Conditions: Hypothalamic Injury-induced Obesity (HIO)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 21
Healthy volunteers: no

Brief summary:
Double-blind, randomized, placebo-controlled, single- center study followed by an open-label extension period.

• The study will have two parts:

* Part 1: 24 weeks double-blind treatment (DB), followed by
* Part 2: 24 weeks open-label extension (OLE) - all subjects still participating at the end of Part 1 will be given an option to continue for additional 24 weeks on the active drug if evaluated eligible by the Investigator

Detailed description:
Part 1 - the double-blind (DB) part: The active medication arm will be given co-administration of 0.5 mg tesofensine/50 mg metoprolol daily for 24 weeks. The placebo arm will receive matching placebo tablets.

Part 2 - the open-label extension (OLE) part: All active participants at the end of the double-blind part will be given the active medication 0.5 mg tesofensine/50 mg metoprolol daily for 24 weeks.

Arms:
arm 1: The active medication arm will be given co-administration of 0.5 mg tesofensine/50 mg metoprolol daily for 24 weeks. arm 2: The placebo arm will receive matching placebo tesofensine and placebo metoprolol.

Interventions: intervention 1: Tesofensine/Metoprolol intervention 2: Placebo
Intervention descriptions: intervention 1: During Part 1 subjects will be randomized to treatment with co-administration of 0.5 mg tesofensine/50mg metoprolol (active medication) intervention 2: During Part 1 subjects will be randomized to matching placebo tesofensine and placebo metoprolol

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol 
 
 
 
 
A 24-WEEK PHASE 2, DOUBLE-BLIND, RANDOMIZED, PLACEBO-
CONTROLLED, SINGLE-CENTER SAFETY AND EFFICACY STUDY TO 
EVALUATE OVERALL SAFETY AND TOLERABILITY OF CO-
ADMINISTRATION OF TESOFENSINE AND METOPROLOL IN SUBJECTS 
WITH HYPOTHALAMIC INJURY-INDUCED OBESITY (HIO), AND WITH 
A 24-WEEK OPEN-LABEL EXTENSION, IN TOTAL 48 WEEKS 
 
 
 
Sponsor:  
 
 
Saniona, A/S 
 
 
 
Baltorpvej 154 
 
 
 
DK2750 Ballerup 
 
 
 
Denmark 
 
 
 
 
 
Protocol number:  
TM005 
Protocol version:   
5.0 
Date:  
 
 
10 December 2019 
 
 
EudraCT number:  
2018-003672-12 
 
 
 
 
 
 
 
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 24-week phase 2, double-blind (DB), randomized, placebo-
controlled, single-center safety and efficacy study to evaluate 
overall safety and tolerability of co-administration of 
tesofensine and metoprolol in subjects with hypothalamic 
injury-induced obesity (HIO), and with a 24-week open-label 
extension, in total 48 weeks. 
 
Study sponsor 
Saniona, A/S
Baltorpvej 154 
DK2750 Ballerup 
Denmark 
Phase 
2a
Number of sites 
1 site; Rigshospitalet (RH), Copenhagen, Denmark
Sample size 
Minimum of 12 and maximum of 25 adult subjects with HIO.
Study design 
 DB, randomized, placebo-controlled, single-center 
study followed by an open-label extension period.  
 The study will have two parts: 
o Part 1: 24 weeks DB treatment, followed by 
o Part 2: 24 weeks open-label extension – all 
subjects still participating at the end of part 1 
will be given an option to continue for additional 
24 weeks on the active drug if evaluated eligible 
by the investigator 
 During the part 1 subjects will be randomized into either 
the active medication or matching placebo in 2:1 ratio 
 As an integral part of the study all subjects will undergo 
regular dietary and physical activity counseling during 
the study 
 A clinical study report (CSR) will be prepared following 
the completion of the 24-week DB part of the study and 
a separate CSR following finalization of the 24-week 
open labelled study part 
Study timelines 
Q1 2019 – Q2 2020 – the double-blind part. 
Q3 2019 – Q1 2021 – the open-label extension part. 
Investigational 
Medicinal Product 
(IMP) and dosing 
schedule 
Part 1 – the DB part: The active medication arm will be given 
co-administration of 0.5 mg tesofensine/50 mg metoprolol daily 
for 24 weeks. The placebo arm will receive matching placebo 
tablets. 
Part 2 – the open-label extension part: All active participants at 
the end of the DB part will be given the active medication 0.5 
mg tesofensine/50 mg metoprolol daily for 24 weeks.  
Each tablet will be formulated separately; a currently available 
commercial formulation of extended release (ER) metoprolol 
will be used. 
 


 
 
 
 
 
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In case a subject, in the opinion of the investigator, experiences 
an adverse event that by the investigator is suspected to be 
potentially related to an undesirable drug concentration of the 
IMP, the period between dosages can be extended or a drug 
holiday can be implemented in order to optimally manage the 
well-being and safety of the subject. Each of these cases should 
if possible be discussed in advance with the sponsor’s medical 
expert.  
 
Study objectives and 
endpoints 
Primary objectives: 
 To examine overall safety and tolerability of co-
administration of 0.5 mg tesofensine/50 mg metoprolol 
treatment over 24 weeks in subjects with HIO 
 
Secondary objectives: 
 To examine the effect on satiety and appetite from from 
baseline to week 24, from baseline to week 48 and from 
week 24 to week 48 following co-administration of 0.5 
mg tesofensine/50 mg metoprolol treatment in subjects 
with HIO 
 To examine the effect on bodyweight from from 
baseline to week 24, from baseline to week 48 and from 
week 24 to week 48 following co-administration of 0.5 
mg tesofensine/50 mg metoprolol treatment in subjects 
with HIO 
 To examine the effect on body composition from 
baseline to week 24, from baseline to week 48 and from 
week 24 to week 48 following co-administration of 0.5 
mg tesofensine/50 mg metoprolol treatment in subjects 
with HIO 
 To examine the effect on quality of life from baseline to 
week 24, from baseline to week 48 and from week 24 to 
week 48 following co-administration of 0.5 mg 
tesofensine/50 mg metoprolol treatment in subjects with 
HIO 
 To examine effect on craving for something sweet, salty, 
savory and fatty from baseline to week 24, from baseline 
to week 48 and from week 24 to week 48 following co-
administration of 0.5 mg tesofensine/50 mg metoprolol 
treatment in subjects with HIO 
 To examine the effect on thirst from baseline to week 
24, from baseline to week 48 and from week 24 to week 
48 following co-administration of 0.5 mg tesofensine/50 
mg metoprolol treatment in subjects with HIO 
 To examine effect on glycaemic control and lipid profile 
from baseline to week 24, from baseline to week 48 and 
from week 24 to week 48 following co-administration 
of 0.5 mg tesofensine/50 mg metoprolol treatment in 
subjects with HIO 


 
 
 
 
 
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 To examine the effect on heart rate (HR) and blood 
pressure (BP) from baseline to week 24, from baseline 
to week 48 and from week 24 to week 48 following co-
administration of 0.5 mg tesofensine/50 mg metoprolol 
treatment in subjects with HIO 
 To establish profile of trough values of tesofensine, 
metoprolol and N-desmethyl-metabolite (NS2360) 
following co-administration of 0.5 mg tesofensine/50 
mg metoprolol treatment in subjects with HIO: 
o Active arm: the first 24 weeks and then 
continuously up to week 48.  
o Placebo arm: start of treatment at week 25 and 
then continuously up to week 48.  
 To evaluate the effect on BP and HR from baseline to 
week 24 by 24 hours (24H) home monitoring of BP and 
48 H home monitoring of HR. 
 To evaluate overall safety and tolerability from week 24 
to week 48 following co-administration of 0.5 mg 
tesofensine/50 mg metoprolol treatment in subjects with 
HIO. 
 
Primary endpoint 
 Safety and tolerability will be judged from all safety 
data collected in the period, including number and type 
of treatment emergent adverse events, laboratory data, 
BP and HR. 
 
Secondary efficacy endpoints 
 Change in satiety and appetite using the composite 
satiety score (CSS) baseline to week 24, from baseline 
to week 48 and from week 24 to week 48  
 Change in body weight from baseline to week 24, from 
baseline to week 48 and from week 24 to week 48  
 Change in body composition i.e. body fat and lean body 
mass by Dual-energy X-ray absorptiometry (DEXA) 
from baseline to week 24, from baseline to week 48 and 
from week 24 to week 48 
 Change in quality of life by the use of the SF-36 
questionnaire from baseline to week 24, from baseline 
to week 48 and from week 24 to week 48   
 Change in craving for something sweet, salty, savory 
and fatty by the use of Visual Analogue Scale (VAS) 
scales from baseline to week 24, from baseline to week 
48 and from week 24 to week 48   
 Change in thirst by the use of a VAS scale from baseline 
to week 24, from baseline to week 48 and from week 24 
to week 48  
 Change on glycaemic control and lipid profile from 


 
 
 
 
 
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baseline to week 24, from baseline to week 48 and from 
week 24 to week 48 
  Change in waist circumference from baseline to week 
24, from baseline to week 48 and from week 24 to week 
48 
Secondary safety and pharmacokinetic (PK) endpoints 
 Change on HR and BP from baseline to week 48 and 
from week 24 to week 48  
 Trough values of tesofensine, metoprolol and N-
desmethyl-metabolite (NS2360) 
o Active arm: the first 24 weeks and then 
continuously up to week 48.  
o Placebo arm: start of treatment at week 25 and 
then continuously up to week 48.  
 Change of 24H BP/48H HR and QT from baseline to V5 
and V8 and from V5 to V8 measured by home 
monitoring 
 Number and type of adverse events (AEs) from week 24 
to week 48 
Study population 
(inclusion/exclusion 
criteria) 
In total, a minimum of 12 and a maximum of 25 subjects with 
HIO. HIO is defined as obesity developed in relation to 
damage to the hypothalamus, whether it is from an injuring 
trauma, bleeding, infarction, tumor, surgery or irradiation. 
Inclusion criteria 
1. Informed consent obtained before any trial-related 
activities 
2. Males and females, aged 18-75 
3. Confirmed diagnosis of HIO 
4. Body Mass Index (BMI) ≥27 kg/m2 (where 
overweight is related to the HIO) 
5. Well 
managed 
and 
stable 
substitution 
of 
hypopituitarism >2 months as judged by the 
investigator 
6. Normal BP or well managed hypertension (only if 
dose of BP medication(s) has been stable for >2 
months) 
7. Type 2 diabetes is allowed, but the following criteria 
must be met: 
 Hemoglobin A1c (HbA1c) <86mmol/mol 
 Subjects taking glucagon like peptide 1 
(GLP-1) analogues must have been on stable 
dose for >3 months 
 Fasting plasma glucose (FPG) <11.0 mmol/l 
measured on site. 
Exclusion criteria 
1. BP ≥160/90 mmHg 
2. HR ≥ 90, <50 bpm 
3. Hypersensitivity to tesofensine/metoprolol or any 
component of the products 
4. Type 1 diabetes, Cushings disease, acromegaly, 


 
 
 
 
 
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hypophysitis, infiltrative diseases or Prader-Willi 
syndrome 
5. Heart failure New York Heart Association (NYHA) 
level II or greater, decompensated heart failure 
6. Previous myocardial infarction or stroke within the 
last 5 years 
7. Diagnosis of schizophrenia, bipolar disorder, 
personality disorder or other DSM-III disorders, or 
any other psychiatric condition, which in the 
investigator’s opinion will interfere significantly 
with study compliance 
8. Physical impairment, which in the investigator’s 
opinion will interfere significantly with study 
compliance 
9. Any clinically significant cardiac arrhythmia 
10. Treatment with calcium channel blockers and beta 
blockers 
11. Concomitant use of monoaminooxidase inhibitors 
12. Use of recreational medication 
13. Bulimia or anorexia nervosa 
14. Any agent used for weight loss in the past 3 months, 
except GLP-1 compounds 
15. Untreated hypo- or hyperthyroidism 
16. Clinically significant liver (>3x ULN) and/or kidney 
impairment 
17. More than 5% weight loss within the last 3 months 
18. Subject is pregnant or lactating or intends to become 
pregnant or is of childbearing potential and not using 
an adequate contraceptive method (Spiral or 
hormonal contraception, birth control pills, implant, 
transdermal patch, vaginal ring or depot injection) 
19. Male subjects not agreeing to use a condom without 
spermicide 
or 
oil-containing 
products 
(e.g., 
lubricants) during sexual activity with female 
partners of childbearing potential throughout the 
trial until at least 8 weeks after the last 
administration of IMP 
20. Any contraindication for metoprolol according to 
the Summary of Product Characteristics (SmPC), 
e.g. severe peripheral arterial disease, untreated 
pheochromocytoma, 
concomitant 
intravenous 
administration of calcium antagonists of verapamil 
and diltiazem, due to the risk of hypotension, AV 
conduction 
disturbances, 
or 
left 
ventricular 
insufficiency 
21. Subject has lactose intolerance or a rare hereditary 
problem of fructose intolerance, glucose galactose 
malabsorption or sucrase isomaltase insufficiency 
22. Subject is unable to understand and communicate in 


 
 
 
 
 
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Danish language or to understand the protocol 
requirements, 
instructions 
and 
study-related 
restrictions, the nature, scope and possible 
consequences of the clinical study or is unlikely to 
comply 
with 
the 
study 
requirements; 
e.g., 
uncooperative 
attitude 
and 
improbability 
of 
completing the clinical study 
23. PHQ-9 (Patient Health Questionnaire):   
a. If a score of at least 5 in question 1 and 2 
coming from the area of “More than half the 
days” or Nearly every day”  
or  
b. PHQ-9 score ≥ 10 when counts from 
questions 3-5 have been subtracted  
or  
c. If a tic in question 6 in “More than half the 
days” or “Nearly every day” 
or 
d. Any score > 0 on question 9 at screening and 
baseline 
  
24. Any suicidal behaviour within the past 30 days since 
screening 
25. Subject has been enrolled in another clinical study 
within the past three months 
26. Any other clinically meaningful condition, which in 
the opinion of the investigator, would make 
participation potentially unsafe 
Study procedures 
Due to the special nature and the rarity of the investigated 
population, limiting the need to travel and to meet the 
requirement of a reflection period, subjects will be contacted by 
the investigator and potentially interested subjects will 
subsequently receive mailed information describing the study.  
 
Visit 1, Days -7 to -21 
Subjects will be invited for screening. First, informed consent 
process will be completed and signed by the subjects prior to 
any study-related procedures. Then blood will be drawn, 
followed by other screening procedures to establish their 
eligibility for the study. Subjects will be instructed in having 
home 24H BP/48H HR monitoring done, the devices will be put 
on, and instructions handed out. 
 
Visit 2, Day 1 
Blood will be drawn, BP, HR, weight and other endpoints will 
be collected. The first dose of study medication will be 
administered, dietary consulting will be performed and subjects 
will receive study drug supply sufficient for one month’s 
treatment. Subjects will be instructed in home BP monitoring 


 
 
 
 
 
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twice daily before breakfast and dinner (three measurements at 
each time point) once weekly during the whole study. Subjects 
with type 2 diabetes mellitus (T2DM) will be instructed in doing 
weekly 8-point glucose measurements. Subjects will receive a 
diary for BP reporting and if applicable reporting of blood 
glucose (BG). DEXA will need to be scheduled in advance so 
that it can be performed on Day 1.  Devices for home 24H 
BP/48H HR monitoring will be collected. 
 
Days 28-168 DB part  
On Days 28, 56, 84, 112, 140 and 168 (±3 days) the subjects 
will return to the site for safety evaluations, efficacy 
assessments, PK and drug supply (see the flow chart (FC) for 
details). Assessments will include blood sampling, BP, HR, 
weight and various questionnaires. Also, life style counseling 
including dietary and physical activity guidance, will be 
performed. Subjects will always receive study drug supply 
sufficient until next visit. At Day 84 (± 36) subjects will receive 
devices for 24H BP/48H HR home monitoring. 
 
Visit 8 on Day 168 (±3 days) will be the end of the DB part of 
the study and all assessments from the baseline visit (visit 2) 
will be repeated. At Day 168 (÷36/+3) subjects will receive 
devices for 24H BP/48H HR home monitoring.  
 
Days 168 – 336 Open-label part  
On Day 168 (±3 days) (visit 8) all subjects still participating in 
the study if evaluated eligible by the investigator will be invited 
for the open-label extension part where all subjects will be given 
the active medication.  
 
Subjects will be returning monthly for evaluations as described 
in the FC and drug supply. Visit 14 on Day 336 (±3 days) will 
conclude their participation in the study. On that day safety and 
efficacy assessments will be performed and 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 BP. 
 
Subjects who during the study 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 
FC. 
 
Phone visits part 1 and 2:  
At phone visits follow ups will be performed to discuss status 


 
 
 
 
 
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and experiences of AEs, hypoglycemic events, 8-point BG 
measurements, BP and HR measurements, and to reinforce 
behavioural modifications discussed during the counseling 
sessions.  
A follow-up phone visit will be performed 45 days after end of 
treatment to collect any AEs.  
Statistics 
All analyses will be performed in two steps – first after the 
completion of the DB part, then following the completion of the 
open-label extension part.  
Primary endpoint will be analyzed based on the following: 
 The number and type of treatment emergent AEs over 
the first 24 weeks 
 Change in laboratory data (hematology and blood 
chemistry) from baseline to week 24 
 Change in BP and HR from baseline to week 24 
No inferential statistical test will be performed for the primary 
endpoint. 
Continuous efficacy secondary endpoints will be compared 
between treatment arms by means using analysis of covariance 
(ANCOVA) including treatment as fixed factor and baseline 
value as covariate. Estimates and 95% confidence intervals 
(CIs) of treatment differences will be calculated. 
Safety analyses will include all participants who took at least 
one dose of IMP or comparator. 
 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. 
 
AEs will be coded according to Medical Dictionary for 
Regulatory Activities (MedDRA). The number and percentage 
of subjects experiencing AEs 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. 
 


 
 
 
 
 
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INVESTIGATOR STATEMENT 
 
TM005: A 24-week phase 2, DB, randomized, placebo-controlled, single-center safety and 
efficacy study to evaluate overall safety and tolerability of co-administration of 
tesofensine/metoprolol in subjects with Hypothalamic injury-induced obesity (HIO) with a 24-
week open-label extension, in total 48 weeks. 
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, International Conference on 
Harmonization (ICH) Good Clinical Practice (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 (IMP) and the course of the Study. 
 
If required, I will also provide necessary protocol information to the responsible independent 
ethics committee (IEC) and/or to the competent authorities (CA) 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. 
 
____________________________________________________________________ 
 
Principal/Coordinating Investigator 
Signature: 
Date: 
 
Professor Ulla Feldt-Rasmussen, MD, DMSc 
 
Department of Medical Endocrinology and metabolism PE 2132 
Rigshospitalet, Copenhagen University Blegdamsvej 9 
DK-2100 Copenhagen 
Denmark  
 


 
 
 
 
 
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SIGNATURE PAGE 
 
TM005: A 24-week phase 2, DB, randomized, placebo-controlled, single-center safety and 
efficacy study to evaluate overall safety and tolerability of co-administration of 
tesofensine/metoprolol in subjects with HIO with a 24-week open-label extension, in total 48 
weeks 
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 


 
 
 
 
 
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LIST OF STUDY STAFF 
 
Sponsor 
Saniona A/S 
Baltorpvej 154 
DK-2750 Ballerup 
Denmark 
Telephone number: +45 70 705 225 
Email: rdv@saniona.com 
 
Sponsor’s medical expert 
Berit Edsberg, MD 
Senior Medical Advisor 
Saniona A/S 
Baltorpvej 154 
DK-2750 Ballerup 
Denmark 
Telephone number: +45 28350713 
Email: bed@saniona.com 
 
Principal/coordinating 
investigator 
Professor Ulla Feldt-Rasmussen, MD, DMSc 
Department of Medical Endocrinology and metabolism PE 2132 
Rigshospitalet, Copenhagen University Blegdamsvej 9 
DK-2100 Copenhagen 
Denmark 
 
Phone: +4535451023 
 
email: ufeldt@rh.dk 
 
Contract Research Organization 
KLIFO A/S,  
Smedeland 36,  
2600 Glostrup, Denmark 
Telephone number: +45 44 222 900 
Fax number: +45 392 09 045 
Adverse Event Reporting 
KLIFO Pharmacovigilance Service KLIFO A/S,  
Smedeland 36,  
2600 Glostrup, Denmark 
Fax number: +45 39 209 045 
Email: pharmacovigilance@klifo.com 
 
Bioanalytical Laboratory for PK 
analysis 
Covance CRS Limited 
Wooley Road 
Alconbury 
Huntingdon 
Cambridgeshire 
PE28 4HS 
United Kingdom 
Contact Person: Lynn Laugher, Lynn.Laugher@covance.com 
Telephone number: +44 (0)1480 892 030 
 
Clinical biochemical unit, RH 
Klinisk Biokemisk Afdeling - Blegdamsvej, Afsnit 3011, Opgang 3. 1. 
Sal, Inge Lehmanns Vej 5, 2100 København Ø 
 


 
 
 
 
 
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TABLE OF CONTENTS 
LIST OF STUDY STAFF ___________________________________________________________________ 12 
1 
LIST OF ABBREVIATIONS _____________________________________________________________ 16 
2 
GENERAL INFORMATION _____________________________________________________________ 19 
2.1 
Introduction ______________________________________________________________________ 19 
2.2 
Tesofensine _______________________________________________________________________ 20 
2.3 
Metoprolol _______________________________________________________________________ 21 
2.4 
Co-administration of Tesofensine and metoprolol (PK data) _____________________________ 21 
2.5 
Safety in previous clinical studies with Tesofensine _____________________________________ 21 
2.6 
Overdose of Tesofensine ____________________________________________________________ 22 
2.7 
Safety of metoprolol _______________________________________________________________ 22 
2.8 
Safety of co-administration of Tesofensine and metoprolol _______________________________ 22 
2.9 
Risk-benefit assessment ____________________________________________________________ 23 
2.10 
Current treatment strategies ________________________________________________________ 24 
2.11 
Purpose of this study _______________________________________________________________ 24 
3 
STUDY OBJECTIVES AND ENDPOINTS _________________________________________________ 25 
3.1 
Objectives ________________________________________________________________________ 25 
3.2 
Endpoints ________________________________________________________________________ 26 
4 
OVERALL STUDY DESCRIPTION _______________________________________________________ 27 
4.1 
Flow chart: blinded treatment visits 1 - 8 ______________________________________________ 29 
4.2 
Flow chart: open-label treatment visits 9-14 ___________________________________________ 32 
4.3 
Study design ______________________________________________________________________ 35 
4.4 
End of study ______________________________________________________________________ 36 
4.5 
Study participants _________________________________________________________________ 36 
4.6 
Inclusion criteria __________________________________________________________________ 37 
4.7 
Exclusion criteria __________________________________________________________________ 37 
4.8 
Screening failures _________________________________________________________________ 38 
4.9 
Premature discontinuation of study medication ________________________________________ 38 
4.10 
Discontinuation ___________________________________________________________________ 38 
4.11 
Withdrawal ______________________________________________________________________ 39 
4.12 
Replacement of withdrawn subjects __________________________________________________ 40 
4.13 
Lost to follow-up __________________________________________________________________ 40 
4.14 
Premature study discontinuation ____________________________________________________ 40 
4.15 
Study site ________________________________________________________________________ 40 
4.16 
Study duration ____________________________________________________________________ 40 
4.17 
Benefits and risks for study participants ______________________________________________ 42 
5 
TREATMENT OF STUDY PARTICIPANTS ________________________________________________ 43 
5.1 
Description of study medication _____________________________________________________ 43 
5.2 
Identity of investigational products ___________________________________________________ 43 


