Conditions: Confirmed Genetic Diagnosis of Prader-Willi Syndrome
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 18
Healthy volunteers: no

Brief summary:
Two-centre, double-blind, placebo-controlled, randomized, and multiple-dose clinical study followed by two open label extension periods.

Detailed description:
Two-centre, double-blind, placebo-controlled, randomized, and multiple-dose clinical study. Study medication will be administered for 91 days. The study will be conducted in two steps:

* Step 1 - 9 adult subjects with PWS was treated.
* Sponsor review - following the completion of the treatment of the adult subjects, unblinded efficacy, safety, Pharmacokinetic (PK) data as well as all data from the study in subjects with type 2 diabetes (TM001) will be reviewed by sponsor and an interim analysis will be done. Following competent authority positive opinion regarding the interim analysis and unblinded data the study will proceed to:
* Step 2 - 9 adolescent subjects with PWS was treated.
* OLE (Open Label Extension) I - Participation in a 12-week OLE I was offered to subjects who completed Step 2. 8 subjects entered OLE I.
* OLE (Open Label Extension) II - Participation in a 12-week OLE II was offered to subjects who completed OLE I. 6 subjects continued to OLE II.

Arms:
arm 1: Tesofensine + metoprolol administered once a day, in the morning with a meal arm 2: Placebo tablets matching tesofensine + metoprolol administered once a day, in the morning with meal

Interventions: intervention 1: Tesofensine/Metoprolol intervention 2: Placebos
Intervention descriptions: intervention 1: Study medication will be administered for 91 days. intervention 2: Study medication will be administered for 91 days.

Protocol document:
Prot_000.pdf: 
 
 
 
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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 
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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 
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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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Date: 30 January 2019 
 
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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 
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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 

SAP_001.pdf: 
T
GcP-Service 
STATISTICAL ANALYSIS PLAN 
Study Code 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 
Sponsor: 
Saniona, A/ S 
Baltorpvej 1 54 
DK 2750 Ballerup 
Denmark 
Author: 
Leontina Levenzon 
GCP-Service International Ltd. & Co. KG 
Anne-Conway-Str. 2 
28359 Bremen, Germany 
Tel +49 (0)421 89 67 66 31 
Date of document: 
27 December 2017 
Document v ersion: 
Final 1 .0 
The information provided in this document is strictly confidential. No part of this document may be reproduced, 
transmitted or copied in any form nor its contents disclosed to the third parties without prior written consent of 
Saniona, A/ S or a nominated representative. 


Saniona, A/ S 
Study TM002 
Document History 
Version 
Date 
Draft 0.1 
23-May-2017 
Draft 0.2 
30-Jun-2017 
Draft 0.3 
15-Aug-2017 
Final 1 .0 
27-Dec-2017 
CONFIDENTIAL 
Author(s) 
Leontina Levenzon 
Leontina Levenzon 
Leontina Levenzon 
Leontina Levenzon 
Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
Description 
First release 
Section 1 : adaption of versions of 
protocols 
Section 2.3: addition of HQCT in 
the study schedule tabler 
Section 
2.4.2.: 
addit ion 
of 
secondary obj ective (HQCT) 
Section 2 .8: adaption according to 
Protocol Amendments 
Section 1 : adaption of versions of 
protocols 
Finalization 
Page 2 of 33 


Signatures 
1 confirm that this Statistical Analysis Plan (SAP) accurately describes the planned statistical analyses 
to the best of my knowledge and was finalized before breaking the blind. 
Author: 
Review: 
Leontina Levenzon, M.Sc. 
Biostatistician 
GCP-Service lnt. Ldt & Co. KG 
Anne-Conway-StraBe 2 
283 59 Bremen, Germany 
Malte Braitmaier, M.Sc. 
Biostatistician 
GCP·Service lnt. Ldt & Co. KG 
Anne-Conway-StraBe 2 
28359 Bremen, Germany 
Approved: 
Roman Dvorak MD, PhD 
Chief Medical Officer 
Saniona, A/S 
Baltorpvej, 1 54 
DK 2750 Ballerup 
Denmark 
Date 
Signature 
nuc-to.{1 ~-
Date 
Signat e 


Saniona, A/S 
Study TM002 
Table of Contents 
Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
Document History ................................................................................................................ 2 
Signatures ............................................................................................................................ 3 
List of Abbreviations and Key Terms ................................................................................... 7 
1. 
Introduction .................................................................................................................. 9 
2. 
Study Design and Objectives ........................................................................................ 9 
2.1 
Study Design ........................................................................................................... 9 
2.2 
Treatments ........................................................................................................... 10 
2.2.1 
lnvestigational Medicinal Product .................................................................. 10 
2.2.2 
Placebo ........................................................................................................... l 0 
2.3 
Trial Schedule ....................................................................................................... 11 
2.4 
Study Objectives ··········································-····················································· 13 
2.4.1 
Primary Objective ........................................................................................... 13 
2.4.2 
Secondary Objectives ..................................................................................... 13 
2.5 
Study Hypothesis .................................................................................................. 13 
2.6 
Handling of Screening Failures and Withdrawals .................................................. 14 
2.7 
Randomization and Stratification ......................................................................... 14 
2.8 
Blinding ................................................................................................................. 14 
2.9 
Sample Size Calculation ........................................................................................ 14 
2 .1 0 
Planned Safety and PK Analysis ......................................................................... 1 5 
2 .11 
Handling of Changes to Study Protocol. ............................................................ 16 
3. 
Technical Aspects and Coding Conventions ............................................................... 16 
3.1 
Date Coding and Day Numbering ......................................................................... 16 
3.2 
Coding Systems and Conventions ........................................................................ 17 
3.2.1 
Coding of Adverse Events and Medical History .............................................. 17 
3.2.2 
Separation of Medical History from Concomitant Diseases ........................... 17 
3.2.3 
Coding of Medications ................................................................................... 17 
3.2.4 
Separation of Medications .............................................................................. 18 
4. 
Analysis Populations and Subgroups .......................................................................... 1 8 
4.1 
Analysis Populations ............................................................................................. 18 
CONFIDENTIAL 
Page 4 of 33 


Saniona, A/S 
Study TM002 
Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
4.2 
Subgroups ............................................................................................................ 18 
4.3 
Stratification ......................................................................................................... 18 
5. 
Data Handling ............................................................................................................. 19 
5.1 
Handling of Missing Data and Outliers ................................................................. 19 
5.2 
Handling of Data from Screening Failures and Withdrawals ................................. 19 
5.3 
Handling of Multiple Comparisons and Multiple Primary Variables ...................... 19 
5.4 
Data Review .......................................................................................................... 19 
6. 
Variables for Analysis ................................................................................................. 20 
6.1 
Demographics and Baseline Characteristics ......................................................... 20 
6.2 
Efficacy Endpoints ................................................................................................. 20 
6.2. l 
Primary Endpoint ............................................................................................ 20 
6.2.2 
Secondary Endpoints ...................................................................................... 21 
6.3 
Safety Endpoints ................................................................................................... 21 
6.3.1 
Safety Endpoints ............................................................................................ 21 
6.4 
Pharmacokinetic Endpoints .................................................................................. 22 
7. 
Statistical Analysis Methods ....................................................................................... 22 
7.1 Descriptive Statistics .................................................................................................. 22 
7.2 
Rounding Rules ..................................................................................................... 23 
7 .2.1 
Estimates of the Mean and Standard Deviation .............................................. 23 
7.2.2 
Other data ...................................................................................................... 23 
7.3 
Calculation of Study Days and Durations ............................................................. 23 
7.4 
Evaluation of Demographics and Baseline Characteristics .................................... 24 
7.4. l 
Disposition of Patients ................................................................................... 24 
7.4.2 
Demographics and other Baseline Characteristics ......................................... 24 
7.4.3 
Medical History, and Concomitant Diseases .................................................. 24 
7.4.4 
Previous and Concomitant Medication ........................................................... 24 
7.5 
Evaluation of Primary Endpoint ............................................................................. 24 
7.6 
Evaluation of Secondary and Exploratory Variables .............................................. 25 
7. 7 
Evaluation of Safety Variables ............................................................................... 26 
7.8 
Evaluation of Pharmacokinetic Data .................................................................... 27 
CONFIDENTIAL 
Page 5 of 33 


Saniona, A/S 
Study TM002 
Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
8. 
Changes in the Planned Analysis ................................................................................ 28 
9. 
APPENDIX l ................................................................................................................. 29 
CONFIDENTIAL 
Page 6 of 33 


Saniona, A/S 
Study TM002 
List of Abbreviations and Key Terms 
AE 
Adverse Event 
ANCOVA 
Analysis of co-variance 
ATC 
Anatomical Therapeutic Chemical (Classification) 
BMC 
Bone Mineral Conent 
BMD 
Bone Mineral Density 
BMI 
Body-Mass-Index 
BP 
Blood Pressure 
bpm 
Beats per minute 
Cl 
Confidence interval 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
cm 
Centi meter 
CV 
Coefficient of variation 
CZ 
Czech Republic 
DBP 
Diastolic Blood Pressure 
D(E)XA 
Dual (Energy) X-ray Absorptiometry 
DMP 
Data Management Plan 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
FPG 
Fasting Plasma Glucose 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
HbA,c 
Hemoglobin A 1 C 
HQ-CT 
Hyperphagia Questionnaire for Clinical Trials 
HDL 
High-density lipoprotein 
HR 
Heart Rate 
HU 
Hungary 
ICH 
International Conference on Harmonization 
ID 
Identification number 
IMP 
Investigation Medicinal Product 
L 
Liter 
LDL 
Low-density lipoprotein 
LOCF 
Last observation carried forward 
LPLV 
Last Patient Last Visit 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
CONFIDENTIAL 
Page 7 of 33 


Saniona, A/S 
Study TM002 
mg 
mlU 
ml 
Min 
n 
N Miss 
OP 
p 
PK 
PPP 
PT 
F'WS 
SAE 
SAP 
SES 
SBP 
so 
SOP 
SUKL 
WHO-DOE 
CONFIDENTIAL 
Milligram 
Milli-international units per liter 
Milliliter 
Minimum 
Number of subjects 
Number of missing values 
Out-patient 
Phone call 
Pharmacokinetic 
Per Protocol Population 
Preferred term 
Prader-Willi Syndrom 
Serious Adverse Events 
Statistical Analysis Plan 
Safety Evalution Set 
Systolic Blood Pressure 
Standard deviation 
Standard Operating Procedure 
Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
State Institute for Drug Control (Czech Republic) 
World Health Organization - Drug Dictionary Enhanced 
Page 8 of 33 


Saniona, A/ S 
Study TM002 
1. Introduction 
Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
This statistical analysis plan (SAP) contains a more technical and detailed elaboration of the principal 
features of the statistical analyses as described in the study protocol TM002 (dated: 25 July 201 7 
Protocol Amendment Version 1.2 for Hungary and 2 5 July 2017 Protocol Amendment Version 1.3 
for Czech Republic) (CZ) and includes detailed procedures for executing the statistical analysis of 
the primary and secondary variables and other data. In addition, Section 8 of this SAP summarizes 
all changes from the planned analysis known before final ization of this document. The SAP is 
finalised and signed prior to breaking the blind. 
Data management and transfer of data will be carried out in accordance with the data management 
plan (DMP), statistical analysis in accordance with the SAP. 
If changes in the conduct of the statistical analysis are unavoidable the reasons and the effect of 
these changes w ill be documented in the statistical report/clinical study report in full details. 
All statistical activities w ithin the framework of this study w ill be based on the standard operating 
procedures (SOPs) for clinical studies of GCP-Service, as well as the ICH Guideline for Good Clinical 
Practice (ICH-GCP). 
2. Study Design and Objectives 
2.1 
Study Design 
This clinical study is a double-blind , randomized, placebo-controlled, multiple-dose, two-centre 
safety and efficacy study of co-administration of tesofensine/ metoprolol in subjects w ith Prader-Willi 
syndrome (P'vVS). 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 
w ith P'vVS. 
The study w ill be conducted in two steps each w ith two arms where the second step will only start 
fol lowing recommendation after a Data Safety Monitoring Board (DSMB) review and in CZ only a State 
Institute for Drug Control (SUKL) review: 
• 
Step 1: 10-15 adult subjects with P'vVS 
o 
Arm 1: tesofensine 0.50 mg + metoprolol 50 mg administered once a day 
o 
Arm 2: placebo tablets matching tesofensine + metoprolol administered once a day 
• 
Step 2: 1 0-1 5 children with P'vVS 
o 
Arm 1: tesofensine + metoprolol administered once a day. Firstly, an initial t itration 
dose of tesofensine 0.2 5 mg + metoprolol 50 mg w ill be given for the first 4 weeks. 
CONFIDENTIAL 
Page 9 of 33 


Saniona, A/ S 
Study TM002 
Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
Following a favorable review of all safety data for each subject by the site clinician, 
tesofensine 0.50 mg+ metoprolol SO mg will be given for the final 9 weeks. 
o 
Arm 2: placebo tablets matching tesofensine + metoprolol administered once a day 
2.2 
Treatments 
2.2.1 
lnvestigational Medicinal Product 
Tesofensine is a serotonin-noradrenaline-dopamine reuptake inhibitor, for oral administration, 
which is manufactured, packed and labelled by Delpharm in Reims (France). Its chemical name is 
( 1 R,2 R,3 S,SS)-3-(3 ,4-d ich lorophenyl)-2-(ethoxymethyl)-8-methyl-8-azabicyclo 
octane. 
Designated 
contractors will supply study medications directly. 
Metoprolol 
is 
a 
beta] -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 Step 1 (adult subjects with PWS), 0.5 mg of tesofensine and 50 mg of extended release 
metoprolol or matching placebo will be administered. 
Following Step 1, an independent DSMB will review unblinded data from Step 1, including PK, and 
w ill attest that it is safe to proceed to Step 2 in children as described in the clinical study protocol. 
In the Step 2 (children with PWS), tesofensine 0.50 mg + metoprolol 50 mg administered once a day, 
in the morning w ith a meal - first, initial titration dose of tesofensine 0.25 mg+ metoprolol SO mg 
w ill be given for the first 4 weeks, in the morning w ith a meal. Following a favorable review of all 
safety data for each subject by the investigator, tesofensine 0.50 mg+ metoprolol SO mg will be 
given for the final 9 weeks (the above proposed dosing plan can be adjusted by the DSMB, if needed). 
The lnvestigational Medicinal Product (IMP) is a kit of one tablet of tesofensine and one tablet of 
metoprolol, both formulated for oral use once a day, or a matching placebo. For Step 2 Day 28-91 
two blinded kits A and B will be prepared (kit A - per protocol dose of IMP, kit B - lower dose of IMP). 
Tesofensine 0.2 5 mg and 0.50 mg are identical in size, shape and weight. 
2.2.2 
Placebo 
The placebo formulation is identical in presentation and appearance to the tesofensine and 
metoprolol tablets but includes only the excipient s; it does not contain any active ingredients. 
CONFIDENTIAL 
Page 1 0 of 33 


Saniona, A/S 
Study TM002 
2.3 
Trial Schedule 
Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
Study medication w ill be administered for ninety {91) days (+2 days after the final assessments w ith 
half-dose of metoprolol). 
Following all baseline assessments, eligible subjects will be randomly assigned to one of the two 
arms (3:2, IMP: placebo). 
Screening visit is combined with the baseline and randomization visit (Day 0, Visit 1 ). All requested 
screening assessments and baseline blood draws and tests will be performed before randomization. 
After the Day 0, subjects will visit the site on Days 7, 28, 56 and 91 (Visits 2, 5, 9, 14) for efficacy 
and safety evaluations and medication supply (in total 5 personal visits at the site are requested). 
On Day 91 subjects w ill come for the final personal visit. 
On Days 14, 21, 35, 42, 49, 63 , 70, 77, 84 (Visits 3, 4, 6, 7, 8, 10, 11, 12, 13) phone call follow ups 
w ill be performed. These phone calls will be used to provide additional reassurance regarding the 
safety of the subjects and collection of AEs. 
On Day 1 OS (Visit 1 5) a phone call will be performed to check subjects' status and potential AE(s). 
This w ill conclude their participation in the study. 
The study schedule is displayed in Table 1 
Table 1: Study schedu le 
Visit 
1 
2 
3,4 
5 
6, 7,8 
9 
10, 11 , 12, 
14 
15 
Screening 
F-up 
/Baseline/ 
Randomiz 
ation 
OP 
OP 
p 
OP 
p 
p 
p 
OP 
p 
Day 
0 
7 
14 
28 
35 
56 
63 
9 1 
105 
2 1 
42 
70 
49 
77 
84 
Obtaining written 
X 
Informed Content, 
Inclusion/Exclusion 
Generating screening 
X 
number 
CONFIDENTIAL 
Page 11 of 33 


Saniona, A/S 
Study TM002 
Demographic 
information 
Medical/medication 
history 
Physical exam 
Vital signs 
Randomization 
Safety review for 
uptitration 
Weight, waist 
circumference 
Height, calculation of 
BMI 
HQ-CT 
ECG 
Hematology 
Blood chemistry 
FPG, HbA 1 c 
Lipids, insulin 
DEXA 
PK sample 
Lifestyle consultation 
Drug dispensation 
AEs 
Drug accountability 
Concomitant 
medication 
Urinary pregnancy test 
Subject card 
dispensation 
CONFIDENTIAL 
X 
X 
X 
X 
X 
X 
X 
*x 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
** 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 1 2 of 33 


Saniona, A/S 
Study TM002 
Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
Diary dispensation 
Diary review 
Diary collection 
Dispense Follow-up 
diary list 
End of study form 
OP: Out-patient 
P: Phone Call 
X 
* only step 2 - IMP dose incr ease 
X 
** two half doses of metoprolol should be dispensed 
2.4 
Study Objectives 
2.4.1 
Primary Objective 
The primary objective of this clinical trial is: 
X 
X 
X 
X 
X 
• 
To examine the effect of co-administration of tesofensine/metoprolol on body weight in 
subjects w ith PWS. 
2.4.2 
Secondary Objectives 
In addition, further objectives are 
• 
To establish pharmacokinetic profile of tesofensine and metoprolol in subjects with PWS, 
X 
• 
To examine the change in hyperphagia-related behaviour in subj ects 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 subj ects with PWS, 
• 
To examine the effect of co-administration of tesofensine/metoprolol on HR and BP in 
subjects w ith 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. 
2.5 
Study Hypothesis 
As this is an explorative study no formal study hypothesis will be tested but the study results may 
be used to generate study hypotheses for possible subsequent studies. 
CONFIDENTIAL 
Page 1 3 of 33 


Saniona, A/S 
Study TM002 
2.6 
Handling of Screening Failures and Withdrawals 
Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
Enrolment will continue until a total of 10-15 adult subjects and 10-1 5 pediatric subjects are 
randomized. Randomized subjects who withdraw or are withdrawn from the study for any reason 
before completion are called "withdrawals". Withdrawals may be replaced, so that there are as close 
as possible to the minimum of 1 O completers in each step of the study. 
A participant who fails during the screening phase, before randomisation, for any reason, e.g. 
because of violation against the eligibility criteria, is regarded as "screening failure". Subjects 
excluded during the screening period may be coinsidered for another selection visit at a later date 
but will need to undergo complete rescreening. 
2.7 
Randomization and Stratification 
A centre-stratified block randomization with fixed block size is used. For each step of the study, one 
randomization list with complete blocks is prepared. This is done to achieve a balanced distribution 
of subject characteristics between the two treatment groups within each study centre and step of 
the study as far as possible. Subjects will be randomly assigned to the two study groups in a 3:2 
fashion (IMP:Placebo). A more detailed description of the randomization procedure is given in the 
Randomization Plan version 2.0, dated 24. August 2017. 
2.8 
Blinding 
The study will be double blind. Neither the investigators nor the subjects will be informed about the 
type of subject, s medication. In general, emergency unblinding is to be done only when absolutely 
necessary for the clinical management of an individual subject and where stopping the blinded 
medication is not sufficient in the opinion of the investigator. 
A more detailed description of the blinding and unblinding procedure is given in the Randomization 
Plan version 2.0, dated 24 August 2017 and the study protocol TM002. 
2.9 
Sample Size Calculation 
As this is an explorative study no formal sample size or power calculation was performed. The 
chosen sample size is a balance between exposiing the lowest possible number of subjects to the 
IMP, while still being able to compare the effects of tesofensine/ metoprolol treatment vs. placebo. 
Each site should randomize a minimum of five eligible adult and a minimum of five eligible pediatric 
patients. In total there should be randomized a minimum of 20 and a maximum of 30 patients, 10-
1 5 male and female adult and 1 0-1 5 male and female pediatric subjects with confirmed diagnosis 
of PWS. 
CONFIDENTIAL 
Page 1 4 of 33 


Saniona, A/ S 
Study TM002 
2.10 
Planned Safety and PK Analysis 
Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
Deviations from the initially planned analysis described below, specifically the conduct of an early 
safety and PK analysis w ith 9 subjects without the involvement of a Data Safety Monitoring Board 
(DSMB) and the State Institute for Drug Control (SUKL), are described in section 8. 
According to the study protocol TM002 (dated: 25 July 2017 Protocol Amendment Version 1 .2 for 
Hungary and 25 July 2017 Protocol Amendment Version 1.3 for Czech Republic), a review of 
unblinded efficacy, safety and PK data as well as all data from the study in subjects w ith type 2 
diabetes (TM00l ) will be performed by an independent Data Safety Monitoring Board (DSMB) and 
the State Institute for Drug Control (SUKL) after LPLV (Last Patient Last Visit) of Step 1 (adult subjects 
w ith PWS only). The independent DSMB will be created for this study and w ill be comprised of experts 
in the area of metabolic diseases, pediatric endocrinology, cardiovascular, clinical pharmacology, 
and statistics. A CRO statistician who will not be involved in the conduct of the study will prepare an 
unblinded data package w ith efficacy, safety and PK data from Step 1. In addition, the DSMB for HU 
and SUKL for CZ w ill have available unblinded data from the ongoing Phase 2 study in subjects with 
T2DM (TM00l ), and the DSMB will provide answers to the Sponsor to the following questions: 
1) Based on the presented safety data, is it safe to proceed to Step 2, children (~ 12 years of 
age) w ith PW syndrome "as is"? Any recommended modifications to the protocol? 
2) Based on the provided PK data, do you recommend proceeding at the recommended dose 
of 0.5/ 50 mg (0.25/ 50 mg for the first 4 weeks, if considered safe by the investigator 
increased to 0.5/ 50 mg) or would you recommend a different dose? If a different dose is 
recommended, please specify the dose of tesofensine and/ or metoprolol. 
Safety criteria: There will be no set pre-defined criteria as to what constitutes a safety signal which 
would be considered serious enough not to recommend administration of the study drug to children. 
The DSMB w ill be asked to comprehensively evaluate the provided data and determine the resulting 
risk/ benefit for the pediatric subj ects and make their recommendation accordingly. 
PK criteria: if the 90% confidence interval of a log-transformed exposure measure (mean trough 
concentrations from all follow-up samples (i.e. excluding the baseline sample collected prior to 
treatment w ith the study medication) collected from all adult participants for bot h metoprolol and 
tesofensine) fal ls completely within the range 8096 of the 0.25 mg dose and 1 25% of the 1.0 mg dose 
previously measured t rough concentrations in obese adult subjects in the study TIPO-1 , the 
exposure achieved in the adult subjects will be considered in the expected safe range and no dose 
adjustment for the pediatric patients should be necessary. If the 90% confidence interval fal ls outside 
CONFIDENTIAL 
Page 1 5 of 33 


