Conditions: Type 2 Diabetes Mellitus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 60
Healthy volunteers: no

Brief summary:
Safety and Efficacy Study of Tesofensine/Metoprolol Treatment in Subjects With Type 2 Diabetes Mellitus

Detailed description:
This is a double-blind, randomized, placebo-controlled, multiple-dose, two-center, safety and efficacy study of co-administration of tesofensine/metoprolol treatment in subjects with T2DM. Study medication will be administered for ninety (90) days (+2 days after the final assessments with half-dose of metoprolol). Following all baseline assessments, eligible subjects will be randomly assigned to one of the two arms (1:1).

Arms:
arm 1: Oral tablets Tesofensine/Metoprolol arm 2: Placebo tablets matching oral Tesofensine/Metoprolol

Interventions: intervention 1: Tesofensine/Metoprolol intervention 2: Placebo
Intervention descriptions: intervention 1: Tesofensine 0.5 mg + Metoprolol 100 mg intervention 2: None

Protocol document:
Prot_000.pdf: 
    
 
Version: 4.0  
Protocol number: TM001 
 
 
Date: 09 Mar 2016 
 
 
  
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, 
MULTIPLE-DOSE, TWO-CENTRE, SAFETY AND EFFICACY 
STUDY OF CO-ADMINISTRATION OF 
TESOFENSINE/METOPROLOL TREATMENT IN SUBJECTS WITH 
TYPE 2 DIABETES MELLITUS 
  
 
 
Sponsor:   
 
Saniona, A/S 
 
 
 
Baltorpvej 154 
 
 
 
DK2750 Ballerup 
 
 
 
Denmark 
 
 
 
 
 
Protocol number: 
TM001 
EudraCT number: 
2015-005522-19 
 
 
 
 
 
 
 
 
 
The information contained in this document is provided in confidence. It is understood that 
this information will not be disclosed to others without prior agreement with Saniona A/S, 
according to the statement in the clinical study protocol, and in accordance with the 
confidentiality agreement. 


 
 
 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
 
Study Title 
A double-blind, randomized, placebo-controlled, multiple-dose, 
two-center, safety and efficacy study of co-administration of 
tesofensine/metoprolol treatment in subjects with type 2 
diabetes mellitus (T2DM) 
Study Sponsor 
Saniona, A/S 
Baltorpvej 154 
DK2750 Ballerup 
Denmark 
Phase 
2a 
Number of sites 
2 sites (Units) in Germany
Sample size 
60, 30 per treatment group (2 groups)
Study design 
Two-center, double-blind, placebo-controlled, randomized, and 
multiple-dose clinical study 
Study timelines 
January 2016 – December 2016
IMP and Dosing 
schedule 
Arm 1) tesofensine 0.5 mg + metoprolol 100 mg 
administered once a day, in the morning with a meal (the first 2 
days a loading dose of 1.0 mg/d of tesofensine will be given) 
or  
Arm 2) Placebo tablets matching oral tesofensine + metoprolol 
administered once a day, in the morning with meal (the first 2 
days a loading dose of 1.0 mg/d of placebo tesofensine will be 
given)  
Each tablet will be formulated separately; a currently available 
commercial formulation of metoprolol, MetoHEXAL® 100 mg 
retard, will be used. 
Study objectives 
Primary objective: 
• To compare the effects of co-administration of 
tesofensine/ metoprolol treatment vs. placebo on 24-
hour mean heart rate 
Secondary objectives: 
• To compare the effects of co-administration of 
tesofensine/ metoprolol treatment vs. placebo on 
systolic and diastolic blood pressure 
• To demonstrate a positive effect of co-administration of 
tesofensine/ metoprolol treatment on: 
o body weight 
o glycaemic endpoints 
o body composition (liver fat) 
• To evaluate overall safety and tolerability of co-
administration of tesofensine/metoprolol treatment 
Study population 
(inclusion/exclusion 
criteria) 
60 males and females subjects with confirmed diagnosis of 
T2DM between 18-70 years 
Inclusion criteria 
1. Males and females 


 
 
 
 
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2. Confirmed diagnosis of T2DM (either by being on  
anti-diabetic medication or by confirmed or repeated 
laboratory findings) 
3. 18-70 years of age 
4. Normal BP or well managed hypertension (only if 
dose of BP medication(s) has been stable for at least 
two months) 
5. Normal lipid profile or well managed dyslipidemia 
(only if dose of lipid-lowering medication(s) has 
been stable for at least 2 months) 
6. No history of CV or any other major disease 
7. On any dose of metformin stable for at least two 
months, or 
8. On any dose of metformin plus one other oral 
antidiabetic agent (except TZDs); the other oral 
agent will be washed out prior to randomization 
9. HbA1c ≥7.0% 
Exclusion criteria 
1. BP >140/90 (excluding white-coat hypertension; 
therefore, if a repeated measurement shows values 
within the range, the subject can be included in the 
trial) 
2. HbA1c > 8.5% 
3. Fasting plasma glucose > 200 mg/dl at screening 
4. HR ≥ 90, <50 bpm 
5. BMI < 27 kg/m2 
6. Hypersensitivity to tesofensine/metoprolol 
7. Heart failure class II or greater according to the New 
York Heart Association (NYHA) or decompensated 
heart failure 
8. History of myocardial infarction or stroke within 12 
months prior to enrolment 
9. History of coronary revascularization or angioplasty 
in the last 12 months prior to enrolment 
10. Patients reporting angina in the last 6 months prior 
to enrolment 
11. Treatment with insulin and/or other injectable anti-
diabetic medications, or TZDs 
12. Any clinically significant cardiac arrhythmia 
13. Treatment with calcium channel blockers or beta 
blockers or their combination 
14. Current treatment with medications which should 
not be co-administered according to the excluded 
medications list (Appendix I) 
15. Concomitant use of monoaminooxidase inhibitors 
16. Bulimia or anorexia nervosa 
17. Any agent used for weight loss within the last 3 
months 


 
 
 
 
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18. Patients with history of major depressive disorder or 
any history of suicide attempt/ideation  
19. Patients with family history of severe psychiatric 
diseases 
20. Patients using selective serotonin reuptake inhibitors 
(SSRIs), antidepressants or anxiolytics. 
21. PHQ-9 (Patient Health Questionannire) score ≥ 10 
or any score > 0 on question 9 
22. Females of childbearing potential who are pregnant, 
breast-feeding or intend to become pregnant or are 
not using highly effective contraceptive methods or 
postmenopausal women being amenorrheic for less 
than 1 year and not using highly effective 
contraceptive methods 
23. Contraindications to administration of metoprolol 
per current summary of product characteristics 
24. Untreated hypo- or hyperthyroidism 
25. Clinically significant liver (>3xULN) and/or kidney 
impairment (GFR <45 ml/min) 
26. More than 5% weight loss within the last 3 months 
27. Any clinically significant history of hypotension 
28. Any other clinically meaningful condition, in the 
opinion of the investigator, which would make 
participation potentially unsafe 
29. Inability to undergo a MRS scan for any reason 
Study procedures 
Following screening, eligible subjects will be instructed to 
maintain their diet, metformin treatment, anti-hypertensive  and 
dyslipidemic  management, if any. Any other anti-diabetic 
treatments will be washed out. 
Within three to 28 days following the screening, the subjects 
will be admitted to the Unit in the evening (Day -2) and 
undergo all the baseline assessments, including the 24-h 
endpoint assessments, starting the following morning (Day -1).  
The next morning (Day 1) randomization will be performed and 
the first dose of study medication will be administered, lifestyle 
(dietary) counselling will be performed and subjects will 
receive medication supply for up to 8 days.  
On Days 7, 14, 21, 28, 42, 56, and 70 the subjects will come 
back to the Unit for basic safety evaluations and medication 
supply.  
Dispense of study medication will be done for either for 8 days 
(visits 2, 3, 4, 5), 15 days (visits 6, 7, 8) or 20 days (visit 9).  
Visits on days 28 and 56 will also include some additional 
assessments (see the schedule of events for details).  
On Day 89 the subjects will come in for the final admission. 
Final 24-h endpoint assessments will be initiated on Day 90, 
which will also be the last day the subjects receive the study 


 
 
 
 
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medication.  
On Day 91 the subjects will be released.  In order to gradually 
reduce the dose of metoprolol and avoid potential undesirable 
fluctuation in blood pressure, the subjects will be given two 
dosages of half-dose of metoprolol to be taken at home, one 
dosage each day over the next two days.  
Subjects in study arm 1) will receive the active medication, 
subjects in arm 2) will receive placebo.  
On Day 98 a phone call visit for a safety check will be 
performed and will be followed by a final visit at the Unit on 
Day 110 for a final efficacy and safety assessments. This will 
conclude subjects’ participation in the study.   
Subjects who during the study (throughout the whole trial) 
exceed predefined values of FPG >220 mg/dl (12.2 mmol/l) on 
two consecutive mornings, should contact the investigator to 
have the FPG checked at the unit. If FPG is still >220 mg/dl 
(12.2 mmol/l) or if HbA1c is ≥9% during an on-site 
measurement, the subject should be withdrawn from the study 
and will be referred to his/her personal physician for further 
treatment. Subjects who during the treatment period exceed BP 
systolic values >160, <100 mmHg, or diastolic >100, <60 
mmHg on two consecutive mornings and confirmed at the 
investigational site will be withdrawn from the study. 
Statistics 
The primary endpoint will be compared between treatment 
arms by means of an ANCOVA model including treatment as 
fixed factor and baseline value as covariate. Least square means  
and 95% confidence of treatment differences will be estimated. 
Analysis will be based on the Per Protocol Population.  
Analysis of safety endpoints will include all subjects of the 
Safety Analysis Set. Continuous data will be summarized using 
non-missing counts, mean, standard deviation, median, 
minimum, and maximum. Categorical data will be summarized 
using counts and percentages. Frequencies of AEs will be 
analyzed using a logistic regression model. Odds ratios, p-
values, and 95% confidence intervals for the comparisons 
between treatments will be estimated. Other secondary and 
exploratory endpoints will be analyzed using the same 
procedure as described for the primary endpoint. 
As this is an explorative study no formal sample size 
calculation was done. The chosen sample size is a balance 
between exposing the lowest possible number of patients to the 
study medications, while still being able to compare the effects 
of co-administration of tesofensine/metoprolol treatment vs. 
placebo. 
 


 
 
 
 
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INVESTIGATOR STATEMENT 
 
 
TM001: A double-blind, randomized, placebo-controlled, multiple-dose, two-center, safety 
and efficacy study of co-administration of tesofensine/metoprolol treatment in subjects with 
type 2 diabetes mellitus (T2DM). 
I understand that this Clinical Study Protocol contains information that is confidential and 
proprietary to Saniona A/S. I hereby declare, that I will keep all information obtained from my 
participation in this Clinical Study confidential unless otherwise agreed in writing. 
 
I have read the Clinical Study Protocol and I understand the information. With my signature, I 
agree to conduct this Study in accordance with the protocol, ICH-GCP guidelines, Declaration 
of Helsinki and with all applicable local law and regulatory requirements.  
 
I will discuss the contents of this Clinical Study Protocol to all those authorized study staff, 
which will assist me in conducting this study in order to ensure that they are fully informed 
about the Investigational Medicinal Product (IMP) and the course of the Study. 
 
If required, I will also provide necessary protocol information to the responsible Ethics 
Committee (EC) and/or to the Regulatory Authorities (BfArM) 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. 
 
Grit Andersen, MD 
____________________________________________________________________ 
 
Coordinating Investigator 
Signature: 
Date: 
Profil Institut für Stoffwechselforschung GmbH 
Hellersbergstr. 9 
D-41460 Neuss 
Germany 
 
 


 
 
 
 
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SIGNATURE PAGE 
 
 
TM001: A double-blind, randomized, placebo-controlled, multiple-dose, two-center, safety 
and efficacy study of co-administration of tesofensine/metoprolol treatment in subjects with 
type 2 diabetes mellitus (T2DM). 
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 
____________________________________________________________________ 
 
Medical Director 
Signature: 
Date: 
Saniona, A/S 
Baltorpvej 154 
DK2750 Ballerup 
Denmark 
 
 
Tim Heise, MD 
____________________________________________________________________ 
 
Lead Scientist 
Signature: 
Date: 
Profil Institut für Stoffwechselforschung GmbH 
Hellersbergstr. 9 
D-41460 Neuss 
Germany 


 
 
 
 