 
 
 
 
 
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5.3 
Supply, packaging, labelling and storage ______________________________________________ 43 
5.4 
Procedures to assure double blinding _________________________________________________ 44 
5.5 
IMP handling procedures at the site __________________________________________________ 44 
5.6 
Labels for study medication _________________________________________________________ 44 
5.7 
Packaging and destruction __________________________________________________________ 45 
5.8 
Handling of the study medication ____________________________________________________ 45 
5.9 
Supply and storage of the study medication ___________________________________________ 45 
5.10 
Study medication compliance _______________________________________________________ 45 
5.11 
Screening and randomization _______________________________________________________ 46 
5.12 
Un-blinding ______________________________________________________________________ 46 
5.13 
Dispensation of study medication ____________________________________________________ 47 
5.14 
Accountability of the study medication _______________________________________________ 47 
5.15 
Concomitant medication ____________________________________________________________ 47 
5.16 
Prohibited medication ______________________________________________________________ 48 
6 
STUDY PROCEDURES _________________________________________________________________ 48 
6.1 
Site procedures ___________________________________________________________________ 48 
6.2 
Laboratory evaluations _____________________________________________________________ 53 
6.3 
Total amount of blood ______________________________________________________________ 54 
6.4 
Home measurements by subjects _____________________________________________________ 54 
7 
SAFETY REPORTING __________________________________________________________________ 57 
7.1 
Definitions _______________________________________________________________________ 57 
7.2 
Adverse event _____________________________________________________________________ 57 
7.3 
Unexpected adverse reaction ________________________________________________________ 59 
7.4 
Serious adverse event ______________________________________________________________ 59 
7.5 
Suspected unexpected serious adverse reaction _________________________________________ 59 
7.6 
Procedures for recording adverse events ______________________________________________ 59 
7.7 
Reporting of adverse events _________________________________________________________ 60 
7.7.1 
Adverse events of Special Interest and Reporting Procedures ________________________ 60 
7.7.2 
Pre-existing conditions _________________________________________________________ 61 
7.7.3 
Overdose _____________________________________________________________________ 61 
7.7.4 
Pregnancy ____________________________________________________________________ 62 
7.7.5 
Water retention and/or hyponatremia ____________________________________________ 62 
7.7.6 
Hypoglycemic events in subjects with T2DM ______________________________________ 62 
7.7.7 
Development of depression ______________________________________________________ 63 
7.8 
Reporting procedures for serious adverse events _______________________________________ 63 
7.9 
Follow-up of adverse events _________________________________________________________ 64 
8 
DESCRIPTION OF STATISTICAL METHODS _____________________________________________ 65 
8.1 
Description of statistical methods ____________________________________________________ 65 
8.2 
Sample size calculation _____________________________________________________________ 65 
8.3 
Selection of subjects for analyses _____________________________________________________ 65 
8.4 
Statistical methods _________________________________________________________________ 66 


 
 
 
 
 
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8.5 
Analysis of the primary endpoint ____________________________________________________ 66 
8.6 
Analysis of the secondary endpoints __________________________________________________ 66 
8.7 
Safety criteria _____________________________________________________________________ 67 
8.8 
Handling of missing and doubtful data _______________________________________________ 67 
8.9 
Interim analysis ___________________________________________________________________ 67 
9 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS _______________________________________ 68 
9.1 
Source data _______________________________________________________________________ 68 
9.2 
Subject identification list and screening log ____________________________________________ 69 
10 QUALITY CONTROL AND QUALITY ASSURANCE ________________________________________ 70 
10.1 
Definitions _______________________________________________________________________ 70 
10.2 
Audits and inspections _____________________________________________________________ 70 
11 ETHICS ______________________________________________________________________________ 71 
11.1 
Basic principles and ethical considerations ____________________________________________ 71 
11.2 
Approvals ________________________________________________________________________ 71 
11.3 
Ethics committee __________________________________________________________________ 71 
11.4 
Regulatory authority _______________________________________________________________ 71 
11.5 
Protocol modifications _____________________________________________________________ 71 
11.6 
Subject information and informed consent ____________________________________________ 71 
11.7 
Participant confidentiality __________________________________________________________ 72 
11.8 
Investigator qualification ___________________________________________________________ 72 
12 DATA HANDLING AND RECORD KEEPING ______________________________________________ 73 
12.1 
Data collection and documentation ___________________________________________________ 73 
12.2 
Study monitoring and source data verification _________________________________________ 73 
12.3 
Data management plan _____________________________________________________________ 73 
12.4 
Case report forms _________________________________________________________________ 73 
12.5 
Investigator file ___________________________________________________________________ 74 
12.6 
Used subject and medication logs ____________________________________________________ 74 
12.7 
Protocol compliance _______________________________________________________________ 74 
12.8 
Record keeping ___________________________________________________________________ 74 
13 FINANCE AND INSURANCE ___________________________________________________________ 76 
13.1 
Compensation to investigator _______________________________________________________ 76 
13.2 
Insurance and indemnity ___________________________________________________________ 76 
14 PUBLICATION POLICY ________________________________________________________________ 77 
14.1 
Reporting and publication __________________________________________________________ 77 
15 REFERENCES ________________________________________________________________________ 78 
8. APPENDICES _________________________________________________________________________ 80 
8.7 
Appendix 1 - List of prohibited medication ____________________________________________ 80 
8.8 
Appendix 2 – Instruction in diet and physical activity ___________________________________ 81 
8.9 
Appendix 3 – PHQ9 questionnaire ___________________________________________________ 85 


 
 
 
 
 
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LIST OF ABBREVIATIONS  
 
AE 
Adverse event 
°C 
Degrees Celsius 
A/S 
Aktieselskab 
ADR 
Adverse drug reaction 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
BEE 
Basal energy expenditure 
BMI 
Body Mass Index 
BG 
Blood glucose 
BP 
Blood pressure 
Bpm 
Beats per minute 
CA 
Competent authorities 
CI 
Confidence interval  
Cm 
Centimeter 
CRF 
Case report form 
CRH 
Corticotropin releasing hormone 
CRO 
Contract Research Organization 
CRA 
Clinical Research Associate 
CSR 
Clinical study report 
CSS 
Composite satiety score  
CYP 
Cytochrome P450 
DAT 
Dementia of Alzheimer type 
DB 
Double-blind 
DBL 
Database lock  
DBR 
Database release 
DDI 
Drug-drug interaction 
DEXA 
Dual-energy X-ray absorptiometry 
Dl 
Deciliter 
DM 
Drug metabolism 
DMP 
Data Management Plan 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ER 
Extended release 
FC 
Flow chart 
FDC 
Fixed-dose combination 
FFA  
Free fatty acid  
FPG 
Fasting Plasma Glucose  
FSH 
Follicle-stimulating hormone  
GCP 
Good Clinical Practice 
GHRH 
Growth hormone-releasing hormone 
GIP 
Gastric inhibitory polypeptide 
GLP-1 
Glucagon like peptide 1 
HbA1C 
Hemoglobin A1c 
HDL 
High-density lipoprotein 
HIO 
Hypothalamic injury-induced obesity 
HR 
Heart rate 


 
 
 
 
 
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HRQoL 
Health related quality of life 
IB 
Investigator brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent ethics committee 
IMP 
Investigational Medicinal Product 
INR 
International Normal Ration 
IP 
In-person 
IR 
Immediate release 
kg 
Kilogram 
l 
Liter 
LDL 
Low-density lipoprotein 
LOCF 
Last observation carried forward 
LPLV 
Last patient last visit  
LSLV 
Last Subject Last Visit 
MAO 
Monoamine oxidase  
MedDRA 
Medical Dictionary for Regulatory Activities 
MHP 
Mental Health Practitioner 
mg 
Milligram 
mITT 
Modified intention-to-treat population  
ml 
Milliliter 
mmHg 
Millimeter of mercury 
mmol 
Millimol 
N (No) 
Number 
ng 
Nanogram 
NSAIDs 
Non-Steroide Anti-Inflammatoriske Drugs  
NYHA 
New York Heart Association 
OTC 
Over the counter 
PD 
Parkinson’s disease 
Ph 
Phone 
PHQ9 
Patient health questionnaire 9 
PI 
Principal investigator 
PK 
Pharmacokinetic 
PPP 
Per Protocol Population 
PWS 
Prader-Willi syndrome 
Q 
Quarter 
QA 
Quality assurance 
QC 
Quality control 
RH 
Rigshospitalet  
SAE 
Serious Adverse Event 
SAP 
Statistical analysis plan 
SD 
Standard Deviation 
SF36 
Short Form 36 Quality of Life Questionnaire 
SOP 
Standard Operating Procedure 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
T2DM 
Type 2 diabetes mellitus 
TEAEs 
Treatment Emergent Adverse Events  
TEE 
Total energy expenditure 


 
 
 
 
 
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Tmax 
Time of the maximum  
TRH 
Thyrotropin-releasing hormone 
TSH 
Thyroidea Stimulating Hormone  
TZD 
Thiazolidinediones 
ULN 
Upper Limit of Normal range 
USA 
United States of America 
VAS 
Visual Analogue Scale 
WHO DD 
World Health Organization Drug Dictionary 
 


 
 
 
 
 
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1 GENERAL INFORMATION 
1.1 Introduction 
Hypothalamus is an important site for appetite regulation and energy expenditure. It is a central 
neuroendocrine area in the midbrain that integrates afferent stimuli from the vagus nerve and 
from peripheral hormones that reflect the nutritional state, such as leptin, ghrelin, peptide YY 
and insulin (6-8). The output from the hypothalamus includes humoral regulation of appetite 
and metabolic rate through corticotropin releasing hormone (CRH), somatostatin, growth 
hormone-releasing hormone (GHRH), and Thyrotropin-releasing hormone (TRH) released 
from the parvocellular neurons to the anterior pituitary gland, and through efferent signaling to 
the limbic system and via vagal- and sympathetic nerve fibers (8-10).  
 
HIO is the significant weight gain that can occur after extensive suprasellar operations or other 
lesions to the hypothalamus (1-5). Patients with HIO can have a greater sensation of hunger 
than controls (11). Reported energy intake ranges from below normal to hyperphagia (12-14). 
These patients are less physically active and have a lower basal metabolic rate than obese 
controls (12,15), however, these findings are not consistent (16).  
 
The complexity of the syndrome requires simultaneous targeting of the multitude of 
mechanisms that are deranged in the HIO patients, while taking into consideration the 
autonomous dysfunction that can potentially render this population more vulnerable to the 
effects of sympathomimetics on heart rate (HR) (17).  
 
In a number of case-control studies (number of cases 23 to 25) in patients with hypopituitarism 
that were well substituted, it has been demonstrated that these subjects had a decreased urinary 
excretion of epinephrine, that obese patients had a higher level of fasting Gastric inhibitory 
polypeptide (GIP) and lean female patients had higher leptin levels compared to Body Mass 
Index (BMI) matched controls. It was found that energy expenditure, fasting glucagon like 
peptide 1 (GLP-1), c-peptide, plasma glucose, and insulin were comparable between patients 
and controls (26,27). The effect of sibutramine, diet and exercise on body weight was studied 
in the same population (28): 90 % (n=9) of hypopituitary patients achieved a 5% weight loss, 
and 60% (n=6) lost  >10% weight within 11 months 
 
A wide range of pharmacological treatments has been attempted in  patients with HIO in small 
studies, such as sympathomimetics like dexamphetamine, ephedrine and caffeine, T3 mono 
treatment, GLP-1 analogues and octreotide with varying results (18-24). A literature review 
looked at the effect of bariatric surgery in patients with HIO, and found that gastric bypass was 
the most effective treatment for weight reduction with loss of -33.7 kg (95% CI -80.7; +13.3) 
after 12 months (n = 6) (25). 
  
Given the mechanism of action of tesofensine and the results from clinical studies in other 
patient populations it is anticipated that treatment with tesofensine could have a significant 
impact on appetite, satiety, food craving and weight in patients with HIO. 
 
 
 
 


 
 
 
 
 
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1.2 Tesofensine 
Tesofensine increases neurotransmission for serotonin, noradrenaline and dopamine by 
inhibiting their presynaptic re-uptake, and thereby reduces appetite/increases satiety (serotonin 
and noradrenaline), increases energy expenditure (noradrenaline) and reduces food craving 
(dopamine). 
 
Tesofensine was initially noted to cause a notable weight loss in overweight subjects with 
Parkinson’s disease (PD) and dementia of Alzheimer type (DAT), even though no attempts to 
promote weight control were included in these studies.  The weight reducing effect was 
confirmed in a subsequent phase 2 clinical study in obese subjects (TIPO-1), exceeding 
benchmarks set by the regulatory agencies for approval of weight loss agents (29).  Although 
tesofensine was generally well tolerated in these studies, an increase of blood pressure (BP) of 
1–5 mmHg and an increase of HR up to 8 beats per minute (bpm) were observed in subjects 
dosed with 0.25 to 1.0 mg of Tesofensine once daily. 
 
These increases could potentially have an adverse impact on the cardiovascular safety in the 
target subject population. This led to the addition of metoprolol, a β1-(cardio) selective 
adrenoceptor blocking agent to mitigate these effects, and provide a favourable benefit/risk 
profile.  
 
To date, co-administration of tesofensine and metoprolol to humans has been investigated in 
three completed clinical studies.  Firstly, a phase 1 drug-drug interaction (DDI) study 
(Q-21125) where a single dose of metoprolol was added to tesofensine administered for 14 days 
to study pharmacokinetics (PK) of both when administered together.  Secondly, a phase 2 study 
in obese and overweight subjects with type 2 diabetes mellitus (T2DM) (TM001) designed to 
provide the proof-of-concept data that addition of metoprolol mitigates the tesofensine-induced 
increase in HR and BP. In both studies, the co-administration of the drugs was generally well 
tolerated and the collected data have provided good base for future investigation of a fixed 
combination of tesofensine and metoprolol (Tesomet) for various indications. Thirdly, a phase 1 
study (TM003) to evaluate PK profile and relative bioavailability of a single dose of the 
Tesomet fixed-dose combination (FDC) tablet and co-administration of tesofensine plus 
commercial metoprolol has been conducted. In the same study the PK profile and relative 
bioavailability of a single dose of the Tesomet FDC tablet was evaluated in the fed state.  
Currently, there is an on-going phase 2 study in adolescents with Prader-Willi syndrome (PWS) 
(TM002). Initial results from the adult part of the study showed a significant effect of Tesomet 
on hyperphagia score and body weight in patients with PWS. Finally, a pharmacodynamic (PD) 
study (TM004) with various dosage combinations of tesofensine and metoprolol to identify the 
ideal dose of metoprolol for any given dose of tesofensine is on-going. 
 
The clinical development program of Tesomet draws heavily on a substantial body of data 
available for tesofensine, for which - despite not being approved or developed as a stand-alone 
agent - there is a complete pre-clinical efficacy and safety data package available and has been 
to date studied in more than 1300 subjects.   
 


 
 
 
 
 
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1.3 Metoprolol 
Metoprolol is a beta1-selective (cardio selective) adrenoceptor blocking agent, for oral 
administration, which was 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 
available as immediate release (IR) and extended release (ER) tablets. Metoprolol succinate 
“Orion” 50 mg retard, containing 50 mg of metoprolol succinate, has been formulated to 
provide a controlled and predictable release of metoprolol for once daily administration. This 
is the formulation selected for this study (for more information please see the SmPC for 
Metoprololsuccinat “Orion”, depottabletter) (30). Metoprolol was approved in the United States 
of America (USA) in 1978 and has since become one of the most widely used drugs ever with 
millions of subject-years of safety data available. 
1.4 Co-administration of Tesofensine and metoprolol (PK data) 
PK data following 24 weeks co-administration of tesofensine and metoprolol are available from 
the study TM001.  Tesofensine, its N-desmethyl-metabolite (NS2360) and metoprolol 
concentrations in plasma were measured pre-dose at baseline and at the end of treatment.  The 
tesofensine PK results obtained in this study are in line with the PK data obtained in the study 
TIPO-1 where tesofensine was administered in similar population of subjects for 24 weeks.  The 
exposures of metoprolol are also in line with those previously published. 
1.5 Safety in previous clinical studies with Tesofensine 
Seventeen phase 1 studies with 359 healthy volunteers have been completed, with 309 subjects 
being exposed to tesofensine. Tesofensine was well tolerated up to and including single oral 
doses of 6.75 mg. Multiple daily doses up to 1.0 mg and loading doses up to 2.0 mg in phase 1 
studies were considered to be well tolerated.  In all single and multiple dose phase 1 studies in 
healthy volunteers, including a study with intravenous infusion up to 1.2 mg in volunteers, no 
changes in vital signs, electrocardiogram (ECG) or laboratory parameters assessed as clinically 
significant by the investigator were observed. No serious adverse events (SAEs) occurred. 
 
Seven phase 2 studies have been completed in subjects with neurodegenerative diseases.    Three 
4-week studies used forced titration and included 62 subjects (60 to 80 years) with possible 
DAT and nine subjects with advanced PD. A total of 53 of them were exposed to tesofensine. 
Tesofensine was well tolerated at all doses, i.e., daily doses up to 2.0 mg for the first 3 days 
(loading doses) followed by daily doses up to 1.0 mg for up to 25 consecutive days. In four 
dose finding studies of 14 weeks’ duration, 1036 subjects with DAT and PD were included and 
796 of them were exposed to doses of 0.125-1.0 mg of tesofensine.   
 
In obese subjects, one dose ranging study of 24 weeks’ duration (NS2330-001, “TIPO-1”) was 
conducted including 203 obese subjects, with 151 of them exposed to 0.25 to 1.0 mg 
tesofensine.  The most frequent adverse events (AEs) in this study were insomnia, dry mouth, 
dizziness, and constipation. These events were dose-dependent and categorized as expected for 
drugs belonging to the same pharmacological class. Beyond that a long-term study, TIPO-4 (an 
extension study of the "TIPO-1"-study with subjects with uncomplicated obesity), over 48 
weeks has been completed. In this study all subjects started on 0.5 mg tesofensine for the first 
24 weeks and could be up-titrated to 1.0 mg. The last 24 weeks all subjects received 0.5 mg. 
 
The emerging efficacy and safety profile of tesofensine from the studies in obese subjects has 
identified a clinically relevant, safe and well tolerated dose range of 0.25 mg up to 0.5 mg. 
 


 
 
 
 
 
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In total, tesofensine has been evaluated in approximately 170 subjects in studies examining the 
metabolic and weight loss effects in overweight and obese subjects and in approximately 
900 subjects in other indications. Based on the pharmacological profile it can be assumed that 
tesofensine causes dopaminergic side effects such as insomnia, agitation, hallucinations, and 
psychoses including delusion, paranoid ideation and depression. The AEs, which were 
commonly reported in all investigated populations, were insomnia, dry mouth, dizziness, and 
constipation, which also expressed dose-dependency. In obese subjects the most frequent AEs 
were dry mouth, headache, nasopharyngitis, nausea, influenza, insomnia, diarrhoea, 
constipation, and back pain. Psychiatric side effects were more frequently reported in the elderly 
population (subjects with PD or DAT).  Psychotic events, such as hallucinations, were also 
observed in this elderly population, mostly with high doses (> 0.75 mg/day). 
 
Undesired effects, which have been observed up to now, comprise: 
 
 Very frequently (> 10%): headache, insomnia, dizziness, somnolence, loss of appetite, lack 
of energy, dry mouth, attention disturbances, cold-like symptoms, diarrhoea, constipation 
 Frequently (< 10%): nausea, vomiting, fast pulse, muscle spasms, sweating, palpitations, 
vertigo, blurry vision, flatulence, abdominal pain or discomfort, tooth pain, fatigue 
 Rarely (< 0.1%): altered state of consciousness, sensory disturbance, agitation and 
persecutory delusion were found in a subject with high doses of tesofensine 
1.6 Overdose of Tesofensine 
Clinical experience with tesofensine in overdose is limited.  Exaggerated dopaminergic action 
should be anticipated with risk of psychotic behaviour, cardiac symptoms (tachycardia, 
palpitations, atrial extrasystolia), orthostatic hypotension, and gastrointestinal symptoms 
(nausea, emesis, diarrhoea). 
1.7 Safety of metoprolol 
Metoprolol is a selective β1 receptor blocker, used in the treatment of, e.g., hypertension, angina 
pectoris, acute myocardial infarction, supraventricular tachycardia, ventricular tachycardia, 
congestive heart failure and prevention of migraine headaches.  
Metoprolol is available as IR and ER tablets and as solution for i.v. injection. 
For further details refer to the SmPC of metoprolol (30).  
1.8 Safety of co-administration of Tesofensine and metoprolol 
To date, tesofensine tablet and metoprolol tablet have been co-administered to humans in 
three completed clinical studies.  For more details please see section 1.2 in the DDI study 
(Q-21125), as well as in the TM003 and the phase 2 TM001 the co-administration of the drugs 
was generally well tolerated.  No new or unexpected safety findings have been observed in the 
study compared to previous studies with tesofensine alone. 
 


 
 
 
 
 
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1.9 Risk-benefit assessment 
The anticipated benefits are reduction in appetite and body weight, body fat, and increased 
satiety. In addition, attitude towards food and eating should be favourably influenced. 
 
The TM005 protocol has been designed to minimize the risk to participating subjects:  strict in- 
and exclusion criteria are implemented to minimize potential risks and subjects will be 
monitored to detect AEs during the study and followed appropriately to ensure resolution of 
AEs. Metoprolol has already been approved for years, therefore side effects are well known.   
Subjects who are overweight with confirmed diagnosis of HIO will be eligible for the study 
only if they do not meet any contraindications or the listed special warnings from metoprolol 
Summary of Product Characteristics (SmPC). Subjects will only be eligible to participate if they 
do not have co-morbidities typical for obesity such as hypertension, diabetes or any 
cardiovascular conditions that are not under control.   
 