Saniona, A/ S 
Study TM002 
Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
the 80-12 5% range the exposures will be considered sufficiently "different" from the expected values 
and a dosing adj ustment should be considered by the DSMB for HU and DSMB and SULK for CZ. 
2.11 
Handling of Changes to Study Protocol 
Any deviations from planned analyses, the reasons for such deviations, and all alternative or 
addit ional statistical analyses that may be planned before breaking the blind, respectively, will be 
described in amendments to the study protocol and/ or the SAP. All deviations and/ or alterations 
from the statistical analyses described in the protocol, especially those after database lock w ill be 
summarized in the clinical project report. 
All statistical analyses not pre-specified by the SAP and run after data lock will be considered as 
addit ional/exploratory analyses. 
3. Technical Aspects and Coding Conventions 
All programs will be written using SAS® (SAS Institute Inc., Cary, North Carolina, United States of 
America [USA]), version 9.4 or higher. Tables, listings and figures w ill be provided in separate PDF 
documents and w ill contain a separate table of contents. Courier New will be used as font for all 
tables and listings. In headings, titles and listings only the fi rst word will be capitalised. A 
noncommittal list of all tables and listings can be found in the Appendix. 
A minimum font size of 8 points will be used for the tables, corresponding to a linesize of 140 digits 
and a pagesize of 52 lines for an output in DIN A4 format. All tables should be self-explaining. 
Therefore, necessary information should be available in the footnotes. The footnote and tit le of each 
table will be left-adjusted while the table will be centered. 
For listings, a minimum font size of 8 points with the linesize and pagesize as defined above will be 
used to produce the output in DIN A4 format. Footnotes, t it les and listings will be left-adjusted. 
Missing data will be represented on subject listings as blank field for text field or "." for numeric 
variables. Derived data will be marked by '#'. Listings w ill be sorted by site, treatment and screening 
number (equivalent to subject identification number) unless specified otherwise. 
3.1 
Date Coding and Day Numbering 
The format for presentation of date variables will be DDMMMYYYY. The format for presentation of 
time variables will be hh:mm. 
CONFIDENTIAL 
Page 1 6 of 33 


Saniona, A/ S 
Study TM002 
Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
If dates are partially given, they will be completed, if necessary for the calculation of durations, 
according to a worst-case imputation. Dates with missing years will only be imputed if the correct 
year is obvious. 
Deviations will be documented and explained. 
3.2 
Coding Systems and Conventions 
3.2.1 
Coding of Adverse Events and Medical History 
Adverse event (AE), medical history and concomitant diseases terms are assigned to a lowest level 
term (LLT) and a preferred term (PD and will be classified by high level term (HLT), high level group 
term (HLGT) and system organ class (SOC) according to the Medical Dictionary for Regulatory 
Activities (MedDRA) version in effect at the time the database is closed. Details are described in the 
DMP. 
3.2.2 
Separation of Medical History from Concomitant Diseases 
Separation of medical history from concomitant diseases w ill be done by comparison of the stop 
date of the medical condition with the start of study treatment. Each medical condition will be 
allocated unambiguously either to medical history or concomitant diseases. 
• 
Medical history: If the stop date is before start of treatment, the medical condition is 
allocated to medical history. If the stop date is partially given and unambiguously before 
start of treatment, the medical condition is also allocated to medical history. Furthermore, if 
the stop date is missing and the medical condit ion is not known to be ongoing, findings 
coded as "Surgical and medical procedures" are also allocated to medical history. 
• 
Concomitant diseases: If the stop date is at or after start of treatment or t he medical 
condit ion is ongoing, the medical condition is allocated to concomitant diseases. 
Furthermore, if the stop date is missing and the medical condition is not known to be active 
at start of study, the worst case is assumed for find ings not coded as "Surgical and medical 
procedures". Consequently, the medical condition is allocated to concomitant diseases. 
3.2.3 
Coding of Medications 
Previous and concomitant medications will be coded using WHO-ODE (World Health Organization -
Drug Dictionary Enhanced) based on different Anatomical Therapeutic Chemical Classification (ATC) 
code levels. Details are described in the DMP. 
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3.2.4 
Separation of Medications 
Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
Separation of previous medications and concomitant medications will be done by comparison of the 
stop date of the medication with the start of study treatment. Each medication will be allocated 
unambiguously either to previous or concomitant medications. 
• 
Previous medications: If the stop date is before start of treatment, the medication is 
allocated to previous medications. If the stop date is partially given and unambiguously after 
start of treatment, the therapy is allocated to previous medications. 
• 
Concomitant medications: If the stop date is at or after start of treatment or the medication 
is ongoing, the medication is allocated to concomitant medications. Furthermore, if the stop 
date is missing , the worst case is assum ed. Consequently , the medication is allocated to 
concomitant medications. If the stop date is partially given and implies stop date after start 
of treatment, the medication is also allocated to concomitant medications. 
4. Analysis Populations and Subgroups 
4.1 
Analysis Populations 
Within the framework of this study, the following two main populations are analysed: 
• 
The Per Protocol Population (PPP) includes all randomized subjects without any maj or 
protocol violations. Subjects in the PPP wil l contribute to the evaluation 'as treated'. 
• 
The Safety Evaluation Set (SES) includes all subjects receiving at least one dose of the 
investigational product or its comparator. Subjects in the SES will contribute to the 
evaluation 'as treated'. 
4.2 
Subgroups 
The primary analysis for each endpoint will be using the combined data from steps 1 and 2 of this 
study. In addition, subgroup analyses are planned for step 1 and step 2 of this study to evaluate 
differences between t reated adults and children. 
4.3 
Stratification 
Not applicable. 
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Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
5. Data Handling 
5.1 
Handling of Missing Data and Outliers 
Since all analyses are explorative and with reference to the low sample size per step of this study, it 
is not planned to replace or impute missing data by complex imputation methods. Instead data will 
be used as available and analysis will be performed on observed cases only. The appropriateness of 
this procedure w ill be discussed during the blind data review and, if applicable, the handling of 
missing data w ill be adapted. 
For outliers, i.e. impossible or implausible values, queries are raised to the investigator before hard 
lock of the database. The investigator will either confirm or correct the value. Subsequently, the 
corrected or confirmed value is used for the analysis. If applicable, analysis will be performed with 
and without outliers to show robustness of the results. Complete exclusion of values should be only 
done in exceptional cases and is only valid for impossible and very implausible values w ith obvious 
justification. The decision to exclude data points from the statistical analysis is the joint 
responsibility of the Sponsor, the investigator and the CRO statistician. 
5.2 
Handling of Data from Screening Failures and Withdrawals 
In case of screening fai lures, the data will be listed but not further analyzed. The number of 
screening fai lures w ill be provided in a figure and a table for the disposition of subjects. 
Data from withdrawals will be used as available without imputation. The number of early withdrawals 
and the corresponding reasons will be provided in a figu re and a table for the disposition of subjects. 
5.3 
Handling of Multiple Comparisons and Multiple Primary Variables 
As all data analyses in this study are explorative and w ill be interpreted accordingly, no adjustment 
for multiple comparisons is necessary. 
5.4 
Data Review 
Before data are released for statistical analysis, a blinded review of all data will take place to identify 
protocol deviations that may potentially affect t he results. This review will be performed without 
revealing which treatment the subjects are assigned to. The blinding of the treatment w ill be 
maintained for everyone involved in allocating subjects to the analysis sets until data are released 
for statistical analysis. Furthermore, outliers will be identified by data review according to ICH-E9 
(5), and a fake randomization. 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 
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Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
exclude data points from the statistical analysis is the joint responsibility of the Sponsor, the 
investigator and the CRO statistician. 
For review of the pharmacokinetic data, additional care needs to be taken to avoid premature 
unblinding of the reviewers due to drug concentration levels being recorded for each subject. 
Therefore, subject IDs will be replaced by a randomly selected 5-digit fake ID (one per subject) by 
an independent person not involved in the conduct, data review or analysis of the study. The list 
used for assignment of fake IDs to subject IDs will be stored in a secure location without access for 
any person involved in the trial. The PK data will be sorted anew by fake ID, the visit number 
(VISITNUM) and the analyzed drug (PCTEST), to ensure that the order of subjects does not give an 
indication of the true subject ID. This modified list will then be provided for data review. After 
complete review all issues will be traced back to the subject ID using the list used for assignment of 
fake IDs to subject IDs and querries will be solved or subjects excluded from the analysis as 
determined during the data review process. 
The subjects or observations to be excluded and the reason for their exclusion will be documented 
and signed by those responsible prior to datab ase 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. 
6. Variables for Analysis 
6.1 
Demographics and Baseline Characteristics 
The following demographic and baseline characteristics will be evaluated: 
• 
Demographic information (race, gender, age, height, weight, BMI, waist circumference) 
• 
Medical history, concomitant diseases, previous and concomitant medications 
• 
Baseline characteristics (vital signs, ECG, physical examination) 
• 
Laboratory tests and measurements (fat mass, fat free mass, bone mineral density (BMD), 
bone mineral content (BMC), HbA,c, Cholesterol, HDL, LDL, Triglyceride, Insulin, FPG) 
6.2 
Efficacy Endpoints 
6.2. l 
Primary Endpoint 
The following primary variable is evaluated: 
• 
Percent change from baseline to end of treatment in body weight 
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Study TM002 
Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
6.2.2 
Secondary Endpoints 
The following secondary endpoints are planned: 
• 
Change from baseline to end of treatment in body weight [kg] 
• 
Change from baseline to end of treatment in fat- and fat-free mass [%) by dual X-ray 
absorptiometry (DEXA) 
• 
Change from baseline to end of treatment in fat- and fat-free mass [g] by dual X-ray 
absorptiometry (DEXA) 
• 
Change from baseline to end of treatment in bone mineral density (BMD) [g/ cm2 ] and bone 
mineral content (BMC) [g) by dual X-ray absorptiometry (DEXA) 
• 
Change from baseline to end of treatment of HbA1e [%) 
• 
Change from baseline to end of treatment in fasting plasma glucose (FPG) [mmol/L) 
• 
Change from baseline to end of treatment in waist circumference [cm] 
• 
Change from baseline to end of treatment in insulin [mlU/ L) 
• 
Change from baseline to end of treatment in lipid profile (Cholesterol, HDL, LDL, Triglyceride) 
[mmol/L)) 
• 
Change from baseline to end of treatment in total HQ-CT score 
6.3 
Safety Endpoints 
6.3. l 
Safety Endpoints 
Safety endpoints include: 
• 
Incidence of AEs, SAEs (serious adverse events), 
• 
Blood analysis: 
o 
Hematology: 
blood count (erythrocytes, hemoglobin, hematocrit, leukocytes), 
differential 
blood 
count (neutrophils, lymphocytes, 
monocytes, eosinophils, 
basophils) and platelets 
o 
Blood 
chemistry: 
creatinine, 
gamma 
glutamyl 
transferase, 
aspartate 
aminotransferase, alkaline phosphatase, glomerular filtration rate (GFR) and urea 
• 
Electrocardiogram (ECG): 
o 
Interpretation (normal/abnormal) 
o 
Change from baseline to end of treatment in R-R, P-R, QRS and Q-T intervals 
• 
Vital signs: 
o 
Change from baseline to end of treatment in mean HR [bpm) 
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Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
o 
Change from baseline to end of treatment in mean SBP [mm Hg] 
o 
Change from baseline to end of treatment in mean DBP [mmHg) 
o 
Change from baseline to end of treatment in body temperature ['CJ 
o 
Change from baseline to end of treatment in respiratory rate [breaths/ min] 
• 
Physical examination 
o 
Change from baseline to end of treatment in examination findings (normal/ abnormal 
(NCS)/ abnormal (CS)/ not done) of different body systems (Head, ear, eye, nose and 
throat, respiratory system, cardiovascular system, abdomen, central and peripheral 
nervous system, lymph nodes, skin, skelet and other body system) 
6.4 
Pharmacokinetic Endpoints 
• 
Steady state concentrations of tesofensine and metoprolol as measured by trough values 
7. Statistical Analysis Methods 
7.1 
Descriptive Statistics 
The default summary statistics for quantitative variables will be the number of non-missing 
observations (n), number of missing values (N missing), arithmetic mean, geometric mean (if 
applicable), standard deviation (SO), coefficient of variation (CV), lower quartile (Q 1 ), upper quartile 
(Q3), minimum (min), median, and maximum (max) for those subjects with data available. 
For categorical variables, the number (n) and percentage (%) of subjects per category will be the 
default summary presentation, and, if applicable, the number of missing values is prov ided in a 
"Missing" category. Missing data will not be included in the calculation of percentages as only 
available data are used, except if a subject did only answer specific questions of a questionnaire. 
Percentages will be calculated using a denominator of all subjects in a specified population or 
treatment group. The denominator will be specified in a footnote to the tables for clarification if 
necessary. If missing data occur within population specified as denominator, they will not be 
included in the calculation of percentages, except if a subject did only answer specific questions of 
a questionnaire. 
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7.2 
Rounding Rules 
7.2.1 
Estimates of the Mean and Standard Deviation 
Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
When using actual data, the mean and standard deviation are both calculated to 2 extra places than 
the actual data and the result is rounded to one more decimal place than the original data, w ith a 
maximum of 2 decimal places. 
When mean values of repeated measurements are used for calculation of summary statistics, the 
mean and standard deviation are both calculated to one more decimal place than the used mean 
values and the result is rounded to the same number of decimal places given for the mean values of 
repeated measurements used for calculation, with a maximum of 2 decimal places. 
7.2.2 
Other data 
Quartiles, CV and median are always presented w ith the same number of decimal places as the 
mean. Minimum and maximum are always provided with the same number of decimal places as the 
data used. For estimates of proportions always 4 decimal places are used for the computation and 
the result is rounded to 3 decimal places. If proportions are displayed as percentage, 1 decimal 
place is displayed. For example, a proportion of 0 .655 will be presented in percentage as 65 .5%. 
7.3 
Calculation of Study Days and Durations 
Study days and, if applicable and meaningful, durations w ill be determined by comparing the 
respective date to the date of the first administration of the study medication. 
• 
If the respective date is on or after the date of the first administration of the study 
medication: 
Study day/ Duration = Date (e.g. date of visit) - Date of first administration+ 1 
• 
If the respective date precedes the date of the first administration of the study medication: 
Study day/ Duration = Date (e.g. date of medical history event) - Date of first 
administration 
Time to onset and duration of adverse events will be calculated as follows: 
• 
Time to onset = start date of AE - date of first treatment [+ 1 for AE starting after start of 
treatment] 
• 
Duration of adverse event = stop date - onset/ worsening date+ 1 
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Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
7.4 
Evaluation of Demographics and Baseline Characteristics 
7.4.1 
Disposition of Patients 
Subject disposition w ill be tabulated including the numbers of screened subjects, screening failures, 
subjects exposed to study product, subjects completing the study and subjects in the PPP and SES. 
Subjects withdrawn from the study will be listed along w ith the primary reason for withdrawal. In 
addit ion, the primary reason for withdrawal will be tabulated. 
Furthermore, a summary of the time to study termination is provided per treatment group. 
7.4.2 
Demographics and other Baseline Characteristics 
Demographic information (race, gender, age, height, weight, BMI, waist circumference), baseline 
characteristics (vital signs, ECG, physical examination) and laboratory tests and measurements w ill 
be summarized by treatment group and step of the study (including a total column) using the default 
descriptive statistics for subjects in the PPP and SES. 
7.4.3 
Medical History, and Concomitant Diseases 
Absolute and relative frequencies (n, %) of medical history and concomitant diseases w ill be 
described by treatment group based on MedDRA system organ class and preferred term levels for 
the PPP and SES. 
7.4.4 
Previous and Concomitant Medication 
Absolute and relative frequencies (n, %) of prev ious and concomitant medication will be provided by 
treatment group based on Anatomical Therapeutic Chemical (ATC) Classification code levels 2 and 
3 for the PPP and SES. 
7.5 
Evaluation of Primary Endpoint 
The primary endpoint is 
• 
Percent change from baseline to end of treatment in body weight 
and will be calculated by: 
%-change = (Weight at end of treatment - Weight at baseline) / (Weight at baseline * 1 00 
where, according to the protocol, end of treatment is defined as Visit 14 (Day 91 ). 
The primary endpoint will be presented and analysed based on the PPP. 
Percent change from baseline in body weight will be summarized per Step and in total, by treatment 
group and visit via mean, , median, standard deviation, coefficient of variation (CV), lower quartile 
(Ql), upper quartile (Q3), minimum and maximum value). Moreover, complete listings of individual 
values for the primary endpoint will be provided. Figures displaying the values for individual subjects 
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Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
(spaghetti plots) as well as figures displaying mean and standard deviation for percentage change 
from baseline in body weight at each visit per treatment group by Step and in total will also be 
provided. 
The primary endpoint percent change from base I ine to end of t reatment will be compared between 
treatment arms by means of an AN COVA model including Step, site and treatment as fixed factors 
and baseline value as covariate. Estimates and 95% confidence interval of treatment differences will 
be calculated. The procedure for this analysis might be adapted during the blinded data review 
meeting. The primary analysis will be using the combined data from Steps 1 and 2; secondary 
analyses will be carried out for each step separately. The critical value w ill be set on a two-sided 
significance level of 5%. 
For the ANCOVA the following SAs·-code is recom mended: 
proc glm data = <name of primary analysis data set>; 
class step site treatment_group; 
model chg_from_base = step site treatment_group baseline; 
lsmeans treatment / cl e stderr pdiff; 
estimate 'Difference IMP versus Placebo' 
treatment 1 -1; 
run; 
quit; 
The ANCOVA w ill be repeated with the data of all subjects in the PPP with available weight 
measurement as sensitivity analysis. For withdrawals, change from baseline w ill be imputed 
according to the last observation carried forward (LOCF) method using the last weight measurement 
before study termination. 
7.6 
Evaluation of Secondary and Exploratory Variables 
The analysis of secondary and exploratory variables w ill be based on the PPP. The secondary and 
exploratory variables will be summarized per Step and in total by treatment group and visit and, 
where applicable, changes from baseline will be provided using standard descriptive statistics 
(mean, geometric mean (if applicable), median, standard deviation, coefficient of variation (CV), 
lower quartile (Ql), upper quartile (Q3), minimum and maximum value). Individual (spaghetti plots) 
and mean and standard deviation curves over treatment duration will be plotted by treatment per 
Step and in total. 
Change from baseline analysis to the end of treatment for the corresponding secondary and 
exploratory endpoints will be performed using ANCOVA, logistic regression models as applicable. 
For continuous variables, the ANCOVA model will be analogous to the model used for the primary 
endpoint. pvalues, 95% confidence intervals and, if applicable, odds ratios for the comparison 
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Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
between treatments will be estimated. Also, the primary analysis of secondary endpoints w ill be 
using the combined data from Steps 1 and 2; secondary analyses will be carried out for each step 
separately. The critical values for each two-sidedl and one-sided statistical test will be based on a 
significance level of 5% and 2.5%, respectively. Figures displaying the mean and standard deviation 
of the raw data at each visit per treatment group will be also provided. Moreover, complete listings 
of individual values for all secondary and exploratory endpoints will be provided. 
A 9-item score will be calculated for the HQ-CT. Change in HQ-CT answers (by question and in total) 
w ill be calculated as (answer at visit 2, 5, 9 or H) minus (answer at screening visit (visit 1)) and 
presented using standard descriptive statistics (mean), median, standard deviation, coefficient of 
variation (CV), lower quartile (Ql), uppe quartile (Q3), minimum and maximum value). Scores for 
each question range from O to 4 (with a higher score indicating a worse outcome), resulting in a 
maximum 9-item sum of 436. A decrease in total score (compared to the baseline assessment) 
indicates an improvement in hyperphagia. If less than three questions have not been answered by a 
subject, the missing answers will be imputed by the mean score of all available answers. In case of 
more missing answers, the total scores will not be calculated. Results will be presented by treatment 
per Step and in total. 
Subject compliance [%) will be calculated as 1 00 x (number of tablets dispended - number of tablets 
returned)/(number of days of treatment) and will be calculated for both study drugs separately. The 
compliance w ill be summarized using standard descriptive statistics (mean, standard deviation, 
coefficient of variation (CV), lower quartile (Ql ), upper quartile (Q3), minimum and maximum value 
and listed per subject as well. 
7.7 
Evaluation of Safety Variables 
The analysis of the safety variables described in Section 6.3 will be based on the SES. Values will be 
summarized by treatment per Step and in total, using non-missing counts, mean, standard deviation, 
median, lower quartile (Ql ), upper quartile (Q3), minimum, and maximum for continuous data. 
Categorical data will be summarized using counts and percentages. Change from baseline to end of 
treatment analysis for vital signs will be done as described in Section 7.6. 
All AEs occurring afterthe randomization of the subject w ill be reported as AE (any AEs that occurred 
between screening and randomization will be rep,orted in medical history, but not as an AE). 
Incidences (number and percentage of subjects experiencing adverse events) per treatment group 
w ill be calculated for AEs on the system organ class (SOC) level and on the preferred term (PT) level 
(i.e., total, by step, by intensity, by relationship and by outcome). Listings and tables displaying 
incidences for AEs leading to discontinuation, serious AEs, treatment-related serious AEs and deaths 
w ill also be provided. 
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Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
Differences in the incidence of treatment-related AEs between treatment groups will be analyzed 
using a logistic regression model w ith Step and treatment as fixed factor. This model might be 
adapted during the blind data review depending on the amount and quality of data. Odds ratios, p-
values, and 95% confidence intervals corresponding to the logistic regression model will be 
estimated for the comparisons between treatments. 
The following basic SAS code is used for the analysis and expanded if needed: 
proc logistic data=<name of safety analysis data set> plots(only)=effect; 
class Step treatment_grou p; 
model 
<binary variable for occurrence of treatment-related 
AE 
(1 / 0)> 
Step 
treatment_group; 
run; 
In addit ion, the t ime to the first treat ment-related adverse event and treat ment-related serious 
adverse event w ill be calculated by Step and in total and displayed in Kaplan-Meier curves. 
The findings of the physical examinations are summarized by number (n) and percentage (%) of 
subjects per category (Normal/Abnormal (NCS)/Abnormal (CS)/ Not done) per Step and in total by 
treatment group and visit each body system (Head, ear, eye, nose and throat, respiratory system, 
cardiovascular system, abdomen, central and peripheral nervous system, lymph nodes, skin, skelet 
and other body system). In addition, shift tables will be provided to further evaluate the change 
before first administration of the medication and the end of treatment. 
ECG data, vital signs as well as laboratory data (hematology and blood chemistry) w ill be summarized 
as continuous data by treatment group and visit per Step and in total. In addition, where available, 
the interpretation of the measured data (Normal/Abnormal (NCS)/Abnormal (CS)/ Not done) w ill be 
analyzed as the findings of the physical examinations. 
7.8 
Evaluation of Pharmacokinetic Data 
Drug concentrations will be summarized by descriptive statistics for both metoprolol and 
tesofensine using only the data from subj ects exposed to the IMP. To take into account that 
pharmacokinetic parameters are often lognormally distributed, the geometric mean and t he 
geometric coefficient of variation will be calculated addit ionally. The geometric mean is defined as 
the nth root of the product of n concentration measurements. The geometric coefficient of variation 
can be easily obtained by subtracting 1 from the geometric standard deviation and multiplication 
w ith 100. 
In addition, the 90% confidence interval of a log-transformed exposure measure (mean trough 
concentrations from all follow-up samples (i.e. excluding the baseline sample collected prior to 
treatment w ith the study medication) collected from all adult participants for both metoprolol and 
tesofensine) will be provided. Furthermore, figu res w ill be provided detailing the concentration of 
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Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
metoprolol/ tesofensine over time since first ex posure to metoprolol/tesofensine and the log-
transformed mean concentration over time since first exposure to metoprolol/tesofensine. 
It should be noted that values below the lower limit of quantification will be excluded from the 
analysis, since the subjects are considered not to be exposed to the IMP in this case. The number of 
subjects in the IMP group with a value below the lower limit of quantification during the treatment 
phase will be listed in a footnote to the corresponding table. 
8. Changes in the Planned Analysis 
The analysis of this study is described in the study protocol TM002 (dated: 2 5 July 201 7 Protocol 
Amendment Version 1 .2 for Hungary and 25 July 201 7 Protocol Amendment Version 1 .3 for Czech 
Republic), Nevertheless, minor changes to the conduct of the analysis have to be performed and are 
described below in detail. 
At the request of the Sponsor, an unblinded safety and PK analysis not planned in the study protocol 
TM002 (dated as described above) is conducted based on the data of nine adult patients included 
in the study at the time of finalization of this SAP. This deviation from the initial plan to have 10-20 
randomized subjects w ith PWS results is deemed necessary since there are no subjects available at 
the participating sites anymore. Depending on the results of this unblinded 
analysis including 
efficacy, safety and PK data, next steps will be propsed, including potential pediatric plan by the 
Sponsor. Before any new patients are enrolled th e updated plan will be submitted for approval to 
respective regulatory authorities and ECs as outlined in the study protocol. For this unblinded safety 
and PK analysis, all data will be used as available and no analysis of subgroups (SES, PPP) w ill be 
performed. This is deemed necessary due to the low number of subjects that w ill be analysed. As 
the safety and PK analysis is only performed with subjects of the first phase of the study, Step and 
subgroup will not be included as factors for the analysis. 
The wording of the primary endpoint was changed from "Percent change from baseline to end of 
treatment in mean body weight" to "Percent change from baseline to end of treatment in body 
weight" to address that no replicated measurements were performed during the body weight 
assessment at a visit. That means that the relative change of body weight as assessed by single 
measurements performed at the screening visit and the end of treatment is calculated. The same 
applies to the secondary endpoint "Change from baseline to end of treatment in body weight (kg)". 
If the study stops after Step 1 the statistical analysis w ill be based on the data available from Step 1 
according to this SAP. 
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9. APPENDIX 1 
Tables 
14.1 
Study subjects 
14.1 .1 
Disposition of subjects 
Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
14.1 .1.1 
Number of subjects enrolled, by site and total 
14.1 .1 .2 
Number of subjects per visit 
14.1.1.3 
Discontinuation, eligible subjects 
14.1 .2 
Protocol deviations and other reasons for exclusion from analysis sets, 
randomized subjects 
14.1 .3 
Demographics and other baseline characteristics, SES and PPP 
14.1 .3.1 
Demographics 
14.1 .3.2 
Vital signs 
14.1 .3.3 
ECG 
14.1 .3.4 
Physical examination 
14.1 .3.5 
Laboratory tests and measurements 
14.1 .4 
Medical history and concomitant diseases, SES and PPP 
14.1 .4.1 
Medical history by System Organ Class and Preferred Term 
14.1 .4.2 
Concomitant diseases by System Organ Class and Preferred Term 
14.1 .5 
Previous and concomitant medications, SES and PPP 
14.1 .5.1 
Previous medication by ATC level 
14.1 .5.2 
Concomitant medication by ATC level 
14.1 .6. 
Extent of exposure and treatment compliance, SES and PPP 
14.1 .6.1 
Duration of exposure [days, SES] 
14.1 .6.2 
Compliance [%], SES and PPP 
14.2 
Efficacy and pharmacokinetic data, PPP 
14.2.1 
Primary endpoint 
14.2.1.1 
Change over time in body weight[%] 
14.2.1.2 
Change over time in body weight[%], summary of ANCOVA 
14.2.2 
Secondary endpoints 
14.2.2.1 
Change over time in body weight [kg] 
14.2.2.2 
Change over time in body weight [kg], summary of ANCOVA 
14.2.2.3 
Change over time in fat- and fat-free mass[%] by DEXA 
14.2.2.4 
Change over time in fat- and fat-free mass [%] by DEXA, summary of 
ANCOVA 
14.2.2.5 
Change over time in fat- and fat-free mass [g] by DEXA 
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14.2.2.6 
14.2.2.7 
14.2.2.8 
14.2.2.9 
14.2.2.10 
14.2.2.11 
14.2.2.12 
14.2.2.13 
14.2.2.14 
14.2.2.15 
14.2.2.16 
14.2.2.17 
14.2.2.18 
14.2.2.19 
14.2.2.20 
14.2.2.21 
14.3 
14.3.2 
14.3.2.1 
14.3.2.2 
14.3.2.3 
14.3.2.4 
14.3.2.5 
14.3.2.6 
14.3.2.7 
14.3.2.8 
14.3.3 
14.3.3.1 
14.3.3.2 
14.3.3.3 
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Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
Change over time in fat- and fat-free mass [g] by DEXA, summary of 
ANCOVA 
Change over time in bone mineral density (BMD) [g/cm2 ) and bone 
mineral content (BMC) [g] by DEXA 
Change over time in bone mineral density (BMD) [g/cm2 ] and bone 
mineral content (BMC) [g] by DEXA, summary of ANCOVA 
Change over time in HbA 1 c [%) 
Change over time in HbA 1 c [%], summary of AN COVA 
Change over time in fasting plasma glucose [mmol/L) 
Change over time in fasting plasma glucose [mmol/L], summary of 
ANCOVA 
Change over time in waist circumference [cm) 
Change over time in waist circumference [cm], summary of ANCOVA 
Change over time in insulin [mlU/L) 
Change over time in insulin [mlU/L], summary of ANCOVA 
Change over time in lipid profile (cholesterol, HDL, LDL, triglyceride) 
Change over time in lipid profile (cholesterol, HDL, LDL, triglycer ide), 
summary of ANCOVA 
Changer over time in hyperphagia questionnaire for clinical trials 
(HQ-CT) 
Shift tables for interpretation, HQ-CT 
Steady state concentrations of tesofensine and metroprolol 
Safety data, SES 
Adverse events 
Overall summary of adverse events 
Number(%) of subjects w ith AEs and number of AEs by System Organ 
Class and Preferred Term 
Number(%) of subjects w ith AEs by worst causal relationship 
Number(%) of subjects w ith AE by worst intensity 
Number(%) of subj ects with AEs by worst causal relationship and worst 
intensity 
Number(%) of subjects w ith AEs by worst outcome 
Number of subjects with AEs by worst causal relationship and worst 
outcome 
Number(%) of subjects w ith treatment-related AEs 
Deaths, other serious and significant adverse events 
Serious AEs, listing of subjects 
Treatment-related serious AEs, listing of subjects 
Deaths, listing of al I serious AEs of subj ects who died 
Page 30 of 33 