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TABLE OF CONTENTS 
 
1 
LIST OF ABBREVIATIONS ____________________________________________________________ 11 
2 
GENERAL INFORMATION ____________________________________________________________ 12 
2.1 
INTRODUCTION ________________________________________________________________ 12 
3 
STUDY OBJECTIVES AND ENDPOINTS_________________________________________________ 14 
3.1 
OBJECTIVES ___________________________________________________________________ 14 
3.2 
ENDPOINTS (Baseline = Day -1/1; End of treatment = Day 90/91) ________________________ 14 
4 
OVERALL STUDY DESCRIPTION ______________________________________________________ 14 
4.1 
STUDY FLOW CHART: VISITS 1 - 6 (all visits are ±1 day) _____________________________ 16 
4.2 
STUDY FLOW CHART: VISITS 7 - 12 (all visits are ±1 day) ____________________________ 18 
4.3 
STUDY DESIGN _________________________________________________________________ 19 
Visit 1 Screening (Day -28 to -5) _________________________________________________________ 19 
Baseline visit 2a (Day -2 to -1): __________________________________________________________ 20 
Randomization visit 2b (Day 1): __________________________________________________________ 21 
Treatment period: _____________________________________________________________________ 22 
Visits 3, 4 and 5 (Day 7, 14, 21) __________________________________________________________ 22 
Phone call visit on Day 98 will be scheduled and subjects will be invited for the final follow up visit on Day 
110. ________________________________________________________________________________ 25 
Visit 11 Follow-up (Day 98) - Telephone contact_____________________________________________ 25 
Visit 12 End of study (Day 110) __________________________________________________________ 25 
4.4 
END OF STUDY _________________________________________________________________ 25 
4.5 
STUDY PARTICIPANTS _________________________________________________________ 26 
4.6 
INCLUSION CRITERIA __________________________________________________________ 26 
4.7 
EXCLUSION CRITERIA _________________________________________________________ 26 
4.8 
SCREENING FAILURES _________________________________________________________ 27 
4.9 
DISCONTINUATION CRITERIA __________________________________________________ 27 
4.10 
WITHDRAWAL CRITERIA ______________________________________________________ 27 
4.11 
REPLACEMENT OF WITHDRAWN SUBJECTS ____________________________________ 28 
4.12 
PREMATURE STUDY DISCONTINUATION ________________________________________ 28 
4.13 
EARLY TERMINATION OF A STUDY SITE ________________________________________ 28 
4.14 
STUDY SITES ___________________________________________________________________ 28 
4.15 
STUDY DURATION _____________________________________________________________ 29 
4.16 
BENEFITS AND RISKS FOR STUDY PARTICIPANTS _______________________________ 29 
5 
TREATMENT OF STUDY PARTICIPANTS _______________________________________________ 30 
5.1 
DESCRIPTION OF STUDY MEDICATION _________________________________________ 30 
Investigational Medicinal Product ________________________________________________________ 30 
Placebo _____________________________________________________________________________ 30 
5.2 
PROCEDURES TO ASSURE DOUBLE BLINDING ___________________________________ 30 
5.3 
IMP HANDLING PROCEDURES AT THE UNIT’S PHARMACY _______________________ 31 
5.4 
LABELS FOR STUDY MEDICATION ______________________________________________ 33 


 
 
 
 
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5.5 
PACKAGING AND DESTRUCTION _______________________________________________ 33 
5.6 
HANDLING OF THE STUDY MEDICATION ________________________________________ 33 
5.7 
SUPPLY AND STORAGE OF THE STUDY MEDICATION ____________________________ 33 
Study medication supplies_______________________________________________________________ 33 
Study medication storage _______________________________________________________________ 34 
5.8 
STUDY MEDICATION COMPLIANCE _____________________________________________ 34 
5.9 
SCREENING AND RANDOMISATION _____________________________________________ 34 
5.10 
UNBLINDING ___________________________________________________________________ 35 
5.11 
DISPENSATION OF STUDY MEDICATION ________________________________________ 35 
5.12 
ACCOUNTABILITY OF THE STUDY MEDICATION ________________________________ 35 
5.13 
CONCOMITANT MEDICATION __________________________________________________ 36 
5.14 
PROHIBITED MEDICATION _____________________________________________________ 36 
5.15 
STUDY PROCEDURES AND OTHER EXAMINATIONS ______________________________ 36 
Informed Consent _____________________________________________________________________ 36 
Vital Signs ___________________________________________________________________________ 36 
Physical Examination __________________________________________________________________ 36 
Blood pressure measurement ____________________________________________________________ 36 
5.16 
LABORATORY EVALUATIONS __________________________________________________ 39 
5.17 
SUBJECTS’ DIARIES /CARDS ____________________________________________________ 40 
6 
SAFETY REPORTING _________________________________________________________________ 40 
6.1 
DEFINITIONS __________________________________________________________________ 40 
6.2 
ADVERSE EVENT _______________________________________________________________ 40 
6.3 
UNEXPECTED ADVERSE REACTION _____________________________________________ 42 
6.4 
SERIOUS ADVERSE EVENT _____________________________________________________ 42 
6.5 
SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION _______________________ 43 
6.6 
PROCEDURES FOR RECORDING ADVERSE EVENTS ______________________________ 43 
6.7 
REPORTING OF ADVERSE EVENTS ______________________________________________ 43 
Pre-existing Conditions _________________________________________________________________ 44 
Overdose ____________________________________________________________________________ 44 
Pregnancy ___________________________________________________________________________ 44 
6.8 
REPORTING PROCEDURES FOR SERIOUS ADVERSE EVENTS _____________________ 45 
6.9 
FOLLOW-UP OF ADVERSE EVENTS ______________________________________________ 46 
6.10 
DEVELOPMENT SAFETY UPDATE REPORTS _____________________________________ 46 
7 
DESCRIPTION OF STATISTICAL METHODS ____________________________________________ 46 
7.1 
DESCRIPTION OF STATISTICAL METHODS ______________________________________ 46 
7.2 
SAMPLE SIZE CALCULATION ___________________________________________________ 47 
7.3 
SELECTION OF SUBJECTS FOR ANALYSES ______________________________________ 47 
7.4 
STATISTICAL METHODS ________________________________________________________ 47 
7.5 
ANALYSIS OF THE PRIMARY ENDPOINT ________________________________________ 48 
7.6 
ANALYSIS OF THE SECONDARY & EXPLORATORY ENDPOINTS __________________ 48 
7.7 
SAFETY CRITERIA _____________________________________________________________ 48 


 
 
 
 
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7.8 
INTERIM ANALYSIS ____________________________________________________________ 49 
No interim analysis is planned. ___________________________________________________________ 49 
8 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ______________________________________ 49 
8.1 
SOURCE DATA _________________________________________________________________ 49 
8.2 
SUBJECT IDENTIFICATION LIST AND SCREENING LOG __________________________ 50 
9 
QUALITY CONTROL AND QUALITY ASSURANCE ________________________________________ 50 
9.1 
DEFINITIONS __________________________________________________________________ 50 
Quality Assurance _____________________________________________________________________ 50 
Quality Control _______________________________________________________________________ 50 
9.2 
AUDITS AND INSPECTIONS _____________________________________________________ 51 
10 ETHICS _____________________________________________________________________________ 51 
10.1 
BASIC PRINCIPLES AND ETHICAL CONSIDERATIONS ____________________________ 51 
10.2 
APPROVALS ___________________________________________________________________ 51 
10.3 
ETHICS COMMITTEE ___________________________________________________________ 51 
10.4 
REGULATORY AUTHORITY _____________________________________________________ 51 
10.5 
PROTOCOL MODIFICATIONS ___________________________________________________ 51 
10.6 
SUBJECT INFORMATION AND INFORMED CONSENT _____________________________ 52 
10.7 
PARTICIPANT CONFIDENTIALITY ______________________________________________ 52 
10.8 
INVESTIGATOR QUALIFICATION _______________________________________________ 52 
11 DATA HANDLING AND RECORD KEEPING _____________________________________________ 53 
11.1 
DATA COLLECTION AND DOCUMENTATION ____________________________________ 53 
11.2 
STUDY MONITORING AND SOURCE DATA VERIFICATION ________________________ 53 
11.3 
DATA MANAGEMENT PLAN_____________________________________________________ 53 
11.4 
CASE REPORT FORMS (CRFS) ___________________________________________________ 53 
11.5 
INVESTIGATOR FILE ___________________________________________________________ 54 
11.6 
USED SUBJECT AND MEDICATION LOGS ________________________________________ 54 
11.7 
PROTOCOL COMPLIANCE ______________________________________________________ 54 
11.8 
RECORD KEEPING _____________________________________________________________ 54 
12 FINANCE AND INSURANCE __________________________________________________________ 55 
12.1 
COMPENSATION TO INVESTIGATOR ____________________________________________ 55 
12.2 
INSURANCE AND INDEMNITY ___________________________________________________ 55 
13 PUBLICATION POLICY _______________________________________________________________ 55 
13.1 
REPORTING AND PUBLICATION ________________________________________________ 55 
14 REFERENCES _______________________________________________________________________ 56 
15 Appendices ___________________________________________________________________________ 57 
15.1 
Appendix I: table of recommended concomitant medication use _________________________ 577 
15.2 
Appendix II: The Patient Health Questionnaire (PHQ-9; Version in German) _____________ 599 
 
 


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


 
 
 
 
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2 GENERAL INFORMATION 
 
2.1 
INTRODUCTION 
Etiology and treatment of diabetes mellitus   
There are about 280 million people worldwide suffering from Type 2 diabetes (T2DM) and 
this number is increasing every year. T2DM is the most common form of diabetes, which is 
caused by a combination of factors, including insulin resistance, inadequate insulin secretion, 
and excessive or inappropriate glucagon secretion. There is now undisputable body of 
evidence linking the increasing incidence and prevalence of T2DM with obesity (1), more 
specifically excessive accumulation of body fat in certain compartments, particularly the liver 
(2). The presence of obesity, visceral and hepatic adiposity leads to cellular and systemic 
dysfunction at many levels – dysregulated glucose production and release by the liver, altered 
response to insulin signalling, impaired glucose uptake by insulin responsive tissues, 
pancreatic beta cell dysfunction, release of inflammatory and pro-coagulant factors, altered 
metabolism on insulin itself, and many others (3). 
 
Lifestyle changes, particularly those aimed at reducing body fat are a staple of treatment of all 
subjects with T2DM worldwide. Indeed, weight loss of 5-10% of bodyweight, irrespective of 
how it is achieved, is associated with improvements in cardiovascular risk profiles and reduce 
incidence of type 2 diabetes. The Diabetes Prevention Program proved that people with pre-
diabetes at high risk of developing type 2 diabetes could sharply lower their risk by losing 
weight through regular physical activity and a diet low in fat and calories (4). In 2009, a 
follow-up study of Diabetes Prevention Program Outcomes Study showed that the benefits of 
weight loss lasted for at least 10 years after the original study began (5). This benefit of 
weight loss has been repeatedly proven with other means of inducing weight loss (6,7). 
Overall, it is now clear that reduction in body weight (fat) has direct benefits on both 
developing T2DM and improving glycaemic control in those with overt T2DM. 
 
Current treatment strategies 
Lifestyle changes, particularly improved diet and increased physical activity remain a 
cornerstone of modern management of subjects with T2DM. However, only very motivated 
individuals can achieve adequate, long-term, glycaemic control with lifestyle intervention 
only. Thus, almost all subjects with the disease require pharmacological therapy very soon 
and many of them ultimately need some form of insulin replacement. Pharmacologic therapy 
of T2DM has changed dramatically in the last 10 years, with new drugs and drug classes 
becoming available. Availability of variety of drugs with different mechanisms of action 
allowed the use of combination therapy, often with improvement in glycaemic control, which 
was previously beyond the reach of medical therapy. More importantly, combination therapy 
can significantly delay need for insulin replacement.  
 
Despite all of these advances treatment of T2DM remains an area of unmet medical need as 
none of the therapies actually treats the underlying pathology: they are all symptomatic and 
the disease invariably progresses with many deleterious consequences. Thus, novel therapies 
are needed, particularly those able to directly address the underlying causes of the diseases. 
 
Overview of tesofensine  
Tesofensine was initially studied for the treatment of Parkinson and Alzheimer’s diseases. 


 
 
 
 
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However, clinical studies showed only a limited efficacy of tesofensine, but weight loss was 
noted in majority of participants, despite the fact that they did not attempt to lose weight. 
Tesofensine is an inhibitor of monoamine presynaptic reuptake of the neurotransmitters 
noradrenaline, dopamine and serotonin. This means it influences these chemicals in the brain 
to suppress appetite. Tesofensine demonstrated strong weight reducing effects in Phase 2 
clinical studies in obese subjects, exceeding benchmarks set by the regulatory agencies for 
approval of weight loss agents (8). Also, post-hoc analysis of the data from the Phase 2 
obesity study showed that individuals with pre-diabetes in these studies experienced a 
favorable reduction in body weight and glycaemic endpoints while on tesofensine.  
 
In general, tesofensine was well tolerated in humans. However, blood pressure and heart rate 
increase observed with the therapeutically relevant doses of tesofensine (0.25 mg and 0.5 mg) 
were 1–3 mmHg and up to 8 bpm, respectively (8). These increases could potentially have an 
adverse impact on the cardiovascular safety in the target subject population. This lead to the 
addition of metoprolol to mitigate these effects and provide a favorable benefit/risk profile. 
For more information on tesofensine please see the Investigators’ Brochure (Version 12). 
  
Overview of metoprolol 
Metoprolol is a beta1-selective (cardio selective) adrenoceptor blocking agent, for oral 
administration, which has been approved in the 70’s and has been one of the most widely 
prescribed medicines to date. It is indicated for hypertension, angina pectoris and heart failure. 
It is now available as extended-release tablets. MetoHEXAL® 100 mg retard, containing 100 
mg of metoprolol tartrate, has been formulated to provide a controlled and predictable release 
of metoprolol for once-daily administration. This is also the formulation selected for this 
study (for more information please see the Summary of Product Characteristics of 
MetoHEXAL® 100 mg retard ). 
 
Overview of tesofensine/metoprolol 
In a pre-clinical study in rats the co-administration of tesofeninse+metoprolol showed a HR 
and BP profile similar to placebo (vehicle) while the weight-reducing efficacy was maintained 
(9). In addition, in a drug-drug interaction study in healthy male subjects addition of short 
acting metoprolol on the background of chronic dosing with tesofensine showed a short term, 
but substantial, reduction in HR previously increased by tesofensine. Taken together, the 
available data support the concomitant use of tesofensine and a beta-blocker such as 
metoprolol as an investigational agent for the proposed indication of treatment of T2DM. 
 