Increases in HR and BP may occur due to tesofensine dosing and decreases in HR and BP may 
occur due metoprolol dosing, thus these effects should be mitigated following administration 
of Tesomet.  Subjects with untreated hyper- or hypotension will not be eligible for the study. 
Vital signs will be measured at all visits and weekly home measures will be done.  Home 
monitoring of 24H BP/48H HR will be done between screening and baseline, and at Day 84 (± 
36) and at Day 168 (÷36/+3). 
 
In the TM001 study 60 overweight or obese patients with T2DM were treated with for 3 months 
with either co-administration of tesofensine 0.5 mg/metoprolol 100 mg ER or matching 
placebo. In total one case of palpitations and one case of tachycardia were reported. None of 
the treatment emergent events were serious and no death occurred during the study. 
In general, cardiovascular AEs were most frequently reported in the elderly population, which 
was characterized by significant co-morbidities, including cardiovascular conditions.  Serious 
cardiovascular AEs were reported only in PD/DAT subjects, in 2% of the subjects in the 
tesofensine group and in 4% in the placebo group.  No clear dose-dependency was observed for 
any of the cardiovascular events reported in any target population. No serious or severe 
cardiovascular AEs have been reported to date in obese subjects. 
 
Psychiatric AEs appeared to be associated with high single doses or forced titration of 
tesofensine and, importantly, in an age group (elderly) and populations (subjects with 
Parkinson´s or Alzheimer´s disease) different from the population of this study. Insomnia 
occurred as most prominent psychiatric event but only at higher loading doses. Psychotic events 
seen in healthy volunteers were associated either with a single dose treatment with more than 
> 6 mg of tesofensine, or with multiple doses of more than 2 mg/day of tesofensine.  
In obese subjects (TIPO-1), a dose ranging study of 24 weeks’ duration was conducted 
including 203 obese subjects, with 151 of them exposed to 0.25 to 1.0 mg tesofensine. The most 
frequent AEs in these studies were insomnia, dry mouth, dizziness, and constipation.  These 
events were dose-dependent and categorized as expected for drugs belonging to same 
pharmacological class.  
 
In the TM001 a few cases of anxiety, insomnia, restlessness and sleep disorders were reported. 
 
In conclusion, data from the clinical studies do not suggest that tesofensine 0.25 mg and 0.5 mg 
once daily in obese or obese subjects with diabetes or up to 2 mg/day (for 7 days) in healthy 


 
 
 
 
 
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volunteers will be associated with a clinically significant undesirable psychiatric adverse effect 
profile.   
Also, no additional risks are expected by the co-administration compared to those known for 
dosing of tesofensine and metoprolol alone. 
1.10 Current treatment strategies 
Currently, there are no treatments approved for HIO. Various available strategies for weight 
loss are tried with mixed results. 
1.11 Purpose of this study 
The purpose of this study is to investigate the overall safety and tolerability as well as effect on 
satiety, appetite and weight loss of co-administration of tesofensine/metoprolol treatment in 
subjects with HIO. 


 
 
 
 
 
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2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 Objectives 
Primary objectives:    
 To examine overall safety and tolerability of co-administration of 0.5 mg tesofensine/50 
mg metoprolol treatment over 24 weeks in subjects with HIO 
 
Secondary objectives: 
 To examine the effect on satiety and appetite from baseline to week 24, and from 
baseline to week 48 and from week 24 to week 48 following co-administration of 0.5 
mg tesofensine/50 mg metoprolol treatment in subjects with HIO 
 To examine the effect on bodyweight from baseline to week 24, from baseline to week 
48 and from week 24 to week 48 following co-administration of 0.5 mg tesofensine/50 
mg metoprolol treatment in subjects with HIO 
 To examine the effect on body composition from baseline to week 24, from baseline to 
week 48 and from week 24 to week 48 following co-administration of 0.5 mg 
tesofensine/50 mg metoprolol treatment in subjects with HIO 
 To examine the effect on quality of life from baseline to week 24, from baseline to week 
48 and from week 24 to week 48 following co-administration of 0.5 mg tesofensine/50 
mg metoprolol treatment in subjects with HIO 
 To examine effect on craving for something sweet, salty, savory and fatty from baseline 
to week 24, from baseline to week 48 and from week 24 to week 48 following co-
administration of 0.5 mg tesofensine/50 mg metoprolol treatment in subjects with HIO 
 To examine the effect on thirst from baseline to week 24, from baseline to week 48 and 
from week 24 to week 48 following co-administration of 0.5 mg tesofensine/50 mg 
metoprolol treatment in subjects with HIO 
 To examine effect on glycemic control and lipid profile from baseline to week 24, from 
baseline to week 48 and from week 24 to week 48 following co-administration of 0.5 
mg tesofensine/50 mg metoprolol treatment in subjects with HIO 
 To examine the effect on HR and BP from baseline to week 24, from baseline to week 
48 and from week 24 to week 48 following co-administration of 0.5 mg tesofensine/50 
mg metoprolol treatment in subjects with HIO 
 To establish profile of trough values of tesofensine,  N-desmethyl-metabolite (NS2360) 
and metoprolol following co-administration of 0.5 mg tesofensine/50 mg metoprolol 
treatment in subjects with HIO: 
o Active arm: the first 24 weeks and then continuously up to week 48.  
o Placebo arm: start of treatment at week 25 and then continuously up to week 48.  
 To evaluate the effect on BP and HR from baseline to week 24 by 24H home monitoring 
of BP and 48 H home monitoring of HR 
 To evaluate overall safety and tolerability from week 24 to week 48 following co-
administration of 0.5 mg tesofensine/50 mg metoprolol treatment in subjects with HIO 
 
 


 
 
 
 
 
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2.2 Endpoints 
Primary endpoint 
 Safety and tolerability will be judged from all safety data collected in the period, 
including Treatment Emergent Adverse Events (TEAEs), laboratory data, BP and HR 
measurements  
 
Secondary efficacy endpoints 
 Change in satiety and appetite using the composite satiety score (CSS) from baseline to 
week 24, from baseline to week 48 and from week 24 to week 48  
 Change in body weight from baseline to week 24, baseline to week 48 and from week 
24 to week 48  
 Change in body composition i.e. body fat and lean body mass by dual-energy X-ray 
absorptiometry (DEXA) from baseline to week 24, from baseline to week 48 and from 
week 24 to week 48 
 Change in quality of life by the use of the SF-36 questionnaire from baseline to week 
24, from baseline to week 48 and from week 24 to week 48   
 Change in craving for something sweet, salty, savory and fatty by the use of VAS scales 
from baseline to week 24, from baseline to week 48 and from week 24 to week 48   
 Change in thirst by the use of a VAS scale from baseline to week 24, from baseline to 
week 48 and from week 24 to week 48  
 Change on glycaemic control and lipid profile from baseline to week 24, from baseline 
to week 48 and from week 24 to week 48  
 Change in waist circumference from baseline to week 24, from baseline to week 48 and 
from week 24 to week 48 
 
Secondary safety endpoints 
 Change on HR and BP from baseline to week 24, from baseline to week 48 and from 
week 24 to week 48  
 Trough values of tesofensine, metoprolol and N-desmethyl-metabolite (NS2360)  
o Active arm: the first 24 weeks and then continuously up to week 48.  
o Placebo arm: start of treatment at week 25 and then continuously up to week 48.  
 Change of 24H BP/48H HR and QT from baseline to week 12 and week 24 and from 
week 12 to week 24 measured by home monitoring 
 Number and frequency of AE’s and SAE’s from week 24 to week 48 
 
 
 


 
 
 
 
 
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TM005 
CONFIDENTIAL 
 
Final Version 5.0 
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10 December2019 
 
 
3 OVERALL STUDY DESCRIPTION 
This is a 24-week double-blind (DB), randomized, placebo-controlled, single-center, safety and 
efficacy study to evaluate overall safety and tolerability of co-administration of 
tesofensine/metoprolol in subjects with HIO with a 24-week open-label extension, in total 48 
weeks. The study will have two parts: 
o Part 1: 24 weeks DB treatment, followed by 
o Part 2: 24 weeks open-label – all subjects still participating at the end of part 1 
will be given an option to continue for additional 24 weeks on the active drug if 
evaluated eligible by the investigator 
 
 During part 1 subjects will be randomized to either treatment with co-administration of 
0.5 mg tesofensine/50 mg metoprolol (active medication) or matching placebo in 2:1 
ratio 
 Subjects with T2DM will be stratified evenly to the two treatment arms during 
randomization  
 As an integral part of the study all subjects will undergo regular lifestyle counseling, 
including guidance in diet, physical activity as well as behavioural modification, during 
both the part 1 and the part 2 portion of the study 
 
Assessments conducted during each visit are described in the flow chart (FC). Subjects will be 
fasting for all visits, except the screening visit. 
 
Screening (visit 1, day -7 to -21): Subjects who give the written informed consent will be 
screened for the study. Subjects will be instructed in having home 24H BP/48H HR monitoring 
done, the devices will be put on, and instructions handed out. 
 
Baseline (visit 2, Day 1): Blood will be drawn, BP, HR, weight and other endpoints will be 
collected. Fasting Plasma Glucose (FPG) will be measured on site to ensure eligibility for the 
study. The FPG measured at Klinisk Biokemisk Afdeling, RH will be the Baseline value. 
Devices for 24H BP/48H HR will be collected. 
 
DEXA will need to be scheduled in advance so that it can be performed on Day 1.   
 
Randomization (visit 2, Day 1): Following the completion of all Baseline assessments on Day 
1, eligible subjects will be randomized to DB treatment with co-administration of 
tesofensine/metoprolol. The first dose of study medication will be administered on Day 1. 
Lifestyle counseling will be performed and subjects will receive sufficient study medication 
until next visits as well as BP meter, diaries and blood glucose (BG)-meter (if applicable). 
 
Treatment period part 1 (visit 2-8): after the Day 1, subjects will visit the site on Days 28, 
56, 84, 112, 140 and 168 (±3 days) for safety evaluations, efficacy, PK assessments and 
medication supply until Day 168 (visit 8). Assessment will include blood sampling, vital signs, 
weight and various questionnaires. Also, lifestyle counseling will be performed. The subjects 
will always receive sufficient study medication until next visit as well as a new diary at each 
visit. At visit 5, Day 84 (± 36) and at visit 8, Day 168 (÷36/+3) devices for home 24H BP/48H 
HR will be handed out and collected after mutual agreement between the individual subject and 
the investigator. A phone visit follow-up will be performed at Days 14, 42, 70, 98, 126, 154 
and 182 to discuss status and experiences of AEs, hypoglyaemic events, 8-point BG 
measurements, BP and HR measurements. 


 
 
 
 
 
Saniona A/S 
Clinical Study Protocol 
TM005 
CONFIDENTIAL 
 
Final Version 5.0 
Page 28 of 85 
10 December2019 
 
 
 
Final visit part 1: Visit 8 will be the end of the DB part of the study and all assessments from 
the Baseline (visit 2) will be repeated. 
 
Treatment period part 2 (visit 8-14, Day 168-336): On Day 168 (±3 days) (visit 8) all subjects 
still participating in the study if evaluated eligible by the investigator, will be invited for the 
open-label extension part where all subjects will be given the same dose of tesofensine and 
metoprolol. A phone visit follow-up will be performed at Days 210, 238, 266, 294 and 322 to 
discuss status and experiences of AEs, hypoglycaemic events, 8-point BG measurements, BP 
and HR measurements. 
 
Subjects will be return monthly for evaluations as described in the FC as well as drug supply. 
 
Final visit part 2: At visit 14 subjects will conclude their participation in the study. On that 
day safety and efficacy assessments will be performed and 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 BP. 
 
Follow-up: 45 days (+3 days) after end of treatment a follow-up visit (phone visit) must be 
performed to discuss experiences of AE’s since last dose of trial product.  
 
 


 
 
 
 
 
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Clinical Study Protocol 
TM005 
CONFIDENTIAL 
 
Final Version 5.0 
Page 29 of 85 
10 December2019 
 
 
3.1 Flow chart: blinded treatment visits 1 - 8  
 
 
Screening 
Randomization 
Visit type 
End of part 1 
Phone 
Site 
Phone  
Site 
Phone  
Site 
Phone  
Site  
Phone  
Site 
Phone  
Visit number 
1 
2 
2.1 
3 
3.1 
4 
4.1 
5 
5.1 
6 
6.1 
7 
7.1 
8 
Days in relation to visit 2 
-21 
 to-7 
1 
14 
28 
42 
56 
70 
84 
98 
112 
126 
140 
154 
168 
Visit window, days 
-3 
±3 
±3 
±3 
±3  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
SUBJECT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
In/ Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Subject Card dispensing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant illness  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lifestyle counseling 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
ECG 
X 
 
 
 
 
 
 
X 
 
 
 
  
 
X 
DEXA 
 
X 
 
 
 
 
 
 
 
 
 
  
 
X 
AEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diabetes history and 
diabetes complications2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Body examination 
Physical examination3 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Vital signs 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 


 
 
 
 
 
Saniona A/S 
Clinical Study Protocol 
TM005 
CONFIDENTIAL 
 
Final Version 5.0 
Page 30 of 85 
10 December2019 
 
 
 
Screening 
Randomization 
Visit type 
End of part 1 
Phone 
Site 
Phone  
Site 
Phone  
Site 
Phone  
Site  
Phone  
Site 
Phone  
Visit number 
1 
2 
2.1 
3 
3.1 
4 
4.1 
5 
5.1 
6 
6.1 
7 
7.1 
8 
Days in relation to visit 2 
-21 
 to-7 
1 
14 
28 
42 
56 
70 
84 
98 
112 
126 
140 
154 
168 
Visit window, days 
-3 
±3 
±3 
±3 
±3  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
SUBJECT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Waist circumference 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Laboratory examination 
Hematology 
X 
X 
 
 
 
 
 
X  
 
 
 
  
 
X 
Blood chemistry 
X 
X 
 
X9 
 
X9 
 
 X 
 
X9 
 
X9  
 
X 
Infectious serology 
X 
X 
 
 
 
 
 
X 
 
 
 
  
 
X 
HbA1C 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Lipids 
X 
X 
 
 
 
 
 
X 
 
 
 
  
 
X 
Endocrine examination4 
 
X 
 
X10 
 
X10 
 
X 
 
X10 
 
X10 
 
X 
Blood pregnancy test5 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Fasting plasma glucose 
(FPG) 
 
X6 
 
X 
 
X 
 
X 
 
X 
 
X  
 
X 
Blood samples for future 
examination7 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Blood samples for back-
up 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
PK sample 
 
X 
 
 
 
 
 
X  
 
 
 
  
 
X 
Questionnaires 
Satiety and appetite 
Questionnaires 
  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Assessment of craving  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Assessment of thirst  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
SF-36 questionnaire  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
PHQ-9 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 


 
 
 
 
 
Saniona A/S 
Clinical Study Protocol 
TM005 
CONFIDENTIAL 
 
Final Version 5.0 
Page 31 of 85 
10 December2019 
 
 
 
Screening 
Randomization 
Visit type 
End of part 1 
Phone 
Site 
Phone  
Site 
Phone  
Site 
Phone  
Site  
Phone  
Site 
Phone  
Visit number 
1 
2 
2.1 
3 
3.1 
4 
4.1 
5 
5.1 
6 
6.1 
7 
7.1 
8 
Days in relation to visit 2 
-21 
 to-7 
1 
14 
28 
42 
56 
70 
84 
98 
112 
126 
140 
154 
168 
Visit window, days 
-3 
±3 
±3 
±3 
±3  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
SUBJECT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication 
Medication dispensing 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Medication 
accountability 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Dispense meters/ diaries, review of home measures 
Home monitoring of 
24H BP/48H HR 
X 
 
 
 
 
 
 
X8 
 
 
 
 
 
X8 
Dispensation BP 
monitor 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review of home 
measured BP and HR 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispensing of BG meter2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review of home 
measured BG and 
Hypoglycaemic events2 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diary dispensation 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Diary review 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Diary collection 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Open-Label Extension start 
Open-label extension 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
1: Demographics: Date of birth, sex and race 
2:T2DM subjects only  
3: Physical examination: Include heart, lung, head and neck exam, and abdominal, neurological and dermatological examination 
4: Endocrine examination: IGF-1,, free T4, prolactin, LH, Follicle-stimulating hormone (FSH), testosterone (men), oestrodiol (women) 
5: Female subjects of childbearing potential only 
6: Plasma glucose at randomization: On site FPG   is used for randomized. The FPG measured at Klinisk Biokemisk Afdeling, RH is the 
baseline value. 


 
 
 
 
 
Saniona A/S 
Clinical Study Protocol 
TM005 
CONFIDENTIAL 
 
Final Version 5.0 
Page 32 of 85 
10 December2019 
 
 
7: Blood samples for future examination: free fatty acid (FFA), Ghrelin, Glucagon Like Peptide 1 (GLP-1), Gastric inhibitory polypeptide 
(GIP), adiponectin, leptin 
8: Devices for home monitoring of 24H BP/48H heart rate (HR) will be put on at Day 84 (± 36) and at Day 168 (÷36/+3) and collected after 
mutual agreement between the individual subject and the investigator. 
9: Only creatinine and electrolyte 
10: Only Thyroidea Stimulating Hormone (TSH) and free T4 
3.2 Flow chart: open-label treatment visits 9-14 
 
Visit type 
End of trial 
Follow-up - Phone 
Phone 
Site 
Phone  
Site 
Phone  
Site 
Phone  
Site  
Phone  
Site 
Phone  
Visit number 
8.1 
9 
9.1 
10 
10.1 
11 
11.1 
12 
12.1 
13 
13.1 
14 
14.1 
Days in relation to visit 2 
182 
196 
210 
224 
238 
252 
266 
280 
294 
308 
322 
336 
459 
Visit window, days 
±3 
±3 
±3  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
+3 
SUBJECT 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lifestyle counseling 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
 
 
 
 
 
X 
 
 
 
  
 
X 
 
DEXA 
 
 
 
 
 
 
 
 
 
  
 
X 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body examination 
 
Physical examination1 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Vital signs 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Body weight 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Waist circumference 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Laboratory examination 
 
Hematology 
 
 
 
 
 
X  
 
 
 
  
 
X 
 
Blood chemistry 
 
X7 
 
X7 
 
 X 
 
X7 
 
X7  
 
X 
 
Infectious serology 
 
 
 
 
 
X 
 
 
 
  
 
X 
 
HbA1C 
 
 
 
 
 
X 
 
 
 
 
 
X 
 


 
 
 
 
 
Saniona A/S 
Clinical Study Protocol 
TM005 
CONFIDENTIAL 
 
Final Version 5.0 
Page 33 of 85 
10 December2019 
 
 
 
Visit type 
End of trial 
Follow-up - Phone 
Phone 
Site 
Phone  
Site 
Phone  
Site 
Phone  
Site  
Phone  
Site 
Phone  
Visit number 
8.1 
9 
9.1 
10 
10.1 
11 
11.1 
12 
12.1 
13 
13.1 
14 
14.1 
Days in relation to visit 2 
182 
196 
210 
224 
238 
252 
266 
280 
294 
308 
322 
336 
459 
Visit window, days 
±3 
±3 
±3  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
+3 
SUBJECT 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipids 
 
 
 
 
 
X 
 
 
 
  
 
X 
 
Endocrine examination2 
 
X8 
 
X8 
 
X 
 
X8 
 
X8 
 
X 
 
Blood pregnancy test3 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
FPG 
 
X 
 
X 
 
X 
 
X 
 
X  
 
X 
 
Blood samples for future 
examination4 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Blood samples for back-
up 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
PK sample 
 
 
 
 
 
X  
 
 
 
  
 
X 
 
Questionnaires 
 
Satiety and appetite 
Questionnaires 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Assessment of craving  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Assessment of thirst  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
SF-36 questionnaire  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
PHQ-9 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Medication 
 
Medication dispensing 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X6 
 
Medication 
accountability 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Dispense diaries and review home measures 
 


 
 
 
 
 
Saniona A/S 
Clinical Study Protocol 
TM005 
CONFIDENTIAL 
 
Final Version 5.0 
Page 34 of 85 
10 December2019 
 
 
 
Visit type 
End of trial 
Follow-up - Phone 
Phone 
Site 
Phone  
Site 
Phone  
Site 
Phone  
Site  
Phone  
Site 
Phone  
Visit number 
8.1 
9 
9.1 
10 
10.1 
11 
11.1 
12 
12.1 
13 
13.1 
14 
14.1 
Days in relation to visit 2 
182 
196 
210 
224 
238 
252 
266 
280 
294 
308 
322 
336 
459 
Visit window, days 
±3 
±3 
±3  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
+3 
SUBJECT 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of home 
measured BP and HR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Review of home 
measured BG, 
Hypoglycaemic events5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Diary dispensation 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Diary review 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Diary collection 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
End of study 
End of Study Form 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
1: Physical examination: Include heart, lung, head and neck exam, and abdominal, neurological and dermatological exam 
2: Endocrine examination: IGF-1, TSH, free T4, prolactin, LH, FSH, testosterone (men), oestrodiol (women) 
3: Female subjects of childbearing potential only 
4: Blood samples for future examination: FFA, Ghrelin, GLP-1, GIP, adiponectin, leptin 
5: T2DM subjects only, during the whole study subjects with T2DM will be asked to do 8-point home BG check once weekly 
6: Dispensation of two half-doses of metoprolol 
7: Only creatinine and electrolyte 
8: Only TSH and free T4 
9: After end of treatment (Last dose of Tesofensine/Tesofensine Placebo) 
 


 
 
 
 
 
Saniona A/S 
Clinical Study Protocol 
TM005 
CONFIDENTIAL 
 
Final Version 5.0 
Page 35 of 85 
10 December2019 
 
 
3.3 Study design 
Visit 1 screening (Day -21 to -7)  
Potentially eligible subjects will be given written and verbal information about the protocol, 
study design and potential risk and benefits according to procedures described in section 5. At 
screening, subjects will be provided with a subject card stating that they are participating in a 
trial and giving contact address(es) and telephone number(s) of relevant trial site staff. Subjects 
should be instructed to return the card to the investigator at the last trial visit or to destroy the 
card after the last visit. 
 
For other screening procedures Please see FC 
 
Visit 2 baseline visit /randomization (Day 1):   
On Day 1, following the completion of all baseline assessments, the investigator will randomize 
subject into one of the treatment arms. The first administration of study medication will be 
administered at site with investigator, and subject will receive sufficient study medication until 
next visit.   
 
Given the value measured on site of the FPG ≥ 11.0 mmol/l and all other laboratory results are 
within the requested limits, the subjects can be invited for an unscheduled visit to have only the 
FPG re-tested, both on site and at Klinisk Biokemisk Afdeling, RH. Given the on site value of 
FPG is < 11.0 mmol/l, the subject can be randomized. The re-tested FPG value at Klinisk 
Biokemisk Afdeling, RH laboratory, should be entered into the electronic case report form 
(eCRF) as baseline. 
 
Life style counseling including guidance in diet, physical activity and behavioural modification 
will be performed.  
 