Saniona, A/S 
Study TM002 
14.3.3.4 
14.3 .4 
14.3.4.1 
14.3 .4.2 
14.3 .4.3 
1 4.3 .4.4 
14.3.4.5 
14.3.5 
14.3.5.1 
14.3.5.2 
14.3.5.3 
14.3.5.4 
14.3.5.5 
14.3.5.6 
14.3.6 
14.3.6.1 
14.3.6.2 
14.3.6.3 
14.3.6.4 
14.3.6.5 
Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
AEs leading to discontinuation, listing of subjects 
Vital signs 
Change over time in mean heart rate [bpm] 
Change over time in mean systolic blood pressure [mmHg] 
Change over time in mean diastolic blood pressure [mm Hg] 
Change over time in temperature re] 
Change over time in respiratory rate [breaths/min] 
Laboratory data 
Summary statistics for measurements, hematology 
Summary statistics for interpretation, hematology 
Shift tables for interpretation, hematology 
Summary statistics for measurements, blood chemistry 
Summary statistics for interpretation, blood chemistry 
Shift tables for interpretation, blood chemistry 
Other safety data 
Summary statistics for measurements, electrocardiography 
Summary statistics for interpretation, electrocardiography 
Shift tables for interrpretation, electrocardiography 
Summary statistics for interpretation, physical examination 
Shift tables for interrpretation, physical examination 
The selection, naming and numeration of the tables is not mandatory but might be adapted in 
accordance with the described analyses in this SAP. 
Listings 
16.2 
16.2.1 
16.2.1.1 
16.2.1.1.1 
16.2.1 .1.2 
16.2.1.1.3 
16.2.1.1.4 
16.2.1.1.5 
16.2.1.2 
16.2.1.2.1 
16.2.1.2.2 
16.2.1.23 
CONFIDENTIAL 
Subject data listing 
Study subjects 
Disposition of subjects 
Screening failures 
Site numbers andprinciple investigators 
Site numbers and treatment group sorted by screening number 
Informed coment and randomization 
Visit dates and discontinuation 
Protocol deviations 
Inclusion criteria, definition 
Exclusion criteria, definition 
Subjects witlh violation of inclusion / exclusion criteria 
Page31 of33 


Saniona, A/S 
Study TM002 
16.2.1.2.4 
16.2.1.3 
16.2.1.3.1 
16.2.1.3.2 
16.2.1.3.3 
16.2.1.4 
16.2.1.4.1 
16.2.1.4.2 
16.2.1.5 
16.2.1.5.1 
16.2.1.5.2 
16.2.1.5.3 
16.2.1.5 .4 
16.2.2 
16.2.2.1 
16.2.2.1.1 
16.2.2.2 
16.2.2.2.1 
16.2.2.2.2 
16.2.2.2.3 
16.2.2.2.4 
16.2.2.2 .5 
16.2.2.2.6 
16.2.2.2.7 
16.2.2.2.8 
16.2.2.2.9 
16.2.2.2.10 
16.2.3 
16.2.3.1 
16.2.3.2 
16.2.3.3 
16.2.3.3.1 
16.2.3.3.2 
16.2.3.3.3 
16.2.3.4 
16.2.3.5 
16.2.3.6 
CONFIDENTIAL 
Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
Protocol deviations and other reason for exclusion fro m 
analysis sets, assignment to analysis set 
Demographic data and other baseline characteristics 
Demographics 
Findings in medical history 
Findings in concomitant diseases 
Previous and concomitant medications 
Previous medication 
Concomitant medication 
Extent of exposure, treatment compliance 
Study drug record 
Study drug administration 
Extent of exposure [days] 
Derived compliance data 
Efficacy and pharmacokinetic data 
Primary endpoint 
Change in body weight [%] 
Secondary endpoints 
Change in body weight [kg] 
Change in fat- and fat-free mass [g, %] 
Change in bone mineral density (BMD) [g/cm 2 ) and bone 
mineral conctent (BMC) [g) 
Change in HbAl c [%) 
Fasting plasma glucose [mmol/I) 
Waist circumference [cm) 
Insulin [mlU/I] 
Lipid profile (cholesterol, HDL, LDL, triglycerider) 
Hyperphagia questionnaire for clinical trials (HQ-CT) 
Drug concentration measurement 
Safety data 
Adverse events listiing 
Vital signs 
ECG 
ECG, interpr€tation 
ECG, notable results 
ECG, quantitative results 
Physical examination 
Laboratory data 
Electrocard iograpy 
Page 32 of 33 


Saniona, A/S 
Study TM002 
16.2.3.7 
Statistical Analysis Plan - Final 1.0 
27-Dec-2017 
Urine pregnancy test for women of childbearing potential 
The selection, naming and numeration of the listingsis not mandatory but might be adapted in 
accordance w ith the described analyses in this SAP. 
Figures 
14.1.1.1 
14.2.1.1 
14.2.2.1 
14.2.2.2 
14.2.2.3 
14.2.2.4 
14.2.2.5 
14.2.2.6 
14.2.2.7 
14.2.2.8 
14.3.2.1 
14.3.3.1 
Disposition of subjects 
Change over time in mean body weight [%] 
Change over time in body weight [kg] 
Change over time in mean heart rate [bpm] 
Change over time in mean systolic blood pressure [mmHg] 
Change over time in mean diastolic blood pressure [mmHg] 
Change over time in HbA 1 c [%] 
Change over time in fasting plasma glucose [mmol/I] 
Change over time in waist circumference [cm] 
Change over time in score of hyperphagia questionnaire for clinical trials (HQ-
cn 
Time to occurrence of first treatment-related AE 
T ime to occurrence of first treatment-related SAE 
The selection, naming and numeration of the figures are not mandatory but might be adapted in 
accordance w ith the described analyses in this SAP. 
CONFIDENTIAL 
Page 33 of 33 


 
GCP-Service 
STATISTICAL ANALYSIS PLAN 
Study Code 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 
Sponsor: 
Saniona, A/S 
Baltorpvej l 54 
DK 2750 Ballerup 
Denmark 
Author: 
Andreas Beust 
GCP-Service International Ltd. & Co. KG 
Anne-Conway-Str. 2 
28359 Bremen, Germany 
Tel +49 (0)421 89 67 66 31 
Date of document: 
18 January 2019 
Document version: 
Final l .1 
The information provided in this document is strictly confidential. No part of this document may be reproduced, 
transmitted or copied in any form nor its contents disclosed to the third parties without prior written consent of 
Saniona, A/Sor a nominated representative. 


 
Saniona, A/S 
Study TM002 
Document History 
Version 
Date 
Draft 0.1 
23-May-2017 
Draft 0.2 
30-Jun-2017 
Draft 0.3 
l 5-Aug-2017 
Final 1.0 
27-Dec-2017 
Final l. l 
18-Jan-2019 
CONFIDENTIAL 
Author(s) 
Leontina Levenzon 
Leontina Levenzon 
Leontina Levenzon 
Leontina Levenzon 
Andreas Beust 
Statistical Analysis Plan - Final l. l 
l 8-Jan-2019 
Description 
First release 
Section l : adaption of versions of 
protocols 
Section 2.3: addition of HQCT in 
the study schedule tabler 
Section 
2.4.2.: 
addition 
of 
secondary objective (HQCT) 
Section 2.8: adaption according to 
Protocol Amendments 
Section l : adaption of versions of 
protocols 
Finalization 
Update according to new protocol 
version 
Page 2 of 34 


Saniona, A/S 
Study TM002 
Signatures 
Statistical Analysis Plan - Final l. l 
l 8-Jan-2019 
I confirm that this Statistical Analysis Plan (SAP) accurately describes the planned statistical analyses 
to the best of my knowledge and was finalized before breaking the blind. 
Author: 
Review: 
Andreas Beust, PhD. 
Blostatlstician 
GCP·Service lnt. Ldt & Co. KG 
Anne-Conway-StraBe 2 
28359 Bremen, Germany 
Shobhit Agrawal, M.Sc. 
Biostatistician 
GCP-Service lnt. Ldt & Co. KG 
Anne-Conway-StraBe 2 
28359 Bremen, Germany 
Approved: 
Roman Dvorak MD, PhD 
Chief Medical Officer 
Saniona, A/S 
Baltorpvej, l 54 
DK 2750 Ballerup 
Denmark 
CONFIDENTIAL 
lAJM! 2o,<_«. 4f'r:;ef2 
Date 
Signature 
Dat 
Signature 
Date 
Signature 
Page 3 of 34 


Saniona, A/S 
Study TM002 
Table of Contents 
Statistical Analysis Plan - Final l. l 
l 8-Jan-2019 
Document History ........................................................................................................... 2 
Signatures ....................................................................................................................... 3 
List of Abbreviations and Key Terms ................................................................................ 7 
l. 
Introduction ............................................................................................................. 9 
2. 
Study Design and Objectives ..................................................................................... 9 
2.1 
Study Design ...................................................................................................... 9 
2.2 
Treatments ....................................................................................................... l O 
2.2. l 
lnvestigational Medicinal Product ................................................................ l 0 
2.2.2 
Placebo ...................................................................................................... 11 
2.3 
Trial Schedule ................................................................................................... 11 
2.4 
Study Objectives ............................................................................................... 13 
2.4. l 
Primary Objective ....................................................................................... 13 
2.4.2 
Secondary Objectives .................................................................................. 14 
2.5 
Study Hypothesis .............................................................................................. 14 
2.6 
Handling of Screening Failures and Withdrawals ................................................ 14 
2.7 
Randomization and Stratification ...................................................................... 14 
2.8 
Blinding ............................................................................................................ l 5 
2.9 
Sample Size Calculation .................................................................................... l 5 
2.10 
Planned Safety and PK Analysis ...................................................................... l 5 
2.11 
Handling of Changes to Study Protocol .......................................................... 16 
3. 
Technical Aspects and Coding Conventions ............................................................ 16 
3.1 
Date Coding and Day Numbering ...................................................................... 17 
3.2 
Coding Systems and Conventions ..................................................................... 17 
3.2. l 
Coding of Adverse Events and Medical History ............................................ 17 
3.2.2 
Separation of Medical History from Concomitant Diseases .......................... 17 
3.2.3 
Coding of Medications ................................................................................ 18 
3.2.4 
Separation of Medications .......................................................................... 18 
4. 
Analysis Populations and Subgroups ....................................................................... 18 
4.1 
Analysis Populations ......................................................................................... 18 
CONFIDENTIAL 
Page 4 of 34 


Saniona, A/S 
Study TM002 
Statistical Analysis Plan - Final l. l 
l 8-Jan-2019 
4.2 
Subgroups ........................................................................................................ 19 
4.3 
Stratification ..................................................................................................... 19 
5. 
Data Handling ........................................................................................................ 19 
5.1 
Handling of Missing Data and Outliers .............................................................. 19 
5.2 
Handling of Data from Screening Failures and Withdrawals ............................... 19 
5.3 
Handling of Multiple Comparisons and Multiple Primary Variables .................... 20 
5.4 
Data Review ...................................................................................................... 20 
6. 
Variables for Analysis ............................................................................................. 20 
6.1 
Demographics and Baseline Characteristics ....................................................... 20 
6.2 
Efficacy Endpoints ............................................................................................. 21 
6.2.l 
PrimaryEndpoint ........................................................................................ 21 
6.2.2 
Secondary Endpoints .................................................................................. 21 
6.3 
Safety Endpoints ............................................................................................... 21 
6.4 
Pharmacokinetic Endpoints ............................................................................... 22 
7. 
Statistical Analysis Methods .................................................................................... 22 
7 .1 Descriptive Statistics ............................................................................................... 22 
7.2 
Rounding Rules ................................................................................................. 23 
7.2. l 
Estimates of the Mean and Standard Deviation ............................................ 23 
7.2.2 
Other data .................................................................................................. 23 
7.3 
Calculation of Study Days and Durations ........................................................... 23 
7.4 
Evaluation of Demographics and Baseline Characteristics .................................. 24 
7.4. l 
Disposition of Patients ................................................................................ 24 
7.4.2 
Demographics and other Baseline Characteristics ....................................... 24 
7.4.3 
Medical History, and Concomitant Diseases ................................................ 24 
7.4.4 
Previous and Concomitant Medication ........................................................ 24 
7.5 
Evaluation of Primary Endpoint ......................................................................... 24 
7.6 
Evaluation of Secondary and Exploratory Variables ............................................ 25 
7.7 
Evaluation of Safety Variables ........................................................................... 26 
7.8 
Evaluation of Pharmacokinetic Data .................................................................. 28 
CONFIDENTIAL 
Page 5 of 34 


 
 
 
 
 
Saniona, A/S 
Study TM002 
Statistical Analysis Plan - Final l. l 
l 8-Jan-2019 
8. 
Changes in the Planned Analysis ............................................................................. 28 
9. 
APPENDIX l ............................................................................................................ 30 
CONFIDENTIAL 
Page 6 of 34 


Saniona, A/S 
Study TM002 
List of Abbreviations and Key Terms 
AE 
ANCOVA 
ATC 
BMC 
BMD 
BMI 
BP 
bpm 
Cl 
CRF 
CRO 
cm 
cm 2 
CV 
cz 
DBP 
D(E)XA 
DMP 
DSMB 
ECG 
eCRF 
FPG 
GCP 
GFR 
HbA1c 
HQ-CT 
HDL 
HLGT 
HLT 
HR 
HU 
ICH 
ID 
IMP 
Kg 
L 
LDL 
CONFIDENTIAL 
Adverse Event 
Analysis of co-variance 
Anatomical Therapeutic Chemical (Classification) 
Bone Mineral Conent 
Bone Mineral Density 
Body-Mass-Index 
Blood Pressure 
Beats per minute 
Confidence interval 
Case Report Form 
Contract Research Organization 
Centi meter 
Square centimeter 
Coefficient of variation 
Czech Republic 
Diastolic Blood Pressure 
Dual (Energy) X-ray Absorptiometry 
Data Management Plan 
Data Safety Monitoring Board 
Electrocardiogram 
electronic Case Report Form 
Fasting Plasma Glucose 
Good Clinical Practice 
Glomerular Filtration Rate 
Hemoglobin Al C 
Hyperphagia Questionnaire for Clinical Trials 
High-density lipoprotein 
Highest Level Group Term 
Highest Level Term 
Heart Rate 
Hungary 
International Conference on Harmonization 
Identification number 
Investigation Medicinal Product 
Kilogramme 
Liter 
Low-density lipoprotein 
Statistical Analysis Plan - Final l. l 
l 8-Jan-2019 
Page 7 of 34 


 
Saniona, A/S 
Study TM002 
LLT 
LOCF 
Max 
MedDRA 
mg 
mlU 
ml 
min 
Min 
mmHg 
mmol 
n 
N missing 
OP 
p 
PK 
PPP 
PT 
PWS 
SAE 
SAP 
SES 
SBP 
SD 
soc 
SOP 
SUKL 
WHO-ODE 
CONFIDENTIAL 
Lowest Level Term 
Last observation carried forward 
Maximum 
Medical Dictionary for Regulatory Activities 
Milligram 
Milli-international units per liter 
Milliliter 
Minute 
Minimum 
Millimeter of mercury 
Mi Iii mole 
Number of subjects 
Number of missing values 
Out-patient 
Phone call 
Pharmacoki netic 
Per Protocol Population 
Preferred term 
Prader-Willi Syndrom 
Serious Adverse Events 
Statistical Analysis Plan 
Safety Evalution Set 
Systolic Blood Pressure 
Standard deviation 
System Organ Class 
Standard Operating Procedure 
Statistical Analysis Plan - Final l. l 
l 8-Jan-2019 
State Institute for Drug Control (Czech Republic) 
World Health Organization - Drug Dictionary Enhanced 
Page 8 of 34 


 
 
Saniona, A/S 
Study TM002 
1. Introduction 
Statistical Analysis Plan - Final l. l 
l 8-Jan-2019 
This statistical analysis plan (SAP) contains a more technical and detailed elaboration of the principal 
features of the statistical analyses as described in the study protocol TM002 (dated: 13 March 2018 
Protocol Amendment Version l .4 for Hungary and 09 February 2018 Protocol Amendment Version 
l .5 for Czech Republic) (CZ) and includes detailed procedures for executing the statistical analysis 
of the primary and secondary variables and other data. In addition, Section 8 of this SAP summarizes 
all changes from the planned analysis as described in the SAP version l .0 as as known before 
finalization of this document. As the study is performed in two steps (Step l and Step 2), the SAP is 
updated and signed after Step l and prior to breaking the blind for Step 2. 
Data management and transfer of data will be carried out in accordance with the data management 
plan (DMP), statistical analysis in accordance with the SAP. 
If changes in the conduct of the statistical analysis are unavoidable, the reasons and the effect of 
these changes will be documented in the statistical report/clinical study report in full details. 
All statistical activities within the framework of this study will be based on the standard operating 
procedures (SOPs) for clinical studies of GCP-Service, as well as the ICH Guideline for Good Clinical 
Practice (ICH-GCP). 
2. Study Design and Objectives 
2.1 
Study Design 
This clinical study is 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). 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 PWS. 
The study will be conducted in two steps, each with two arms. The second step will only start 
following an unblinded interim analysis• by the Sponsor and in CZ following the review and approval 
of the State Institute for Drug Control (SUKL; the HU regulatory authority did not request this review): 
• The unblinded interim analysis was conducted in January 2018 after nine of the envisioned ten to twenty patients of Step 1 
were randomized and have finished treatment. The interim analysis results were reviewed by the Sponsor, but not the Data 
CONFIDENTIAL 
Page 9 of 34 


