless otherwise agreed in writing. 
 
 
Jørgen Drejer, PhD 
___________________________________________________________________ 
 
CEO 
Signature: 
Date: 
Saniona, A/S 
Baltorpvej 154 
DK2750 Ballerup 
Denmark 
 
 
Roman V Dvorak, MD, PhD 
____________________________________________________________________ 
 
Clinical and Regulatory Lead 
Signature: 
Date: 
Saniona, A/S 
Baltorpvej 154 
DK2750 Ballerup 
Denmark 
 
 
Leontina Levenzon, M. Sc. 
____________________________________________________________________ 
 
Biostatistician 
Signature: 
Date: 
GCP-Service International Ltd. & Co.KG 
Anne-Conway-Str. 2 
28359 Bremen 
Germany 

 
 
 
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TABLE OF CONTENTS 
 
2	  
ABBREVIATIONS INDEX _____________________________________________________________ 11	  
3	  
INTRODUCTION AND STUDY RATIONALE _____________________________________________ 12	  
3.1	  
CLINICAL BACKGROUND ________________________________________________________ 12	  
4	  
STUDY OBJECTIVES AND ENDPOINTS _________________________________________________ 14	  
4.1	  
OBJECTIVES ____________________________________________________________________ 14	  
4.2	  
ENDPOINTS (Baseline = Day 0; End of double-blind treatment = Day 90, end of first OLE = Day 
180, end of second OLE = Day 270) ________________________________________________________ 14	  
5	  
OVERALL STUDY DESCRIPTION ______________________________________________________ 15	  
5.1	  
STUDY VISIT DESCRIPTION ______________________________________________________ 16	  
Visit 21 (Day 300 (30±3 days) Final follow-up –– personal visit _________________________________ 18	  
End of study (Day 300) _________________________________________________________________ 18	  
5.2	  
END OF STUDY __________________________________________________________________ 19	  
5.3	  
STUDY PARTICIPANTS ___________________________________________________________ 19	  
5.4	  
DISCONTINUATION CRITERIA ___________________________________________________ 19	  
5.5	  
WITHDRAWAL CRITERIA ________________________________________________________ 19	  
5.6	  
PREMATURE STUDY DISCONTINUATION _________________________________________ 20	  
5.7	  
EARLY TERMINATION OF A STUDY SITE _________________________________________ 20	  
5.8	  
STUDY SITES ____________________________________________________________________ 20	  
5.9	  
STUDY DURATION _______________________________________________________________ 20	  
5.10	  
TOTAL STUDY DURATION ______________________________________________________ 20	  
5.11	  
BENEFITS AND RISKS FOR STUDY PARTICIPANTS _______________________________ 20	  
6	  
TREATMENT OF STUDY PARTICIPANTS= identical to the first OLE _________________________ 22	  
6.1	  
DESCRIPTION OF STUDY MEDICATION __________________________________________ 22	  
Investigational Medicinal Product _________________________________________________________ 22	  
6.2	  
IMP BLINDING AND HANDLING PROCEDURES - KLIFO ____________________________ 23	  
6.3	  
IMP HANDLING PROCEDURES – STUDY SITE _____________________________________ 23	  
6.4	  
LABELS FOR STUDY MEDICATION _______________________________________________ 23	  
6.5	  
PACKAGING AND DESTRUCTION ________________________________________________ 24	  
6.6	  
STUDY MEDICATION COMPLIANCE ______________________________________________ 24	  
6.7	  
OPEN LABEL SUBJECT NUMBER _________________________________________________ 24	  
6.8	  
UNBLINDING ____________________________________________________________________ 24	  
6.9	  
DISPENSATION OF STUDY MEDICATION _________________________________________ 24	  
6.10	  
ACCOUNTABILITY OF THE STUDY MEDICATION ________________________________ 24	  
6.11	  
CONCOMITANT MEDICATION __________________________________________________ 25	  
6.12	  
PROHIBITED MEDICATIONS ____________________________________________________ 25	  
6.13	  
STUDY PROCEDURES AND OTHER EXAMINATIONS ______________________________ 25	  
Informed Consent for the second OLE _____________________________________________________ 25	  
Vital Signs ___________________________________________________________________________ 26	  

 
 
 
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Physical Examination __________________________________________________________________ 26	  
Blood pressure measurement _____________________________________________________________ 26	  
6.14	  
LABORATORY EVALUATIONS __________________________________________________ 27	  
6.15	  
SUBJECTS’ DIARIES /CARDS ____________________________________________________ 28	  
7	  
SAFETY REPORTING _________________________________________________________________ 28	  
7.1	  
DEFINITIONS ____________________________________________________________________ 28	  
7.2	  
ADVERSE EVENT ________________________________________________________________ 29	  
7.3	  
GRADING OF ADVERSE EVENT SEVERITY ________________________________________ 29	  
7.4	  
CAUSALITY OF AE _______________________________________________________________ 29	  
7.5	  
OUTCOME OF AE ________________________________________________________________ 30	  
7.6	  
UNEXPECTED ADVERSE REACTION ______________________________________________ 30	  
7.7	  
SERIOUS ADVERSE EVENT _______________________________________________________ 30	  
7.8	  
SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION ________________________ 31	  
7.9	  
RECORDING OF ADVERSE EVENTS _______________________________________________ 31	  
Pre-existing Conditions _________________________________________________________________ 31	  
Overdose ____________________________________________________________________________ 31	  
Pregnancy ___________________________________________________________________________ 31	  
7.10	  
REPORTING PROCEDURE OF SERIOUS ADVERSE EVENTS _______________________ 32	  
7.11	  
FOLLOW-UP OF ADVERSE EVENTS ______________________________________________ 32	  
7.12	  
ANNUAL SAFETY REPORTS _____________________________________________________ 33	  
8	  
DESCRIPTION OF STATISTICAL METHODS ____________________________________________ 33	  
8.1	  
DESCRIPTION OF STATISTICAL METHODS _______________________________________ 33	  
8.2	  
SAMPLE SIZE CALCULATION ____________________________________________________ 33	  
8.3	  
SELECTION OF SUBJECTS FOR ANALYSES _______________________________________ 33	  
8.4	  
STATISTICAL METHODS _________________________________________________________ 34	  
8.5	  
ANALYSIS OF THE PRIMARY ENDPOINT __________________________________________ 35	  
8.6	  
ANALYSIS OF THE SECONDARY & EXPLORATORY ENDPOINTS ___________________ 35	  
8.7	  
SAFETY CRITERIA ______________________________________________________________ 35	  
9	  
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ______________________________________ 36	  
9.1	  
SOURCE DATA __________________________________________________________________ 36	  
9.2	  
SUBJECT IDENTIFICATION LIST AND SCREENING LOG ___________________________ 37	  
10	   QUALITY CONTROL AND QUALITY ASSURANCE ________________________________________ 37	  
10.1	  
DEFINITIONS ___________________________________________________________________ 37	  
Quality Assurance _____________________________________________________________________ 37	  
Quality Control _______________________________________________________________________ 37	  
10.2	  
AUDITS AND INSPECTIONS _____________________________________________________ 38	  
11	   ETHICS _____________________________________________________________________________ 38	  
11.1	  
BASIC PRINCIPLES AND ETHICAL CONSIDERATIONS ____________________________ 38	  
11.2	  
APPROVALS ____________________________________________________________________ 38	  
11.3	  
ETHICS COMMITTEE ___________________________________________________________ 38	  

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11.4	  
REGULATORY AUTHORITY _____________________________________________________ 38	  
11.5	  
PROTOCOL MODIFICATIONS ___________________________________________________ 39	  
11.6	  
SUBJECT INFORMATION AND INFORMED CONSENT _____________________________ 39	  
11.7	  
PARTICIPANT CONFIDENTIALITY ______________________________________________ 40	  
12	   DATA HANDLING AND RECORD KEEPING _____________________________________________ 40	  
12.1	  
DATA COLLECTION AND DOCUMENTATION ____________________________________ 40	  
12.2	  
STUDY MONITORING, SOURCE DATA VERIFICATION AND DATA MANAGEMENT _ 40	  
12.3	  
DATA MANAGEMENT PLAN _____________________________________________________ 41	  
12.4	  
CASE REPORT FORMS (CRFS) ___________________________________________________ 41	  
12.5	  
INVESTIGATOR FILE ___________________________________________________________ 41	  
12.6	  
LOGS __________________________________________________________________________ 41	  
12.7	  
PROTOCOL COMPLIANCE ______________________________________________________ 41	  
12.8	  
RECORD KEEPING _____________________________________________________________ 41	  
13	   FINANCE AND INSURANCE ___________________________________________________________ 42	  
13.1	  
COMPENSATION TO INVESTIGATOR ____________________________________________ 42	  
13.2	  
INSURANCE AND INDEMNITY ___________________________________________________ 42	  
14	   PUBLICATION POLICY _______________________________________________________________ 42	  
14.1	  
REPORTING AND PUBLICATION ________________________________________________ 42	  
15	   REFERENCES _______________________________________________________________________ 43	  
16	   Appendices ___________________________________________________________________________ 44	  
16.1
Appendix I: table of recommended concomitant medication use __________________________ 44	  
16.2
STUDY FLOW CHART: VISITS 17 - 21 (all visits are ±3 day) ___________________________ 45	  
17.1
Hyperphagia Questionnaire for Clinical Trials (HQ-CT) ________________________________ 47	  

 
 
 
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2 
ABBREVIATIONS INDEX 
ADR 
Adverse Drug Reaction 
RA 
Regulatory Authority 
ALT 
Alanine Aminotrasferase 
kg 
Kilogram 
ANCOVA 
Analysis of co-variance 
l 
Liter 
AST 
Aspartate Aminotrasferase 
LDL 
Low-density lipoprotein 
ATC 
Anatomical Therapeutic Chemical Classification 
LPLV 
Last Patient Last Visit 
AUC 
Area Under the Plasma Concentration  
MedDRA 
Medical Dictionary for Regulatory 
Activities 
A/S 
Aktieselskab 
MDD 
Major Depressive Disorder 
BMI 
Body Mass Index 
mg 
Milligram 
BP 
Blood Pressure 
mL 
Milliliter 
Bpm 
Beats per minute 
mmHg 
Millimeter of mercury 
BMI 
Body Mass Index 
mmol 
Millimol 
CI 
Confidence Interval  
N 
No 
Cm 
Centimeter 
N (No) 
Number 
Cmax 
Maximum measured plasma concentration  
ng 
Nanogram 
CRF 
Case Report Form 
NYHA 
New York Heart Association 
CRO 
Contract Research Organization 
OLE 
Open Label Extension 
CYP 
Cytochrome P450 
OP 
Out-patient 
CV 
Coefficient of Variation 
OTC 
Over the Counter 
CV 
Cardio Vascular 
P 
Phone 
CVD 
Cardio Vascular Disease 
PK 
Pharmacokinetic 
°C 
Degrees Celsius 
PK/DM 
Pharmacokinetics/Drug Metabolism 
DBP 
Diastolic Blood Pressure 
PPP 
Per-Protocol Population 
DDI 
Drug-drug Interaction 
PWS 
Prader Willi Syndrom 
Dl 
Deciliter 
Q 
Quarter 
DMP 
Data Management Plan 
QA 
Quality Assurance 
DSMB 
Data Safety Monitoring Board  
QC 
Quality Control 
DXA 
Dual X-ray absorptiometry 
SAE 
Serious Adverse Event 
ECG 
Electrocardiogram 
SAP 
Statistical Analysis Plan 
EC 
Ethic Committee  
SBP 
Systolic Blood Pressure 
eCRF 
Electronic Case Report Form 
SD 
Standard Deviation 
EMEA 
European Agency for the Evaluation of Medical 
Products 
SOP 
Standard Operating Procedure 
EU 
European Union 
SUSAR 
Suspected Unexpected Serious Adverse 
Reactions 
FPG 
Fasting Plasma Glucose  
Tmax 
Time of the maximum  
GCP 
Good Clinical Practice 
TZD 
Thiazolidinediones 
HDL 
High-density lipoprotein 
T2MD 
Type 2 diabetes mellitus 
HbA1C 
Hemoglobin A1c 
ULN 
Upper Limit of Normal range 
HQCT 
Hyperphagia Questionnaire for Clinical Trials  
 
USA 
United States of America 
HR 
Heart Rate 
WHO DD 
World Health Organization Drug 
Dictionary 
IB 
Investigator Brochures 
 
 
ICH 
International Conference on Harmonization 
 
 
IEC 
Independent Ethics Committee 
 
 
IMP 
Investigation Medicinal Product 
 
 

 
 
 
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3 
INTRODUCTION AND STUDY RATIONALE  
 
3.1 
CLINICAL BACKGROUND 
Etiology and treatment of Prader- Willi syndrome   
Prader-Willi syndrome is a complex genetic condition caused by an abnormality on the long 
arm of chromosome 15 (q11-q13) that affects many parts and organ systems of the body. In 
infancy, this condition is characterized by weak muscle tone (hypotonia), feeding difficulties, 
poor growth, and delayed development. Beginning in childhood, affected individuals develop 
an insatiable appetite, which leads to chronic overeating (hyperphagia) and obesity. Many 
subjects with Prader-Willi syndrome, particularly those with obesity, also develop type 2 
diabetes mellitus (T2DM) and other related co-morbidities early in life often leading to 
development of cardiovascular disease and early death. 
 
Subjects with Prader-Willi syndrome typically have mild to moderate intellectual impairment 
and learning disabilities. Behavioral problems are common, including temper outbursts, 
stubbornness, and compulsive behavior such as picking at the skin. Sleep abnormalities can 
also occur. Additional features of this condition include distinctive facial features such as a 
narrow forehead, almond-shaped eyes, and a triangular mouth; short stature; and small hands 
and feet. Some people with Prader-Willi syndrome have unusually fair skin and light-colored 
hair. Both affected males and affected females have underdeveloped genitals. Puberty is 
delayed or incomplete, and most affected individuals are unable to have children (infertile). 
(1) 
 
Prader-Willi syndrome affects an estimated 1 in 10,000 to 30,000 people worldwide. Most 
cases of Prader-Willi syndrome are not inherited, particularly those caused by a deletion in the 
paternal chromosome 15 or by maternal uniparental disomy. These genetic changes occur as 
random events during the formation of reproductive cells (eggs and sperm) or in early 
embryonic development. Affected subjects typically have no history of the disorder in their 
family. 
 
Rarely, a genetic change responsible for Prader-Willi syndrome can be inherited. For 
example, it is possible for a genetic change that abnormally inactivates genes on the paternal 
chromosome 15 to be passed from one generation to the next. (1) 
 
Current treatment strategies 
There is currently no specific treatment for this syndrome. Growth hormone has been 
routinely used to help with growth and to increase muscle mass, which allows greater physical 
activity. As other diseases develop as the subjects age, eg, T2DM, hypertension, dyslipidemia 
or psychiatric disorders, these are managed per local practice and treatment standards. 
 
Overview of tesofensine  
Tesofensine was initially studied for the treatment of Parkinson and Alzheimer’s diseases. 
However, clinical studies showed only a limited efficacy of tesofensine, but weight loss was 
noted in majority of participants, despite the fact that they did not attempt to lose weight. 
Tesofensine is an inhibitor of monoamine presynaptic reuptake of the neurotransmitters 
noradrenaline, dopamine and serotonin. This means it influences these chemicals in the brain 

 
 
 
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to suppress appetite. Tesofensine demonstrated strong weight reducing effects in Phase 2 
clinical studies in obese subjects, exceeding benchmarks set by the regulatory agencies for 
approval of weight loss agents (2). Also, post-hoc analysis of the data from the Phase 2 
obesity study showed that individuals with pre-diabetes in this study experienced a favorable 
reduction in body weight and glycaemic endpoints while on tesofensine.  
 
In general, tesofensine was well tolerated in humans with the most commonly observed side 
effects of dry mouth, headache, insomnia, and nausea However, blood pressure and heart rate 
increase were observed. With the therapeutically relevant doses of tesofensine (0.25 mg and 
0.5 mg) an increase in blood pressure (BP) of 1–3 mmHg and an increase in heart rate (HR) 
up to 8 bpm were seen (2). Currently, there are no data indicating that these effects of 
tesofensine would translate into increased risk of cardiovascular (CV) events; however, these 
increases could hypothetically have an adverse impact on the cardiovascular safety in certain 
individuals.. This lead to the addition of metoprolol to mitigate these effects and further 
ensure a favorable benefit/risk profile. For more information on tesofensine please see the 
Investigators’ Brochure (Version 12). 
  
Overview of metoprolol 
Metoprolol is a beta1-selective (cardio selective) adrenoceptor-blocking agent, for oral 
administration, which has been approved in the 70’s and has been one of the most widely 
prescribed medicines to date. It is indicated for hypertension, angina pectoris and heart failure. 
It is now available as extended-release tablets. Metoprolol extended release, has been 
formulated to provide a controlled and predictable release of metoprolol for once-daily 
administration. This is also the formulation selected for this study (for more information 
please see the Summary of Product Characteristics of metoprolol). 
 
Overview of tesofensine/metoprolol 
In a pre-clinical study in rats the co-administration of tesofensine + metoprolol showed a HR 
and BP profile similar to placebo (vehicle) while the weight-reducing efficacy was maintained 
(3). In addition, in a drug-drug interaction study in healthy male subjects addition of short 
acting metoprolol on the background of chronic dosing with tesofensine showed a short term, 
but substantial, reduction in HR previously increased by tesofensine. Co-administration of 
tesofensine (0.5 mg qd) and metoprolol (100 mg qd) is currently being studied in a Phase 2a 
proof-of-concept study in 60 subjects with T2DM at two sites in Germany. Taken together, 
the available data support the concomitant use of tesofensine and a beta-blocker such as 
metoprolol as an investigational agent for the proposed indication of treatment of obesity and 
related co-morbidities in subjects with Prader-Willi syndrome. 
 
Purpose of the Comparison to Placebo 
Double blind, placebo-controlled design is the gold standard in evaluation of efficacy and 
safety of new drugs. It provides the most rigorous and unbiased evaluation of the true effects 
of an intervention. This design was chosen because it is critical to thoroughly assess the 
efficacy of co-administration of tesofensine/metoprolol in subjects with Prader-Willi 
syndrome. 
 
Purpose of this study 
The purpose of this study is to investigate the safety and efficacy of co-administration of 
tesofensine/metoprolol treatment versus placebo in adult and pediatric subjects with Prader-

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Willi syndrome. 
4 
STUDY OBJECTIVES AND ENDPOINTS 
4.1 
OBJECTIVES 
Primary objective:   
•
To examine the effect of co-administration of tesofensine/metoprolol on body weight
in subjects with PWS in an open labeled extension
Secondary objectives: 
•
To establish pharmacokinetic profile of tesofensine and metoprolol in subjects with
PWS
•
To examine the change in hyperphagia-related behavior in subjects with PWS by use
of the Hyperphagia Questionnaire for Clinical Trials (HQ-CT)
•
To examine the effect of co-administration of tesofensine/metoprolol on glycemic
control and lipid profile in subjects with PWS
•
To examine the effect of co-administration of tesofensine/metoprolol on HR and BP in
subjects with PWS
•
To examine the effects of co-administration of tesofensine/metoprolol on body
composition in subjects with PWS
•
To evaluate overall safety and tolerability of co-administration of the
tesofensine/metoprolol in subjects with PWS
4.2 
ENDPOINTS (Baseline = Day 0; End of double-blind treatment = Day 
90, end of first OLE = Day 180, end of second OLE = Day 270) 
Primary endpoint 
•
Percent change from baseline to end of treatment periods in mean body weight
Secondary endpoints 
•
Steady state concentrations of tesofensine and metoprolol as measured by trough
values
•
Uptake and initial plateau concentrations of metoprolol as measured by samples taken
2 and 4 hours after dose administration
•
Change from baseline to end of the treatment periods in total HQCT score
•
Change from baseline to end of treatment periods in mean body weight (kg)
•
Change from baseline to end of treatment periods in fat- and fat-free mass (%) by dual
X-ray absorptiometry (DEXA)
•
Change from baseline to end of treatment periods in HR (bpm), SBP (mmHg), DBP
(mmHg)
•
AEs, clinical labs, ECG
Exploratory endpoints: 
•
Change from baseline to end of treatment periods in FPG, insulin
•
Change from baseline to end of treatment periods in lipid profile
•
Change from baseline to end of treatment periods in waist circumference (cm)

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5 
OVERALL STUDY DESCRIPTION 
This is a second open label extension study of the double-blind, randomized, placebo-
controlled, multiple-dose, multi-centre, safety and efficacy study of co-administration of 
tesofensine/metoprolol treatment in subjects with Prader-Willi syndrome. This open label 
extension is a follow up of the first OLE, which   included 8 children with PWS (Protocol 
Amendment 1.5). 
Subjects who complete first OLE (12 weeks) will be invited to participate in the second open 
label extension phase. Participation will be based on the judgment of the Investigators 
whether or not it is safe for the subject to continue in the extension study. Study medication 
will be administered for ninety (90) days (+2 days after the final assessments with half-dose 
of metoprolol). 
In the second OLE all subjects deemed eligible by the PI will receive tesofensine 0.125 mg 
(0.25 mg every second day)  + metoprolol ER 25 mg (Metoprolol Orion 25 mg) administered 
once a day, in the morning with a meal. Those patients who tolerated the 0.125/25 mg 
tesofensine/metoprolol dose well in the first OLE will receive 0.25 mg of tesofensine with 25 
mg of metoprolol ER.   
In case a patient, in the opinion of the PI, experiences an adverse event that by the PI is 
suspected to be potentially related to an undesirable drug concentration of the investigational 
medication, the investigators at each site, based on their discretion, can extend the period 
between dosages of the IMP or implement a drug holiday, or reduce the dose (those on 0.25 
mg of tesofensine) in order to optimally manage the wellbeing and safety of the patient. Each 
of these cases should be discussed in advance with the Sponsor’s medical monitor. 
Subjects (together with their parents/guardians/caregivers (where applicable according to 
existing country legislation)) who give the written informed consent for the second open label 
extension part will continue in the study. If not, subject will finish the study based on the 
Protocol Amendment 1.5. 
Opel label period: after the Day 180 (Visit 17), subjects will visit the site every month for 
efficacy and safety evaluations and medication supply (in total 4 personal visits at the site are 
requested). Study procedures in the second extension part are the same as in the first OLE.  
If possible subjects will be asked to stay at the site for the collection of blood for PK of 
metoprolol 2 and 4 hours after dose administration – the blood for these samples will be 
collected once from each patient (only if it hasn’t been collected during the first OLE), but to 
allow for greater flexibility accounting for their unstable and unpredictable nature, it is 
included during every on site visit. 

 
 
 
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End of treatment visit: On Visit 20 (Day 270) subjects will come for the final treatment 
visit. During the Visit 20 the blood will be collected for metabolic endpoint as well as safety 
measurements. Subjects will also receive two days of half-dose dose of metoprolol to take at 
home in order to gradually reduce the dose of metoprolol to avoid potential undesirable 
fluctuation in blood pressure.  
End of study: On Visit 21 (Day 300) the subjects will be invited for the final safety check, 
BP/HR assessment and PK sampling (30 days after last dose), which will conclude their 
participation in the study. 
 
Phone calls in-between the onsite visits will be used to provide additional reassurance 
regarding the safety of the subjects and collect adverse events. 
 
Subjects who exceed predefined values of HbA1c>10%, FPG >11.0 mmol/l or BP>160/110 
mmHg will be treated at the discretion of the investigator per established guidelines to 
improve the patients glycaemic/BP control while remaining in the study. 
 
Assessments conducted during each visit are described in the schedule of events, Appendix 
16.2. 
 