Subject will receive the BP meter and instruction for home measurements of BP and HR.  
Subjects will be instructed to do home monitoring of BP and HR twice daily before breakfast 
and dinner (three measurements each time point), once weekly during the whole study. Subjects 
will receive a diary for BP and HR reporting.  
On days where blood test for PK sampling is taken, time of last dose of study medication should 
be noted as well.  
 
Subjects with T2DM will also receive BG meters and belonging auxiliaries as well as a diary 
for BG reporting. These subjects will be asked to do and record the following: once weekly 8-
points BG measurements date and glucose level when experiencing hypoglycemia episodes.  
 
A DEXA scan will also be performed at this visit.  
 
For further procedures to be done at visit 2, please refer to the FC.  
 
 
 


 
 
 
 
 
Saniona A/S 
Clinical Study Protocol 
TM005 
CONFIDENTIAL 
 
Final Version 5.0 
Page 36 of 85 
10 December2019 
 
 
Treatment period part 1:  
 
Visits 3, 4, 5, 6, 7 (Day 28, 56, 84, 112, 140 (±3 days))  
For procedures to be done please see FC. 
 
Additional unscheduled visits may be performed if considered clinically necessary by the 
investigator. The investigations planned for the next scheduled visit will be performed. 
 
Visit 2.1; 3.1; 4.1;5.1;6.1;7.1- phone visits 
A phone visits follow ups will be performed to discuss status and experiences of AEs, 
hypoglycemic events, 8-point BG measurements, BP and HR measurements, and to reinforce 
behavioural modifications discussed during the counseling sessions.  
 
Visit 8 (Day 168 (±3 days))  
Visit 8 is considered to be a more detailed visit for efficacy assessments – end of DB part. For 
procedures to be done please see FC. 
 
Open-label extension part 2: 
 
Visit 9, 10, 11, 12, 13 (Day 196, 224, 252, 280, 308 (±3 days)) 
For procedures to be done please see FC. 
 
Visit 8.1; 9.1;10.1;11.1;12.1;13.1- phone visits 
A phone visit follow-up will be performed to discuss status and experiences of AEs, 
hypoglycemic events, 8-point BG measurements, BP and HR measurements.  
 
Visit 14 end of part 2, end of study (Day 336 (±3 days))  
Visit 14 is considered to be a final study visit, last patient last visit (LPLV). For procedures to 
be done please see FC. This visit 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.  
 
Follow-up: A follow-up phone visit must be performed 45 days (+3 days) after end of treatment 
to discuss experiences of AE’s since last dose of trial product.  
If the subjects withdraw treatment before visit 14, the follow-up must be made 45 days (+3 
days) after the last day of administration of trial product.  
3.4 End of study 
The end of study is defined by LPLV for TM005. If a subject discontinues from the study 
medication during the treatment period, a visit will be organized at which the assessments 
planned for Day 336 will be performed. If a subject refuse to attend a visit, the investigator 
should make every effort to obtain the information over the telephone from the subject 
regarding safety.  
3.5 Study participants 
The target population is adult subjects suffering from HIO. Subjects will mainly be recruited 
from local population around the site. This study will be conducted at one investigational site 
in Denmark. Subjects who fulfill all of the following inclusion criteria and none of the exclusion 
criteria are eligible to enter the baseline phase of the study. 


 
 
 
 
 
Saniona A/S 
Clinical Study Protocol 
TM005 
CONFIDENTIAL 
 
Final Version 5.0 
Page 37 of 85 
10 December2019 
 
 
3.6 Inclusion criteria 
1. Informed consent obtained before any trial-related activities 
2. Males and females, aged 18-75 
3. Confirmed diagnosis of HIO 
4. BMI ≥27 kg/m2 (where overweight is related to the HIO) 
5. Well managed and stable substitution of hypopituitarism >2 months as judged by 
the investigator 
6. Normal BP or well managed hypertension (only if dose of BP medication(s) has 
been stable for >2 months) 
7. Type 2 diabetes is allowed, but the following criteria must be met: 
 Hemoglobin A1c (HbA1c) <86 mmol/mol 
 Subjects taking GLP-1 analogues must have been on stable dose for >3 
months 
 FPG <11.0 mmol/l measured on site 
3.7 Exclusion criteria 
1. BP ≥160/90 mmHg 
2. HR ≥ 90, <50 bpm 
3. Hypersensitivity to tesofensine/metoprolol or any component of the products 
4. Type 1 diabetes, Cushings disease, acromegaly, hypophysitis, infiltrative diseases 
or PWS 
5. Heart failure New York Heart Association (NYHA) level II or greater, 
decompensated heart failure 
6. Previous myocardial infarction or stroke within the last 5 years 
7. Diagnosis of schizophrenia, bipolar disorder, personality disorder or other DSM-III 
disorders, or any other psychiatric condition, which in the investigator’s opinion will 
interfere significantly with study compliance 
8. Physical impairment, which in the investigator’s opinion will interfere significantly 
with study compliance 
9. Any clinically significant cardiac arrhythmia 
10. Treatment with calcium channel blockers and beta blockers 
11. Concomitant use of monoaminooxidase inhibitors 
12. Use of recreational medication 
13. Bulimia or anorexia nervosa 
14. Any agent used for weight loss in the past 3 months, except GLP-1 compounds 
15. Untreated hypo- or hyperthyroidism 
16. Clinically significant liver (>3x ULN) and/or kidney impairment 
17. More than 5% weight loss within the last 3 months 
18. Subject is pregnant or lactating or intends to become pregnant or is of childbearing 
potential and not using an adequate contraceptive method (Spiral or hormonal 
contraception, birth control pills, implant, transdermal patch, vaginal ring or depot 
injection) 
19. Male subjects not agreeing to use a condom without spermicide or oil-containing 
products (e.g., lubricants) during sexual activity with female partners of 
childbearing potential throughout the trial until at least 8 weeks after the last 
administration of IMP 
20. Any contraindication for metoprolol according to the SmPC, e.g. severe peripheral 
arterial 
disease, 
untreated 
pheochromocytoma, 
concomitant 
intravenous 
administration of calcium antagonists of verapamil and diltiazem, due to the risk of 


 
 
 
 
 
Saniona A/S 
Clinical Study Protocol 
TM005 
CONFIDENTIAL 
 
Final Version 5.0 
Page 38 of 85 
10 December2019 
 
 
hypotension, AV conduction disturbances, or left ventricular insufficiency 
21. Subject has lactose intolerance or a rare hereditary problem of fructose intolerance, 
glucose galactose malabsorption or sucrase isomaltase insufficiency 
22. Subject is unable to understand and communicate in Danish language or to 
understand the protocol requirements, instructions and study-related restrictions, the 
nature, scope and possible consequences of the clinical study or is unlikely to 
comply with the study requirements; e.g., uncooperative attitude and improbability 
of completing the clinical study 
23. PHQ-9 (Patient Health Questionnaire):   
a. If a score of at least 5 in question 1 and 2 coming from the area of “More 
than half the days” or Nearly every day” 
or  
b. PHQ-9 score ≥ 10 when counts from questions 3-5 have been subtracted  
or  
c. If a tic in question 6 in “More than half the days” or “Nearly every day” 
or 
d. Any score > 0 on question 9 at screening and baseline 
24. Any suicidal behaviour within the past 30 days since screening 
25. Subject has been enrolled in another clinical study within the past three months 
26. Any other clinically meaningful condition, which in the opinion of the investigator, 
would make participation potentially unsafe 
3.8 Screening failures 
If a subject fails during the screening phase, before randomization, (e.g. due to the subject’s 
decision, etc.) his/her relevant data will be listed in the screening log and filed in the study 
documents. Date of informed consent, reason for screen failure and any AE’s before 
randomization will be entered in the eCRF.  
3.9 Premature discontinuation of study medication 
A subject may discontinue study medication for several different reasons and after different 
treatment durations.  
The subject may also wish to discontinue study medication, irrespective meeting any criteria. 
In the event of an early termination of study medication, all procedures described for a subject 
completing the study at visit 8 or visit 14 should be performed.  
Subjects discontinuing due to AEs will be followed-up until complete resolution of the AE or 
until there is a satisfactory explanation of the changes observed. 
Subjects discontinuing study medication for any reason will be offered to continue in the trial 
to receive the life style counseling and have the planned study assessments performed.  
Subjects should stay in the trial regardless of adherence to randomized treatment, visit schedule 
or missing assessments. Efforts must be made so that subjects attend and complete all scheduled 
visit procedures.  
Only subjects who decline any further contact with the site in relation to the trial or withdraw 
consent are considered as withdrawn from the trial.  
3.10 Discontinuation 
The subject may be prematurely discontinued from trial product at the discretion of the 
investigator due to a safety concern. 
If a subject meets a discontinuation criterion, the study medication must be immediately 
discontinued and the date should be noted in the medical records and eCRF. 


 
 
 
 
 
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Discontinuation criteria 
Subjects may be discontinued from study medication if any of the following items is met and 
documented: 
 Pregnancy or not using a reliable method of birth control or breastfeeding 
 Investigator’s decision 
 Acute allergic reaction to study medication 
 PHQ-9 (Patient Health Questionnaire):   
a) If a score of at least 5 in question 1 and 2 coming from the area of “More 
than half the days” or Nearly every day” 
or  
b) PHQ-9 score ≥ 10 when counts from questions 3-5 have been subtracted  
or  
c) If a tic in question 6 in “More than haft the days” or “Nearly every day” 
or 
d) Any score > 0 on question 9 at screening and baseline 
 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 of prohibited medications during the 
study 
 Failure to comply with the study stipulations 
 Subject has alanine aminotrasferase (ALT) or aspartate aminotrasferase (AST) ≥ 3 × 
ULN (confirmed by repeat) with  
 
a) Total bilirubin ≥ 2 × ULN without simultaneous ALP ≥ 2 times the ULN 
(confirmed by repeat) 
 
or  
b) International Normal Ration (INR) (will be assessed, if the above criteria are 
reached) > 1.5 times the ULN without simultaneous ALP ≥ 2 times the ULN 
(confirmed by repeat) 
 
or 
c) The appearance or worsening of symptoms potentially related to hepatic 
inflammation, e.g., fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash or eosinophilia in two consecutive measurements 
within 24 hours 
 Subject shows dopaminergic side effects such as agitation, hallucinations, psychoses 
including delusion, paranoid ideation and depression of moderate to severe intensity, 
jeopardizing subject safety and requiring medical intervention and supervision 
3.11 Withdrawal 
The subject may withdraw consent at will at any time. The subject’s request to withdraw from 
the trial must always be respected. Reason for withdrawal will be documented in the subject’s 
source documents and the eCRF.  
 
The end of study form in the eCRF must be completed, and final drug accountability must be 
performed even if the subject is not able to come to the trial site. The case book must be signed. 
Although a subject is not obliged to give his/her reason(s) for withdrawing consent, the 
investigator must make a reasonable effort to ascertain the reason(s), while fully respecting the 
subject’s rights. 


 
 
 
 
 
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Where the reasons are obtained, the primary reason for withdrawing consent must be specified 
in the eCRF. 
 
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 case report form (CRF). 
3.12 Replacement of withdrawn subjects 
Enrolment will continue until a minimum of 12 and a maximum of 25 adult subjects are 
randomized. Subjects excluded during the screening period (Day -21 to -7) may be considered 
for another selection visit at a later date but will need to undergo complete rescreening, except 
if the reason is a FPG > 11.0 mmol/l.  
 
Randomized subjects who withdraw or are withdrawn from the study for any reason will not be 
replaced.  
3.13 Lost to follow-up 
If a subject loses contact with the study staff or does not come for the visits, attempts must be 
made to locate the subject and obtain relevant safety information. A subject cannot be deemed 
lost to follow-up until at least substantial contacts with family/relatives/family physician have 
been attempted. Subject information may be retrieved from other health care professionals, 
medical records or publicly available records. A subject will only be considered lost to follow-
up in case vital status cannot be determined at the time of day 336 for that subject. 
 
3.14 Premature study discontinuation 
The sponsor has the right to terminate this study at any time. If the sponsor, the investigators, 
or the CA 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. The following event shall result in an immediate stop to dosing of all subjects and 
a re-evaluation of the risk-benefit profile: 
 
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 
3.15 Study site 
The study will be conducted at one site in Denmark  
 
3.16 Study duration 
The projected start date for the inclusion of study subjects is:  
 Q1 2019 – Q2 2020 – the double-blind part 


 
 
 
 
 
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 Q3 2019 – Q1 2021 – the open-label extension part 
The individual study duration for one subject is up to 357 days including screening period (21 
days), baseline, together with the blinded treatment part 1 and the open-label treatment part 2 
(336 days). The projected duration of the study is ~12-18 months. The end of study is defined 
by the Last Visit of the Last Subject for TM005. 
 


 
 
 
 
 
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3.17 Benefits and risks for study participants 
It is expected that the combination of tesofensine and metoprolol will be well tolerated. This 
assessment is based on a large body of experiences from previous pre-clinical and clinical 
studies of tesofensine and metoprolol. The study design itself does not increase the risk for the 
subjects since 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 both at home and during 
repeated visits at the site. 
 
Tesofensine  
The majority of treatment related AEs seen in the clinical studies with tesofensine were dry 
mouth, headache, nausea, insomnia, diarrhoea and constipation side effects. A dose-dependent 
pattern was observed for dry mouth and insomnia. The overall withdrawal rate due to AEs in 
clinical studies in the obese population was 13% with tesofensine and 6% with placebo. BP and 
HR increased with the therapeutically relevant doses of tesofensine (0.25 mg and 0.5 mg) were 
1–3 mmHg and up to 8 bpm, respectively.  
 
Metoprolol adverse reactions – post marketing experience  
 
Please see the SmPC of metoprolol succinate “Orion” 50 mg retard (30). 
 
It is anticipated that subject receiving the study medication will experience a reduction in their 
body weight and appetite and improvement in their glycaemic control and/or other clinical 
parameters, beyond what can be achieved by receiving regular dietary and physical activity 
counseling during the study. That could require change in concomitant medication.  


 
 
 
 
 
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4 TREATMENT OF STUDY PARTICIPANTS 
4.1 Description of study medication 
IMP 
Tesofensine is a serotonin-noradrenaline-dopamine re-uptake 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.  
 
Metoprolol is a beta1-selective (cardioselective) adrenoceptor blocking agent, for oral 
administration. It has been formulated into ER tablets to provide a controlled and predictable 
release of metoprolol for once daily administration 
  
For the DB part (part 1), the IMP consists of one carton for each visit containing one bottle of 
tesofensine 0.5 mg and one bottle of metoprolol 50 mg, both formulated for oral use once a day. 
For the open-label extension part (part 2), the IMP consists of one carton for each visit 
containing one bottle of tesofensine 0.5 mg and four blister sheets of 10 tablets of metoprolol 
50 mg each. 
 
Placebo 
The placebo formulation is similar in presentation and appearance to the tesofensine and 
metoprolol tablets but includes only the excipients; it does not contain any active ingredients.  
4.2 Identity of investigational products 
 
Drug Name 
Formulation 
Strength 
Route 
Manufacturer 
Tesofensine 
Film-coated 
tablet 
0.50 mg tesofensine 
Oral 
Delpharm 
Tesofensine placebo  
Film-coated 
tablet 
Not applicable 
Oral 
Delpharm 
Metoprololsuccinat 
”Orion”, depottabletter1 
ER tablet 
50 mg metoprolol 
Oral 
Orion Corporation 
(Finland) 
Metoprolol placebo  
Film-coated 
tablet 
Not applicable 
Oral 
Solural Pharma ApS 
(Denmark) 
ER = extended release 
1 
contains 47.5 mg metoprolol succinate corresponding to 50 mg metoprolol tartrate 
4.3 Supply, packaging, labelling and storage 
IMPs will be supplied by a third party (KLIFO A/S, Smedeland 36, Glostrup, 2600, Denmark) 
contracted by Saniona A/S.  Tesofensine, metoprolol and placebo tablets will be packaged, 
labelled and Qualified Person (QP)-certified according to applicable local and regulatory 
requirements by KLIFO A/S. All supplies of IMPs must be stored in accordance with the 
manufacturer’s instructions.  The IMPs will be stored at the study site in a securely locked area, 
with the temperature monitored, accessible to authorized persons only, until needed for dosing. 
Tesofensine for home-dosing days will be dispensed to the subjects in appropriately labelled 
containers together with instructions of use. 
 


 
 
 
 
 
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4.4 Procedures to assure double blinding 
Part 1 - It is DB, placebo-controlled study, i.e. investigators, site staff and subjects will be 
blinded as to whether they will be allocated to active or placebo treatment. This will be achieved 
by the following procedures: 
 The IMP will look similar to placebo with regard to size, colour and general appearance 
 The labelling of the IMP will identify the study and the investigational product but will 
not indicate the contents. When a patient is ready for randomization, the investigator 
pick the lowest available randomization number from one of two lists; one list for 
patients with Drug Metabolism (DM) and one list for patients without DM  
4.5 IMP handling procedures at the site 
The designated site personnel at the investigational site are responsible for storage of received 
study medication, dispensing and record keeping of the IMP including:  
 Acknowledgment of receipt of the original bottles/ boxes of IMP by signing the receipt 
forms  
 Storing the IMP on site in a secured area with restricted access as instructed on the study 
kits labels 
 Dispensing IMP according to the protocol 
 
An IMP kit will be provided for each patient with a randomization number and enough 
medication for the initial 24 weeks (+ extra). The patient should be supplied form this kit during 
participation in the 24 weeks DB treatment. 
 
Another IMP kit will be provided for each patient with a randomization number and enough 
medication for the open labelled 24 weeks (+ extra) extension period (part 2). The patient should 
be supplied form this kit during participation in the 24 weeks open labelled extension part.  
 
The investigator and designated site personnel are responsible for study medication kits 
accountability. The investigator and designated site personnel are 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 labelling, 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 IMP made by the study subjects. In the event 
of a batch recall, the sponsor or its representative will inform the investigator or designated site 
personnel in writing. Upon receipt, and as instructed, the investigator or designated site 
personnel should immediately contact any study subject in possession of the corresponding 
study medication kits.  
4.6 Labels for study medication 
The label texts will be translated or adjusted as necessary so that they comply with Annex 13, 
Danish laws and regulatory requirements and trial requirements. 
 
 
 


 
 
 
 
 
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4.7 Packaging and destruction 
Medication will be distributed to the subjects in plastic bottles labelled with the appropriate 
randomization number for the DB part (part 1) and study medication number for the open-label 
part. Bottles for the respective IMPs will be identical in colour, size and shape to preserve the 
blinding of the study during part 1. Unused study medication will be collected by the 
investigator and designated site personnel. KLIFO is responsible for central destruction of all 
study medication (partially used and unused). 
4.8 Handling of the study medication 
Study medication will be distributed to the subjects during the visits 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 
12, 13, 14 at the site. First administration will be done on Day 1, at the site. Subjects will be 
asked to use study medication every morning, preferably with the breakfast, and not to crush or 
chew the tablets. Subject will be asked to store the medication at room temperature (15 - 25 °C) 
and protected from light and return the unused study medication on each in-person (IP) visit at 
the site. 
4.9 Supply and storage of the study medication 
Study medication supplies  
Tesofensine, tesofensine placebo and metoprolol placebo will be supplied by the sponsor. 
Commercially available metoprolol 50 mg retard will be purchased directly by KLIFO. IMP 
will be shipped to the site under temperature control and monitoring. The receiving site has to 
confirm the receipt and the condition of the delivery in writing on provided forms. The 
temperature-monitoring device will indicate if the specified shipment conditions were not 
maintained during the transport than the IMP must be quarantined such that it cannot be used 
unintentionally and the sponsor must be contacted immediately. Upon receipt IMP will be 
stored at room temperature (15 - 25 °C) and protected from light in a place with restricted and 
controlled access.  
 
Prior to the initial shipment of the study medication to the site, the following essential 
documents must be available:  
 IEC and CA approval 
 IEC and CA approved subject information/informed consent form (ICF) 
 Clinical Study Protocol signed by the principal investigator (PI) 
 Study agreement/contract signed by the PI 
4.10 Study medication compliance 
The IMPs will be self-administered by the subjects at home. Subjects with compliance for the 
entire study below 80% for any of the study medication (determined by calculating returned 
bottles and count of returned tablets) will be considered protocol violators and will not be 
included in the per protocol analysis. For the monitoring of study medication, subjects will be 
instructed to return all bottles with study medication at each visit, whether full, partially empty, 
or empty. 
 
In case a subject, in the opinion of the investigator, experiences an AE that by the investigator 
is suspected to be potentially related to an undesirable drug concentration of the IMP, the period 
between dosages can be extended or a drug holiday can be implemented in order to optimally 
manage the well-being and safety of the subject. Each of these cases should if possible be 
discussed in advance with the sponsor’s medical expert.  
 


 
 
 
 
 
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4.11 Screening and randomization 
Subjects who sign the informed consent will be identified at the screening visit by a unique 
screening number consisting of a two (2) digit unit number and three (3) digit subject number. 
The screening number together with the study number uniquely identifies every subject eligible 
for the study. Subject numbers will be assigned sequentially in ascending order per unit starting 
with running number 001, 002, 003, etc. 
 
Screening 
number 
Study Number 
Study Unit Number 
Subject Number 
Example:
TM005 
01 
001 
Randomization of eligible subjects to one of the study medication groups will be done at 
baseline visit Day 1, following successful completion of all baseline assessments, using a study 
medication number defined by the center-specific assignment list.  
Subjects will be randomly allocated to either study medication group in a 2:1 randomization by 
selecting the lowest available randomization number at the time of randomization. The 
randomization codes will be generated within the Biometrics Department of the sponsor’s 
Contract Research Organization (CRO) by a statistician and IMP kits for patients will be 
packaged according to this list. The randomization codes and the complete generation procedure 
will be filed at a secure place by sponsor’s CRO statistician until the study database is closed. 
The only person on site with access to the code break sealed envelopes will be the principle 
investigator. The study medication number consists of four digits. In part 1, all kits assigned to 
a subject will have the same randomization number. In part 2, kits assigned to a subject will 
have different study medication numbers between visits. This procedure will be checked by the 
monitor. 
4.12 Un-blinding 
The part 1 of the study will be DB. Neither the investigators nor the subjects will be informed 
about the type of subject´s medication. In general, emergency un-blinding 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. If possible, 
the justification for the un-blinding should be discussed with the sponsor prior to un-blinding 
to ensure that un-blinding is truly necessary and that appropriate steps for subject’s welfare and 
management are being taken.  
When un-blinding for the purpose of expedited safety reporting is required by the CA, this will 
be performed by KLIFO Pharmacovigilance.  
Emergency un-blinding: 
Emergency un-blinding can be performed using sealed envelopes. The randomization code may 
only be un-blinded in case of an emergency situation as described above. Whenever a code is 
broken, the person breaking the code must sign and date the code envelope. The reason for 
breaking the code must be documented in the subject’s medical record. The investigator must 
immediately inform the sponsor about any un-blinding. The information will be forwarded to 
the CA and IEC, if necessary, and the principal PI and the sponsor must decide if the study will 
be continued/discontinued for the remaining subjects. The investigator will forward the 
randomization numbers of un-blinded subjects to the biometrician as soon as un-blinding takes 
place. 