Purpose of the Comparison to Placebo 
Double blind, placebo-controlled design is the gold standard in evaluation of efficacy and 
safety of new drugs. It provides the most rigorous and unbiased evaluation of the true effects 
of an intervention. This design was chosen because it is critical to thoroughly assess whether 
the addition of metoprolol truly mitigates the elevation in HR and BP observed with 
tesofensine 
monotherapy 
as 
well 
as 
the 
efficacy 
of 
co-administration 
of 
tesofensine/metoprolol in the treatment of T2DM. 
 
Purpose of this study 
The purpose of this study is to investigate the safety and efficacy of co-administration of 
tesofensine/metoprolol treatment versus placebo. 


 
 
 
 
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3 STUDY OBJECTIVES AND ENDPOINTS 
 
3.1 
OBJECTIVES 
Primary objective:    
• To compare the effects of co-administration of tesofensine/metoprolol treatment vs. 
placebo on 24-hour mean heart rate 
 
Secondary objectives: 
• To compare the effects of co-administration of tesofensine/metoprolol treatment vs. 
placebo on systolic and diastolic blood pressure 
• To demonstrate a positive effect of co-administration of tesofensine/metoprolol 
treatment on: 
o body weight 
o glycaemic endpoints 
o body composition (liver fat) 
• To 
evaluate 
overall 
safety 
and 
tolerability 
of 
co-administration 
of 
tesofensine/metoprolol treatment 
 
3.2 
ENDPOINTS (Baseline = Day -1/1; End of treatment = Day 90/91) 
Primary endpoint 
• Change from baseline to end of treatment in mean 24 hour HR  
 
Secondary endpoints 
• Change from baseline to end of treatment in mean SBP 
• Change from baseline to end of treatment in mean DBP 
• Change from baseline to end of treatment in body weight 
• Change from baseline to end of treatment in HbA1c 
• Change from baseline to end of treatment in FPG 
• Change from baseline to end of treatment in 9-point blood glucose profile 
 
Other endpoints 
• Change from baseline to end of treatment in liver fat 
• Change in fasting insulin from baseline to end of treatment 
• Change in 1,5 anhydroglucitol from baseline to end of treatment 
• Change from baseline to end of treatment in waist circumference 
• Change from baseline to end of treatment in PHQ-9 score 
• Safety: Adverse events (AEs), clinical laboratory findings, electrocardiogram (ECG) 
• Number and severity of hypoglycaemic events 
 
4 OVERALL STUDY DESCRIPTION 
This is a double-blind, randomized, placebo-controlled, multiple-dose, two-center, safety and 
efficacy study of co-administration of tesofensine/metoprolol treatment in subjects with 
T2DM. Study medication will be administered for ninety (90) days (+2 days after the final 
assessments with half-dose of metoprolol). Following all baseline assessments, eligible 
subjects will be randomly assigned to one of the two arms (1:1). 
 


 
 
 
 
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Screening: Subjects who give the written informed consent will be screened for the study.  
For subjects on any anti-diabetic medications, treatment with all anti-diabetic medications 
except metformin will be washed out. The subjects will return for a baseline visit at the end of 
the wash-out period (1-4 weeks). During the wash-out period the subjects will be asked to 
check the FPG every day.  If during the wash-out period the FPG is >12.2 mmol/l, it should 
be re-checked the next morning. Given the FPG is still >12.2 mmol/l, the subjects should 
contact the investigator to have the FPG level checked at the Unit. If FPG is still >12.2 
mmol/l or if HbA1c is ≥9% during an on-site measurement, the subjects should be withdrawn 
from consideration for the study.  
All subjects will be instructed to maintain their anti-hypertensive and dyslipidemic 
management, if any. Subjects who at screening are receiving diet treatment and/or metformin 
treatment only for their diabetes will be invited for the baseline visit after a minimum of 3 
days (i.e. do not require a washout of other anti-diabetic medication). In addition, mood and 
suicidal ideation will be assessed using a validated PHQ-9 mood scale at screening, baseline 
and on subsequent visits. 
Baseline: Subjects will be admitted to the Unit (investigational site) in the evening of Day -2 
to undergo all baseline assessments. MRS assessment should be performed at Day -2 (in a 
sub-set). BP measurements will be initiated at Day -2 (six (6) BP measurements in total 
should be performed during the course of subject’s admission, until Day 1 morning). The 24-h 
HR monitoring and 9-point glucose profile assessments will start in the morning of Day -1 
and will be completed in the morning of Day 1. Blood draw to establish the baseline for all 
measure endpoints will be drawn in the morning of Day 1.  
 
Randomisation: Following the completion of all baseline assessments on Day 1, eligible 
subjects will be randomized in equal numbers to double-blind treatment with co-
administration of tesofensine/metoprolol or placebo. The first dose of study medication will 
be administered on Day 1 (subjects will also be stratified based on their background anti-
diabetic therapy – on metformin vs. metformin + other agents). Lifestyle (dietary) counselling 
will be performed and subjects will receive medication supply for 8 days and will be released 
from the Unit. 
 
Treatment period: after the Day 1, subjects will visit the Unit weekly - on Days 7, 14, 21 for 
safety evaluations and medication supply until Day 28 (visit 6). Subjects will receive 
medication supply for up to 8 days (dispensed during the visits 3, 4, 5). After the Day 28, 
subjects will be assessed at interval of 2 weeks on Days 42 and 56 (visits 7, 8), and at interval 
of 19 days on Day 70 (visit 9). Study medication will be dispensed for up to 15 days during 
each visit 6, 7, 8 and up to 20 days at visit 9. Visits on days 28 and 56 will also include 
additional assessments for efficacy evaluation. 
 
Final admission: In the afternoon/evening of Day 89 subjects will come in for the final 
admission. MRS assessment should be performed at Day 89 (in a sub-set). BP measurements 
will be initiated at Day 89 (six (6) BP measurements in total should be performed during the 
course of subject’s admission, until Day 91 morning). Final 24-h HR monitoring and 9-point 
glucose profile assessments will be initiated in the morning of Day 90, which will also be the 
last day when subjects receive the study medication. During the Day 90 the blood will be 
collected for metabolic endpoint as well as safety measurements. On Day 91 the 24-h 


 
 
 
 
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assessments will be completed and then subjects will be released and they receive two days of 
half-dose dose of metoprolol to take at home in order to gradually reduce the dose of 
metoprolol and avoid potential undesirable fluctuation in blood pressure; however, only the 
subjects in the study arm 1) will receive the active medication, subjects in the arm 2) will 
receive placebo.  
Final follow up visit: on Day 98 phone call will be performed to check subjects’ status and 
potential AE(s). Subjects will come in for a final efficacy and safety assessment on Day 110. 
This will conclude their participation in the study and subjects will be instructed to go back to 
their primary care physician to restart their regular diabetes management.   
 
Subjects who during the study (throughout the whole trial; from screening until the end of 
study) exceed predefined values of FPG >220 mg/dl (12.2 mmol/l) on two consecutive 
mornings should contact the investigator to have the FPG checked at the unit. If FPG is still 
>220 mg/dl (12.2 mmol/l) or if HbA1c is ≥9% during a on-site measurement,  the subject 
should be withdrawn from the study and will be referred to his/her personal physician for 
further treatment.  
 
Blood pressure measurement devices must be available for the subjects for monitoring BP 
outside the in-house periods and until the follow-up visit. Subjects will be advised to measure 
BP every morning. Subjects who during the treatment period have consecutive measures of 
BP systolic >160, <100 mmHg or diastolic >100, <60 mmHg on two consecutive days must 
contact the investigator. Subjects with symptoms of hypotension must also contact the 
investigator immediately. The subject will be excluded from the study after confirmation at 
investigational site of the BP values outside the mentioned range.  
 
Assessments conducted during each visit are described in the schedule of events. 
 
4.1 
STUDY FLOW CHART: VISITS 1 - 6 (all visits are ±1 day) 
Visit 
1 
 
 
Screening 
 
 
 
OP 
2a 
 
 
Baseline 
 
 
 
IP 
2a 
 
 
Baseline 
 
 
 
IP 
2b 
 
 
Randomisat
ion 
 
 
IP 
3, 4, 5 
 
 
 
 
 
 
OP 
6 
 
 
 
 
 
 
OP 
Day 
-28 to -5* 
-2 
 -1 
1 
7,14,21 
28 
ICF, Inclusion/ 
Exclusion 
X 
X f 
 
 
 
 
Physical examination, 
height, BMI 
X 
 
 
 
 
 
Med. History/ 
demographics 
X 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
PHQ-9 Score 
X 
 
X 
 
Xg 
X 


 
 
 
 
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Admission 
 
X 
 
 
 
 
Release 
 
 
 
X 
 
 
Randomization 
 
 
 
X 
 
 
Administration of first 
dose of IMP at the 
Unit 
 
 
 
 
X 
 
 
24-h HR measurement  
 
 
X 
initiation 
X 
completion 
 
 
BP measurement  
 
X 
initiation 
X 
X 
completion 
 
 
Weight, waist 
circumference 
X 
 
X 
X 
X 
X 
Hematology 
X 
 
 
X 
 
 
Blood chemistry 
X 
 
 
X 
 
 
Infectious serology 
X 
 
 
 
 
 
ECG 
X 
X 
 
 
 
 
FPG 
Xa 
 
X 
X 
X 
X 
HbA1c 
X 
 
 
X 
 
X 
1,5-anhydroglucitol, 
lipids, insulin 
 
 
 
X 
 
X 
9-p glucose profile 
 
 
X 
initiation 
X 
completion 
 
 
MRS (liver fat) b 
 
X 
 
  
 
 
PK sample 
 
 
 
X 
 
 
Lifestyle advice 
 
 
 
X 
 
 
Medication dispensed 
 
 
 
X 
X 
X 
AEs 
 
 
  
X 
X 
X 
Hypoglycaemia 
 
 
X 
X 
X 
X 
Hyperglycemia 
 
 
X 
X 
X 
X 
Medication 
accountability 
 
 
 
 
X 
X 
Concomitant 
medication 
X 
 
X 
X 
X 
X 
Blood pregnancy test c 
X 
 
 
 
 
 


 
 
 
 
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Urine pregnancy test c 
 
 
X 
 
 
X 
Diary dispensation 
X 
 
 
X 
X 
X 
Diary review 
 
X 
X 
X 
X 
X 
Diary collection 
 
X 
 
 
X 
X 
Glucometer 
dispensation 
X 
 
 
 
 
 
BP measurement 
device dispensation h 
 
 
 
Xi 
 
 
Subject card 
dispensation 
X 
 
 
 
 
 
End of study form 
 
 
 
 
 
 
a: During the whole study the subjects will be asked to check the FPG every day 
b.  In a sub-set (Neuss) 
c:  Female subjects of childbearing potential only 
f   Only re-check of exclusion and inclusion criteria 
g Only Day 14 
h Only subjects who do not have an adequate one available 
i Subjects will be requested to measure BP every day until the follow-up visit 
IP = in-patient; OP = out-patient; Ph = phone 
*There will be up to additional 4 weeks in-between screening and admission in those subjects who will need to have their anti-diabetic 
medication washed out. 
 
4.2 
STUDY FLOW CHART: VISITS 7 - 12 (all visits are ±1 day) 
 
Visit 
7 
 
 
 
 
 
OP 
8 
 
 
 
 
 
OP 
9 
 
 
 
 
 
OP 
10 
 
 
 
 
 
IP 
10 
 
 
 
 
 
IP 
10 
 
 
 
 
 
IP 
11 
 
F-up 
 
 
 
Phone 
12 
 
F-up 
 
 
 
OP 
Day 
42 
56 
70 
89 
90 
91 
98 
110 
Physical examination, 
height, BMIg 
 
 
 
 
X 
 
 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
 
X 
PHQ-9 Score 
X 
 
X 
 
 
X 
 
 
Admission 
 
 
 
X 
 
 
 
 
Release 
 
 
 
 
 
X 
 
 
24-h HR measurement  
 
 
 
 
X 
initiation 
 
X 
completi
on 
 
 
BP measurement 
 
 
 
X 
initiation 
X 
X 
completi
 
 


 
 
 
 
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on 
Weight, waist 
circumference 
X 
X 
X 
 
X 
 
 
X h 
Hematology 
 
 
 
 
X 
 
 
 
Blood chemistry 
 
 
 
 
X 
 
 
 
ECG 
 
 
 
X 
 
 
 
 
FPG 
X 
X 
X 
 
X 
X 
 
X 
HbA1c 
 
X 
 
 
X 
 
 
X 
1,5-anhydroglucitol, 
lipids, insulin 
 
X 
 
 
X 
 
 
Xe 
9-p glucose profile 
 
 
 
 
X 
initiation 
X 
completi
on 
 
 
MRS (liver fat) b 
 
 
 
X 
 
 
 
 
PK sample 
 
 
 
 
X 
 
 
 
Urinary pregnancy 
test 
 
X 
 
 
 
 
 
X 
Medication dispensed 
X 
X 
X 
 
 
Xd 
 
 
AEs 
X 
X 
X 
 
X 
X 
X 
X 
Hypoglycaemia 
X 
X 
X 
 
X 
X 
X 
X 
Hyperglycaemia 
X 
X 
X 
 
X 
X 
X 
X 
Medication 
accountability 
X 
X 
X 
 
X 
 
 
 
Concomitant 
medication 
X 
X 
X 
 
X 
X 
X 
X 
Diary dispensation 
X 
X 
X 
X 
 
 
 
 
Diary review 
X 
X 
X 
X 
X 
 
 
X 
Diary collection 
X 
X 
X 
X 
 
 
 
X 
End of study form 
 
 
 
 
 
 
 
X 
b.  In a subset (Neuss) 
d Dispensation of two half-doses of active / placebo metoprolol 
e   Except lipids and insulin 
g  Conducting physical examination (except height and BMI) 
h  Only body weight measurement 
 
4.3 
STUDY DESIGN 
Visit 1 Screening (Day -28 to -5)  
Potentially eligible subjects will be given written information about the protocol, study design 


 
 
 
 
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and potential risk and benefits. Subjects will be given enough time to read the information and 
ask the investigator any questions. Subjects who give written informed consent will be 
assigned a subject screening number and will undergo the screening visit assessments to 
determine their eligibility for the study. 
 