 
 
 
 
 
 
 
Saniona, A/S 
Study TM002 
Statistical Analysis Plan - Final l. l 
l 8-Jan-2019 
• 
Step l: l 0-20 adult subjects with PWS planned, but finished after 9 adult subjects as no 
more subjects were available 
o 
Arm l: tesofensine 0.50 mg + metoprolol 50 mg administered once a day, with the 
morning meal 
o 
Arm 2: placebo tablets matching tesofensine + metoprolol administered once a day, 
with the morning meal 
• 
Step 2: 5-1 5 children with PWS planned 
o 
Arm l: tesofensine 0.125 mg (0.25 mg every second day)+ metroprolol ER 25 mg 
(Metoprolol Orion 2 5 mg) administered once a day, with the morning meal 
o 
Arm 2: placebo tablets matching tesofensine every second day + metoprolol 
administered once a day, with the morning meal 
2.2 
Treatments 
2.2.1 
lnvestigational Medicinal Product 
Tesofensine is a serotonin-noradrenaline-dopamine reuptake inhibitor, for oral administration, 
which is manufactured, packed and labelled by Delpharm in Reims (France). Its chemical name is 
(l R, 2 R,35, 55)-3-(3 ,4-d ich lorophenyl)-2-(ethoxymethyl)-8-methyl-8-azabicyclo 
octane. 
Designated 
contractors will supply study medications directly. 
Metoprolol 
is 
a 
betal -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 Step l (adult subjects with PWS), 0.5 mg of tesofensine and 50 mg of extended release 
metoprolol or matching placebo will be administered. 
Following Step l, an unblinded interim analysis was performed. The Sponsor reviewed the unblinded 
data and a summary of key results from Step l, including PK data, and attested, following 
recommendations by the State Institute for Drug Control (SUKL) for CZ, that it was safe to proceed 
to Step 2 in children as described in the clinical study protocol. 
Safety Monitoring Board (DSMB) as initially planned. This change was introduced for HU with protocol version 1.3, dated 31 
October 201 7, and for CZ with protocol version 1 .4, dated 31 October 201 7. 
CONFIDENTIAL 
Page l O of 34 


 
 
 
Saniona, A/S 
Study TM002 
Statistical Analysis Plan - Final l. l 
l 8-Jan-2019 
In the Step 2 (children with PWS), tesofensine 0.125 mg (0.25 mg every second day)+ metoprolol 
25 mg will be administered once a day, in the morning with a meal. 
2.2.2 
Placebo 
The placebo formulation is identical in presentation and appearance to the tesofensine and 
metoprolol tablets but includes only the excipients; it does not contain any active ingredients. 
2.3 
Trial Schedule 
Study medication will be administered for ninety-two (92) days (+2 days after the final assessments 
with half-dose of metoprolol/placebo). Study procedures in Step l and 2 will be the same, except 
for a comprehensive psychiatric evaluation, which will be included for Step 2 during screening and 
every site visit. 
Following all baseline assessments, eligible subjects will be randomly assigned to one of the two 
arms (3:2, IMP: placebo). 
Screening visit is combined with the baseline and randomization visit (Day 0, Visit l ). All requested 
screening assessments and baseline blood draws and tests will be performed before randomization. 
After the Day 0, subjects will visit the site on Days 7, 28, 56 and 91 (Visits 2, 5, 9, 14) for efficacy 
and safety evaluations, pharmacokinetic (PK) sampling and medication supply. 
On Days 14, 21, 35, 42, 49, 63, 70, 77, 84 (Visits 3, 4, 6, 7, 8, l 0, 11, 12, 13) phone call follow ups 
will be performed. These phone calls will be used to provide additional reassurance regarding the 
safety of the subjects and collection of AEs. 
In Step l, on Day l 05 (Visit l 5) a phone call was performed to check subjects' status and potential 
AE(s). This concluded a subjects' participation in the study. In Step 2, the subjects will be invited 
for the final safety check and PK sampling on Day 121 (30 days after last dose), which will conclude 
their participation in the study. 
The study schedule is displayed in Table l. 
CONFIDENTIAL 
Page 11 of 34 


Saniona, A/S 
Study TM002 
Table l: Study schedule 
Visit 
Day 
Obtaining written 
Informed Content, 
Inclusion/Exclusion 
Generating screening 
number 
Demographic 
information 
Medical/medication 
history 
Psychiatric 
examination* 
Physical examination 
Vital signs 
Randomization 
Weight, waist 
circumference 
Height, calculation of 
BMI 
HQ-CT 
ECG 
Hematology 
Blood chemistry 
FPG, HbA l c 
CONFIDENTIAL 
l 
2 
3,4 
Screening 
/Baseline/ 
Randomiz 
ation 
OP 
OP 
p 
0 
7 
14 
21 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
5 
OP 
28 
X 
X 
X 
X 
X 
X 
X 
Statistical Analysis Plan - Final l. l 
l 8-Jan-2019 
6, 7,8 
9 
l 0, 11, 12, 
14 
15 
13 
F-
Upl 
p 
(O) 
p 
OP 
p 
(O)P 
35 
56 
63 
91 
105 
42 
70 
I 
121 
49 
77 
84 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 12 of 34 


 
 
 
Saniona, A/S 
Study TM002 
Statistical Analysis Plan - Final l. l 
l 8-Jan-2019 
Lipids, insulin 
DEXA 
PK sample 
Lifestyle consultation 
Drug dispensation 
AEs 
Drug accountability 
Concomitant 
medication 
Urinary pregnancy test 
Subject card 
dispensation 
Diary dispensation 
Diary review 
Diary collection 
Dispense Follow-up 
diary list 
End of study form 
OP: Out-patient 
P: Phone Call 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
** 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 Step l: Phone call after study day l 05 / Step 2: Personal visit postponed to study day 121 
* Only applicable for Step 2 
** two half doses of metoprolol should be dispensed 
2.4 
Study Objectives 
2.4.1 
Primary Objective 
The primary objective of this clinical trial is: 
• 
To examine the effect of co-administration of tesofensine/metoprolol on body weight in 
subjects with PWS. 
X 
X 
X 
X 
CONFIDENTIAL 
Page l 3 of 34 


 
 
 
 
 
 
 
 
 
Saniona, A/S 
Study TM002 
2.4.2 
Secondary Objectives 
In addition, further objectives are 
Statistical Analysis Plan - Final l. l 
l 8-Jan-2019 
• 
To establish pharmacokinetic profile of tesofensine and metoprolol in subjects with PWS, 
• 
To examine the change in hyperphagia-related behaviour 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. 
2.5 
Study Hypothesis 
As this is an explorative study no formal study hypothesis will be tested but the study results may 
be used to generate study hypotheses for possible subsequent studies. 
2.6 
Handling of Screening Failures and Withdrawals 
Nine subjects were randomized in Step l. In Step 2, enrolment will continue until a total of 5-1 5 
pediatric subjects are randomized. Randomized subjects who withdraw or are withdrawn from the 
study for any reason before completion are called "withdrawals". Withdrawals may be replaced, so 
that there are as close as possible to the minimum of 5 (Step 2) or l O (Step l) completers in each 
step of the study. 
A participant who fails during the screening phase, before randomisation, for any reason, e.g. 
because of violation against the eligibility criteria, is regarded as "screening failure". Subjects 
excluded during the screening period may be considered for another selection visit at a later date 
but will need to undergo complete rescreening. 
2.7 
Randomization and Stratification 
A centre-stratified block randomization with fixed block size is used. For each step of the study, one 
randomization list with complete blocks is prepared. This is done to achieve a balanced distribution 
of subject characteristics between the two treatment groups within each study centre and step of 
the study as far as possible. Subjects will be randomly assigned to the two study groups in a 3:2 
fashion (IMP:Placebo). A more detailed description of the randomization procedure is given in the 
Randomization Plan version 2.0, dated 24. August 201 7. 
CONFIDENTIAL 
Page 14 of 34 


 
 
Saniona, A/S 
Study TM002 
2.8 
Blinding 
Statistical Analysis Plan - Final l. l 
l 8-Jan-2019 
The study will be double blind. Neither the investigators nor the subjects will be informed about the 
type of subject, s medication. In general, emergency unblinding is to be done only when absolutely 
necessary for the clinical management of an individual subject and where stopping the blinded 
medication is not sufficient in the opinion of the investigator. 
A more detailed description of the blinding and unblinding procedure is given in the Randomization 
Plan version 2.0, dated 24 August 2017 and the study protocol TM002. 
2.9 
Sample Size Calculation 
As this is an explorative study no formal sample size or power calculation was performed. The 
chosen sample size is a balance between exposing the lowest possible number of subjects to the 
IMP, while still being able to compare the effects of tesofensine/ metoprolol treatment vs. placebo. 
Each site should randomize a minimum of five (5) eligible adult and a minimum of three (3) eligible 
pediatric patients. In total there should be randomized a minimum of 14 and a maximum of 29 
patients, 9 male and female adult subjects with confirmed diagnosis of PWS from Step l and 5-1 5 
male and female pediatric subjects with confirmed diagnosis of PWS. 
2.1 O 
Planned Safety and PK Analysis 
With protocol version l .3 (HU) and l .4 (CZ) coming into effect, no DSMB review of study data after 
Step l was performed and instead, an unblinded interim analysis was conducted in January 2018 
after nine instead of the ten patients planned were ultimately randomized. The interim analysis 
results were reviewed by the Sponsor and in CZ by the SUKL (the HU regulatory authority did not 
request such a review). 
A CRO statistician prepared an unblinded data package with efficacy, safety and PK data from Step 
l. The interim analysis provided answers to the Sponsor regarding the following questions: 
l) Based on the presented safety data, is it safe to proceed to Step 2, children (~ l 2 years of 
age) with PW syndrome "as is"? Any recommended modifications to the protocol? 
2) Based on the provided PK data, do you recommend proceeding at the recommended dose 
of 0.25 mg every second day (which is equal to 0.125 mg Tesofensine daily) and metoprolol 
ER 25 mg (Metoprolol Orion 25 mg) every day or would you recommend a different dose? If 
a different dose is recommended, please specify the dose of tesofensine and/or metoprolol. 
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Safety criteria: There were no set pre-defined criteria as to what constitutes a safety signal which 
would be considered serious enough not to recommend administration of the study drug to children. 
For CZ, the SUKL was asked to comprehensively evaluate the provided data and determine the 
resulting risk/benefit for the pediatric subjects and make their recommendation accordingly. 
PK criteria: If the 90% confidence interval (Cl) of a log-transformed exposure measure (mean trough 
concentrations from all follow-up samples,i.e., excluding the baseline sample collected prior to 
treatment with the study medication, collected from all adult participants for both metoprolol and 
tesofensine) after back-transformation falls completely within the range 80% of the 0.25 mg dose 
and 125% of the 1.0 mg dose previously measured trough concentrations in obese adult subjects in 
the study TIPO-1, the exposure achieved in the adult subjects will be considered in the expected 
safe range and no dose adjustment for the pediatric patients should be necessary. If the 90% 
confidence interval falls outside the 80-125% range the exposures will be considered sufficiently 
"different" from the expected values and a dosing adjustment should be considered by the SULK. 
2.11 
Handling of Changes to Study Protocol 
Any deviations from planned analyses, the reasons for such deviations, and all alternative or 
additional statistical analyses that may be planned before breaking the blind, respectively, will be 
described in amendments to the study protocol and/or the SAP. All deviations and/or alterations 
from the statistical analyses described in the protocol, especially those after database lock will be 
summarized in the clinical project report. 
All statistical analyses not pre-specified by the SAP and run after data lock will be considered as 
additional/exploratory analyses. 
3. Technical Aspects and Coding Conventions 
All programs will be written using SAS® (SAS Institute Inc., Cary, North Carolina, United States of 
America [USA]), version 9.4 or higher. Tables, listings and figures will be provided in separate PDF 
documents and will contain a separate table of contents. Courier New will be used as font for all 
tables and listings. In headings, titles and listings only the first word will be capitalised. A 
noncommittal list of all tables and listings can be found in the Appendix. 
A minimum font size of 8 points will be used for the tables, corresponding to a linesize of 140 digits 
and a pagesize of 52 lines for an output in DIN A4 format. All tables should be self-explaining. 
Therefore, necessary information should be available in the footnotes. The footnote and title of each 
table will be left-adjusted while the table will be centered. 
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For listings, a minimum font size of 8 points with the linesize and pagesize as defined above will be 
used to produce the output in DIN A4 format. Footnotes, titles and listings will be left-adjusted. 
Missing data will be represented on subject listings as blank field for text field or "." for numeric 
variables. Derived data will be marked by'#'. Listings will be sorted by site, treatment and screening 
number (equivalent to subject identification number) unless specified otherwise. 
3.1 
Date Coding and Day Numbering 
The format for presentation of date variables will be DDMMMYYYY. The format for presentation of 
time variables will be hh:mm. 
If dates are partially given, they will be completed, if necessary for the calculation of durations, 
according to a worst-case imputation. Dates with missing years will only be imputed if the correct 
year is obvious. 
Deviations will be documented and explained. 
3.2 
Coding Systems and Conventions 
3.2.1 
Coding of Adverse Events and Medical History 
Adverse event (AE), medical history and concomitant diseases terms are assigned to a lowest level 
term (LLT) and a preferred term (PT) and will be classified by high level term (HLT), high level group 
term (HLGT) and system organ class (SOC) according to the Medical Dictionary for Regulatory 
Activities (MedDRA) version in effect at the time the database is closed. Details are described in the 
DMP. 
3.2.2 
Separation of Medical History from Concomitant Diseases 
Separation of medical history from concomitant diseases will be done by comparison of the stop 
date of the medical condition with the start of study treatment. Each medical condition will be 
allocated unambiguously either to medical history or concomitant diseases. 
• 
Medical history: If the stop date is before start of treatment, the medical condition is 
allocated to medical history. If the stop date is partially given and unambiguously before 
start of treatment, the medical condition is also allocated to medical history. Furthermore, if 
the stop date is missing and the medical condition is not known to be ongoing, findings 
coded as "Surgical and medical procedures" are also allocated to medical history. 
• 
Concomitant diseases: If the stop date is at or after start of treatment or the medical 
condition is ongoing, the medical condition is allocated to concomitant diseases. 
Furthermore, if the stop date is missing and the medical condition is not known to be active 
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at start of study, the worst case is assumed for findings not coded as "Surgical and medical 
procedures". Consequently, the medical condition is allocated to concomitant diseases. 
3.2.3 
Coding of Medications 
Previous and concomitant medications will be coded using WHO-DDE (World Health Organization -
Drug Dictionary Enhanced) based on different Anatomical Therapeutic Chemical Classification (ATC) 
code levels. Details are described in the DMP. 
3.2.4 
Separation of Medications 
Separation of previous medications and concomitant medications will be done by comparison of the 
stop date of the medication with the start of study treatment. Each medication will be allocated 
unambiguously either to previous or concomitant medications. 
• 
Previous medications: If the stop date is before start of treatment, the medication is 
allocated to previous medications. If the stop date is partially given and unambiguously after 
start of treatment, the therapy is allocated to previous medications. 
• 
Concomitant medications: If the stop date is at or after start of treatment or the medication 
is ongoing, the medication is allocated to concomitant medications. Furthermore, if the stop 
date is missing, the worst case is assumed. Consequently, the medication is allocated to 
concomitant medications. If the stop date is partially given and implies stop date after start 
of treatment, the medication is also allocated to concomitant medications. 
4. Analysis Populations and Subgroups 
4.1 
Analysis Populations 
Within the framework of this study, the following two main populations are analysed: 
• 
The Per Protocol Population (PPP) includes all randomized subjects without any major 
protocol violations. Subjects in the PPP will contribute to the evaluation 'as treated'. 
• 
The Safety Evaluation Set (SES) includes all subjects receiving at least one dose of the 
investigational product or its comparator. Subjects in the SES will contribute to the 
evaluation 'as treated'. 
• 
The intention to treat (ITT) includes all subjects which receive at least one dose of the 
investigational product or its comparator and have a subsequent assessment of weight. 
Subjects in the ITT will contribute to the evaluation 'as treated'. 
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4.2 
Subgroups 
Statistical Analysis Plan - Final l. l 
l 8-Jan-2019 
The primary analysis for each endpoint will be using the combined data from steps l and 2 of this 
study. In addition, subgroup analyses are planned for step l and step 2 of this study to evaluate 
differences between treated adults and children. 
4.3 
Stratification 
Subjects will be stratified according to study centre. 
5. Data Handling 
5.1 
Handling of Missing Data and Outliers 
Since all analyses are explorative and with reference to the low sample size per step of this study, it 
is not planned to replace or impute missing data by complex imputation methods. Instead data will 
be used as available and analysis will be performed on observed cases only. The appropriateness of 
this procedure will be discussed during the blind data review and, if applicable, the handling of 
missing data will be adapted. 
For outliers, i.e. impossible or implausible values, queries are raised to the investigator before hard 
lock of the database. The investigator will either confirm or correct the value. Subsequently, the 
corrected or confirmed value is used for the analysis. If applicable, analysis will be performed with 
and without outliers to show robustness of the results. Complete exclusion of values should be only 
done in exceptional cases and is only valid for impossible and very implausible values with obvious 
justification. The decision to exclude data points from the statistical analysis is the joint 
responsibility of the Sponsor, the investigator and the CRO statistician. 
5.2 
Handling of Data from Screening Failures and Withdrawals 
In case of screening failures, the data will be listed but not further analyzed. The number of 
screening failures will be provided in a figure and a table for the disposition of subjects. 
Data from withdrawals will be used as available without imputation except for the analysis of the 
primary endpoint, which will be repeated using Last Observation Carried Forward (LOCF) imputations 
as sensitivity analysis. The number of early withdrawals and the corresponding reasons will be 
provided in a figure and a table for the disposition of subjects. 
For those subjects with early termination visits, the data is recorded either in the eCRF for the actual 
visit or into the Visit 14 (day 91) eCRF. In the latter case, these visit assignments will be replaced by 
the scheduled next visit assignment of the subject. 
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5.3 
Handling of Multiple Comparisons and Multiple Primary Variables 
As all data analyses in this study are explorative and will be interpreted accordingly, no adjustment 
for multiple comparisons is necessary. 
5.4 
Data Review 
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. This review will be performed without 
revealing which treatment the subjects are assigned to. The blinding of the treatment will be 
maintained for everyone involved in allocating subjects to the analysis sets until data are released 
for statistical analysis. Furthermore, outliers will be identified by data review according to ICH-E9 
(5), and a 
pseudo 
randomization (randomization simulation / simulated randomization). 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. 
For review of the pharmacokinetic data, additional care needs to be taken to avoid premature 
unblinding of the reviewers due to drug concentration levels being recorded for each subject. 
Therefore, subject IDs will be replaced by a randomly selected 5-digit pseudo - ID (one per subject) 
by an independent person not involved in the conduct, data review or analysis of the study. The list 
used for assignment of fake IDs to subject IDs will be stored in a secure location and will not be 
accessible to any person involved in the trial. The PK data will be sorted anew by pseudo- ID, the 
visit number (VISITNUM) and the analyzed drug (PCTEST), to ensure that the order of subjects does 
not give an indication of the true subject ID. This modified list will then be provided for data review. 
After acomplete review, all issues will be traced back to the subject ID using the list used for 
assignment of pseudo - IDs to subject IDs and queries will be resolved or subjects excluded from 
the analysis as determined during the data review process. 
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. 
6. Variables for Analysis 
6.1 
Demographics and Baseline Characteristics 
The following demographic and baseline characteristics will be evaluated: 
• 
Demographic information (race, gender, age, height, weight, BMI, waist circumference) 
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• 
Medical history, concomitant diseases, previous and concomitant medications 
• 
Baseline characteristics (vital signs, ECG, physical examination, psychiatric examination (Step 
2 only)) 
• 
Laboratory tests and measurements (fat mass, fat free mass, bone mineral density (BMD), 
bone mineral content (BMC), HbAic, Cholesterol, HDL, LDL, Triglyceride, Insulin, FPG) 
6.2 
Efficacy Endpoints 
6.2.1 
Primary Endpoint 
The following primary variable is evaluated: 
• 
Percent change from baseline to end of treatment in body weight 
6.2.2 
Secondary Endpoints 
The following secondary endpoints are planned: 
• 
Change from baseline to end of treatment in body weight [kg] 
• 
Change from baseline to end of treatment in fat- and fat-free mass [%] by dual X-ray 
absorptiometry (DEXA) 
• 
Change from baseline to end of treatment in fat- and fat-free mass [g] by dual X-ray 
absorptiometry (DEXA) 
• 
Change from baseline to end of treatment in bone mineral density (BMD) [g/cm 2 ] and bone 
mineral content (BMC) [g] by dual X-ray absorptiometry (DEXA) 
• 
Change from baseline to end of treatment of HbA,c [%] 
• 
Change from baseline to end of treatment in fasting plasma glucose (FPG) [mmol/L] 
• 
Change from baseline to end of treatment in waist circumference [cm] 
• 
Change from baseline to end of treatment in insulin [mlU/L] 
• 
Change from baseline to end of treatment in lipid profile (Cholesterol, HDL, LDL, Triglyceride) 
[mmol/L]) 
• 
Change from baseline to end of treatment in total HQ-CT score 
6.3 
Safety Endpoints 
Safety endpoints include: 
• 
Incidence of AEs, SAEs (serious adverse events), 
• 
Blood analysis: 
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o 
Hematology: 
blood count (erythrocytes, hemoglobin, hematocrit, leukocytes), 
differential 
blood count (neutrophils, 
lymphocytes, 
monocytes, 
eosinophils, 
basophils) and platelets 
o 
Blood 
chemistry: 
creatinine, 
gamma 
glutamyl 
transferase, 
aspartate 
aminotransferase, alkaline phosphatase, glomerular filtration rate (GFR) and urea 
• 
Electrocardiogram (ECG): 
o 
Interpretation (normal/abnormal) 
o 
Change from baseline to end of treatment in R-R, P-R, QRS and Q-T intervals 
• 
Vital signs: 
o 
Change from baseline to end of treatment in mean HR [bpm] 
o 
Change from baseline to end of treatment in mean SBP [mmHg] 
o 
Change from baseline to end of treatment in mean DBP [mmHg] 
o 
Change from baseline to end of treatment in body temperature [°C] 
o 
Change from baseline to end of treatment in respiratory rate [breaths/min] 
• 
Physical examination 
o 
Change from baseline to end of treatment in examination findings (normal/abnormal 
(NCS)/abnormal (CS)/not done) of different body systems (Head, ear, eye, nose and 
throat, respiratory system, cardiovascular system, abdomen, central and peripheral 
nervous system, lymph nodes, skin, skelet and other body system) 
• 
Psychiatric examination 
o 
Change from baseline to end of treatment in examination findings (normal/ abnormal 
(NCS)/abnormal (CS)/not done) 
6.4 
Pharmacokinetic Endpoints 
• 
Steady state concentrations of tesofensine and metoprolol as measured by trough values 
7. Statistical Analysis Methods 
7.1 
Descriptive Statistics 
The default summary statistics for quantitative variables will be the number of non-missing 
observations (n), number of missing values (N missing). For non-missing observations, arithmetic 
mean, geometric mean (if applicable), standard deviation (SD), coefficient of variation (CV), lower 
quartile (Ql ), upper quartile (Q3), minimum (min), median, and maximum (max) will be calculated 
and reported. 
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For categorical variables, the number (n) and percentage (%) of subjects per category will be the 
default summary presentation, and, if applicable, the number of missing values is provided in a 
"Missing" category. Missing data will not be included in the calculation of percentages as only 
available data are used, except if a subject did only answer specific questions of a questionnaire. 
Percentages will be calculated using a denominator of all subjects in a specified population or 
treatment group. The denominator will be specified in a footnote to the tables for clarification if 
necessary. If missing data occur within population specified as denominator, they will not be 
included in the calculation of percentages, except if a subject did only answer specific questions of 
a questionnaire. 
7.2 
Rounding Rules 
7.2. l 
Estimates of the Mean and Standard Deviation 
When using actual data, the mean and standard deviation are both rounded to one more decimal 
place than the original data, with a maximum of 2 decimal places. 
When mean values of repeated measurements are used for calculation of summary statistics, the 
mean and standard deviation are rounded to the same number of decimal places given for the mean 
values of repeated measurements used for calculation, with a maximum of 2 decimal places. 
7.2.2 
Other data 
Quartiles and median are always presented with the same number of decimal places as the mean. 
Minimum and maximum are always provided with the same number of decimal places as the data 
used. For estimates of proportions, the result is rounded to 3 decimal places. If proportions are 
displayed as percentage, l decimal place is displayed. For example, a proportion of 0.655 will be 
presented in percentage as 65.5%. The coefficient of variation is rounded to two decimals. 
7.3 
Calculation of Study Days and Durations 
Study days and, if applicable and meaningful, durations will be determined by comparing the 
respective date to the date of the first administration of the study medication. 
• 
If the respective date is on or after the date of the first administration of the study 
medication: 
Study day/Duration= Date (e.g. date of visit) - Date of first administration + l 
• 
If the respective date precedes the date of the first administration of the study medication: 
Study day/Duration = Date (e.g. date of medical history event) - Date of first 
administration 
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Time to onset and duration of adverse events will be calculated as follows: 
• 
Time to onset = start date of AE - date of first treatment [+ l for AE starting after start of 
treatment] 
Duration of adverse event= stop date - onset/worsening date + l 
7.4 
Evaluation of Demographics and Baseline Characteristics 
7.4.1 
Disposition of Patients 
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 all three analysis 
populations (SES, PPP and ITT). Subjects withdrawn from the study will be listed along with the 
primary reason for withdrawal. In addition, the primary reason for withdrawal will be tabulated. 
Furthermore, a summary of the time to study termination is provided per treatment group. 
7.4.2 
Demographics and other Baseline Characteristics 
Demographic information (race, gender, age, height, weight, BMI, waist circumference), baseline 
characteristics (vital signs, ECG, physical examination) and laboratory tests and measurements will 
be summarized by treatment group and step of the study (including a total column) using the default 
descriptive statistics for subjects in the PPP,SES and ITT. 
7.4.3 
Medical History, and Concomitant Diseases 
Absolute and relative frequencies (n, %) of medical history and concomitant diseases will be 
described by treatment group based on MedDRA system organ class and preferred term levels for 
all three analysis populations SES. Results will be presented overall and by step. 
7.4.4 
Previous and Concomitant Medication 
Absolute and relative frequencies (n, %) of previous and concomitant medication will be provided by 
treatment group based on Anatomical Therapeutic Chemical (ATC) Classification code levels 2 and 
3 for all three analysis populations SES. Results will be presented overall and by step. 
7.5 
Evaluation of Primary Endpoint 
The primary endpoint is 
• 
Percent change from baseline to end of treatment in body weight 
and will be calculated by: 
%-change = (Weight at end of treatment - Weight at baseline)/ (Weight at baseline) * l 00 
Where, according to the protocol, end of treatment is defined as Visit 14 (Day 91 ). 
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The primary endpoint will be presented and analysed based on the PPP and ITT. 
Percent change from baseline in body weight will be summarized per Step and in total, by treatment 
group and visit via mean, median, standard deviation, coefficient of variation (CV), lower quartile 
(Ql ), upper quartile (Q3), minimum and maximum value). Moreover, complete listings of individual 
values for the primary endpoint will be provided. Figures displaying the values for individual subjects 
(spaghetti plots) as well as figures displaying mean and standard deviation for percentage change 
from baseline in body weight at each visit per treatment group by Step and in total will also be 
provided. 
The primary endpoint percent change from baseline to end of treatment will be compared between 
treatment arms by means of an ANCOVA model including Step, site and treatment as fixed factors 
and baseline value as covariate. Estimates and 95% confidence interval of treatment differences will 
be calculated. The procedure for this analysis might be adapted during the blinded data review 
meeting. The primary analysis will be using the data from Steps l and 2 separately; secondary 
analyses will be carried out for both steps combined. The critical value will be set on a two-sided 
significance level of 5%. 
For the ANCOVA a variation of the following SAS
0-Code is recommended: 
proc glm data= <name of primary analysis data set>; 
class step site treatment_group; 
model chg_from_base = step site treatment_group baseline; 
lsmeans treatment/ cl e stderr pdiff; 
estimate 'Difference IMP versus Placebo' 
treatment l -1; 
run; 
quit; 
The ANCOVA will be repeated with the data of all subjects in the PPP with available weight 
measurement as sensitivity analysis. For withdrawals, change from baseline will be imputed 
according to the last observation carried forward (LOCF) method using the last weight measurement 
before study termination. 
7.6 
Evaluation of Secondary and Exploratory Variables 
The analysis of secondary and exploratory variables will be based on the PPP and ITT. The secondary 
and exploratory variables will be summarized per Step and in total by treatment group and visit and, 
where applicable, changes from baseline will be provided using standard descriptive statistics 
(mean, geometric mean (if applicable), median, standard deviation, coefficient of variation (CV), 
lower quartile (Ql ), upper quartile (Q3), minimum and maximum value). Individual (spaghetti plots) 
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and mean and standard deviation curves over treatment duration will be plotted by treatment per 
Step and in total. 
Change from baseline analysis to the end of treatment for the corresponding secondary and 
exploratory endpoints will be performed using ANCOVA, logistic regression models as applicable. 
For continuous variables, the ANCOVA model will be analogous to the model used for the primary 
endpoint. P-values, 95% confidence intervals and, if applicable, odds ratios for the comparison 
between treatments will be estimated. Also, the primary analysis of secondary endpoints will be 
using the data from Steps l and 2 separately and additional analyses will be carried out for the 
combined data. The critical values for each two-sided and one-sided statistical test will be based on 
a significance level of 5% and 2.5%, respectively. Figures displaying the mean and standard deviation 
of the raw data at each visit per treatment group will be also provided. Moreover, complete listings 
of individual values for all secondary and exploratory endpoints will be provided. 
A 9-item score will be calculated for the HQ-CT. Change in HQ-CT answers (by question and in total) 
will be calculated as (answer at visit 2, 5, 9 or 14) minus (answer at screening visit (visit l )) and 
presented using standard descriptive statistics (mean), median, standard deviation, coefficient of 
variation (CV), lower quartile (Ql ), uppe quartile (Q3), minimum and maximum value). Scores for 
each question range from O to 4 (with a higher score indicating a worse outcome), resulting in a 
maximum 9-item sum of 36. A decrease in total score (compared to the baseline assessment) 
indicates an improvement in hyperphagia. If less than three questions have not been answered by a 
subject, the missing answers will be imputed by the mean score of all available answers. In case of 
more missing answers, the total scores will not be calculated. Results will be presented by treatment 
per Step and in total. 
Subject compliance [%] will be calculated as l 00 x (number of tablets dispended - number of tablets 
returned)/(number of days of treatment) and will be calculated for both study drugs separately. The 
compliance will be summarized using standard descriptive statistics (mean, standard deviation, 
coefficient of variation (CV), lower quartile (Ql ), upper quartile (Q3), minimum and maximum value 
and listed per subject as well. 
7.7 
Evaluation of Safety Variables 
The analysis of the safety variables described in Section 6.3 will be based on the SES. Values will be 
summarized by treatment per Step and in total, using non-missing counts, mean, standard deviation, 
median, lower quartile (Ql ), upper quartile (Q3), minimum, and maximum for continuous data. 
Categorical data will be summarized using counts and percentages. Change from baseline to end of 
treatment analysis for vital signs will be done as described in Section 7.6. 
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All AEs occurring after the randomization of the subject will be reported as AE (any AEs that occurred 
between screening and randomization will be reported in medical history, but not as an AE). 
Incidences (number and percentage of subjects experiencing adverse events) per treatment group 
will be calculated for AEs on the system organ class (SOC) level and on the preferred term (PT) level, 
in total and by step, and by by intensity, by relationship and by outcome. Listings and tables 
displaying incidences for AEs leading to discontinuation, serious AEs, treatment-related serious AEs 
and deaths will also be provided. 
Differences in the incidence of treatment-related AEs between treatment groups will be analyzed 
using a logistic regression model with Step and treatment as fixed factor. This model might be 
adapted during the blind data review depending on the amount and quality of data. Odds ratios, p-
values, and 95% confidence intervals corresponding to the logistic regression model will be 
estimated for the comparisons between treatments. 
A variation of following basic SAS code is recommended for the analysis and expanded if needed: 
proc logistic data=<name of safety analysis data set>; 
class Step treatment_group (ref='0') / param = ref; 
model 
<binary variable 
for 
occurrence 
of treatment-related 
AE 
(l /0)> 
Step 
treatment_group; 
oddsratio Step treatment_group; 
run; 
In addition, the time to the first treatment-related adverse event and treatment-related serious 
adverse event will be calculated by Step and in total and displayed in Kaplan-Meier curves. 
The findings of the physical examinations are summarized by number (n) and percentage (%) of 
subjects per category (Normal/Abnormal (NCS)/Abnormal (CS)/Not done) per Step and in total by 
treatment group and visit each body system (Head, ear, eye, nose and throat, respiratory system, 
cardiovascular system, abdomen, central and peripheral nervous system, lymph nodes, skin, skelet 
and other body system). In addition, shift tables will be provided to further evaluate the change 
before first administration of the medication and the end of treatment. 
ECG data, vital signs as well as laboratory data (hematology and blood chemistry) will be summarized 
as continuous data by treatment group and visit per Step and in total. In addition, where available, 
the interpretation of the measured data (Normal/ Abnormal (NCS)/ Abnormal (CS)/Not done) will be 
analyzed as the findings of the physical examinations. 
Laboratory values will be evaluated in the provided units. Conversions of units will be done as 
necessary for a common analysis. For HbA l c measurements, values recorded in% will be converted 
to mmol/mol using the following formula: 
HbAl c [mmol/mol] = (HbAl c [%] - 2.15) * l 0.929 
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For ALP, ALT, AST and GGT measurements, values recorded in U/L will be converted to ukat/L using 
the following conversion: 
Measurement [U/L] = 0.0167 * Measurement [µkat/L] 
7.8 
Evaluation of Pharmacokinetic Data 
Drug concentrations will be summarized by descriptive statistics for both metoprolol and 
tesofensine using only the data from subjects exposed to the IMP. 
To take into account that 
pharmacokinetic parameters are often lognormally distributed, the geometric mean and the 
geometric coefficient of variation will be calculated additionally. The geometric mean is defined as 
the nth root of the product of n concentration measurements. The geometric coefficient of variation 
can be easily obtained by subtracting l from the geometric standard deviation and multiplication 
with l 00. 
In addition, the 90% confidence interval of a log-transformed exposure measure (mean trough 
concentrations from all follow-up samples (i.e. excluding the baseline sample collected prior to 
treatment with the study medication) collected from all adult participants for both metoprolol and 
tesofensine) will be provided after back-transformation. Furthermore, figures will be provided 
detailing the concentration of metoprolol/tesofensine over time since first exposure to 
metoprolol/tesofensine and the log-transformed mean concentration over time since first exposure 
to metoprolol/tesofensine. 
It should be noted that values below the lower limit of quantification will be excluded from the 
analysis, since the subjects are considered not to be exposed to the IMP in this case. The number of 
subjects in the IMP group with a value below the lower limit of quantification during the treatment 
phase will be listed in a footnote to the corresponding table. 
8. Changes in the Planned Analysis 
The analysis of this study is described in the study protocol TM002 (dated: l 3 March 2018 Protocol 
Amendment Version 1.4 for Hungary and 09 February 2018 Protocol Amendment Version 1.5 for 
Czech Republic). Nevertheless, minor changes to the conduct of the analysis have to be performed 
and are described below in detail. 
The wording of the primary endpoint was changed from "Percent change from baseline to end of 
treatment in mean body weight" to "Percent change from baseline to end of treatment in body 
weight" to address that no replicated measurements were performed during the body weight 
assessment at a visit. That means that the relative change of body weight as assessed by single 
measurements performed at the screening visit and the end of treatment is calculated. The same 
applies to the secondary endpoint "Change from baseline to end of treatment in body weight (kg)". 
CONFIDENTIAL 
Page 28 of 34 