5.1 
STUDY VISIT DESCRIPTION 
Visit 17, Day 180 – Last visit of the first OLE and first visit of the second OLE: 
 
The following procedures will be performed:  
• Signing the Addendum to double blind ICF for the second open label extension 
• Conducting physical examination 
• Measurement of vital signs  
• Measurement of body weight and waist circumference 
• Measurement of height, calculation of BMI 
• Obtaining ECG 
• Performing routine hematology, blood chemistry assessment  
• Collection of blood for efficacy (HbA1c, FPG, lipids, insulin)  
• Collection of blood for PK of steady state concentrations of tesofensine and 
metoprolol as measured by trough values 
• Collection of blood for PK of metoprolol taken 2 and 4 hours after dose administration 
(only if not done already– during the first OLE) 
• Performing the urinary pregnancy test 
• DEXA 
• HQCT 
• AEs assessment 
• Psychiatric examination  
• Assessment of concomitant medications 
• Dispensing the subject diary for the open label extension, study card for second OLE 
• Dispensation of study medication  

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•
Scheduling the next on-site visit and phone call
All diabetic subjects (together with their parents/guardians/caregivers) will be again instructed 
to closely follow the dietary instruction and medical treatment for their diabetes. Subjects 
(together with their parents/guardians/caregivers) will be again educated in and again asked to 
watch for any symptoms or signs of hypoglycemia. Hypoglycaemic episodes must be reported 
to investigator during the phone call visits or personal visit at the site. In case of an 
unexplained hypoglycaemic event (no extra exercise, skipping a meal or alike) the subjects 
(together with their parents/guardians/caregivers) should contact the site. Information about 
providing instruction regarding hypoglycaemic episodes must be recorded in the subject’s 
source data. 
Visit 18, 19 (Day 210, 240 (30 ±3 days) – personal visits: 
The following assessments will be done: 
•
Measurement of vital signs
•
Measurement of body weight and waist circumference
•
Collection of blood for efficacy (HbA1c, FPG, lipids, insulin)
•
Collection of blood for PK of steady state concentrations of tesofensine and
metoprolol as measured by trough values
•
Collection of blood for PK of metoprolol taken 2 and 4 hours after dose administration
(only if not done already)
•
HQCT
•
AEs assessment
•
Psychiatric examination
•
Assessment of concomitant medications
•
Review of subject diary
•
Medication accountability check
•
Scheduling the phone call and subject personal visit
Visit 20 (Day 270 (30±3 days) – End of treatment visit 
The following assessments will be done: 
•
Conducting physical examination
•
Measurement of vital signs
•
Measurement of body weight and waist circumference
•
Obtaining ECG
•
Performing routine hematology, blood chemistry assessment
•
Collection of blood for efficacy (HbA1c, FPG, lipids, insulin)
•
Collection of blood for PK of steady state concentrations of tesofensine and
metoprolol as measured by trough values
•
Collection of blood for PK of metoprolol taken 2 and 4 hours after dose administration
(only if not done already)
•
Performing the urinary pregnancy test
•
DEXA
•
HQCT
•
AEs assessment

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•
Psychiatric examination
•
Assessment of concomitant medications
•
Medication accountability check
•
Dispense of two half-doses of active / placebo medication
•
Collection and review of subject diary
•
Dispensing a follow up diary lists for recording AE and concomitant medication
between last subject visit and a phone call on Day 300
•
Scheduling Final follow up visit on Day 300
Day 270 (morning) will be the last day when subjects receive the study medication. 
On Day 270 subjects will receive a half-dose of the metoprolol dose to take at home, one 
dosage over the next two days in order to gradually reduce the dose of metoprolol and avoid 
potential undesirable fluctuation in blood pressure. 
Phone calls between the on-site visit 
Phone calls in between the onsite visits will be used to provide additional reassurance 
regarding the safety of the subjects and to collect adverse events. Subjects 
(parents/guardians/caregivers) will be asked the following: 
•
Since your last visit, have you experienced or do you currently experience any
symptoms that are not associated with your disease?
•
Any change in concomitant medications
•
Any Hypoglycemic episodes
Visit 21 (Day 300 (30±3 days) Final follow-up –– personal visit 
The following assessments will be done: 
•
AEs
•
Measurement of vital signs
•
Measurement of body weight and waist circumference
•
HQCT
•
Psychiatric examination
•
Concomitant medications
•
Collection of blood for PK
•
Review of subject diary
•
Collection of subject follow up diary
End of study (Day 300) 
Visit 21 is considered as the subject’s end in the study. The “End of Study” or “Early 
termination” (as applicable) must be entered into the eCRF and subject’s source documents 
must be completed. 
Unscheduled visit – if applicable: 
The following assessments will be done: 
•
Conducting physical examination
•
Measurement of vital signs
•
Measurement of body weight and waist circumference

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•
Performing routine hematology, blood chemistry assessment
•
AEs assessment
•
Assessment of concomitant medications
5.2 
END OF STUDY 
The end of study (Day 300) is defined by LPLV for TM002, including the second OLE. If a 
subject withdraws from the study during the treatment period, or has to discontinue for any 
reason, a visit will be organized at which the assessments planned for Visit 20 will be 
performed. If a subject refuses to attend a visit, the investigator should make every effort to 
obtain the information over the telephone from the subject regarding the safety.  
5.3 
STUDY PARTICIPANTS 
All male and female pediatric subjects with confirmed diagnosis of PWS who completed the 
first OLE (12 weeks), will be invited to participate in the second open label extension phase, 
if deemed eligible by the Investigators.    
5.4 
DISCONTINUATION CRITERIA 
The subject or her/his parents/guardians/caregivers has a right to discontinue subject’s study 
participation at any time for any reason. The reason for discontinuation will be documented in 
the subject’s source documents and in the eCRF. In the event of an early termination, all 
procedures described for a subject completing the study as planned for Visit 20 (Day 270) 
should be performed. Subjects discontinuing due to adverse events will be followed-up until 
complete resolution of the adverse event or until there is a satisfactory explanation of the 
changes observed. 
5.5 
WITHDRAWAL CRITERIA 
 Subjects may be withdrawn if any of the following items is met and documented: 
•
Request by subject (withdrawal of informed consent)
•
Request by parents/guardians/caregivers
•
Investigator’s decision
•
Pregnancy
•
Acute allergic reaction to study medication
•
HbA1c ≥ 10%
•
FPG>13.3 mmol/l (repeated on 2 days)
•
Subjects who during the treatment period exceed BP systolic values >160, <100
mmHg, or diastolic >110, <60 mmHg on two consecutive mornings and confirmed at
the investigational site
•
Any event, including hospitalization of the subject in another location where the
investigator will not be able to follow the subject
•
Evidence of the use of recreational medications or prohibited medications during the
study
•
Failure to comply with the study stipulations
•
Severe symptomatic bradycardia (heart rate < 50 bpm) during the study
•
Lost to follow-up. Subjects will be deemed lost to follow-up if they do not return for
scheduled visits without giving a reason, and if the investigator is unable to contact the

 
 
 
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subject directly or indirectly (e.g. via the subject’s family). If a subject does not attend 
a scheduled visit, the investigator will make best efforts to obtain information about 
the subject before considering the subject lost to follow up 
 
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 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 eCRF. 
5.6 
PREMATURE STUDY DISCONTINUATION 
The sponsor has the right to terminate this study at any time. If the sponsor, the investigators, 
or the competent authorities discover conditions arising during the study that indicate the 
study should be halted, it may be terminated after appropriate consultation between the study 
sponsor and the investigator. 
Reasons for terminating the study may include the following: 
• The incidence or severity of AEs in this study indicates a potential health hazard to 
study subjects 
• Subject enrolment is unsatisfactory 
• Data recording is inaccurate or incomplete 
• The sponsor´s decision to suspend or discontinue development of the study medication 
5.7 
EARLY TERMINATION OF A STUDY SITE 
The sponsor may close the site if severe protocol deviations are observed. 
5.8 
STUDY SITES 
The study will be conducted at two sites, one in Czech Republic and one in Hungary. 
 
5.9 
STUDY DURATION 
The expected start date for the inclusion of study subjects is March/April  2019. The 
individual study duration for one subject is up to 16 weeks including treatment period (12 
weeks of the open label period) and the final visit (30 days after the last treatment visit). The 
end of second open label is defined by the Last Visit of the Last pediatric subject, which is 
likely to occur in June/July 2019.  
 
5.10 
TOTAL STUDY DURATION   
The projected duration of the whole study (including Step 2 and both OLEs) is ~15 months. 
The end of TM002 is defined as Last Visit of the Last Pediatric Patient in the second open 
label extension. 
 
5.11 
BENEFITS AND RISKS FOR STUDY PARTICIPANTS 
It is expected that tesofensine and metoprolol combination will be well tolerated. This 
assessment is based on the comprehensive experiences from previous preclinical and clinical 
studies of tesofensine, the availability of metoprolol on the market for many years and the 
present tesofensine/metoprolol investigation in subjects with T2DM. All subjects will receive 
diet consulting, and it is expected that subjects on active treatment will see a reduction in their 
hunger, food craving and body weight. No invasive interventional procedures are planned 

 
 
 
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except blood sampling, which is similar to clinical practice and subjects will be monitored 
thoroughly and rigorously following the first administration of tesofensine and metoprolol, 
and will have weekly contact (personal or telephone contact) to the site throughout the study.  
There were adverse events observed in Step 1 of this study, which lead to premature 
discontinuation of several patients. It is anticipated that these adverse events were driven by 
unexpected high concentration of tesofensine and that the proposed changes in the dosing of 
the IMP in the study protocol proposed for Step 2 and both OLEs should keep the overall 
risk/benefit balance favorable. 
Tesofensine  
The majority of treatment related adverse events seen in the clinical studies with tesofensine 
were dry mouth, headache, nausea, insomnia, diarrhea and constipation side effects. A dose-
dependent pattern was observed for dry mouth and insomnia. The overall withdrawal rate due 
to adverse events in clinical studies in the obese population was 13% with tesofensine and 6% 
with placebo. Blood pressure and heart rate increased with the therapeutically relevant doses 
of tesofensine (0.25 mg and 0.5 mg). An increase in blood pressure of 1–3 mm Hg and in HR 
up to 8 bpm was seen. For more information see the IB. (IB version 12 and any updates 
thereof). 
 
Due to the CNS-located mechanism of action of tesofensine, a monoamine reuptake inhibitor, 
there could be a concern regarding psychiatric side effects. In obese subjects dosed for up to 
24 weeks, common psychiatric symptoms were insomnia and depressed mood. Occurrence of 
insomnia displayed a clear dose-dependency with the highest incidence on the highest dose (1 
mg). Psychotic phenomena, like those encountered in patients with dementia of the 
Alzheimer's type or Parkinson’s disease, were not registered in the population of obese 
subjects. Pooled data from studies NS2330-001 and NS2330-004 did not reveal an increased 
incidence of psychiatric events following long-term extension study, i.e. 18 months of 
treatment. Current data from the clinical studies with obese patients do not suggest that 
tesofensine at doses of 0.25 mg and 0.5 mg once daily are associated with any clinically 
significant undesirable psychiatric profile. (IB version 12 and any updates thereof). 
 
Metoprolol adverse reactions – post marketing experience  
• Blood and lymphatic system: thrombocytopenia, leukopenia, agranulocytosis 
• Cardiovascular: cold extremities, arterial insufficiency (usually of the Raynaud type), 
palpitations, peripheral edema, syncope, chest pain and hypotension 
• Respiratory: wheezing (bronchospasm), dyspnea, rhinitis  
• Central Nervous System: confusion, short-term memory loss, headache, somnolence, 
nightmares, insomnia, anxiety/nervousness, hallucinations, paresthesia 
• Psychiatric: changes in personality, depression 
• Gastrointestinal: nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, 
vomiting, abdominal pain, retroperitoneal fibrosis 
• Hypersensitive Reactions: pruritus 
• Miscellaneous: 
fatigue, 
hyperhidrosis, 
hepatitis, 
increased 
liver 
enzymes, 
musculoskeletal pain, arthralgia, blurred vision, decreased libido, male impotence, 
tinnitus, reversible alopecia, dry eyes, psoriasis-like dermatitis, worsening of psoriasis, 
Peyronie’s disease, sweating, photosensitivity, taste disturbance, gangrene 

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For more information regarding the adverse events please see the Summary of Product 
Characteristics of metoprolol. 
It is anticipated that the subject receiving the study medication will experience a reduction in 
their body weight and improvement in their glycaemic control (if diabetic or pre-diabetic). 
Although tesofensine has not been previously investigated in adult and pediatric subjects with 
Prader-Willi syndrome, based on the highly statistically and clinically meaningful degree of 
weight loss seen in the available literature it is anticipated that participants in this study will 
experience improvement in their glycaemic control (also including those on placebo who will 
receive diet, exercise and lifestyle modification guidance). In addition, all patients will have 
access to a state-of-the-art clinical care that they will receive for the duration of the study. 
Subjects randomized to the placebo arm will receive state of the art clinical study for almost 4 
months with regular visits and multiple sophisticated assessment of their health status, 
including their diabetes, as well as lifestyle guidance from a dietician. Pediatric subjects with 
PWS will be included only after the received positive opinion from respective regulatory 
authorities and ethics committees, which concludes that that no safety concerns arose from 
IMP application in adult PWS patients in Step 1 and TM001. 
6 
TREATMENT OF STUDY PARTICIPANTS= identical to the first 
OLE 
6.1 
DESCRIPTION OF STUDY MEDICATION 
Investigational Medicinal Product 
Tesofensine is a serotonin-noradrenaline-dopamine reuptake inhibitor, for oral administration, 
which is manufactured, packed and labeled by Delpharm in Reims (France). Its chemical 
name 
(IUPAC) 
is 
(1R,2R,3S,5S)-2-Ethoxymethyl-3-(3,4-dichlorophenyl)-8-methyl-8-
azabicyclo[3.2.1]octane,2-hydroxy-1,2,3-propanetricarboxylate (1:1). Designated contractors 
will supply study medications directly. 
Metoprolol is a beta1-selective (cardioselective) adrenoceptor-blocking agent, for oral 
administration. It has been formulated into the extended release tablets to provide a controlled 
and predictable release of metoprolol for once-daily administration. Original extended release 
metoprolol will be purchased and supplied by sponsor CRO directly. 
In the first OLE tesofensine 0.125 mg (0.25 mg every second day) + metoprolol 25 mg was 
administered once a day, in the morning with a meal. In the second OLE all subjects deemed 
eligible by the PI will receive tesofensine 0.125 mg (0.25 mg every second day)  + metoprolol 
ER 25 mg (Metoprolol Orion 25 mg) administered once a day, in the morning with a meal. 
Those patients who tolerated the 0.125/25 mg tesofensine/metoprolol dose well in the first 
OLE will receive 0.25 mg of tesofensine with 25 mg of metoprolol ER.   
In case a patient, in the opinion of the PI, experiences an adverse event that by the PI is 
suspected to be potentially related to an undesirable drug concentration of the investigational 
medication, the investigators at each site, based on their discretion, can extend the period 
between dosages of the IMP or implement a drug holiday, or reduce the dose (those on 0.25 

 
 
 
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mg of tesofensine) in order to optimally manage the wellbeing and safety of the patient. Each 
of these cases should be discussed in advance with the Sponsor’s medical monitor. 
 
6.2 
IMP BLINDING AND HANDLING PROCEDURES - KLIFO 
The contracted CRO Klifo (Denmark) is responsible for the IMP management.  
 
6.3 
IMP HANDLING PROCEDURES – STUDY SITE 
• Klifo is responsible for transferring the IMP to assigned and contracted study site 
pharmacies in Czech Republic and Hungary 
• The site pharmacists (at the both sites) are responsible for acknowledgment of receipt 
of the of IMP by signing the receipt forms  
• Storing the IMP on site pharmacy in a secured area with restricted access under the 
controlled temperature conditions   
• Dispensing IMP to site staff according to the protocol 
Prior to the initial shipment of the study medication to the site(s), the following essential 
documents must be available in the Study Master File:  
• EC/RA approval 
• EC/RA approved subject information/informed consent form 
• Clinical study protocol signed by the principal investigator 
• Study agreement/contract signed by the principal investigator 
 
The investigator is responsible for study medication kits accountability. The site pharmacist is 
responsible for maintaining accurate records of all information relating to the management of 
the study medication. If any quality issues are noticed on receipt or use of the IMP (e.g. 
damaged condition, faults in appearance, errors in the documentation, incorrect labeling, and 
short expiry date) these should be notified promptly to the study monitor and sponsor. The 
investigator should also inform the study monitor/sponsor of any complaints about the study 
medication made by the study subjects.  
In the event of a batch recall, the sponsor or its representative will inform the investigator or 
site pharmacist in writing. Upon receipt, and as instructed, the investigator or site pharmacist 
should immediately contact any study subject in possession of the corresponding study 
medication kits.  
 
6.4 
LABELS FOR STUDY MEDICATION 
The label texts will be translated or adjusted as necessary so that they comply with the 
applicable national laws and regulatory requirements of the country in which the study will be 
conducted. The label text will include the following information as minimum: 
• Name of Sponsor 
• Name of CRO or Investigator 
• Protocol number 
• Subject screening number  
• Dosing instructions 
• Batch number 
• Expiry date 
• The words ‘For clinical study use only’ 
• The words ‘Keep out of reach of children’  

 
 
 
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• Storage conditions 
 
6.5 
PACKAGING AND DESTRUCTION 
Medication will be distributed to the subjects in plastic bottle (tesofensine) and in blisters 
(metoprolol) labeled with the appropriate study medication number. The investigator and site 
pharmacists will collect unused study medication. Klifo is responsible for central destruction 
of all study medication (partially used and unused).. Subjects will be asked to use study 
medication every morning with or right after a meal and not to crush or chew the tablets. 
Metoprolol every morning with or right after a meal and not to crush or chew the tablets and 
Tesofensine every second day. Subject will be asked to store the medication at room 
temperature (15 - 25 °C) and return the unused study medication on visit 20 at the site. 
 
6.6 
STUDY MEDICATION COMPLIANCE 
The investigational medicinal products will be self-administered by the subjects or 
parents/guardians/caregivers at home. For the monitoring of study medication, subjects or 
parents/guardians/caregivers will be instructed to return bottle and blisters with study 
medication at visit 20, whether full, partially empty, or empty. 
 
6.7 
OPEN LABEL SUBJECT NUMBER 
Subjects who sign the informed consent (together with signed informed consent form by subject’s 
parents/guardians/caregivers where applicable according to existing country legislation) will keep 
at Visit 17 their unique screening number consisting of a two (2) digit site number and three (3) 
digit subject number and country abbreviation.  
 
6.8 
UNBLINDING 
Not applicable, it is an open label study. 
 
6.9 
DISPENSATION OF STUDY MEDICATION 
A medication-dispensing log will be kept current by the investigator, detailing the dates and 
quantities of study medication dispensed to each subject. The inventory will be available to 
the monitor to verify products accountability during the study. Any unused reusable study 
medication 
either 
not 
dispensed 
or 
returned 
by 
the 
subject 
or 
subject’s 
parents/guardians/caregivers, including empty bottles/blisters will be accounted for and 
returned to the investigator and destroyed by the Klifo. 
 
6.10 
ACCOUNTABILITY OF THE STUDY MEDICATION 
The investigators will make every effort to encourage subjects together with help of subject’s 
parents/guardians/caregivers to comply with the dosage regimen. A record of the study 
medication dispensed, used and returned will be made at each visit. The investigator, his/her 
designee must maintain an adequate record of the receipt and distribution of all study 
medications using a Drug Accountability Form.  These forms must be available for inspection 
at any time. The investigator will only use the study medications within the framework of this 
clinical study and in accordance with the existing study protocol. The monitor will check and 
document the number of returned bottles/blisters on-site. The delivery to, use by and return 
from the subject or subject’s parents/guardians/caregivers must be documented. All opened 
and unopened bottles/blisters together with remaining contents will be returned by the subject 
or subject’s caregiver/guardian/parents to the site staff and maintained by the investigator in a 

 
 
 
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secure place. The site staff/ monitor will count the returned medication and document in the 
appropriate record before destruction. A written explanation must be given for any 
bottles/blisters that is missing. It is the investigator’s responsibility to instruct the subjects and 
subject’s parents/guardians/caregivers about using and returning of study medication. 
  
6.11 
CONCOMITANT MEDICATION 
Any other concomitant medication taken, as well as any changes in concomitant medication 
will be documented in the subject´s source documentation and eCRF indicating the: 
• Trade name of medication 
• Start date 
• End date / on-going 
• Route of administration 
• Total daily dose and units, and 
• Reason for administration 
 
6.12 
PROHIBITED MEDICATIONS 
For prohibited concomitant medications, please refer to Appendix 1 and Exclusion criteria. 
Paracetamol is an exception and may occasionally be taken by the subjects in the treatment of 
acute pain (e.g. headache or toothache). In such case, the subjects will be asked to keep record 
in the diary. 
 
6.13 
STUDY PROCEDURES AND OTHER EXAMINATIONS  
Informed Consent for the second OLE  
It is the responsibility of the investigator to give each subject (or, if the subjects do not have 
legal 
authority 
to 
provide 
consent 
for 
themselves 
their 
legally 
appointed 
parents/guardians/caregivers where applicable according to existing country legislation) full 
and adequate verbal and written information regarding the objective and procedures of the 
study and the possible risks involved. In pediatric subjects the patient information and 
informed consent forms will be prepared per local legislative requirements. 
  
 
The OLE ICF, approved by the RA/EC, must be given to each subject or 
parents/guardians/caregivers before any study-related procedure is undertaken. The subjects 
must be informed about their right to withdraw from the study at any time. The written 
subject/parents/guardians/caregivers information cannot be changed without prior approval by 
Sponsor and the RA/EC.  Furthermore, it is the responsibility of the investigator to obtain 
signed informed consent from all subjects (or the parents/guardians/caregivers) prior to 
undertaking any study-related procedure. Two original forms for written informed consent 
will be given to the subject/parents/guardian/caregivers for signature. One is to be kept by the 
subject/parents/guardians/caregivers and one is to be filled in the Investigator's Study File. 
  
Due to the special nature of this population, it is possible that they will have caregivers (i.e. a 
person caring for the subject but who is not authorized to provide legally relevant consent in 
relation to the subject’ participation in the study) but who, in the course of the clinical study, 
will help the subject and the study team in administering the treatment, travelling to the site, 
and conduct at home subject’ assessments in compliance with the rules of the clinical study. A 
separate written information sheet for caregivers will be prepared specifying all of the 

 
 
 
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important pieces of information for this person; the document will also explain the role of the 
caregiver in detail. By signing the informed consent the caregiver agrees that the child under 
his/her care will participate in the OLE and he/she will become involved in the clinical trial as 
well, but with limited rights.  
 
Vital Signs 
Vital signs include body temperature, respiratory rate, pulse rate and blood pressure.  
 
Physical Examination 
The physical exam includes: heart, lung, head and neck exam, and abdominal, neurological 
and dermatological exam. 
 
Blood pressure measurement   
• Subject should avoid food immediately before the measurement  
• Subject should go to the toilet before BP measurement. A full bladder can increase 
blood pressure slightly 
• Subject should sit for five minutes in a comfortable position with his/her legs and 
ankles uncrossed and his/her back supported against a chair before and during a 
measurement 
• Subject should be asked to sit quietly before and during monitoring 
• When subject is ready to take his/her blood pressure, subject should be calm and not 
think about stressful things and not to talk at all 
• Subject’s arm must be positioned properly. Same arm must be always used when 
taking subject’s blood pressure. Subject should rest his/her arm, raised the arm to the 
level of his/her heart, and put the arm on a table, desk or chair arm. If needed, a pillow 
or cushion should be placed under subject’s arm to elevate the arm high enough 
• The cuff must be placed on bare skin, not over clothing.  The appropriate sized cuff 
should be always used! 
• Three measurements should be performed, repeat the BP measurement after 3 minutes. 
If the monitor doesn't automatically log blood pressure readings or heart rates, the 
measurement should be repeated until a valid reading is available (for every time point 
there have to be three BP values), given that the procedure is accepted by the subject 
 
Body weight - subject must be undressed with the exception of underwear. 
 
Waist circumference will be measured just after subjects breathe out, in standing position, 
just above hipbones (also in underwear). 
 
Urinary pregnancy test will be done only for any women of childbearing potential at the site 
at the Day 180 and on Day 270. 
 
DEXA will be done using standardized protocol while the subjects wear light clothing at the 
Day 180 and on Day 270. 
 