The following screening procedures will be performed: 
• 
Explanation the study to prospective subjects 
• 
Obtaining written informed consent 
• 
Generating the subject screening number 
• 
Obtaining demographic information and medical/medication history 
• 
Reviewing and checking inclusion/exclusion criteria 
• 
Measurement of vital signs (including body temperature, respiratory rate, pulse rate 
and blood pressure) 
• 
Obtaining ECG 
• 
Measurement of the subject´s body weight, waist circumference, height, calculation 
of BMI 
• 
Conducting physical examination 
• 
Administering the PHQ-9 questionnaire 
• 
Performing routine haematology, blood chemistry assessment and infectious 
serology 
• 
Measuring FPG and HbA1c  
• 
Checking the concomitant medications (wash out of allowed anti-diabetics 
medications, except metformin) 
• 
Performing the blood pregnancy test and providing instructions for acceptable 
method of contraception for women with childbearing potential  
• 
Glucometer dispensation for home glucose monitoring 
• 
Scheduling the overnight baseline visit 
 
Subjects will be provided with a subject card that includes emergency contact details. 
Subjects will be provided with a diary. Subjects will be asked to record the following: date, 
glucose level, any hypoglycaemia episodes, any hyperglycaemia episodes (FPG >220 mg/dl; 
12.2 mmol/l), any other AEs, any other concomitant medication. 
Baseline visit 2a (Day -2 to -1):   
In the late afternoon/evening of the Day -2 (within 28 days after the screening visit), subjects 
will be admitted to the Unit.  
 
On day -2 the following procedures will be done: 
• 
MRS for liver fat (off site, prior to admission) in a subset of subjects 
• 
Collection of subject diary 
• 
Review of subject diary 
• 
Re-check of exclusion and inclusion criteria 
• 
Measurement of vital signs 
• 
Obtaining ECG 
• 
Initiation of BP measurement (1 BP measurement only) 


 
 
 
 
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On Day -1 the following baselines procedures will be performed in this order: 
• 
Performing the urine pregnancy test  
• 
Measurement of vital signs  
• 
Measurement the subject´s body weight and waist circumference 
• 
Administering the PHQ-9 questionnaire 
• 
Collection of blood for FPG measurement 
• 
Initiation of the 24-h HR measurement  
• 
Initiation of the 9-point glucose profile measurement 
• 
Assessment of hypoglycaemia 
• 
Assessment of hyperglycaemia 
• 
Assessment of concomitant medications 
• 
Review of subject diary 
• 
Subjects will stay at the Unit over night 
• 
Measurement of BP (four BP measurements during the day) 
 
Randomization visit 2b (Day 1): 
On Day 1, following the completion of all baseline assessments, the investigator will 
randomize subject into one of the treatment arm. The first administration of study medication 
will be performed at the Unit by the investigator. 
 
On Day 1 the following procedures will be performed: 
• 
Completion of BP measurement (1 BP measurement only) 
• 
Measurement of vital signs  
• 
Measurement of body weight and waist circumference 
• 
Collection of blood for efficacy (HbA1c, FPG, 1,5-anhydroglucitol, lipids, insulin) 
• 
Collection of blood for safety assessments (hematology and blood chemistry)  
• 
Collection of blood for PK baseline 
• 
Completion of the 24-h HR measurement  
• 
Completion the 9-point glucose profile 
• 
AEs assessment 
• 
Assessment of hypoglycaemia 
• 
Assessment of hyperglycaemia 
• 
Assessment of concomitant medications 
• 
Randomization 
• 
Administration of first dose  
• 
Dispensation of subject diary 
• 
Dispensation of BP measurement device (in case the subject does not have an 
adequate one) for home BP monitoring 
• 
Lifestyle (dietary) consultation 
• 
Review of subject diary 
• 
Medication dispensation for 8 days (1+7) 
• 
Releasing the subject from the Unit 
 
Subjects will be asked to record into the diary the following: date, glucose level, BP values, 
taking of the study medication, any hypoglycaemia episodes, any hyperglycaemia episodes, 


 
 
 
 
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hypotension symptoms, any other AEs, any other concomitant medication. 
Treatment period:  
Visits 3, 4 and 5 (Day 7, 14, 21)  
Three weekly visits starting after Randomization (Day 1). Subjects will be seen for the 
following: 
• 
Measurement of vital signs  
• 
Measurement of body weight and waist circumference 
• 
Administering the PHQ-9 questionnaire (only day 14) 
• 
Collection of blood for FPG measurement 
• 
AEs assessment 
• 
Assessment of hypoglycaemia 
• 
Assessment of hyperglycaemia 
• 
Assessment of concomitant medications 
• 
Collection of subject diary 
• 
Review of subject diary 
• 
Dispensation of subject diary for the next visit 
• 
Medication dispensation for 8 days and accountability check 
 
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 6 (Day 28)  
Visit 6 is considered to be a more detailed visit for efficacy assessments. Subjects will be seen 
for the following: 
• 
Performing the urine pregnancy test  
• 
Measurement of vital signs 
• 
Measurement of body weight and waist circumference 
• 
Administering the PHQ-9 questionnaire 
• 
Collection of blood for efficacy (HbA1c, FPG, 1,5-anhydroglucitol, lipids, insulin) 
• 
AEs assessment 
• 
Assessment of hypoglycaemia 
• 
Assessment of hyperglycaemia 
• 
Assessment of concomitant medications 
• 
Collection of subject diary 
• 
Review of subject diary 
• 
Dispensation of subject diary for the next visit 
• 
Medication dispensation for 15 days and accountability check 
• 
Schedule a subject visit in 2 weeks 
 
Visit 7 (Day 42) 
At visit 7 the subjects will be seen for the following: 
• 
Measurement of vital signs  
• 
Measurement of body weight and waist circumference 
• 
Administering the PHQ-9 questionnaire 


 
 
 
 
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• 
Collection of blood for FPG measurement 
• 
AEs assessment 
• 
Assessment of hypoglycaemia 
• 
Assessment of hyperglycaemia 
• 
Assessment of concomitant medications 
• 
Collection of subject diary 
• 
Review of subject diary 
• 
Dispensation of subject diary for the next visit 
• 
Medication dispensation for 15 days and accountability check 
• 
Scheduling a subject visit in 2 weeks 
 
Visit 8 (Day 56)  
At visit 8 the subjects will be seen for the following: 
• 
Performing the urine pregnancy test  
• 
Measurement of vital signs  
• 
Measurement of body weight and waist circumference 
• 
Collection of blood for efficacy (HbA1c, FPG, 1,5-anhydroglucitol, lipids, insulin) 
• 
AEs assessment 
• 
Assessment of hypoglycaemia 
• 
Assessment of hyperglycaemia 
• 
Assessment of concomitant medications 
• 
Collection of subject diary 
• 
Review of subject diary 
• 
Dispensation of subject diary for the next visit 
• 
Medication dispensation for 15 days and accountability check 
• 
Scheduling a subject visit in 2 weeks 
 
Visit 9 (Day 70) 
At visit 9 the subjects will be seen for the following: 
• 
Measurement of vital signs  
• 
Measurement of body weight and waist circumference 
• 
Administering the PHQ-9 questionnaire 
• 
Collection of blood for FPG measurement 
• 
AEs assessment 
• 
Assessment of hypoglycaemia 
• 
Assessment of hyperglycaemia 
• 
Assessment of concomitant medications 
• 
Collection of subject diary 
• 
Review of subject diary 
• 
Dispensation of subject diary for the next visit 
• 
Medication dispensation for 20 days and accountability check 
• 
Scheduling a subject for an admission at the Unit in 19 days 
 
Visit 10 Final admission (Days 89-91) 
On Day 89 in the evening or late afternoon subjects will be admitted to the Unit and all 


 
 
 
 
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returned study medication should be checked.  
 
On Day 89 the following assessments will be done: 
• 
MRS for liver fat (off site, prior to admission) in a subset of subjects 
• 
Measurement of vital signs 
• 
Collection of subject diary 
• 
Review of subject diary 
• 
Dispensation of subject diary (until the end of study) 
• 
Obtaining ECG 
• 
Initiation of BP measurement (1 BP measurement only) 
 
Subjects will be still asked to record into the diary the following: date, glucose level, taking of 
IMP and metoprolol, any hypoglycaemia episodes, any hyperglycaemia episodes, any other 
AEs, any other concomitant medication. 
 
On Day 90 the following final procedures will be performed: 
• 
Measurement of vital signs  
• 
Measurement the subject´s body weight and waist circumference 
• 
Conducting physical examination (except height and BMI) 
• 
Collection of blood for efficacy (HbA1c, FPG, 1,5-anhydroglucitol, lipids, insulin) 
• 
Collection of blood for safety assessments (hematology and blood chemistry)  
• 
Collection of blood for PK  
• 
Initiation of the 24-h HR measurement  
• 
Initiation the 9-point glucose profile measurement 
• 
AEs assessment 
• 
Assessment of hypoglycaemia 
• 
Assessment of hyperglycaemia 
• 
Assessment of concomitant medications 
• 
Medication accountability check 
• 
Review of subject diary  
• 
Measurement of BP (4 BP measurements during the day) 
• 
Subjects will stay at the Unit over night 
Day 90 (morning) will be the last day when subjects receive the study medication. 
 
On Day 91 subjects will be released and given two dosages of half-dose of the metoprolol 
dose taken during the study to take at home, one dosage over the next two days in order to 
gradually reduce the dose of metoprolol and avoid potential undesirable fluctuation in blood 
pressure; however, only the subjects in the study arm 1) will receive the active medication, 
subjects in the arm 2) will receive placebo. For safety purposes the subjects will continue 
measuring BP and annotating the values in the diary until the follow-up visit. The withdrawal 
criteria regarding BP will not apply during these days. 
 
On Day 91 the following final procedures will be performed: 
• 
Completion of BP measurement (1 BP measurement only) 
• 
Measurement of vital signs  
• 
Administering the PHQ-9 questionnaire 


 
 
 
 
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• 
Collection of blood for FPG measurement 
• 
Completion the 24-h HR measurement 
• 
Completion the 9-point glucose profile 
• 
AEs assessment 
• 
Assessment of hypoglycaemia 
• 
Assessment of hyperglycaemia 
• 
Assessment of concomitant medications 
• 
Dispense of two half-doses of active / placebo medication 
• 
Releasing the subject from the Unit 
Phone call visit on Day 98 will be scheduled and subjects will be invited for the final follow 
up visit on Day 110. 
Visit 11 Follow-up (Day 98) - Telephone contact 
At the phone call visit Day 98 the following final procedures will be performed: 
• 
AEs assessment 
• 
Assessment of hypoglycaemia  
• 
Assessment of hyperglycaemia 
• 
Assessment of concomitant medications 
Visit 12 End of study (Day 110)  
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. 
 
On Day 110 the following final procedures will be performed: 
• 
Performing the urine pregnancy test  
• 
Measurement of vital signs + body weight 
• 
Collection of blood for efficacy (HbA1c, FPG, 1,5-anhydroglucitol) 
• 
AEs assessment 
• 
Assessment of hypoglycaemia 
• 
Assessment of hyperglycaemia 
• 
Assessment of concomitant medications 
• 
Review and return of subject diaries 
• 
Completion of “End of study Form” 
4.4 
END OF STUDY  
The end of study is defined by LPLV for TM001. If a subject withdraws from the study 
during the treatment period, or has to discontinue for any reason, a visit will be organized at 
which the assessments planned for Days 28/56 will be performed. If a subject refuses to 
attend a visit, the investigator should make every effort to obtain the information over the 
telephone from the subject regarding the safety. When a subject ends the study, either per 
protocol or before of any reason, he/she will be instructed to immediately contact his/her 
personal primary care physician to resume to his/her entire diabetic treatment.  