 
Saniona, A/S 
Study TM002 
Statistical Analysis Plan - Final l. l 
l 8-Jan-2019 
This does not change the intended analysis but rather more accurately reflects the envisaged 
analysis as described in the protocol. 
Furthermore, the expected minimum enrolment per site was changed from 2 to 3 to ensure a greater 
likelihood of both treamtents being present at each of the sites and the minimum total number of 
subjects was adjusted to reflect the number of subjects randomized during Step l and the minimum 
recruitment for Step 2 as defined in the protocol. Finally, changes were made to the provided 90% 
confidence interval of the mean trough drug concentration. The description now accurately states 
that the confidence interval will not be provided as log-transformed values but will instead be 
transformed back. 
In addition, the following changes were made to the final SAP (version l .0) after unblinded interim 
analysis and in response to changes in the protocol version of HU (CZ) from 1.2 (1.3) to 1.4 (1.5): 
Major changes include the addition of an ITT population, which which will be used for all efficacy 
analyses in addition to the PPS. Further, the analysis of primary and secondary endpoints was 
updated to display separate results per step and in total, as differences between adults and children 
(step l and step 2) are expected based on current knowledge. This is expected to have an influence 
on the outcome of the trial in case strong differences between adults and children are observed. 
However, this will allow for a differentiation in efficacy of the treatment on the two distinct analysis 
populations (adults and children) rather than having a masking effect of combing them. The results 
of this change and the reasons for this decision will be discussed in detail in the Clinical Study 
Report. 
Further major changes include that for those subjects with metroprolol/tesofensine concentrations 
below the lower limit of quantification (LLOQ), instead of not using the values it was conservatively 
assumed that these subjects had a concentration of LLOQ/2. These subjects were now included in 
the analysis. 
Minor cosmetic and wording changes were added for additional clarification. The study design and 
visit schedule were updated to reflect protocol changes. Furthermore, a description of the evaluation 
of the psychiatric examination was that introduced with the protocol amendment was added. The 
description of the Interim Analysis was updated to match the description in the protocol. Also, a 
section was added to describe conversion of laboratory values of different sites required for an 
analysis of all values combined and the rounding rules were updated for additional clarity. The 
stratification section was changed to reflect the centre-stratified randomization that was in place 
already during Step l . 
CONFIDENTIAL 
Page 29 of 34 


Saniona, A/S 
Study TM002 
Statistical Analysis Plan - Final l. l 
l 8-Jan-2019 
9. APPENDIX 1 
Tables 
14. l 
14. l . l 
14.l.l.l 
14.l.l.2 
14.l.l.3 
14. l .2 
14. l .3 
14.1.3.l 
14.1.3.2 
14.1.3.3 
14.1.3.4 
14.1.3.5 
14. l .4 
14.1.4.l 
14. l .4.2 
14. l .5 
14.1.5.l 
14.1.5.2 
14. l .6. 
14. l .6.1 
14. l .6.2 
14.2 
14.2. l 
14.2.l.l 
14.2. l .2 
14.2.2 
14.2.2. l 
14.2.2.2 
14.2.2.3 
14.2.2.4 
14.2.2.5 
CONFIDENTIAL 
Study subjects 
Disposition of subjects 
Number of subjects enrolled, by site and total 
Number of subjects per visit 
Discontinuation, eligible subjects 
Protocol deviations and other reasons for exclusion from analysis sets, 
randomized subjects 
Demographics and other baseline characteristics, SES and PPP 
Demographics 
Vital signs 
ECG 
Physical examination 
Laboratory tests and measurements 
Medical history and concomitant diseases, SES and PPP 
Medical history by System Organ Class and Preferred Term 
Concomitant diseases by System Organ Class and Preferred Term 
Previous and concomitant medications, SES and PPP 
Previous medication by ATC level 
Concomitant medication by ATC level 
Extent of exposure and treatment compliance, SES and PPP 
Duration of exposure [days, SES] 
Compliance [%], SES and PPP 
Efficacy and pharmacokinetic data, PPP 
Primary endpoint 
Change over time in body weight [%] 
Change over time in body weight[%], summary of ANCOVA 
Secondary endpoints 
Change over time in body weight [kg] 
Change over time in body weight [kg], summary of ANCOVA 
Change over time in fat- and fat-free mass [%] by DEXA 
Change over time in fat- and fat-free mass [%] by DEXA, summary of 
ANCOVA 
Change over time in fat- and fat-free mass [g] by DEXA 
Page 30 of 34 


Saniona, A/S 
Study TM002 
14.2.2.6 
14.2.2.7 
14.2.2.8 
14.2.2.9 
14.2.2. l 0 
14.2.2.11 
14.2.2.12 
14.2.2.13 
14.2.2.14 
14.2.2.15 
14.2.2.16 
14.2.2.17 
14.2.2.18 
14.2.2.19 
14.2.2.20 
14.2.2.21 
14.3 
14.3. l 
14.3.l.l 
14.3.1.2 
14.3.1.3 
14.3.1.4 
14.3.l.5 
14.3.l.6 
14.3.1.7 
14.3.1.8 
14.3.1.9 
14.3.2 
14.3.2.l 
14.3.2.2 
CONFIDENTIAL 
Statistical Analysis Plan - Final l. l 
l 8-Jan-2019 
Change over time in fat- and fat-free mass [g] by DEXA, summary of 
ANCOVA 
Change over time in bone mineral density (BMD) [g/cm 2 ] and bone 
mineral content (BMC) [g] by DEXA 
Change over time in bone mineral density (BMD) [g/cm 2] and bone 
mineral content (BMC) [g] by DEXA, summary of ANCOVA 
Change over time in HbA l c [%] 
Change over time in HbA l c [%], summary of ANCOVA 
Change over time in fasting plasma glucose [mmol/L] 
Change over time in fasting plasma glucose [mmol/L], summary of 
ANCOVA 
Change over time in waist circumference [cm] 
Change over time in waist circumference [cm], summary of ANCOVA 
Change over time in insulin [mlU/L] 
Change over time in insulin [mlU/L], summary of ANCOVA 
Change over time in lipid profile (cholesterol, HDL, LDL, triglyceride) 
Change over time in lipid profile (cholesterol, HDL, LDL, triglyceride), 
summary of ANCOVA 
Changer over time in hyperphagia questionnaire for clinical trials 
(HQ-CT) 
Change over time in the overall score from the hyperphagia 
questionnaire for clinical trails (HQ-CT), summary of ANCOVA 
Steady state concentrations of tesofensine and metroprolol 
Safety data, SES 
Adverse events 
Overall summary of adverse events 
Number(%) of subjects with AEs and number of AEs by System Organ 
Class and Preferred Term 
Number(%) of subjects with AEs by worst causal relationship 
Number(%) of subjects with AE by worst intensity 
Number(%) of subjects with AEs by worst causal relationship and worst 
intensity 
Number(%) of subjects with AEs by worst outcome 
Number of subjects with AEs by worst causal relationship and worst 
outcome 
Number(%) of subjects with treatment-related AEs 
Incidences in treatment related AEs, summary of logistics model 
Deaths, other serious and significant adverse events 
Serious AEs, listing of subjects 
Treatment-related serious AEs, listing of subjects 
Page 31 of 34 


Saniona, A/S 
Study TM002 
14.3.2.3 
14.3.2.4 
14.3.3 
14.3.3.l 
14.3.3.2 
14.3.3.3 
14.3.4 
14.3.4.l 
14.3.4.2 
14.3.4.3 
14.3.4.4 
14.3.5 
14.3.5.l 
14.3.5.2 
14.3.5.3 
14.3.5.4 
14.3.5.5 
14.3.5.6 
14.3.5.7 
Statistical Analysis Plan - Final l. l 
l 8-Jan-2019 
Deaths, listing of all serious AEs of subjects who died 
AEs leading to discontinuation, listing of subjects 
Vital signs 
Change over time in mean heart rate [bpm], systolic blood pressure 
[mmHg], diastolic blood pressure [mmHg] 
Change over time in temperature [°C] 
Change over time in respiratory rate [breaths/min] 
Laboratory data 
Summary statistics for hematology 
Summary statistics forblood chemistry 
Shift tables for interpretation, hematology 
Shift tables for interpretation, blood chemistry 
Other safety data 
Summary statistics for measurements, electrocardiography 
Summary statistics for interpretation, electrocardiography 
Shift tables for interpretation, electrocardiography 
Summary statistics for interpretation, physical examination 
Shift tables for interpretation, physical examination 
Summary statistics for interpretation, psychiatric examination 
Shift tables for interpretation, psychiatric examination 
The selection, naming and numeration of the tables is not mandatory but might be adapted in 
accordance with the described analyses in this SAP. 
Listings 
16.2 
16.2. l 
16.2.l.l 
16.2.l.l.l 
16.2.l.l.2 
16.2.l.l.3 
16.2.l.l.4 
16.2.l.l.5 
l 6.2. l .2 
16.2.l.2.l 
16.2.l.2.2 
16.2.1.23 
CONFIDENTIAL 
Subject data listing 
Study subjects 
Disposition of subjects 
Screening failures 
Site numbers and pri nci pie investigators 
Site numbers and treatment group sorted by screening number 
Informed consent and randomization 
Visit dates and discontinuation 
Protocol deviations 
Inclusion criteria, definition 
Exclusion criteria, definition 
Subjects with violation of inclusion/ exclusion criteria 
Page 32 of 34 


Saniona, A/S 
Study TM002 
16.2.1.2.4 
16.2.l.3 
16.2.l.3.l 
16.2.1.3.2 
16.2.1.3.3 
16.2.1.4 
l 6.2. l .4.1 
16.2.1.4.2 
16.2.l.5 
16.2.l.5.l 
16.2.1.5.2 
16.2.1.5.3 
16.2.1.5.4 
16.2.2 
16.2.2. l 
16.2.2.l.l 
16.2.2.2 
16.2.2.2. l 
16.2.2.2.2 
16.2.2.2.3 
16.2.3 
16.2.3. l 
16.2.3.2 
16.2.3.3 
16.2.3.3.l 
16.2.3.3.2 
16.2.3.4 
16.2.3.5 
16.2.3.6 
16.2.3.7 
Statistical Analysis Plan - Final l. l 
l 8-Jan-2019 
Protocol deviations and other reason for exclusion from 
analysis sets, assignment to analysis set 
Demographic data and other baseline characteristics 
Demographics 
Findings in medical history 
Findings in concomitant diseases 
Previous and concomitant medications 
Previous medication 
Concomitant medication 
Extent of exposure, treatment compliance 
Study drug record 
Study drug administration 
Extent of exposure [days] 
Derived compliance data 
Efficacy and pharmacokinetic data 
Primary endpoint 
Change in body weight [%] 
Secondary endpoints 
Vital signs 
Safety data 
Hyperphagia questionnaire for clinical trials (HQ-CT) 
Laboratory values 
Adverse events listing 
Vital signs 
ECG 
ECG, interpretation 
ECG, quantitative results 
Physical examination 
Laboratory data 
Urine pregnancy test for women of childbearing potential 
Psychiatric examination 
The selection, naming and numeration of the listingsis not mandatory but might be adapted in 
accordance with the described analyses in this SAP. 
Figures 
14.l.l.l 
14.2.l.l 
14.2. l .2 
CONFIDENTIAL 
Disposition of subjects 
Change over time in mean body weight [%] 
Change over time in individual body weight [%] 
Page 33 of 34 


Saniona, A/S 
Study TM002 
14.2.2. l 
14.2.2.2 
14.2.2.3.l 
14.2.2.5.l 
14.2.2.7.l 
14.2.2.9. l 
14.2.2.9.2 
14.2.2.11.l 
14.2.2.11.2 
14.2.2.13. l 
14.2.2.13.2 
14.2.2.15.l 
14.2.2.15.2 
14.2.2.17. l 
14.2.2.17.2 
14.2.2.21.l 
14.2.2.21.2 
14.3.2.l 
14.3.3.l 
14.4.l 
14.4.2 
Change over time in body weight [kg] 
Statistical Analysis Plan - Final l. l 
l 8-Jan-2019 
Change over time in individual body weight [kg] 
Change over time in fat- and fat-free mass [%] 
Change over time in fat- and fat-free mass [g] 
Change over time in BMD / BMC 
Change over time in HbA l c [%] 
Change over time in HbA l c [%] by subject 
Change over time in fasting plasma glucose [mmol/I] 
Change over time in fasting plasma glucose [mmol/I] by subject 
Change over time in waist circumference [cm] 
Change over time in individual waist circumference [cm] 
Change over time in insulin [mlU/L] 
Change over time in insulin [mlU/L] by subject 
Change over time in lipids 
Change over time in lipids by subject 
Mean of log-transformed drug concentration by subject 
Change over time in drug concentration by subject 
Time to occurrence of first treatment-related AE 
Time to occurrence of first treatment-related SAE 
Hyperphagia questionnaire: Score over time by subject 
Hyperphagia questionnaire: mean scores over time by treatment groups 
The selection, naming and numeration of the figures are not mandatory but might be adapted in 
accordance with the described analyses in this SAP. 
CONFIDENTIAL 
Page 34 of 34 


 
 
STATISTICAL ANALYSIS PLAN 
 
Study Code 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” 
 
 
 
 
The information provided in this document is strictly confidential. No part of this document may be reproduced, 
transmitted or copied in any form nor its contents disclosed to the third parties without prior written consent of 
Saniona, A/S or a nominated representative. 
 