HQCT - parents/guardian/caregivers will be asked during each personal visit to evaluate the  
food-seeking behavior of the subject with PW. Subjects with PWS are themselves unable to 
consistently and reliably report the severity of their hyperphagia, due to their intellectual 

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limitations. In case that the subject is not at home during the week (for ex. at boarding 
school), parents/guardian/caregivers should ask the teacher or the relevant person about 
subject’s eating behavior during the week and based on the received information, the HQCT 
should be completed.  
6.14 
LABORATORY EVALUATIONS 
Laboratory samples will be collected from subjects at the site, and will be shipped to the local 
laboratory for analysis in ambient conditions. 
The investigator will receive the data from local laboratory. Laboratory results will be 
reviewed, evaluated, signed and dated by the investigator. The investigator must evaluate all 
results outside the reference range and mark whether they are considered to be ‘clinically 
significant’ or ‘not clinically significant’. The signed and dated version of the laboratory 
report will be filed in subject’s medical file. 
The investigator´s evaluation (´normal´, ´abnormal and not clinically significant´ or ´abnormal 
and clinically significant´) will be entered into the eCRF. 
If a laboratory result is considered clinically significant and it fulfills the criteria for a clinical 
laboratory AE, it should be reported in accordance with section 6. Clinically significant 
laboratory findings from the screening visit before the randomization should be recorded as 
concomitant illness. 
The laboratory equipment may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses according to specifications in the 
laboratory standard operating procedures. Such data will not be transferred to the study 
database, but abnormal values will be reported to the investigator. The investigator must 
review all laboratory results for concomitant illnesses and AEs and report these according to 
this protocol. 
•
Hematology: blood count (erythrocytes, hemoglobin, hematocrit, leukocytes),
differential blood count (neutrophils, lymphocytes, monocytes, eosinophils, basophils) 
and platelets, will be analyzed by local laboratory 
•
Blood chemistry: creatinine, gamma glutamyl transferase, aspartate aminotransferase,
alanine aminotransferase, alkaline phosphatase, GFR and urea will be analyzed by
local laboratory
•
HbA1c will be analyzed by local laboratory
•
Lipids (total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides), serum
insulin will be analyzed by local laboratory
•
Fasting plasma glucose - will be analyzed by local laboratory
PK – plasma concentrations of tesofensine/metoprolol will be measured. Each PK blood 
sample must have time of draw attached to it as well as timing of the last dose of the study 
mediation taken prior to the blood draw. The analyses will be done by sponsor selected 
external laboratory: Bioanalytical and ADME Labs. Q2 Solutions, 19 Brown Rd, Ithaca, NY 
14850, USA. 

 
 
 
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6.15 
SUBJECTS’ DIARIES /CARDS 
Subject diaries for the second OLE on Day 180 (Visit 17) and cards will be provided. 
Subject’s caregiver/guardian/parents will be asked on behalf of subject to record in the diary 
the following: date, taking of the study medication, AEs, concomitant medication 
hypoglycemic episodes. 
. 
 
7 
SAFETY REPORTING 
All AEs occurring after the randomization of the subject will be reported as AE (if any AEs 
occurred between screening and randomization will be reported in medical history, but not as 
a AE). The report will include information on onset and stop dates, nature, severity (=grading, 
see below), seriousness, interventions and medications required, and outcome. SAEs will be 
reported to the regulatory authorities and Independent Ethics Committees (IECs) according to 
local regulations, and will be followed-up until the resolution of the event.  
At each visit, subject together with help of subject’s parents/guardians/caregivers will be 
asked:  “Do you currently (or did you) experience any symptoms that are not associated with 
your disease (since the last visit)?” Any symptom is to be entered into the Adverse Event 
eCRF. 
Laboratory or vital signs abnormalities are to be recorded as AEs only if they are medically 
relevant, i.e., symptomatic, requiring corrective study medication, leading to discontinuation 
or fulfill a criterion for an SAE. In the case of chronic disease, if the disease is known and 
documented when the subject enters the study, only worsening (increased frequency and/or 
intensity of the episodes/attacks) will be documented as an AE.  
 
7.1 
DEFINITIONS 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have a causal relationship with this treatment. An adverse event (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. This includes all unintended or 
unforeseeable signs and symptoms, and addition: 
• All suspected IMP adverse reactions 
• Psychological symptoms (including aggressive behavior against themselves or others 
that occur in a temporal association with the use of the drug or medical device, 
independent of a causal relationship with the use) 
• Apparently unrelated illnesses, including the worsening of a preexisting illness  
• Injury or accidents.  Note that if a medical condition is known to have caused the 
injury or accident (a fall secondary to dizziness), the medical condition (dizziness) and 
the accident (fall) should be reported as 2 separate adverse events.  The outcome of the 
accident (hip fracture secondary to the fall) should be recorded in source documents 
• Abnormalities in physiological testing or physical examination findings that require 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] 

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test) 
•
Laboratory abnormalities that require clinical intervention or further investigation
(beyond ordering a repeat [confirmatory] test) unless they are associated with an
already reported clinical event
Each adverse event is to be classified by the investigator as serious or non-serious. 
7.2 
ADVERSE EVENT 
All AEs encountered after the randomization will be recorded in detail indicated in the eCRF, 
regardless of their relationship to the investigational study product as assessed by the 
investigator. The investigator must record all directly observed adverse events and all adverse 
events spontaneously reported by the subject or parents/guardians/caregivers during the study. 
AEs will be coded by use of an internationally recognized dictionary (MedDRA). Details are 
described in the study specific Data Management Plan. 
7.3 
GRADING OF ADVERSE EVENT SEVERITY 
The investigator will use the adjectives MILD, MODERATE, or SEVERE to describe the 
maximum intensity of each adverse event.  For purposes of consistency, these intensity grades 
are defined as follows: 
Mild 
Does not interfere with subject’s usual age-appropriate 
instrumental* activities of daily life (ADL) 
Moderate 
Interferes with subject's usual age-appropriate instrumental* 
activities of daily life (ADL) 
Severe 
Interferes with subject's usual age-appropriate self care** 
activities of daily life (ADL) 
*Instrumental ADL refer to preparing meals, shopping for
groceries or clothes, using the telephone, managing money, etc.
**Self care ADL refer to bathing, dressing and undressing,
feeding self, using the toilet, taking medications, and not
bedridden.
7.4 
CAUSALITY OF AE 
The following scale will be used for rating the causal relationship of the AE to the 
investigational study product: 
Certain: A clinical event, including laboratory test abnormality, occurring in a plausible time 
relationship to drug administration, and which cannot be explained by concurrent disease or 
other drugs or chemicals. The response to withdrawal of the drug (dechallenge) should be 
clinically plausible. The event must be definitive pharmacologically or phenomenologically, 
using a satisfactory rechallenge procedure if necessary. 
Probable/Likely: A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, unlikely to be attributed to concurrent disease or 
other drugs or chemicals, and which follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not required to fulfill this definition. 

 
 
 
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Possible: A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, but which could also be explained by concurrent 
disease or other drugs or chemicals. Information on drug withdrawal may be lacking or 
unclear. 
Unlikely or Unrelated: A clinical event, including a laboratory test abnormality, with a 
temporal relationship to drug administration that makes a causal relationship improbable, and 
in which other drugs, chemicals or underlying disease provide plausible explanations. 
or 
The event may or may not follow a reasonable temporal sequence from administration of the 
investigational study medication and is clearly related to other factors, such as other drugs, 
chemicals, underlying disease, therapeutic intervention, or concomitant therapy. 
Actual changes in severity or causal relationship of a medical occurrence require the 
completion of a new line in the AE form in the CRF. 
 
7.5 
OUTCOME OF AE 
The outcome type and the follow-up of subjects with AEs should be specified. Outcome of 
adverse event may include at time of last observation: Recovered / resolved; Not recovered / 
not resolved; Recovered / resolved with squeal; Fatal; Unknown. 
 
AEs requiring therapy must be treated by recognized standards of medical care to protect the 
health and welfare of the subject. Appropriate equipment and medicines must be available to 
ensure the best possible treatment of emergency situations. Action(s) taken: Study treatment 
withdrawn; Dose reduced; Dose increased; Dose not changed; Unknown; Not applicable. 
 
7.6 
UNEXPECTED ADVERSE REACTION 
An Unexpected Adverse Reaction is an Adverse Drug Reaction (ADR), the nature or severity 
of which is not consistent with the applicable product information, e.g. investigator's brochure 
for an unauthorized study treatment, or Summary of Product Characteristics for an authorized 
product. 
 
7.7 
SERIOUS ADVERSE EVENT  
A serious adverse event (SAE) is any adverse event that at any dose is 
- 
Fatal 
- 
Life-threatening 
- 
Results in a persistent disability or incapacity 
- 
Results in a congenital abnormality or birth-defect 
- 
Results in or prolongs in-patient hospitalization; or 
- 
Is otherwise classified as medically significant 
Elective surgeries are not considered as SAEs and do not have to be reported as such. 
In this context, the term life threatening refers to an event in which the subject was at 
immediate risk of death at the time of the event; it does NOT refer to an event, which might 
have caused death if it would have been more severe. 

 
 
 
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In general, hospitalization signifies that the subject has been detained at the hospital or 
emergency ward (usually involving at least an overnight stay) for observation and/or 
treatment that would not have been appropriate in the physician's office or outpatient setting. 
When in doubt as to whether ‘hospitalization' occurred or was necessary, the AE should be 
considered serious. Hospitalization for elective surgery or routine clinical procedures that are 
not the result of an AE (e.g., elective surgery for a pre-existing condition) need not be 
considered AEs.  
 
Any important medical event that may not be immediately life threatening or result in death or 
hospitalization but, based upon appropriate medical judgment, may jeopardize the subject or 
may require medical or surgical intervention to prevent one of the other outcomes listed in the 
definition above should also be reported as a SAE.  Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization. 
 
Hospitalization for diagnostic or therapeutic procedures in the absence of any associated AE 
will not be considered as a SAE, except when otherwise required by Regulatory Authorities.   
 
7.8 
SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION  
A suspected unexpected serious adverse reaction is an adverse reaction that is both 
unexpected (not consistent with the applicable product information) and meets the definition 
of a Serious Adverse Event. 
 
7.9 
RECORDING OF ADVERSE EVENTS 
At each visit/assessment/call after the randomization, all adverse events, either observed by 
the investigator, or reported by the subject or parents/guardians/caregivers spontaneously, or 
reported in response to a direct question, must be evaluated by the investigator and recorded 
in subject´s source documentation and on the AE form of the eCRF. 
Pre-existing Conditions 
Pre-existing conditions or hospitalization for elective surgery or routine clinical procedures 
that are not the result of an adverse event need not be considered adverse events. Pre-existing 
condition should be recorded in subject´s source documentation and on the medical history 
form of the eCRF. 
Overdose 
An overdose of the tesofensine is defined in this study as six times of single dose and 
metoprolol as four 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.  
 
Pregnancy 
Female subjects must be instructed to notify the investigator immediately if they become 
pregnant during the study. Pregnancies occurring during the study must be reported by the 
investigational staff within 24 hours of their knowledge. Study medications will be 
immediately discontinued and study medications will not be tapered. Follow-up information 

 
 
 
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regarding the outcome of the pregnancy and any postnatal sequelae in the infant will be 
required. Pregnancy will be recorded as an AE in all cases. It will be classified as an SAE 
only if it fulfills SAE criteria. eCRF will be completed and pregnant subjects will be follow-
up until the outcome of the pregnancy has been determined.  
 
 
7.10 
REPORTING PROCEDURE OF SERIOUS ADVERSE EVENTS 
The investigator must complete and submit an SAE report for all SAEs, regardless of the 
causal relationship to study medication as soon as possible, in any case within 24 hours of 
having received information on the event. The initial report can be followed by a follow-up 
report as soon as the investigator obtains more specific information on the event.  
 
Any serious AE must be reported by investigator to the Sponsor´s delegate for 
Pharmacovigilance within 24 hr by fax or email: 
 
Address:  
Institute of Clinical Pharmacology 
Hannover Medical School, Carl-Neuberg-Str. 1 
D-30625 Hannover, Germany 
Telephone:   +49-511-532-3959 
Fax: 
 
+49-511-53216-2794 
Email:  
sae-reporting@mh-hannover.de 
 
Care should be taken to ensure that the subject's identity is protected and the subject’s 
identifiers in the clinical study are not included on any copy of source documents provided to 
the sponsor. Post-study SAEs may be reported in an expedited manner to the sponsor at the 
investigator´s discretion. 
All data updates should be recorded in the eCRF as appropriate, and further documentation as 
well as additional information (e.g. laboratory data, concomitant medication, subject status) 
should be sent (by e-mail) to the sponsor within 24 hours of knowledge. In addition, every 
effort should be made to document further any SAE that is fatal or life threatening within 1 
week (7 days) following initial notification.  
The sponsor’s delegate for pharmacovigilance will make expedited reports of all SAEs that 
are both unexpected and causally related to the IMP, to the Regulatory Authorities, IECs as 
appropriate and to the investigators at other investigational sites. In addition, the sponsor’s 
delegate for pharmacovigilance may make expedited reports of all SAEs that are expected and 
causally related to the IMPs to the Competent Authorities, according to the European 
directive 2001/20/EC and the local regulations. The sponsor’s delegate for pharmacovigilance 
will report all safety observations made during the conduct of the study in the clinical study 
report. Details of SAE case exchange between the Sponsor´s delegate for pharmacovigilance, 
the Sponsor, National Competent Authorities and Ethics Committees will be set forth in a 
separate Safety Management Plan.  
7.11 
FOLLOW-UP OF ADVERSE EVENTS  
The investigator must ensure that follow-up of the subject is appropriate to the nature of the 
event, and that follow-up continues until the event is stabilized or resolved. The investigator 

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must immediately inform the sponsor of any secondary worsening that meets at least one 
criterion for seriousness. The investigator should take all appropriate measures to ensure the 
safety of the subjects, in particular he or she should follow up the outcome of any AEs until 
they return to normal or the subject’s condition stabilizes.  
Subjects who have experienced SAEs must be followed up until clinical recovery is complete 
and laboratory results have returned to normal, or until progression has been stabilized. This 
may imply that follow-up will continue after the subject has left the clinical study and that 
additional investigations may be requested by the sponsor. If the follow-up of the subject is 
not done by the investigator him or herself (e.g. hospitalization followed by a specialist or the 
subject 's general practitioner), the investigator will do everything to establish or maintain 
contact with the person or department in charge of follow-up of the subject to obtain any 
follow-up information.  
If the investigator learns of an SAE within 30 days after the end of the study, this should be 
reported to the sponsor within 24 hours from the investigator becoming aware of the event, 
regardless of whether or not there is a causal relationship with the IMP.   
7.12 
ANNUAL SAFETY REPORTS 
Once yearly or upon request by the National Competent Authorities the Sponsor’s delegate 
for pharmacovigilance will write down an Annual Safety Report, which will adhere to the 
Development Safety Update Report (DSUR) format (ICH E2F guideline) and contain a list of 
Serious Adverse Events an analysis of the study’s subjects’ safety. This report will be sent to 
Regulatory Authorities and to the IECs in the 60 days after the anniversary of the first 
inclusion. Details of DSUR preparation, review and submission will be set forth in a separate 
Safety Management Plan.  
When the Step 2 double-blind part is completed, it will be unblinded and reported, even 
though the OLE will still be ongoing. 
8 
DESCRIPTION OF STATISTICAL METHODS 
8.1 
DESCRIPTION OF STATISTICAL METHODS 
CRO selected and designated by the Sponsor will be responsible for the statistical analysis. 
The statistical planning and conduct of analyses of the data from this study will follow the 
principles defined in relevant ICH guidelines and CRO’s biostatistical standard operating 
procedures (SOPs). A general description of the statistical methods to be used is given in this 
chapter, specific details will be provided in the Statistical Analysis Plan (SAP), which will be 
prepared before data base lock. All statistical analyses will be performed using SAS® (SAS 
Institute Inc., Cary, North Carolina, United States of America [USA]), version 9.4 or later. 
8.2 
SAMPLE SIZE CALCULATION 
As this is an explorative study no formal sample size calculation was done. Eligible patients 
are restricted to completers from step 2 in the double-blind part of the study. 
8.3 
SELECTION OF SUBJECTS FOR ANALYSES 
The following analysis sets are defined in accordance with the ICH-E9 guidance (5): 

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Full Analysis Set (FAS) 
Includes all randomized and treated subjects with post-dose data collected. Subjects in the 
FAS will contribute to the evaluation ‘as treated’ 
Per-Protocol Population (PPP):  
Includes all randomized and treated subjects without any major protocol violations. Subjects 
in the PPP will contribute to the evaluation ‘as treated’.  
Safety Analysis Set:  
Includes all subjects receiving at least one dose of the investigational product or its 
comparator. Subjects in the safety set will contribute to the evaluation ‘as treated’.   
The primary analyses of primary and secondary endpoints will be based on the FAS. 
Sensitivity analyses will be based on the PPP. The analyses of the safety endpoints will be 
based on the Safety Analysis Set.  
Before data are released for statistical analysis, a blinded review of all data will take place to 
identify protocol deviations that may potentially affect the results. Furthermore, outliers will 
be identified by data review according to ICH-E9 (5). In addition, protocol deviations, which 
may potentially affect the results, will be identified and it will be evaluated if subjects and/or 
data should be excluded from the analysis. Obviously erroneous data points may be excluded 
from the analyses. The decision to exclude data points from the statistical analysis is the joint 
responsibility of the sponsor, the investigator and the CRO statistician.  
The subjects or observations to be excluded and the reason for their exclusion will be 
documented and signed by those responsible prior to database release. The documentation 
will be stored together with the remaining study documentation. The subjects and 
observations excluded from analysis sets, and the reason for this will be described in the 
clinical study report. 
8.4 
STATISTICAL METHODS 
All primary and secondary endpoints will be summarized by treatment and visit using 
descriptive statistics. Continuous endpoints are summarized by the arithmetic mean, 
geometric mean (when applicable), median, standard deviation, coefficient of variation (CV 
when applicable), minimum and maximum value. If appropriate 95% confidence intervals for 
the mean will be given in addition Categorical endpoints are summarized by the number (N) 
and percentage (%). Moreover, complete listings of individual values for all endpoints will be 
provided. Individual and mean curves for the 24-h profiles will be plotted by treatment and 
visit over the sampling period. Further figures will be chosen and described in the SAP. 
Subject disposition will be tabulated including the numbers of screened subjects, screening 
failures, subjects exposed to study product, subjects completing the study and subjects in the 
FAS, PPP and Safety Analysis Set. Subjects withdrawn from the study will be listed including 
the primary reason for withdrawal. 

 
 
 
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8.5 
ANALYSIS OF THE PRIMARY ENDPOINT 
Primary endpoint will be summarized with mean estimate, standard deviation, range and 95% 
confidence interval for the mean. The impact of treatment allocation in the double-blind part 
will be checked graphically. 
 
8.6 
ANALYSIS 
OF 
THE 
SECONDARY 
& 
EXPLORATORY 
ENDPOINTS 
 
Continuous data will be summarized using non-missing counts, mean, standard deviation, 
median, minimum, maximum and 95% confidence interval for the mean when appropriate. 
Categorical data will be summarized using counts and percentages. The impact of treatment 
allocation in the double-blind part will be checked graphically. 
 
Tesofensine and metoprolol concentration will be summarized for each assessment point 
including measures of geometric means and coefficient of variation. The individual PK data 
collected during the double-blind (Step 2) and the open extension phases will further be 
presented graphically 
Adverse events will be coded according to MedDRA. The number and percentage of subjects 
experiencing adverse events in each treatment group will be tabulated by MedDRA system 
organ class and preferred term.  
 
Secondary endpoints evaluated will be (not a complete list): 
• 
Change from baseline to end of treatment in mean HR 
• 
Change from baseline to end of treatment in mean SBP 
• 
Change from baseline to end of treatment in mean DBP 
• 
Change from baseline to end of treatment in HQCT 
• 
Change from baseline to end of treatment in HbA1c 
• 
Change from baseline to end of treatment in insulin 
• 
Change from baseline to end of treatment in lipids 
• 
Change from baseline to end of treatment in FPG 
• 
Change from baseline to end of treatment in fasting insulin 
• 
Change from baseline to end of treatment in waist circumference 
• 
Change from baseline to end of treatment in fat- and fat-free mass 
• 
PK levels collected for tesofensine and metoprolol 
 
Other secondary endpoints may be added and will be described in the SAP. 
 
8.7 
SAFETY CRITERIA 
• 
AEs 
• 
Clinical labs (Hematology, Blood Chemistry) 
• 
ECG 
• 
Vital signs 
• 
Physical examination 
 
The safety endpoints will be based on the Safety Analysis Set. Continuous data will be 
summarized using non-missing counts, mean, standard deviation, median, minimum, and 
maximum. Categorical data will be summarized using counts and percentages. 

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9 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
Source data are all the information in original records and certified copies of original records 
of clinical findings, observations, or other activities pertaining to the study, which are 
necessary for the reconstruction and evaluation of the study. The investigator will ensure 
direct access to these source data to the study monitor, auditor, ethical committee and regulatory 
inspector. 
For each subject enrolled, the investigator will indicate in the source record(s) that the subject 
participates in this study. The investigator will maintain adequate case histories for each 
subject enrolled. Source records should be preserved for the maximum period of time 
permitted by local regulations. 
Permission for direct access to subject’s data will be sought in writing by the investigator and 
from the subject or parents/guardians/caregivers as part of the informed consent procedure. 
This gives permission to examine, analyze, verify and reproduce any records and reports that 
are important to the evaluation of the study. Any party (e.g., domestic and foreign Regulatory 
Authorities, study monitor and auditors) with direct access must take all reasonable 
precautions within the constraints of the applicable regulatory requirement(s) to maintain the 
confidentiality of the subject’s identities and sponsor’s proprietary information. It is the 
monitor’s responsibility to verify that each subject has consented, in writing, to direct access. 
It is to be ensured by the investigator that documents that are given to Saniona A/S or its 
representatives do not contain the name or address of the subject, or other information that 
would affect the anonymity of the subject. 
The investigator will enter the following data in the source records of the subject: demographic 
information, medical history, concomitant medication, clinical findings from physical 
examination, vital signs, finding from urine pregnancy tests (if applicable), notes concerning the 
study procedures, study medication and all adverse events. 
9.1 
SOURCE DATA 
Source data is information included in the original records and/or certified copies of original 
records from clinical results, observations or other activities pertaining to the study, which are 
necessary in order to reconstruct and evaluate a clinical study. The investigator will ensure 
direct access to these source data to the study monitor, sponsor’s representative, auditor, ethical 
committee and regulatory authority. 
For each enrolled subject, the investigator will specify that the subject is taking part in this 
study. The investigator will maintain adequate case histories and proper notes for each of the 
included subjects. Source data will be archived for the maximum period of time permitted by 
local requirements. 
The following documentation is considered as source documentation for this study: 
•
The informed consents and the subject’s medical files (including laboratory reports)
serve as source data
•
Subjects’ diaries

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The following information must be entered in the subject’s source documents: 
•
Subject identification number
•
Gender, body measurement
•
Medical history and concomitant illness
•
Concomitant medication
•
Unambiguous reference to the clinical study (clinical study number, subject screening
and randomization number)
•
Information on inclusion/ exclusion criteria
•
Informed consent process
•
All visit dates
•
Details of study medication administration (start and end dates, study medication
number, randomization confirmation)
•
Physical examination and result done at each visit and phone calls
•
Information about the occurrence, improvement, or worsening of AE(s)/ concomitant
illness
9.2 
SUBJECT IDENTIFICATION LIST AND SCREENING LOG 
In order to permit easy identification of the individual subject during and after the clinical 
study, the investigator is responsible for keeping an up-dated “Subject Randomization List". 
For completeness the monitor will review this document. A “Screening Log” that reports all 
subjects that were seen to determine eligibility for inclusion in the clinical study also has to be 
completed by the investigator. The Subject Screening Log and Subject Randomization Log 
may be combined in one list. 
10 
QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 
DEFINITIONS 
Quality Assurance 
A quality assurance (QA) audit as well as a regulatory inspection may be performed to 
determine if the rights and the well-being of the subjects enrolled were protected and if the 
study was conducted as per protocol, ICH GCP and applicable regulatory requirements, and if 
the data relevant for the evaluation of the investigational medicinal product were reported to 
the sponsor. The involved CRO will implement a QA system for their respective study-related 
activities. 
Quality Control 
The monitor will visit the site at periodic intervals in order to check the source data and 
records pertaining to the study, to make sure that the investigator follows the study protocol 
and to verify the completeness, correctness and accuracy of all CRF entries compared to 
source data. The investigator will offer the monitor maximum cooperation, in order to find a 
prompt solution to any possible discrepancies or inaccuracies.  

 
 
 
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10.2 
AUDITS AND INSPECTIONS 
An independent quality control unit may audit the study protocol, the documentation and, if 
applicable, the performance of the study and the clinical study report to ensure that the study 
will be performed in accordance with ICH-GCP guidelines, FDA requirements and other 
regulatory requirements. The investigator will make all study-related source data and records 
available to a medically qualified quality assurance auditor mandated by the sponsor, or to 
regulatory inspectors, after reasonable notice. The main purposes of an audit or inspection are 
to confirm that the rights and welfare of the subjects have been adequately protected, and that 
all data relevant for the assessment of safety and effectiveness of the investigational medicinal 
product have been reported to the sponsor. 
 
11 
ETHICS 
11.1 
BASIC PRINCIPLES AND ETHICAL CONSIDERATIONS 
This study will be conducted in accordance with the ethical principles that have their origins 
in the Declaration of Helsinki. The study and any subsequent amendment(s) will be reviewed 
by an Independent Ethics Committee (IEC). The study will be conducted in compliance with 
the protocol, ICH GCP regulations and the applicable regulatory requirements. The regulatory 
application or submission for regulatory approval will be made by the sponsor’s CRO as 
required by national law. 
 
11.2 
APPROVALS 
The sponsor will authorize a CRO for submitting the documents to the IEC and RA. 
 
11.3 
ETHICS COMMITTEE  
This protocol, a sample subject information sheet and informed consent form, and any other 
materials provided to the subjects and/or parents/guardians/caregivers where applicable 
according to existing country legislation will be submitted to the appropriate IEC. The study 
approval letter must be available before any subject is exposed to a study-related procedure, 
including screening tests for eligibility. During the study, the following documents will be 
sent to the IEC for their review: 
• Changes to the Investigator’s Brochure 
• Reports of adverse events that are serious, unlisted and associated with the IMP  
• All protocol amendments and revised informed consent forms (if any) 
The sponsor’s CRO will provide a safety update of the study to the local IEC including line 
listings, individual reports of SUSARs, if applicable, and a discussion of AEs annually, or 
more frequently if requested based on valid legislation requirements. At the end of the study, 
the investigator will notify the IEC/RA about the study completion. Furthermore, he/she will 
provide the synopsis of the final report to the RA/IEC within one year after the end of the 
clinical study.  
 
11.4 
REGULATORY AUTHORITY 
The study including all relevant documentation and information need to be submitted to the 
relevant Regulatory Authority for notification or approval according to valid legislation 
requirements. 
 

 
 
 
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11.5 
PROTOCOL MODIFICATIONS 
If it turns out during the study that some procedures cannot be conducted according to the 
clinical study protocol, the principal investigator has to be informed immediately by the study 
personnel. The principal investigator will be responsible for informing the clinical monitor or 
the clinical project manager of the issue. It will then be decided if a protocol amendment has 
to be written and approved by the RA/IEC before the study can continue. Any amendment 
becomes part of the clinical study protocol. 
 
The amended protocol will be approved and signed by the relevant personnel at Saniona A/S 
and by the principal investigator. The investigator should not implement any deviation from, 
or changes of the protocol, without agreement by Saniona A/S and prior review and 
documented approval/favorable opinion of the appropriate IEC and, if legally required, 
Regulatory Authority, except where necessary to eliminate an immediate hazard to the 
subjects, or when the change(s) that were approved by Saniona A/S involve only logistical or 
administrative aspects of the study. 
 
11.6 
SUBJECT INFORMATION AND INFORMED CONSENT 
RA/IEC approval of the written Subject Information and Informed Consent (for subjects/ 
parents/guardians/caregivers where applicable according to existing country legislation) must 
be obtained prior to their use. This consent form contains a phrase by which consent is given 
for the access to the non-personalized data by the sponsor, national and regulatory authorities. 
In addition, it states that the subject is free to withdraw from the study at any time without any 
negative consequences. The Subject Information gives a complete and comprehensive 
explanation of the significance, nature, extent and possible risks of the study.  
The informed consent form must be signed, with name and date noted by the subject and/or 
parents/guardians/caregivers where applicable according to valid country legislation. The 
investigator will complete the informed consent section of the eCRF for each subject enrolled. 
If new information becomes available that potentially affects the subject’s safety or 
willingness to continue in the study, or if a protocol amendment is issued that affects subject’s 
safety, study procedures or any aspects of the study that may influence the subject’s 
willingness to continue in the study, the subject information leaflet and informed consent 
form will be revised. After the new documents have received approval from the RA/IEC in 
accordance with applicable regulations, the subject/parents/guardians/caregivers where 
applicable according to existing country legislation will be asked to sign the new consent 
form to confirm his or her willingness to continue in the study. 
 
Each subject and/or parents/guardians/caregivers will be informed that his/her source records 
may be reviewed by the monitor, a quality assurance auditor or an IEC/Regulatory Authority 
inspector, in accordance with applicable regulations. All personal information which the 
subject will reveal to the investigator and which does not pertain to the study will be considered 
confidential. 
 

 
 
 
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11.7 
PARTICIPANT CONFIDENTIALITY 
The investigator will ensure that the subject's anonymity will be preserved. On eCRFs or any 
other documents submitted to the sponsor, the subjects will not be identified by their names, 
but by a study specific identification code. Documents not intended for the sponsor, i.e. the 
confidential subject identification code, original consent forms and source records will be 
maintained by the investigator as strictly confidential and in a secured place. The subjects will 
be informed that all their study results will be handled in strictest confidence. 
 
12 
DATA HANDLING AND RECORD KEEPING 
12.1 
DATA COLLECTION AND DOCUMENTATION 
Relevant study data for statistical analysis and study report are to be recorded in the eCRFs. 
Subject’s data have to be reported on the eCRFs in an anonymous fashion, the subject only 
being identified by the subject number. The investigator will be responsible for the 
completeness, accuracy and legibility of the information in the eCRF and other study 
documents. The study monitors then have to check the eCRFs against the source documents 
for accuracy and validity as per the monitoring schedule, as applicable. Upon completion of 
the examination, eCRF completion is expected at each Unit to ensure quality of data and 
subject safety. Once eCRFs are completed, they will be available for review by the study 
monitor and CRO Clinical Data Management. Completed eCRFs will be reviewed remotely 
for logical discrepancies. The study monitor will ensure that all data queries and subsequent 
amendments in the eCRF documentation are made according to GCP guidelines. 
 
12.2 
STUDY MONITORING, SOURCE DATA VERIFICATION AND 
DATA MANAGEMENT  
Clinical Data Management is the responsibility of the CRO. All Data Management procedures 
will be detailed in a separate document known as the Data Management Plan (DMP). The 
DMP will also describe the Clinical Data Management System (CDMS) that will be used to 
collect data with an electronic Case Report Form (eCRF) in detail. For each enrolled study 
participant an eCRF will be maintained. ECRFs must be kept current to reflect subject status 
at each phase during the course of study. Data on subjects collected on eCRFs during the 
study will be documented in an anonymous fashion and contains an electronic audit trail.  
In compliance with 21 CRF part 11 each user of the CDMS will be assigned a unique user 
name and will be allocated to a special user role. This special user role controls the user’s 
permissions in the electronic data capture system depending on the function within the study. 
All staff involved in the study in each site has to be instructed how to maintain the eCRF and 
therefore be able to edit eCRF entries. The investigator will be responsible for the 
completeness, accuracy and legibility of the information in the eCRF and other study 
documents. The study monitors then have to check the eCRF against the source documents for 
accuracy and validity as per the monitoring schedule, as applicable. Upon completion of the 
examination, eCRF completion is expected at each site to ensure quality of data and subject 
safety. Once eCRFs are completed, they will be available for review by the study monitor and 
CRO Clinical Data Management. Completed eCRFs will be reviewed remotely for logical 
discrepancies. The study monitor will ensure that all data queries and subsequent amendments 
in the eCRF documentation are made according to GCP guidelines. 
 

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12.3 
DATA MANAGEMENT PLAN  
The complete Data Management process will be described in detail and agreed on in the Data 
Management Plan for this study. 
12.4 
CASE REPORT FORMS (CRFS) 
The Data Management Department will provide the eCRFs. All further information regarding 
the eCRFs and the data flow will be described and agreed on in the Data Management Plan 
for this study. 
Database Lock 
After all data are entered, all queries are solved and quality control procedures have been 
completed respectively each subject’s evaluability is determined, the database will be 
authorized for lock. Electronic case report form data per site will be provided to the 
responsible investigator at the end of the study and will need to be retained by the 
investigator. The complete data will be provided to the sponsor at the close of the study for 
archiving. 
In exceptional circumstances, when critical reasons justify, there may be a need to perform 
updates to the database after it has been locked. A database that is locked and released for 
analysis will only be unlocked if an error is identified that will significantly affect the 
statistical outcome of the analysis of the efficacy parameters or change the safety profile of 
the study.  
12.5 
INVESTIGATOR FILE 
The investigator will be responsible for keeping all records so that the course of the study is 
duly documented. Copies of essential documents related to the study must be filed by the 
investigator as required by ICH GCP and applicable regulatory requirements. No document 
concerning the study may be destroyed without prior written agreement between the 
investigator and the sponsor. Should the investigator elect to assign the study documents to 
another party, or to move them to another location, the sponsor must be informed without 
delay. 
12.6 
LOGS 
The investigator or/and site pharmacists will be responsible for recording and keeping all 
records regarding study medication shipment; dispensing and accountability records and these 
must be filed by the investigator as required by GCP and applicable regulatory requirements. 
The investigator will ensure an adequate confidentiality of the subjects' identification list 
providing the only connection between source data, and anonymous data in the eCRF for the 
sponsor. The investigator will ensure that this secret list is maintained securely for a period of 
15 years at minimum. 
12.7 
PROTOCOL COMPLIANCE 
The investigator agrees by signing the protocol that the study will be conducted in compliance 
with the protocol, ICG GCP and the applicable regulatory requirements. 
12.8 
RECORD KEEPING 
To enable evaluations and/or audits from regulatory authorities or Sponsor, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 

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information to link records, e.g., case report forms and hospital records), all original signed 
informed consent forms, copies of all case report forms, source documents, and detailed 
records of treatment disposition.  The records should be retained by the investigator according 
to local regulations or as specified in the Clinical Trial Agreement, whichever is longer. 
If the investigator relocates, retires, or for any reason withdraws from the study, Sponsor 
should be prospectively notified.  The study records must be transferred to an acceptable 
designee, such as another investigator, another institution, or to Sponsor.  The investigator 
must obtain Sponsor’s written permission before disposing of any records. 
13 
FINANCE AND INSURANCE 
13.1 
COMPENSATION TO INVESTIGATOR 
Financial contracts will be signed between the sponsor and the investigator (or a 
representative of the hospital/clinic/unit) before commencement of the study.  
13.2 
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 Saniona A/S together with help of the contracted CRO.  
14 
PUBLICATION POLICY 
14.1 
REPORTING AND PUBLICATION 
CRO will prepare a study report 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. In accord with 
standard editorial and ethical practice, the sponsor will support publication of multicentre 
studies only in their entirety and not as individual site data. Sites or investigators must not 
publish any data from this study without obtaining prior written permission from the Sponsor. 

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15 
REFERENCES 
1. https://ghr.nlm.nih.gov/condition/prader-willi-syndrome
2. Astrup A, Madsbad S, Breum L, et al. Effect of tesofensine on bodyweight loss, body
composition, and quality of life in obese patients: a randomised, double-blind,
placebo-controlled trial. Lancet 2008;372:1916-1913.
3. Bentzen BH, Grunnet, M, Hyveled-Nielsen, L. Anti-Hypertensive Treatment
Preserves Appetite Suppression While Preventing Cardiovascular Adverse Effects of
Tesofensine in Rats. Obesity 2013;21:985-992.
4. ICH Harmonised Tripartite Guideline. Good Clinical Practice [Internet]. 1996 [cited
2015 Oct 28]. Available from:
https://firstclinical.com/regdocs/doc/?db=ICH_E6_Good_Clinical_Practice

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16 
Appendices 
16.1
Appendix I: table of recommended concomitant medication use 
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 
Y 
N 
Prohibited for 2 weeks prior to 
randomisation, however, hypnotics 
and/or anxiolytics at a stable dose 
for at least 4 weeks prior to 
screening and up to the follow-up 
visit could be allowed, i.e.up to 
zolpidem (10 mg/day), choral 
hydrate (1 g/day), triazolam (0.5 
mg/day), or lorazepam (1 mg/day) 
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 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 
Drug Class 
Episodic Use 
Chronic Use 
Comment 
Tricyclic antidepressants 
N 
N 
Drug inducing ocular toxicity Chloroquine 
Hydrochloroquine 
N 
N 
Non-drugs 

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Weight loss supplements 
N 
N 
Anti-depression, anxiety, epilepsy, psychotics OTC, 
supplements  
N 
N 
16.2
STUDY FLOW CHART: VISITS 17 - 21 (all visits are ±3 day) 
Visit 
17 
Equal to last visit 
of first OLE 
Treatment 
18 
Treatment 
19 
Treatment 
20 
End of 
Treatment 
21 
End of study 
Day 
180 
210  (30 
days ± 3 
days) 
240 (30 
days ± 3 
days) 
270 (30 
days ± 3 
days) 
300 (30 days 
± 3 days) 
Obtaining second 
Addendum to double blind 
ICF for the second OLE part 
x 
Subject screening number 
(keeping the same as in Step 
2 and the first OLE) 
x 
Psychiatric examination 
x 
x 
x 
x 
x 
Physical examination 
x 
x 
Vital signs 
x 
x 
x 
x 
x 
Weight, waist circumference 
x 
x 
x 
x 
x 
Height, calculation of BMI 
x 
HQCT 
x 
x 
x 
x 
x 
ECG 
x 
x 
Hematology 
x 
x 
Blood chemistry 
x 
x 
FPG, HbA1c 
x 
x 
x 
x 
Lipids, insulin 
x 
x 
x 
x 
DEXA 
x 
x 
PK sample 
x** 
x** 
x** 
x** 
x 
Drug dispensation and 
accountability 
x 
x 
x 
*x

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AEs 
x 
x 
x 
x 
x 
Concomitant medication 
x 
x 
x 
x 
x 
Urinary pregnancy test 
x 
x 
Diary dispensation, Subject 
card for OLE dispensation 
x 
Diary review 
x 
x 
x 
x 
Diary collection 
x 
x 
Dispense Follow-up diary 
list 
x 
End of study form 
x 
*two half doses of metoprolol should be dispensed
** Blood samples of metoprolol taken 2 and 4 hours after dose administration – to be done only
once in each patient during the study, if not done during the first OLE. Time point for dosing
and the two blood samples should be noted!
Phone calls in-between the onsite visits will be used to provide additional reassurance 
regarding the safety of the subjects and collect adverse events. 
Visit 
17.1 
Phone call 
18.1 
17 
Ph
one 
call 
19.1 
Phone call 
20.1 
Phone call 
Frequency 
Once per month 
Once per month 
Once per month 
Once per month 
AEs 
X 
X 
X 
X 
Hypoglycemic episodes (at 
DM subjects) 
X 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 

 
 
 
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17.1 
Hyperphagia Questionnaire for Clinical Trials (HQ-CT) 
Instructions: 
The following items refer to the person in your care and assessment of his/her food-related 
behavior during the past 2 weeks.     
 
 
 (1) During the past 2 weeks, how upset did the person generally become when denied a 
desired food? 
□ Not at all upset  
□ A little upset 
□ Moderately upset 
□ Very upset 
□ Extremely upset 
 
(2) During the past 2 weeks, how often did the person try to bargain or manipulate to get more 
food at meals? 
□ Never 
□ Up to 2 times a week 
□ 3 to 6 times a week 
□ Every day 
□ Several times a day 
 
 
(3) During the past 2 weeks, how often did the person forage through trash for food? 
□ Never 
□ 1 time 
□ 2 times 
□ 3 times 
□ 4 or more times 
 
(4) During the past 2 weeks, how often did the person get up at night to food seek? 
□ Never 
□ 1 time 
□ 2 times 
□ 3 times 
□ 4 or more times 
 
 
 

 
 
 
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(5) During the past 2 weeks, how persistent was the person in asking or looking for food after 
being told “no” or “no more”? 
□ Not at all persistent 
□ A little persistent 
□ Moderately persistent 
□ Very persistent 
□ Extremely persistent 
 
(6) During the past 2 weeks, outside of normal meal times, how much time did the person 
generally spend asking or talking about food? 
□ Less than 5 minutes a day 
□ 5 to 15 minutes a day 
□ 15 to 30 minutes a day 
□ 30 minutes to 1 hour a day 
□ More than 1 hour a day 
 (7) During the past 2 weeks, how often did the person try to sneak or steal food (that you are 
aware of)? 
□ Never 
□ 1 time 
□ 2 times 
□ 3 times 
□ 4 or more times 
 
(8) During the past 2 weeks, when others tried to stop the person from asking about food, how 
distressed did he or she generally appear?  
□ Not at all distressed  
□ A little distressed 
□ Moderately distressed 
□ Very distressed 
□ Extremely distressed 
 
(9) During the past 2 weeks, how often did food-related behavior interfere with the person’s 
normal daily activities, such as self-care, recreation, school, or work? 
□ Never 
□ Up to 2 times a week 
□ 3 to 6 times a week 
□ Every day 
□ Several times a day 
 
 

 
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CLINICAL STUDY PROTOCOL 
 
 
A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, 
MULTIPLE-DOSE, MULTI-CENTER SAFETY AND EFFICACY STUDY OF 
CO-ADMINISTRATION OF TESOFENSINE/METOPROLOL IN SUBJECTS 
WITH PRADER-WILLI SYNDROME  
“SECOND 12 WEEKS OPEN LABEL EXTENSION” 
 
 
  
  
 
 
Sponsor:  
 
 
Saniona, A/S 
 
 
 
Baltorpvej 154 
 
 
 
DK2750 Ballerup 
 
 
 
Denmark 
 
 
 
 
 
Protocol number: 
 
TM002 
EudraCT number: 
 
2016-003694-18 
 
 
 
 
 
 
 
 
 
 
 
The information contained in this document is provided in confidence. It is understood that 
this information will not be disclosed to others without prior agreement with Saniona A/S, 
according to the statement in the clinical study protocol, and in accordance with the 
confidentiality agreement. 
The information contained in this document is provided in confidence. It is understood that 
this information will not be disclosed to others without prior agreement with Saniona A/S, 
according to the statement in the clinical study protocol, and in accordance with the 
confidentiality agreement. 

 
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CLINICAL STUDY PROTOCOL SYNOPSIS  
 
Study Title 
A double-blind, randomized, placebo-controlled, multiple-dose, 
multi-center safety and efficacy study of co-administration of 
tesofensine/metoprolol in subjects with Prader-Willi syndrome 
“Second 12 weeks open label extension” 
Study Sponsor 
Saniona, A/S 
Baltorpvej 154 
DK2750 Ballerup 
Denmark 
Study Phase 
2a 
Number of sites 
2 sites; one in Czech Republic and one in Hungary  
Number of subjects 
Subjects who completed the first open label phase phase (12 
weeks) will be invited to participate in second open label 12 
weeks extension phase. 
A subject’s participation in the second 12 weeks open label 
extension (OLE) study will be based on the Investigators’ 
judgment on whether or not it is safe for the subject to continue 
in the extension study. 
Study design 
Two-centre, multiple-dose clinical study. The second open 
label 12 weeks extension study will be initiated immediately 
during the Visit 17 (Day 180) of the first OLE part (12 weeks), 
which will then become the baseline visit of the second OLE, 
and study medication will be administered, without 
interruption, for another 90 days.  
 Previously approved part: Step 2 – 5-15 children with 
PWS. Study medication (0.125/25 mg) was 
administered for ninety one (91) days (+2 days after the 
final assessments with half-dose of metoprolol) in those 
who did not continue in the OLE) and first OLE where 
all eligible patients have been receiving 0.125/25 mg). 
  
 Second open label extension: All subjects who 
completed the first OLE and are deemed eligible by the 
Investigators will be invited to participate in the second 
open label extension for another 12 weeks followed by a 
final visit one month after the last dose of the study 
medication for a safety review and PK sampling. 
 
 Those patients who refuse to participate in the second 
OLE, or are not deemed eligible by the Investigators, 
will complete the final visit (Visit 18) 1 month after the 

 
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last dose in the first OLE is taken (Visit 17). 
Study timelines  
Q3 2018 – Q2 2019 
Study treatment and 
Dosing schedule 
In the second open label extension all subjects deemed 
eligible by the PI will receive:  tesofensine 0.125 mg (0.25 mg 
every second day) + metoprolol ER 25 mg (Metoprolol Orion 
25 mg) administered once a day, in the morning with a meal. 
Those 
patients 
who 
tolerated 
the 
0.125/25 
mg 
tesofensine/metoprolol dose well in the first OLE will receive 
0.25 mg of tesofensine with 25 mg of metoprolol ER.   
 In case a patient, in the opinion of the PI, experiences an 
adverse event that by the PI are suspected to be potentially 
related to 
an undesirable drug concentration 
of the 
investigational medication, the investigators at each site, based 
on their discretion, can extend the period between dosages of 
the IMP or implement a drug holiday, or reduce the dose (those 
on 0.25 mg of tesofensine) in order to optimally manage the 
wellbeing and safety of the patient. Each of theses cases should 
be discussed in advance with the Sponsor’s medical monitor. 
Each tablet will be formulated separately; a currently available 
commercial formulation of extended-release metoprolol will be 
used. 
Study objectives  
  
Primary objective: 
 To examine the effect of co-administration of 
tesofensine/metoprolol on body weight in subjects with 
PWS in an open labeled extension study 
Secondary objectives: 
 To establish pharmacokinetic profile of tesofensine and 
metoprolol in subjects with PWS  
• 
To examine the change in hyperphagia-related behavior 
in subjects with PWS by use of the Hyperphagia 
Questionnaire for Clinical Trials (HQ-CT) 
 To examine the effect of co-administration of 
tesofensine/metoprolol on glycaemic control and lipid 
profile in subjects with PWS 
 To examine the effect of co-administration of 
tesofensine/metoprolol on HR and BP in   subjects with 
PWS 
 To examine the effects of co-administration of 
tesofensine/metoprolol 
on 
body 
composition 
in  
subjects with PWS 
 To evaluate overall safety and tolerability of co-
administration 
of 
the 
tesofensine/metoprolol 
in  
subjects with PWS 
Study population 
(inclusion/exclusion 
criteria) 
All male and female pediatric subjects with confirmed 
diagnosis of PWS who completed the double blind phase (12 

 
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weeks) and the first OLE, will be invited to participate in the 
second open label 12 weeks extension phase, if deemed eligible 
by the Investigators. 
 If subject/parents decide to not participate in OLE, subject will 
finish the study based by completing the study as described 
previously. 
Study procedures 
Subjects who have completed the first OLE will continue in the 
second open label extension, starting on Visit 17 (Day 180) for 
another 12 weeks.   
Study procedures in the second OLE are the same as during the 
first OLE.  
Subjects will be invited for the monthly visits (30 days ± 3 
days) to the site for safety evaluations, and some additional 
efficacy assessments and PK (see the schedule of events for 
details). (Visit 18 Day 210; Visit 19 Day 240) 
Between the on-site visits one phone call follow up will be 
performed once per month. 
 
On Day 270 (Visit 20) the subjects will be given two days of 
half dose of metoprolol to take at home in order to gradually 
reduce the dose of metoprolol and avoid potential undesirable 
fluctuation in blood pressure. 
On Day 300 (Visit 21)  the subjects will be invited for the final 
safety check, BP/HR assessment and PK sampling (30 days 
after last dose), which will conclude their participation in the 
study.   
 
Subjects who exceed predefined values of HbA1c (>10%), FPG 
>11.0 mmol/l) or BP>160/100 mmHg will be treated at the 
discretion of the investigator per established guidelines to 
improve the subjects glycaemic/BP control while remaining in 
the study. 
Assessments conducted during each visit are described in the 
schedule of events.  
Statistics 
The primary endpoint (percent change in body weight) will be 
summarized with mean estimate, standard deviation, range and 
95% confidence interval for the mean. Impact of treatment 
allocation in the double-blind part will be checked graphically. 
Safety analyses will include all participants who took at least 
one dose of IMP and efficacy analyses all treated participants 
with post-dose data recorded (full analysis set). Continuous 
data will be summarized using non-missing counts, mean, 

 
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standard deviation, median, minimum, maximum and, if 
appropriate, 95% confidence interval for the mean. Categorical 
data will be summarized using counts and percentages. 
Adverse events will be coded according to MedDRA. The 
number and percentage of subjects experiencing adverse events 
in each treatment group will be tabulated by MedDRA system 
organ class and preferred term.  
 
Sample size estimate, power calculation: 
As this is an exploratory study, no formal sample size or power 
calculation was performed. Eligible patients are restricted to the 
completers from the first OLE. 
 
 
 

 
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INVESTIGATOR STATEMENT 
 
 
TM002: A double-blind, randomized, placebo-controlled, multiple-dose, multi-center safety 
and efficacy study of co-administration of tesofensine/metoprolol in subjects with Prader-
Willi syndrome “Second 12 weeks open label extension”. 
 
I understand that this Clinical Study Protocol contains information that is confidential and 
proprietary to Saniona A/S. I hereby declare, that I will keep all information obtained from my 
participation in this Clinical Study confidential unless otherwise agreed in writing. 
 
I have read the Clinical Study Protocol and I understand the information. With my signature, I 
agree to conduct this Study in accordance with the protocol, ICH-GCP guidelines, Declaration 
of Helsinki and with all applicable local law and regulatory requirements.  
 
I will discuss the contents of this Clinical Study Protocol to all those authorized study staff, 
which will assist me in conducting this study in order to ensure that they are fully informed 
about the Investigational Medicinal Product and the course of the Study. 
 
If required, I will also provide necessary protocol information to the responsible Ethics 
Committee and/or to the Regulatory Authorities under the following condition: the contents of 
this Clinical Study Protocol will not be used in any other clinical study and may not be 
disclosed to any other person or entity without prior written permission of Saniona A/S. 
 
Any supplemental information that may be added to this document is also confidential and 
proprietary to Saniona A/S and must be kept in confidence in the same manner as the contents 
of this Clinical Study Protocol. 
 
____________________________________________________________________ 
 
Principle Investigator 
Signature: 
Date: 
 
 

 
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SIGNATURE PAGE 
 
 
TM002: A double-blind, randomized, placebo-controlled, multiple-dose, multi-center safety 
and efficacy study of co-administration of tesofensine/metoprolol in subjects with Prader-
Willi syndrome “Second 12 weeks open label extension”. 
 
We hereby declare that this Clinical Study Protocol was prepared scientifically accurately and 
in full compliance with the current regulatory guidelines. 
With our signatures, we agree to conduct the Study in accordance with the protocol, ICH-
GCP guidelines, Declaration of Helsinki and with all applicable local law and regulatory 
requirements. Moreover, we will keep all information obtained in this Study confidential 
unless otherwise agreed in writing. 
 
 
Jørgen Drejer, PhD 
___________________________________________________________________ 
 
CEO 
Signature: 
Date: 
Saniona, A/S 
Baltorpvej 154 
DK2750 Ballerup 
Denmark 
 
 
Roman V Dvorak, MD, PhD 
____________________________________________________________________ 
 
Chief Medical Officer 
Signature: 
Date: 
Saniona, A/S 
Baltorpvej 154 
DK2750 Ballerup 
Denmark 
 
 
Leontina Levenzon, M. Sc. 
____________________________________________________________________ 
 
Biostatistician 
Signature: 
Date: 
GCP-Service International Ltd. & Co.KG 
Anne-Conway-Str. 2 
28359 Bremen 
Germany 

 
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TABLE OF CONTENTS 
 
2 
ABBREVIATIONS INDEX _____________________________________________________________ 11 
3 
INTRODUCTION AND STUDY RATIONALE _____________________________________________ 12 
3.1 
CLINICAL BACKGROUND ________________________________________________________ 12 
4 
STUDY OBJECTIVES AND ENDPOINTS_________________________________________________ 14 
4.1 
OBJECTIVES ____________________________________________________________________ 14 
4.2 
ENDPOINTS (Baseline = Day 0; End of double-blind treatment = Day 90, end of first OLE = Day 
180, end of second OLE = Day 270) ________________________________________________________ 14 
5 
OVERALL STUDY DESCRIPTION ______________________________________________________ 15 
5.1 
STUDY VISIT DESCRIPTION ______________________________________________________ 16 
Visit 21 (Day 300 (30±3 days)) ) Final follow-up –– personal visit _______________________________ 18 
End of study (Day 300) _________________________________________________________________ 18 
5.2 
END OF STUDY __________________________________________________________________ 19 
5.3 
STUDY PARTICIPANTS __________________________________________________________ 19 
5.4 
DISCONTINUATION CRITERIA ___________________________________________________ 19 
5.5 
WITHDRAWAL CRITERIA________________________________________________________ 19 
5.6 
PREMATURE STUDY DISCONTINUATION _________________________________________ 20 
5.7 
EARLY TERMINATION OF A STUDY SITE _________________________________________ 20 
5.8 
STUDY SITES ____________________________________________________________________ 20 
5.9 
STUDY DURATION _______________________________________________________________ 20 
5.10 
TOTAL STUDY DURATION ______________________________________________________ 20 
5.11 
BENEFITS AND RISKS FOR STUDY PARTICIPANTS _______________________________ 20 
6 
TREATMENT OF STUDY PARTICIPANTS= identical to the first OLE _________________________ 22 
6.1 
DESCRIPTION OF STUDY MEDICATION __________________________________________ 22 
Investigational Medicinal Product ________________________________________________________ 22 
6.2 
IMP HANDLING PROCEDURES - KLIFO ___________________________________________ 22 
6.3 
IMP HANDLING PROCEDURES – STUDY SITE _______________________________________ 22 
6.4 
LABELS FOR STUDY MEDICATION _______________________________________________ 23 
6.5 
PACKAGING AND DESTRUCTION ________________________________________________ 23 
6.6 
STUDY MEDICATION COMPLIANCE ______________________________________________ 24 
6.7 
OPEN LABEL SUBJECT NUMBER _________________________________________________ 24 
6.8 
UNBLINDING ____________________________________________________________________ 24 
6.9 
DISPENSATION OF STUDY MEDICATION _________________________________________ 24 
6.10 
ACCOUNTABILITY OF THE STUDY MEDICATION ________________________________ 24 
6.11 
CONCOMITANT MEDICATION __________________________________________________ 24 
6.12 
PROHIBITED MEDICATIONS ____________________________________________________ 25 
6.13 
STUDY PROCEDURES AND OTHER EXAMINATIONS ______________________________ 25 
Informed Consent for the second OLE _____________________________________________________ 25 
Vital Signs ___________________________________________________________________________ 25 
Physical Examination __________________________________________________________________ 25 
Blood pressure measurement ____________________________________________________________ 25 

 
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6.14 
LABORATORY EVALUATIONS __________________________________________________ 26 
6.15 
SUBJECTS’ DIARIES ____________________________________________________________ 27 
7 
SAFETY REPORTING _________________________________________________________________ 27 
7.1 
DEFINITIONS ___________________________________________________________________ 28 
7.2 
ADVERSE EVENT ________________________________________________________________ 28 
7.3 
GRADING OF ADVERSE EVENT SEVERITY ________________________________________ 28 
7.4 
CAUSALITY OF AE ______________________________________________________________ 29 
7.5 
OUTCOME OF AE ________________________________________________________________ 29 
7.6 
UNEXPECTED ADVERSE REACTION ______________________________________________ 30 
7.7 
SERIOUS ADVERSE EVENT _______________________________________________________ 30 
7.8 
SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION ________________________ 30 
7.9 
RECORDING OF ADVERSE EVENTS _______________________________________________ 30 
Pre-existing Conditions _________________________________________________________________ 31 
Overdose ____________________________________________________________________________ 31 
Pregnancy ___________________________________________________________________________ 31 
7.10 
REPORTING PROCEDURE OF SERIOUS ADVERSE EVENTS ________________________ 31 
7.11 
FOLLOW-UP OF ADVERSE EVENTS ______________________________________________ 32 
7.12 
ANNUAL SAFETY REPORTS _____________________________________________________ 32 
8 
DESCRIPTION OF STATISTICAL METHODS ____________________________________________ 33 
8.1 
DESCRIPTION OF STATISTICAL METHODS _______________________________________ 33 
8.2 
SAMPLE SIZE CALCULATION ____________________________________________________ 33 
8.3 
SELECTION OF SUBJECTS FOR ANALYSES _______________________________________ 33 
8.4 
STATISTICAL METHODS _________________________________________________________ 34 
8.5 
ANALYSIS OF THE PRIMARY ENDPOINT __________________________________________ 34 
8.6 
ANALYSIS OF THE SECONDARY & EXPLORATORY ENDPOINTS ___________________ 34 
8.7 
SAFETY CRITERIA ______________________________________________________________ 35 
9 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ______________________________________ 35 
9.1 
SOURCE DATA __________________________________________________________________ 35 
9.2 
SUBJECT IDENTIFICATION LIST AND SCREENING LOG ___________________________ 36 
10 QUALITY CONTROL AND QUALITY ASSURANCE ________________________________________ 36 
10.1 
DEFINITIONS __________________________________________________________________ 36 
Quality Assurance _____________________________________________________________________ 36 
Quality Control _______________________________________________________________________ 37 
10.2 
AUDITS AND INSPECTIONS _____________________________________________________ 37 
11 ETHICS _____________________________________________________________________________ 37 
11.1 
BASIC PRINCIPLES AND ETHICAL CONSIDERATIONS ____________________________ 37 
11.2 
APPROVALS ___________________________________________________________________ 37 
11.3 
ETHICS COMMITTEE ___________________________________________________________ 37 
11.4 
REGULATORY AUTHORITY _____________________________________________________ 38 
11.5 
PROTOCOL MODIFICATIONS ___________________________________________________ 38 
11.6 
SUBJECT INFORMATION AND INFORMED CONSENT _____________________________ 38 

 
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11.7 
PARTICIPANT CONFIDENTIALITY ______________________________________________ 39 
12 DATA HANDLING AND RECORD KEEPING _____________________________________________ 39 
12.1 
DATA COLLECTION AND DOCUMENTATION ____________________________________ 39 
12.2 
STUDY MONITORING, SOURCE DATA VERIFICATION AND DATA MANAGEMET ___ 39 
12.3 
DATA MANAGEMENT PLAN _____________________________________________________ 39 
12.4 
CASE REPORT FORMS (CRFS) ___________________________________________________ 40 
12.5 
INVESTIGATOR FILE ___________________________________________________________ 40 
12.6 
LOGS __________________________________________________________________________ 40 
12.7 
PROTOCOL COMPLIANCE ______________________________________________________ 40 
12.8 
RECORD KEEPING _____________________________________________________________ 40 
13 FINANCE AND INSURANCE __________________________________________________________ 41 
13.1 
COMPENSATION TO INVESTIGATOR ____________________________________________ 41 
13.2 
INSURANCE AND INDEMNITY ___________________________________________________ 41 
14 PUBLICATION POLICY _______________________________________________________________ 41 
14.1 
REPORTING AND PUBLICATION ________________________________________________ 41 
15 REFERENCES _______________________________________________________________________ 42 
16 Appendices ___________________________________________________________________________ 43 
16.1 
Appendix I: table of recommended concomitant medication use __________________________ 43 
16.2 
STUDY FLOW CHART: VISITS 17 - 21 (all visits are ±3 day) ___________________________ 44 
16.3 
Hyperphagia Questionnaire for Clinical Trials (HQ-CT) ________________________________ 46 
 
 
 

 
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2 
ABBREVIATIONS INDEX 
ADR 
Adverse Drug Reaction 
RA 
Regulatory Authority 
ALT 
Alanine Aminotrasferase 
kg 
Kilogram 
ANCOVA 
Analysis of co-variance 
l 
Liter 
AST 
Aspartate Aminotrasferase 
LDL 
Low-density lipoprotein 
ATC 
Anatomical Therapeutic Chemical Classification 
LPLV 
Last Patient Last Visit 
AUC 
Area Under the Plasma Concentration  
MedDRA 
Medical Dictionary for Regulatory 
Activities 
A/S 
Aktieselskab 
MDD 
Major Depressive Disorder 
BMI 
Body Mass Index 
mg 
Milligram 
BP 
Blood Pressure 
mL 
Milliliter 
Bpm 
Beats per minute 
mmHg 
Millimeter of mercury 
BMI 
Body Mass Index 
mmol 
Millimol 
CI 
Confidence Interval  
N 
No 
Cm 
Centimeter 
N (No) 
Number 
Cmax 
Maximum measured plasma concentration  
ng 
Nanogram 
CRF 
Case Report Form 
NYHA 
New York Heart Association 
CRO 
Contract Research Organization 
OLE 
Open Label Extension 
CYP 
Cytochrome P450 
OP 
Out-patient 
CV 
Coefficient of Variation 
OTC 
Over the Counter 
CV 
Cardio Vascular 
P 
Phone 
CVD 
Cardio Vascular Disease 
PK 
Pharmacokinetic 
°C 
Degrees Celsius 
PK/DM 
Pharmacokinetics/Drug Metabolism 
DBP 
Diastolic Blood Pressure 
PPP 
Per-Protocol Population 
DDI 
Drug-drug Interaction 
PWS 
Prader Willi Syndrom 
Dl 
Deciliter 
Q 
Quarter 
DMP 
Data Management Plan 
QA 
Quality Assurance 
DSMB 
Data Safety Monitoring Board  
QC 
Quality Control 
DXA 
Dual X-ray absorptiometry 
SAE 
Serious Adverse Event 
ECG 
Electrocardiogram 
SAP 
Statistical Analysis Plan 
EC 
Ethic Committee  
SBP 
Systolic Blood Pressure 
eCRF 
Electronic Case Report Form 
SD 
Standard Deviation 
EMEA 
European Agency for the Evaluation of Medical 
Products 
SOP 
Standard Operating Procedure 
EU 
European Union 
SUKL 
State Institute for Drug Control 
FPG 
Fasting Plasma Glucose  
SUSAR 
Suspected Unexpected Serious Adverse 
Reactions 
GCP 
Good Clinical Practice 
Tmax 
Time of the maximum  
HDL 
High-density lipoprotein 
TZD 
Thiazolidinediones 
HbA1C 
Hemoglobin A1c 
T2MD 
Type 2 diabetes mellitus 
HQCT 
Hyperphagia Questionnaire for Clinical Trials  
 
ULN 
Upper Limit of Normal range 
HR 
Heart Rate 
USA 
United States of America 
IB 
Investigator Brochures 
WHO DD 
World Heath Organization Drug 
Dictionary 
ICH 
International Conference on Harmonization 
 
 
IEC 
Independent Ethics Committee 
 
 
IMP 
Investigation Medicinal Product 
 
 
 
 
 

 
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3 
INTRODUCTION AND STUDY RATIONALE  
 
3.1 
CLINICAL BACKGROUND 
Etiology and treatment of Prader- Willi syndrome   
Prader-Willi syndrome is a complex genetic condition caused by an abnormality on the long 
arm of chromosome 15 (q11-q13) that affects many parts and organ systems of the body. In 
infancy, this condition is characterized by weak muscle tone (hypotonia), feeding difficulties, 
poor growth, and delayed development. Beginning in childhood, affected individuals develop 
an insatiable appetite, which leads to chronic overeating (hyperphagia) and obesity. Many 
subjects with Prader-Willi syndrome, particularly those with obesity, also develop type 2 
diabetes mellitus (T2DM) and other related co-morbidities early in life often leading to 
development of cardiovascular disease and early death. 
 
Subjects with Prader-Willi syndrome typically have mild to moderate intellectual impairment 
and learning disabilities. Behavioral problems are common, including temper outbursts, 
stubbornness, and compulsive behavior such as picking at the skin. Sleep abnormalities can 
also occur. Additional features of this condition include distinctive facial features such as a 
narrow forehead, almond-shaped eyes, and a triangular mouth; short stature; and small hands 
and feet. Some people with Prader-Willi syndrome have unusually fair skin and light-colored 
hair. Both affected males and affected females have underdeveloped genitals. Puberty is 
delayed or incomplete, and most affected individuals are unable to have children (infertile). 
(1) 
 
Prader-Willi syndrome affects an estimated 1 in 10,000 to 30,000 people worldwide. Most 
cases of Prader-Willi syndrome are not inherited, particularly those caused by a deletion in the 
paternal chromosome 15 or by maternal uniparental disomy. These genetic changes occur as 
random events during the formation of reproductive cells (eggs and sperm) or in early 
embryonic development. Affected subjects typically have no history of the disorder in their 
family. 
 
Rarely, a genetic change responsible for Prader-Willi syndrome can be inherited. For 
example, it is possible for a genetic change that abnormally inactivates genes on the paternal 
chromosome 15 to be passed from one generation to the next. (1) 
 
Current treatment strategies 
There is currently no specific treatment for this syndrome. Growth hormone has been 
routinely used to help with growth and to increase muscle mass, which allows greater physical 
activity. As other diseases develop as the subject’s age, eg, T2DM, hypertension, 
dyslipidemia or psychiatric disorders, these are managed per local practice and treatment 
standards. 
 
Overview of tesofensine  
Tesofensine was initially studied for the treatment of Parkinson and Alzheimer’s diseases. 
However, clinical studies showed only a limited efficacy of tesofensine, but weight loss was 
noted in majority of participants, despite the fact that they did not attempt to lose weight. 
Tesofensine is an inhibitor of monoamine presynaptic reuptake of the neurotransmitters 
noradrenaline, dopamine and serotonin. This means it influences these chemicals in the brain 
to suppress appetite. Tesofensine demonstrated strong weight reducing effects in Phase 2 

 
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clinical studies in obese subjects, exceeding benchmarks set by the regulatory agencies for 
approval of weight loss agents (2). Also, post-hoc analysis of the data from the Phase 2 
obesity study showed that individuals with pre-diabetes in this study experienced a favorable 
reduction in body weight and glycaemic endpoints while on tesofensine.  
 
In general, tesofensine was well tolerated in humans with the most commonly observed side 
effects of dry mouth, headache, insomnia, and nausea However, blood pressure and heart rate 
increase were observed. With the therapeutically relevant doses of tesofensine (0.25 mg and 
0.5 mg) an increase in blood pressure (BP) of 1–3 mmHg and an increase in heart rate (HR) 
up to 8 bpm were seen (2). Currently, there are no data indicating that these effects of 
tesofensine would translate into increased risk of cardiovascular (CV) events; however, these 
increases could hypothetically have an adverse impact on the cardiovascular safety in certain 
individuals.. This lead to the addition of metoprolol to mitigate these effects and further 
ensure a favorable benefit/risk profile. For more information on tesofensine please see the 
Investigators’ Brochure (Version 13). 
  
Overview of metoprolol 
Metoprolol is a beta1-selective (cardio selective) adrenoceptor-blocking agent, for oral 
administration, which has been approved in the 70’s and has been one of the most widely 
prescribed medicines to date. It is indicated for hypertension, angina pectoris and heart failure. 
It is now available as extended-release tablets. Metoprolol extended release, has been 
formulated to provide a controlled and predictable release of metoprolol for once-daily 
administration. This is also the formulation selected for this study (for more information 
please see the Summary of Product Characteristics of metoprolol). 
 
Overview of tesofensine/metoprolol 
In a pre-clinical study in rats the co-administration of tesofensine + metoprolol showed a HR 
and BP profile similar to placebo (vehicle) while the weight-reducing efficacy was maintained 
(3). In addition, in a drug-drug interaction study in healthy male subjects addition of short 
acting metoprolol on the background of chronic dosing with tesofensine showed a short term, 
but substantial, reduction in HR previously increased by tesofensine. Co-administration of 
tesofensine (0.5 mg qd) and metoprolol (100 mg qd) is currently being studied in a Phase 2a 
proof-of-concept study in 60 subjects with T2DM at two sites in Germany. Taken together, 
the available data support the concomitant use of tesofensine and a beta-blocker such as 
metoprolol as an investigational agent for the proposed indication of treatment of obesity and 
related co-morbidities in subjects with Prader-Willi syndrome. 
 
Purpose of the Comparison to Placebo 
Double blind, placebo-controlled design is the gold standard in evaluation of efficacy and 
safety of new drugs. It provides the most rigorous and unbiased evaluation of the true effects 
of an intervention. This design was chosen because it is critical to thoroughly assess the 
efficacy of co-administration of tesofensine/metoprolol in subjects with Prader-Willi 
syndrome. 
 
Purpose of this study 
The purpose of this study is to investigate the safety and efficacy of co-administration of 
tesofensine/metoprolol treatment versus placebo in adult and pediatric subjects with Prader-
Willi syndrome. 
 
 

 
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4 
STUDY OBJECTIVES AND ENDPOINTS 
 
4.1 
OBJECTIVES  
Primary objective:    
 To examine the effect of co-administration of tesofensine/metoprolol on body weight 
in subjects with PWS in an open labeled extension 
 
Secondary objectives: 
 To establish pharmacokinetic profile of tesofensine and metoprolol in subjects with 
PWS 
 To examine the change in hyperphagia-related behavior in subjects with PWS by use 
of the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) 
 To examine the effect of co-administration of tesofensine/metoprolol on glycemic 
control and lipid profile in subjects with PWS 
 To examine the effect of co-administration of tesofensine/metoprolol on HR and BP in 
subjects with PWS 
 To examine the effects of co-administration of tesofensine/metoprolol on body 
composition in subjects with PWS 
 To evaluate overall safety and tolerability of co-administration of the 
tesofensine/metoprolol in subjects with PWS  
 
 
4.2 
ENDPOINTS (Baseline = Day 0; End of double-blind treatment = Day 
90, end of first OLE = Day 180, end of second OLE = Day 270) 
Primary endpoint 
 Percent change from baseline to end of treatment periods in mean body weight  
Secondary endpoints 
 Steady state concentrations of tesofensine and metoprolol as measured by trough 
values 
 Uptake and initial plateau concentrations of metoprolol as measured by samples taken 
2 and 4 hours after dose administration 
 Change from baseline to end of the treatment periods in total HQCT score  
 Change from baseline to end of treatment periods in mean body weight (kg) 
 Change from baseline to end of treatment periods in fat- and fat-free mass (%) by dual 
X-ray absorptiometry (DEXA) 
 Change from baseline to end of treatment periods in HR (bpm), SBP (mmHg), DBP 
(mmHg) 
 AEs, clinical labs, ECG  
 
Exploratory endpoints: 
 Change from baseline to end of treatment periods in FPG, insulin 
 Change from baseline to end of treatment periods in lipid profile 
 Change from baseline to end of treatment periods in waist circumference (cm) 
 
 

 
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5 
OVERALL STUDY DESCRIPTION 
This is a second open label extension study of the double-blind, randomized, placebo-
controlled, multiple-dose, multi-centre, safety and efficacy study of co-administration of 
tesofensine/metoprolol treatment in subjects with Prader-Willi syndrome. This open label 
extension is a follow up of the first OLE, which included 8 children with PWS (Protocol 
Amendment 1.6). 
 
 Subjects who complete first OLE (12 weeks) will be invited to participate in the second open 
label extension phase. Participation will be based on the judgment of the Investigators 
whether or not it is safe for the subject to continue in the extension study. Study medication 
will be administered for ninety (90) days (+2 days after the final assessments with half-dose 
of metoprolol).  
In the second OLE all subjects deemed eligible by the PI will receive tesofensine 0.125 mg 
(0.25 mg every second day)  + metoprolol ER 25 mg (Metoprolol Orion 25 mg) administered 
once a day, in the morning with a meal. Those patients who tolerated the 0.125/25 mg 
tesofensine/metoprolol dose well in the first OLE will receive 0.25 mg of tesofensine with 25 
mg of metoprolol ER.   
  
In case a patient, in the opinion of the PI, experiences an adverse event that by the PI is 
suspected to be potentially related to an undesirable drug concentration of the investigational 
medication, the investigators at each site, based on their discretion, can extend the period 
between dosages of the IMP or implement a drug holiday, or reduce the dose (those on 0.25 
mg of tesofensine) in order to optimally manage the wellbeing and safety of the patient. Each 
of these cases should be discussed in advance with the Sponsor’s medical monitor. 
 
 
Subjects together with their parents/guardians/caregivers (where applicable according to 
existing country legislation) who give the written informed consent for the second open label 
extension part will continue in the study. If not, subject will finish the study based on the 
Protocol Amendment 1.6. 
 
Opel label period: after the Day 180 (Visit 17), subjects will visit the site every month for 
efficacy and safety evaluations and medication supply (in total 4 personal visits at the site are 
requested). Study procedures in the second extension part are the same as in the first OLE.  
If possible subjects will be asked to stay at the site for the collection of blood for PK of 
metoprolol 2 and 4 hours after dose administration – the blood for these samples will be 
collected once from each patient (only if it hasn’t been collected during the first OLE), but to 
allow for greater flexibility accounting for their unstable and unpredictable nature, it is 
included during every on site visit. 
 

 
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End of treatment visit: On Visit 20 (Day 270) subjects will come for the final treatment 
visit. During the Visit 20 the blood will be collected for metabolic endpoint as well as safety 
measurements. Subjects will also receive two days of half-dose dose of metoprolol to take at 
home in order to gradually reduce the dose of metoprolol to avoid potential undesirable 
fluctuation in blood pressure. 
End of study: On Visit 21 (Day 300) the subjects will be invited for the final safety check, 
BP/HR assessment and PK sampling (30 days after last dose), which will conclude their 
participation in the study.   
 
Phone calls in-between the onsite visits will be used to provide additional reassurance 
regarding the safety of the subjects and collect adverse events. 
 
Subjects who exceed predefined values of HbA1c>10%, FPG >11.0 mmol/l or BP>160/110 
mmHg will be treated at the discretion of the investigator per established guidelines to 
improve the patients glycaemic/BP control while remaining in the study. 
 
Assessments conducted during each visit are described in the schedule of events, Appendix 
16.2. 
 
5.1 
STUDY VISIT DESCRIPTION 
 
Visit 17, Day 180 – Last visit of the first OLE and first visit of the second Open label 
extension study: 
 
The following procedures will be performed:  
 Signing the Addendum to double blind ICF for the second open label extension 
 Conducting physical examination 
 Measurement of vital signs  
 Measurement of body weight and waist circumference 
 Measurement of height, calculation of BMI 
 Obtaining ECG 
 Performing routine hematology, blood chemistry assessment  
 Collection of blood for efficacy (HbA1c, FPG, lipids, insulin)  
 Collection of blood for PK of steady state concentrations of tesofensine and 
metoprolol as measured by trough values 
 Collection of blood for PK of metoprolol taken 2 and 4 hours after dose administration 
(only if not done already) 
 Performing the urinary pregnancy test 
 DEXA 
 HQCT 
 AEs assessment 
 Psychiatric examination  
 Assessment of concomitant medications 
 Dispensing the subject diary for the open label extension, study card for second OLE 
 Dispensation of study medication  
 Scheduling the next on-site visit and phone call  

 
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All diabetic subjects (together with their parents/guardians/caregivers) will be again instructed 
to closely follow the dietary instruction and medical treatment for their diabetes. Subjects 
(together with their parents/guardians/caregivers) will be again educated in and again asked to 
watch for any symptoms or signs of hypoglycemia. Hypoglycaemic episodes must be reported 
to investigator during the phone call visits or personal visit at the site. In case of an 
unexplained hypoglycaemic event (no extra exercise, skipping a meal or alike) the subjects 
(together with their parents/guardians/caregivers) should contact the site. Information about 
providing instruction regarding hypoglycaemic episodes must be recorded in the subject’s 
source data. 
 
Visit 18, 19 (Day 210, 240 (30±3 days) – personal visits: 
 
The following assessments will be done: 
 Measurement of vital signs  
 Measurement of body weight and waist circumference 
 Collection of blood for efficacy (HbA1c, FPG, lipids, insulin)  
 Collection of blood for PK of steady state concentrations of tesofensine and 
metoprolol as measured by trough values 
 Collection of blood for PK of metoprolol taken 2 and 4 hours after dose administration 
(only if not done already)  
 HQCT 
 AEs assessment 
 Psychiatric examination  
 Assessment of concomitant medications 
 Review of subject diary 
 Medication accountability check 
 Scheduling the phone call and subject personal visit  
 
Visit 20 (Day 270, (30±3 days)) – End of treatment visit 
The following assessments will be done: 
 Conducting physical examination 
 Measurement of vital signs  
 Measurement of body weight and waist circumference 
 Obtaining ECG 
 Performing routine hematology, blood chemistry assessment  
 Collection of blood for efficacy (HbA1c, FPG, lipids, insulin)  
 Collection of blood for PK of steady state concentrations of tesofensine and 
metoprolol as measured by trough values 
 Collection of blood for PK of metoprolol taken 2 and 4 hours after dose administration 
(only if not done already) 
 Performing the urinary pregnancy test 
 DEXA 
 HQCT 
 AEs assessment 
 Psychiatric examination  
 Assessment of concomitant medications 
 Medication accountability check 

 
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 Dispense of two half-doses of metoprolol medication 
 Collection and review of subject diary 
 Dispensing a follow up diary lists for recording AE and concomitant medication 
between last subject visit on Day 300 
 Scheduling Final visit on Day 300 
 
 
Day 270 (morning) will be the last day when subjects receive the study medication. 
 
On Day 270 subjects will receive a half-dose of the metoprolol dose to take at home, one 
dosage over the next two days in order to gradually reduce the dose of metoprolol and avoid 
potential undesirable fluctuation in blood pressure.  
 
Phone calls between the on-site visit 
Phone calls in between the onsite visits will be used to provide additional reassurance 
regarding the safety of the subjects and to collect adverse events. Subjects 
(parents/guardians/caregivers) will be asked the following: 
 Since your last visit, have you experienced or do you currently experience any 
symptoms that are not associated with your disease? 
 Any change in concomitant medications 
 Any Hypoglycemic episodes  
Visit 21 (Day 300 (30±3 days)) ) Final follow-up –– personal visit 
The following assessments will be done: 
 AEs 
 Measurement of vital signs  
 Measurement of body weight and waist circumference 
 HQCT 
 Psychiatric examination  
 Concomitant medications 
 Collection of blood for PK 
 Review of subject diary 
 Collection of subject follow up diary  
End of study (Day 300)  
Visit 21 is considered as the subject’s end in the study. The “End of Study” or “Early 
termination” (as applicable) must be entered into the eCRF and subject’s source documents 
must be completed. 
 
Unscheduled visit – if applicable: 
The following assessments will be done: 
 Conducting physical examination 
 Measurement of vital signs  
 Measurement of body weight and waist circumference 
 Performing routine hematology, blood chemistry assessment  
 AEs assessment 
 Assessment of concomitant medications 
 

 
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5.2 
END OF STUDY  
The end of study (Day 300) is defined by LPLV for TM002, including the second OLE. If a 
subject withdraws from the study during the treatment period, or has to discontinue for any 
reason, a visit will be organized at which the assessments planned for Visit 20 will be 
performed. If a subject refuses to attend a visit, the investigator should make every effort to 
obtain the information over the telephone from the subject regarding the safety.  
 
5.3 
STUDY PARTICIPANTS 
All male and female pediatric subjects with confirmed diagnosis of PWS who completed the 
first OLE (12 weeks), will be invited to participate in the second open label extension phase, 
if deemed eligible by the Investigators.    
 
5.4 
DISCONTINUATION CRITERIA 
The subject or her/his parents/guardians/caregivers has a right to discontinue subject’s study 
participation at any time for any reason. The reason for discontinuation will be documented in 
the subject’s source documents and in the eCRF. In the event of an early termination, all 
procedures described for a subject completing the study as planned for Visit 20 (Day 270) 
should be performed. Subjects discontinuing due to adverse events will be followed-up until 
complete resolution of the adverse event or until there is a satisfactory explanation of the 
changes observed. 
 
5.5 
WITHDRAWAL CRITERIA 
 Subjects may be withdrawn if any of the following items is met and documented: 
 Request by subject (withdrawal of informed consent) 
 Request by parents/guardians/caregivers 
 Investigator’s decision 
 Pregnancy  
 Acute allergic reaction to study medication 
 HbA1c ≥ 10% 
 FPG>13.3 mmol/l (repeated on 2 days) 
 Any event, including hospitalization of the subject in another location where the 
investigator will not be able to follow the subject 
 Evidence of the use of recreational medications or prohibited medications during the 
study 
 Failure to comply with the study stipulations 
 Severe symptomatic bradycardia (heart rate < 50 bpm) during the study 
 Lost to follow-up. Subjects will be deemed lost to follow-up if they do not return for 
scheduled visits without giving a reason, and if the investigator is unable to contact the 
subject directly or indirectly (e.g. via the subject’s family). If a subject does not attend 
a scheduled visit, the investigator will make best efforts to obtain information about 
the subject before considering the subject lost to follow up 
 
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 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 eCRF. 

 
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5.6 
PREMATURE STUDY DISCONTINUATION 
The sponsor has the right to terminate this study at any time. If the sponsor, the investigators, 
or the competent authorities discover conditions arising during the study that indicate the 
study should be halted, it may be terminated after appropriate consultation between the study 
sponsor and the investigator. 
Reasons for terminating the study may include the following: 
 The incidence or severity of AEs in this study indicates a potential health hazard to 
study subjects 
 Subject enrolment is unsatisfactory 
 Data recording is inaccurate or incomplete 
 The sponsor´s decision to suspend or discontinue development of the study medication 
5.7 
EARLY TERMINATION OF A STUDY SITE 
The sponsor may close the site if severe protocol deviations are observed.  
5.8 
STUDY SITES 
The study will be conducted at two sites, one in Czech Republic and one in Hungary. 
 
5.9 
STUDY DURATION 
The expected start date for the second open label part is planned for March/April 2019. The 
individual study duration for one subject is up to 16 weeks including treatment period (12 
weeks of the open label period) and the final visit (30 days after the last treatment visit). The 
end of second open label is defined by the Last Visit of the Last pediatric subject, which is 
likely to occur in June/July 2019.  
 
5.10 
TOTAL STUDY DURATION   
The projected duration of the whole study (including Step 2 and both OLEs) is ~15months. 
The end of TM002 is defined as Last Visit of the Last Pediatric Patient in the second open 
label extension. 
 
5.11 
BENEFITS AND RISKS FOR STUDY PARTICIPANTS 
It is expected that tesofensine and metoprolol combination will be well tolerated. This 
assessment is based on the comprehensive experiences from previous preclinical and clinical 
studies of tesofensine, the availability of metoprolol on the market for many years and the 
present tesofensine/metoprolol investigation in subjects with T2DM. All subjects will receive 
diet consulting, and it is expected that subjects on active treatment will see a reduction in their 
hunger, food craving and body weight. No invasive interventional procedures are planned 
except blood sampling, which is similar to clinical practice and subjects will be monitored 
thoroughly and rigorously following the first administration of tesofensine and metoprolol, 
and will have weekly contact (personal or telephone contact) to the site throughout the study.  
There were adverse events observed in Step 1 of this study, which lead to premature 
discontinuation of several patients. It is believed these adverse events were driven by 
unexpectedly high concentration of tesofensine and that the proposed changes in the dosing of 
the IMP in the study protocol proposed for Step 2 and both OLEs should keep the overall 
risk/benefit balance favorable. 

 
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Tesofensine  
The majority of treatment related adverse events seen in the clinical studies with tesofensine 
were dry mouth, headache, nausea, insomnia, diarrhea and constipation side effects. A dose-
dependent pattern was observed for dry mouth and insomnia. The overall withdrawal rate due 
to adverse events in clinical studies in the obese population was 13% with tesofensine and 6% 
with placebo. Blood pressure and heart rate increased with the therapeutically relevant doses 
of tesofensine (0.25 mg and 0.5 mg). An increase in blood pressure of 1–3 mm Hg and in HR 
up to 8 bpm was seen. For more information see the IB. (IB version 13 and any updates 
thereof). 
 
Due to the CNS-located mechanism of action of tesofensine, a monoamine reuptake inhibitor, 
there could be a concern regarding psychiatric side effects. In obese subjects dosed for up to 
24 weeks, common psychiatric symptoms were insomnia and depressed mood. Occurrence of 
insomnia displayed a clear dose-dependency with the highest incidence on the highest dose (1 
mg). Psychotic phenomena, like those encountered in patients with dementia of the 
Alzheimer's type or Parkinson’s disease, were not registered in the population of obese 
subjects. Pooled data from studies NS2330-001 and NS2330-004 did not reveal an increased 
incidence of psychiatric events following long-term extension study, i.e. 18 months of 
treatment. Current data from the clinical studies with obese patients do not suggest that 
tesofensine at doses of 0.25 mg and 0.5 mg once daily are associated with any clinically 
significant undesirable psychiatric profile. (IB version 13 and any updates thereof). 
 
Metoprolol adverse reactions – post marketing experience  
 Blood and lymphatic system: thrombocytopenia, leukopenia, agranulocytosis 
 Cardiovascular: cold extremities, arterial insufficiency (usually of the Raynaud type), 
palpitations, peripheral edema, syncope, chest pain and hypotension 
 Respiratory: wheezing (bronchospasm), dyspnea, rhinitis  
 Central Nervous System: confusion, short-term memory loss, headache, somnolence, 
nightmares, insomnia, anxiety/nervousness, hallucinations, paresthesia 
 Psychiatric: changes in personality, depression 
 Gastrointestinal: nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, 
vomiting, abdominal pain, retroperitoneal fibrosis 
 Hypersensitive Reactions: pruritus 
 Miscellaneous: 
fatigue, 
hyperhidrosis, 
hepatitis, 
increased 
liver 
enzymes, 
musculoskeletal pain, arthralgia, blurred vision, decreased libido, male impotence, 
tinnitus, reversible alopecia, dry eyes, psoriasis-like dermatitis, worsening of psoriasis, 
Peyronie’s disease, sweating, photosensitivity, taste disturbance, gangrene 
 
For more information regarding the adverse events please see the Summary of Product 
Characteristics of metoprolol. 
 
It is anticipated that the subject receiving the study medication will experience a reduction in 
their body weight and improvement in their glycaemic control (if diabetic or pre-diabetic). 
Although tesofensine has not been previously investigated in adult and pediatric subjects with 
Prader-Willi syndrome, based on the highly statistically and clinically meaningful degree of 
weight loss seen in the available literature it is anticipated that participants in this study will 
experience improvement in their glycaemic control (also including those on placebo who will 
receive diet, exercise and lifestyle modification guidance). In addition, all patients will have 
access to a state-of-the-art clinical care that they will receive for the duration of the study. 

 
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Subjects randomized to the placebo arm will receive state of the art clinical study for almost 4 
months with regular visits and multiple sophisticated assessment of their health status, 
including their diabetes, as well as lifestyle guidance from a dietician. Pediatric subjects with 
PWS are being included only after the Sponsor received positive opinion from SUKL, which   
concludes that that no safety concerns arose from IMP application in adult PWS patients in 
Step 1 and TM001. 
 
6 
TREATMENT OF STUDY PARTICIPANTS= identical to the first 
OLE 
6.1 
DESCRIPTION OF STUDY MEDICATION 
Investigational Medicinal Product 
Tesofensine is a serotonin-noradrenaline-dopamine reuptake inhibitor, for oral administration, 
which is manufactured, packed and labeled by Delpharm in Reims (France). Its chemical 
name (IUPAC) is (1R,2R,3S,5S)-2-Ethoxymethyl-3-(3,4-dichlorophenyl)-8-methyl-8-
azabicyclo[3.2.1]octane,2-hydroxy-1,2,3-propanetricarboxylate (1:1). Designated contractors 
will supply study medications directly. 
 
Metoprolol is a beta1-selective (cardioselective) adrenoceptor-blocking agent, for oral 
administration. It has been formulated into the extended release tablets to provide a controlled 
and predictable release of metoprolol for once-daily administration. Original extended release 
metoprolol will be purchased and supplied by sponsor CRO directly. 
 
In the first Open label (children with PWS), tesofensine 0.125 mg (0.25 mg every second day) 
+ metoprolol 25 mg was administered once a day, in the morning with a meal. In the second 
OLE all subjects deemed eligible by the PI will receive tesofensine 0.125 mg (0.25 mg every 
second day)  + metoprolol ER 25 mg (Metoprolol Orion 25 mg) administered once a day, in 
the 
morning 
with 
a 
meal. 
Those 
patients 
who 
tolerated 
the 
0.125/25 
mg 
tesofensine/metoprolol dose well in the first OLE will receive 0.25 mg of tesofensine with 25 
mg of metoprolol ER.   
 
 
In case a patient in the opinion of the PI experience an adverse event that by the PI are 
suspected to be potentially related to an undesirable drug concentration of the investigational 
medication the investigators at each site, based on their discretion, can extend the period 
between dosages of the IMP or implement a drug holiday or reduce the dose (those on 0.25 
mg of tesofensine) in order to optimally manage the wellbeing and safety of the patient. Each 
of theses cases should be discussed in advance with the Sponsor’s medical monitor. 
 
6.2 
IMP HANDLING PROCEDURES - KLIFO 
The contracted CRO Klifo (Denmark) is responsible for the IMP management.  
 
6.3 
IMP HANDLING PROCEDURES – STUDY SITE 
 Klifo is responsible for transferring the IMP to assigned and contracted study site 
pharmacies in Czech Republic and Hungary 
 The site pharmacists (at both sites) are responsible for acknowledgment of receipt of 
the of IMP by signing the receipt forms  
 Storing the IMP on site pharmacy in a secured area with restricted access under the 

 
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controlled temperature conditions   
 Dispensing IMP to site staff according to the protocol 
 
Prior to the initial shipment of the study medication to the site(s), the following essential 
documents must be available in the Study Master File:  
 EC/RA approval 
 EC/RA approved subject information/informed consent form 
 Clinical study protocol signed by the principal investigator 
 Study agreement/contract signed by the principal investigator 
 
 
The investigator is responsible for study medication kits accountability. The site pharmacist is 
responsible for maintaining accurate records of all information relating to the management of 
the study medication. If any quality issues are noticed on receipt or use of the IMP (e.g. 
damaged condition, faults in appearance, errors in the documentation, incorrect labeling, and 
short expiry date) these should be notified promptly to the study monitor and sponsor. The 
investigator should also inform the study monitor/sponsor of any complaints about the study 
medication made by the study subjects.  
In the event of a batch recall, the sponsor or its representative will inform the investigator or 
site pharmacist in writing. Upon receipt, and as instructed, the investigator or site pharmacist 
should immediately contact any study subject in possession of the corresponding study 
medication kits.  
 
6.4 
LABELS FOR STUDY MEDICATION 
The label texts will be translated or adjusted as necessary so that they comply with the 
applicable national laws and regulatory requirements of the country in which the study will be 
conducted. The label text will include the following information as minimum: 
 Name of Sponsor 
 Name of CRO or Investigator 
 Protocol number 
 Subject screening number  
 Dosing instructions 
 Batch number 
 Expiry date 
 Visit number 
 The words ‘For clinical study use only’ 
 The words ‘Keep out of reach of children’  
 Storage conditions 
 
6.5 
PACKAGING AND DESTRUCTION 
Medication will be distributed to the subjects in plastic bottle (tesofensine) and in blisters 
(metoprolol) labeled with the appropriate study medication number. The investigator and site 
pharmacists will collect unused study medication. Klifo is responsible for central destruction 
of all study medication (partially used and unused). Subjects will be asked to use Metoprolol 
every morning with or right after a meal and not to crush or chew the tablets and Tesofensine 
every second day. Subject will be asked to store the medication at room temperature (15 - 25 
°C) and return the unused study medication on visit 20 at the site. 
 

 
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6.6 
STUDY MEDICATION COMPLIANCE 
The investigational medicinal products will be self-administered by the subjects or 
parents/guardians/caregivers at home. For the monitoring of study medication, subjects or 
parents/guardians/caregivers will be instructed to return bottle and blisters with study 
medication at visit 20, whether full, partially empty, or empty. 
 
6.7 
OPEN LABEL SUBJECT NUMBER 
Subjects who sign the informed consent (together with signed informed consent form by 
subject’s parents/guardians/caregivers where applicable according to existing country 
legislation) will keep at the Visit 17 their unique screening number consisting of a two (2) 
digit site number and three (3) digit subject number and country abbreviation.  
 
6.8 
UNBLINDING 
Not applicable, it is an open label study. 
 
6.9 
DISPENSATION OF STUDY MEDICATION 
A medication-dispensing log will be kept current by the investigator, detailing the dates and 
quantities of study medication dispensed to each subject. The inventory will be available to 
the monitor to verify products accountability during the study. Any unused reusable study 
medication 
either 
not 
dispensed 
or 
returned 
by 
the 
subject 
or 
subject’s 
parents/guardians/caregivers, including empty bottles/blisters will be accounted for and 
returned to the investigator and destroyed by the Klifo. 
 
6.10 
ACCOUNTABILITY OF THE STUDY MEDICATION 
The investigators will make every effort to encourage subjects together with help of subject’s 
parents/guardians/caregivers to comply with the dosage regimen. A record of the study 
medication dispensed, used and returned will be made at each visit. The investigator, his/her 
designee must maintain an adequate record of the receipt and distribution of all study 
medications using a Drug Accountability Form.  These forms must be available for inspection 
at any time. The investigator will only use the study medications within the framework of this 
clinical study and in accordance with the existing study protocol. The monitor will check and 
document the number of returned bottles/blisters on-site. The delivery to, use by and return 
from the subject or subject’s parents/guardians/caregivers must be documented. All opened 
and unopened bottles/blisters, together with remaining contents, will be returned by the 
subject or subject’s caregiver/guardian/parents to the site staff and maintained by the 
investigator in a secure place. The site staff/ monitor will count the returned medication and 
document in the appropriate record before destruction. A written explanation must be given 
for any bottle/blister that is missing. It is the investigator’s responsibility to instruct the 
subjects and subject’s parents/guardians/caregivers about using and returning of study 
medication. 
  
6.11 
CONCOMITANT MEDICATION 
Any other concomitant medication taken, as well as any changes in concomitant medication 
will be documented in the subject´s source documentation and eCRF indicating the: 
 Trade name of medication 
 Start date 
 End date / on-going 
 Route of administration 
 Total daily dose and units, and 

 
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 Reason for administration 
 
6.12 
PROHIBITED MEDICATIONS 
For prohibited concomitant medications, please refer to Appendix 1 and Exclusion criteria. 
Paracetamol is an exception and may occasionally be taken by the subjects in the treatment of 
acute pain (e.g. headache or toothache). In such case, the subjects will be asked to keep record 
in the diary. 
 
6.13 
STUDY PROCEDURES AND OTHER EXAMINATIONS  
Informed Consent for the second OLE  
It is the responsibility of the investigator to give each subject (or, if the subjects do not have 
legal 
authority 
to 
provide 
consent 
for 
themselves 
their 
legally 
appointed 
parents/guardians/caregivers where applicable according to existing country legislation) full 
and adequate verbal and written information regarding the objective and procedures of the 
study and the possible risks involved. In pediatric subjects the patient information and 
informed consent forms will be prepared per local legislative requirements. 
  
The OLE ICF, approved by the RA/EC, must be given to each subject or 
parents/guardians/caregivers before any study-related procedure is undertaken. The subjects 
must be informed about their right to withdraw from the study at any time. The written 
subject/parents/guardians/caregivers information cannot be changed without prior approval by 
Sponsor and the RA/EC.  Furthermore, it is the responsibility of the investigator to obtain 
signed informed consent from all subjects (or the parents/guardians/caregivers) prior to 
undertaking any study-related procedure. Two original forms will be given to the 
subject/parents/guardian/caregivers 
for 
signature. 
One 
is 
to 
be 
kept 
by 
the 
subject/parents/guardians/caregivers and one is to be filed in the Investigator's Study File. 
  
Due to the special nature of this population, it is possible that they will have caregivers (i.e. a 
person caring for the subject but who is not authorized to provide legally relevant consent in 
relation to the subject’ participation in the study) but who, in the course of the clinical study, 
will help the subject and the study team in administering the treatment, travelling to the site, 
and conduct at home subject’ assessments in compliance with the rules of the clinical study. A 
separate written information sheet for caregivers will be prepared specifying all of the 
important pieces of information for this person; the document will also explain the role of the 
caregiver in detail. By signing the informed consent the caregiver agrees that the child under 
his/her care will participate in the OLE and he/she will become involved in the clinical trial as 
well, but with limited rights.  
 
Vital Signs 
Vital signs include body temperature, respiratory rate, pulse rate and blood pressure.  
 
Physical Examination 
The physical exam includes: heart, lung, head and neck exam, and abdominal, neurological 
and dermatological exam. 
 
Blood pressure measurement   
 Subject should avoid food immediately before the measurement  
 Subject should go to the toilet before BP measurement. A full bladder can increase 
blood pressure slightly 

 
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 Subject should sit for five minutes in a comfortable position with his/her legs and 
ankles uncrossed and his/her back supported against a chair before and during a 
measurement 
 Subject should be asked to sit quietly before and during monitoring 
 When subject is ready to take his/her blood pressure, subject should be calm and not 
think about stressful things and not to talk at all 
 Subject’s arm must be positioned properly. Same arm must be always used when 
taking subject’s blood pressure. Subject should rest his/her arm, raised the arm to the 
level of his/her heart, and put the arm on a table, desk or chair arm. If needed, a pillow 
or cushion should be placed under subject’s arm to elevate the arm high enough 
 The cuff must be placed on bare skin, not over clothing.  The appropriate sized cuff 
should be always used! 
 Three measurements should be performed, repeat the BP measurement after 3 minutes. 
If the monitor doesn't automatically log blood pressure readings or heart rates, the 
measurement should be repeated until a valid reading is available (for every time point 
there have to be three BP values), given that the procedure is accepted by the subject 
 
Body weight - subject must be undressed with the exception of underwear. 
 
Waist circumference will be measured just after subjects breathe out, in standing position, 
just above hipbones (also in underwear). 
 
Urinary pregnancy test will be done only for any women of childbearing potential at the site 
at the Day 180 and on Day 270.   
 
DEXA will be done using standardized protocol while the subjects wear light clothing at the 
Day 180 and on Day 270 
 
HQCT - parents/guardian/caregivers will be asked during each personal visit to evaluate the  
food-seeking behavior of the subject with PW. Subjects with PWS are themselves unable to 
consistently and reliably report the severity of their hyperphagia, due to their intellectual 
limitations.  In case that the subject is not at home during the week (for ex. at boarding 
school), parents/guardian/caregivers should ask the teacher or the relevant person about 
subject’s eating behavior during the week and based on the received information, the HQCT 
should be completed.  
 
 
6.14 
LABORATORY EVALUATIONS 
Laboratory samples will be collected from subjects at the site, and will be shipped to the local 
laboratory for analysis in ambient conditions. 
 
The investigator will receive the data from local laboratory. Laboratory results will be 
reviewed, evaluated, signed and dated by the investigator. The investigator must evaluate all 
results outside the reference range and mark whether they are considered to be ‘clinically 
significant’ or ‘not clinically significant’. The signed and dated version of the laboratory 
report will be filed in subject’s medical file. 
 
The investigator´s evaluation (´normal´, ´abnormal and not clinically significant´ or ´abnormal 
and clinically significant´) will be entered into the eCRF. 

 
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If a laboratory result is considered clinically significant and it fulfills the criteria for a clinical 
laboratory AE, it should be reported in accordance with section 6. Clinically significant 
laboratory findings from the screening visit before the randomization should be recorded as 
concomitant illness. 
 
The laboratory equipment may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses according to specifications in the 
laboratory standard operating procedures. Such data will not be transferred to the study 
database, but abnormal values will be reported to the investigator. The investigator must 
review all laboratory results for concomitant illnesses and AEs and report these according to 
this protocol. 
 Hematology: blood count (erythrocytes, hemoglobin, hematocrit, leukocytes), 
differential blood count (neutrophils, lymphocytes, monocytes, eosinophils, basophils) 
and platelets, will be analysed by local laboratory 
 Blood chemistry: creatinine, gamma glutamyl transferase, aspartate aminotransferase, 
alanine aminotransferase, alkaline phosphatase, GFR and urea will be analyzed by 
local laboratory 
 HbA1c will be analyzed by local laboratory 
 Lipids (total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides), serum 
insulin will be analyzed by local laboratory 
 Fasting plasma glucose - will be analyzed by local laboratory 
 
PK – plasma concentrations of tesofensine/metoprolol will be measured. Each PK blood 
sample must have time of draw attached to it as well as timing of the last dose of the study 
mediation taken prior to the blood draw. The analyses will be done by sponsor selected 
external laboratory: Bioanalytical and ADME Labs. Q2 Solutions, 19 Brown Rd, Ithaca, NY 
14850, USA. 
 
6.15 
SUBJECTS’ DIARIES  
Subject diaries for the second open label extension on Day 180 (Visit 17) will be provided. 
Subject’s caregiver/guardian/parents will be asked on behalf of subject to record in the diary 
the following: date, taking of the study medication, AEs, concomitant medication, 
hypoglycemic episodes. 
 
7 
SAFETY REPORTING 
All AEs occurring after the randomization of the subject will be reported as AE (if any AEs 
occurred between screening and randomization will be reported in medical history, but not as 
a AE). The report will include information on onset and stop dates, nature, severity (=grading, 
see below), seriousness, interventions and medications required, and outcome. SAEs will be 
reported to the regulatory authorities and Independent Ethics Committees (IECs) according to 
local regulations, and will be followed-up until the resolution of the event.  
At each visit, subject together with help of subject’s parents/guardians/caregivers will be 
asked:  “Do you currently (or did you) experience any symptoms that are not associated with 
your disease (since the last visit)?” Any symptom is to be entered into the Adverse Event 
eCRF. 
Laboratory or vital signs abnormalities are to be recorded as AEs only if they are medically 

 
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relevant, i.e., symptomatic, requiring corrective study medication, leading to discontinuation 
or fulfill a criterion for an SAE. In the case of chronic disease, if the disease is known and 
documented when the subject enters the study, only worsening (increased frequency and/or 
intensity of the episodes/attacks) will be documented as an AE.  
 
7.1 
DEFINITIONS 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have a causal relationship with this treatment. An adverse event (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. This includes all unintended or 
unforeseeable signs and symptoms, and addition: 
 All suspected IMP adverse reactions 
 Psychological symptoms (including aggressive behavior against themselves or others 
that occur in a temporal association with the use of the drug or medical device, 
independent of a causal relationship with the use) 
 Apparently unrelated illnesses, including the worsening of a preexisting illness  
 Injury or accidents.  Note that if a medical condition is known to have caused the 
injury or accident (a fall secondary to dizziness), the medical condition (dizziness) and 
the accident (fall) should be reported as 2 separate adverse events.  The outcome of the 
accident (hip fracture secondary to the fall) should be recorded in source documents 
 Abnormalities in physiological testing or physical examination findings that require 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] 
test) 
 Laboratory abnormalities that require clinical intervention or further investigation 
(beyond ordering a repeat [confirmatory] test) unless they are associated with an 
already reported clinical event 
Each adverse event is to be classified by the investigator as serious or non-serious. 
 
7.2 
ADVERSE EVENT 
All AEs encountered after the randomization will be recorded in detail indicated in the eCRF, 
regardless of their relationship to the investigational study product as assessed by the 
investigator. The investigator must record all directly observed adverse events and all adverse 
events spontaneously reported by the subject or parents/guardians/caregivers during the study. 
AEs will be coded by use of an internationally recognized dictionary (MedDRA). Details are 
described in the study specific Data Management Plan. 
 
7.3 
GRADING OF ADVERSE EVENT SEVERITY 
The investigator will use the adjectives MILD, MODERATE, or SEVERE to describe the 
maximum intensity of each adverse event.  For purposes of consistency, these intensity grades 
are defined as follows: 
 
Mild 
Does not interfere with subject’s usual age-appropriate 
instrumental* activities of daily life (ADL) 
Moderate 
Interferes with subject's usual age-appropriate instrumental* 
activities of daily life (ADL) 

 
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Severe 
Interferes with subject's usual age-appropriate self care** 
activities of daily life (ADL) 
 
*Instrumental ADL refer to preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc. 
**Self care ADL refer to bathing, dressing and undressing, 
feeding self, using the toilet, taking medications, and not 
bedridden. 
 
7.4 
CAUSALITY OF AE 
The following scale will be used for rating the causal relationship of the AE to the 
investigational study product: 
Certain: A clinical event, including laboratory test abnormality, occurring in a plausible time 
relationship to drug administration, and which cannot be explained by concurrent disease or 
other drugs or chemicals. The response to withdrawal of the drug (dechallenge) should be 
clinically plausible. The event must be definitive pharmacologically or phenomenologically, 
using a satisfactory rechallenge procedure if necessary. 
 
Probable/Likely: A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, unlikely to be attributed to concurrent disease or 
other drugs or chemicals, and which follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not required to fulfill this definition. 
 
Possible: A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, but which could also be explained by concurrent 
disease or other drugs or chemicals. Information on drug withdrawal may be lacking or 
unclear. 
Unlikely or Unrelated: A clinical event, including a laboratory test abnormality, with a 
temporal relationship to drug administration that makes a causal relationship improbable, and 
in which other drugs, chemicals or underlying disease provide plausible explanations. 
or 
The event may or may not follow a reasonable temporal sequence from administration of the 
investigational study medication and is clearly related to other factors, such as other drugs, 
chemicals, underlying disease, therapeutic intervention, or concomitant therapy. 
Actual changes in severity or causal relationship of a medical occurrence require the 
completion of a new line in the AE form in the CRF. 
 
7.5 
OUTCOME OF AE 
The outcome type and the follow-up of subjects with AEs should be specified. Outcome of 
adverse event may include at time of last observation: Recovered / resolved; Not recovered / 
not resolved; Recovered / resolved with squeal; Fatal; Unknown. 
 
AEs requiring therapy must be treated by recognized standards of medical care to protect the 
health and welfare of the subject. Appropriate equipment and medicines must be available to 
ensure the best possible treatment of emergency situations. Action(s) taken: Study treatment 
withdrawn; Dose reduced; Dose increased; Dose not changed; Unknown; Not applicable. 
 

 
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7.6 
UNEXPECTED ADVERSE REACTION 
An Unexpected Adverse Reaction is an Adverse Drug Reaction (ADR), the nature or severity 
of which is not consistent with the applicable product information, e.g. investigator's brochure 
for an unauthorized study treatment, or Summary of Product Characteristics for an authorized 
product. 
 
7.7 
SERIOUS ADVERSE EVENT  
A serious adverse event (SAE) is any adverse event that at any dose is 
- 
Fatal 
- 
Life-threatening 
- 
Results in a persistent disability or incapacity 
- 
Results in a congenital abnormality or birth-defect 
- 
Results in or prolongs in-patient hospitalization; or 
- 
Is otherwise classified as medically significant 
Elective surgeries are not considered as SAEs and do not have to be reported as such. 
In this context, the term life threatening refers to an event in which the subject was at 
immediate risk of death at the time of the event; it does NOT refer to an event, which might 
have caused death if it would have been more severe. 
In general, hospitalization signifies that the subject has been detained at the hospital or 
emergency ward (usually involving at least an overnight stay) for observation and/or 
treatment that would not have been appropriate in the physician's office or outpatient setting. 
When in doubt as to whether ‘hospitalization' occurred or was necessary, the AE should be 
considered serious. Hospitalization for elective surgery or routine clinical procedures that are 
not the result of an AE (e.g., elective surgery for a pre-existing condition) need not be 
considered AEs.  
 
Any important medical event that may not be immediately life threatening or result in death or 
hospitalization but, based upon appropriate medical judgment, may jeopardize the subject or 
may require medical or surgical intervention to prevent one of the other outcomes listed in the 
definition above should also be reported as a SAE.  Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization. 
 
Hospitalization for diagnostic or therapeutic procedures in the absence of any associated AE 
will not be considered as a SAE, except when otherwise required by Regulatory Authorities.   
 
7.8 
SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION  
A suspected unexpected serious adverse reaction is an adverse reaction that is both 
unexpected (not consistent with the applicable product information) and meets the definition 
of a Serious Adverse Event. 
 
7.9 
RECORDING OF ADVERSE EVENTS 
At each visit/assessment/call after the randomization, all adverse events, either observed by 
the investigator, or reported by the subject or parents/guardians/caregivers spontaneously, or 
reported in response to a direct question, must be evaluated by the investigator and recorded 
in subject´s source documentation and on the AE form of the eCRF. 

 
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Pre-existing Conditions 
Pre-existing conditions or hospitalization for elective surgery or routine clinical procedures 
that are not the result of an adverse event need not be considered adverse events. Pre-existing 
condition should be recorded in subject´s source documentation and on the medical history 
form of the eCRF. 
Overdose 
An overdose of the tesofensine is defined in this study as six times of single dose and 
metoprolol as four 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.  
 
Pregnancy 
Female subjects must be instructed to notify the investigator immediately if they become 
pregnant during the study. Pregnancies occurring during the study must be reported by the 
investigational staff within 24 hours of their knowledge. Study medications will be 
immediately discontinued and study medications will not be tapered. Follow-up information 
regarding the outcome of the pregnancy and any postnatal sequelae in the infant will be 
required. Pregnancy will be recorded as an AE in all cases. It will be classified as an SAE 
only if it fulfills SAE criteria. eCRF will be completed and pregnant subjects will be follow-
up until the outcome of the pregnancy has been determined.  
 
 
7.10 
REPORTING PROCEDURE OF SERIOUS ADVERSE EVENTS 
The investigator must complete and submit an SAE report for all SAEs, regardless of the 
causal relationship to study medication as soon as possible, in any case within 24 hours of 
having received information on the event. The initial report can be followed by a follow-up 
report as soon as the investigator obtains more specific information on the event.  
 
Any serious AE must be reported by investigator to the Sponsor´s delegate for 
Pharmacovigilance within 24 hr by fax or email: 
 
Address:  
Institute of Clinical Pharmacology 
Hannover Medical School, Carl-Neuberg-Str. 1 
D-30625 Hannover, Germany 
Telephone:   +49-511-532-3959 
Fax: 
 
+49-511-53216-2794 
Email:  
sae-reporting@mh-hannover.de 
 
Care should be taken to ensure that the subject's identity is protected and the subject’s 
identifiers in the clinical study are not included on any copy of source documents provided to 
the sponsor. Post-study SAEs may be reported in an expedited manner to the sponsor at the 
investigator´s discretion. 
All data updates should be recorded in the eCRF as appropriate, and further documentation as 
well as additional information (e.g. laboratory data, concomitant medication, subject status) 
should be sent (by e-mail) to the sponsor within 24 hours of knowledge. In addition, every 

 
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effort should be made to document further any SAE that is fatal or life threatening within 1 
week (7 days) following initial notification.  
The sponsor’s delegate for pharmacovigilance will make expedited reports of all SAEs that 
are both unexpected and causally related to the IMP, to the Regulatory Authorities, IECs as 
appropriate and to the investigators at other investigational sites. In addition, the sponsor’s 
delegate for pharmacovigilance may make expedited reports of all SAEs that are expected and 
causally related to the IMPs to the Competent Authorities, according to the European 
directive 2001/20/EC and the local regulations. The sponsor’s delegate for pharmacovigilance 
will report all safety observations made during the conduct of the study in the clinical study 
report. Details of SAE case exchange between the Sponsor´s delegate for pharmacovigilance, 
the Sponsor, National Competent Authorities and Ethics Committees will be set forth in a 
separate Safety Management Plan.  
7.11 
FOLLOW-UP OF ADVERSE EVENTS  
The investigator must ensure that follow-up of the subject is appropriate to the nature of the 
event, and that follow-up continues until the event is stabilized or resolved. The investigator 
must immediately inform the sponsor of any secondary worsening that meets at least one 
criterion for seriousness. The investigator should take all appropriate measures to ensure the 
safety of the subjects, in particular he or she should follow up the outcome of any AEs until 
they return to normal or the subject’s condition stabilizes.  
 
Subjects who have experienced SAEs must be followed up until clinical recovery is complete 
and laboratory results have returned to normal, or until progression has been stabilized. This 
may imply that follow-up will continue after the subject has left the clinical study and that 
additional investigations may be requested by the sponsor. If the follow-up of the subject is 
not done by the investigator him or herself (e.g. hospitalization followed by a specialist or the 
subject 's general practitioner), the investigator will do everything to establish or maintain 
contact with the person or department in charge of follow-up of the subject to obtain any 
follow-up information.  
 
If the investigator learns of an SAE within 30 days after the end of the study, this should be 
reported to the sponsor within 24hours from the investigator becoming aware of the event, 
regardless of whether or not there is a causal relationship with the IMP.   
 
7.12 
ANNUAL SAFETY REPORTS 
Once yearly or upon request by the National Competent Authorities the Sponsor’s delegate 
for pharmacovigilance will write down an Annual Safety Report, which will adhere to the 
Development Safety Update Report (DSUR) format (ICH E2F guideline) and contain a list of 
Serious Adverse Events an analysis of the study’s subjects’ safety. This report will be sent to 
Regulatory Authorities and to the IECs in the 60 days after the anniversary of the first 
inclusion. Details of DSUR preparation, review and submission will be set forth in a separate 
Safety Management Plan.  
When the Step 2 double-blind part is completed, it will be unblinded and reported, even 
though the OLE will still be ongoing. 
 

 
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8 
DESCRIPTION OF STATISTICAL METHODS 
8.1 
DESCRIPTION OF STATISTICAL METHODS 
CRO selected and designated by the Sponsor will be responsible for the statistical analysis. 
The statistical planning and conduct of analyses of the data from this study will follow the 
principles defined in relevant ICH guidelines and CRO’s biostatistical standard operating 
procedures (SOPs). A general description of the statistical methods to be used is given in this 
chapter, specific details will be provided in the Statistical Analysis Plan (SAP), which will be 
prepared before data base lock. All statistical analyses will be performed using SAS® (SAS 
Institute Inc., Cary, North Carolina, United States of America [USA]), version 9.4 or later. 
 
8.2 
SAMPLE SIZE CALCULATION 
As this is an explorative study no formal sample size calculation was done. Eligible patients 
are restricted to completers from step 2 in the double-blind part of the study. 
 
8.3 
SELECTION OF SUBJECTS FOR ANALYSES 
The following analysis sets are defined in accordance with the ICH-E9 guidance (5): 
 
Full Analysis Set (FAS) 
Includes all randomized and treated subjects with post-dose data collected. Subjects in the 
FAS will contribute to the evaluation ‘as treated’. 
 
Per-Protocol Population (PPP):  
Includes all randomized and treated subjects without any major protocol violations. Subjects 
in the PPP will contribute to the evaluation ‘as treated’.  
 
Safety Analysis Set:  
Includes all subjects receiving at least one dose of the investigational product or its 
comparator. Subjects in the safety set will contribute to the evaluation ‘as treated’.   
 
The primary analyses of primary and secondary endpoints will be based on the FAS. 
Sensitivity analyses will be based on the PPP. The analyses of the safety endpoints will be 
based on the Safety Analysis Set.  
 
Before data are released for statistical analysis, a blinded review of all data will take place to 
identify protocol deviations that may potentially affect the results. Furthermore, outliers will 
be identified by data review according to ICH-E9 (5). In addition, protocol deviations, which 
may potentially affect the results, will be identified and it will be evaluated if subjects and/or 
data should be excluded from the analysis. Obviously erroneous data points may be excluded 
from the analyses. The decision to exclude data points from the statistical analysis is the joint 
responsibility of the sponsor, the investigator and the CRO statistician.  
 
The subjects or observations to be excluded and the reason for their exclusion will be 
documented and signed by those responsible prior to database release. The documentation 
will be stored together with the remaining study documentation. The subjects and 
observations excluded from analysis sets, and the reason for this will be described in the 
clinical study report. 
 

 
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8.4 
STATISTICAL METHODS 
All primary and secondary endpoints will be summarized by treatment and visit using 
descriptive statistics. Continuous endpoints are summarized by the arithmetic mean, 
geometric mean (when applicable), median, standard deviation, coefficient of variation (CV, 
when applicable), minimum and maximum value. If appropriate 95% confidence intervals for 
the mean will be given in addition. Categorical endpoints are summarized by the number (N) 
and percentage (%). Moreover, complete listings of individual values for all endpoints will be 
provided. Individual and mean curves for the 24-h profiles will be plotted by visit over the 
sampling period. Further figures will be chosen and described in the SAP. Subject disposition 
will be tabulated including the numbers of screened subjects, screening failures, subjects 
exposed to study product, subjects completing the study and subjects in the FAS, PPP and 
Safety Analysis Set. Subjects withdrawn from the study will be listed including the primary 
reason for withdrawal. 
 
8.5 
ANALYSIS OF THE PRIMARY ENDPOINT 
Primary endpoint will be summarized with mean estimate, standard deviation, range and 95% 
confidence interval for the mean. The impact of treatment allocation in the double-blind part 
will be checked graphically. 
 
8.6 
ANALYSIS 
OF 
THE 
SECONDARY 
& 
EXPLORATORY 
ENDPOINTS 
 
Continuous data will be summarized using non-missing counts, mean, standard deviation, 
median, minimum, maximum and 95% confidence interval for the mean when appropriate. 
Categorical data will be summarized using counts and percentages. The impact of treatment 
allocation in the double-blind part will be checked graphically. 
 
Tesofensine and metoprolol concentration will be summarized for each assessment point 
including measures of geometric means and coefficient of variation. The individual PK data 
collected during the double-blind (Step 2) and the open extension phase will further be 
presented graphically.  
 
 
Adverse events will be coded according to MedDRA. The number and percentage of subjects 
experiencing adverse events in each treatment group will be tabulated by MedDRA system 
organ class and preferred term.  
 
Secondary endpoints evaluated will be (not a complete list): 
• 
Change from baseline to end of treatment in mean HR 
• 
Change from baseline to end of treatment in mean SBP 
• 
Change from baseline to end of treatment in mean DBP 
• 
Change from baseline to end of treatment in HQCT 
• 
Change from baseline to end of treatment in HbA1c 
• 
Change from baseline to end of treatment in insulin 
• 
Change from baseline to end of treatment in lipids 
• 
Change from baseline to end of treatment in FPG 
• 
Change from baseline to end of treatment in fasting insulin 
• 
Change from baseline to end of treatment in waist circumference 
• 
Change from baseline to end of treatment in fat- and fat-free mass 

 
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• 
PK levels collected for tesofensine and metoprolol 
 
Other secondary endpoints may be added and will be described in the SAP. 
 
8.7 
SAFETY CRITERIA 
• 
AEs 
• 
Clinical labs (Hematology, Blood Chemistry) 
• 
ECG 
• 
Vital signs 
• 
Physical examination 
 
The safety endpoints will be based on the Safety Analysis Set. Continuous data will be 
summarized using non-missing counts, mean, standard deviation, median, minimum, and 
maximum. Categorical data will be summarized using counts and percentages. 
 
 
9 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
Source data are all the information in original records and certified copies of original records 
of clinical findings, observations, or other activities pertaining to the study, which are 
necessary for the reconstruction and evaluation of the study. The investigator will ensure 
direct access to these source data to the study monitor, auditor, ethical committee and regulatory 
inspector. 
 
For each subject enrolled, the investigator will indicate in the source record(s) that the subject 
participates in this study. The investigator will maintain adequate case histories for each 
subject enrolled. Source records should be preserved for the maximum period of time 
permitted by local regulations. 
 
Permission for direct access to subject’s data will be sought in writing by the investigator and 
from the subject or parents/guardians/caregivers as part of the informed consent procedure. 
This gives permission to examine, analyze, verify and reproduce any records and reports that 
are important to the evaluation of the study. Any party (e.g., domestic and foreign Regulatory 
Authorities, study monitor and auditors) with direct access must take all reasonable 
precautions within the constraints of the applicable regulatory requirement(s) to maintain the 
confidentiality of the subject’s identities and sponsor’s proprietary information. It is the 
monitor’s responsibility to verify that each subject has consented, in writing, to direct access. 
It is to be ensured by the investigator that documents that are given to Saniona A/S or its 
representatives do not contain the name or address of the subject, or other information that 
would affect the anonymity of the subject. 
 
The investigator will enter the following data in the source records of the subject: demographic 
information, medical history, concomitant medication, clinical findings from physical 
examination, vital signs, finding from urine pregnancy tests (if applicable), notes concerning the 
study procedures, study medication and all adverse events. 
 
9.1 
SOURCE DATA 
Source data is information included in the original records and/or certified copies of original 
records from clinical results, observations or other activities pertaining to the study, which are 
necessary in order to reconstruct and evaluate a clinical study. The investigator will ensure 

 
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direct access to these source data to the study monitor, sponsor’s representative, auditor, ethical 
committee and regulatory authority. 
 
For each enrolled subject, the investigator will specify that the subject is taking part in this 
study. The investigator will maintain adequate case histories and proper notes for each of the 
included subjects. Source data will be archived for the maximum period of time permitted by 
local requirements. 
 
The following documentation is considered as source documentation for this study: 
 The informed consents and the subject’s medical files (including laboratory reports) 
serve as source data 
 Subjects’ diaries 
 
The following information must be entered in the subject’s source documents: 
 Subject identification number 
 Gender, body measurement 
 Medical history and concomitant illness 
 Concomitant medication 
 Unambiguous reference to the clinical study (clinical study number, subject screening 
and randomization number) 
 Information on inclusion/ exclusion criteria 
 Informed consent process  
 All visit dates 
 Details of study medication administration (start and end dates, study medication 
number, randomization confirmation) 
 Physical examination and result done at each visit and phone calls 
 Information about the occurrence, improvement, or worsening of AE(s)/ concomitant 
illness 
 
9.2 
SUBJECT IDENTIFICATION LIST AND SCREENING LOG 
In order to permit easy identification of the individual subject during and after the clinical 
study, the investigator is responsible for keeping an up-dated “Subject Randomization List". 
For completeness the monitor will review this document. A “Screening Log” that reports all 
subjects that were seen to determine eligibility for inclusion in the clinical study also has to be 
completed by the investigator. The Subject Screening Log and Subject Randomization Log 
may be combined in one list. 
 
10 
QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 
DEFINITIONS 
Quality Assurance 
A quality assurance (QA) audit as well as a regulatory inspection may be performed to 
determine if the rights and the well-being of the subjects enrolled were protected and if the 
study was conducted as per protocol, ICH GCP and applicable regulatory requirements, and if 
the data relevant for the evaluation of the investigational medicinal product were reported to 
the sponsor. The involved CRO will implement a QA system for their respective study-related 
activities. 

 
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Quality Control 
The monitor will visit the site at periodic intervals in order to check the source data and 
records pertaining to the study, to make sure that the investigator follows the study protocol 
and to verify the completeness, correctness and accuracy of all CRF entries compared to 
source data. The investigator will offer the monitor maximum cooperation, in order to find a 
prompt solution to any possible discrepancies or inaccuracies.  
 
10.2 
AUDITS AND INSPECTIONS 
An independent quality control unit may audit the study protocol, the documentation and, if 
applicable, the performance of the study and the clinical study report to ensure that the study 
will be performed in accordance with ICH-GCP guidelines, FDA requirements and other 
regulatory requirements. The investigator will make all study-related source data and records 
available to a medically qualified quality assurance auditor mandated by the sponsor, or to 
regulatory inspectors, after reasonable notice. The main purposes of an audit or inspection are 
to confirm that the rights and welfare of the subjects have been adequately protected, and that 
all data relevant for the assessment of safety and effectiveness of the investigational medicinal 
product have been reported to the sponsor. 
 
11 
ETHICS 
11.1 
BASIC PRINCIPLES AND ETHICAL CONSIDERATIONS 
This study will be conducted in accordance with the ethical principles that have their origins 
in the Declaration of Helsinki. The study and any subsequent amendment(s) will be reviewed 
by an Independent Ethics Committee (IEC). The study will be conducted in compliance with 
the protocol, ICH GCP regulations and the applicable regulatory requirements. The regulatory 
application or submission for regulatory approval will be made by the sponsor’s CRO as 
required by national law. 
 
11.2 
APPROVALS 
The sponsor will authorize a CRO for submitting the documents to the IEC and RA. 
 
11.3 
ETHICS COMMITTEE  
This protocol, a sample subject information sheet and informed consent form, and any other 
materials provided to the subjects and/or parents/guardians/caregivers where applicable 
according to existing country legislation will be submitted to the appropriate IEC. The study 
approval letter must be available before any subject is exposed to a study-related procedure, 
including screening tests for eligibility. During the study, the following documents will be 
sent to the IEC for their review: 
 Changes to the Investigator’s Brochure 
 Reports of adverse events that are serious, unlisted and associated with the IMP  
 All protocol amendments and revised informed consent forms (if any) 
The sponsor’s CRO will provide a safety update of the study to the local IEC including line 
listings, individual reports of SUSARs, if applicable, and a discussion of AEs annually, or 
more frequently if requested based on valid legislation requirements. At the end of the study, 
the investigator will notify the IEC/RA about the study completion. Furthermore, he/she will 
provide the synopsis of the final report to the RA/IEC within one year after the end of the 
clinical study.  
 

 
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11.4 
REGULATORY AUTHORITY 
The study including all relevant documentation and information need to be submitted to the 
relevant Regulatory Authority for notification or approval according to valid legislation 
requirements. 
 
11.5 
PROTOCOL MODIFICATIONS 
If it turns out during the study that some procedures cannot be conducted according to the 
clinical study protocol, the principal investigator has to be informed immediately by the study 
personnel. The principal investigator will be responsible for informing the clinical monitor or 
the clinical project manager of the issue. It will then be decided if a protocol amendment has 
to be written and approved by the RA/IEC before the study can continue. Any amendment 
becomes part of the clinical study protocol. 
 
The amended protocol will be approved and signed by the relevant personnel at Saniona A/S 
and by the principal investigator. The investigator should not implement any deviation from, 
or changes of the protocol, without agreement by Saniona A/S and prior review and 
documented approval/favorable opinion of the appropriate IEC and, if legally required, 
Regulatory Authority, except where necessary to eliminate an immediate hazard to the 
subjects, or when the change(s) that were approved by Saniona A/S involve only logistical or 
administrative aspects of the study. 
 
11.6 
SUBJECT INFORMATION AND INFORMED CONSENT 
RA/IEC approval of the written Subject Information and Informed Consent (for subjects/ 
parents/guardians/caregivers where applicable according to existing country legislation) must 
be obtained prior to their use. This consent form contains a phrase by which consent is given 
for the access to the non-personalized data by the sponsor, national and regulatory authorities. 
In addition, it states that the subject is free to withdraw from the study at any time without any 
negative consequences. The Subject Information gives a complete and comprehensive 
explanation of the significance, nature, extent and possible risks of the study.  
The informed consent form must be signed, with name and date noted by the subject and/or 
parents/guardians/caregivers where applicable according to valid country legislation. The 
investigator will complete the informed consent section of the eCRF for each subject enrolled. 
If new information becomes available that potentially affects the subject’s safety or 
willingness to continue in the study, or if a protocol amendment is issued that affects subject’s 
safety, study procedures or any aspects of the study that may influence the subject’s 
willingness to continue in the study, the subject information leaflet and informed consent 
form will be revised. After the new documents have received approval from the RA/IEC in 
accordance with applicable regulations, the subject/parents/guardians/caregivers where 
applicable according to existing country legislation will be asked to sign the new consent 
form to confirm his or her willingness to continue in the study. 
 
Each subject and/or parents/guardians/caregivers will be informed that his/her source records 
may be reviewed by the monitor, a quality assurance auditor or an IEC/Regulatory Authority 
inspector, in accordance with applicable regulations. All personal information which the 
subject will reveal to the investigator and which does not pertain to the study will be considered 
confidential. 
 

 
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11.7 
PARTICIPANT CONFIDENTIALITY 
The investigator will ensure that the subject's anonymity will be preserved. On eCRFs or any 
other documents submitted to the sponsor, the subjects will not be identified by their names, 
but by a study specific identification code. Documents not intended for the sponsor, i.e. the 
confidential subject identification code, original consent forms and source records will be 
maintained by the investigator as strictly confidential and in a secured place. The subjects will 
be informed that all their study results will be handled in strictest confidence. 
 
12 
DATA HANDLING AND RECORD KEEPING 
12.1 
DATA COLLECTION AND DOCUMENTATION 
Relevant study data for statistical analysis and study report are to be recorded in the eCRFs. 
Subject’s data have to be reported on the eCRFs in an anonymous fashion, the subject only 
being identified by the subject number. The investigator will be responsible for the 
completeness, accuracy and legibility of the information in the eCRF and other study 
documents. The study monitors then have to check the eCRFs against the source documents 
for accuracy and validity as per the monitoring schedule, as applicable. Upon completion of 
the examination, eCRF completion is expected at each Unit to ensure quality of data and 
subject safety. Once eCRFs are completed, they will be available for review by the study 
monitor and CRO Clinical Data Management. Completed eCRFs will be reviewed remotely 
for logical discrepancies. The study monitor will ensure that all data queries and subsequent 
amendments in the eCRF documentation are made according to GCP guidelines. 
 
12.2 
STUDY MONITORING, SOURCE DATA VERIFICATION AND 
DATA MANAGEMET  
Clinical Data Management is the responsibility of the CRO. All Data Management procedures 
will be detailed in a separate document known as the Data Management Plan (DMP). The 
DMP will also describe the Clinical Data Management System (CDMS) that will be used to 
collect data with an electronic Case Report Form (eCRF) in detail. For each enrolled study 
participant an eCRF will be maintained. ECRFs must be kept current to reflect subject status 
at each phase during the course of study. Data on subjects collected on eCRFs during the 
study will be documented in an anonymous fashion and contains an electronic audit trail.  
In compliance with 21 CRF part 11 each user of the CDMS will be assigned a unique user 
name and will be allocated to a special user role. This special user role controls the user’s 
permissions in the electronic data capture system depending on the function within the study. 
All staff involved in the study in each site has to be instructed how to maintain the eCRF and 
therefore be able to edit eCRF entries. The investigator will be responsible for the 
completeness, accuracy and legibility of the information in the eCRF and other study 
documents. The study monitors then have to check the eCRF against the source documents for 
accuracy and validity as per the monitoring schedule, as applicable. Upon completion of the 
examination, eCRF completion is expected at each site to ensure quality of data and subject 
safety. Once eCRFs are completed, they will be available for review by the study monitor and 
CRO Clinical Data Management. Completed eCRFs will be reviewed remotely for logical 
discrepancies. The study monitor will ensure that all data queries and subsequent amendments 
in the eCRF documentation are made according to GCP guidelines. 
 
12.3 
DATA MANAGEMENT PLAN  
The complete Data Management process will be described in detail and agreed on in the Data 
Management Plan for this study. 

 
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12.4 
CASE REPORT FORMS (CRFS) 
The Data Management Department will provide the eCRFs. All further information regarding 
the eCRFs and the data flow will be described and agreed on in the Data Management Plan 
for this study. 
 
Database Lock  
After all data are entered, all queries are solved and quality control procedures have been 
completed respectively each subject’s evaluability is determined, the database will be 
authorized for lock. Electronic case report form data per site will be provided to the 
responsible investigator at the end of the study and will need to be retained by the 
investigator. The complete data will be provided to the sponsor at the close of the study for 
archiving. 
In exceptional circumstances, when critical reasons justify, there may be a need to perform 
updates to the database after it has been locked. A database that is locked and released for 
analysis will only be unlocked if an error is identified that will significantly affect the 
statistical outcome of the analysis of the efficacy parameters or change the safety profile of 
the study.  
12.5 
INVESTIGATOR FILE 
The investigator will be responsible for keeping all records so that the course of the study is 
duly documented. Copies of essential documents related to the study must be filed by the 
investigator as required by ICH GCP and applicable regulatory requirements. No document 
concerning the study may be destroyed without prior written agreement between the 
investigator and the sponsor. Should the investigator elect to assign the study documents to 
another party, or to move them to another location, the sponsor must be informed without 
delay. 
 
12.6 
LOGS 
The investigator or/and site pharmacists will be responsible for recording and keeping all 
records regarding study medication shipment; dispensing and accountability records and these 
must be filed by the investigator as required by GCP and applicable regulatory requirements. 
The investigator will ensure an adequate confidentiality of the subjects' identification list 
providing the only connection between source data, and anonymous data in the eCRF for the 
sponsor. The investigator will ensure that this secret list is maintained securely for a period of 
15 years at minimum. 
 
12.7 
PROTOCOL COMPLIANCE 
The investigator agrees by signing the protocol that the study will be conducted in compliance 
with the protocol, ICG GCP and the applicable regulatory requirements. 
 
12.8 
RECORD KEEPING 
To enable evaluations and/or audits from regulatory authorities or Sponsor, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, e.g., case report forms and hospital records), all original signed 
informed consent forms, copies of all case report forms, source documents, and detailed 
records of treatment disposition.  The records should be retained by the investigator according 
to local regulations or as specified in the Clinical Trial Agreement, whichever is longer. 
 

 
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If the investigator relocates, retires, or for any reason withdraws from the study, Sponsor 
should be prospectively notified.  The study records must be transferred to an acceptable 
designee, such as another investigator, another institution, or to Sponsor.  The investigator 
must obtain Sponsor’s written permission before disposing of any records. 
 
13 
FINANCE AND INSURANCE 
13.1 
COMPENSATION TO INVESTIGATOR 
Financial contracts will be signed between the sponsor and the investigator (or a 
representative of the hospital/clinic/unit) before commencement of the study.  
 
13.2 
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 Saniona A/S together with help of the contracted CRO.  
 
14 
PUBLICATION POLICY 
14.1 
REPORTING AND PUBLICATION 
CRO will prepare a study report 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. In accord with 
standard editorial and ethical practice, the sponsor will support publication of multicentre 
studies only in their entirety and not as individual site data. Sites or investigators must not 
publish any data from this study without obtaining prior written permission from the Sponsor. 
 
 

 
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15 
REFERENCES 
  
1. https://ghr.nlm.nih.gov/condition/prader-willi-syndrome 
2. Astrup A, Madsbad S, Breum L, et al. Effect of tesofensine on bodyweight loss, body 
composition, and quality of life in obese patients: a randomised, double-blind, 
placebo-controlled trial. Lancet 2008;372:1916-1913. 
3. Bentzen BH, Grunnet, M, Hyveled-Nielsen, L. Anti-Hypertensive Treatment 
Preserves Appetite Suppression While Preventing Cardiovascular Adverse Effects of 
Tesofensine in Rats. Obesity 2013;21:985-992. 
4. ICH Harmonised Tripartite Guideline. Good Clinical Practice [Internet]. 1996 [cited 
2015 Oct 28]. Available from: 
https://firstclinical.com/regdocs/doc/?db=ICH_E6_Good_Clinical_Practice 
 
 

 
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16 
Appendices 
16.1 
Appendix I: table of recommended concomitant medication use 
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 
Y 
N 
Prohibited for 2 weeks prior to 
randomisation, however, hypnotics 
and/or anxiolytics at a stable dose 
for at least 4 weeks prior to 
screening and up to the follow-up 
visit could be alowed, i.e.up to 
zolpidem (10 mg/day), choral 
hydrate (1 g/day), triazolam (0.5 
mg/day), or lorazepam (1 mg/day) 
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 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 
 
Drug Class 
Episodic Use 
Chronic Use 
Comment 
Tricyclic antidepressants 
N 
N 
Drug inducing ocular toxicity Chloroquine 
Hydrochloroquine 
N 
N 
Non-drugs 
Weight loss supplements 
N 
N 

 
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Anti-depression, anxiety, epilepsy, psychotics OTC, 
supplements  
N 
N 
 
16.2 
STUDY FLOW CHART: VISITS 17 - 21 (all visits are ±3 day) 
 
 
Visit 
17 
 
Equal to last visit 
of first OLE 
 
Treatment 
18 
 
 
Treatment 
19 
 
 
Treatment 
20 
 
 
End of 
Treatment 
 
21 
 
 
End of study 
 
 
Day 
180 
210 (30 days 
± 3 days) 
240(30 days 
± 3 days) 
270(30 days 
± 3 days) 
300(30 days 
± 3 days) 
Obtaining second 
Addendum to double blind 
ICF for the second open 
label part 
X 
 
 
 
 
Subject screening number 
(keeping the same as in 
Step2 and the first OLE) 
X 
 
 
 
 
Psychiatric examination  
x 
x 
x 
x 
x 
Physical examination 
x 
 
 
x 
 
Vital signs 
x 
x 
x 
x 
x 
Weight, waist circumference 
x 
x 
x 
x 
x 
Height, calculation of BMI 
 
x 
 
 
 
 
HQCT 
x 
x 
x 
x 
x 
ECG 
x 
 
 
x 
 
Hematology 
x 
 
 
x 
 
Blood chemistry 
x 
 
 
x 
 
FPG, HbA1c 
x 
x 
x 
x 
 
Lipids, insulin 
x 
x 
x 
x 
 
DEXA 
x 
 
 
x 
 
PK sample 
x** 
x** 
x** 
x** 
x 
Drug dispensation and 
accountability 
x 
x 
x 
*x 
 
AEs 
x 
x 
x 
x 
x 

 
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Concomitant medication 
x 
x 
x 
x 
x 
Urinary pregnancy test 
x 
 
 
x 
 
Diary dispensation, Subject 
card for OLE dispensation 
x 
 
 
 
 
Diary review 
 
x 
x 
x 
x 
Diary collection 
 
 
 
x 
x 
Dispense Follow-up diary 
list 
 
 
 
x 
 
End of study form 
 
 
 
 
x 
 
*two half doses of metoprolol should be dispensed 
** Blood samples of metoprolol taken 2 and 4 hours after dose administration– to be done only 
once in each patient during the study. Time point for dosing and the two blood samples should 
be noted! 
 
 
 
 
Phone calls in-between the onsite visits will be used to provide additional reassurance 
regarding the safety of the subjects and collect adverse events. 
 
Visit 
17.1  
Phone call 
18.1 
Phone call 
19.1 
Phone call 
20.1 
Phone call 
Frequency  
Once per month 
Once per month 
Once per month 
Once per month 
AEs 
X 
X 
X 
X 
Hypoglycemic episodes (at 
DM subjects) 
X 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 
 
 
 

 
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16.3 
Hyperphagia Questionnaire for Clinical Trials (HQ-CT) 
Instructions: 
The following items refer to the person in your care and assessment of his/her food-related 
behavior during the past 2 weeks.     
 
 
 (1) During the past 2 weeks, how upset did the person generally become when denied a 
desired food? 
□ Not at all upset  
□ A little upset 
□ Moderately upset 
□ Very upset 
□ Extremely upset 
 
(2) During the past 2 weeks, how often did the person try to bargain or manipulate to get more 
food at meals? 
□ Never 
□ Up to 2 times a week 
□ 3 to 6 times a week 
□ Every day 
□ Several times a day 
 
 
(3) During the past 2 weeks, how often did the person forage through trash for food? 
□ Never 
□ 1 time 
□ 2 times 
□ 3 times 
□ 4 or more times 
 
(4) During the past 2 weeks, how often did the person get up at night to food seek? 
□ Never 
□ 1 time 
□ 2 times 
□ 3 times 
□ 4 or more times 
 
 
 

 
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(5) During the past 2 weeks, how persistent was the person in asking or looking for food after 
being told “no” or “no more”? 
□ Not at all persistent 
□ A little persistent 
□ Moderately persistent 
□ Very persistent 
□ Extremely persistent 
 
(6) During the past 2 weeks, outside of normal meal times, how much time did the person 
generally spend asking or talking about food? 
□ Less than 5 minutes a day 
□ 5 to 15 minutes a day 
□ 15 to 30 minutes a day 
□ 30 minutes to 1 hour a day 
□ More than 1 hour a day 
 (7) During the past 2 weeks, how often did the person try to sneak or steal food (that you are 
aware of)? 
□ Never 
□ 1 time 
□ 2 times 
□ 3 times 
□ 4 or more times 
 
(8) During the past 2 weeks, when others tried to stop the person from asking about food, how 
distressed did he or she generally appear?  
□ Not at all distressed  
□ A little distressed 
□ Moderately distressed 
□ Very distressed 
□ Extremely distressed 
 
(9) During the past 2 weeks, how often did food-related behavior interfere with the person’s 
normal daily activities, such as self-care, recreation, school, or work? 
□ Never 
□ Up to 2 times a week 
□ 3 to 6 times a week 
□ Every day 
□ Several times a day 
 

TM002 
 
CLINICAL STUDY PROTOCOL 
VERSIONS OVERVIEW 
 
TM002: A double-blind, randomized, placebo-controlled, multiple-dose, multi-centre safety and efficacy study of co-
administration of tesofensine/metoprolol in subjects with Prader-Willi syndrome (PWS) 
Saniona, A/S 
 
HUNGARY 
Version 
Date 
Approved by RA 
Approved by EC 
List of changes 
1.0 
25 September 
2016 
22 December 2016 
13 December 2016 
N/A 
1.1 
16 February 2017 
28 April 2017 
20 April 2017 
HQCT questionnaire added, 
Update of timelines of the clinical trial 
1.2 
25 July 2017 
26 September 2017 
18 September 2017 
Decrease of dose of tesofensin to 0,25mg 
Maximum number of randomized patients was increased to 20 
Wording of inclusion criteria No.7 was changed to „Growth 
hormone is allowed; but subject must be on a stable dose of 
growth hormone >2 months“ 
Update of timelines of the clinical trial 
Address of central laboratories (PK analysis) was changed 
1.3 
31 October 2017 
03 January 2018 
21 December 2017 
An unblinded interim analysis after Step 1 will be performed by 
Sponsor and interim analysis will be done 
Information about PK samples unblinding was added 
Step 2 will start only after RA/EC positive opinion regarding to 
interim analysis and unblinded data 
Chapter „Data safety monitoring board“ changed to „Interim 
analysis“ 
Update of timelines of the clinical trial 
 
 

TM002 
 
CLINICAL STUDY PROTOCOL 
VERSIONS OVERVIEW 
1.4 
13 March 2018 
24 May 2018 
02 May 2018 
Dose reduction of tesofersin and metoprolol in pediatric patients. 
Psychiatric examinations are added to each patient visit. 
Change in Follow up, V15. 
Data on the duration of the clinical trial were updated.  
Exclusion criterium No. 7 was extended. 
The minimum number of patients was adjusted to 5. 
1.5 
26 September 
2018 
12 November 2018 
30 October 2018 
An Open label extension was added to the trial. OLE will be 
directly linked to Step II. The last study visit of Step II will be the 
first visit of OLE. 
1.6 
31 January 2019 
26 February 2019 
13 February 2019 
A prolongation of the OLE phase was added to the trial. It will be 
directly linked to the OLE. The last study visit of OLE will be the 
first visit of the OLE II, thus there will be no discontinuation of 
medication of patients. 
The dosing schedule has been changed. Expected end is on Jun 
2019.  
 
Updated: 26.08.2019 

TM002 
 
CLINICAL STUDY PROTOCOL 
VERSIONS OVERVIEW 
 
TM002: A double-blind, randomized, placebo-controlled, multiple-dose, multi-centre safety and efficacy study of co-
administration of tesofensine/metoprolol in subjects with Prader-Willi syndrome (PWS) 
Saniona, A/S 
 
CZECH REPUBLIC 
Version 
Date 
Approved by RA 
Approved by EC 
List of changes 
1.0 
25 September 
2016 
Not approved, changes 
in protocol requested by 
SUKL during initial 
review 
12 October 2016 
N/A 
1.1 
12 November 
2016 
18 January 2017 
4 January 2017 
SUKL as a Czech RA was added to paragraphs where information 
about SUKL oversight/approval is needed  
Dietary instructions for patient suffered from diabetes were added  
Wording of paragraph „UNBLINDING“ was updated 
1.2 
16 February 2017 
22 March 2017 
29 March 2017 
HQCT questionnaire added, 
Update of timelines of the clinical trial  
1.3 
25 July 2017 
10 August 2017 
16 August 2017 
Decrease of dose of tesofensin to 0,25mg 
Maximum number of randomized patients was increased to 20 
Wording of inclusion criteria No.7 was changed to „Growth 
hormone is allowed; but subject must be on a stable dose of 
growth hormone “>2 months“ 
Update of timelines of the clinical trial 
Address of central laboratories was added 
1.4 
31 October 2017 
4 December 2017 
6 December 2017 
An unblinded interim analysis after Step 1 will be performed by 
Sponsor and interim analysis will be done, 
SUKL will be given all the unblided data for review  
Step 2 will start only after SUKL positive opinion regarding to 

TM002 
 
CLINICAL STUDY PROTOCOL 
VERSIONS OVERVIEW 
interim analysis and unblinded data 
1.5 
09 Feb 2018 
10 April 2018 
28 March 2018 
Dose reduction of tesofensine and metoprolol in pediatric 
patients. Psychiatric examinations are added to each patient visit. 
Change in Follow up, V15. 
Data on the duration of the clinical trial were updated.  
Exclusion criterium No. 7 was extended. 
The minimum number of patients was adjusted to 5. 
1.6 
09 September 
2018 
05 November 2018 
10 October 2018 
For CZ only. Open Label Phase was added.  
Visit V14 (last visit of step II) will be simultaneously first visit of 
OLE Phase for participated patient. 
To the Protocol Name was added „A 12 Weeks Open Label 
Extension. 
New exclusion and inclusion criteria were created.  
Overall study description was extended.  
Study procedure for V14-V18 are described in this Protocol. 
End of OLE was predicted to be in April/May 2019. 
Manufacture of IMP was changed. 
Unblinding is not applicable in OLE. 
For patient in OLE remain the same screening number as in step 2.  
 
1.7 
30 January 2019 
06 February 2019 
27 February 2019 
Second Open Label Phase was added. Last visit V17 of OLE will be 
first visit of OLE II.  
To the Protocol Name was added „Second 12 Weeks Open Label 
Extension. Inclusion and exclusion criteria were updated. 
Estimated end of study is on Jun 2019. 
 
 
Updated: 04.03.2019