 
 
 
 
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4.5 
STUDY PARTICIPANTS 
The target population is adult subjects suffering from T2DM. Subjects will be recruited from 
local population around the Units. This study will be conducted at two investigational sites 
(Units) in Germany. Subjects who fulfil all of the following inclusion criteria and none of the 
exclusion criteria are eligible to enter the baseline phase of the study. 
4.6 
INCLUSION CRITERIA 
1. Males and females 
2. Confirmed diagnosis of T2DM (either by being on anti-diabetic medication or by 
confirmed or repeated laboratory findings) 
3. 18-70 years of age 
4. Normal BP or well managed hypertension (only if dose of BP medication(s) has been 
stable for at least 2 months) 
5. Normal lipid profile or well managed dyslipidemia (only if dose of lipid-lowering 
medication(s) has been stable for at least 2 months) 
6. No history of CV or any other major disease 
7. On any dose of metformin stable for at least two months, or 
8. On any dose of metformin plus one other oral antidiabetic agent (except TZDs); the 
other oral agent will be washed out prior to randomization 
9. HbA1c ≥7.0% 
4.7 
EXCLUSION CRITERIA 
1. BP >140/90 (excluding white-coat hypertension; therefore, if a repeated measurement 
shows values within the range, the subject can be included in the trial) 
2. HbA1c > 8.5% 
3. Fasting plasma glucose > 200 mg/dl at screening 
4. HR ≥ 90, <50 bpm 
5. BMI < 27 kg/m2 
6. Hypersensitivity to tesofensine/metoprolol 
7. Heart failure class II or greater according to the New York Heart Association (NYHA) 
or decompensated heart failure 
8. History of myocardial infarction or stroke within 12 months prior to enrolment 
9. History of coronary revascularisation or angioplasty in the last 12 months prior to 
enrolment 
10. Patients reporting angina in the last 6 months prior to enrolment 
11. Treatment with insulin and/or other injectable anti-diabetic medications, or TZDs 
12. Any clinically significant cardiac arrhythmia 
13. Treatment with calcium channel blockers or beta blockers or their combination 
14. Current treatment with medications which should not be co-administered according to 
the excluded medications list (Appendix I) 
15. Concomitant use of monoaminooxidase inhibitors 
16. Bulimia or anorexia nervosa 
17. Any agent used for weight loss within the last 3 months 
18. Patients with history of major depressive disorder or any history of suicide 
attempt/ideation 
19. Patients with family history of severe psychiatric diseases  
20. Patients using selective serotonin reuptake inhibitors (SSRIs), antidepressants or 
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21. PHQ-9 score ≥ 10 or any score > 0 on question 9 
22. Females of childbearing potential who are pregnant, breast-feeding or intend to 
become pregnant or are not using highly effective contraceptive methods (highly 
effective contraceptive methods are considered those with a failure rate less than 1% 
undesired pregnancies per year including surgical sterilisation, hormonal intrauterine 
devices (coil), sexual abstinence or a surgically sterilised partner) or postmenopausal 
women being amenorrheic for less than 1 year and not using highly effective 
contraceptive methods 
23. Contraindications to administration of metoprolol per current summary of product 
characteristics 
24. Untreated hypo- or hyperthyroidism 
25. Clinically significant liver (>3xULN) and/or kidney impairment (GFR <45 ml/min) 
26. More than 5% weight loss within the last 3 months 
27. Any clinically significant history of hypotension 
28. Any other clinically meaningful condition, in the opinion of the investigator, which 
would make participation potentially unsafe 
29. Inability to undergo a MRS scan for any reason 
4.8 
SCREENING FAILURES 
If a subject fails during the screening phase, before randomisation, (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. 
4.9 
DISCONTINUATION CRITERIA 
The subject has a right to discontinue study participation at any time for any reason. The 
reason for discontinuation will be documented in the subject’s source documents and in the 
eCRF. In the event of an early termination, all procedures described for a subject completing 
the study Days 28/56 should be performed. Subjects discontinuing due to adverse events will 
be followed-up until complete resolution of the adverse event or until there is a satisfactory 
explanation of the changes observed. 
4.10 WITHDRAWAL CRITERIA 
 Subjects may be withdrawn if any of the following items is met and documented: 
• Request by subject (withdrawal of informed consent) 
• Pregnancy or not using a reliable method of birth control 
• Investigator’s decision 
• Acute allergic reaction to study medication 
• Deterioration of glycaemic control which will require additional medical management 
as defined in the rescue criteria from T2DM 
• Subjects who during the whole duration of the study exceed predefined values of FPG 
>220 mg/dl (12.2 mmol/l) on two consecutive mornings and confirmed at the 
investigational site  
• HbA1c ≥9% in any on-site measurement 
• Subjects who during the treatment period exceed BP systolic values >160, <100 
mmHg, or diastolic >100, <60 mmHg on two consecutive mornings and confirmed at 
the investigational site 
• Any event, including hospitalization of the subject in another location where the 


 
 
 
 
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investigator will not be able to follow the subject 
• Evidence of the use of recreational medications or prohibited medications during the 
study 
• Failure to comply with the study stipulations 
• Score of PHQ questionnaire ≥ 10 during the study or any score > 0 on question 9 
• Severe symptomatic bradycardia (heart rate < 50 bpm) during the study 
• Lost to follow-up. Subjects will be deemed lost to follow-up if they do not return for 
scheduled visits without giving a reason, and if the investigator is unable to contact the 
subject directly or indirectly (e.g. via the subject’s family). If a subject does not attend 
a scheduled visit, the investigator will make best efforts to obtain information about 
the subject before considering the subject lost to follow up 
 
The sponsor reserves the right to request the withdrawal of a subject due to protocol 
deviation, administrative or any other valid and ethical reason. If an investigator judges a 
subject to be at medical risk by complying with the protocol, he or she may discontinue the 
participation of the subject. The circumstances surrounding the decision must be discussed 
with the sponsor and recorded in the subject’s source documents and eCRF. 
 
4.11 REPLACEMENT OF WITHDRAWN SUBJECTS 
Enrolment will continue until a total of 60 subjects are randomized. Subjects excluded during 
the screening period (Day -28 to -5) may be considered for another selection visit at a later 
date but will need to undergo complete rescreening. Randomized subjects who withdraw or 
are withdrawn from the study for any reason will not be replaced.  
4.12 PREMATURE STUDY DISCONTINUATION 
The sponsor has the right to terminate this study at any time. If the sponsor, the investigators, 
or the competent authorities discover conditions arising during the study that indicate the 
study should be halted, it may be terminated after appropriate consultation between the study 
sponsor and the investigator. 
Reasons for terminating the study may include the following: 
• The incidence or severity of AEs in this study indicates a potential health hazard to 
study subjects 
• Subject enrolment is unsatisfactory 
• Data recording is inaccurate or incomplete 
• The sponsor´s decision to suspend or discontinue development of the study medication 
4.13 EARLY TERMINATION OF A STUDY SITE 
The sponsor may close the Unit if no subjects are recruited within four weeks after initiation 
of the Unit or if severe protocol deviations are observed. Depending on overall enrolment, a 
new country may be selected by the sponsor. 
4.14 STUDY SITES 
The study will be conducted at two Units in Germany, randomizing 60 eligible subjects. It is 
recommended that each Unit should randomize at least 15 and no more than 40 eligible 
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4.15 STUDY DURATION 
The projected start date for the inclusion of study subjects is Q1 2016. The individual study 
duration for one subject is up to 138 days including screening period, baseline, the treatment 
period and the final visit. The projected duration of the study is ~12 months. The end of study 
is defined by the Last Visit of the Last Patient for TM001. 
 
4.16 BENEFITS AND RISKS FOR STUDY PARTICIPANTS 
It is expected that tesofensine and metoprolol combination will be well tolerated. This 
assessment is based on a large body of experiences from previous preclinical 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 Unit. 
 
Tesofensine  
The majority of treatment related adverse events 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 adverse events in clinical studies in the obese population was 13% with tesofensine and 6% 
with placebo. Blood pressure and heart rate increased with the therapeutically relevant doses 
of tesofensine (0.25 mg and 0.5 mg) were 1–3 mmHg and up to 8 bpm, respectively. For more 
information see the IB. (IB version 12 and any updates thereof). 
Due to the CNS-located mechanism of action of tesofensine, a monoamine reuptake inhibitor, 
there could be a concern regarding psychiatric side effects. In obese subjects dosed for up to 
24 weeks, common psychiatric symptoms were insomnia and depressed mood. Occurrence of 
insomnia displayed a clear dose-dependency with the highest incidence on the highest dose (1 
mg). Psychotic phenomena, like those encountered in patients with dementia of the 
Alzheimer's type or Parkinson’s disease, were not registered in the population of obese 
subjects. Pooled data from studies NS2330-001 and NS2330-004 did not reveal an increased 
incidence of psychiatric events following long-term extension study, i.e. 18 months of 
treatment. Current data from the clinical studies with obese patients do not suggest that 
tesofensine at doses of 0.25 mg and 0.5 mg once daily are associated with any clinically 
significant undesirable psychiatric profile. (IB version 12 and any updates thereof). 
 
Metoprolol adverse reactions – post marketing experience  
• Blood and lymphatic system: thrombocytopenia, leukopenia, agranulocytosis 
• Cardiovascular: cold extremities, arterial insufficiency (usually of the Raynaud type), 
palpitations, peripheral edema, syncope, chest pain and hypotension 
• Respiratory: wheezing (bronchospasm), dyspnea, rhinitis  
• Central Nervous System: confusion, short-term memory loss, headache, somnolence, 
nightmares, insomnia, anxiety/nervousness, hallucinations, paresthesia 
• Psychiatric: changes in personality, depression 
• Gastrointestinal: nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, 
vomiting, abdominal pain, retroperitoneal fibrosis 
• Hypersensitive Reactions: pruritus 


 
 
 
 
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• Miscellaneous: 
fatigue, 
hyperhidrosis, 
hepatitis, 
increased 
liver 
enzymes, 
musculoskeletal pain, arthralgia, blurred vision, decreased libido, male impotence, 
tinnitus, reversible alopecia, dry eyes, psoriasis-like dermatitis, worsening of psoriasis, 
Peyronie’s disease, sweating, photosensitivity, taste disturbance, gangrene 
 
For more information regarding the adverse events please see the  Summary of Product 
Characteristics of MetoHEXAL® 100 mg retard. 
 
It is anticipated that the subject receiving the study medication will experience a reduction in 
their body weight and improvement in their glycaemic control. Although tesofensine has not 
been previously investigated in patients with T2DM, based on the highly statistically and 
clinically meaningful degree of weight loss and the available literature it is anticipated that 
participants in this trial will experience improvement in their glycaemic control (including 
those on placebo who will receive diet, exercise and lifestyle modification guidance). In 
addition, all patients will have access to a state-of-the-art clinical care that they will receive 
for the duration of the study. Subjects randomized to the placebo arm will receive state of the 
art clinical study for almost 5 months with regular visits and multiple sophisticated 
assessment of their health status, including their diabetes, as well as lifestyle guidance from a 
dietician.  
5 TREATMENT OF STUDY PARTICIPANTS 
5.1 
DESCRIPTION OF STUDY MEDICATION 
Investigational Medicinal Product 
Tesofensine is a serotonin-noradrenaline-dopamine reuptake inhibitor, for oral administration, 
which is manufactured, packed and labelled by Delpharm in Reims (France). Its chemical 
name 
is 
(1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-2-(ethoxymethyl)-8-methyl-8-azabicyclo 
octane. Designated contractors will supply study medications directly to the sponsor CRO’s 
pharmacies. 
 
Metoprolol is a beta1-selective (cardioselective) adrenoceptor blocking agent, for oral 
administration. It has been formulated into the extended release tablets to provide a controlled 
and predictable release of metoprolol for once-daily administration. Original extended release 
metoprolol will be purchased and supplied by sponsor CRO directly and distribute to the 
sponsor CRO’s pharmacies. 
 
The IMP is a kit of one tablet of tesofensine 0.5mg and one tablet of metoprolol 100 mg, both 
formulated for oral use once a day. 
 
Placebo 
The placebo formulation is identical in presentation and appearance to the tesofensine and 
metoprolol tablets but includes only the excipients; it does not contain any active ingredients.  
 
5.2 
PROCEDURES TO ASSURE DOUBLE BLINDING 
It is double-blind, placebo-controlled study, i.e. investigators, site staff (except pharmacists) 
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: 
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appearance 
• The labelling of the IMP will identify the study and the investigational product but 
will not indicate the contents 
• Randomization will be performed by a third party and the site staff will not have 
access to the actual treatment assignments (except pharmacists) 
• Only the site pharmacist will be able to match the randomization list and treatment 
assignment and he/she will be dispensing the study medication to the investigator; 
however, at no time he/she will be in contact with the subjects  
 
5.3 
IMP HANDLING PROCEDURES AT THE UNIT’S PHARMACY 
The designated pharmacist at the Unit (investigational site) is responsible for storage of 
received study medication, blinding, 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 Unit in a secured area with restricted access as instructed on the 
study kits labels 
• Blinding the IMP and repacking 
• Dispensing IMP according to the protocol 
 
Randomization will be balanced by using the randomization list. The investigator will obtain 
the randomization number and ask pharmacist to prepare the relevant IMP for subjects. At the 
time of dispensing, the pharmacist will write the randomisation number and the visit name on 
each kit on spaces reserved for this purpose. 
 
The investigator and pharmacist are responsible for study medication kits accountability. The 
pharmacist is responsible for maintaining accurate records of all information relating to the 
management of the study medication. If any quality issues are noticed on receipt or use of the 
IMP (e.g. damaged condition, faults in appearance, errors in the documentation, incorrect 
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 
pharmacist in writing. Upon receipt, and as instructed, the investigator or pharmacist should 
immediately contact any study subject in possession of the corresponding study medication 
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IMP kit 
Placebo kit 
Kits supplied at 
the visit 2 will 
consist of: 
 
Medication for Day 2: 
1 
kit 
containing 
2 
tablets 
of 
tesofensine 0.5mg and 1 tablet of 
MetoHEXAL® 100 mg retard   
(First 2 days a loading dose of 1.0 
mg/d of tesofensine will be given, one 
dose will be already given the Unit at 
Day 1.) 
 