 
Sponsor: Saniona, A/S 
Baltorpvej 154 
DK 2750 Ballerup 
Denmark 
Author:  
 
Andreas Beust 
GCP-Service International Ltd. & Co. KG 
Anne-Conway-Str. 2 
28359 Bremen, Germany 
Tel   +49 (0)421 20 80 98 51 
 
 
Date of document: 
 
     Document version: 
08 August 2019 
 
Final 1.2 
GCP-Service 
Lt 


Saniona, A/S 
Study TM002 
 
Statistical Analysis Plan – Final 1.2 
10-Aug-2019 
 
 
CONFIDENTIAL 
 
Page 2 of 38 
Document History 
Version 
Date 
Author(s) 
Description 
Draft 0.1 
23-May-2017 
Leontina Levenzon  
First release 
Draft 0.2 
30-Jun-2017 
Leontina Levenzon 
Section 1: adaption of versions of 
protocols 
Section 2.3: addition of HQCT in 
the study schedule tabler 
Section 
2.4.2.: 
addition 
of 
secondary objective (HQCT) 
Section 2.8: adaption according to 
Protocol Amendments 
Draft 0.3 
15-Aug-2017 
Leontina Levenzon 
Section 1: adaption of versions of 
protocols  
Final 1.0 
27-Dec-2017 
Leontina Levenzon 
Finalization 
Final 1.1 
18-Jan-2019 
Andreas Beust 
Update according to new protocol 
version 
Final 1.2 
08-Aug-2019 
Andreas Beust 
Update to cover analysis of open 
lable extension (OLE) 1 and 2 
 
 
 


Saniona, A/S 
Study TM002 
 
Statistical Analysis Plan – Final 1.2 
10-Aug-2019 
 
 
CONFIDENTIAL 
 
Page 3 of 38 
Signatures 
I confirm that this Statistical Analysis Plan (SAP) accurately describes the planned statistical analyses 
to the best of my knowledge and was finalized before breaking the blind. 
 
Author: 
Andreas Beust, PhD. 
Biostatistician 
GCP-Service Int. Ldt & Co. KG 
Anne-Conway-Straße 2 
28359 Bremen, Germany 
 
Date 
 
Signature 
 
 
 
 
Review: 
Dennis Neuschwander, M.Sc. 
Biostatistician 
GCP-Service Int. Ldt & Co. KG 
Anne-Conway-Straße 2 
28359 Bremen, Germany 
 
 
Date 
 
Signature 
 
 
 
 
Approved: Roman Dvorak MD, PhD 
Chief Medical Officer 
Saniona, A/S 
Baltorpvej, 154 
DK 2750 Ballerup 
Denmark 
 
 
Date 
 
Signature 
 
 
 
 
 


Saniona, A/S 
Study TM002 
 
Statistical Analysis Plan – Final 1.2 
10-Aug-2019 
 
 
CONFIDENTIAL 
 
Page 4 of 38 
Table of Contents 
Document History ........................................................................................................... 2 
Signatures ....................................................................................................................... 3 
List of Abbreviations and Key Terms ................................................................................ 7 
1. 
Introduction ............................................................................................................. 9 
2. 
Study Design and Objectives ..................................................................................... 9 
2.1 
Study Design ...................................................................................................... 9 
2.2 
Treatments ....................................................................................................... 11 
2.2.1 
Investigational Medicinal Product ................................................................ 11 
2.2.2 
Placebo ...................................................................................................... 11 
2.3 
Trial Schedule ................................................................................................... 12 
2.4 
Study Objectives ............................................................................................... 18 
2.4.1 
Primary Objective ....................................................................................... 18 
2.4.2 
Secondary Objectives .................................................................................. 18 
2.5 
Study Hypothesis .............................................................................................. 18 
2.6 
Handling of Screening Failures and Withdrawals ................................................ 19 
2.7 
Randomization and Stratification ...................................................................... 19 
2.8 
Blinding ............................................................................................................ 19 
2.9 
Sample Size Calculation .................................................................................... 19 
2.10 
Planned Safety and PK Analysis ...................................................................... 20 
2.11 
Handling of Changes to Study Protocol .......................................................... 20 
3. 
Technical Aspects and Coding Conventions ............................................................ 21 
3.1 
Date Coding and Day Numbering ...................................................................... 21 
3.2 
Coding Systems and Conventions ..................................................................... 22 
3.2.1 
Coding of Adverse Events and Medical History ............................................ 22 
3.2.2 
Separation of Medical History from Concomitant Diseases .......................... 22 
3.2.3 
Coding of Medications ................................................................................ 22 
3.2.4 
Separation of Medications .......................................................................... 22 
4. 
Analysis Populations and Subgroups ....................................................................... 23 
4.1 
Analysis Populations ......................................................................................... 23 


Saniona, A/S 
Study TM002 
 
Statistical Analysis Plan – Final 1.2 
10-Aug-2019 
 
 
CONFIDENTIAL 
 
Page 5 of 38 
4.2 
Subgroups ........................................................................................................ 23 
4.3 
Stratification ..................................................................................................... 24 
5. 
Data Handling ........................................................................................................ 24 
5.1 
Handling of Missing Data and Outliers .............................................................. 24 
5.2 
Handling of Data from Screening Failures and Withdrawals ............................... 24 
5.3 
Handling of Multiple Comparisons and Multiple Primary Variables .................... 25 
5.4 
Data Review ...................................................................................................... 25 
6. 
Variables for Analysis ............................................................................................. 25 
6.1 
Demographics and Baseline Characteristics....................................................... 25 
6.2 
Efficacy Endpoints ............................................................................................. 26 
6.2.1 
Primary Endpoint ........................................................................................ 26 
6.2.2 
Secondary Endpoints .................................................................................. 26 
6.3 
Safety Endpoints ............................................................................................... 26 
6.4 
Pharmacokinetic Endpoints ............................................................................... 27 
7. 
Statistical Analysis Methods .................................................................................... 27 
7.1 Descriptive Statistics............................................................................................... 27 
7.2 
Rounding Rules ................................................................................................. 28 
7.2.1 
Estimates of the Mean and Standard Deviation ............................................ 28 
7.2.2 
Other data .................................................................................................. 28 
7.3 
Calculation of Study Days and Durations ........................................................... 28 
7.4 
Evaluation of Demographics and Baseline Characteristics .................................. 29 
7.4.1 
Disposition of Patients ................................................................................ 29 
7.4.2 
Demographics and other Baseline Characteristics ....................................... 29 
7.4.3 
Medical History, and Concomitant Diseases ................................................ 29 
7.4.4 
Previous and Concomitant Medication ........................................................ 29 
7.5 
Evaluation of Primary Endpoint ......................................................................... 29 
7.6 
Evaluation of Secondary and Exploratory Variables ............................................ 30 
7.7 
Evaluation of Safety Variables ........................................................................... 31 
7.8 
Evaluation of Pharmacokinetic Data .................................................................. 33 


Saniona, A/S 
Study TM002 
 
Statistical Analysis Plan – Final 1.2 
10-Aug-2019 
 
 
CONFIDENTIAL 
 
Page 6 of 38 
8. 
Changes in the Planned Analysis ............................................................................. 33 
9. 
APPENDIX 1 ............................................................................................................ 34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Saniona, A/S 
Study TM002 
 
Statistical Analysis Plan – Final 1.2 
10-Aug-2019 
 
 
CONFIDENTIAL 
 
Page 7 of 38 
List of Abbreviations and Key Terms  
AE 
 
Adverse Event 
ANCOVA 
Analysis of co-variance 
ATC 
 
Anatomical Therapeutic Chemical (Classification) 
BMC 
 
Bone Mineral Conent 
BMD 
 
Bone Mineral Density 
BMI 
 
Body-Mass-Index 
BP 
 
Blood Pressure 
bpm 
 
Beats per minute 
 
CI 
 
Confidence interval 
CRF  
 
Case Report Form 
CRO 
 
Contract Research Organization 
cm 
 
Centimeter 
cm² 
 
Square centimeter 
CV 
 
Coefficient of variation 
CZ 
 
Czech Republic 
DBP  
 
Diastolic Blood Pressure 
D(E)XA  
Dual (Energy) X-ray Absorptiometry 
DMP 
 
Data Management Plan  
DSMB  
Data Safety Monitoring Board 
ECG 
 
Electrocardiogram 
eCRF 
 
electronic Case Report Form 
FPG 
 
Fasting Plasma Glucose 
GCP 
 
Good Clinical Practice 
GFR 
 
Glomerular Filtration Rate 
HbA1C  
Hemoglobin A1C 
HQ-CT  
Hyperphagia Questionnaire for Clinical Trials 
HDL 
 
High-density lipoprotein 
HLGT  
Highest Level Group Term 
HLT 
 
Highest Level Term 
HR 
 
Heart Rate 
HU 
 
Hungary 
ICH 
 
International Conference on Harmonization 
ID 
 
Identification number 
IMP 
 
Investigation Medicinal Product 
Kg 
 
Kilogramme 
L 
 
Liter 
LDL 
 
Low-density lipoprotein 


Saniona, A/S 
Study TM002 
 
Statistical Analysis Plan – Final 1.2 
10-Aug-2019 
 
 
CONFIDENTIAL 
 
Page 8 of 38 
LLT 
 
Lowest Level Term 
LOCF  
Last observation carried forward 
Max 
 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities  
mg 
 
Milligram 
mIU 
 
Milli-international units per liter 
mL 
 
Milliliter 
min 
 
Minute 
Min 
 
Minimum 
mmHg  
Millimeter of mercury 
mmol  
Millimole 
n 
 
Number of subjects 
 
N missing 
Number of missing values 
OLE 
 
Open Label Extension 
OP 
 
Out-patient 
P 
 
Phone call 
PK 
 
Pharmacokinetic 
PPP 
 
Per Protocol Population 
PT 
 
Preferred term  
PWS 
 
Prader-Willi Syndrom 
SAE 
 
Serious Adverse Events 
SAP 
 
Statistical Analysis Plan 
SES 
 
Safety Evalution Set 
SBP 
 
Systolic Blood Pressure 
SD  
 
Standard deviation 
SOC 
 
System Organ Class 
SOP 
 
Standard Operating Procedure 
SUKL 
 
State Institute for Drug Control (Czech Republic) 
WHO-DDE 
World Health Organization - Drug Dictionary Enhanced 
 
 


Saniona, A/S 
Study TM002 
 
Statistical Analysis Plan – Final 1.2 
10-Aug-2019 
 
 
CONFIDENTIAL 
 
Page 9 of 38 
1.  Introduction 
This statistical analysis plan (SAP) contains a more technical and detailed elaboration of the principal 
features of the statistical analyses as described in the study protocol TM002 (latest versions dated: 
31 January 2019 Protocol Amendment Version 1.6 for Hungary and 30 January 2019 Protocol 
Amendment Version 1.7 for Czech Republic) (CZ) and includes detailed procedures for executing 
the statistical analysis of the primary and secondary variables and other data. In addition, Section 8 
of this SAP summarizes all changes from the planned analysis as described in the SAP version 1.1 
as known before finalization of this document. As the study has been extended beyond the originally 
envisaged steps 1 and 2 to encompass two open label extensions (OLE), this SAP is updated and 
signed prior to the evaluation of both open label extensions. 
Data management and transfer of data will be carried out in accordance with the data management 
plan (DMP), statistical analysis in accordance with this SAP.  
If changes in the conduct of the statistical analysis are unavoidable, the reasons and the effect of 
these changes will be documented in the statistical report/clinical study report in full details. 
All statistical activities within the framework of this study will be based on the standard operating 
procedures (SOPs) for clinical studies of GCP-Service, as well as the ICH Guideline for Good Clinical 
Practice (ICH-GCP).  
2. Study Design and Objectives 
2.1 
Study Design  
This clinical study is 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). 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 PWS. 
 


Saniona, A/S 
Study TM002 
 
Statistical Analysis Plan – Final 1.2 
10-Aug-2019 
 
 
CONFIDENTIAL 
 
Page 10 of 38 
The study was conducted in two steps, each with two arms. The second step was started following 
an unblinded interim analysisa by the Sponsor, and in CZ  following the review and approval of the 
State Institute for Drug Control (SUKL; the HU regulatory authority did not request this review):   
• 
Step 1: 10-20 adult subjects with PWS planned, but finished after 9 adult subjects as  no 
more subjects were available 
o 
Arm 1: tesofensine 0.50 mg + metoprolol 50 mg administered once a day, with the 
morning meal 
o 
Arm 2: placebo tablets matching tesofensine + metoprolol administered once a day, 
with the morning meal 
• 
Step 2: 5-15 children with PWS planned, but finished after 9 pediatric subjects as no more 
subjects were available 
o 
Arm 1: tesofensine 0.125 mg (0.25 mg every second day) + metroprolol ER 25 mg 
(Metoprolol Orion 25 mg) administered once a day, with the morning meal  
o 
Arm 2: placebo tablets matching tesofensine every second day + metoprolol 
administered once a day, with the morning meal 
 
All eligible participants of Step 2 were offered to continue the trial in an open label extension for an 
initial 12 weeks (OLE1; according to protocol amendments 1.5 (HU) and 1.6 (CZ)), in which all 
participants received the following doses: 
• 
Tesofensine 0.125 mg (0.25 mg every second day) and Metoprolol ER 25 mg (Metoprolol 
Orion 25 mg) administered once a day, with the morning meal 
 
All eligible participants of the first open label extension were offered a second extension of 12 
weeks (according to protocol amendments 1.6 (HU) and 1.7 (CZ)), in which all particpants received 
the following doses: 
• 
Tesofensine 0.125 mg (0.25 mg every second day) and Metoprolol ER 25 mg (Metoprolol 
Orion 25 mg) administered once a day, with the morning meal 
• 
For all patients tolerating the OLE1 doses well, the dose was increased to 0.25 mg 
Tesofensine and 25 mg Metoprolol ER administered once a day, with the morning meal 
 
 
 
a The unblinded interim analysis was conducted in January 2018 after nine of the envisioned ten to twenty patients of Step 1 
were randomized and have finished treatment. The interim analysis results were reviewed by the Sponsor, but not the Data 
Safety Monitoring Board (DSMB) as initially planned. This change was introduced for HU with protocol version 1.3, dated 31 
October 2017, and for CZ with protocol version 1.4, dated 31 October 2017. 


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Study TM002 
 
Statistical Analysis Plan – Final 1.2 
10-Aug-2019 
 
 
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Page 11 of 38 
In case a patient, in the opinion of the PI, experienced an adverse event that, by the PI, was suspected 
to be potentially related to an undesirable drug concentration of the investigational medication, the 
investigators at each site, based on their discretion, was allowed to modify the treatment schedule 
of the patients in order to optimally manage the wellbeing and safety of the patient. 
2.2 
Treatments 
2.2.1 
Investigational Medicinal Product 
Tesofensine is a serotonin-noradrenaline-dopamine reuptake inhibitor, for oral administration, 
which is manufactured, packed and labelled by Delpharm in Reims (France). Its chemical name is 
(1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-2-(ethoxymethyl)-8-methyl-8-azabicyclo 
octane. 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 Step 1 (adult subjects with PWS), 0.5 mg of tesofensine and 50 mg of extended release 
metoprolol or matching placebo was administered. 
 
Following Step 1, an unblinded interim analysis was performed. The Sponsor reviewed the unblinded 
data and a summary of key results from Step 1, including PK data, and attested, following 
recommendations by the State Institute for Drug Control (SUKL) for CZ, that it was safe to proceed 
to Step 2 in children as described in the clinical study protocol. 
 
In the Step 2 (children with PWS), tesofensine 0.125 mg (0.25 mg every second day) + metoprolol 
25 mg were administered once a day, in the morning with a meal. For OLE1 (initial 12 weeks 
extensions), participants of the Step 2 trial that continued were treated with tesofensine 0.125 mg 
(0.25 mg every second day) + metoprolol 25 mg (once a day). For OLE2 (second 12 weeks extension), 
participants that tolerated the OLE1 dose well were allowed to be treated at 0.25 mg tesofensine 
and 25 mg metoprolol per day. Patients that experienced, in the opinion of the PI, an adverse event 
potentially related to the investigational medication, could be treated with a reduced dose or 
alternative dosing schedule to optimally manage the wellbeing and safety of the patient. 
2.2.2 
Placebo 
The placebo formulation is identical in presentation and appearance to the tesofensine and 
metoprolol tablets but includes only the excipients; it does not contain any active ingredients. 


Saniona, A/S 
Study TM002 
 
Statistical Analysis Plan – Final 1.2 
10-Aug-2019 
 
 
CONFIDENTIAL 
 
Page 12 of 38 
2.3 
Trial Schedule  
Study medication was administered for ninety-two (92) days (+2 days after the final assessments 
with half-dose of metoprolol/placebo) during Step 1 and Step 2 of the trial. Study medication was 
administered for ninety (90) days (+2 days after the final assessments with half-dose of metoprolol) 
during OLE1 and OLE2. Study procedures in Step 1 and 2 were the same, except for a comprehensive 
psychiatric evaluation, which was included for Step 2 during screening and every site visit. Study 
procedures in the OLE1 and OLE2 part of the trial followed the the described assessments of Step 2, 
with differences in the scheduling (see Table 2, 3 and 4, 5, respectively). 
Following all baseline assessments, eligible subjects were randomly assigned to one of the two arms 
(3:2, IMP: placebo).  
For Step 1 and 2, screening visit was combined with the baseline and randomization visit (Day 0, 
Visit 1). All requested screening assessments and baseline blood draws and tests were performed 
before randomization.  
 
After the Day 0, subjects visited the site on Days 7, 28, 56 and 91 (Visits 2, 5, 9, 14) for efficacy and 
safety evaluations, pharmacokinetic (PK) sampling and medication supply.  
 
On Days 14, 21, 35, 42, 49, 63, 70, 77, 84 (Visits 3, 4, 6, 7, 8, 10, 11, 12, 13) phone call follow ups 
were performed. During the OLE parts of the study, phone calls were performed once per month 
between visits (see Table 3, 5). These phone calls were used to provide additional reassurance 
regarding the safety of the subjects and collection of AEs.  
 
In Step 1, on Day 105 (Visit 15) a phone call was performed to check subjects’ status and potential 
AE(s). This  concluded a subjects’ participation in the study. In Step 2, the subjects were invited for 
the final safety check and PK sampling on Day 121 (30 days after last dose), which concluded their 
participation in the study. An exception to this was the participation in the OLE1 part of the study, 
for which the day 91 visit during Step 2 was used as Baseline visit. For those patients participating 
in the OLE1, the day 210 visit (30 days after last dose) concluded their participation in the study. An 
exception to this was the participation in the OLE2 part of the study, for which the day 180 visit 
during OLE1 was used as Baseline visit. For those patients participating in the OLE2, the day 300 
visit (30 days after last dose) concluded their participation. 
The study schedules for Part 2, OLE1 and OLE2 are displayed in Table 1, 2 and 3, and 4 and 5, 
respectively. 
 