 
 
 
 
 
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Routine un-blinding: 
After terminating the study, establishing the statistical analysis plan (SAP), locking the clinical 
data base and the data clearing/blind review procedure are finished, a formal Blind Review 
Report will be presented to the sponsor. After final acceptance of this report, the sponsor will 
authorize the biometrician to perform study un-blinding. Formal records will be kept on 
measures and dates of each step. 
4.13 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, including empty bottles will be 
accounted for and returned to the investigator and destroyed by the KLIFO. 
4.14 Accountability of the study medication 
The investigators will make every effort to encourage subjects 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 on site. The delivery to, use 
by and return from the subject must be documented. All opened and unopened bottles, together 
with remaining contents, will be returned by the subject 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 that is missing. It is the investigator’s responsibility to instruct the subjects about 
using and returning of study medication. 
4.15 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 CRF indicating the: 
 Trade name of medication 
 Start date 
 End date / on-going 
 Route of administration 
 Total daily dose and units, and 
 Reason for administration 
 
Any medicinal product, prescribed or over the counter (OTC), including herbal and other 
nontraditional remedies, is considered a concomitant medication.  Prior and concomitant 
medication use will be recorded for the 30 days prior to screening until Day 336.  Prior and 
concomitant medication use is not permitted from 2 weeks before admission until discharge 
(occasional use of paracetamol up to 2 g/day or other Non-Steroide Anti-Inflammatoriske 
Drugs (NSAIDs) and hormonal contraception is permitted). However, concomitant medication 
use may be warranted for the treatment of AEs, a list of prohibited medication is provided in 
Appendix 8.7, with emergencies being the exemption. 


 
 
 
 
 
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4.16 Prohibited medication 
Please refer to Exclusion Criteria and to Appendix 8.7 
5 STUDY PROCEDURES  
5.1 Site procedures 
Informed consent  
The subject will receive an original of the written subject information containing a complete 
and comprehensive explanation of the significance, nature, extent and possible risks of the 
study, duties concerning insurance and the statement that the subject is free to withdraw from 
the study at any time without any negative consequences. In addition, the investigator will 
carry out an oral information session during which the subjects will be given sufficient time 
and opportunity to clarify remaining questions. After this, one original forms for written 
informed consent will be given to the subjects for signature. One copy is to be kept by the 
subject and one is to be filled in the investigator's Study File. The investigator will confirm 
that each individual subject has received an explanation in accordance with the study protocol 
and has signed the appropriate consent form. 
 
Demography will be recorded at screening and consists of: 
 Date of birth  
 Sex 
 Race 
 
Medical history  
Medical history is a medical event that the subject has experienced in the past. Only relevant 
and significant medical history as judged by the investigator should be recorded. Findings of 
specific medical history described below should be entered on the specific forms. 
 
ECG 
An ECG will be performed at the visits specified in the FC. 
The investigator or delegate must sign, date and interpret the ECG by using the following 
categories: 
 Normal 
 Abnormal: Diagnose and statement of whether the result is clinically significant? 
(Yes/No) 
Clinically significant is an abnormality that suggests a disease and/or organ toxicity and is of a 
severity that requires active management. Active management includes active treatment or 
further investigations, for example, change of medicine dose or more frequent follow-up due to 
the abnormality. If the result is clinically significant, the investigator must report such an 
abnormal finding as an AE or SAE. 
 
ECG performed at screening will be considered as baseline. 
 
Concomitant illness  
A concomitant illness is any illness that is present at the start of the trial (i.e., at the screening 
visit) or found as a result of a screening procedure or other trial procedures performed before 
exposure to trial product. 
Any change to a concomitant illness should be recorded during the trial. Any clinically 
significant worsening of a concomitant illness must be reported as an AE. 


 
 
 
 
 
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Concomitant medication 
A concomitant medication is any medication, other than the trial product, which is taken during 
the trial, including the screening and follow-up periods. Details of any concomitant medication 
must be recorded at visit 1. Changes in concomitant medication must be recorded at each visit 
as they occur. The investigator must assess the concomitant medication at every visit for any 
changes. 
The information collected for each concomitant medication includes trade name or generic 
name, indication, start date and stop date or continuation. 
If a change in concomitant medication is due to an AE, then this must be reported according to 
Section 6.2 .  
 
Vital signs 
Vital signs include body temperature, pulse rate and BP.  
 
BP 
For BP, measurement with a precision of minimum 2 mmHg must be performed. The value 
must be used to evaluate eligibility of the subject in relation to exclusion criterion no 1. This 
means, that if the BP value obtained at visit 1 and/or visit 2 exceed BP>160/90 mmHg, the 
mean value from the 24H BP measurements between visit 1 and 2 can be used to evaluate 
eligibility of the subject in relation to exclusion criterion no 1. The method for measuring 
systolic and diastolic BP needs to follow the standard clinical practice at site, but as a minimum, 
the following guideline must be adhered to: 
Avoid caffeine, smoking and exercise at least 30 minutes prior to measuring the BP. BP should 
be measured in a sitting position, with the legs uncrossed, the back and arms supported. The 
subject should be sitting for five minutes before the measurement is taken. The same arm and 
an appropriate cuff size should be used for BP measurements at all visits. 
Subjects who during the study exceed predefined values BP>160/100 mmHg will be treated at 
the discretion of the investigator per established guidelines to improve the subjects BP control 
while remaining in the study. 
 
Physical examination 
Physical examination will be performed at the visits specified in the FC. Physical examination 
should include heart, lung, head and neck exam, and abdominal, neurological and 
dermatological exam, and must be recorded in the subject’s medical record and eCRF. Any 
abnormal, clinically significant findings at screening (visit 1) must be recorded as a concomitant 
illness. 
 
Body weight  
The body weight should be measured at all site visits without shoes, on an empty bladder and 
only wearing light clothing. It should be measured on a digital scale to the nearest 0.1 kg using 
the same scale throughout the trial. The scale must be calibrated yearly as a minimum. 
BMI will be calculated according to below equation with weight assessment from visit 1 data 
and must be in accordance with inclusion criterion 2.  
BMI will be calculated as follows: 
BMI = weight (kg)/height2 (m2)  
Height is measured at screening without shoes to the nearest cm with one decimal. 
 
Waist circumference  


 
 
 
 
 
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Will be measured at the specified visits (see FC) and is defined as the abdominal circumference 
located midway between the lower rib margin and the iliac crest. Waist circumference is 
measured in the horizontal plane and rounded to the nearest cm using a non-stretchable 
measuring tape. The same measuring tape should be used throughout the trial. The subject 
should be measured in a standing position and wearing light clothing. The subject should be 
standing, feet together with arms at the side and waist accessible. The tape should touch the 
skin but not compress soft tissue and twists in the tape should be avoided. The subject should 
be asked to breathe normally. 
 
Pregnancy test 
Female subjects of childbearing potential must be instructed to use adequate contraceptive 
methods (please see below) throughout the trial and until 8 weeks after end of treatment. 
Blood pregnancy test will be done for any woman of childbearing potential at the site at every 
visit. 
Further, urine stick pregnancy tests will be performed before every DXA scan, if applicable by 
local procedures.  
 
Contraception requirements 
Subjects should be informed of the potential risks associated with becoming pregnant or 
fathering a child while enrolled in the trial.  
 
Female subjects: 
Women of childbearing potential must be using highly effective methods of birth control 
(Spiral or hormonal contraception, birth control pills, implant, transdermal patch, vaginal 
ring or depot injection). 
The subjects should be using the same method for 3 months prior to screening and continued 
until at least 8 weeks after the last administration of IMP.  
 
Female subjects are considered to be of non-childbearing potential, when they are either: 
 surgically sterile (hysterectomy and/or bilateral oophorectomy and/or bilateral 
salpingectomy and/or bilateral tubal ligation), or  
 post-menopausal, i.e., 12 months of amenorrhea with an appropriate clinical profile 
(e.g., age appropriate, history of vasomotor symptoms) or for women < 60 years the 
follicle-stimulating hormone (FSH) level is > 40 mIU/ml.  
 
Male subjects: 
Male subjects must use a condom without spermicide or oil-containing products (e.g., 
lubricants) during sexual activity with female partners of childbearing potential throughout the 
trial until at least 8 weeks after the last administration of IMP.  Female sexual partners of male 
subjects should be willing to avoid pregnancy according to the above-described methods. 
 
DEXA for determination of body composition 
Fat mass of abdomen and liver will be determined non-invasively using DEXA. The DEXA 
machine will be operated according to local specifications.  
 
Diabetic history and diabetes complications: 
For T2DM subjects the following information must be collected regarding their diabetes history 
and related complications.  
 History of hypoglycemic events: 


 
 
 
 
 
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o Awareness hypoglycaemia (yes / no) 
o Type (minor/major/nocturnal) 
o Frequency 
 Date of diagnosis of T2DM 
 Information regarding diabetes complications including date of onset in case of: 
o Diabetic retinopathy 
o Diabetic neuropathy 
o Diabetic nephropathy 
o Macroangiopathy (including peripheral vascular disease) 
Diabetes history and diabetes complications, must be recorded on the designated form in the 
eCRF. 
 
HbA1C 
Blood samples will be drawn at the specified visits (see flowchart) for measurement of HbA1c. 
Subjects who during the study exceed predefined values of HbA1c (>10%) and FPG >11.0 
mmol/l) will be treated at the discretion of the investigator per established guidelines to improve 
the subjects glycaemic control while remaining in the study. 
 
Fasting plasma glucose 
FPG is measured at specified visits (see flowchart) in order to evaluate metabolic control. The 
subject must attend these visits fasting.  
FPG measured at visit 2 will be considered as baseline. 
 
Fasting requirements 
The subjects should be fasting when attending some visits, please see FC. 
Fasting is defined as at least 8 hours without food and drink intake, except water and other 
prescribed medication. Trial product and other glucose lowering agents should be withheld on 
the day of the visit until blood sampling has been performed. If the subject attends a fasting 
visit in a non-fasting state, the blood sampling should be re-scheduled within the visit window. 
 
Study questionnaires and VAS scales: 
Study questionnaires are used to collect clinical data for all subjects enrolled in the study at the 
visits specified in the FC. The questionnaires are linguistically validated to fluent language of 
all subjects participating. The VAS scales are psychometric measuring instruments designed to 
document the characteristics of disease-related symptom. The questionnaires and VAS scales 
must be completed by the subject and should preferably be completed after conclusion of all 
fasting-related activities, but before any other visit-related activities. Subjects should be given 
the opportunity to complete the questionnaires by themselves without interruption.  
 
Questionnaires and VAS scales used in the study: 
 The CSS = (satiety + fullness + (100−prospective food intake) + (100−hunger))/4. VAS 
scales (satiety, fullness, prospective food intake and hunger) are used to examine the 
effects on satiety and appetite 
 VAS scales measurements of craving on something sweet, salty, savory and fatty ( mean 
of the four) to examine the effects on craving 
 VAS scale to examine the effects on thirst 
 SF-36: To examine the effects on quality of life  
 PHQ-9 (Patient Health Questionnaire) score to assess development of depression. 
 


 
 
 
 
 
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Short Form 36 v2.0 acute 
Short Form 36 v2.0 acute (SF-36) is a 36-item, patient-reported survey of patient health. SF-36 
measures the subject’s overall HRQoL (health related quality of life) on eight domains: physical 
functioning, role functioning, bodily pain, general health, vitality, social functioning, role 
emotional and mental health. 
 
PHQ-9: 
The PHQ-9 is a multipurpose instrument for screening, diagnosing, monitoring and measuring 
the severity of depression.  
 The PHQ-9 incorporates DSM-IV depression diagnostic criteria with other leading 
major depressive symptoms into a brief self-report tool. 
 The tool rates the frequency of the symptoms which factors into the scoring severity 
index. 
 Question 9 on the PHQ-9 screens for the presence and duration of suicide ideation. 
 A follow-up, non-scored question on the PHQ-9 screens and assigns weight to the 
degree to which depressive problems have affected the patient’s level of function.  
In addition, great care will be exerted during the course of obtaining medical history, 
particularly focusing on psychiatric diseases and should any signs of on-going depression be 
found, these subjects will not be included into the study, as in accordance with exclusion criteria 
7 and 23. 
 
Home monitoring of 24H BP/48H HR 
Home monitoring of 24H BP/48H HR will be done between screening and baseline, and at Day 
84 (± 36) and at Day 168 (÷36/+3). 
 
Subjects will be instructed in having home 24H BP monitoring done, the devices will be put on 
at the Medical Endocrinology Department, RH, and a written instruction will be handed out. 
 
The result of 24H BP home monitoring will be evaluated by the investigators at the Medical 
Endocrinology Department, RH. 
 
The device for 48H HR home monitoring will be put on at the Cardiology department B, RH, 
instruction will be provided and a written instruction handed out. 
 
The result of the 48H home monitoring will be evaluated by a cardiologist from Cardiology 
department B, RH, and the result provided as in a PDF document. 
 
Data from the 24H BP/48H HR home monitoring will be evaluated blinded before database 
release (DBR) and be kept blinded until after DBR. 
 
Lifestyle counseling 
All subjects will receive a written guide in diet modification, physical activity and behavioural 
modifications, but also a verbal guidance in connection to the visit by a qualified dietician. For 
further instructions, please refer to Appendix 8.8. 
 
Diet modifications  
Subjects will receive guidance to follow an energy reduced and moderate low fat diet. The goal 
is a macronutrient distribution in the diet of app 30% energy from fat, app 20% energy from 
protein and app 50% energy from carbohydrates.  


 
 
 
 
 
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An energy restriction of app -300 kcal/day =4,2 kilojoule (KJ) will be based on a calculation of 
body composition and hereafter be multiplied by 1.3-1.5 PAL (Physical Activity Level) 
dependent of the subject’s physical activity level)  
 
Physical activity: 
All subjects will receive guidance in physical activity. The subject will be guided to 30 min 
physical activity pr day.  
 
Behavioural modification: 
Subjects will receive guidance in behavioural modifications including techniques for sticking 
to their life style change. 
5.2 Laboratory evaluations 
Laboratory samples will be collected from subjects at the site, and will be shipped to the Klinisk 
Biokemisk department at RH for analysis in ambient conditions, except samples for PK, future 
tests and back-up.  
The investigator will receive the data from laboratory safety analyzes from Klinisk Biokemisk 
department at RH and will review, evaluate, sign and date the laboratory report and enter the 
data into the eCRFs. 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. 
The investigator´s evaluation will be entered in the eCRF and will be part of the laboratory 
results transferred to the sponsor. If a laboratory result is considered clinically significant and 
it fulfils the criteria for a clinical laboratory AE, it should be reported in accordance with section 
6.2. Clinically significant laboratory findings from the screening visit should be recorded as 
concomitant illness. 
The laboratory equipment may provide analyzes not requested in the protocol but produced 
automatically in connection with the requested analyzes 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 (except for samples for future tests and back-up samples) 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 Klinisk Biokemisk department at RH. 
 Blood chemistry: creatinine, electrolyte, gamma glutamyl transferase, aspartate 
aminotransferase, ALT, alkaline phosphatase, GFR and urea will be analyzed by Klinisk 
Biokemisk department at RH. 
 Infectious serology: Hepatitis B surface antigen, Hepatitis C antibodies, HIV-1/2 
combi will be analyzed by Klinisk Biokemisk department at RH. 
 HbA1c will be analyzed by Klinisk Biokemisk department at RH. 
 Lipids (total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density 
lipoprotein (LDL) cholesterol, triglycerides), will be analyzed by Klinisk Biokemisk 
department at RH. 
 FPG test before taking the BG test, subject will not be allowed to eat anything for at 
least eight hours. FPG will be measured on site to ensure eligibility for the study. The 
FPG measured by Klinisk Biokemisk department at RH will be the baseline value. 
 Endocrine examination: IGF-1, TSH, free T4, prolactin, LH, FSH, testosterone (men), 


 
 
 
 
 
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oestradiol (women) will be analyzed by Klinisk Biokemisk department at RH. 
 Blood samples for future tests: free fatty acid (FFA), Ghrelin, GLP-1, GIP, 
adiponectin, leptin. The evaluation will be done by investigator selected external 
laboratory. The samples will be stored in a coded research biobank in Endokrinologisk 
laboratory at RH until analysis.  
 Blood samples for back-up: Samples are collected to ensure back-up material for” 
future tests”, or to evaluate new ideas in a later research project.  Research of new ideas 
will have to await accept from the IEC of a new research project and permission from 
the individual subjects. The samples will be stored in a coded research biobank in 
Endokrinologisk laboratory at RH until analysis. 
 PK Sampling will be evaluated for presence/absence of tesofensine/metoprolol and N-
desmethyl-metabolite (NS2360). The evaluation will be done by sponsor selected 
external laboratory Covance. The samples should be stored at site until further 
instructions are provided by sponsor.  
5.3 Total amount of blood 
Each subject will have less than 400 ml of blood collected over the course of the entire study 
(from Screening to End of Study, but not including repeat or additional tests ordered by the 
investigator), which presents no undue risk to the subjects. 
 
Approximate total amount of blood for each subject 
Assessment 
Sample Volume 
(ml) 
Number of Samples 
Total Blood Volume 
(ml) 
Pharmacokinetics (tesofensine, N-
desmethyl-metabolite (NS2360) 
metoprolol)  
7.5 
5 
37.5 
Lipids   
4.0 
5 
 24 
Hematology and infectious 
serology1 
  
5 
0 
HbA1c 
3.0 
5 
15 
FPG 
2.0 
13 
  
Blood chemistry and blood 
pregnancy test 
3 
14 
42 
Endocrine examination 
12.0 
5 
60 
TSH and free T41 
0 
8 
0 
Blood samples for future tests 
17.0 
5 
85 
Blood samples for back-up 
24.0 
5 
120 
Total Blood Volume2 per Subject in entire study 
 383.5 ml 
1 Infectious serology and pregnancy test will be performed on the sample collected for hematology and clinical 
chemistry, as applicable.   
2 Excluding repeat laboratory investigations. 
5.4 Home measurements by subjects 
Subjects will be asked to perform several procedures at home and will be asked to record the 
following in the diary: 
 BP and HR 


 
 
 
 
 
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 Subjects will carry devices for Home monitoring of 24H BP/48H HR between screening 
and baseline, and at Day 84 (± 36) and at Day 168 (÷36/+3) 
 Date and time for taking study medication the day before a visit where PK samples are 
taken 
T2DM subjects will be requested to further record the following; 
 8-point BG profile 
 Hypoglycemic events 
 
The subjects should be clearly instructed in the procedures and this should be documented in 
the subject’s medical records.  
 
BP and HR 
Subject will receive a BP meter for measuring BP and HR at home. Subjects will be instructed 
to measure their BP and HR two times a day, before breakfast and before dinner (three 
measurements each time point), ones weekly during the whole study. The subject must note 
down the three values for each measurement for respectively BP and HR. The subjects will be 
instructed in how to use the device and the instruction should be repeated at regular intervals as 
needed and documented in the medical record. Subjects should also be instructed in how to 
record the results of the BP and HR measurements correctly in the diaries. Data must be 
transcribed into the eCRF during or following the site visit.  
 
The subject must be instructed to follow below procedure: 
 Subject should avoid food immediately before the measurement. Subject should go to 
the toilet before BP measurement. A full bladder can increase BP 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 BP and pulse, 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 BP. 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 appropriately sized cuff 
should be always used! 
 Three measurements should be performed 
 The subject must note down the three measurements in the diary 
 
Date and time for taking study medication before a visit 
The day before a visit, the subject must note down in the diary, the date and time for taking 
study medication. This must be entered into the eCRF during or following the visit. 
 
8-point BG measurement 
T2DM subjects will be provided with a BG meter including auxiliaries. The subjects will be 
instructed in how to use the device and the instruction should be repeated at regular intervals as 
needed and documented in the medical record for the subject. 
 
Subjects should be instructed in how to record the results of the 8-point BG measurements in 


 
 
 
 
 
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the diaries. The record of each BG value should include date, time and value.  
 
Subjects will be instructed to perform 8-point BG measurement once weekly.  
The BG measurement should be measured and recorded in the diary at the time points listed 
below. The record of each BG measurement must include date, actual time point and the plasma 
glucose value.  
 
Time points for 8-point BG measurement 
 Before breakfast 
 90 min after start of breakfast 
 Before lunch 
 90 minutes after start of lunch 
 Before dinner 
 90 min after start of dinner 
 At bedtime 
 Before breakfast 
 
Data must be transcribed into the eCRF during or following the site visit.  
 
Hypoglycemic events 
If the subject experiences a hypoglycemic event, the following should be recorded in the diary: 
 Date and time of hypoglycaemic episode  
 The plasma glucose level before treating the episode (if available) 
 Whether the episode was symptomatic  
 Whether the subject was able to treat him/herself  
 
This information must be entered into the eCRF during or following the visit.  
 
Home monitoring of 24H BP/48H HR 
Home monitoring of 24H BP/48H HR will be done between screening and baseline, and at Day 
84 (± 36) and at Day 168 (÷36/+3). 
 
Subjects will be instructed in having home 24H BP monitoring done, the devices will be put on 
at the Medical Endocrinology Department, RH, and a written instruction will be handed out. 
 
The device for 48H HR home monitoring will be put on at the Cardiology department B, RH, 
instruction will be provided and a written instruction handed out. 
 
 


 
 
 
 
 
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6 SAFETY REPORTING 
All AEs occurring after the randomization of the subject will be reported. The report will 
include information on onset and stop dates, nature, severity, duration, interventions and 
medications required. SUSARs will be reported to the CA and IECs according to local 
regulations, and will be followed-up until the resolution of the event.  
6.1 Definitions 
An AE is any unintended medical occurrence in a subject in a clinical study who is treated with 
a drug or medical device. This includes all unintended or unforeseeable signs and symptoms, 
including abnormal laboratory findings, diseases and psychological symptoms, including 
aggressive behaviour 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.  
6.2 Adverse event 
All AEs encountered after the randomization and first doses of IMP given (treatment emergent 
AE) will be recorded in detail indicated in the eCRF, regardless of their relationship to the 
investigational study product as assessed by the investigator. It is the responsibility of the 
investigator to document all AEs, which occur during the study. AEs will be coded by use of 
an internationally recognized dictionary. Details are described in the study specific data 
management plan (DMP). 
Intensity of AEs: 
The following three-point rating scale will be used for rating the intensity of each AE: 
 
Mild:
Awareness of signs or symptoms, no interference with daily activities
 
 
Moderate: 
Symptoms cause discomfort with some interference with daily activities 
(disturbing) 
Severe: 
The subject is unable to work or conduct usual daily activities (disabling) 
 
Causality of AEs: 
The following five-point scale will be used for rating the causal relationship of the AE to the 
investigational study product: 
 
Not related: 
The AE is clearly not related to the study treatment - i.e. another cause of the 
event is most plausible; and/or a clinically plausible temporal sequence is 
inconsistent with the onset of the event and the study treatment administration; 
and/or a causal relationship is considered biologically implausible. 
 
 
Unlikely:
In cases where sufficient information exists to establish beyond reasonable 
doubt that study treatment causality was not likely to be the cause of the event 
then such reports should be classified as unlikely related. 
 
 
Possible:
An event that follows a reasonable temporal sequence from administration of 
the study treatment follows a known or expected response pattern to the 
suspected study treatment, but that could readily have been produced by a 
number of other factors. 
 
 


 
 
 
 
 
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Probable: 
For inclusion in this category it is recommended that all the following 
minimum criteria should be complied with: 
1. There should be a reasonable association in time between the administration 
of the study treatment and onset and duration of the reported event. 
2. The description of the clinical phenomena should be consistent with, or at 
least plausible, given the known pharmacology and toxicology of the study 
treatment. 
3. There should be no other equally plausible explanation(s) of the case. In 
particular, concurrent use of other medicinal products (and possible drug 
interactions) or intercurrent disease should be taken into account in the 
assessment. 
 
 
Definitely 
related 
The AE is clearly related to the study treatment – i.e. an event that follows a 
reasonable temporal sequence from administration of the study treatment, 
follows a known or expected response pattern to the suspected treatment, that 
is confirmed by improvement on stopping and reappearance of the event on 
repeated exposure and that could not be reasonably explained by the known 
characteristics of the Subject’s clinical state. 
Outcome of AEs: 
Outcome of AE may include at time of last observation: 
Recovered / resolved 
Recovering / resolving 
Not recovered / not resolved 
Recovered / resolved with sequelae 
Fatal 
Unknown 
The outcome type and duration of the follow-up of subjects with AEs should be specified. 
 
Action Taken with the study treatment/IMP for AEs: 
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 stopped/withdrawn 
Decreased frequency of dosing (or drug holiday) 
Dose not changed 
Unknown 
Not applicable 
 


 
 
 
 
 
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6.3 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 (IB) 
for an unauthorized study treatment, or SmPC for an authorized product. 
6.4 Serious adverse event  
A SAE is any untoward medical occurrence or effect that at any dose: 
Results in death 
Life threatening 
Requires hospitalization or prolongation of existing hospitalization 
Results in persistent or significant disability/incapacity 
Or causes a congenital anomaly/birth defect 
Or is judged as medically important condition 
 
Life threatening AE  
An AE is life threatening when the subject is at immediate risk of death from the event as it 
occurred; i.e. it does not include a reaction, which if it had occurred in a more serious form 
might have caused death.  
 
Hospitalization  
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 out- 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.  
 
Disabling/incapacitating AE  
An AE is incapacitating or disabling if it results in a substantial and/or permanent disruption of 
the subject’s ability to carry out normal everyday activities. 
 
Medically important condition 
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be immediately 
life threatening or result in death or hospitalization, but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes listed in the definition above. These 
should also usually be considered serious.  
 
Any event, which resulted into a fatal outcome, must be fully documented and reported, 
including if the death occurred within four weeks after treatment end and regardless of causality 
relationship to the investigational study product. 
6.5 Suspected unexpected serious adverse reaction  
The suspected unexpected serious adverse reaction (SUSAR) is an adverse reaction, whose 
nature or severity is not consistent with the applicable product information.  
6.6 Procedures for recording adverse events  
AEs will be collected with a non-leading question at each clinic visit and at phone visits: “Have 
you had any new or worsening health problems since the last visit?” as well as by reporting 


 
 
 
 
 
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those events directly observed and spontaneously reported by the subject. Clearly related signs, 
symptoms and abnormal diagnostic procedures should preferably be grouped together and 
recorded as a single diagnosis or syndrome whenever possible.  
 
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.  
6.7 Reporting of adverse events 
At each visit/assessment/call after the randomization, all AEs, either observed by the 
investigator, or reported by the subject 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 CRF. 
 
7.7.1 Adverse events of Special Interest and Reporting Procedures 
Adverse Event of Special Interest (AESI) is a noteworthy event for a product or class of 
products that a sponsor wants to monitor carefully. It can be serious or non-serious, or it be a 
potential precursor or prodrome for more serious medical conditions in susceptible individuals.  
AESI have been identified based upon mode of action for the investigational product and 
previous experience with the investigational product and falls into the categories of psychiatric 
disorders and cardiovascular disorders.  
In case of an AESI sponsor advice investigator to consider to make a timely referral to 
psychiatrist or cardiologist as appropriate, pending on the patient’s clinical condition and the 
type of AESI.  
 
For Psychiatric disorders the AESI areas is listed below 
 Mood disorders and disturbances including various types of depressions, where 
the patient may present affect alterations, emotional and mood disturbances such as 
anger and mood swings as well as depressive disorders including major or suicidal 
depression  
 
 Dissociative disorders, where the patient may present various forms such as 
dissociative amnesia, identity disorder or de-personalization/ de-realization disorder 
 
 Disturbances in thinking and perception, where the patient may present delusional 
symptoms, thinking disturbances, hallucinations and perception disturbances 
 
 Manic and bipolar mood disorders and disturbances, where the patient may 
present various forms of bipolar disorders and various mood alterations such as 
hypomania/mania 
 
 Schizophrenia and other psychotic disorders, where the patient may present various 
forms of psychotic disorders, delusional disorders as well as Schizoaffective and 
schizophreniform disorders 
 


 
 
 
 
 
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 Suicidal and self-injurious behaviors, where patient may present suicidal ideation, 
suicide attempt, suicide threat or other forms 
 
For Cardiovascular disorders the AESI areas is listed below 
 Cardiac arrhythmias, the patient may present rate and rhythm disorders including 
but not limited to supraventricular arrhythmias, ventricular arrhythmias including 
cardiac arrest 
 
 Cardiac disorders, signs and symptoms, where the patient may present various 
cardiac hypertensive complications such as hypertensive heart disease or cardiomegaly 
 
 Vascular hypertensive disorders, where the patient may present malignant 
hypertension complications including hypertension complications such as 
cardiomegaly and other types of hypertension such as procedural hypertension or 
essential hypertension 
 
Reporting: The investigator must complete and submit an AESI report and in any case within 
72 hours of having received information on the AESI. The initial report can be followed by a 
follow-up report as soon as the investigator obtains more specific information on the event. 
All AESIs must be reported by investigator to the KLIFO Pharmacovigilance within 72 hr. 
Such events will be documented in the best possible detail on the AESI Report Form and can 
also be transmitted to the sponsor by email within 72hr. The contact information of the 
KLIFO Pharmacovigilance department is as follows:  
Email: pharmacovigilance@klifo.com  
or fax: +45 39 209 045  
 
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.  
If the investigator learns of an AESI occurring to a subject after the treatment of that subject 
has ended, this should be reported to the sponsor within 72 hours from the investigator 
becoming aware of the event. AESIs identified by the investigator after the end of the trial 
should be reported to the sponsor within 72 hours from the investigator becoming aware of 
the event.  
 
 
7.7.2 Pre-existing conditions 
Pre-existing conditions or hospitalization for elective surgery or routine clinical procedures that 
are not the result of an AE need not be considered AEs. Pre-existing condition should be 
recorded in subject´s source documentation and on the medical history form of the CRF. 
 
7.7.3 Overdose 
Overdose is unlikely to occur in this study. Standard symptomatic support measures should be 
used in the case of excessive pharmacological effects or overdose. No antidotes are available.  
At intoxication, symptomatic treatment with dopamine D2-receptor antagonist haloperidol 


 
 
 
 
 
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should be considered. 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 KLIFO Pharmacovigilance using the same expedited reporting 
timelines as for SAEs (within 24 hours).  
 
7.7.4 Pregnancy 
Any pregnancy that occurs in a female subject or the female partner of a male subject during 
trial participation until at least 8 weeks after the last administration of IMP must be reported to 
KLIFO Pharmacovigilance on a pregnancy report form using the same expedited reporting 
timelines as for SAEs (within 24 hours). The investigator will arrange for the pregnant person 
to be counseled by a specialist to discuss the risks of continuing with the pregnancy and the 
possible effects on the fetus. Monitoring of the pregnant person should continue until the 
outcome of the pregnancy is known. The pregnancy must be followed-up to determine outcome 
(including spontaneous miscarriage, elective termination, normal birth, or congenital 
abnormality) and status of mother and child, even if the subject was discontinued from the study 
medication. All data related to pregnancy, pregnancy outcome, and SAE associated with 
pregnancy will also be recorded in a safety database maintained by KLIFO Pharmacovigilance 
Service. Consent to report information regarding pregnancy outcomes has to be obtained from 
the mother and the (where possible) the father. 
 
7.7.5 Water retention and/or hyponatremia 
Patients with hypothalamic obesity may take medication such as desmopressin and precautions 
to avoid hyponatremia must be taken in case of concomitant treatment with drugs which are 
known to induce syndrome of inappropriate antidiuretic hormone secretion (SIADH) such 
tricyclic 
antidepressants, 
selective 
serotonin 
reuptake 
inhibitors, 
chlorpromazine, 
carbamazepine and NSAIDs. 
Additive antidiuretic effect between Tensofensine and desmopressin has not been confirmed 
but based on mechanism of action, as a non-selective inhibitor of serotonin reuptake, it may be 
anticipated that an additive antidiuretic effect of Tensofensine may lead to increased risk of 
water retention and/or hyponatremia. 
Patients should carefully have the serum sodium monitored and in case of decreasing values, 
patients should be called for unscheduled visits.  
 
 
7.7.6 Hypoglycemic events in subjects with T2DM 
Plasma glucose should always be measured and recorded when a hypoglycaemic episode is 
suspected. 
All plasma glucose values: 
 ≤ 3.9 mmol/l (70 mg/dl) or 
 > 3.9 mmol/l (70 mg/dl) when they occur in conjunction with hypoglycaemic symptoms 
should be recorded by the subject. These must be transcribed into the eCRF throughout 
the study. 
 
The record should include the following information: 


 
 
 
 
 
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• 
Date and time of hypoglycaemic episode  
• 
The plasma glucose level before treating the episode (if available) 
• 
Whether the episode was symptomatic  
• 
Whether the subject was able to treat him/herself  
 
The answer to the question: “Was subject able to treat him/herself?” must be answered “No” if 
oral carbohydrate, glucagon or IV glucose had to be administered to the subject by another 
person. Oral carbohydrate should not be given if the subject is unconscious. 
 
A hypoglycaemic episode form must be filled in for each hypoglycaemic episode. If the 
hypoglycaemic episode fulfils the criteria for an SAE then a SAE form and a safety information 
form must be filled in. 
 
Classification of hypoglycaemic episodes: 
Minor hypoglycaemic episode 
• 
≤3.9 mmol/l (70 mg/dl), or  
• 
>3.9 mmol/l (70 mg/dl) when they occur in conjunction with hypoglycaemic symptoms 
Major hypoglycaemic episode 
• 
If oral carbohydrate, glucagon or IV glucose was administrated to the subject by another 
person 
Nocturnal hypoglycaemic episode 
• 
A hypoglycaemic episode occurred between 24:00 – 06:00. 
 
7.7.7 Development of depression 
In case of depression or suicidal ideation/behaviour, it should be evaluated if the subject fulfils 
the criteria for discontinuation from the trial (section 4.10.1). The event must be reported as an 
AE. Appropriate treatment and careful monitoring of the subject should be initiated as per local 
clinical practice. A subject should be referred to a Mental Health Practitioner (MHP) if he/she 
has: 
1. symptoms of moderate or more severe depression, 
2. or any suicidal behaviour, 
3. or any suicidal thoughts with some intent to act, irrespective of whether accompanied by a 
specific plan. 
In case the subject refuses to consult the MHP, the investigator must state in the medical records 
whether it is considered safe for the subject to stay in the trial. 
6.8 Reporting procedures for 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. All SAEs must be 
reported by investigator to the KLIFO Pharmacovigilance within 24 hr. Such events will be 
documented in the best possible detail on the SAEs Report Form and can be also transmitted to 
the sponsor by email within 24hr. The contact information of the KLIFO Pharmacovigilance 
department is as follows: 
 
Email: pharmacovigilance@klifo.com  
or fax: +45 39 209 045 


 
 
 
 
 
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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.  
If the investigator learns of a SAE occurring to a subject after the treatment of that subject has 
ended, 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. 
SAEs identified by the investigator after the end of the trial should be reported to the sponsor 
within 24 hours from the investigator becoming aware of the event, if the causality to the 
investigational study product cannot be excluded. 
 
All data updates should be recorded in the CRF as appropriate, and further documentation as 
well as additional information (e.g. laboratory data, concomitant medication, subject status) 
should be sent (by email) to the sponsor within 24hours 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.  
KLIFO will make expedited reports of all SAEs that are both unexpected and causally related 
to the IMP, to the CA, IECs as appropriate and to the investigators.  
6.9 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.  
 
 
 
 
 


 
 
 
 
 
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7 DESCRIPTION OF STATISTICAL METHODS 
7.1 Description of statistical methods  
KLIFO 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 KLIFO’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 
SAP, which will be prepared before data base lock after DB part. Should any changes of the 
statistical analysis be implemented, they will be described in the corresponding section of the 
final study report. All statistical analyses will be performed using SAS® (SAS Institute Inc., 
Cary, North Carolina, United States of America [USA]), version 9.3 or later. 
7.2 Sample size calculation 
As this is an exploratory study formal sample size calculation was not performed. 
7.3 Selection of subjects for analyses 
The following analysis sets are defined in accordance with the ICH-E9 guidance (10): 
 
Modified intention-to-treat population (mITT): 
Includes all randomized subjects that have non-missing baseline assessment and at least one 
post-baseline assessment. Subjects will be included into mITT population separately for the DB 
and open-label phase. Subjects in the mITT Population will contribute to the evaluation ‘as 
randomized’. 
 
Per protocol population:  
Includes all randomized subjects without any major protocol violations. Subjects in the Per 
Protocol Population (PPP) will contribute to the evaluation ‘as randomized’.  
 
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 analyses of the primary and secondary safety endpoints will be based on the Safety Analysis 
Set.  
Analyses of secondary efficacy endpoints will be based on the mITT Population. Additionally, 
sensitivity analysis may be performed on the PPP in case mITT and PPP differ.  
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 group the subjects are assigned to. The blinding 
of the treatment groups will be maintained for those involved in allocating subjects to the 
analysis sets (including, but not limited to:  Statistician, Statistical Programmers, Data 
Managers, and Medical Expert of Saniona) until data are released for statistical analysis. The 
results of the PK measurements must not be entered in the database prior to database lock 
(DBL). Furthermore, outliers will be identified by data review according to ICH-E9 (10), and 
a dummy-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.  


 
 
 
 
 
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The subjects or observations to be excluded and the reason for their exclusion will be 
documented and signed by those responsible prior to DBR. 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 (CSR). The 
un-blinding will take place after the last subject last visit (LSLV) of the double blinded part. 
7.4 Statistical methods 
All analyses will be performed in two steps – first after the completion of the DB part, then 
following the completion of the open-label extension part. As the primary endpoint is at week 
24, no data will be changed that could affect the endpoints after un-blinding. 
All primary and secondary endpoints will be summarized by treatment and visit using 
descriptive statistics. Continuous endpoints will be summarized by non-missing counts, mean, 
median, standard deviation, minimum and maximum value. Categorical endpoints will be 
summarized by frequency counts (N) and percentages (%). 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 
mITT population, PPP and Safety Analysis Set. Subjects withdrawn from the study will be 
listed including the primary reason for withdrawal. The primary reasons for withdrawal will be 
summarized. 
7.5 Analysis of the primary endpoint 
No inferential statistical test will be performed for the primary endpoint. 
Safety and tolerability will be judged based on the following: 
 The number and type of TEAEs during the first 24 weeks 
 Change in laboratory data (hematology and blood chemistry) from Baseline to week 24 
 Change in BP and HR from Baseline to week 24 
  
Each TEAE will be evaluated for duration, severity, seriousness, and causal relationship to the 
study drug.  The action taken and the outcome will also be reported. 
The TEAEs will be summarized overall. The number and percentage of subjects 
experiencing any TEAE will be summarized and presented by system organ class and 
preferred term.  The TEAEs will also be presented by severity, by relationship to study 
drug, and by seriousness. 
Laboratory data, BP and HR will be listed. Any abnormalities will be reported, clinically 
relevant or significant abnormalities will be additionally flagged. 
Changes in Laboratory data, BP and HR from baseline to week 24 will be summarized 
descriptively by treatment arms. Shift tables will also be provided.  
A more detailed description will be provided in the SAP. 
 
7.6 Analysis of the secondary endpoints 
Continuous secondary efficacy endpoints will be compared between treatment arms by means 
using analysis of covariance (ANCOVA) including treatment as fixed factor and baseline value 
as covariate. Estimates and 95% confidence intervals (CIs) of treatment differences will be 
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First, changes from baseline to week 48 will be compared between treatment arms. 
Additionally, changes from week 24 to week 48 may be compared between treatment arms. 
When comparing changes from week 24 to week 48 the baseline value will still be Day 1 value. 
7.7 Safety criteria  
Addition to analyzes related to the primary endpoint the following safety criteria will be 
analyzed: 
• 
AEs 
• 
Clinical labs (Hematology, Blood Chemistry) 
• 
ECG 
• 
Vital signs 
• 
Physical examination 
• 
Home monitoring 24H BP/48H HR  
 All safety analyses will be based on the Safety Analysis Set.  
Continuous data will be summarized separately for DB and open-label parts using non-missing 
counts, mean, standard deviation, median, minimum, and maximum. Categorical data will be 
summarized separately for DB and open-label parts using counts and percentages. 
7.8 Handling of missing and doubtful data 
Data queries will be generated either in the eCRF or send to investigator via email for missing 
and doubtful data.  The responsible investigator will answer the query and confirm or correct 
data.  
“Last observation carried forward (LOCF)” approach will be used as the main method for 
handling of missing data. Additionally, data without imputation will be used for sensitivity 
analysis. 
7.9 Interim analysis 
No interim analysis is planned.  
 


 
 
 
 
 
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8 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. Patients will get direct access to the eCRF to answer the electronic 
questionnaires and VAS scales; the eCRF will therefore contain source data for these 
questionnaires and VAS scales. 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 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 CA, 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 medical record for 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 AEs. 
8.1 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 CA. 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. The eCRF can be used as source data for data not required to 
the written the patient medical records at site e.g. drug accountability and questionnaires. The 
investigator will complete a source data location list defining where the source of each data 
point is recorded. 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 


 
 
 
 
 
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 Known duration of HIO 
 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 
8.2 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 Identification List”. The 
monitor for completeness 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.  
 


 
 
 
 
 
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9 QUALITY CONTROL AND QUALITY ASSURANCE 
9.1 Definitions 
Quality assurance (QA) 
A 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 IMP were reported to the sponsor. The involved CRO will implement a QA 
system for their respective study-related activities. 
 
Quality control (QC) 
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.  
9.2 Audits and inspections 
The investigator will make all study-related source data and records available to a medically 
qualified QA 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 IMP have been reported to the sponsor. 
 


 
 
 
 
 
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10 ETHICS 
10.1 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 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. 
10.2 Approvals 
The sponsor will authorize a CRO for submitting the documents to the IEC and CA.  
10.3 Ethics committee  
This protocol, a sample subject information sheet and ICF, and any other materials provided to 
the subjects 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 IB 
 Reports of AEs that are serious, unlisted and associated with the IMP  
 All protocol amendments and revised ICFs (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 and CA about the study completion. Furthermore, he/she will 
provide the synopsis of the final report to the IEC and CA within one year after the end of the 
clinical study.  
10.4 Regulatory authority 
The study including all relevant documentation and information need to be submitted to the 
relevant CA for notification or approval according to valid legislation requirements. 
10.5 Protocol modifications 
Changes to the protocol during the study will be documented as amendments. The amended 
protocol will be approved and signed by the relevant personnel at Saniona A/S and by the 
investigator. Depending on the contents of the amendment and local legal requirements, the 
amendment will be submitted to the relevant IEC and, where necessary, to the relevant CA. 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/favourable opinion of 
the appropriate IEC and, if legally required, CA, 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. 
10.6 Subject information and informed consent 
Before subjects enter the study and any study-related assessments are performed, the 
investigator will explain them the nature of the study, its purpose and associated procedures, 
the expected duration, and potential benefits, constraints and risks associated with the study. 
The subjects will also be given written information, which has been approved by the IEC. 
Subjects will be given sufficient time to consider their participation and all of their questions 


 
 
 
 
 
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will be answered. The subjects will also be informed of their right to withdraw from the study 
at any time without giving a reason. The informed consent form must be signed, with name 
and date noted by the subject. The investigator will complete the informed consent section of 
the CRF 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 IEC, the 
subject will be asked to sign the new consent form to confirm his or her willingness to 
continue in the study. Each subject will be informed that his/her source records may be 
reviewed by the monitor, a QA auditor or an IEC/CA 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. 
10.7 Participant confidentiality  
The investigator will ensure that the subject's anonymity will be preserved. On CRFs 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. 
10.8 Investigator qualification  
The investigator will be informed of the methods for rating relevant study outcomes and for 
completing CRFs in order to reduce discrepancies between participating investigators and 
study sites. The investigator will be kept informed of important data, which relate to the safe 
use of the investigational study product as the study proceeds. 


 
 
 
 
 
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11 DATA HANDLING AND RECORD KEEPING 
11.1 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 and randomization 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 site to ensure quality of 
data and subject safety. Data entered in the eCRFs will be available for review by the study 
monitor and KLIFO Clinical Data Management.  The eCRF data will be reviewed remotely for 
logical discrepancies, missing values and trends. The study monitor will ensure that all data 
queries and subsequent amendments in the eCRF documentation are made according to GCP 
guidelines. 
11.2 Study monitoring and source data verification 
The study monitor will contact and visit the investigator periodically to review all study-related 
source data/records, verify the adherence to the protocol and the completeness, correctness and 
accuracy of all eCRF entries compared to source data. The Clinical Research Associate (CRA) 
will review data remotely as preparation for onsite visits. The investigator will cooperate with 
the monitor to ensure that any discrepancies identified are resolved. The investigator will 
allocate adequate time for such monitoring activities. The investigator will also ensure that the 
study monitor or other compliance or QA reviewer is given access to all the above noted study-
related documents and study-related facilities (e.g. pharmacy, etc.), and has adequate space to 
conduct the monitoring visit. Details regarding monitoring are included in the Study Monitoring 
Plan. 
 
In general, during monitoring visits the monitor will ensure that the study is being conducted 
according to the protocol, ICH GCP guidelines and other applicable regulations, and will 
compare the eCRF entries to original source data. He or she will also make sure the informed 
consent procedure has been appropriately carried out and will ensure that all SAEs have been 
reported within applicable timeframes. He or she will also ensure that IMP accountability has 
been maintained and will, after completion of the study, perform final accountability and 
arrange for the return or destruction of IMP. 
11.3 Data management plan  
Data Management is the responsibility of the CRO KLIFO. The complete Data Management 
process will be described in detail and agreed on in the DMP for this study. 
11.4 Case report forms 
The Data Management Department of KLIFO will provide the eCRFs. All further information 
regarding the eCRFs and the data flow will be described and agreed on in the DMP for this 
study. 


 
 
 
 
 
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DBL  
When the last patient has completed week 24, all data entry, validation and medical encoding 
activities will be finalized before the database will be locked. All data pertaining to the first 24 
weeks will be locked before un-blinding the treatment for analysis. 
When the last patient has completed week 48, all data will be cleaned all unnecessary user 
privileges to the study will be removed, except for the data manager who will perform the DBL. 
The audit trail report will be reviewed to ensure that no data pertaining to the first 24 weeks 
have been changed and if this is the case, each change will be described on the CSR for week 
48. 
 
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.  
11.5 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. 
11.6 Used subject and medication logs 
The investigator or 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 CRF for the sponsor. The 
investigator will ensure that this secret list is maintained securely for a period of 25 years at 
minimum. 
11.7 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. 
11.8 Record keeping 
The investigator must retain the informed consent documentation, disposition of the study 
medication, eCRFs, subjects’ source documents, and other source data for at least 15 years or 
until there are no pending or contemplated marketing applications in an ICH region or at least 
2 years have elapsed since the formal discontinuation of the clinical development of the study 
medicine. It is the responsibility of the sponsor to inform the investigator as to when these 
documents no longer need to be retained. If the investigator retires, or for any other reason 
withdraws from the responsibility for maintaining records for the period of time required, 
custody of the records may be transferred to another person who will accept responsibility for 
the records. Notice of such a transfer must be given in writing to the sponsor. 
In addition, the sponsor will retain copies / originals (as appropriate) of any study-related 
documents in the Study Master File for at least 15 years or until there are no pending or 


 
 
 
 
 
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contemplated marketing applications in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of the clinical development of the study product. 


 
 
 
 
 
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12 FINANCE AND INSURANCE 
12.1 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.  
12.2 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.  


 
 
 
 
 
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13 PUBLICATION POLICY 
13.1 Reporting and publication 
KLIFO will prepare a study report after completion of the DB 24-week treatment and another 
study report after the completion of the entire 48 weeks. The sponsor representative will sign 
the final study report intended to be submitted to the CA. 
 
The results of this study may be published or presented at scientific meetings. The sponsor 
will be responsible for publication of all the data generated in this study.  
 
 
 


 
 
 
 
 
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14 REFERENCES 
1. Müller HL. Craniopharyngioma and hypothalamic injury: Latest insights into 
consequent eating disorders and obesity. Curr Opin Endocrinol Diabetes Obes. 
2016;23(1):81–9.  
2. Lustig RH, Post SR, Srivannaboon K, Rose SR, Danish RK, Burghen G a, et al. Risk 
factors for the development of obesity in children surviving brain tumors. J Clin 
Endocrinol Metab. 2003;88(2):611–6.  
3. Rosenfeld A, Arrington D, Miller J, Olson M, Gieseking A, Etzl M, et al. A review of 
childhood and adolescent craniopharyngiomas with particular attention to 
hypothalamic obesity. Vol. 50, Pediatric Neurology. 2014. p. 4–10.  
4. Skorzewska A, Lal S, Waserman J, Guyda H. Abnormal food-seeking behaviour after 
surgery for craniopharyngioma. Neuropsychobiology. 1989;21(1):17–20.  
5. Müller HL, Gebhardt U, Teske C, Faldum A, Zwiener I, Warmuth-Metz M, et al. Post-
operative hypothalamic lesions and obesity in childhood craniopharyngioma: Results 
of the multinational prospective trial KRANIOPHARYNGEOM 2000 after 3-year 
follow-up. Eur J Endocrinol. 2011;  
6. Woods SC, D’Alessio D a. Central control of body weight and appetite. J Clin 
Endocrinol Metab. 2008;93(11 Suppl 1):S37–50.  
7. Alquier T, Kahn BB. Peripheral signals set the tone for central regulation of 
metabolism. Endocrinology. 2004.  
8. Timper K, Brüning JC. Hypothalamic circuits regulating appetite and energy 
homeostasis: pathways to obesity. Dis Model Mech. 2017;  
9. Hochberg I, Hochberg Z. Hypothalamic Obesity 172. EndocrDev. 2010;17(1421–7082 
(Print)):185–96.  
10. Lustig RH. Hypothalamic obesity after craniopharyngioma: Mechanisms, diagnosis, 
and treatment. Vol. 2, Frontiers in Endocrinology. 2011.  
11. Roemmler-Zehrer J, Geigenberger V, Störmann S, Ising M, Pfister H, Sievers C, et al. 
Specific behaviour, mood and personality traits may contribute to obesity in patients 
with craniopharyngioma. Clin Endocrinol (Oxf). 2015;  
12. Harz KJ, Müller HL, Waldeck E, Pudel V, Roth C. Obesity in Patients with 
Craniopharyngioma: Assessment of Food Intake and Movement Counts Indicating 
Physical Activity. J Clin Endocrinol Metab. 2003;88(11):5227–31.  
13. Stieg M, Buchfelder M, Stalla G. Neuropsychiatric aspects in a rare case of 
hypothalamic obesity. Exp Clin Endocrinol Diabetes. 2014;  
14. G. B, M. F, C. J, T. R, A. T. Beneficial results of sleeve-gastrectomy in a 12-year old 
girl with massive hyperphagia after surgery for craniopharyngeoma. Obesity Surgery. 
2011.  
15. Shaikh MG, Grundy RG, Kirk JMW. Reductions in basal metabolic rate and physical 
activity contribute to hypothalamic obesity. J Clin Endocrinol Metab. 2008;  
16. Lloret-Linares C, Faucher P, Coupaye M, Alili R, Green A, Basdevant A, et al. 
Comparison of body composition, basal metabolic rate and metabolic outcomes of 
adults with Prader Willi syndrome or lesional hypothalamic disease, with primary 
obesity. Int J Obes. 2013;  
17. Mong S, Pomeroy SL, Cecchin F, Juraszek A, Alexander ME. Cardiac Risk After 
Craniopharyngioma Therapy. Pediatr Neurol. 2008;38(4):256–60.  


 
 
 
 
 
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18. Ismail D, O’Connell MA, Zacharin MR. Dexamphetamine use for management of 
obesity and hypersomnolence following hypothalamic injury. Vol. 19, Journal of 
Pediatric Endocrinology and Metabolism. 2006. p. 129–34.  
19. Mason PW, Krawiecki N, Meacham LR. The use of dextroamphetamine to treat 
obesity and hyperphagia in children treated for craniopharyngioma. Arch Pediatr 
Adolesc Med. 2002;156(9):887–92.  
20. Greenway FL, Bray GA. Treatment of hypothalamic obesity with caffeine and 
ephedrine. Endocr Pract [Internet]. 2008;14(6):697–703. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/18996788 
21. Van Santen HM, Schouten-Meeteren AY, Serlie M, Meijneke RWH, Van Trotsenburg 
AS, Verberne H, et al. Effects of T3 treatment on brown adipose tissue and energy 
expenditure in a patient with craniopharyngioma and hypothalamic obesity. J Pediatr 
Endocrinol Metab. 2015;28(1–2):53–7.  
22. Fernandes JK, Klein MJ, Ater JL, Kuttesch JF, Vassilopoulou-Sellin R. 
Triiodothyronine supplementation for hypothalamic obesity. Metabolism. 
2002;51(11):1381–3.  
23. Zoicas F, Droste M, Mayr B, Buchfelder M, Schöfl C. GLP-1 analogues as a new 
treatment option for hypothalamic obesity in adults: report of nine cases. Eur J 
Endocrinol [Internet]. 2013;168(5):699–706. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/23392214 
24. Ando T, Haraguchi A, Matsunaga T, Natsuda S, Yamasaki H, Usa T, et al. Liraglutide 
as a Potentially Useful Agent for Regulating Appetite in Diabetic Patients with 
Hypothalamic Hyperphagia and Obesity. Intern Med. 2014;  
25. Bretault M, Boillot  a, Muzard L, Poitou C, Oppert JM, Barsamian C, et al. Clinical 
review: Bariatric surgery following treatment for craniopharyngioma: a systematic 
review and individual-level data meta-analysis. J Clin Endocrinol Metab [Internet]. 
2013;98(6):2239–46. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23533238 
26. Mersebach H, Svendsen OL, Astrup A, Feldt-Rasmussen U. Abnormal 
Sympathoadrenal Activity, but Normal Energy Expenditure in Hypopituitarism. J Clin 
Endocrinol Metab. 2003;88(12):5689–95.  
27. Mersebach H, Svendsen OL, Holst JJ, Astrup A, Feldt-Rasmussen U. Comparisons of 
leptin, incretins and body composition in obese and lean patients with hypopituitarism 
and healthy individuals. Clin Endocrinol (Oxf). 2003;58(1):65–71.  
28. Mersebach H, Klose M, Svendsen OL, Astrup A, Feldt-Rasmussen U. Combined 
dietary and pharmacological weight management in obese hypopituitary patients. 
Obes Res. 2004;12(11):1835–43.  
29. Colman E. Food and Drug Administration’s Obesity Drug Guidance Document: A 
Short History. Circulation 2012;125(17):2156-2164  
30. SmPC of metoprolol ER tablets.  Metoprololsuccinat ”Orion”, depottabletter, Orion 
Corporation (Finland), SPC dated 19. July 2018 
 
 


 
 
 
 
 
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8. APPENDICES 
8.7 
Appendix 1 - List of prohibited medication 
Drug Class 
Episodic 
Use 
Chronic 
Use 
Comment 
Antiarrhythmic (Amiodarone, quinidine) 
N 
N 
Strong inhibitor of CYP2D6 
Antiretroviral (Ritonavir) 
N 
N 
Strong inhibitor of CYP2D6 
Anorectic agents 
N 
N 
 
Antiandrogens (abiraterone, cyproterone 
acetate, finasteride) 
N 
N 
 
Antihistamines 
Y 
N 
Topical antihistamines – always approved 
Antiepileptic drugs 
N 
N 
 
Antidepressant drugs 
N 
N 
 
Anti-anxiety drugs 
N 
N 
 
Anti-Parkinsonian drugs  
N 
N 
 
Anti-Dementia drugs donepezil and galantamin
N 
N 
 
Antifungal (terbinafine) 
N 
N 
Moderate inhibitor of  CYP2D6 
Muscarinreceptor blocker darifenacin 
N 
N 
Moderate inhibitor of  CYP2D6 
Barbiturates 
N 
N 
 
Benzodiazepines 
N 
N 
 
Beta- blockers 
N 
N 
Per protocol 
Buproprion (non-SSRI antidepressant) 
N 
N 
Strong inhibitor of  CYP2D6 
Calcium channel blockers 
N 
N 
Per protocol 
Carbonic anhydrase inhibitors (e.g., 
acetazolamide, dichlorphenamide, 
dorzolamide, methazolamide) 
N 
N 
 
Cinacalcet (calcimimetic) 
N 
N 
Strong inhibitor of  CYP2D6 
Dopamine re-uptake inhibitors (e.g., 
bupropion) 
N 
N 
 
Glucocorticoids 
Y 
N 
Substitution dosages of hydrocortisone 
accepted 
Hypnotic sedative (glutethimide) 
N 
N 
Strong inducer of  CYP2D6 
H2-receptor antagonist (cimetidine) 
N 
N 
Weak inhibitor of  CYP2D6 
Immunosuppressives 
N 
N 
 
Insulin and/or other injectable anti-diabetic 
medications, or thiazolidinediones (TZDs) 
N 
N 
Per protocol 
Lithium 
N 
N 
 
Monoamine oxidase (MAO) inhibitors 
N 
N 
 
Opioids, cannabinidiols 
N 
N 
 
Oral hypoglycemic 
- 
- 
Per protocol 
Orlistat 
N 
N 
 
Phenothiazines 
N 
N 
 
Selective serotonin re-uptake inhibitors (SSRIs)
N 
N 
 
Serotonin and norepinephrine re-uptake 
inhibitors (SNRIs) 
N 
N 
 
 
 
 


 
 
 
 
 
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8.8 
Appendix 2 – Instruction in diet and physical activity 
All patients will receive written instructions in exercise, behaviour modification and dietary 
instruction, but they will also careful instructions at frequent visits by a registered dietician. 
 
See below for description of the exercise, behaviour modification and dietary instruction. 
 
Physical activity 
All participants will receive instructions to be physically active at least 30 minutes per day.  
www.bevaegdigforlivet.dk, www.altomkost.dk (de 10 kostråd) 
Behaviour modification   
All participants will receive instruction on behavioural modification. The behavioural 
modification involves techniques to change unhealthy lifestyle  
 
Material:  
www.altomkost.dk: de 10 kostråd,  
https://ernaeringsfokus.dk/materialer-og-links/materialer-til-bestilling-og-dowload/vidste-du-
at https://hjerteforeningen.dk 
 
Dietary intervention 
All participants will be instructed to follow a low-calorie, moderately low fat diet. The target 
macronutrient composition of the diet is: Approx. 30% of total energy from fat, approx. 20 % 
from protein and approx. 50% from carbohydrate.  
 
The diet is designed to provide -300 kcal/d (1 kilocalorie (kcal) = 4.2 kilo joule (kJ)) less than 
the individually estimated energy requirement based on an initial estimated resting metabolic 
rate based on estimates of body composition, and subsequently multiplied by 1.3 -1.5 (PAL).  
 
Subjects are given oral and written instructions relating to these targets, using individually 
tailored diet prescription plans [example below]. The subjects themselves purchase all food 
items 
 
Calculation of total energy expenditure 
Harris Benedict equation for calculation of total energy expenditure (TEE) using basal energy 
expenditure (BEE) and physical activity level (PAL): 
TEE = BEE * PAL 


 
 
 
 
 
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BEE 
For men,  
BEE = 66 + (13.8 x weight/kg) + (5 x height/cm) - (6.8 x age/years) 
For women,  
BEE = 655 + (9.5 x weight/kg) + (1.8 x height/cm) - (4.7 x age/years) 
Physical activity level (PAL) 
PAL is estimated at 1.3 for most participants 
PAL is estimated at 1.5 for very active participants (> 2 hours a week of high intensity sport, 
e.g., cycling, spinning, running, rowing, etc.) 
 
Calorie-restricted diet 
Calorie-restricted diet = TEE – 300 kcal 
Example: 
70-year-old man 
Weight 90 kg 
Height 170 cm 
(BMI: 31 kg/m2) 
PAL: 1.3 
BEE = 66 + (13.8 x 90) + (5 x 170) – (6.8 x 70) 
       = 1682 kcal/d 
TEE = BEE * PAL 
        = 1682 x 1.3 
        = 2187 kcal/d 
Calorie-restricted diet: 2187 kcal – 300 kcal 
       = 1887 kcal (~8 MJ) 
 


 
 
 
 
 
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Dietary counseling 
The first meeting: The dietitian will ask the participant about dietary habits, patterns and 
preferences for food etc. The participants’ answers will be used to prepare a personal diet plan 
that furthermore meets the macronutrient distribution of approx. 30 E% from fat, about 20 E% 
from protein and about 50 E% from carbohydrate and -300 kcal less than the individually 
estimated energy requirement per day. 
 
The diet plan is prepared in such a way that it is possible for the participant to choose for 
example different breakfast suggestions, so the participant has the opportunity to choose for 
example bread one day and oatmeal the next. 
 
Additional guidance material 
In combination with the diet plan, the participants will be guided to follow the official Danish 
dietary advice and recipes from the Danish Heart Association and the like. 
www.altomkost.dk, www.hjerteforeningen.dk, www.ernaeringsfokus.dk.  


 
 
 
 
 
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Example of a diet plan of 8000 kJ 
Morning: 
1 slice of 
Rye bread 
 
1 slice of 
wholemeal bread 
 
Scraped  
Butter/margarine 
 
1 slice of 
Cheese 30+ 
2 teaspoon
Jam
 
1 glass 
Milk (max. 0,5 %)      
 
 
 
 
 
 
Snack:
1 
Fruit
 
10 pieces  
Almonds/nuts 
 
 
 
Lunch: 
2 slices of 
Rye bread 
 
Scraped  
Butter/margarine 
 
4 x 
Cold cuts: ex: egg, fish, lean meat, cottage cheese 
2 teaspoon of
Mayonnaise or similar
 
½ plate of 
Vegetables 
 
 
 
 
 
 
Snack: 
2 slices of 
Whole grain crispbread OR 
 
1 slice of  
Rye bread/wholemeal bread 
 
2 slices of 
Cheese 30+ 
1
Fruit
 
 
 
 
 
 
Dinner: 
3 medium 
Potatoes OR 
 
2½ dl 
Boiled rice/pasta 
 
150 gram 
Meat/fish/poultry 
 
½ plate of 
Vegetables 
½ dl
Low fat sauce 
 
 
 
 
 
 
Snack: 
1½ dl  
Yogurt natural 0,5% 
3 table spoon 
Muesli 
 
 
 
 
Beverages: Water, sparkling water, sugar-free lemonade and soft drinks, coffee, tea 
 
 
 
 


 
 
 
 
 
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8.9 
Appendix 3 – PHQ9 questionnaire 

SAP_001.pdf: 
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Statistical Analysis Plan 
 
 
   Protocol No.:   TM005 
A 24-WEEK PHASE 2, DOUBLE-BLIND, RANDOMIZED, PLACEBO-
CONTROLLED, SINGLE-CENTER SAFETY AND EFFICACY STUDY TO 
EVALUATE OVERALL SAFETY AND TOLERABILITY OF 
COADMINISTRATION OF TESOFENSINE AND METOPROLOL IN 
SUBJECTS WITH HYPOTHALAMIC INJURY-INDUCED OBESITY (HIO), 
AND WITHA 24-WEEK OPEN-LABEL EXTENSION, IN TOTAL 48 WEEKS 
 
 
 
 
    Sponsor:                                 Saniona A/S, Denmark 
    Version:  
    Final 1.0  
    Issue Date:  
    17-May-2019 
 
 
 




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Version History 
Version 
Date 
Changes 
Version 1.0 
17.05.2019 
Initial Version 
 
 


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Table of Contents 
Version History ............................................................................................................................................. 3 
List of Tables ................................................................................................................................................ 6 
LIST OF ABBREVIATIONS ....................................................................................................................... 7 
1. 
INTRODUCTION ................................................................................................................................ 9 
2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................................................................ 9 
2.1 
Study Objectives ........................................................................................................................... 9 
2.1.1 
Primary Objective ................................................................................................................. 9 
2.1.2 
Secondary Objectives ............................................................................................................ 9 
2.2 
Study Endpoints .......................................................................................................................... 10 
2.2.1 
Primary Endpoint ................................................................................................................ 10 
2.2.2 
Secondary Efficacy Endpoints ............................................................................................ 10 
2.2.3 
Secondary Safety and PK Endpoints................................................................................... 11 
3. 
OVERALL STUDY DESIGN AND PLAN ....................................................................................... 11 
3.1 
General Study Design ................................................................................................................. 11 
3.2 
Sample Size Estimation and Power ............................................................................................ 11 
3.3 
Study Population ......................................................................................................................... 11 
3.4 
Treatment Administered ............................................................................................................. 11 
3.5 
Randomization ............................................................................................................................ 12 
3.6 
Blinding and Unblinding ............................................................................................................. 12 
4. 
STATISTICAL METHODS ............................................................................................................... 13 
4.1 
General Considerations ............................................................................................................... 13 
4.2 
Definitions of Analysis Sets ........................................................................................................ 13 
4.3 
Statistical Definitions and Algorithms ........................................................................................ 14 
4.3.1 
Baseline ............................................................................................................................... 14 
4.3.2 
Pooling of Centers ............................................................................................................... 14 
4.3.3 
Handling of Dropouts and Missing Data ............................................................................ 14 
4.3.4 
Analysis Software ............................................................................................................... 14 
5. 
PROTOCOL DEVIATIONS AND DISPOSITION OF SUBJECTS ................................................. 15 
5.1 
Disposition of Subjects ............................................................................................................... 15 
5.2 
Protocol Deviations ..................................................................................................................... 15 


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6. 
BACKGROUND INFORMATION ................................................................................................... 15 
6.1 
Demographics and Baseline Characteristics ............................................................................... 15 
6.2 
Medical History .......................................................................................................................... 15 
7. 
PRIOR AND CONCOMITANT MEDICATIONS ............................................................................ 15 
8. 
COMPLIANCE AND EXPOSURE ................................................................................................... 16 
9. 
SAFETY AND TOLERABILITY ANALYSIS ................................................................................. 16 
9.1 
Analysis of Primary Endpoint ..................................................................................................... 16 
9.2 
Analysis of Secondary Safety Endpoints .................................................................................... 17 
9.3 
Additional Description of Safety Analysis ................................................................................. 17 
9.3.1 
Adverse Events ................................................................................................................... 17 
9.3.2 
Clinical Laboratory Evaluations ......................................................................................... 18 
9.3.3 
Electrocardiograms ............................................................................................................. 18 
9.3.4 
Vital Signs ........................................................................................................................... 19 
9.3.5 
Physical Examination .......................................................................................................... 19 
10. 
PHARMACOKINETIC ANALYSIS ............................................................................................. 19 
11. 
EFFICACY ANALYSIS................................................................................................................. 19 
12. 
INTERIM ANALYSIS ................................................................................................................... 20 
13. 
CHANGES IN THE PLANNED ANALYSIS ............................................................................... 20 
14. 
MOCK TABLES, LISTINGS AND FIGURES (TLFS) ................................................................. 20 
15. 
REFERENCES ............................................................................................................................... 20 
 
 
 
 


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List of Tables 
Table 1: Abbreviations .................................................................................................................................. 7 
 
 
 
 


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LIST OF ABBREVIATIONS 
 
Table 1: Abbreviations 
AE 
Adverse Event       
°C 
Degrees Celsius       
ADR 
Adverse Drug Reaction      
ANCOVA Analysis of Covariance      
AUC 
Area Under the Curve    
BMI 
Body Mass Index      
BP 
Blood Pressure       
CRF 
Case Report Form      
CRO 
Contract Research Organization      
CSS 
Composite Satiety Score      
DB 
Double-Blind        
DBL 
Database Lock       
DBP 
Diastolic Blood Pressure      
DEXA 
Dual-energy X-ray Absorptiometry      
ECG 
Electrocardiogram        
eCRF 
Electronic Case Report Form     
FPG 
Fasting Plasma Glucose      
GCP 
Good Clinical Practice      
HbA1C 
Hemoglobin A1c       
HR 
Heart Rate       
ICH 
International Conference on Harmonization     
IMP 
Investigation Medicinal Product      
kg 
Kilogram        
l 
Liter        
MedDRA 
Medical Dictionary for Regulatory Activities    
mg 
Milligram        
mITT 
Modified Intention-to-treat  
mL 
Milliliter        
N 
(No) Number       
PK 
Pharmacokinetic        
PPP 
Per Protocol Population      
SAE 
Serious Adverse Event      
SAP 
Statistical Analysis Plan      
SBP 
Systolic Blood Pressure      
SD 
Standard Deviation       
SOP 
Standard Operating Procedure      
T2DM 
Type 2 Diabetes Mellitus     


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TEAEs 
Treatment Emergent Adverse Events     
Tmax 
Time of the Maximum Plasma Drug Level  
VAS 
Visual Analogue Scale 
WHO DD 
World Health Organization Drug Dictionary 
 
 


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1. INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the statistical methods that will be used during the 
analysis and reporting of the data collected under TM005.  
The scope of this SAP includes presentation of disposition, demographic and other baseline data, 
safety and efficacy analyses.  
Mock tables, figures, and listings (TFLs) shells will be provided in separate supporting 
documents. 
This SAP should be read in conjunction with the study protocol and case report forms (CRFs). 
This version of the SAP has been developed using Protocol Version 2.0 dated 11-JAN-2019 and 
eCRFs.  
 
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1 Study Objectives 
2.1.1 Primary Objective  
• To examine overall safety and tolerability of coadministration of 0.5 mg tesofensine/50 
mg metoprolol treatment over 24 weeks in subjects with HIO 
 
2.1.2 Secondary Objectives  
• To examine the effect on satiety and appetite from Baseline to week 24, from Baseline to 
week 48 and from week 24 to week 48 following co-administration of 0.5 mg 
tesofensine/50 mg metoprolol treatment in subjects with HIO 
• To examine the effect on bodyweight from Baseline to week 24, from Baseline to week 
48 and from week 24 to week 48 following co-administration of 0.5 mg tesofensine/50 
mg metoprolol treatment in subjects with HIO 
• To examine the effect on body composition from Baseline to week 24, from Baseline to 
week 48 and from week 24 to week 48 following co-administration of 0.5 mg 
tesofensine/50 mg metoprolol treatment in subjects with HIO 
• To examine the effect on quality of life from Baseline to week 24, from Baseline to week 
48 and from week 24 to week 48 following co-administration of 0.5 mg tesofensine/50 
mg metoprolol treatment in subjects with HIO 
• To examine effect on craving for something sweet, salty, savory and fatty from Baseline 
to week 24, from Baseline to week 48 and from week 24 to week 48 following co-
administration of 0.5 mg tesofensine/50 mg metoprolol treatment in subjects with HIO 
• To examine the effect on thirst from Baseline to week 24, from Baseline to week 48 and 
from week 24 to week 48 following co-administration of 0.5 mg tesofensine/50 mg 
metoprolol treatment in subjects with HIO 
• To examine effect on glycaemic control and lipid profile from Baseline to week 24, from 
Baseline to week 48 and from week 24 to week 48 following coadministration of 0.5 mg 
tesofensine/50 mg metoprolol treatment in subjects with HIO 


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• To examine the effect on HR and BP from Baseline to week 24, from Baseline to week 
48 and from week 24 to week 48 following co-administration of 0.5 mg tesofensine/50 
mg metoprolol treatment in subjects with HIO 
• To establish profile of trough values of tesofensine and metoprolol following co-
administration of 0.5 mg tesofensine/50 mg metoprolol treatment in subjects with HIO: 
o Active arm: the first 24 weeks and then continuously up to week 48. 
o Placebo arm: start of treatment at week 25 and then continuously up to week 48. 
• To evaluate the effect on BP and HR from Baseline to week 24 by 24 hours (24H) home 
monitoring of BP and 48 H home monitoring of HR. 
• To evaluate overall safety and tolerability from week 24 to week 48 following co-
administration of 0.5 mg tesofensine/50 mg metoprolol treatment in subjects with HIO. 
 
 
2.2 Study Endpoints 
2.2.1  Primary Endpoint 
Safety and tolerability will be judged from all safety data collected in the period, including 
number and type of treatment emergent adverse events, laboratory data, blood pressure and heart 
rate. 
 
 
2.2.2 Secondary Efficacy Endpoints 
• Change in satiety and appetite using the composite satiety score (CSS) from Baseline to week 
24, from Baseline to week 48 and from week 24 to week 48 
• Change in body weight from Baseline to week 24, from Baseline to week 48 and from week 24 
to week 48 
• Change in body composition i.e. body fat and lean body mass by Dual-energy X-ray 
absorptiometry (DEXA) from Baseline to week 24, from Baseline to week 48 and from week 24 
to week 48 
• Change in quality of life by the use of the SF-36 questionnaire from Baseline to week 24, from 
Baseline to week 48 and from week 24 to week 48 
• Change in craving for something sweet, salty, savory and fatty by the use of Visual Analogue 
Scale (VAS) scales from Baseline to week 24, from Baseline to week 48 and from week 24 to 
week 48 
• Change in thirst by the use of a VAS scale from Baseline to week 24, from Baseline to week 48 
and from week 24 to week 48 
• Change on glycaemic control and lipid profile from Baseline to week 24, from Baseline to 
week 48 and from week 24 to week 48 
• Change in waist circumference from Baseline to week 24, from Baseline to week 48 and from 
week 24 to week 48 
 
 


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2.2.3 Secondary Safety and PK Endpoints 
• Change on HR and BP from Baseline to week 48 and from week 24 to week 48 
• Trough values of tesofensine and metoprolol 
       o Active arm: the first 24 weeks and then continuously up to week 48. 
       o Placebo arm: start of treatment at week 25 and then continuously up to week 48. 
• Change of 24H BP/48H HR and QT from Baseline to V5 and V8 and from V5 to V8 measured 
by home monitoring 
• Number and type of AE’s from week 24 to week 48 
 
3. OVERALL STUDY DESIGN AND PLAN 
3.1 General Study Design  
This is a double-blind, randomized, placebo-controlled, single-center study followed by an open-
label extension period. 
The study will have two parts: 
• Part 1: 24 weeks double-blind treatment, followed by 
• Part 2: 24 weeks open-label extension – all subjects still participating at the end of Part 1 
will be given an option to continue for additional 24 weeks on the active drug if evaluated 
eligible by the Investigator. 
As an integral part of the study all subjects will undergo regular dietary and physical activity 
counseling during the study. 
A Clinical Study Report (CSR) will be prepared following the completion of the 24-week 
double-blind part of the study and a separate CSR following finalization of the 24-week open 
labeled study part, including data and analysis from Baseline to week 24 and week48. 
 
3.2 Sample Size Estimation and Power 
As this is an exploratory study formal sample size or power calculation was not performed. 
 
3.3 Study Population 
In total, a minimum of 12 and a maximum of 25 subjects with HIO. HIO is defined as obesity 
developed in relation to damage to the hypothalamus, whether it is from an injuring trauma, 
bleeding, infarction, tumor, surgery or irradiation. 
3.4 Treatment Administered 
Part 1 – the double-blind part: The active medication arm will be given co-administration of 0.5 
mg tesofensine/50 mg metoprolol daily for 24 weeks. The placebo arm will receive matching 
placebo tablets. 
Part 2 – the open-label extension part: All active participants at the end of the double-blind part 
will be given the active medication 0.5 mg tesofensine/50 mg metoprolol daily for 24 weeks. 
 


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3.5 Randomization  
During the Part 1 subjects will be randomized into either the active medication or matching 
placebo in 2:1 ratio. 
There will be 2 stratification groups (subjects with T2DM and without diabetes). Each 
stratification group will be randomized in 2:1 ratio. 
Stratified block randomization will be performed. 
Randomization of eligible subjects to one of the study medication groups will be done at 
Baseline visit Day 1, following successful completion of all baseline assessments, using a study 
medication number defined by the assignment list. 
Subjects will be randomly allocated to either study medication group in a 2:1 randomization by 
selecting the lowest available randomization number at the time of randomization.  
The randomization codes will be generated within the Biometrics Department of the sponsor’s 
Contract Research Organization (CRO) by a randomization statistician and IMP kits for patients 
will be packaged according to this list. The randomization codes and the complete generation 
procedure will be filed at a secure place by sponsor’s CRO statistician until the study database is 
closed. Study statistician, data managers and statistical programmers will not have access to the 
randomization list prior to the database lock. The only person on site with access to the code 
break sealed envelopes will be the principle investigator. The study medication number consists 
of four digits. In part 1, all kits assigned to a subject will have the same randomization number. 
In part 2, kits assigned to a subject will have different study medication numbers between visits. 
This procedure will be checked by the monitor. 
 
3.6 Blinding and Unblinding 
Part 1 - It is double-blind, placebo-controlled study, i.e. investigators, site staff and subjects will 
be blinded as to whether they will be allocated to active or placebo treatment. This will be 
achieved by the following procedures: 
The IMP will look similar to placebo with regard to size, color and general appearance 
The labelling of the IMP will identify the study and the investigational product but will not 
indicate the contents. When a patient is ready for randomization, the investigator picks the lowest 
available randomization number from one of two lists; one list for patients with DM and one list 
for patients without DM 
In general, emergency un-blinding 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. If possible, the justification for the un-blinding should be 
discussed with the sponsor prior to unblinding to ensure that unblinding is truly necessary and 
that appropriate steps for subject’s welfare and management are being taken. 


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4. STATISTICAL METHODS 
 
4.1 General Considerations 
All analyses will be performed in two steps – first after the completion of the double-blind part, 
then following the completion of the open-label extension part. As the primary endpoint is at 
week 24, no data will be changed that could affect the endpoints after unblinding. During the 
open-label extension all subjects will receive the study drug. The treatment arms during the 
open-label extension will be based on the treatments assigned during the double-blind phase, and 
analysis will be done from Baseline to week 24 and 48 and from week 24 to week 48.  
All primary and secondary endpoints will be summarized by treatment and visit using descriptive 
statistics. 
 
Continuous endpoints will be summarized by non-missing counts, mean, median, standard 
deviation, minimum and maximum value. Categorical endpoints will be summarized by 
frequency counts (N) and percentages (%). Moreover, complete listings of individual values for 
all endpoints will be provided. In general, the denominator for the percentage calculation will be 
based upon the total number of subjects in the study population for the treatment groups, unless 
otherwise specified. The denominator for by-visit displays will be the number of subjects in the 
relevant study population with non-missing data at each visit. 
Formatting for Dates and Times 
• Dates only – ddmmmyyyy; 
• Times only – hh:mm or hh:mm.ss (as appropriate); 
• Dates and times – ddmmmyyyy hh:mm or ddmmmyyyy hh:mm:ss (as appropriate). 
The minimum and maximum will be reported with the same degree of precision (i.e, the same 
number of decimal places) as the observed data. Measures of location (mean and median) will be 
reported to 1 degree of precision more than the observed data and measures of spread (SD) will 
be reported to 2 degrees of precision more than the observed data. 
Percentages will be presented to 1 decimal place, unless otherwise specified. 
Unless otherwise indicated, all statistical tests will be conducted at the 0.05 significance level 
using 2-tailed tests, and P values will be reported. 
 
4.2 Definitions of Analysis Sets 
The following analysis sets are defined in accordance with the ICH-E9 guidance1: 
 
Modified Intention-to-treat Population (mITT): 


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Includes all randomized subjects that have non-missing baseline assessment and at least one 
post-baseline assessment. Subjects will be included into mITT population separately for the 
double-blind and open-label phase. Subjects in the mITT Population will contribute to the 
evaluation ‘as randomized’. 
 
Per Protocol Population (PPP): 
Includes all randomized subjects without any major protocol violations. Subjects in the PPP will 
contribute to the evaluation ‘as randomized’. 
 
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’. 
 
4.3 Statistical Definitions and Algorithms 
4.3.1 Baseline 
The last observation recorded prior to the first dose of treatment will be used as the baseline 
observation for all calculations of change from baseline.  
 
4.3.2 Pooling of Centers 
Not applicable as this is a single-center study. 
 
4.3.3 Handling of Dropouts and Missing Data 
Data queries will be generated either in the eCRF or sent to investigator via email for missing 
and doubtful data. The responsible investigator will answer the query and confirm or correct 
data. 
“Last observation carried forward (LOCF)” approach will be used as the main method for 
handling of missing data. Additionally, data without imputation will be used for sensitivity 
analysis. 
 
 
4.3.4 Analysis Software 
 
All summaries and statistical analyses will be generated using SAS® version 9.3 or later. 
 
 
 


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5. PROTOCOL 
DEVIATIONS 
AND 
DISPOSITION 
OF 
SUBJECTS  
 
5.1 Disposition of Subjects 
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 
mITT population, PPP and Safety Analysis Set. Subjects withdrawn from the study will be listed 
including the primary reason for withdrawal. The primary reasons for withdrawal will be 
summarized. 
 
5.2 Protocol Deviations 
Protocol deviations will be listed. Protocol deviations will be tabulated by treatment group and 
overall for the Safety Population. 
 
6. BACKGROUND INFORMATION 
6.1 Demographics and Baseline Characteristics 
Summary statistics for age, gender, race, ethnicity, height in cm, weight in kg, and BMI will be 
presented by treatment group and overall. These analyses will be conducted for the Safety 
population.  
 
6.2 Medical History 
The number and percent of subjects reporting various medical histories, grouped by MedDRA 
system organ class and preferred term (coded using MedDRA v.<21.1>), will be tabulated by 
treatment group. This analysis will be conducted for the Safety Population. 
 
7. PRIOR AND CONCOMITANT MEDICATIONS 
Medications that started prior to the start of the study drug will be considered prior medications 
whether or not they were stopped prior to the first dose of study drug. Any medications (other 
than the study drug) continuing or starting post the first dose of study drug will be considered to 
be concomitant. If a medication starts prior to the first dose of study drug and continues after the 
first dose of study drug it will be considered both prior and concomitant. 


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Prior and concomitant medications will be summarized descriptively by treatment group and 
overall using counts and percentages. 
Prior medications will be presented separately from concomitant medications.  
Medications will be coded using WHODrug v. B3. 
 
8. COMPLIANCE AND EXPOSURE 
Study drug administration data will be listed.  
Study medication compliance (determined by calculating returned bottles and count of returned 
tablets) data will be summarized by treatment group, overall, and by visit for the Safety 
Population. 
 
9. SAFETY AND TOLERABILITY ANALYSIS 
All Safety analysis will be performed on the Safety Analysis Set. 
 
Continuous data will be summarized separately for double-blind and open-label (Baseline to 
week 24, Baseline to week 48 and from week 24 to week 48) parts using non-missing counts, 
mean, standard deviation, median, minimum, and maximum. Categorical data will be 
summarized separately for double-blind and open-label (Baseline to week 24, Baseline to week 
48 and from week 24 to week 48) parts using counts and percentages. 
 
9.1 Analysis of Primary Endpoint 
 
No inferential statistical test will be performed for the primary endpoint. 
 
Safety and tolerability will be judged based on the following: 
• The number and type of Treatment Emergent Adverse Events (TEAEs) during the first 24 
weeks 
• Change in laboratory data (hematology and blood chemistry) from Baseline to week 24 
• Change in blood pressure and heart rate from Baseline to week 24 
 
Each TEAE will be evaluated for duration, severity, seriousness, and causal relationship to the 
study drug. The action taken and the outcome will also be reported. The TEAEs will be 
summarized overall. The number and percentage of subjects experiencing any TEAE will be 


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summarized and presented by system organ class and preferred term. The TEAEs will also be 
presented by severity, by relationship to study drug, and by seriousness. 
 
Laboratory data, BP and HR will be listed. Any abnormalities will be reported, clinically 
relevant or significant abnormalities will be additionally flagged. 
Changes in Laboratory data, BP and HR from Baseline to week 24 will be summarized 
descriptively by treatment arms. Shift tables will also be provided. BP and HR from both Visit 
measurements as well as from home monitoring will be analyzed. Figures of BP and HR from 
Baseline to week 24 from both Visit measurements as well as from home monitoring will be 
prepared. 
 
9.2 Analysis of Secondary Safety Endpoints 
Secondary safety analysis will be performed the same way as the primary safety analysis. 
Treatment allocation during double-blind and open-label part is described in Section 4.1 General 
Considerations. 
 
The number and type of AEs from week 24 to week 48 will be analyzed. 
Changes in blood pressure and heart rate from baseline to week 48 and from week 24 to week 48 
from both Visit measurements as well as from home monitoring will be summarized 
descriptively by treatment arms. Figures of BP and HR from Baseline to week 48 and from week 
24 to week 48 from both Visit measurements as well as from home monitoring will be prepared. 
 
Changes in 24H BP/48H HR and QT from Baseline to week 12 and week 24 and from 
week 12 to week 24 measured by home monitoring will be tabulated. Figures of mean values of 
BP and HR from Baseline, week12 and week 24 will be prepared. Data describing potential 
changes in heart rhythm and diagnosis will be tabulated and summarized.  
 
9.3 Additional Description of Safety Analysis 
9.3.1 Adverse Events 
Adverse events will be coded using the MedDRA version 21.1 thesaurus. 
A TEAE will be defined as an adverse event encountered after the first dose of IMP given.  
 
In the AE data listings, all AEs will be displayed. Four groups will be presented; from Baseline 
to week 24 on active medication (A), from baseline to week 24 on placebo (P), from week 24-48 
on AA and from week 24-48 on PA. Each AE is to be evaluated for duration, severity, 
seriousness, and causal relationship to the study drug.  The action taken and the outcome must 
also be recorded. AEs that are not treatment emergent will be flagged. 
All adverse events, grouped by MedDRA system organ class and preferred term, will be 
summarized by treatment group and overall. In the case of multiple occurrences of the same 
within the same subject, each subject will only be counted once for each system organ class or 
preferred term. 


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The number and percent of subjects reporting treatment emergent AEs, grouped by MedDRA 
system organ class and preferred term, will be tabulated by severity, relationship to study drug, 
and by treatment group.  
In the summaries showing severity and relationship to study medication at each level of 
summarization (System Organ Class and Preferred Term) subjects who reported more than one 
adverse event will be counted only once for the maximum severity (mild, moderate, severe) and 
strongest relationship (not related, unlikely, possible, probable, definitely related).   
If a particular event is missing the severity and/or relationship, then the strongest possible 
severity or relationship will be assumed for analysis (severity = severe, relationship = definitely 
related). 
A treatment related AE is any AE with a relationship to the study drug of possible, probable, and 
definitely related. 
A summary of incidence rates (frequencies and percentages) of AEs leading to discontinuation of 
study drug, grouped by MedDRA system organ class and preferred term, will be prepared by 
treatment group and overall.  
A data listing of AEs leading to discontinuation of study drug will also be provided, displaying 
details of the event(s) captured on the CRF. 
Any deaths that occur during the study will be listed. 
Serious adverse events will be listed.  The number and percent of subjects reporting SAEs, 
grouped by MedDRA system organ class and preferred term, will be tabulated by severity, 
relationship to study drug and by treatment group. The same split of four groups as for AEs will 
be prepared. 
 
9.3.2 Clinical Laboratory Evaluations 
Laboratory test results will be listed. 
Laboratory values that are outside the normal range will be flagged in data listings. 
Laboratory test results will be summarized descriptively by treatment and visit as both observed 
values and change from baseline values. 
The number of subjects with clinical laboratory values below, within, or above the normal range 
by visit and in relation to baseline will be tabulated for each clinical laboratory analyte by 
treatment group (shift table). 
 
9.3.3 Electrocardiograms 
ECG results (normal/abnormal) will be listed. Clinically significant abnormalities will be 
flagged. 
Descriptive summaries will be presented for ECG measures of QT interval and HR. These 
summaries will be presented by visit and treatment group. 


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The number and percentage of subjects with normal and abnormal ECG results will be 
summarized by treatment group.  
 
9.3.4 Vital Signs 
Descriptive summaries of actual values and changes from baseline will be calculated for body 
temperature, pulse rate, and blood pressure.  
Clinically relevant abnormalities of BP and HR should be flagged. 
Vital signs values that are outside the normal range will be flagged in data listings. Shift tables will also 
be provided. 
9.3.5  Physical Examination 
Physical examination results(normal/abnormal) will be listed and summarized by body system, 
by time points and treatment group. 
 
10. PHARMACOKINETIC ANALYSIS 
Trough values of tesofensine and metoprolol will be listed and summarized descriptively. A 
figure with the concentrations of tesofensine and metoprolol versus time will be prepared. 
 
11. EFFICACY ANALYSIS 
Analyses of efficacy endpoints will be based on the mITT Population. 
Additionally, sensitivity analysis may be performed on the PPP in case mITT and PPP differ. 
Continuous secondary efficacy endpoints will be compared between treatment arms by means 
using Analysis of Covariance (ANCOVA) including treatment as fixed factor and baseline value 
as covariate. Estimates and 95% confidence intervals of treatment differences will be calculated. 
During the double-blind phase changes from Baseline to week 24 will be compared between 
treatment arms. 
 
During the open-label extension, the treatment arms will be based on the treatments assigned 
during the double-blind phase. 
 First, changes from Baseline to week 24 then between Baseline and week 48 will be compared 
between treatment arms.  Additionally, changes from week 24 to week 48 may be compared 
between treatment arms.  When comparing changes from Baseline to week 48 and from week 24 
to week 48 the Baseline value will still be Day 1 value. 
 


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12. INTERIM ANALYSIS 
No interim analysis is planned. 
 
13. CHANGES IN THE PLANNED ANALYSIS 
The Statistical Analysis Plan (SAP) will be finalized before the database lock. Should any 
additional changes of the statistical analysis be implemented, they will be described in the 
corresponding section of the final study report. 
 
14. MOCK TABLES, LISTINGS AND FIGURES (TLFS) 
The study TLF shells will be provided in a separate document, which will show the content and 
format of all tables, listings, and figures in detail. 
All ICH required data in the database will be presented in data listings.  
Data will be displayed as described in this SAP and in the supporting, separate TFL shells 
document(s).  
If there is no data available for a table or listing (e.g., no deaths occurred in the study), the 
planned output will be displayed as “No data to report”. 
 
15. REFERENCES 
 
1. US Federal Register. (1998) International Conference on Harmonization; Guidance on 
Statistical Principles for Clinical Trials. Department of Health and Human Services: Food 
and Drug Administration [Docket No. 97D-0174]. Federal Register Volume 63, Number 
179, pages 49583-49598. September 16, 1998.