Medication for Day 3-7: 
1 plastic bottle containing 7 tablets of 
tesofensine  
 
and 1 plastic bottle containing 7 
tablets of MetoHEXAL® 100 mg 
retard   
the medication will be sufficient for 8 
days (1 extra day to allow for 
flexibility between scheduled visits). 
Medication for Day 2: 
1 kit containing 2 tablets of 
placebo 
matching 
tesofensine 
0.5mg and 1 tablet of placebo 
matching MetoHEXAL® 100 mg 
retard   
 
 
 
 
Medication for Day 3-7: 
1 plastic bottle containing placebo 
matching 7 tablets of tesofensine 
0.5mg 
and 1 plastic bottle containing 
placebo matching 7 tablets of 
MetoHEXAL® 100 mg retard   
the medication will be sufficient 
for 8 days (1 extra day to allow for 
flexibility 
between 
scheduled 
visits).  
Kits supplied at 
the visit 3,4,5 
will consist of:  
 
1 plastic bottle containing 8 tablets of 
tesofensine  
and 1 plastic bottle containing 8 
tablets of MetoHEXAL® 100 mg 
retard   
 
1 pack of medication (2 bottles) will 
be sufficient for 8 days (1 extra day to 
allow 
for 
flexibility 
between 
scheduled visits). 
1 plastic bottle containing placebo 
matching 8 tablets of tesofensine  
and 1 plastic bottle containing 
placebo matching 8 tablets of 
MetoHEXAL® 100 mg retard   
 
1 pack of medication (2 bottles) 
will be sufficient for 8 days (1 
extra day to allow for flexibility 
between scheduled visits).  
Kits supplied at 
the visit 6,7,8 
will consist of:  
 
1 plastic bottle containing 15 tablets of 
tesofensine  
and 1 plastic bottle containing 15 
tablets of MetoHEXAL® 100 mg 
retard  (1 extra day to allow for 
flexibility between scheduled visits). 
1 plastic bottle containing placebo 
matching 15 tablets of tesofensine 
 and 1 plastic bottle containing 
placebo matching 15 tablets of 
MetoHEXAL® 100 mg retard  (1 
extra day to allow for flexibility 
between scheduled visits). 
Kits supplied at 
the visit 9 will 
consist of:  
 
1 plastic bottle containing 20 tablets of 
tesofensine  
and 1 plastic bottle containing 20 
tablets of MetoHEXAL® 100 mg 
retard  (1 extra day to allow for 
flexibility between scheduled visits). 
1 plastic bottle containing placebo 
matching 20 tablets of tesofensine 
 and 1 plastic bottle containing 
placebo matching 20 tablets of 
MetoHEXAL® 100 mg retard  (1 
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between scheduled visits). 
5.4 
LABELS FOR STUDY MEDICATION 
The label texts will be translated or adjusted as necessary so that they comply with the 
applicable national laws and regulatory requirements of the country in which the study will be 
conducted. The label text will include the following information as minimum: 
• Name of Sponsor 
• Name of CRO or Investigator 
• Protocol number 
• Dosing instructions 
• Batch number 
• Expiry date 
• Randomization number (double-blind) 
• Visit number 
• The words ‘For clinical study use only’ 
• The words ‘Keep out of reach of children’  
• Storage conditions 
 
5.5 
PACKAGING AND DESTRUCTION 
Medication will be distributed to the subjects in plastic bottles labelled with the appropriate 
study medication number. Bottles for the respective investigational medicinal products will be 
identical in colour, size and shape to preserve the blinding of the study. Unused study 
medication will be collected by the investigator and pharmacists. Sponsor’s CRO is 
responsible for central destruction of all study medication (partially used and unused). 
 
5.6 
HANDLING OF THE STUDY MEDICATION 
Study medication will be distributed to the subjects during the visits 2, 3, 4, 5, 6, 7, 8, 9 at the 
Unit. First administration will be done on Day 1, at the Unit. Subjects will be asked to use 
study medication every morning with or right after a meal and not to crush or chew the 
tablets. Subject will be asked to store the medication at room temperature (15 - 25 °C) and 
return the unused study medication on each in-person visit at the Unit. 
 
5.7 
SUPPLY AND STORAGE OF THE STUDY MEDICATION 
Study medication supplies  
Tesofensine and tesofensine placebo will be supplied by the sponsor. MetoHEXAL® 100 mg 
retard and MetoHEXAL® 100 mg retard placebo will be purchased directly by Profil. IMP 
will be shipped to the Units under temperature control and monitoring. The receiving Unit 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 


 
 
 
 
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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 Unit(s), the following essential 
documents must be available in the Study Master File:  
• IEC/RA approval 
• IEC/RA approved subject information/informed consent form 
• Clinical study protocol signed by the principal investigator 
• Study agreement/contract signed by the principal investigator 
Study medication storage 
All study medication must be stored at the Unit’s pharmacies, in restricted place at room 
temperature (15 - 25 °C)   
 
5.8 
STUDY MEDICATION COMPLIANCE 
The investigational medicinal products 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. 
 
5.9 
SCREENING AND RANDOMISATION 
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: 
TM001 
01 
001 
 
TM001 
02 
001 
 
Randomization of eligible subjects to one of the study medication groups will be done at 
Baseline visit 2b 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 1:1 randomization 
(with stratification for the anti-diabetic treatment, those on metformin only or metformin plus 
other agents). The randomization codes will be generated within the Biometrics Department 
of the sponsor’s CRO by a statistician. The randomization list will be used for the 
randomization procedure. 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 Unit with access to the randomization list and assignments will be the 
designated pharmacist. The study medication number consists of four digits. All kits assigned 


 
 
 
 
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to a subject will have the same study medication number. This procedure will be checked by 
the monitor. 
 
5.10 UNBLINDING 
The study will be double blind. Neither the investigators nor the subjects will be informed 
about the type of subject´s medication. In general, emergency unblinding is to be done only 
when absolutely necessary for the clinical management of an individual subject and where 
stopping the blinded medication is not sufficient in the opinion of the investigator. The 
justification for the unblinding should always 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.  
In addition, the study medication code may be unblinded by the sponsor if unblinded 
reporting of a serious adverse event that is both unexpected and reasonably associated with 
the use of the IMP is required by Regulatory or other local Competent Authorities.  
Emergency Unblinding: 
Emergency unblinding can be performed using sealed envelopes. The randomization code 
may only be unblinded in case of an emergency situation as described above. Opening of the 
code envelope must be documented with providing justification for unblinding. The 
investigator must immediately inform the sponsor about any unblinding. The information will 
be forwarded to the Regulatory Authority and IEC, if necessary, and 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. 
Routine Unblinding: 
After terminating the study, establishing the statistical analysis plan, 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 unblinding. Formal records will be kept on 
measures and dates of each step. 
 
5.11 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 Unit. 
 
5.12 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, 


 
 
 
 
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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. 
  
5.13 CONCOMITANT MEDICATION 
Any other concomitant medication taken, as well as any changes in concomitant medication 
will be documented in the subject´s source documentation and eCRF indicating the: 
• Trade name of medication 
• Start date 
• End date / on-going 
• Route of administration 
• Total daily dose and units, and 
• Reason for administration 
 
5.14 PROHIBITED MEDICATION 
Any anti-diabetic medication oral or injectable (except metformin), calcium-channel blockers, 
beta-blockers (except metoprolol), monoaminooxidase inhibitors. For additional prohibited 
concomitant medication, please refer to Exclusion Criteria. 
Paracetamol is an exception and may occasionally be taken by the subjetcs in the treatment of 
acute pain (e.g. headache or toothache). In such case, the subjects will be asked to keep record 
in the diary. 
 
5.15 STUDY PROCEDURES AND OTHER EXAMINATIONS  
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, two original forms for written 
informed consent will be given to the subjects for signature. One 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. 
 
Vital Signs 
Vital signs include body temperature, respiratory rate, pulse rate and blood pressure.  
 
Physical Examination 
The physical exam includes: heart, lung, head and neck exam, and abdominal, neurological 
and dermatological exam. 
 
Blood pressure measurement   
• Subject should avoid food immediately before the measurement. Tobacco, caffeine 
and alcohol will not be allowed during the entire in-house period. 


 
 
 
 
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• Subject should go to the toilet before BP measurement. A full bladder can increase 
blood pressure slightly 
• Subject should sit for five minutes in a comfortable position with his/her legs and 
ankles uncrossed and his/her back supported against a chair before and during a 
measurement 
• Subject should be asked to sit quietly before and during monitoring 
• When subject is ready to take his/her blood pressure, subject should be calm and not 
think about stressful things and not to talk at all 
• Subject’s arm must be positioned properly. Same arm must be always used when 
taking subject’s blood pressure. Subject should rest his/her arm, raised the arm to the 
level of his/her heart, and put the arm on a table, desk or chair arm. If needed, a pillow 
or cushion should be placed under subject’s arm to elevate the arm high enough. 
• The cuff must be placed on bare skin, not over clothing.  The appropriate sized cuff 
should be always used! 
• Three measurements should be performed, repeat the BP measurement after 3 minutes. 
If the monitor doesn't automatically log blood pressure readings or heart rates, the 
measurement should be repeated until a valid reading is available (for every time point 
there have to be three BP values). 
 
BP as an endpoint will be measured as following: 
 
First admission at the Unit (Day -2, Day -1, Day 1):   
• Evening Day -2 (~9 PM) 
• Morning of Day -1 pre-breakfast (~6 AM ) 
• Noon Day -1 (~12 PM ) 
• Pre-dinner Day -1 (~6 PM) 
• Midnight Day -1 (~12 AM) 
• Morning Day 1 (~6 AM ) 
 
Second admission at the Unit (Day 89, Day 90, Day 91): 
• Evening Day 89 (~9 PM) 
• Morning of Day 90 pre-breakfast (~6 AM ) 
• Noon Day 90 (~12 PM ) 
• Pre-dinner Day 90 (~6 PM) 
• Midnight Day 90 (~12 AM) 
• Morning Day 91 (~6 AM ) 
 
The average of those six measurements (each measurement should be a mean of three separate 
measurements) will be the mean SBP/DBP used as a secondary endpoint. Those six BP 
measurements will also be plotted over time and looked at as an exploratory endpoint. 
 
Body weight - subject must be undressed with the exception of underwear. 
 
Waist circumference will be measured just after subjects breathe out, in standing position, 
just above hipbones (also in underwear). 
 


 
 
 
 
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Blood pregnancy test will be done for any women of childbearing potential at the Unit at the 
Screening. 
 
Urinary pregnancy test will be done for any women of childbearing potential at the Unit at 
the Baseline, and on Days 28,  and 110. 
 
24-hour HR monitoring: monitoring will be based on Telemetrie measurements. HR as an 
endpoint will be measured as following: 
 
• First admission at the Unit (Day -2, Day -1, Day 1):  monitoring will start at ~7 
AM on Day -1, approximately 24 hours before first dosing. Monitoring will be 
carried out to complete at least 24 hours of measurement. The data interval for 
analysis will be based on the beginning of the measurement and the completion of 
the 24 hours. 
 
• Second admission at the Unit (Day 89, Day 90, Day 91): monitoring will start at 
~7 AM on Day 90, one hour before last dosing. Monitoring will be carried out to 
complete at least 24 hours of measurement. The data interval for analysis will be 
based on the beginning of the measurement and the completion of the 24 hours. 
 
During the monitoring time the subjects will be allowed to walk around his/her room and the 
clinic facilities. Subjects will not be allowed to perform any additional physical activity apart 
from that resulting from the routine activities in the clinic. 
 
Subjects will be requested to adopt a resting position for the time corresponding to 13 hours 
after the initiation of the measurement (~8 PM). Subjects will be asked to remain for one hour 
in a supine position and not to fall asleep. Passive activities such as reading or watching will 
be allowed during this time.  
 
MRS for determination of liver fat 
Lipid content of abdomen and liver will be determined non-invasively using 1H (proton) 
Magnetic resonance spectroscopy (MRS) on a 3-Tesla clinical magnetic resonance imaging 
scanner. MRS is a technique that can be used in the characterization of tissue. During the 
scans, the subjects will receive a buzzer to let the researcher know when they are 
uncomfortable and they will remain in contact with the researcher via an intercom 
communication system. 
1H MRS will be used to quantify the lipid content in the liver. The intensity of the lipid signal 
will be expressed as the lipid/water ratio. During the 1H MRS measurement in liver, the 
subject will be asked to breath in the rhythm of the measurement (a 4s rhythm) to minimize 
motion artefacts. The procedure will last ~60 minutes. 
 
9-point profiles for blood glucose  
 
Sample no. 
Approx. hour1 
Nominal timing 
Blood Glucose
1 
08:00 h 
Before breakfast 
X
2 
10:00 h 
2 hours after breakfast 
X
3 
12:00 h 
Before lunch 
X
4 
14:00 h 
2 hours after lunch 
X 


 
 
 
 
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Sample no. 
Approx. hour1 
Nominal timing 
Blood Glucose
5 
18:00 h 
Before dinner 
X 
6 
20:00 h 
2 hours after dinner 
X 
7 
22:00 h 
Before going to bed 
X 
82 
03:00 h 
Bed time 
X 
92 
08:00 h 
Fasting day after 
X 
 
1 The actual time of sampling is approximate; the nominal timing should be followed in any 
case (time windows: within 30 min before start of meal, 2 hours ± 30 min from start of meal, 
no time window for bedtime blood glucose sample). 
2 This sample is taken in the morning of the following day 
Standardized meal will be provided by the Unit. 
 
PHQ-Questionnaire 
The PHQ-9 (Appendix II) was originally developed as a screener for depression in primary 
care and is commonly used in medical settings. The PHQ-9 demonstrated a strong correlation 
with a well-established measure of depression, and a score ≥ 13 demonstrated good sensitivity 
(83%) and specificity (72%) to that end (10).  
The questionnaire consists of 9 questions with a rating corresponding to the answer of the 
subject. The scores range from 0 to 27. Question 9 assesses suicidal ideation, and in this study 
any score > 0 at screening will be considered as suicidal ideation and such subjects will not be 
included in the study. PHQ-9 will be performed at screening, baseline, days 14, 28, 42, 70 and 
91. If at any moment PHQ ≥ 10 or the score of question 9 > 0 the subjects will be withdrawn 
from the study. 
 