 


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Study TM002 
 
Statistical Analysis Plan – Final 1.2 
10-Aug-2019 
 
 
CONFIDENTIAL 
 
Page 13 of 38 
Table 1: Study schedule Step 1/2 
Visit 
1 
 
Screening
/Baseline/ 
Randomiz
ation  
 
 
OP 
2 
 
 
 
 
 
 
 
OP 
3, 4 
 
 
 
 
 
 
 
P 
5 
 
 
 
 
 
 
 
OP 
6, 7, 8 
 
 
 
 
 
 
 
P 
9 
 
 
 
 
 
 
 
(O)
P 
10, 11, 12, 
13 
 
 
 
 
 
 
P 
14 
 
 
 
 
 
 
 
OP 
15 
 
F-
up1 
 
 
 
 
 
(O)P 
Day 
0 
7 
14  
21 
28 
35  
 42  
 49 
56 
63  
70  
77 
84 
91 
105
/ 
121 
Obtaining written 
Informed Content, 
Inclusion/Exclusion 
x 
 
 
 
 
 
 
 
 
Generating screening 
number 
x 
 
 
 
 
 
 
 
 
Demographic 
information 
x 
 
 
 
 
 
 
 
 
Medical/medication 
history 
x 
 
 
 
 
 
 
 
 
Psychiatric 
examination* 
x 
x 
 
x 
 
x 
 
x 
x 
Physical examination 
x 
 
 
 
 
 
 
x 
 
Vital signs 
x 
x 
 
x 
 
x 
 
x 
 
Randomization 
x 
 
 
 
 
 
 
 
 
Weight, waist 
circumference 
x 
x 
 
x 
 
x 
 
x 
 
Height, calculation of 
BMI 
x 
 
 
 
 
 
 
 
 
HQ-CT 
x 
x 
 
x 
 
x 
 
x 
 
ECG 
x 
 
 
 
 
 
 
x 
 
Hematology 
x 
 
 
x 
 
 
 
x 
 
Blood chemistry 
x 
 
 
x 
 
 
 
x 
 
FPG, HbA1c 
x 
  
 
x 
  
x 
  
x 
 


Saniona, A/S 
Study TM002 
 
Statistical Analysis Plan – Final 1.2 
10-Aug-2019 
 
 
CONFIDENTIAL 
 
Page 14 of 38 
OP: Out-patient 
P: Phone Call  
1 Step 1: Phone call after study day 105 / Step 2: Personal visit postponed to study day 121 
* Only applicable for Step 2 
** two half doses of metoprolol should be dispensed 
 
 
Lipids, insulin 
x 
 
 
x 
 
x 
 
x 
 
DEXA 
x 
 
 
 
 
 
 
x 
 
PK sample 
x 
  
 
x 
 
x 
 
x 
x 
Lifestyle consultation 
x 
 
 
 
 
 
 
 
 
Drug dispensation 
x 
x 
 
x 
 
x 
 
**
x 
 
AEs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Drug accountability 
 
x 
 
x 
 
x 
 
x 
 
Concomitant 
medication 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinary pregnancy test 
x 
 
 
 
 
 
 
x 
 
Subject card 
dispensation 
x 
 
 
 
 
 
 
 
 
Diary dispensation 
x 
 
 
 
 
 
 
 
 
Diary review 
 
x 
 
x 
 
x 
 
x 
 
Diary collection 
 
 
 
 
 
 
 
x 
 
Dispense Follow-up 
diary list 
 
 
 
 
 
 
 
x 
 
End of study form 
 
 
 
 
 
 
 
 
x 


Saniona, A/S 
Study TM002 
 
Statistical Analysis Plan – Final 1.2 
10-Aug-2019 
 
 
CONFIDENTIAL 
 
Page 15 of 38 
Table 2: Study schedule OLE1 
Visit 
14 
 
Equal to last 
visit of part 2 
 
Treatment 
15 
 
Treatment 
16 
 
Treatment 
17 
 
End of 
Treatment 
18 
 
End of study 
Day 
91 
120 (28 days 
± 3 days) 
150(28 days 
± 3 days) 
180(28 days 
± 3 days) 
210(28 days 
± 3 days) 
Obtaining 
the 
Addendum to double 
blind ICF for the open 
label part  
x 
 
 
 
 
Subject 
screening 
number (keeping the 
same as in Step2)  
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  
Lifestyle consultation  
x  
 
 
 
 
Drug dispensation 
x  
 
 
x  
 
AEs  
x  
x  
x  
x  
x  
Drug accountability  
  
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 


Saniona, A/S 
Study TM002 
 
Statistical Analysis Plan – Final 1.2 
10-Aug-2019 
 
 
CONFIDENTIAL 
 
Page 16 of 38 
** Blood samples of metoprolol taken 2 and 4 hours after dose administration. Time point for 
dosing and the two blood samples should be noted! 
 
Table 3: Phone call schedule OLE1 
Visit  
14.1  
Phone call  
15.1  
Phone call  
16.1  
Phone call  
17.1  
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 
 
 
 


Saniona, A/S 
Study TM002 
 
Statistical Analysis Plan – Final 1.2 
10-Aug-2019 
 
 
CONFIDENTIAL 
 
Page 17 of 38 
Table 4: Study schedule OLE2 
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  
Lifestyle consultation  
x  
 
 
 
 
Drug dispensation 
x  
 
 
x  
 
AEs  
x  
x  
x  
x  
x  
Drug accountability  
  
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 


Saniona, A/S 
Study TM002 
 
Statistical Analysis Plan – Final 1.2 
10-Aug-2019 
 
 
CONFIDENTIAL 
 
Page 18 of 38 
** 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! 
 
Table 5: Phone call schedule OLE2 
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 
 
2.4 
Study Objectives 
2.4.1 
Primary Objective 
The primary objective of this clinical trial is:  
• 
To examine the effect of co-administration of tesofensine/metoprolol on body weight in 
subjects with PWS. 
2.4.2 
Secondary Objectives 
In addition, further objectives are  
• 
To establish pharmacokinetic profile of tesofensine and metoprolol in subjects with PWS, 
• 
To examine the change in hyperphagia-related behaviour 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. 
2.5 
Study Hypothesis 
As this is an explorative study no formal study hypothesis will be tested but the study results may 
be used to generate study hypotheses for possible subsequent studies. 


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Study TM002 
 
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10-Aug-2019 
 
 
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Page 19 of 38 
2.6 
Handling of Screening Failures and Withdrawals 
Nine subjects were randomized in Step 1 and Step 2, each. Of the nine patients participating in Step 
2, eight continued into the OLE1 phase of the trial, of which five continued to the OLE2 phase of the 
trial. 
A participant who failed during the screening phase, before randomisation, for any reason, e.g. 
because of violation against the eligibility criteria, was regarded as “screening failure”. Subjects 
excluded during the screening period could have been considered for another selection visit at a 
later date but needed to undergo complete rescreening. 
2.7 
Randomization and Stratification 
A centre-stratified block randomization with fixed block size was used. For each step of the study, 
one randomization list with complete blocks was prepared. This was done to achieve a balanced 
distribution of subject characteristics between the two treatment groups within each study centre 
and step of the study as far as possible. Subjects were randomly assigned to the two study groups 
in a 3:2 fashion (IMP:Placebo). A more detailed description of the randomization procedure is given 
in the Randomization Plan version 2.0, dated 24. August 2017. 
For the OLE part of the study, all included subjects received the IMP, irrespective of their previous 
allocation. 
2.8 
Blinding 
Step 1 and 2 of the study were conducted double blind. Neither the investigators nor the subjects 
were informed about the type of subject´s medication. In general, emergency unblinding had to be 
done only when absolutely necessary for the clinical management of an individual subject and where 
stopping the blinded medication was not sufficient in the opinion of the investigator.  
 
A more detailed description of the blinding and unblinding procedure is given in the Randomization 
Plan version 2.0, dated 24 August 2017 and the study protocol TM002. 
2.9 
Sample Size Calculation 
As this is an explorative study, no formal sample size or power calculation was performed. The 
chosen sample size is a balance between exposing the lowest possible number of subjects to the 
IMP, while still being able to compare the effects of tesofensine/ metoprolol treatment vs. placebo. 


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Study TM002 
 
Statistical Analysis Plan – Final 1.2 
10-Aug-2019 
 
 
CONFIDENTIAL 
 
Page 20 of 38 
2.10 
Planned Safety and PK Analysis 
With protocol version 1.3 (HU) and 1.4 (CZ) coming into effect, no DSMB review of study data after 
Step 1 was performed and instead, an unblinded interim analysis was conducted in January 2018 
after nine instead of the ten patients planned were ultimately randomized. The interim analysis 
results were reviewed by the Sponsor and in CZ by the SUKL (the HU regulatory authority did not 
request such a review).  
A CRO statistician prepared an unblinded data package with efficacy, safety and PK data from Step 
1. The interim analysis provided answers to the Sponsor regarding the following questions: 
 
1) Based on the presented safety data, is it safe to proceed to Step 2, children (≥12 years of 
age) with PW syndrome “as is”? Any recommended modifications to the protocol? 
 
2) Based on the provided PK data, do you recommend proceeding at the recommended dose 
of 0.25 mg every second day (which is equal to 0.125 mg Tesofensine daily) and metoprolol 
ER 25 mg (Metoprolol Orion 25 mg) every day or would you recommend a different dose? If 
a different dose is recommended, please specify the dose of tesofensine and/or metoprolol. 
 
Safety criteria: There were no set pre-defined criteria as to what constitutes a safety signal which 
would be considered serious enough not to recommend administration of the study drug to children. 
For CZ, the SUKL was asked to comprehensively evaluate the provided data and determine the 
resulting risk/benefit for the pediatric subjects and make their recommendation accordingly. 
 
PK criteria: If the 90% confidence interval (CI) of a log-transformed exposure measure (mean trough 
concentrations from all follow-up samples,i.e., excluding the baseline sample collected prior to 
treatment with the study medication, collected from all adult participants for both metoprolol and 
tesofensine) after back-transformation falls completely within the range 80% of the 0.25 mg dose 
and 125% of the 1.0 mg dose previously measured trough concentrations in obese adult subjects in 
the study TIPO-1, the exposure achieved in the adult subjects will be considered in the expected 
safe range and no dose adjustment for the pediatric patients should be necessary. If the 90% 
confidence interval falls outside the 80-125% range the exposures will be considered sufficiently 
“different” from the expected values and a dosing adjustment should be considered by the SULK.  
2.11 
Handling of Changes to Study Protocol 
Any deviations from planned analyses, the reasons for such deviations, and all alternative or 
additional statistical analyses that may be planned before breaking the blind, respectively, will be 
described in amendments to the study protocol and/or the SAP. All deviations and/or alterations 
from the statistical analyses described in the protocol, especially those after database lock will be 
summarized in the clinical project report. 


Saniona, A/S 
Study TM002 
 
Statistical Analysis Plan – Final 1.2 
10-Aug-2019 
 
 
CONFIDENTIAL 
 
Page 21 of 38 
All statistical analyses not pre-specified by the SAP and run after data lock will be considered as 
additional/exploratory analyses. 
3. Technical Aspects and Coding Conventions 
All programs will be written using SAS® (SAS Institute Inc., Cary, North Carolina, United States of 
America [USA]), version 9.4 or higher. Tables, listings and figures will be provided in separate PDF 
documents and will contain a separate table of contents. For each analysis (Step 2, Step 2 and OLE1, 
Step 2, OLE1 and OLE2, OLE1 alone, OLE2 alone), separate documents will be prepared. Tables for 
each analysis will additionally be split into different documents based on their content as follows: 
• 
Baseline/Demographics/Disposition 
• 
Efficacy data 
• 
Safety data 
• 
Other 
Courier New will be used as font for all tables and listings. In headings, titles and listings only the 
first word will be capitalised. A noncommittal list of all tables and listings can be found in the 
Appendix.  
A minimum font size of 8 points will be used for the tables, corresponding to a linesize of 140 digits 
and a pagesize of 52 lines for an output in DIN A4 format. All tables should be self-explaining. 
Therefore, necessary information should be available in the footnotes. The footnote and title of each 
table will be left-adjusted while the table will be centered. 
For listings, a minimum font size of 8 points with the linesize and pagesize as defined above will be 
used to produce the output in DIN A4 format. Footnotes, titles and listings will be left-adjusted. 
Missing data will be represented on subject listings as blank field for text field or “.” for numeric 
variables. Derived data will be marked by ‘#’. Listings will be sorted by site, treatment and screening 
number (equivalent to subject identification number) unless specified otherwise. 
3.1 
Date Coding and Day Numbering 
The format for presentation of date variables will be DDMMMYYYY. The format for presentation of 
time variables will be hh:mm. 
If dates are partially given, they will be completed, if necessary for the calculation of durations, 
according to a worst-case imputation. Dates with missing years will only be imputed if the correct 
year is obvious. 
Deviations will be documented and explained. 


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Study TM002 
 
Statistical Analysis Plan – Final 1.2 
10-Aug-2019 
 
 
CONFIDENTIAL 
 
Page 22 of 38 
3.2 
Coding Systems and Conventions 
3.2.1 
Coding of Adverse Events and Medical History 
Adverse event (AE), medical history and concomitant diseases terms are assigned to a lowest level 
term (LLT) and a preferred term (PT) and will be classified by high level term (HLT), high level group 
term (HLGT) and system organ class (SOC) according to the Medical Dictionary for Regulatory 
Activities (MedDRA) version in effect at the time the database is closed. Details are described in the 
DMP. 
3.2.2 
Separation of Medical History from Concomitant Diseases 
Separation of medical history from concomitant diseases will be done by comparison of the stop 
date of the medical condition with the start of study treatment, referring to the start of treatment 
during Step 2 of the trial. Each medical condition will be allocated unambiguously either to medical 
history or concomitant diseases.  
• 
Medical history: If the stop date is before start of treatment, the medical condition is 
allocated to medical history.  If the stop date is partially given and unambiguously before 
start of treatment, the medical condition is also allocated to medical history. Furthermore, if 
the stop date is missing and the medical condition is not known to be ongoing, findings 
coded as “Surgical and medical procedures” are also allocated to medical history. 
• 
Concomitant diseases: If the stop date is at or after start of treatment or the medical 
condition is ongoing, the medical condition is allocated to concomitant diseases. 
Furthermore, if the stop date is missing and the medical condition is not known to be active 
at start of study, the worst case is assumed for findings not coded as “Surgical and medical 
procedures”. Consequently, the medical condition is allocated to concomitant diseases. 
3.2.3 
Coding of Medications 
Previous and concomitant medications will be coded using WHO-DDE (World Health Organization -
Drug Dictionary Enhanced) based on different Anatomical Therapeutic Chemical Classification (ATC) 
code levels. Details are described in the DMP. 
3.2.4 
Separation of Medications 
Separation of previous medications and concomitant medications will be done by comparison of the 
stop date of the medication with the start of study treatment, referring to the start of treatment 
during Step 2 of the trial. Each medication will be allocated unambiguously either to previous or 
concomitant medications. 


Saniona, A/S 
Study TM002 
 
Statistical Analysis Plan – Final 1.2 
10-Aug-2019 
 
 
CONFIDENTIAL 
 
Page 23 of 38 
• 
Previous medications: If the stop date is before start of treatment, the medication is 
allocated to previous medications.  If the stop date is partially given and unambiguously after 
start of treatment, the therapy is allocated to previous medications. 
• 
Concomitant medications: If the stop date is at or after start of treatment or the medication 
is ongoing, the medication is allocated to concomitant medications. Furthermore, if the stop 
date is missing, the worst case is assumed. Consequently, the medication is allocated to 
concomitant medications. If the stop date is partially given and implies stop date after start 
of treatment, the medication is also allocated to concomitant medications. 
4. Analysis Populations and Subgroups 
4.1 
Analysis Populations 
Within the framework of this study, the following two main populations are analysed:  
• 
The Per Protocol Population (PPP) includes all randomized subjects without any major 
protocol violations. Subjects in the PPP will contribute to the evaluation ‘as treated’. 
• 
The Safety Evaluation Set (SES) includes all subjects receiving at least one dose of the 
investigational product or its comparator. Subjects in the SES will contribute to the 
evaluation ‘as treated’. 
• 
The intention to treat (ITT) includes all subjects which receive at least one dose of the 
investigational product or its comparator and have a subsequent assessment of weight. 
Subjects in the ITT will contribute to the evaluation ‘as treated’. 
For the evaluation of the OLE1 and OLE2 parts of the study (analyses 2-5 as described in section 
4.2), the analysis will only be performed for the SES and ITT populations. 
4.2 
Subgroups 
The analysis for the Step 2 and OLE1 and OLE2 will be performed sequentially as follows: 
1. Based on Step 2 data, for all patients that were enrolled in the Step 2 part of the trial 
2. Based on Step 2 and OLE1 data, for all patients that were enrolled in the OLE1 part of the 
trial 
3. Based on Step 2, OLE1 and OLE2 data, for all patients that were enrolled in the OLE2 part of 
the trial 
4. Based on OLE1 data, for all patients that were enrolled in the OLE1 part of the trial 
5. Based on OLE2 data, for all patients that were enrolled in the OLE2 part of the trial 
The definition for baseline and end of treatment vary for the five subgroups as follows: 


Saniona, A/S 
Study TM002 
 
Statistical Analysis Plan – Final 1.2 
10-Aug-2019 
 
 
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1. Baseline is defined as baseline of Step 2 (Visit 1) and End of Treatment (EoT) is defined as 
Visit 14 of Step 2 
2. Baseline is defined as baseline of Step 2 (Visit 1) and EoT is defined as Visit 17 of OLE1 
3. Baseline is defined as baseline of Step 2 (Visit 1) and EoT is defined as Visit 20 of OLE2 
4. Baseline is defind as Visit 14 of Step 2/OLE1 and EoT is defined as Visit 17 of OLE1 
5. Baseline is defined as Visit 17 of OLE1/OLE2 and EoT is defined as Visit 20 of OLE2  
For subgroups 4 and 5, only the following parameters will be analyzed: 
• 
Body weight 
• 
Waist circumference 
• 
Hyperphagia score 
• 
Heart rate 
• 
Blood pressure 
4.3 
Stratification 
Subjects will be stratified according to study centre.  
5. Data Handling  
5.1 
Handling of Missing Data and Outliers 
Since all analyses are explorative and with reference to the low sample size per step of this study, it 
is not planned to replace or impute missing data by complex imputation methods. Instead data will 
be used as available and analysis will be performed on observed cases only. 
For outliers, i.e. impossible or implausible values, queries are raised to the investigator before hard 
lock of the database. The investigator will either confirm or correct the value. Subsequently, the 
corrected or confirmed value is used for the analysis. If applicable, analysis will be performed with 
and without outliers to show robustness of the results. Complete exclusion of values should be only 
done in exceptional cases and is only valid for impossible and very implausible values with obvious 
justification. The decision to exclude data points from the statistical analysis is the joint 
responsibility of the Sponsor, the investigator and the CRO statistician. 
5.2 
Handling of Data from Screening Failures and Withdrawals 
In case of screening failures, the data will be listed but not further analyzed. The number of 
screening failures will be provided in a figure and a table for the disposition of subjects.  
Data from withdrawals will be used as available without imputation except for the analysis of the 
primary endpoint, which will be repeated using Last Observation Carried Forward (LOCF) imputations 


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as sensitivity analysis if meaningful. The number of early withdrawals and the corresponding reasons 
will be provided in a figure and a table for the disposition of subjects. 
For those subjects with early termination visits, the data is recorded either in the eCRF for the actual 
visit or into the End of Treatment (EoT) eCRF. In the latter case, these visit assignments will be 
replaced by the scheduled next visit assignment of the subject. 
5.3 
Handling of Multiple Comparisons and Multiple Primary Variables 
As all data analyses in this study are explorative and will be interpreted accordingly, no adjustment 
for multiple comparisons is necessary. 
5.4 
Data Review  
Before data are released for statistical analysis, a review of all data of OLE1 and OLE2 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. 
6. Variables for Analysis 
6.1 
Demographics and Baseline Characteristics 
The following demographic and baseline characteristics will be evaluated: 
• 
Demographic information (race, gender, age, height, weight, BMI, waist circumference)  
• 
Medical history, concomitant diseases, previous and concomitant medications 
• 
Baseline characteristics (vital signs, ECG, physical examination, psychiatric examination (Step 
2 only))  
• 
Laboratory tests and measurements (fat mass, fat free mass, bone mineral density (BMD), 
bone mineral content (BMC), HbA1c, Cholesterol, HDL, LDL, Triglyceride, Insulin, FPG) 


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6.2 
Efficacy Endpoints 
6.2.1 
Primary Endpoint 
The following primary variable is evaluated: 
• 
Percent change from baseline to end of treatment in body weight 
6.2.2 
Secondary Endpoints 
The following secondary endpoints are planned: 
• 
Change from baseline to end of treatment in total HQ-CT score  
• 
Change from baseline to end of treatment in body weight [kg] 
• 
Change from baseline to end of treatment in fat- and fat-free mass [%] by dual X-ray 
absorptiometry (DEXA) 
• 
Change from baseline to end of treatment in fat- and fat-free mass [g] by dual X-ray 
absorptiometry (DEXA) 
• 
Change from baseline to end of treatment in bone mineral density (BMD) [g/cm²] and bone 
mineral content (BMC) [g] by dual X-ray absorptiometry (DEXA) 
• 
Change from baseline to end of treatment of HbA1c [%] 
• 
Change from baseline to end of treatment in fasting plasma glucose (FPG) [mmol/L] 
• 
Change from baseline to end of treatment in waist circumference [cm] 
• 
Change from baseline to end of treatment in insulin [mIU/L] 
• 
Change from baseline to end of treatment in lipid profile (Cholesterol, HDL, LDL, Triglyceride) 
[mmol/L])  
6.3 
Safety Endpoints 
Safety endpoints include: 
• 
Incidence of AEs, SAEs (serious adverse events),  
• 
Blood analysis: 
o 
Hematology:  blood count (erythrocytes, hemoglobin, hematocrit, leukocytes), 
differential blood count (neutrophils, lymphocytes, monocytes, eosinophils, 
basophils) and platelets 
o 
Blood 
chemistry: 
creatinine, 
gamma 
glutamyl 
transferase, 
aspartate 
aminotransferase, alkaline phosphatase, glomerular filtration rate (GFR) and urea 
• 
Electrocardiogram (ECG): 


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o 
Interpretation (normal/abnormal) 
o 
Change from baseline to end of treatment in R-R, P-R, QRS and Q-T intervals 
• 
Vital signs: 
o 
Change from baseline to end of treatment in mean HR [bpm] 
o 
Change from baseline to end of treatment in mean SBP [mmHg] 
o 
Change from baseline to end of treatment in mean DBP [mmHg] 
o 
Change from baseline to end of treatment in body temperature [°C] 
o 
Change from baseline to end of treatment in respiratory rate [breaths/min] 
• 
Physical examination 
o 
Change from baseline to end of treatment in examination findings (normal/abnormal 
(NCS)/abnormal (CS)/not done) of different body systems (Head, ear, eye, nose and 
throat, respiratory system, cardiovascular system, abdomen, central and peripheral 
nervous system, lymph nodes, skin, skelet and other body system) 
• 
Psychiatric examination 
o 
Change from baseline to end of treatment in examination findings (normal/ abnormal 
(NCS)/abnormal (CS)/not done) 
6.4 
Pharmacokinetic Endpoints 
• 
Steady state concentrations of tesofensine and metoprolol as measured by trough values 
7. Statistical Analysis Methods 
7.1 
Descriptive Statistics 
The default summary statistics for quantitative variables will be the number of non-missing 
observations (n), number of missing values (N missing). For non-missing observations,  arithmetic 
mean, geometric mean (if applicable), standard deviation (SD), coefficient of variation (CV), lower 
quartile (Q1), upper quartile (Q3), minimum (min), median, and maximum (max) will be calculated 
and reported. 
For categorical variables, the number (n) and percentage (%) of subjects per category will be the 
default summary presentation, and, if applicable, the number of missing values is provided in a 
“Missing” category. Missing data will not be included in the calculation of percentages as only 
available data are used, except if a subject did only answer specific questions of a questionnaire. 