5.16 LABORATORY EVALUATIONS 
Laboratory samples will be collected from subjects at the Unit, and will be shipped to the 
central laboratory (MLM Medical Labs GmbH, Dohrweg 63, 41066 Mönchengladbach, 
Germany) for analysis in ambient conditions. 
 
The investigator will receive the data from laboratory safety analyses from the central 
laboratory and will review, evaluate, sign and date the laboratory report electronically. 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 electronically. 
 
The investigator´s evaluation (´normal´, ´abnormal and not clinically significant´ or ´abnormal 
and clinically significant´) will be entered with the program Labor Master plan at the CRO 
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 analyses not requested in the protocol but produced 
automatically in connection with the requested analyses according to specifications in the 
laboratory standard operating procedures. Such data will not be transferred to the study 
database, but abnormal values will be reported to the investigator. The investigator must 


 
 
 
 
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review all laboratory results for concomitant illnesses and AEs and report these according to 
this protocol. 
• Hematology: blood count (erythrocytes, hemoglobin, hematocrit, leukocytes), 
differential blood count (neutrophils, lymphocytes, monocytes, eosinophils, basophils) 
and platelets, will be analysed by central laboratory. 
• Blood chemistry: creatinine, gamma glutamyl transferase, aspartate aminotransferase, 
alanine aminotransferase, alkaline phosphatase, GFR and urea will be analysed by 
central laboratory. 
• Infectious serology: Hepatitis B surface antigen, Hepatitis C antibodies, HIV-1/2 
combi  
• HbA1c will be analysed by central laboratory. 
• 1,5-anhydroglucitol, lipids (total cholesterol, HDL cholesterol, LDL cholesterol, 
triglycerides), serum insulin will be analysed by central laboratory. 
• Fasting plasma glucose test before taking the blood glucose test, subject will not be 
allowed to eat anything for at least eight hours. Blood will be drawn and analysed at 
the Unit. 
PK Sampling will be evaluated for presence/absence of tesofensine/metoprolol. The 
evaluation will be done by sponsor selected external laboratory: Bioanalytical and 
ADME Labs. Q2 Solutions, a Quintiles Quest Joint Venture, Molenstraat 110, 5342 
CC, Oss. The Netherlands 
 
5.17 SUBJECTS’ DIARIES /CARDS 
Subject diaries and cards will be provided. Subjects will be asked to record in the diary 
depending on the study period the following: date, glucose level and time for assessment, BP 
values, taking of the study medication, any signs of hypoglycaemia, any signs of 
hyperglycaemia, any hypotension symptoms, any other AEs, any other concomitant 
medication. 
 
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. Possible SAEs will be reported to the regulatory authorities and 
Independent Ethics Committees (IECs) according to local regulations, and will be followed-
up until the resolution of the event.  
6.1 
DEFINITIONS 
An adverse event (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 will be recorded in detail indicated in the eCRF, 
regardless of their relationship to the investigational study product as assessed by the 


 
 
 
 
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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. 
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 adverse event 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. 
 
 
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 
The adverse event is clearly related to the study treatment – i.e. an event that 


 
 
 
 
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related 
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 adverse event 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 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 withdrawn 
Dose reduced 
Dose increased 
Dose not changed 
Unknown 
Not applicable 
 
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 
for an unauthorized study treatment, or summary of product characteristics for an authorized 
product. 
 
6.4 
SERIOUS ADVERSE EVENT  
A serious adverse event (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.  
 


 
 
 
 
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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-patient 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 every-day 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  
A suspected unexpected serious adverse reaction is an adverse reaction that is both 
unexpected (not consistent with the applicable product information) and meets the definition 
of a Serious Adverse Event. 
 
6.6 
PROCEDURES FOR RECORDING ADVERSE EVENTS  
AEs will be collected with a non-leading question at each clinic visit: “Have you had any new 
or worsening health problems since the last visit?” as well as by reporting 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 fulfil 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 adverse events, 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 eCRF. 


 
 
 
 
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Pre-existing Conditions 
Pre-existing conditions or hospitalization for elective surgery or routine clinical procedures 
that are not the result of an adverse event need not be considered adverse events. Pre-existing 
condition should be recorded in subject´s source documentation and on the medical history 
form of the eCRF. 
Overdose 
An overdose of the tesofensine is defined in this study as greater than 3mg single dose and 
metoprolol as a daily dose > 400 mg with occurrence of clinical symptoms. If a subject or any 
unintended other person not part of the study has an accidental or intentional overdose of the 
IMP, even if the consequences are not serious, the overdose must be reported to the sponsor 
immediately (within 24 hours). The procedure for reporting SAEs should be followed.  
 
Pregnancy 
Female subjects must be instructed to notify the investigator immediately if they become 
pregnant during the study. Pregnancies occurring during the study must be reported by the 
investigational staff within 24 hours of their knowledge of the event using the AE Form. Any 
subject who becomes pregnant during participation in this study must be promptly withdrawn 
from the study. Study medications will be immediately discontinued and study medications 
will not be tapered. Follow-up information regarding the outcome of the pregnancy and any 
postnatal sequelae in the infant will be required. Pregnancy will be recorded as an AE in all 
cases. It will be classified as an SAE only if it fulfils SAE criteria. ECRF will be completed 
and pregnant subjects will be follow-up until the outcome of the pregnancy has been 
determined.  
 
Hypoglycaemia 
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: 
• 
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 
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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. 
 
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.  
 
Any serious AE or unexpected ADR must be reported by investigator to the 
pharmacovigilance department by fax +49-511-53216-2794 within 24 hr. Such events will be 
documented in the best possible detail on the Serious Adverse Event Report Form and must 
be also transmitted to the sponsor by email within 24hr.  
 
The contact information of the pharmacovigilance department is as follows: 
 
Address:  
Institute of Clinical Pharmacology 
Hannover Medical School, Carl-Neuberg-Str. 1 
D-30625 Hannover, Germany 
Telephone:   +49-511-532-3959 
Fax: 
 
+49-511-53216-2794 
Email:  
sae-reporting@mh-hannover.de 
 
The investigator must also send (preferably by e-mail) photocopies of all reports of all 
examinations carried out and the dates, on which these examinations were performed, to the 
pharmacovigilance officer:  
Email: sae-reporting@mh-hannover.de 
Care should be taken to ensure that the subject's identity is protected and the subject’s 
identifiers in the clinical study are not included on any copy of source documents provided to 
the sponsor. Post-study SAEs may be reported in an expedited manner to the sponsor if the 
causality to the investigational study product is possible or probable. 
All data updates should be recorded in the eCRF as appropriate, and further documentation as 
well as additional information (e.g. laboratory data, concomitant medication, subject status) 
should be sent (by e-mail) to the sponsor within 24hours of knowledge. In addition, every 
effort should be made to document further any SAE that is fatal or life threatening within 1 
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The sponsor’s CRO will make expedited reports of all SAEs that are both unexpected and 
causally related to the IMP, to the Regulatory Authorities, IECs as appropriate and to the 
investigators at other investigational sites. In addition, the sponsor’s CRO may make 
expedited reports of all SAEs that are expected and causally related to the IMPs to the 
Competent Authorities, according to the European directive 2001/20/EC and the local 
regulations. The sponsor’s CRO will report all safety observations made during the conduct of 
the study in the clinical study report. 
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.  
 
If the investigator learns of an SAE within 30 days after the end of the study, this should be 
reported to the sponsor within 24hours from the investigator becoming aware of the event, 
regardless of whether or not there is a causal relationship with the IMP.   
 
6.10 DEVELOPMENT SAFETY UPDATE REPORTS 
At the anniversary date of the first inclusion, the Profil’s hired pharmacovigilance department 
will write down a Safety Report, which will contain an exhaustive list of Serious Adverse 
Events susceptible to be linked to the study medication, including expected and unexpected 
adverse events and an analysis of the study’s subjects’ safety. This report will be sent to 
Regulatory Authorities and to the IECs in the 60 days after the anniversary of the first 
inclusion. 
 
7 DESCRIPTION OF STATISTICAL METHODS 
7.1 
DESCRIPTION OF STATISTICAL METHODS 
Profil Institut für Stoffwechselforschung GmbH, Neuss, Germany, 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 Profil’s biostatistical 
standard operating procedures (SOPs). A general description of the statistical methods to be 
used is given in this chapter, specific details will be provided in the Statistical Analysis Plan 
(SAP), which will be prepared before data base lock. All statistical analyses will be performed 
using SAS® (SAS Institute Inc., Cary, North Carolina, United States of America [USA]), 
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7.2 
SAMPLE SIZE CALCULATION 
As this is an explorative study no formal sample size calculation was done. The chosen 
sample size is a balance between exposing the lowest possible number of patients to the IMP, 
while still being able to compare the effects of tesofensine/ metoprolol treatment vs. placebo. 
 
7.3 
SELECTION OF SUBJECTS FOR ANALYSES 
The following analysis sets are defined in accordance with the ICH-E9 guidance (11): 
 
Per-Protocol Population (PPP):  
includes all randomized subjects without any major protocol violations. Subjects in the PPP 
will contribute to the evaluation ‘as treated’.  
 
Safety Analysis Set:  
Includes all subjects receiving at least one dose of the investigational product or its 
comparator. Subjects in the safety set will contribute to the evaluation ‘as treated’.   
 
Analyses of primary and secondary endpoints will be based on the PPP. The analysis of the 
safety endpoints will be based on the Safety Analysis Set.  
 
Before data are released for statistical analysis, a blinded review of all data will take place to 
identify protocol deviations that may potentially affect the results. This review will be 
performed without revealing which IMP the subjects are assigned to. The blinding of the 
IMPs will be maintained for everyone involved in allocating subjects to the analysis sets until 
data are released for statistical analysis. Furthermore, outliers will be identified by data review 
according to ICH-E9 (11), and a fake randomisation. In addition, protocol deviations, which 
may potentially affect the results, will be identified and it will be evaluated if subjects and/or 
data should be excluded from the analysis. Obviously erroneous data points may be excluded 
from the analyses. The decision to exclude data points from the statistical analysis is the joint 
responsibility of the sponsor, the investigator and the CRO statistician.  
The subjects or observations to be excluded and the reason for their exclusion will be 
documented and signed by those responsible prior to database release. The documentation 
will be stored together with the remaining study documentation. The subjects and 
observations excluded from analysis sets, and the reason for this will be described in the 
clinical study report. 
 
7.4 
STATISTICAL METHODS 
All primary and secondary endpoints will be summarised by treatment and visit using 
descriptive statistics. Continuous endpoints are summarised by the arithmetic mean, 
geometric mean, median, standard deviation, coefficient of variation (CV), minimum and 
maximum value. Categorical endpoints are summarised by the number (N) and percentage 
(%). Moreover, complete listings of individual values for all endpoints will be provided. 
Individual and mean curves for the 24h- 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, 
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Safety Analysis Set. Subjects withdrawn from the study will be listed including the primary 
reason for withdrawal. 
 
7.5 
ANALYSIS OF THE PRIMARY ENDPOINT 
The primary endpoint will be derived from the individual heart rate measurements of the 24-h 
profile. The means of all individual concentrations per visit will be calculated. The primary 
endpoint will be analysed without transformation, if a l-normal distribution can be shown. In 
case of non-normal distribution alternatives will be described in the SAP. As this study will 
be conducted at two centres, it will be checked before any analysis, if a centre-effect may 
exist. If this is the case, the analysis has to be provided per centre. Otherwise the analysis can 
be conducted as described below. The primary endpoint will be compared between treatment 
arms by means of an ANCOVA model including treatment as fixed factor and baseline value 
as covariate. Least square means and 95% confidence of treatment differences will be 
estimated.  
 
7.6 
ANALYSIS OF THE SECONDARY & EXPLORATORY ENDPOINTS 
• 
Change from baseline (visit 2a) to end of treatment in mean SBP 
• 
Change from baseline (visit 2a) to end of treatment in mean DBP 
• 
Change from baseline (visit 2a2b) to end of treatment in body weight 
• 
Change from baseline (visit 2b) to end of treatment in HbA1c 
• 
Change from baseline (visit 2a) to end of treatment in FPG 
• 
Change from baseline (visit 2a) to end of treatment in 9-point blood glucose profiles 
(AUC) 
• 
Change from baseline (visit 2a) to end of treatment in liver fat 
• 
Change in fasting insulin from baseline (visit 2b) to end of treatment  
• 
Change in 1,5 anhydroglucitol from baseline (visit 2b) to end of treatment 
• 
Change from baseline (visit 2a) to end of treatment in waist circumference 
• 
Change from baseline (visit 2a) to end of treatment in PHQ-9 score 
• 
Other secondary endpoints may be added and will be described in the SAP 
The individual data per visit and time point will be presented as well as the mean values of the 
24-h profiles (if applicable). The analysis will be conducted as described for the primary 
endpoint. 
 
7.7 
SAFETY CRITERIA 
• 
AEs 
• 
Number and severity of hypoglycaemic events 
• 
Clinical labs (Haematology, Blood Chemistry) 
• 
ECG 
• 
Vital signs 
• 
Physical examination 
• 
PHQ-9 scores 
 
The safety endpoints will be based on the Safety Analysis Set. Continuous data will be 
summarized using non-missing counts, mean, standard deviation, median, minimum, and 
maximum. Categorical data will be summarized using counts and percentages. 
Frequency analysis of AEs between treatments will be done using a logistic regression model 
with treatment as fixed factor. Odds ratios, p-values, and 95% confidence intervals for the 


 
 
 
 
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comparisons between treatments will be estimated. A more detailed description will be done 
in the SAP. 
 