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Percentages will be calculated using a denominator of all subjects in a specified population or 
treatment group. The denominator will be specified in a footnote to the tables for clarification if 
necessary. If missing data occur within population specified as denominator, they will not be 
included in the calculation of percentages, except if a subject did only answer specific questions of 
a questionnaire. 
7.2 
Rounding Rules 
7.2.1 
Estimates of the Mean and Standard Deviation 
When using actual data, the mean and standard deviation are both rounded to one more decimal 
place than the original data, with a maximum of 2 decimal places.  
When mean values of repeated measurements are used for calculation of summary statistics, the 
mean and standard deviation are rounded to the same number of decimal places given for the mean 
values of repeated measurements used for calculation, with a maximum of 2 decimal places. 
7.2.2 
Other data 
Quartiles and median are always presented with the same number of decimal places as the mean. 
Minimum and maximum are always provided with the same number of decimal places as the data 
used. For estimates of proportions, the result is rounded to 3 decimal places. If proportions are 
displayed as percentage, 1 decimal place is displayed. For example, a proportion of 0.655 will be 
presented in percentage as 65.5%. The coefficient of variation is rounded to two decimals. 
7.3 
Calculation of Study Days and Durations 
Study days and, if applicable and meaningful, durations will be determined by comparing the 
respective date to the date of the first administration of the study medication (referring to the start 
of administration during Step 2 of the trial with exception of the analysis done on data of OLE1 or 
OLE2 only).  
• 
If the respective date is on or after the date of the first administration of the study 
medication: 
Study day/Duration = Date (e.g. date of visit) - Date of first administration + 1 
• 
If the respective date precedes the date of the first administration of the study medication: 
Study day/Duration = Date (e.g. date of medical history event) - Date of first 
administration 
Time to onset and duration of adverse events will be calculated as follows: 


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• 
Time to onset = start date of AE - date of first treatment [+1 for AE starting after start of 
treatment]  
Duration of adverse event = stop date – onset/worsening date + 1  
7.4 
Evaluation of Demographics and Baseline Characteristics 
7.4.1 
Disposition of Patients 
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 all analysis 
populations (SES, PPP and ITT). Subjects withdrawn from the study will be listed along with the 
primary reason for withdrawal. In addition, the primary reason for withdrawal will be tabulated. 
Furthermore, a summary of the time to study termination is provided per treatment group. 
7.4.2 
Demographics and other Baseline Characteristics  
Demographic information (race, gender, age, height, weight, BMI, waist circumference), baseline 
characteristics (vital signs, ECG, physical examination) and laboratory tests and measurements will 
be summarized by treatment group and step of the study (including a total column) using the default 
descriptive statistics for subjects in the PPP, SES and ITT.  
7.4.3 
Medical History, and Concomitant Diseases  
Absolute and relative frequencies (n, %) of medical history and concomitant diseases will be 
described by treatment group based on MedDRA system organ class and preferred term levels for 
all three analysis populations  SES. Results will be presented overall and by step. 
7.4.4 
Previous and Concomitant Medication 
Absolute and relative frequencies (n, %) of previous and concomitant medication will be provided by 
treatment group based on Anatomical Therapeutic Chemical (ATC) Classification code levels 2 and 
3 for all three analysis populations SES. Results will be presented overall and by step.  
7.5 
Evaluation of Primary Endpoint 
The primary endpoint is  
• 
Percent change from baseline to end of treatment in body weight 
and will be calculated by: 
 
%-change = (Weight at end of treatment – Weight at baseline) / (Weight at baseline) * 100 
Where end of treatment and baseline are defined as described in section 4.2. 
 
The primary endpoint will be presented and analysed based on the PPP and ITT for each subgroup.  


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Percent change from baseline in body weight will be summarized per subgroup and visit, by 
treatment group during Step 2 and in total, via mean, median, standard deviation, coefficient of 
variation (CV), lower quartile (Q1), upper quartile (Q3), minimum and maximum value). Moreover, 
complete listings of individual values for the primary endpoint will be provided. Figures displaying 
the values for individual subjects (spaghetti plots) as well as figures displaying mean and standard 
deviation for percentage change from baseline in body weight at each visit per treatment group by 
Step and in total will also be provided.  
 
The primary endpoint percent change from baseline to end of treatment will be compared between 
treatment groups during Step 2 and in total by means of an ANCOVA model including site and 
treatment (the latter not for the total analysis) as fixed factors and baseline value as covariate. 
Estimates and 95% confidence interval of treatment differences will be calculated. The critical value 
will be set on a two-sided significance level of 5%. 
For the ANCOVA a variation of the following SAS®-Code is recommended: 
proc glm data = <name of primary analysis data set>; 
      
class site treatment_group; 
      
model chg_from_base = site treatment_group baseline; 
 
lsmeans treatment / cl e stderr pdiff; 
 
estimate ‘Difference IMP versus Placebo’    treatment 1 -1; 
run; 
quit; 
The ANCOVA will be repeated with the data of all subjects in the PPP with available weight 
measurement as sensitivity analysis. For withdrawals, change from baseline will be imputed 
according to the last observation carried forward (LOCF) method using the last weight measurement 
before study termination, if meaningful. 
 
7.6 
Evaluation of Secondary and Exploratory Variables 
The analysis of secondary and exploratory variables will be based on the ITT for each subgroup. The 
secondary and exploratory variables will be summarized by treatment during Step 2 and in total, 
and by visit. Where applicable, changes from baseline will be provided using standard descriptive 
statistics (mean, geometric mean (if applicable), median, standard deviation, coefficient of variation 
(CV), lower quartile (Q1), upper quartile (Q3), minimum and maximum value). Individual (spaghetti 
plots) and mean and standard deviation curves over treatment duration will be plotted by treatment 
during Step 2 and in total. 
 
Change from baseline analysis to the end of treatment for the corresponding secondary and 
exploratory endpoints will be performed using ANCOVA models,. For continuous variables, the 


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ANCOVA model will be analogous to the model used for the primary endpoint. Treatment 
differenceswith 95% confidence intervals and p-values for the comparison between treatments will 
be estimated. The critical values for each two-sided statistical test will be based on a significance 
level of 5. Figures displaying the mean and standard deviation of the raw data at each visit by 
treatment during Step 2 and in total will be also provided. Moreover, complete listings of individual 
values for all secondary and exploratory endpoints will be provided.  
A 9-item score will be calculated for the HQ-CT. Change in HQ-CT answers (by question and in total) 
will be calculated as (answer at respective visit) minus (answer at baseline (see section 4.2 for 
definitions)) and presented using standard descriptive statistics (mean), median, standard deviation, 
coefficient of variation (CV), lower quartile (Q1), uppe quartile (Q3), minimum and maximum value). 
Scores for each question range from 0 to 4 (with a higher score indicating a worse outcome), 
resulting in a maximum 9-item sum of 36. A decrease in total score (compared to the baseline 
assessment) indicates an improvement in hyperphagia. If less than three questions have not been 
answered by a subject, the missing answers will be imputed by the mean score of all available 
answers. In case of more missing answers, the total scores will not be calculated. Results will be 
presented by treatment during Step 2 and in total. 
Subject compliance [%] will be calculated as 100 x (number of tablets dispended – number of tablets 
returned)/(number of days of treatment) and will be calculated for both study drugs separately. The 
compliance will be summarized using standard descriptive statistics (mean, standard deviation, 
lower quartile (Q1), upper quartile (Q3), minimum and maximum value and listed per subject as 
well. 
7.7 
Evaluation of Safety Variables 
The analysis of the safety variables described in Section 6.3 will be based on the SES. Values will be 
summarized by treatment during Step 2 and in total, using non-missing counts, mean, standard 
deviation, median, lower quartile (Q1), upper quartile (Q3), minimum, and maximum for continuous 
data. Categorical data will be summarized using counts and percentages. Change from baseline to 
end of treatment analysis for vital signs will be done with an ANCOVA model as described in Section 
7.6. 
All AEs occurring after the randomization of the subject will be reported as AE (any AEs that occurred 
between screening and randomization will be reported in medical history, but not as an AE).  
Incidences (number and percentage of subjects experiencing adverse events) per treatment during 
Step 2 and in total will be calculated for AEs on the system organ class (SOC) level and on the 
preferred term (PT) level, by intensity, by relationship and by outcome. Listings and tables displaying 
incidences for AEs leading to discontinuation, serious AEs, treatment-related serious AEs and deaths 
will also be provided.  


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Differences in the incidence of treatment-related AEs between treatment groups will be analyzed for 
the Step 2 data only using a logistic regression model with treatment as fixed factor. Odds ratios, 
p-values, and 95% confidence intervals corresponding to the logistic regression model will be 
estimated for the comparisons between treatments.  
A variation of following basic SAS code is recommended for the analysis and expanded if needed: 
proc logistic data=<name of safety analysis data set>;  
 
class treatment_group (ref=’0’) / param = ref; 
model <binary variable for occurrence of treatment-related AE (1/0) within patient> = 
treatment_group; 
oddsratio treatment_group; 
      run; 
 
In addition, the time to the first treatment-related adverse event and treatment-related serious 
adverse event will be calculated by treatment during Step 2 and in total and displayed in Kaplan-
Meier curves considering all data from Step 2 to end of OLE2 (subgroup 3 only). For those patients 
that received placebo during Step 2 and continued to OLE1 of the trial, an additional analysis will be 
performed using the start date of treatment with IMP (Visit 14) for the time to event analysis. 
The findings of the physical examinations are summarized by number (n) and percentage (%) of 
subjects per category (Normal/Abnormal (NCS)/Abnormal (CS)/Not done) per treatment during Step 
2 and in total, for each body system (Head, ear, eye, nose and throat, respiratory system, 
cardiovascular system, abdomen, central and peripheral nervous system, lymph nodes, skin, skelet 
and other body system). In addition, shift tables will be provided to further evaluate the change 
before first administration of the medication and the end of treatment (definitions of section 4.2 
apply). 
ECG data, vital signs as well as laboratory data (hematology and blood chemistry) will be summarized 
as continuous data by treatment during Step 2 and in total as well as by visit. In addition, where 
available, the interpretation of the measured data (Normal/Abnormal (NCS)/Abnormal (CS)/Not 
done) will be analyzed as the findings of the physical examinations.  
Laboratory values will be evaluated in the provided units. Conversions of units will be done as 
necessary for a common analysis. For HbA1c measurements, values recorded in % will be converted 
to mmol/mol using the following formula:  
HbA1c [mmol/mol] = (HbA1c [%] - 2.15) * 10.929  
For ALP, ALT, AST and GGT measurements, values recorded in U/L will be converted to ukat/L using 
the following conversion: 
 
Measurement [U/L] = 0.0167 * Measurement [µkat/L] 


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7.8 
Evaluation of Pharmacokinetic Data  
Drug concentrations will be summarized by descriptive statistics for both metoprolol and 
tesofensine using only the data from subjects exposed to the IMP.  To take into account that 
pharmacokinetic parameters are often lognormally distributed, the geometric mean and the 
geometric coefficient of variation will be calculated additionally. The geometric mean is defined as 
the nth root of the product of n concentration measurements. The geometric coefficient of variation 
can be easily obtained by subtracting 1 from the geometric standard deviation and multiplication 
with 100. Results will be displayed by visit, and additionally by time point (h0/h2/h4) for the OLE1 
and OLE2 part of the trial. 
8. Changes in the Planned Analysis  
The analysis of this study is described in the study protocol TM002 (for Step 2: dated: 13 March 
2018 Protocol Amendment Version 1.4 for Hungary and 09 February 2018 Protocol Amendment 
Version 1.5 for Czech Republic; for OLE1: dated: 26 September 2018 Protocol Amendment Version 
1.5 for Hugnary and 09 September 2018 Protocol Amendment Version 1.6 for Czech Republic; for 
OLE2: dated: 31 January 2019 Protocol Amendment Version 1.6 for Hungary and 30. January 2019 
Protocol Amendment Version 1.7 for Czech Republic). Nevertheless, minor changes to the conduct 
of the analysis have to be performed and are described below in detail. 
The wording of the primary endpoint was changed from “Percent change from baseline to end of 
treatment in mean body weight” to “Percent change from baseline to end of treatment in body 
weight” to address that no replicated measurements were performed during the body weight 
assessment at a visit. That means that the relative change of body weight as assessed by single 
measurements performed at the screening visit and the end of treatment is calculated. The same 
applies to the secondary endpoint “Change from baseline to end of treatment in body weight (kg)”. 
This does not change the intended analysis but rather more accurately reflects the envisaged 
analysis as described in the protocol. 
In addition, the following changes were made to the final SAP (version 1.1) after unblinded interim 
analysis: 
The analysis was updated to display separate results for the defind subgroups and to allow for the 
display of results in total and based on the treatment each subject received during Step 2, as 
differences in the outcome are expected based on the different lengths of treatment.  
Minor cosmetic and wording changes were added for additional clarification. The study design and 
visit schedule were updated to reflect protocol changes.  
 


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9. APPENDIX 1   
Tables  
14.1 
 
Study subjects 
14.1.1  
 
Disposition of subjects 
14.1.1.1 
 
 
Number of subjects enrolled, by site and total 
14.1.1.2 
 
 
Number of subjects per visit 
14.1.1.3 
 
 
Discontinuation, eligible subjects 
14.1.2 
Protocol deviations and other reasons for exclusion from analysis sets, 
randomized subjects 
14.1.3  
 
Demographics and other baseline characteristics, SES and PPP 
14.1.3.1 
 
 
Demographics 
14.1.3.2 
 
 
Vital signs 
14.1.3.3 
 
 
ECG 
14.1.3.4 
 
 
Physical examination  
14.1.3.5 
 
 
Laboratory tests and measurements 
14.1.4  
 
Medical history and concomitant diseases, SES and PPP  
14.1.4.1 
 
 
Medical history by System Organ Class and Preferred Term 
14.1.4.2 
 
 
Concomitant diseases by System Organ Class and Preferred Term 
14.1.5  
 
Previous and concomitant medications, SES and PPP 
14.1.5.1 
 
 
Previous medication by ATC level 
14.1.5.2 
 
 
Concomitant medication by ATC level 
14.1.6.  
 
Extent of exposure and treatment compliance, SES and PPP 
14.1.6.1 
 
 
Duration of exposure [days, SES] 
14.1.6.2 
 
 
Compliance [%], SES and PPP 
 
 
14.2 
 
Efficacy and pharmacokinetic data, PPP 
14.2.1  
 
Primary endpoint 
14.2.1.1 
 
 
Change over time in body weight [%] 
14.2.1.2 
 
 
Change over time in body weight [%], summary of ANCOVA 
14.2.2  
 
Secondary endpoints 
14.2.2.1 
 
 
Change over time in body weight [kg] 
14.2.2.2 
 
 
Change over time in body weight [kg], summary of ANCOVA 
14.2.2.3 
 
 
Change over time in fat- and fat-free mass [%] by DEXA 
14.2.2.4 
Change over time in fat- and fat-free mass [%] by DEXA, summary of 
ANCOVA 
14.2.2.5 
 
 
Change over time in fat- and fat-free mass [g] by DEXA 


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14.2.2.6 
Change over time in fat- and fat-free mass [g] by DEXA, summary of 
ANCOVA 
14.2.2.7 
Change over time in bone mineral density (BMD) [g/cm²] and bone 
mineral content (BMC) [g] by DEXA 
14.2.2.8 
Change over time in bone mineral density (BMD) [g/cm²] and bone 
mineral content (BMC) [g] by DEXA, summary of ANCOVA 
14.2.2.9 
 
 
Change over time in HbA1c [%] 
14.2.2.10 
 
 
Change over time in HbA1c [%], summary of ANCOVA 
14.2.2.11 
 
 
Change over time in fasting plasma glucose  [mmol/L] 
14.2.2.12 
 
 
Change over time in fasting plasma glucose [mmol/L], summary of 
 
 
 
 
ANCOVA 
14.2.2.13 
 
 
Change over time in waist circumference [cm] 
14.2.2.14 
 
 
Change over time in waist circumference [cm], summary of ANCOVA 
14.2.2.15 
 
 
Change over time in insulin [mIU/L] 
14.2.2.16 
 
 
Change over time in insulin [mIU/L], summary of ANCOVA 
14.2.2.17 
 
 
Change over time in lipid profile (cholesterol, HDL, LDL, triglyceride)  
14.2.2.18 
Change over time in lipid profile (cholesterol, HDL, LDL, triglyceride), 
summary of ANCOVA 
14.2.2.19 
 
 
Changer over time in hyperphagia questionnaire for clinical trials  
 
 
 
 
(HQ-CT) 
14.2.2.20 
Change over time in the overall score from the hyperphagia 
questionnaire for clinical trails (HQ-CT), summary of ANCOVA 
14.2.2.21 
 
 
Steady state concentrations of tesofensine and metroprolol 
 
 
14.3 
 
Safety data, SES 
14.3.1  
 
Adverse events 
14.3.1.1 
 
 
Overall summary of adverse events 
14.3.1.2 
 
 
Number (%) of subjects with AEs and number of AEs by System Organ 
 
 
 
 
Class and Preferred Term 
14.3.1.3 
 
 
Number (%) of subjects with AEs by worst causal relationship 
14.3.1.4 
 
 
Number (%) of subjects with AE by worst intensity 
14.3.1.5 
Number (%) of subjects with AEs by worst causal relationship and worst 
intensity 
14.3.1.6 
 
 
Number (%) of subjects with AEs by worst outcome 
14.3.1.7 
Number of subjects with AEs by worst causal relationship and worst 
outcome 
14.3.1.8 
 
 
Number (%) of subjects with treatment-related AEs  
14.3.1.9 
 
 
Incidences in treatment related AEs, summary of logistics model 
14.3.2  
 
Deaths, other serious and significant adverse events 
14.3.2.1 
 
 
Serious AEs, listing of subjects 
14.3.2.2 
 
 
Treatment-related serious AEs, listing of subjects 


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14.3.2.3 
 
 
Deaths, listing of all serious AEs of subjects who died 
14.3.2.4 
 
 
AEs leading to discontinuation, listing of subjects 
14.3.3  
 
Vital signs 
14.3.3.1 
Change over time in mean heart rate [bpm], systolic blood pressure 
[mmHg], diastolic blood pressure [mmHg] 
14.3.3.2 
 
 
Change over time in temperature [°C] 
14.3.3.3 
 
 
Change over time in respiratory rate [breaths/min] 
14.3.4  
 
Laboratory data 
14.3.4.1 
 
 
Summary statistics for hematology 
14.3.4.2 
 
 
Summary statistics forblood chemistry 
14.3.4.3 
 
 
Shift tables for interpretation, hematology 
14.3.4.4 
 
 
Shift tables for interpretation, blood chemistry 
14.3.5  
 
Other safety data 
14.3.5.1 
 
 
Summary statistics for measurements, electrocardiography 
14.3.5.2 
 
 
Summary statistics for interpretation, electrocardiography 
14.3.5.3 
 
 
Shift tables for interpretation, electrocardiography 
14.3.5.4 
 
 
Summary statistics for interpretation, physical examination 
14.3.5.5 
 
 
Shift tables for interpretation, physical examination 
14.3.5.6 
 
 
Summary statistics for interpretation, psychiatric examination 
14.3.5.7 
 
 
Shift tables for interpretation, psychiatric examination 
 
The selection, naming and numeration of the tables is not mandatory but might be adapted in 
accordance with the described analyses in this SAP. 
 
Listings 
16.2 
 
Subject data listing 
16.2.1  
 
Study subjects 
16.2.1.1 
 
 
Disposition of subjects 
16.2.1.1.1 
 
 
 
Screening failures 
16.2.1.1.2 
 
 
 
Site numbers andprinciple investigators 
16.2.1.1.3 
 
Site numbers and treatment group sorted by screening number 
16.2.1.1.4 
 
 
 
Informed consent and randomization 
16.2.1.1.5 
 
 
 
Visit dates and discontinuation 
16.2.1.2 
 
 
Protocol deviations 
16.2.1.2.1 
 
 
 
Inclusion criteria, definition 
16.2.1.2.2 
 
 
 
Exclusion criteria, definition 
16.2.1.23 
 
 
 
Subjects with violation of inclusion / exclusion criteria 


Saniona, A/S 
Study TM002 
 
Statistical Analysis Plan – Final 1.2 
10-Aug-2019 
 
 
CONFIDENTIAL 
 
Page 37 of 38 
16.2.1.2.4 
Protocol deviations and other reason for exclusion from 
analysis sets, assignment to analysis set 
16.2.1.3 
 
 
Demographic data and other baseline characteristics 
16.2.1.3.1 
 
 
 
Demographics 
16.2.1.3.2 
 
 
 
Findings in medical history 
16.2.1.3.3 
 
 
 
Findings in concomitant diseases 
16.2.1.4 
 
 
Previous and concomitant medications 
16.2.1.4.1 
 
 
 
Previous medication 
16.2.1.4.2 
 
 
 
Concomitant medication 
16.2.1.5 
 
 
Extent of exposure, treatment compliance 
16.2.1.5.1 
 
 
 
Study drug record 
16.2.1.5.2 
 
 
 
Study drug administration 
16.2.1.5.3 
 
 
 
Extent of exposure [days] 
16.2.1.5.4 
 
 
 
Derived compliance data 
16.2.2   
 
Efficacy and pharmacokinetic data 
16.2.2.1 
 
 
Primary endpoint 
16.2.2.1.1 
 
 
 
Change in body weight [%] 
16.2.2.2 
 
 
Secondary endpoints 
16.2.2.2.1 
 
 
 
Vital signs 
16.2.2.2.2 
 
 
 
Hyperphagia questionnaire for clinical trials (HQ-CT) 
16.2.2.2.3 
Laboratory values 
16.2.3  
 
Safety data 
16.2.3.1 
 
 
Adverse events listing 
16.2.3.2 
 
 
Vital signs 
16.2.3.3 
 
 
ECG 
16.2.3.3.1 
 
 
 
ECG, interpretation 
16.2.3.3.2 
 
 
 
ECG, quantitative results 
16.2.3.4 
 
 
Physical examination 
16.2.3.5 
 
 
Laboratory data 
16.2.3.6 
 
 
Urine pregnancy test for women of childbearing potential 
16.2.3.7 
 
 
Psychiatric examination 
The selection, naming and numeration of the listingsis not mandatory but might be adapted in 
accordance with the described analyses in this SAP. 
 
Figures 
14.1.1.1 
 
Disposition of subjects  
14.2.1.1  
 
Change over time in mean body weight [%] 
14.2.1.2 
 
Change over time in individual body weight [%] 


Saniona, A/S 
Study TM002 
 
Statistical Analysis Plan – Final 1.2 
10-Aug-2019 
 
 
CONFIDENTIAL 
 
Page 38 of 38 
14.2.2.1 
 
Change over time in body weight [kg] 
14.2.2.2 
 
Change over time in individual body weight [kg] 
14.2.2.3.1 
 
Change over time in fat- and fat-free mass [%] 
14.2.2.5.1 
 
Change over time in fat- and fat-free mass [g] 
14.2.2.7.1 
 
Change over time in BMD / BMC 
14.2.2.9.1 
 
Change over time in HbA1c [%] 
14.2.2.9.2 
 
Change over time in HbA1c [%] by subject 
14.2.2.11.1 
 
Change over time in fasting plasma glucose [mmol/l] 
14.2.2.11.2 
 
Change over time in fasting plasma glucose [mmol/l] by subject 
14.2.2.13.1 
 
Change over time in waist circumference [cm] 
14.2.2.13.2 
 
Change over time in individual waist circumference [cm] 
14.2.2.15.1 
 
Change over time in insulin [mIU/L] 
14.2.2.15.2 
 
Change over time in insulin [mIU/L] by subject 
14.2.2.17.1 
 
Change over time in lipids 
14.2.2.17.2 
 
Change over time in lipids by subject 
14.2.2.21.1 
 
Mean of log-transformed drug concentration by subject 
14.2.2.21.2 
 
Change over time in drug concentration by subject 
14.3.2.1 
 
Time to occurrence of first treatment-related AE 
14.3.3.1 
 
Time to occurrence of first treatment-related SAE 
14.4.1  
 
Hyperphagia questionnaire: Score over time by subject 
14.4.2  
 
Hyperphagia questionnaire: mean scores over time by treatment groups 
 
  
The selection, naming and numeration of the figures are not mandatory but might be adapted in 
accordance with the described analyses in this SAP. 
 


.. 
Sanlona, A/S 
StudyTM002 
Signatures 
Statistical Analysis Plan - Final 1.2 
10-Aug-2019 
I confirm that this Statistical Analysis Plan (SAP) accurately describes the planned statistical analyses 
to the best of my knowledge and was finalized before breaking the blind. 
Author: 
Review: 
Andreas Beust, PhD. 
Blostatistician 
GCP-Service lnt. Ldt & Co. KG 
Anne-Conway-StraBe 2 
28359 Bremen, Germany 
Dennis Neuschwander, M.Sc. 
Biostatistician 
GCP-Service lnt. Ldt & Co. KG 
Anne-Conway-StraBe 2 
28359 Bremen, Germany 
Approved: 
Roman Dvorak MD, PhD 
Chief Medical Officer 
Saniona, A/S 
Baltorpvej, 1 54 
DK 2750 Ballerup 
Denmark 
CONFIDENTIAL 
Date 
Signature 
Date 
Signature 
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