7.8 
INTERIM ANALYSIS 
No interim analysis is planned. 
 
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. 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, 
analyse, verify and reproduce any records and reports that are important to the evaluation of 
the study. Any party (e.g., domestic and foreign Regulatory Authorities, study monitor and 
auditors) with direct access must take all reasonable precautions within the constraints of the 
applicable regulatory requirement(s) to maintain the confidentiality of the subject’s identities 
and sponsor’s proprietary information. It is the monitor’s responsibility to verify that each 
subject has consented, in writing, to direct access. It is to be ensured by the investigator that 
documents that are given to Saniona A/S or its representatives do not contain the name or 
address of the subject, or other information that would affect the anonymity of the subject. 
 
The investigator will enter the following data in the source records of the subject: demographic 
information, medical history, concomitant medication, clinical findings from physical 
examination, vital signs, finding from urine pregnancy tests (if applicable), notes concerning the 
study procedures, study medication and all adverse events. 
 
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 regulatory authority. 
 
For each enrolled subject, the investigator will specify that the subject is taking part in this 
study. The investigator will maintain adequate case histories and proper notes for each of the 
included subjects. Source data will be archived for the maximum period of time permitted by 
local requirements. 
 
The following documentation is considered as source documentation for this study: 


 
 
 
 
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• 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 
• Known duration of T2DM 
• 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. The Subject Screening Log and Subject Identification Log may 
be combined in one list. 
 
9 QUALITY CONTROL AND QUALITY ASSURANCE 
9.1 
DEFINITIONS 
Quality Assurance 
A quality assurance (QA) audit as well as a regulatory inspection may be performed to 
determine if the rights and the well-being of the subjects enrolled were protected and if the 
study was conducted as per protocol, ICH GCP and applicable regulatory requirements, and if 
the data relevant for the evaluation of the investigational medicinal product were reported to 
the sponsor. The involved CRO will implement a QA system for their respective study-related 
activities. 
Quality Control 
The monitor will visit the Unit 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 eCRF entries compared to 
source data. The investigator will offer the monitor maximum cooperation, in order to find a 
prompt solution to any possible discrepancies or inaccuracies.  
 


 
 
 
 
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9.2 
AUDITS AND INSPECTIONS 
The investigator will make all study-related source data and records available to a medically 
qualified quality assurance auditor mandated by the sponsor, or to regulatory inspectors, after 
reasonable notice. The main purposes of an audit or inspection are to confirm that the rights 
and welfare of the subjects have been adequately protected, and that all data relevant for the 
assessment of safety and effectiveness of the investigational medicinal product have been 
reported to the sponsor. 
 
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 Independent Ethics Committee (IEC). The study will be conducted in compliance with 
the protocol, ICH GCP regulations and the applicable regulatory requirements. The regulatory 
application or submission for regulatory approval will be made by the sponsor’s CRO as 
required by national law. 
 
10.2 APPROVALS 
The sponsor will authorize a CRO for submitting the documents to the IEC and BfArM. 
 
10.3 ETHICS COMMITTEE  
This protocol, a sample subject information sheet and informed consent form, 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 Investigator’s Brochure 
• Reports of adverse events that are serious, unlisted and associated with the IMP  
• All protocol amendments and revised informed consent forms (if any) 
The sponsor’s CRO will provide a safety update of the study to the local IEC including line 
listings, individual reports of SUSARs, if applicable, and a discussion of AEs annually, or 
more frequently if requested based on valid legislation requirements. At the end of the study, 
the investigator will notify the IEC/RA about the study completion. Furthermore, he/she will 
provide the synopsis of the final report to the RA/IEC within one year after the end of the 
clinical study.  
 
10.4 REGULATORY AUTHORITY 
The study including all relevant documentation and information need to be submitted to the 
relevant Regulatory Authority for notification or approval according to valid legislation 
requirements. 
 
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 
Regulatory Authority. The investigator should not implement any deviation from, or changes 


 
 
 
 
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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, Regulatory 
Authority, except where necessary to eliminate an immediate hazard to the subjects, or when 
the change(s) that were approved by Saniona A/S involve only logistical or administrative 
aspects of the study. 
 
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 
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 eCRF for each subject 
enrolled. 
 
If new information becomes available that potentially affects the subject’s safety or 
willingness to continue in the study, or if a protocol amendment is issued that affects subject’s 
safety, study procedures or any aspects of the study that may influence the subject’s 
willingness to continue in the study, the subject information leaflet and informed consent 
form will be revised. After the new documents have received approval from the 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 
quality assurance auditor or an IEC/Regulatory Authority inspector, in accordance with 
applicable regulations. All personal information which the subject will reveal to the investigator 
and which does not pertain to the study will be considered confidential. 
 
10.7 PARTICIPANT CONFIDENTIALITY 
The investigator will ensure that the subject's anonymity will be preserved. On eCRFs or any 
other documents submitted to the sponsor, the subjects will not be identified by their names, 
but by a study specific identification code. Documents not intended for the sponsor, i.e. the 
confidential subject identification code, original consent forms and source records will be 
maintained by the investigator as strictly confidential and in a secured place. The subjects will 
be informed that all their study results will be handled in strictest confidence. 
 
10.8 INVESTIGATOR QUALIFICATION 
The investigator will be informed of the methods for rating relevant study outcomes and for 
completing eCRFs 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. The investigator will be responsible for the 
completeness, accuracy and legibility of the information in the eCRF and other study 
documents. The study monitors then have to check the eCRFs against the source documents 
for accuracy and validity as per the monitoring schedule, as applicable. Upon completion of 
the examination, eCRF completion is expected at each Unit to ensure quality of data and 
subject safety. Once eCRFs are completed, they will be available for review by the study 
monitor and CRO Clinical Data Management. Completed eCRFs will be reviewed remotely 
for logical discrepancies. The study monitor will ensure that all data queries and subsequent 
amendments in the eCRF documentation are made according to GCP guidelines. 
 
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 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 quality assurance 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. For this study, the 
average number of the monitoring visits is intended to be 3-4 monitoring visits/Unit (initiation 
and close-out visit is not included). 
 
In general, during monitoring visits the monitor will ensure that the study is being conducted 
according to the protocol, International Conference on Harmonization Good Clinical Practice 
(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 Profil Institut für Stoffwechselforschung GmbH, 
Neuss Germany. The complete Data Management process will be described in detail and 
agreed on in the Data Management Plan for this study. 
 
11.4 CASE REPORT FORMS (CRFS) 
The Data Management Department of Profil Institut für Stoffwechselforschung GmbH will 
provide the CRFs. All further information regarding the CRFs and the data flow will be 
described and agreed on in the Data Management Plan for this study. 
 
Database Lock  
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will be locked. All unnecessary user privileges to the study will be removed, except for the 
data manager who will perform the database lock.  
 
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 eCRF for the sponsor. The 
investigator will ensure that this secret list is maintained securely for a period of 15 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 
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 Profil.  
 
13 PUBLICATION POLICY 
13.1 REPORTING AND PUBLICATION 
Profil will prepare a study report after the completion of the study. The sponsor representative 
will sign the final study report intended to be submitted to Regulatory Authorities. 
 
The results of this study may be published or presented at scientific meetings. The sponsor 
will be responsible for publication of all the data generated in this study. In accord with 
standard editorial and ethical practice, the sponsor will support publication of multicentre 
studies only in their entirety and not as individual site data.  


 
 
 
 
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14 REFERENCES 
  
1. Hu FB, Manson JE, Stampfer MJ, et al. Diet, Lifestyle, and Risk of Type 2 Diabetes 
Mellitus in Women. NEJM 2001;345:790-7. 
2. Fabbrini E, Magkos F, Mohammed BS, et al. Intrahepatic fat, not visceral fat, is linked 
with metabolic complications of obesity. PNAS 2009;106:15430-5. 
3. Taylor R. Type 2 diabetes Etiology and Reversibility. Diabetes Care 2013;36:1047-
1055. 
4. Diabetes Prevention Program Research Group. Reduction in the Incidence of Type 2 
Diabetes with Lifestyle Intervention or Metformin. NEJM 2002;346:393-403. 
5. Diabetes Prevention Program Research Group. 10-year follow-up of diabetes 
incidence and weight loss in the Diabetes Prevention Program Outcomes Study. 
Lancet 2009;374:1677-86. 
6. Torgerson JS, Hauptman J, Boldrin MN, Sjostrom L.  Xenical in the Prevention of 
Diabtes in Obese Subjects (XENDOS) Study. Diabetes Care 2004;27:155-161. 
7. Garvey TW, Ryan DH, Henry R, et al.  Prevention of Type 2 Diabetes in Subjects 
With Prediabetes and Metabolic Syndrome Treated With Phentermine and Topiramate 
Extended-Release. Diabetes Care 2014:37:912-921.  
8. Astrup A, Madsbad S, Breum L, et al. Effect of tesofensine on bodyweight loss, body 
composition, adn quality of life in obese patients: a randomised, double-blind, 
placebo-controlled trial. Lancet 2008;372:1906-1913. 
9. Bentzen BH, Grunnet, M, Hyveled-Nielsen, L. Anti-Hypertensive Treatment Preserves 
Appetite Suppression While Preventing Cardiovascular Adverse Effects of 
Tesofensine in Rats. Obesity 2013;21:985-992. 
10. Beard C, Hsu K, Rifkin LS, Busch AB, Björgvinsson T. Validation of the PHQ-9 in a 
psychiatric sample. J. Affect. Disord. 2016; 15:193:267-73. 
11. ICH Harmonised Tripartite Guideline. Good Clinical Practice [Internet]. 1996 [cited 
2015 Oct 28]. Available from: 
https://firstclinical.com/regdocs/doc/?db=ICH_E6_Good_Clinical_Practice 
 
 
 
 
 
 


 
 
 
 
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15 Appendices 
 
15.1 Appendix I: table of recommended concomitant medication use 
 
 
Drug Class
Episodic Use
Chronic Use
Comment
Antiarrhythmic (Amiodarone, quinidine) 
N 
N 
Strong inhibitor of  CYP2D6 
Antiretroviral (Ritonavir) 
N 
N 
Strong inhibitor of  CYP2D6 
Anorectic agents 
N 
N 
 
Antiandrogens (Abiraterone, Cyproterone acetate, 
Finasteride) 
N 
N 
 
Antihistamines 
Y 
N 
Topical antihistamines – always 
approved 
Antiepileptic drugs , 
N 
N 
 
Antidepressant drugs 
N 
N 
 
Anti-anxiety drugs 
N 
N 
 
Anti-Parkinsonian drugs  
N 
N 
 
Anti-Dementia drugs Donepezil and Galantamin 
N 
N 
 
Antifungal (terbinafine) 
N 
N 
Moderate inhibitor of  CYP2D6 
Muscarinreceptor blocker Darifenacin 
N 
N 
Moderate inhibitor of  CYP2D6 
Barbiturates 
N 
N 
 
Benzodiazepines 
Y 
N 
Prohibited for 2 weeks prior to 
randomisation, however, hypnotics 
and/or anxiolytics at a stable dose 
for at least 4 weeks prior to 
screening and up to the follow-up 
visit could be alowed, i.e.up to 
zolpidem (10 mg/day), choral 
hydrate (1 g/day), triazolam (0.5 
mg/day), or lorazepam (1 mg/day) 
Beta- blockers 
N 
N 
 Per protocol 
Buproprion (non-SSRI antidepressant) 
N 
N 
 Strong inhibitor of  CYP2D6 
Calcium channel blockers 
N 
N 
 Per protocol 
Carbonic anhydrase inhibitors (e.g., acetazolamide, 
dichlorphenamide, dorzolamide, methazolamide) 
N 
N 
 
Cinacalcet (calcimimetic)
N
N
Strong inhibitor of  CYP2D6
Dopamine reuptake inhibitors (e.g. bupropion) 
N 
N 
 
Glucocorticoids 
Y 
N 
 
Hypnotic sedative (glutethimide) 
N 
N 
Strong inducer of  CYP2D6 
H2-receptor antagonist (cimetidine) 
N 
N 
Weak inhibitor of  CYP2D6 
Immunosuppressives 
N 
N 
 
Insulin and/or other injectable anti-diabetic 
medications, or TZDs 
N 
N 
Per protocol 
Lithium
N
N
Monoamine oxidase (MAO) inhibitors 
N 
N 
 
Opioids, cannabinidiols
N
N
Oral hypoglycemics
-
-
Per protocol
Orlistat
N
N
Phenothiazines 
N 
N 
 
Selective serotonin reuptake inhibitors (SSRIs) 
N 
N 
 
Serotonin and norepinephrine reuptake inhibitors 
(SNRIs) 
N 
N 
 
 
 
 
 


 
 
 
 
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Drug Class
Episodic Use
Chronic Use
Comment
Tricyclic antidepressants 
N 
N 
 
Drug inducing ocular toxicity Chloroquine 
Hydrochloroquine 
N 
N 
 
Non-drugs
 
 
 
Weight loss supplements 
N 
N 
 
Anti-depression, anxiety, epilepsy, psychotics OTC, 
supplements  
N 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
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15.2 Appendix II: The Patient Health Questionnaire (PHQ-9; Version in 
German) 
 

SAP_001.pdf: