Clinical trial NCT03488719
Conditions: Phase 1
Sponsor: Saniona
Start date: 2018-07-11; Completion date: 2019-06-06
Enrollment: 37 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
A Phase 1 Study to Examine Pharmacodynamic Interaction Between Tesofensine and Metoprolol on 24-hours Mean Heart Rate

Detailed description:
In this study, the dose-response relationship between tesofensine and metoprolol will be examined and thus the optimal dose of metoprolol to mitigate the effects of tesofensine on heart rate (HR) will be determined. HR is the primary endpoint because in the previous studies it has been shown to be the most affected safety endpoint by the effects of tesofensine.

After enrolment of 37 subjects, 2 Subjects (0115 and 0147) in dose cohort 2 experienced prolonged tachycardia (\> 120 beats per minute (bpm) lasting for 30 min) documented in Holter Electrocardiogram (ECG) recording (a stopping criteria of the study). Therefore, the study was temporarily halted on 22 November 2018. Subsequent to the temporary halt, Saniona reviewed all the available data in January and February 2019 and determined that the results obtained from the completed participants were sufficiently robust to answer the questions for which the trial was designed. Therefore, Saniona decided to permanently end the trial on 20 February 2019.

Arms: arm 1: Tesofensine 0.25 mg once daily for 23 days (loading dose of 1.0 mg for the first 3 days), plus a single dose of 25 mg, 50 mg or 100 mg metoprolol extended release (ER) in random order on Day 15, Day 18 and Day 21, respectively. arm 2: Tesofensine 0.50 mg once daily for 23 days (loading dose of 2.0 mg for the first 3 days), plus a single dose of 25 mg, 50 mg or 100 mg metoprolol extended release (ER) in random order on Day 15, Day 18 and Day 21, respectively. arm 3: Tesofensine 0.75 mg (0.25 mg + 0.50 mg) once daily for 23 days (loading dose of 2.0 mg \[4 tablets of 0.50 mg\] for the first 5 days), plus a single dose of 25 mg, 50 mg or 100 mg metoprolol extended release (ER) in random order on Day 15, Day 18 and Day 21, respectively.
Interventions: intervention 1: Metoprolol Succinate 25 MG intervention 2: Metoprolol Succinate 50 MG intervention 3: Metoprolol Succinate 100 MG
Intervention descriptions: intervention 1: A single dose of 25 mg metoprolol ER in the morning of Day 15, Day 18 or Day 21 approximately 30 minutes after start of a standard breakfast and together with the tesofensine dose. intervention 2: A single dose of 50 mg metoprolol ER in the morning of Day 15, Day 18 or Day 21 approximately 30 minutes after start of a standard breakfast and together with the tesofensine dose. intervention 3: A single dose of 100 mg metoprolol ER in the morning of Day 15, Day 18 or Day 21, approximately 30 minutes after start of a standard breakfast and together with the tesofensine dose.

Protocol documents:
Prot_000.pdf: 
Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 1 of 97 
14 June 2018 
 
Clinical Study Protocol 
A Phase 1 Study to Examine Pharmacodynamic Interaction Between 
Tesofensine and Metoprolol on 24-hours Mean Heart Rate 
 
Sponsor: 
Saniona A/S 
Baltorpvej 154 
DK-2750 Ballerup 
Denmark 
Contract Research Organization: 
PAREXEL International GmbH 
Early Phase Clinical Unit 
Klinikum Westend, Haus 31 
Spandauer Damm 130 
14050 Berlin, Germany 
Principal Investigator: 
Dr. med. Astrid Breitschaft 
PAREXEL Study Number: 
238081 
Sponsor Study Number: 
TM004 
EudraCT Number:  
2018-000660-28 
IMP Names: 
Tesofensine, metoprolol 
Development Phase: 
Phase 1, pharmacodynamic interaction 
Version (Date) of Previous Protocol: 
Final 1.0 (03 April 2018) 
Date of Protocol: 
Final 2.0, 14 June 2018, incorporates Amendment 
No. 01 
This clinical study will be conducted in accordance with the International Council for Harmonisation Tripartite 
Guideline for Good Clinical Practice (GCP) (E6), the Declaration of Helsinki (Version 1996), the protocol and with 
other applicable regulatory requirements. 
Confidentiality Statement 
This document contains confidential information of Saniona A/S.  Do not copy or distribute without written 
permission from the Sponsor. 
 
 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 2 of 97 
14 June 2018 
 
SUMMARY OF CHANGES OF AMENDMENT 1 
The final Version 1.0 of this protocol (protocol final version f1.0, dated 03 April 2018) was 
submitted to the German Authorities (BfArM) and the Berlin Ethics Committee. In addition, 
typographical errors were also corrected and linguistics as well as administrative changes were 
made by means of this amendment. 
This amendment 1.0 serves to incorporate the following items as requested by the BfArM and 
the Ethics Committee: 
A restriction with regard to the maximum number of subjects that might be replaced due to other 
reasons than adverse events (AEs) related to the investigational medicinal products has been 
added (up to 25% in the study). 
To specify in more detail which aspects of the medical history and which exact findings during 
physical examination will lead to exclusion of a subject, threshold values for HbA1c to exclude 
diabetic subjects (inclusion criterion 7) and creatinine to exclude subjects with renal impairment 
(exclusion criterion 7) as well as threshold values for alanine aminotransferase (ALT) and 
aspartate aminotransferase (AST) (exclusion criterion 4) to exclude subjects with liver diseases 
have been added. 
A rationale has been added to justify the inclusion of subjects with a body mass index (BMI) of 
up to 40 kg/m2, in order to clarify that the obese subjects to be included will have to be otherwise 
healthy and without comorbidities.  
To clarify that no comorbidities shall be expected, wording was added that subjects to be 
include, though overweight, are healthy.  
Pregnant and lactating females have been excluded from participation. 
Contraindications, warnings and precautionary measures listed in the Summary of Product 
Characteristics (SPC) of metoprolol have been added to the exclusion criteria. 
With regard to concomitant medications restrictions it was added that the use of any prescribed 
or non-prescribed drugs is prohibited before admission also for five half-lives of the respective 
drug, if this is results in more than 2 weeks. 
The psychodiagnostic self-rating instruments (Generalized Anxiety Disorder Assessment 
[GAD-7] and Patient Health Questionnaire-9 [PHQ-9]) have been added to the Screening-
procedure, to ensure that no subjects with disposition to neuropsychiatric disorders (like anxiety 
disorders or depression) or to suicidal ideation or self-harm will be included. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 3 of 97 
14 June 2018 
 
Pregnancy tests have been added for the end of trial visits as well as during Follow-up to test for 
absence of pregnancy throughout the complete period where highly effective methods of 
contraception have to be used.  In addition it has been added that a pregnancy test will be 
performed whenever clinically indicated. 
A stopping criterion has been added to ensure termination of the study in case of occurrence of 
psychiatric AE. 
References have been added referring to the Investigator Brochure (IB) of tesofensine. 
The risk-benefit assessment section has been updated to reflect that psychiatric events occurred 
in an age group and population completely different from the one to be included in this study.  
No serious or severe cardiovascular AEs have been reported to date. 
These changes affected the following sections: 
 
 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 4 of 97 
14 June 2018 
 
 
Protocol Amendment No. 1 
 
Sections Affected 
Changes and Reasons 
Protocol Synopsis 
Study Design, 
Inclusion Criteria, Exclusion Criteria, 
Criteria for Evaluation, 
Added to study design that dosing of tesofensine will be performed 
"approximately 30 minutes" after start of breakfast.  
Exchanged "within" with "approximately" in study design with regard to 
metoprolol-dosing 30 minutes after start of a standard breakfast. 
Changed that subjects  will be withdrawn due to other reasons than 
"tesofensine related AEs" to " investigational medicinal product 
(IMP)-related AEs" in the study design, and added that that only "(up to 
25% in the study)" subjects withdrawn due to other reasons than IMP-
related AEs will be replaced.   
Inclusion criterion 3 (on the inclusion of obese but healthy subjects) has 
been added. 
The previous inclusion criterion 4 on BMI has been deleted. 
An inclusion criterion requiring HbA1c < 6.5% at Screening has been 
added. 
"Metabolic acidosis" has been added to exclusion criterion 1. 
Threshold values for specific liver function tests have been added 
(exclusion criterion 4) 
It has been added to exclusion criterion 5 that for diastolic blood 
pressure (DBP) and systolic blood pressure (SBP) value-determination 
the mean of triplicate measurements will be used. 
Exclusion criterion 6 on cardiac parameters (QTc) has been amended, 
now using the mean of 3 measurements to determine electrocardiogram 
(ECG) parameters.  The previous exclusion criterion 13 has been moved 
here as well (to exclude clinically significant cardiac arrhythmia). Also 
added were several cardiac conditions to reflect the contraindications 
stated in the SPC of metoprolol. 
Subjects with a creatinine value above the upper limit of normal (ULN) 
are now excluded by criterion 7. 
Exclusion criterion 9 (on use of any prescribed or non-prescribed drugs) 
has been amended by addition of "or five half-lives of the drug, 
whichever is longer ". 
Exclusion criterion 16 has been amended (on participation in any 
clinical study) has been amended by addition of "or five half-lives of the 
drug, whichever is longer" and deletion of "provided that the clinical 
study did not entail a biological compound with a long t1/2 ". 
The psychodiagnostic self-rating instruments (PHQ-9 and GAD-7) have 
been added (criterion 17). 
Exclusion of pregnant or lactating subjects was added (criterion 21). 
Those contraindications for metoprolol that have not explicitly been 
mentioned in other exclusion criteria have now been added as exclusion 
criterion 24. 
Exclusion criterion 25 has been amended to exclude also a rare 
hereditary problem of fructose intolerance, glucose galactose 
malabsorption or sucrase isomaltase insufficiency. 
The last exclusion criterion ( number 30) has been amended to exclude 
ultrarapid CYP2D6 metabolizers in addition to poor metabolizers 
Secondary Endpoints have been clarified, to reflect that maximum and 
minimum heart rate (HR)24 are abbreviated by HRmax and HRmin. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 5 of 97 
14 June 2018 
 
List of Abbreviations and Definition of 
Terms 
Updated. 
Introduction, Section 1 
Third paragraph has been updated by adding that 2 of the 3 studies with 
co-administation of tesofensine and metoprol have been completed. 
Added a reference to the Tesofensine IB.  
Introduction, Pharmacokinetics, 
Section 1.1 
Changed reference in section on tesofensine from Tesomet IB to 
Tesofensine IB.   
Introduction, Pharmacokinetics, 
Section 1.1.3 
Changed title of section by deleting "Tesomet" and keeping part in 
brackets. Added a reference to the Tesofensine IB. 
Introduction, Rationale for the Clinical 
Study, Section 1.2.1 
Added study number "NS2330-001, (“TIPO-1”)" to first sentence in 
second paragraph and moved last 3 sentences of same paragraph directly 
behind the first sentence. 
Added a paragraph on long-term studies. 
Number of subjects that have been included in studies on tesofensine 
(examining the metabolic and weight loss effects in patients) has been 
changed from 800 to 900. 
Added a reference to the Tesofensine IB. 
Introduction, Rationale for the Clinical 
Study, Section  1.2.3 
Number of studies in which tesofensine tablet and metoprolol tablet 
have been co-administered to humans has been changed from 3 to 4. 
Added that studies Q-21125 and TM001 have been completed and that 
"third" refers to study TM003. 
Risk-Benefit Assessment, Section 1.3 
Reference to "Tesomet"-IB changed to "Tesofensine IB". Wording has 
been added with regard to low risk of metoprolol administration, since 
healthy subjects will be included. In addition paragraphs have been 
added discussing psychiatric and cardiovascular risks based on previous 
studies. In addition it has been added that at Screening the 
psychodiagnostic self-rating instruments (PHQ-9 and GAD-7) will be 
performed to exclude subjects with a predisposition to neuropsychiatric 
disorders like anxiety disorders or depression or to suicidal ideation or 
self-harm. A reference to the Tesofensine IB has been added. 
Overview, Section 3.1 
Corrections were made to reflect that dosing of tesofensine will be 
performed "approximately 30 minutes" after start of breakfast.  
In addition, with regard to metoprolol-dosing "within 30 minutes after 
start of breakfast" has been exchanged with "approximately…". 
Figure 1 and Figure 2 
An addition has been made to Day 23, to reflect that before each PK 
sample or at corresponding time of the day resting 12-lead ECG, blood 
pressure (BP) and pulse will be assessed. 
Endpoints, Section 3.2 
Secondary Endpoints have been clarified, to reflect that maximum and 
minimum HR24 are abbreviated by HRmax and HRmin 
Justification of the Study Design, 
Section 3.3 
Changes have been made to reflect that not only poor, but also ultrarapid 
metabolizers will be excluded from participation in this study. 
Stopping Criteria and Termination of 
the Clinical Study, Section 3.4 
A psychiatric stopping criterion has been added 
Study Population, Section 4 
A paragraph has been added to explain that subjects with obesity grade 1 
and 2 will be included and why this is justified, with regard to safety. 
Number of subjects, Section 4.1 
Added that only "(up to 25% in the study)" subjects will be withdrawn 
due to other reasons than to IMP-related AEs and that only healthy 
subjects will be included. 
Inclusion Criteria, Section 4.2 
Inclusion criterion 3 (on the inclusion of obese but healthy subjects) has 
been added. 
The previous inclusion criterion 4 on BMI has been deleted. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 6 of 97 
14 June 2018 
 
An inclusion criterion requiring a HbA1c < 6.5% at Screening has been 
added. 
Exclusion Criteria, Section 4.3 
"Metabolic acidosis" has been added to exclusion criterion 1. 
Threshold values for specific liver function tests have been added 
(exclusion criterion 4) 
It has been added to exclusion criterion 5 that for DBP and SBP value-
determination the mean of triplicate measurements will be used. 
Exclusion criterion 6 on cardiac parameters (QTc) has been amended, 
now using the mean of 3 measurements to determine ECG parameters.  
The previous exclusion criterion 13 has been moved here as well (to 
exclude clinically significant cardiac arrhythmia). Also added were 
several cardiac conditions to reflect the contraindications stated in the 
SPC of metoprolol. 
Subjects with a creatinine value above ULN are now excluded by 
criterion 7. 
Exclusion criterion 9 (on use of any prescribed or non-prescribed drugs) 
has been amended by addition of "or five half-lives of the drug, 
whichever is longer ". 
Exclusion criterion 16 has been amended (on participation in any 
clinical study) has been amended by addition of "or five half-lives of the 
drug, whichever is longer " and deletion of "provided that the clinical 
study did not entail a biological compound with a long t1/2 ". 
The psychodiagnostic self-rating instruments (PHQ-9 and GAD-7) have 
been added (criterion 17). 
Exclusion of pregnant or lactating subjects was added (criterion 21). 
Those contraindications for metoprolol that have not explicitly been 
mentioned in other exclusion criteria have now been added as exclusion 
criterion 24. 
Exclusion criterion 25 has been amended to exclude also a rare 
hereditary problem of fructose intolerance, glucose galactose 
malabsorption or sucrase isomaltase insufficiency. 
The last exclusion criterion (number 30) has been amended to exclude 
ultrarapid CYP2D6 metabolizers in addition to poor metabolizers. 
Subject Withdrawal and Replacement,  
Section 4.4 
Changed to reflect that subjects  will be withdrawn due to other reasons 
than "tesofensine related AEs" to "IMP-related AEs" in the study design, 
and added that that only "(up to 25% in the study)" subjects will be 
withdrawn due to other reasons than to IMP-related AEs 
Administration of Investigational 
Medicinal Products, 5.6 
Added to study design that dosing of tesofensine will be performed 
"approximately 30 minutes" after start of breakfast.  
Exchanged "within" with "approximately" in study design with regard to 
metoprolol-dosing 30 minutes after start of a standard breakfast 
Compliance, Section 5.7 
 Wording adapted (no change of content) 
Blinding and Breaking the Blind, 
Section 5.8 
Specified that a glass of water corresponds to 240 mL. It has been added 
that subjects can drink an additional 200 ml of water if needed for 
swallowing the tablets. 
Medical History, Demographic and 
Other Baseline Information, Section 
6.1 
A third bullet has been added to medical history i.e. family history of 
psychiatric disorders. 
Recording of Adverse Events, Section 
6.2.1.2 
It has been added that causality of AEs will be assessed separately for 
tesofensine and metoprolol 
Assessment of Adverse Events, Section 
6.2.1.3 
It has been added that causality of AEs will be assessed separately for 
tesofensine and metoprolol 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 7 of 97 
14 June 2018 
 
Reporting of Serious Adverse Events, 
6.2.1.4 
The address (email and FAX) to send the SAE Report Form to has been 
changed from PAREXEL to KLIFO Pharmacovigilance Service. "Year 
of birth" has been changed to "Age". It has been added that details can 
be found in the SMP. 
Pregnancy, Section 6.2.1.6 
A section on pregnancy has been added. 
Clinical Laboratory Assessments, 
Table 3 
HbA1c has been added (only Screening). 
Vital Signs, Section 6.2.3 
It has been added that measurements will be taken as triplicates and that 
mean of these 3 values will be used to assess eligibility. 
Standard 12-lead Electrocardiograms, 
Section 6.2.4 
It has been added that measurements will be taken as triplicates and that 
mean of these 3 values will be used to assess eligibility. 
Patient Health Questionnaire-9 
(PHQ-9) and Generalized Anxiety 
Disorder Assessment (GAD-7), Section 
6.2.6 
A section on PHQ-9 and GAD-7 has been added. 
Pharmacodynamic Variables 6.4 
Added the following: “With regard to HRmin and HRmax the minute in 
which the minimum and the minute in which the maximum HR occurred 
will be determined over the 24 hour period”. 
Schedule of Assessments, Table 5 and 
Table 6  
The psychodiagnostic self-rating instruments (PHQ-9 and GAD-7) have 
been added at Screening.  The footer has been updated, with regard to 
footnote d and e (referring to days on which triplicate measurements will 
be performed). 
HbA1c has been added to Screening. 
It has been added that a pregnancy tests will be performed whenever 
deemed necessary and that additional tests will be performed on Day 24 
and at the Follow-up (FU) call at home. 
Only to the Flowchart of Cohort 3 a BP and pulse-measurement has 
been added for Days 4 and 5. 
Interim Analyses; Section 8.11 
Details have been added. 
Reference list, Section 10 
The IB of Tesofensine has been added. 
 






Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 10 of 97 
14 June 2018 
 
LIST OF STUDY STAFF 
Sponsor 
Saniona A/S 
Baltorpvej 154 
DK-2750 Ballerup 
Denmark 
Telephone number: +45 70 705 225 
Email: rdv@saniona.com 
 
Sponsor’s Medical Expert 
Roman V. Dvorak, MD, PhD 
Chief Medical Officer 
Saniona A/S 
Baltorpvej 154 
DK-2750 Ballerup 
Denmark 
Telephone number: +1401 932 2944 
Email: rdv@saniona.com 
 
Principal Investigator 
Dr. med. Astrid Breitschaft 
PAREXEL International GmbH 
Early Phase Clinical Unit Berlin 
Klinikum Westend, Haus 31 
Spandauer Damm 130 
14050 Berlin 
Germany 
Telephone number: +49 (0)30 30685 4254 
Email: Astrid.Breitschaft@parexel.com 
 
Contract Research Organization 
PAREXEL International GmbH 
Early Phase Clinical Unit Berlin 
Klinikum Westend, Haus 31 
Spandauer Damm 130 
14050 Berlin 
Germany 
Telephone number: +49 (0)30 30685 0 
Fax number: +49 (0)30 30685 7017 
 
Adverse Event Reporting 
KLIFO Pharmacovigilance Service KLIFO A/S,  
Smedeland 36,  
2600 Glostrup,  
Denmark 
Fax number: +45 39 209 045 
Email: pharmacovigilance@klifo.com 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 11 of 97 
14 June 2018 
 
Bioanalytical Laboratory 
Envigo CRS Limited 
Woolley Road  
Alconbury  
Huntingdon  
Cambridgeshire 
PE28 4HS 
United Kingdom 
Contact Person: Lynn Laugher 
Telephone number: +44 (0)1480 892 030 
Fax number: +44 (0)1480 892 362 
 
Safety Laboratory and 
Genotyping for CYP2D6 
Synlab Analytics &Services Germany GmbH 
Turmstr. 21 (House M) 
10559 Berlin 
Germany 
Tel: +49 (0)30 396 08 513 
Fax: +49 (0)30 396 08 543 
 
Laboratory for Urinalysis/Urine 
Drug Screen/PK Sample 
Processing 
PAREXEL International GmbH 
Spandauer Damm 130 
14050 Berlin 
Germany 
Tel: +49 (0)30 30 685 335 
Fax: +49 (0)30 30 685 7010 
 
 
 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 12 of 97 
14 June 2018 
 
PROTOCOL SYNOPSIS 
Protocol Title 
A Phase 1 Study to Examine Pharmacodynamic Interaction Between 
Tesofensine and Metoprolol on 24-hours Mean Heart Rate 
Study Numbers 
PAREXEL Study No.: 238081 
Sponsor Protocol No.: TM004 
Development Phase 
Phase 1, pharmacodynamic interaction 
Sponsor 
Saniona A/S 
Principal Investigator 
Dr. med. Astrid Breitschaft 
Study Center 
PAREXEL International GmbH 
Early Phase Clinical Unit Berlin 
Klinikum Westend, Haus 31 
Spandauer Damm 130 
14050 Berlin, Germany 
The study will be conducted at a single center (PAREXEL International 
GmbH, Early Phase Clinical Unit Berlin). 
Study Objectives 
Primary objective: 
To determine the optimal dose of metoprolol to mitigate the effect of 
tesofensine on heart rate (HR) 
Secondary objectives: 
• 
To confirm that addition of metoprolol mitigates the effect of tesofensine 
on HR 
• 
To examine the concentration-response relationship between tesofensine 
and metoprolol on HR and blood pressure (BP) 
• 
Assess the time dependence of tesofensine effect on HR by comparing HR 
data under tesofensine alone  
• 
Safety and tolerability of tesofensine alone and co-administration of 
tesofensine and metoprolol 
 
Study Design 
This is a randomized, open-label for tesofensine and single-blind for 
metoprolol, parallel-arm study in 60 male and female subjects who meet the 
inclusion and none of the exclusion criteria for the study. 
Each subject will participate in a Screening Period (Day -28 to Day -3), a 
Baseline Period (Day -2 to Day -1) and a Treatment Period (Day 1 to Day 24) 
and will have 2 Follow-up phone calls (Day 30 and Day 50).   
The Treatment Period will comprise: 
• 
In Cohorts 1 and 2, an initial in-house stay (Day -2 to Day 3) until the last 
loading dose of tesofensine has been administered on Day 3   
or 
In Cohort 3, an initial in-house stay until the third loading dose tesofensine has 
been administered on Day 3 
• 
In Cohorts 1 and 2, a home-dosing period (Day 4 to Day 12, once daily 
dosing to achieve steady state of tesofensine with an ambulatory visit in the 
clinical unit on Day 7)  
 
or 
In Cohort 3, 2 ambulatory visits on Days 4 and 5 with administration of the 4th 
and 5th loading dose, followed by a home-dosing period (Day 6 to Day 12, 
once daily dosing to achieve steady state of tesofensine with an ambulatory 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 13 of 97 
14 June 2018 
 
visit in the clinical unit on Day 7)   
and  
• 
A second in-house stay (Day 13 to Day 24).  Safety evaluations will be 
performed on Day 30 and Day 50 (end-of-study [EoS]) after last dosing over 
the phone. 
A total of 60 subjects will be randomly assigned to one of the following 
treatment cohorts: 
Cohort 1 (20 subjects): tesofensine 0.25 mg once daily for 23 days (loading 
dose of 1.0 mg for the first 3 days)  
Cohort 2 (20 subjects): tesofensine 0.50 mg once daily for 23 days (loading 
dose of 2.0 mg for the first 3 days)  
Cohort 3 (20 subjects): tesofensine 0.75 mg (0.25 mg + 0.50 mg) once daily 
for 23 days (loading dose of 2.0 mg [4 tablets of 0.50 mg] for the first 5 days)  
Dosing of tesofensine will be performed approximately 30 minutes after start 
of breakfast.  Timing and quantity of meals will be consistent on 
pharmacokinetic (PK) and pharmacodynamic (PD) days, i.e., on Day -1, 
Day 13, Day 14, Day 15, Day 17, Day 18, Day 20, Day 21 and Day 23. 
In addition, each subject will receive a single dose of 25 mg, 50 mg or 100 mg 
metoprolol extended release (ER) in random order in the morning of Day 15, 
Day 18 and Day 21, respectively, approximately 30 minutes after start of a 
standard breakfast and together with the tesofensine dose. 
For each subject assessments (24-hour ECG, blood sampling for PK of 
metoprolol and tesofensine [Day 15, Day 18 and Day 21 only], blood sampling 
for PK of tesofensine [Day 13, Day 14 and Day 23 only] and 12-lead ECG, BP 
and pulse before each blood sampling for PK) will be performed to examine 
the dose-response relationship in combination of tesofensine and metoprolol:  
o 
On the day before start of investigational medicinal product (IMP) 
dosing (on Day -1) 
At tesofensine steady state  
o 
On Day 14 and 15 (before and after the 1st metoprolol dose) 
o 
On Day 17 and 18 (before and after the 2nd metoprolol dose) 
o 
On Day 20 and 21 (before and after the 3rd metoprolol dose) 
o 
And on Day 23 (tesofensine alone) 
In addition, safety assessments will be performed throughout the study.  
Day 16, Day 19 and Day 22 will be wash-out days for metoprolol. 
At each dosing of metoprolol, a metoprolol placebo tablet will be administered 
in addition to the metoprolol tablet in order to mask the dose level of 
metoprolol.  
On in-house dosing days (i.e., Day 1 to Day 3, Day 7 and Day 13 to Day 23 
and, in addition in Cohort 3, Day 4 and Day 5), the Investigator or a designee 
will administer the IMP(s), i.e., tesofensine, metoprolol and placebo, to the 
subjects approximately 30 minutes after start of the breakfast.  From Day 4 to 
Day 6 (Cohorts 1 and 2) or on Day 6 (Cohort 3) and from Day 8 to Day 12 (all 
cohorts), subject will self-administer a single dose of tesofensine 
approximately 30 minutes after start of a breakfast. 
For each of the treatment groups, blood samples will be collected pre-dose and 
at designated time points post dosing.  Pharmacodynamic (PD) assessments 
(24-hour Holter-ECG, 12-lead ECG, BP and pulse) will be performed pre-dose 
and at designated time points post dosing.  Subjects will be discharged from 
the clinical unit after the 48 hours post-dose assessments have been completed 
on Day 3.  Subjects will have a home-dosing period (from Day 4 to Day 6 
[Cohorts 1 and 2] or on Day 6 [Cohort 3] and from Day 8 to Day 12 [all 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 14 of 97 
14 June 2018 
 
cohorts]) with once daily dosing to achieve steady state of tesofensine with an 
ambulatory visit in the clinical unit (on Day 7) and a second in-house stay 
(Day 13 to Day 24).  At the Safety Follow-up phone calls (on Day 30 and 
Day 50), subjects will be asked regarding adverse events (AE), and 
concomitant medications. 
The total duration for each subject will be up to 78 days, including Screening 
and Follow-up period. 
Investigational Medicinal 
Products 
• 
Tesofensine, film-coated tablet, 0.25 mg: 
o 
Oral dose of 4 tablets once daily from Day 1 to Day 3, Cohort 1 only 
(loading dose of 1.0 mg) 
o 
Oral dose of 1 tablet once daily from Day 4 to Day 23, Cohort 1 
only 
o 
Oral dose of 1 tablet once daily from Day 6 to Day 23, Cohort 3 
only 
• 
Tesofensine, film-coated tablet, 0.50 mg: 
 
o 
Oral dose of 4 tablets once daily from Day 1 to Day 3, Cohort 2 only 
(loading dose of 2.0 mg) 
o 
Oral dose of 4 tablets once daily from Day 1 to Day 5, Cohort 3 only 
(loading dose of 2.0 mg) 
o 
Oral dose of 1 tablet once daily from Day 4 to Day 23, Cohort 2 
only 
o 
Oral dose of 1 tablet once daily from Day 6 to Day 23, Cohort 3 
only 
o 
Metoprolol, 25 mg ER tablet (Metoprololsuccinat “Orion” 25 mg, 
depottabletter; each tablet contains 23.75 mg metoprolol succinate 
equivalent to 25 mg metoprolol tartrate; manufacturer: Orion Corporation, 
[Finland]) 
o 
Single oral dose of 1 tablet in each subject of Cohort 1, Cohort 2 and 
Cohort 3, on Day 15, Day 18 or Day 21 
• 
Metoprolol, 50 mg ER tablet (Metoprololsuccinat “Orion” 50 mg, 
depottabletter; each tablet contains 47.5 mg metoprolol succinate 
equivalent to 50 mg metoprolol tartrate; manufacturer: Orion Corporation, 
[Finland]) 
o 
Single oral dose of 1 tablet in each subject of Cohort 1, Cohort 2 and 
Cohort 3, on Day 15, Day 18 or Day 21 
• 
Metoprolol, 100 mg ER tablet (Metoprololsuccinat “Orion” 100 mg, 
depottabletter; each tablet contains 95 mg metoprolol succinate equivalent 
to 100 mg metoprolol tartrate; manufacturer: Orion Corporation, 
[Finland]) 
o 
Single oral dose of 1 tablet in each subject of Cohort 1, Cohort 2 and 
Cohort 3, on Day 15, Day 18 or Day 21 
• 
Metoprolol placebo film-coated tablet; manufacturer: Solural Pharma ApS 
(Denmark) 
o 
Single oral dose of 1 tablet in each subject at each metoprolol dosing 
i.e., on Day 15, Day 18 and Day 21 
Each subject will receive tablets for all days with self-administration of 
tesofensine. Subjects in Cohort 1 will receive 0.25 mg tablets, subjects in 
Cohort 2 will receive 0.50 mg tablets and subjects in Cohort 3 will receive 
2 containers – one with 0.25 mg tablets and one with 0.50 mg tablets. 
Number of Subjects 
A total of 60 subjects are planned for enrollment.  The subjects will be 
randomly assigned to one of the 3 treatment cohorts with 20 subjects per 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 15 of 97 
14 June 2018 
 
cohort.  Reasonable efforts will be made to achieve gender balance; at least 
8 subjects of each gender will be included into each cohort.  Subjects 
withdrawn due to other reasons than IMP-related AEs may be replaced (up to 
25% in the study) after mutual agreement between Principal Investigator and 
Sponsor.  Overweight and obese subjects will be included in order to 
investigate the effects in the target population. 
Study Population 
Inclusion Criteria 
Subjects who meet the following criteria will be considered eligible to 
participate in the clinical study: 
1. Subject voluntarily agrees to participate in this study and signs an 
Independent Ethics Committee (IEC)-approved informed consent prior to 
performing any of the Screening procedures. 
2. Male and female subjects between 18 to 60 years of age, inclusive, at 
Screening. 
3. Overweight and obese subjects with a body mass index (BMI) between 
≥ 27 and < 40 kg/m2 at Screening but otherwise healthy. 
4. Non-smokers (or other nicotine use) as determined by history (no nicotine 
use over the past 6 months) and by urine cotinine concentration (< 500 ng/mL) 
at Screening and admission. 
5. No clinically relevant deviation or finding in pre-study medical evaluation 
(medical history, physical examination, vital signs, 12-lead ECG and clinical 
laboratory evaluations). 
6. HbA1c < 6.5% at Screening. 
7. Subject is willing to adhere to the contraception requirements details in 
Section 7.5.2 of the clinical study protocol. 
 
Exclusion Criteria 
Subjects who meet one or more of the following criteria will not be considered 
eligible to participate in the clinical study: 
1. Subject has history or evidence of any clinically significant cardiovascular, 
gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, metabolic 
(e.g., diabetes, metabolic acidosis), urologic, pulmonary (e.g., asthma or 
chronic obstructive pulmonary disease), neurologic, dermatologic, psychiatric, 
renal, and/or other major disease or malignancy as judged by the Investigator. 
2. Subject has any disorder that would interfere with the absorption, 
distribution, metabolism or excretion of drugs. 
3. Subject 
has 
a 
clinically 
significant 
abnormality 
following 
the 
Investigator’s review of the physical examination, ECG and clinical study 
protocol-defined clinical laboratory tests at Screening or admission to the 
clinical unit or has any concurrent disease or condition that, in the opinion of 
the Investigator, would make the subject unsuitable for participation in the 
clinical study.  One re-test is allowed, if (a) test result(s) is outside the limits. 
4. History or presence of liver disease or liver injury, as indicated by 
abnormal liver function tests including:  
• 
aspartate aminotransferase (AST) > 1.2 x upper limit of 
normal (ULN) 
• 
alanine aminotransferase (ALT) > 1.1 x ULN  
5. Subject has a pulse < 50 or > 90 bpm; systolic blood pressure (SBP) 
< 90 mmHg or > 140 mmHg; diastolic blood pressure (DBP) < 50 mmHg or 
> 90 mmHg (using the mean of triplicate measurements) at Screening or 
admission.  One re-test is allowed, if (a) test result(s) is outside these limits. 
6. History of any clinically significant cardiac arrhythmia.  Subject has a 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 16 of 97 
14 June 2018 
 
corrected QT interval using Fridericia’s formula (QTcF) interval > 450 msec or 
2nd or 3rd degree atrioventricular (AV) block, high-grade sinoatrial block or PQ 
interval > 0.24 seconds at Screening (using the mean of triplicate 
measurements).  If a mean ECG parameter of a triplicate ECG exceeds the 
limits above, an additional triplicate ECG may be taken.  If this also gives an 
abnormal result, the subject will be excluded. Also the following cardiac 
conditions will lead to exclusion of the subjects: Untreated heart failure 
(pulmonary oedema, impaired blood flow or hypotension) and continuous or 
intermittent treatment leading to an increased contractility of the heart muscle 
(beta-receptor agonism); Sick sinus syndrome; cardiogenic shock; severe 
peripheral arterial circulatory disturbances. 
7. Has a creatinine value exceeding the ULN. 
8. Subject has positive test for hepatitis B surface antigen (HBsAg), or 
hepatitis B core antibody (indicative of active hepatitis B), hepatitis A virus 
antibodies (immunoglobulin M), hepatitis C virus (HCV) antibodies or human 
immunodeficiency virus (HIV) 1 and/or -2 antibodies. 
9. Use of any prescribed or non-prescribed drugs (including vitamins, natural 
and herbal remedies, e.g., St. John’s Wort) in the 2 weeks prior to admission, 
or 5 half-lives of the drug, whichever is longer, except for the occasional use of 
paracetamol (up to 2 g/day) or other non-steroidal anti-inflammatory drugs 
(NSAIDs) and hormonal contraception for female subjects. 
10. Subject has history of alcohol and/or illicit drug abuse within 2 years of 
entry. 
11. Subject has positive urine drug test (e.g., cocaine, amphetamines, 
barbiturates, opiates, benzodiazepines, cannabinoids) or alcohol test at 
Screening or at admission. 
12. History of drinking > 168 g (males) and > 84 g (females) pure alcohol per 
week (10 g pure alcohol = 259 mL of beer [5%] or 35 mL of spirits [35%] or 
100 mL of wine [12%] within 3 months prior to admission to the clinical unit. 
13. Subject consumes more than 600 mg caffeine per day (e.g., more than 
3 cups of coffee containing 200 mg caffeine per cup) within the 4 weeks before 
admission or the subject is unwilling to avoid consumption of coffee and 
caffeine-containing beverages within 48 hours prior to admission until 
discharge from the clinical unit. 
14. Subject is unwilling to avoid use of alcohol or alcohol-containing foods, 
medications or beverages, within 48 hours prior to Screening and from 
admission until discharge from the clinical unit. 
15. Any significant blood loss, donated one unit (450 mL) of blood or more, 
or received a transfusion of any blood or blood products within 60 days, or 
donated plasma within 7 days prior to the admission to the clinical unit. 
16. Participation in any clinical study within 3 months or 5 half-lives of the 
drug, whichever is longer, prior to the expected date of IMP administration, or 
participation in more than 3 clinical studies within 12 months. 
17. Subject with a relevant history or with a present psychiatric disorder, 
including depression, suicidal ideation, or eating disorders (e.g., bulimia or 
anorexia nervosa). Subjects with a medical history of relevant psychiatric 
disorders or known and relevant family history or evidence of anxiety disorders 
or depression as judged by the Investigator using the Generalized Anxiety 
Disorder Assessment (GAD-7) and Patient Health Questionnaire-9 (PHQ-9) at 
Screening. Any of the following will lead to exclusion of the subject: 
• 
Subject has a GAD-7 mood scale score ≥ 10 
• 
Subject has a score ≥ 10 on the PHQ-9 questionnaire 
• 
Subject selects a response of “1, 2 or 3” to question number 9 on the 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 17 of 97 
14 June 2018 
 
PHQ-9 questionnaire regarding potential for suicidal thoughts or 
ideation (independent of the total score of the PHQ-9). 
18. Use of any agent used for weight loss within the last 3 months. 
19. More than 5% weight loss within the last 3 months. 
20. Hypo- or hyperthyroidism. 
21. Subject is pregnant or lactating. 
22. Subject is unwilling to abstain from vigorous exercise from 48 hours prior 
to admission until discharge. 
23. Subject has a history of hypersensitivity to the IMPs or any of the 
excipients or to medicinal products with similar chemical structures. 
24. Any contraindication for metoprolol, e.g. severe peripheral arterial disease, 
untreated pheochromocytoma, concomitant intravenous administration of 
calcium antagonists of verapamil and diltiazem, due to the risk of hypotension, 
AV conduction disturbances, or left ventricular insufficiency. 
25. Subject has lactose intolerance or a rare hereditary problem of fructose 
intolerance, 
glucose 
galactose 
malabsorption 
or 
sucrase 
isomaltase 
insufficiency. 
26. Subject is unable to understand and communicate in German language or 
to understand the protocol requirements, instructions and study-related 
restrictions, the nature, scope and possible consequences of the clinical study 
or is unlikely to comply with the study requirements; e.g., uncooperative 
attitude and improbability of completing the clinical study. 
27. Subject has previously been enrolled in this clinical study. 
28. Vulnerable subjects defined as individuals whose willingness to volunteer 
in a clinical study may be unduly influenced by the expectation, whether 
justified or not, of benefits associated with participation, or of a retaliatory 
response from senior members of a hierarchy in case of refusal to participate 
(e.g., persons in detention, minors and those incapable of giving consent). 
29. Subject is the Investigator or any Sub-Investigator, research assistant, 
pharmacist, study coordinator, other staff or relative thereof directly involved 
in the conduct of the study or employee of the Sponsor or PAREXEL. 
30. Poor or ultrarapid CYP2D6 metabolizer. 
Criteria for Evaluation 
Primary Endpoint 
The dose of metoprolol which will result in no change in M24HR for each 
respective dose of tesofensine – this will be calculated from a dose-response 
relationship with the dose of metoprolol as independent variable and change in 
M24HR induced by various doses of metoprolol given to patients on steady-
state dose of tesofensine as the dependent variable. The dose for no change in 
M24HR derived from above calculation and the corresponding 95% CI will be 
calculated for each dose of tesofensine. 
 
Secondary Endpoints 
• 
The difference in increase in M24HR caused by tesofensine alone 
(calculated as the difference between the M24HR at pre-tesofensine baseline 
and the mean of M24HR on Days 14, 17, 20 and 23) and the reduction in 
M24HR following each of the 3 metoprolol doses (M24HR on Day 15, 18 or 
21) 
• 
Mean and absolute change in M24HR between pre-tesofensine baseline 
(Day -1) and after tesofensine alone (Day 14, Day 17, Day 20 and Day 23) 
• 
Mean and absolute change in M24HR after tesofensine co-administered 
with metoprolol (Day 15, Day 18 and Day 21) 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 18 of 97 
14 June 2018 
 
• 
Maximum and minimum HR24 (HRmax and HRmin) values after 
tesofensine alone (Day 14, Day 17, Day 20, and Day 23) 
• 
HRmax and HRmin values after tesofensine co-administered with 
metoprolol (Day 15, Day 18 and Day 21) 
• 
Time of HRmin and HRmax after tesofensine alone (Day 14, Day 17, 
Day 20 and Day 23) 
• 
Time of HRmin and HRmax after tesofensine co-administered with 
metoprolol (Day 15, Day 18 and Day 21) 
• 
Mean HR during a designated quiet hour and a designated period after 
tesofensine alone (Day 14, Day 17, Day 20 and Day 23) 
• 
Mean HR during a designated quiet hour and a designated period after 
tesofensine co-administered with metoprolol (Day 15, Day 18 and Day 21) 
• 
HR after at least 10 minutes rest before each PK sampling time point or 
the corresponding time point (Day -1, Day 13 [pre-dose only], Day 14, Day 15, 
Day 17, Day 18, Day 20, Day 21 and Day 23) 
• 
SBP and DBP values after at least 10 minutes rest before each PK 
sampling time point or the corresponding time point (Day -1, Day 13 [pre-dose 
only], Day 14, Day 15, Day 17, Day 18, Day 20, Day 21 and Day 23) 
The following PK parameters will be determined: 
• 
Ctrough of tesofensine on Day 13, Day 14, Day 15, Day 18, Day 21 and 
Day 23 
• 
Cmax of metoprolol on Day 15, Day 18, and Day 21 
• 
Tmax of metoprolol on Day 15, Day 18, and Day 21 
• 
AUC0-24 of metoprolol on Day 15, Day 18, and Day 21 
• 
Relation between metoprolol concentration and HR will be explored by 
tesofensine dose 
• 
A PK-PD curve for each dose of tesofensine will be generated with PK 
parameters (AUC0-24 and Cmax) of metoprolol on the X-axis and change in 
M24HR on the y-axis.  The X-axis intercept and the corresponding 95% CI 
will be calculated for each dose of tesofensine 
 
Safety Endpoints 
The following safety variables will be recorded at specified time points during 
the study: 
• 
Vital signs (supine BP, pulse and body temperature ) 
• 
Twelve-lead electrocardiogram (ECG) 
• 
Clinical laboratory tests (hematology, clinical chemistry and urinalysis) 
• 
Adverse event assessments 
• 
Concomitant medication assessments 
• 
Physical examinations 
 
Statistical Methods 
Sample Size Considerations 
No formal sample size calculation has been performed. 
With a sample size of N=20 with 80% power assuming the same within-subject 
variability in HR as observed in the study TM001 (within-subject variability = 
5%) a mean difference of 3.3 beats per minute can be detected within a 
tesofensine cohort.  This detectable difference is smaller than the increase in 
HR induced by all 3 studied doses of tesofensine in the study TIPO-1; thus, 
20 subjects per cohort should provide adequate sample size for the purpose of 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 19 of 97 
14 June 2018 
 
this Phase 1 study. 
Data Presentation/Statistics 
• 
The mean and absolute change in M24HR after tesofensine alone will be 
calculated as the difference between the mean of the 3 pre-administration 
measurements on Day 14, Day 17 and Day 20 and the post-administration 
measurement on Day 23 and pre-tesofensine baseline (Day -1) and summarized 
descriptively by treatment. 
• 
The mean and absolute change in M24HR after tesofensine co-
administered with 3 different doses of metoprolol will be calculated as the 
difference between each mean of the 3 metoprolol doses on Days 15, 18 and 
21, and pre-tesofensine baseline (Day -1) and summarized descriptively by 
treatment. 
• 
The mean maximum and minimum HR24 values after tesofensine alone 
and when co-administered with 3 different doses of metoprolol will be 
summarized descriptively by treatment. 
• 
The time of minimum heart rate (HRmin) and maximum heart rate 
(HRmax) after tesofensine alone and when co-administered with 3 different 
doses of metoprolol will be summarized descriptively by treatment. 
• 
Mean SBP and DBP values after tesofensine alone and when co-
administered with 3 different doses of metoprolol will be summarized 
descriptively by treatment.  
• 
Mean HR during a designated quite hour and a designated period will be 
summarized descriptively by treatment.  
• 
M24HR on Days 14, 17, 20 and 23 will be compared by means of analysis 
of variance (ANOVA) with random subjects nested under sequence.  In this 
analysis there will be no period effect and treatment effect (such as metoprolol 
dose) other than the fixed days. 
• 
Change from pre-tesofensine baseline (Day -1) of M24HR on Days 15, 18 
and 21 will be compared by means of ANOVA with random subjects nested 
under sequence and fixed Day (Day 15, 18 and 21 will play the role of period 
in a conventional cross-over) and treatments. In this analysis the metoprolol 
dose will be distinguishing between treatments.  
• 
Boxplots will be made on M24HR for Days -1, 14, 15, 17, 18, 20, 21 and 
23 and will be displayed using treatment and treatment plus visit (for 
tesofensine days). 
A cross-over ANOVA model will be used to reduce change from baseline 
M24HR data to mean levels for each dose (adjusting for subject, day and 
treatment effects).  A straight line linear regression will be used to fit the 
means to log dose.  Based on the regression equation a dose for no effect will 
be estimated.  Confidence intervals will be determined using a bootstrap 
method. 
Details of the modelling will be provided in the statistical analysis plan (SAP). 
In case the linear model linking M24HR to log dose is clearly not satisfactory, 
an alternative strategy may be employed, for instance, by interpolation between 
2 adjacent doses. The need and approaches for such analysis will be discussed 
after the initial analysis is finished. 
The relation between metoprolol concentration and HR will be explored using 
plots of HR or time-matched change from baseline HR against concentration 
by tesofensine dose.  The plots will possibly be augmented with local 
regression lines and confidence intervals. 
A straight line regression will be used to fit change from baseline M24HR 
against PK parameters (AUC0-24 and Cmax) of metoprolol for each tesofensine 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 20 of 97 
14 June 2018 
 
dose.  Based on the regression equation a parameter value for no effect will be 
estimated.  Confidence intervals will be determined using a bootstrap method. 
Details of the analysis and/or additional approaches will be provided in the 
SAP. 
A population PK-PD model may be developed if deemed appropriate on the 
data from this study with the final objective of describing relative contribution 
to the final effect of plasma exposure to tesofensine and metoprolol, simulating 
optimal dose regimen for multiple administration and evaluate effect of 
covariates (e.g., polymorphism of PK, body weight, gender) on the overall 
effect. 
Details of the analysis will be in case included in a separate Data Analysis Plan 
and outcome of the modelling will be reported separately. 
 
All demographic, safety, PD and PK data will be listed and summarized in 
tabular format by descriptive statistics as appropriate.  Descriptive statistics 
will be applied and presented by treatment group.  No imputation of missing 
data will be performed but for PK the trapezoidal method will handle missing 
data by interpolation over a single time point where PK is missing.  Summary 
statistics of the PK parameters will be presented by treatment and dose-
normalized when relevant.  Pharmacokinetics data may also be displayed 
graphically as appropriate.  A SAP will be issued as a separate document, 
providing detailed methods for the analyses. 
 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 21 of 97 
14 June 2018 
 
TABLE OF CONTENTS 
SIGNATURE PAGE ...................................................................................................................... 8 
SIGNATURE PAGE ...................................................................................................................... 9 
LIST OF STUDY STAFF ............................................................................................................. 10 
PROTOCOL SYNOPSIS ............................................................................................................. 12 
TABLE OF CONTENTS .............................................................................................................. 21 
List of Tables ............................................................................................................................. 25 
List of Figures ........................................................................................................................... 25 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................. 26 
1. 
INTRODUCTION ................................................................................................................. 29 
1.1. 
Pharmacokinetics ........................................................................................................... 30 
1.1.1. 
Tesofensine ............................................................................................................. 30 
1.1.2. 
Metoprolol............................................................................................................... 31 
1.1.3. 
Co-administration of Tesofensine and Metoprolol ................................................. 32 
1.2. 
Rationale for the Clinical Study ..................................................................................... 32 
1.2.1. 
Safety in Previous Clinical Studies with Tesofensine ............................................ 32 
1.2.2. 
Safety of Metoprolol ............................................................................................... 34 
1.2.3. 
Safety of Co-administration of Tesofensine and Metoprolol ................................. 34 
1.3. 
Risk-benefit Assessment ................................................................................................ 35 
2. 
STUDY OBJECTIVES ......................................................................................................... 37 
2.1. 
Primary Objective .......................................................................................................... 37 
2.2. 
Secondary Objectives ..................................................................................................... 37 
3. 
OVERALL DESIGN AND PLAN OF THE STUDY........................................................... 38 
3.1. 
Overview ........................................................................................................................ 38 
3.2. 
Endpoints ........................................................................................................................ 43 
3.2.1. 
Primary Endpoint .................................................................................................... 43 
3.2.2. 
Secondary Endpoints .............................................................................................. 43 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 22 of 97 
14 June 2018 
 
3.2.3. 
Safety Endpoints ..................................................................................................... 44 
3.3. 
Justification of the Study Design ................................................................................... 44 
3.4. 
Stopping Criteria and Termination of the Clinical Study .............................................. 45 
4. 
STUDY POPULATION ........................................................................................................ 48 
4.1. 
Number of Subjects ........................................................................................................ 48 
4.2. 
Inclusion Criteria ............................................................................................................ 48 
4.3. 
Exclusion Criteria ........................................................................................................... 49 
4.4. 
Subject Withdrawal and Replacement ........................................................................... 52 
5. 
INVESTIGATIONAL MEDICINAL PRODUCT ................................................................ 55 
5.1. 
Identity of the Investigational Medicinal Products ........................................................ 55 
5.2. 
Dose Rationale Including Time of Dosing ..................................................................... 55 
5.3. 
Supply, Packaging, Labeling and Storage ...................................................................... 57 
5.4. 
Drug Accountability, Dispensing and Destruction ........................................................ 57 
5.5. 
Subject Identification and Randomization ..................................................................... 58 
5.5.1. 
Screening Numbers ................................................................................................. 58 
5.5.2. 
Randomization Numbers ........................................................................................ 58 
5.5.3. 
Randomization ........................................................................................................ 59 
5.6. 
Administration of Investigational Medicinal Products .................................................. 59 
5.7. 
Compliance..................................................................................................................... 59 
5.8. 
Blinding and Breaking the Blind .................................................................................... 59 
5.9. 
Prior and Concomitant Medications ............................................................................... 61 
5.10. 
Treatment of Overdose ............................................................................................... 61 
6. 
MEASUREMENTS AND METHODS OF ASSESSMENT ................................................ 62 
6.1. 
Medical History, Demographic and Other Baseline Information .................................. 62 
6.2. 
Safety Variables ............................................................................................................. 63 
6.2.1. 
Adverse Events ....................................................................................................... 63 
6.2.2. 
Clinical Laboratory Assessments ............................................................................ 68 
6.2.3. 
Vital Signs ............................................................................................................... 70 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 23 of 97 
14 June 2018 
 
6.2.4. 
Standard 12-lead Electrocardiograms ..................................................................... 70 
6.2.5. 
Physical Examinations ............................................................................................ 71 
6.2.6. 
Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder 
Assessment (GAD-7) ............................................................................................................. 71 
6.3. 
Pharmacokinetics Variables ........................................................................................... 72 
6.3.1. 
Blood Sample Collection ........................................................................................ 72 
6.4. 
Pharmacodynamic Variables .......................................................................................... 73 
6.5. 
Total Amount of Blood .................................................................................................. 73 
7. 
STUDY CONDUCT.............................................................................................................. 74 
7.1. 
Schedule of Assessments ............................................................................................... 74 
7.2. 
Order of Assessments ..................................................................................................... 81 
7.3. 
Early Termination .......................................................................................................... 81 
7.4. 
End-of-Study .................................................................................................................. 81 
7.5. 
Restrictions ..................................................................................................................... 81 
7.5.1. 
Dietary and Fluid Restrictions ................................................................................ 81 
7.5.2. 
Contraception Requirements ................................................................................... 82 
7.5.3. 
Other Restrictions ................................................................................................... 83 
8. 
STATISTICAL METHODS.................................................................................................. 84 
8.1. 
Study Population ............................................................................................................ 84 
8.1.1. 
Analysis Populations ............................................................................................... 84 
8.2. 
General Considerations .................................................................................................. 84 
8.3. 
Protocol Deviations ........................................................................................................ 85 
8.4. 
Subject Disposition ........................................................................................................ 85 
8.5. 
Demographic and Anthropometric Information and Baseline Characteristics .............. 85 
8.6. 
Prior and Concomitant Medication and Drug Administration ....................................... 86 
8.7. 
Exposure ......................................................................................................................... 86 
8.8. 
Safety Analyses .............................................................................................................. 86 
8.8.1. 
Adverse Events ....................................................................................................... 86 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 24 of 97 
14 June 2018 
 
8.8.2. 
Clinical Laboratory Tests ........................................................................................ 86 
8.8.3. 
Vital Signs ............................................................................................................... 87 
8.8.4. 
Standard 12-lead Electrocardiogram ....................................................................... 87 
8.8.5. 
Physical Examination.............................................................................................. 87 
8.9. 
Pharmacokinetic Analyses ............................................................................................. 87 
8.10. 
Pharmacodynamic Analyses ....................................................................................... 88 
8.10.1. 
Regression Analysis ............................................................................................ 89 
8.10.2. 
Pharmacokinetic-Pharmacodynamic Analysis .................................................... 89 
8.10.3. 
Pharmacokinetic-Pharmacodynamic Modelling ................................................. 89 
8.11. 
Interim Analyses ......................................................................................................... 90 
8.12. 
Determination of Sample Size .................................................................................... 90 
9. 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS ................................................ 91 
9.1. 
Data Quality Assurance .................................................................................................. 91 
9.1.1. 
Data Collection ....................................................................................................... 91 
9.1.2. 
Data Management ................................................................................................... 92 
9.2. 
Access to Source Data/Documents ................................................................................ 92 
9.3. 
Archiving Study Documents .......................................................................................... 93 
9.4. 
Good Clinical Practice ................................................................................................... 93 
9.5. 
Informed Consent ........................................................................................................... 93 
9.6. 
Protocol Approval and Amendment(s) .......................................................................... 94 
9.7. 
Insurance and Indemnity ................................................................................................ 94 
9.8. 
Confidentiality Data Protection ...................................................................................... 95 
9.9. 
Publication Policy .......................................................................................................... 95 
10. 
REFERENCE LIST ........................................................................................................... 96 
11. 
APPENDICES ................................................................................................................... 97 
11.1. 
Appendix 1 - List of Prohibited Medication ............................................................... 97 
 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 25 of 97 
14 June 2018 
 
List of Tables 
Table 1 
Identity of Investigational Products ............................................................................ 55 
Table 2 
Assessment of Relationship of Adverse Events to Investigational Product ............... 65 
Table 3 
Clinical Laboratory Assessments ............................................................................... 69 
Table 4 
Approximate Total Amount of Blood for Each Subject ............................................. 73 
Table 5 
Schedule of Assessments for Cohort 1 and Cohort 2 ................................................. 75 
Table 6 
Schedule of Assessments for Cohort 3 ....................................................................... 78 
 
List of Figures 
Figure 1 
Study Flow Overview – Cohort 1 and Cohort 2 ......................................................... 41 
Figure 2 
Study Flow Overview – Cohort 3 ............................................................................... 42 
 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 26 of 97 
14 June 2018 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
AUC0-24 
Area under the concentration-time curve from pre-dose (time 0) 
until 24 hours post-dose 
AV 
Atrioventricular  
BMI 
Body mass index 
BP 
Blood pressure 
bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CL/F 
Total body clearance 
Cmax 
Maximum plasma concentration 
CPK 
Creatine phosphokinase 
CSR 
Clinical study report 
CV 
Cardiovascular 
CYP 
Cytochrome P450 
DAT 
Dementia of Alzheimer type 
DBP 
Diastolic blood pressure 
DDI 
Drug-drug interaction 
DMP 
Data management plan 
ECG 
Electrocardiogram 
EoS 
End-of-study 
ER 
Extended release 
eSDR 
Electronic source data report 
FDA 
Food and Drug Administration 
FDC 
Fixed-dose combination 
FSH 
Follicle-stimulating hormone  


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 27 of 97 
14 June 2018 
 
Abbreviation 
Definition 
GAD-7 
Generalized Anxiety Disorder-7 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
Hb 
Hemoglobin 
HbA1c  
Glycosylated hemoglobin 
HBsAg 
Hepatitis B surface antigen 
HCT 
Hematocrit 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
HRmin 
Minimum heart rate in 24 hours 
HRmax 
Maximum heart rate in 24 hours 
i.v. 
Intravenous 
IB 
Investigator’s Brochure 
ICD 
Informed consent document 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IR 
Immediate release 
IUD 
Intrauterine device 
LDH 
Lactate dehydrogenase 
M24HR 
Mean heart rate of 24 hours 
MAO 
Monoamine oxidase 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
NSAID 
Non-steroidal anti-inflammatory drug 
OTC 
Over-the-counter 
PD 
Pharmacodynamic(s) 
PHQ-9 
Patient Health Questionnaire-9 
PK 
Pharmacokinetic(s) 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 28 of 97 
14 June 2018 
 
Abbreviation 
Definition 
PT 
Preferred Term 
QP 
Qualified Person 
QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected for heart rate using Bazett’s correction 
QTcF 
QT interval corrected for heart rate using Fridericia’s correction 
RA 
Regulatory authority 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SMP 
Safety management plan 
SNRI 
Serotonin and norepinephrine reuptake inhibitor 
SOC 
System organ class 
SOP 
Standard operating procedure 
SPC 
Summary of Product Characteristics 
SSRI 
Selective serotonin reuptake inhibitor 
t½ 
Terminal elimination half-life 
T2DM 
Type 2 diabetes mellitus 
TEAE 
Treatment emergent adverse event 
Tmax 
Time of maximum plasma concentration 
TSH 
Thyroid-stimulating hormone 
TZD 
Thiazolidinediones 
ULN 
Upper limit of normal 
USA 
United States of America 
WBC 
White blood cell 
WHO-DD 
World Health Organization Drug Dictionary 
λz 
The terminal elimination rate constant 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 29 of 97 
14 June 2018 
 
1. 
INTRODUCTION 
Tesofensine was initially noted to cause a marked weight loss in overweight patients with 
Parkinson’s disease and dementia of Alzheimer type (DAT), even though no attempts to promote 
weight control were included in the study.  The weight reducing effect was confirmed in a 
subsequent Phase 2 clinical study in obese subjects (TIPO-1), exceeding benchmarks set by the 
regulatory agencies for approval of weight loss agents [1].  Although tesofensine was generally 
well tolerated in these studies, an increase of blood pressure (BP) of 1–5 mmHg and an increase 
of heart rate (HR) up to 8 beats per minute (bpm) were observed in patients dosed with 0.25 to 
1.0 mg of tesofensine once daily.  
Historically, cardiovascular (CV) safety and the need for a favorable CV safety profile has been 
a critical requirement and hurdle for approval in the area of endocrine and metabolic, thus, it has 
been concluded that any increase in HR and/or BP constitutes an unacceptable safety risk and 
significantly impacts the overall benefit/risk profile of tesofensine.  Consequently, it has been 
decided by Saniona not to develop tesofensine as a stand-alone therapy.  Instead, Saniona 
decided to develop combination product (Tesomet): tesofensine combined with metoprolol, a 
β1-(cardio-selective) selective adrenoceptor-blocking agent, in order to mitigate the increase in 
BP and HR.  
To date, co-administration of tesofensine and metoprolol to human has been investigated in 
3 clinical studies of which 2 have been completed.  First, a Phase 1 drug-drug interaction study 
(Q-21125) where a single dose of metoprolol was added to tesofensine administered for 14 days 
to study pharmacokinetics (PK) of both when administered together.  Second, a Phase 2 study in 
obese and overweight patients with type 2 diabetes mellitus (T2DM) (TM001) designed to 
provide the proof-of-concept data that addition of metoprolol mitigates the tesofensine-induced 
increase in HR and BP.  In both studies, the co-administration of the drugs was generally well 
tolerated and the collected data have provided good base for future investigation of a fixed 
combination of tesofensine and metoprolol (Tesomet) for various indications.  Third, the clinical 
part of a Phase 1 study with the new fixed-dose combination multi-layer tablet Tesomet (TM003) 
has just been completed.   
 
Currently, there is an ongoing Phase 2 study in patients with Prader-Willi syndrome (TM002). 
In addition, the clinical development program of Tesomet draws heavily on a substantial body of 
data available for tesofensine, for which - despite not being approved or developed as a 
stand-alone agent - there is a complete pre-clinical efficacy and safety data package available and 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 30 of 97 
14 June 2018 
 
has been to date studied in more than 1300 subjects.  Also, metoprolol was approved in the 
United States of America (USA) in 1978 and has since become one of the most widely used 
drugs ever with millions of patient-years of safety data available. 
Given the mechanism of action, available pre-clinical and clinical data, it is anticipated that 
Tesomet could be developed for a variety of indications such as treatment of obesity, T2DM, 
pre-diabetes, Prader-Willi syndrome, binge eating disorder, etc.   
For more information please see the Tesomet Investigator’s Brochure (IB) [2] and 
Tesofensine IB [3]. 
1.1. 
Pharmacokinetics 
1.1.1. 
Tesofensine 
In man the clearance after oral administration was low (total body clearance [CL/F] 30 to 
40 mL/min) and tesofensine was shown to have a long half-life (t1/2) of about 9 days (220 hours).  
In all species including man the volume of distribution exceeded the total volume of body water, 
indicating that tesofensine was extensively distributed into the tissues.  The protein binding was 
about 91%. 
Tesofensine was mainly metabolized to the N-desmethyl-metabolite (NS2360), which was the 
only metabolite found in human plasma.  NS2360 was shown to have a longer half-life than 
tesofensine, i.e., approximately 16 days (374 hours) in man and have an exposure of 31 to 34% 
of the parent compound at steady state.  In vivo data indicated that NS2360 was responsible for 
approximately 6% of the activity.  Similarly to animals, the kidney in man seems to play only a 
minor role in the clearance of tesofensine in man (about 15 to 20%). 
The PK profile in man was linear after single and multiple doses over all doses tested.  No 
relevant differences in the PK of healthy elderly subjects, patients with mild DAT or Parkinson’s 
disease were observed.  Similarly, no differences were observed between Japanese and 
Caucasians or between recreational drug abusers and non-abusers.  No relevant changes of the 
PK in subjects with mild renal impairment were observed, but an increase in exposure (of about 
30%) occurred in subjects with moderate and severe renal impairment.  Steady state plasma 
concentrations in the target population (obese patients) did not differ significantly from that in 
healthy volunteers.  The relative bioavailability of tesofensine was not significantly affected by 
food intake.  Based on cross-study comparison with intravenous (i.v.) data the absolute 
bioavailability after oral administration was estimated to be > 90%.  Investigation of cytochrome 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 31 of 97 
14 June 2018 
 
P450 2D6 (CYP2D6) and CYP3A4 interaction in man did not indicate clinically relevant PK 
interactions. 
For further details refer to the IB of tesofensine [3]. 
1.1.2. 
Metoprolol 
Adults: In man, absorption of metoprolol is rapid and complete.  Plasma levels following oral 
administration of conventional metoprolol tablets, however, approximate 50% of levels 
following intravenous administration, indicating about 50% first-pass metabolism.  Metoprolol 
crosses the blood-brain barrier and has been reported in the cerebrospinal fluid in a concentration 
78% of the simultaneous plasma concentration.  
Plasma levels achieved are highly variable after oral administration.  Only a small fraction of the 
drug (about 12%) is bound to human serum albumin.  Metoprolol is a racemic mixture of R- and 
S-enantiomers, and is primarily metabolized by CYP2D6.  When administered orally, it exhibits 
stereoselective metabolism that is dependent on oxidation phenotype.  Elimination is mainly by 
biotransformation in the liver, and the plasma t1/2 ranges from approximately 3 to 7 hours.  Less 
than 5% of an oral dose of metoprolol is recovered unchanged in the urine; the rest is excreted by 
the kidneys as metabolites that appear to have no beta-blocking activity.  
Following intravenous administration of metoprolol, the urinary recovery of unchanged drug is 
approximately 10%.  The systemic availability and half-life of metoprolol in patients with renal 
failure do not differ to a clinically significant degree from those in normal subjects. 
Consequently, no reduction in metoprolol succinate dosage is usually needed in patients with 
chronic renal failure. 
Metoprolol is metabolized predominantly by CYP2D6, an enzyme that is absent in about 8% of 
Caucasians (poor metabolizers) and in about 2% of most other populations.  CYP2D6 can be 
inhibited by a number of drugs.  Poor metabolizers and extensive metabolizers who 
concomitantly use CYP2D6 inhibiting drugs will have increased (several-fold) metoprolol blood 
levels, decreasing metoprolol's cardioselectivity [4].  
In comparison to conventional metoprolol, the plasma metoprolol levels following 
administration of MetoHEXAL® 100 mg (metoprolol succinate extended release [ER] tablets) 
are characterized by lower peaks, longer time to peak and significantly lower peak to trough 
variation.  The peak plasma levels following once daily administration of MetoHEXAL average 
one-fourth to one-half the peak plasma levels obtained following a corresponding dose of 
conventional metoprolol, administered once daily or in divided doses.  At steady state the 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 32 of 97 
14 June 2018 
 
average bioavailability of metoprolol following administration of MetoHEXAL, across the 
dosage range of 50 to 400 mg once daily, was 77% relative to the corresponding single or 
divided doses of conventional metoprolol.  Nevertheless, over the 24-hour dosing interval, 
β1-blockade is comparable and dose-related (see Section Clinical Pharmacology of Tesomet IB 
[2]).  The bioavailability of metoprolol shows a dose-related, although not directly proportional, 
increase with dose and is not significantly affected by food following MetoHEXAL 
administration. 
1.1.3. 
Co-administration of Tesofensine and Metoprolol 
PK data when tesofensine and metoprolol were co-administered chronically are available from 
the study TM001.  Tesofensine, its N-desmethyl-metabolite (NS2360) and metoprolol 
concentrations in plasma were measured pre-dose at baseline and at the end of treatment.  The 
tesofensine PK results obtained in this study are in line with the PK data obtained in the study 
TIPO-1 where tesofensine was administered in similar population of patients for 24 weeks.  The 
exposures of metoprolol are also in line with those previously published. 
For further details refer to the Tesomet IB [2], Tesofensine IB [3] and Summary of Product 
Characteristics (SPC) of metoprolol ER tablets [4]. 
1.2. 
Rationale for the Clinical Study 
It has been decided to develop a fixed-dose combination tablets with tesofensine and metoprolol, 
with metoprolol mitigating the increases in BP and HR caused by tesofensine.  In this study, the 
dose-response relationship between tesofensine and metoprolol will be examined and thus the 
optimal dose of metoprolol to mitigate the effects of tesofensine on HR will be determined.  HR 
is the primary endpoint because in the previous studies it has been shown to be the most affected 
safety endpoint by the effects of tesofensine. 
1.2.1. 
Safety in Previous Clinical Studies with Tesofensine 
Sixteen Phase 1 studies with 339 healthy volunteers have been completed, with 289 subjects 
being exposed to tesofensine.  Tesofensine was well tolerated up to and including single oral 
doses of 6.75 mg.  Multiple daily doses up to 1.0 mg and loading doses up to 2.0 mg in Phase 1 
studies were considered to be well tolerated.  In all single and multiple dose Phase 1 studies in 
healthy volunteers, including a study with intravenous infusion up to 1.2 mg in volunteers, no 
changes in vital signs, electrocardiogram (ECG) or laboratory parameters assessed as clinically 
significant by the Investigator were observed, and no serious adverse events (SAEs) occurred. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 33 of 97 
14 June 2018 
 
Seven Phase 2 studies have been completed in patients with neurodegenerative diseases and one 
Phase 2 study in patients with obesity (NS2330-001, “TIPO-1”).  In obese patients, one dose 
ranging study of 24 weeks’ duration was conducted including 203 obese patients, with 151 of 
them exposed to 0.25 to 1.0 mg tesofensine.  The most frequent adverse events (AEs) in this 
study were insomnia, dry mouth, dizziness, and constipation.  These events were dose-dependent 
and categorized as expected for drugs belonging to the same pharmacological class.  Three 
4-week studies used forced-titration and included 62 patients (60 to 80 years) with possible DAT 
and 9 patients with advanced Parkinson’s disease.  A total of 53 of them were exposed to 
tesofensine.  Tesofensine was well tolerated at all doses, i.e., daily doses up to 2.0 mg for the 
first 3 days (loading doses) followed by daily doses up to 1.0 mg for up to 25 consecutive days.  
In 4 dose finding studies of 14 weeks’ duration, 1036 DAT and Parkinson’s disease patients were 
included and 796 of them were exposed to doses of 0.125-1.0 mg of tesofensine.   
Also a long-term study, TIPO-4 (an extension study of the "TIPO-1"-study with patients with 
uncomplicated obesity), over 48 weeks has been completed.  In this study all patients started on 
0.5 mg tesofensine for the first 24 weeks and could be uptitrated to 1.0 mg.  The last 24 weeks all 
patients received 0.5 mg.  Pooled data from these studies did not indicate increased incidence of 
cardiovascular events or reveal an increased incidence in any of the psychiatric AEs. 
In conclusion, tesofensine has shown a robust, dose-dependent effect on weight loss in the target 
population of obese patients and a benign safety profile in toxicological and clinical studies 
compatible with its pharmacological profile.  The emerging efficacy and safety profile of 
tesofensine from the studies in obese patients has identified a clinically relevant, safe and well 
tolerated dose range of 0.25 mg up to 6.75 mg. 
Tesofensine has been evaluated in approximately 170 subjects in studies examining the 
metabolic and weight loss effects in overweight and obese patients and in approximately 
900 patients in other indications. 
Based on the pharmacological profile it can be assumed that tesofensine causes dopaminergic 
side effects such as insomnia, agitation, hallucinations, psychoses including delusion, paranoid 
ideation and depression. 
The AEs which were commonly reported in all investigated populations were insomnia, dry 
mouth, dizziness, and constipation, which also expressed dose-dependency.  In obese patients the 
most frequent AEs were dry mouth, headache, nasopharyngitis, nausea, influenza, insomnia, 
diarrhea, constipation, and back pain.  Psychiatric side effects were more frequently reported in 
the elderly population (patients with Parkinson’s disease or DAT).  Psychotic events, such as 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 34 of 97 
14 June 2018 
 
hallucinations, were also observed in this elderly population, mostly with high doses 
(> 0.75 mg/day). 
Undesired effects which have been observed up to now comprise: 
• Very frequently (> 10%): headache, insomnia, dizziness, somnolence, loss of appetite, lack 
of energy, dry mouth, attention disturbances, cold-like symptoms, diarrhea, constipation 
• Frequently (< 10%): nausea, vomiting, fast pulse, muscle spasms, sweating, palpitations, 
vertigo, blurry vision, flatulence, abdominal pain or discomfort, tooth pain, fatigue 
• Rarely (< 0.1%): altered state of consciousness, sensory disturbance, agitation and 
persecutory delusion were found in a subject with high doses of tesofensine. 
Overdose 
Clinical experience with tesofensine in overdose is limited.  Exaggerated dopaminergic action 
should be anticipated with risk of psychotic behavior, cardiac symptoms (tachycardia, 
palpitations, atrial extrasystolia), orthostatic hypotension, and gastrointestinal symptoms (nausea, 
emesis, diarrhea). 
For further details refer to the Tesomet IB [2] and Tesofensine IB [3]. 
1.2.2. 
Safety of Metoprolol 
Metoprolol is a selective β1 receptor blocker, used in the treatment of, e.g., hypertension, angina 
pectoris, acute myocardial infarction, supraventricular tachycardia, ventricular tachycardia, 
congestive heart failure and prevention of migraine headaches.  
Metoprolol is available as IR and ER tablets and as solution for i.v. injection. 
For further details refer to the SPC of metoprolol [4].  
1.2.3. 
Safety of Co-administration of Tesofensine and Metoprolol 
To date, tesofensine tablet and metoprolol tablet have been co-administered to humans in 
4 clinical studies.  Firstly, a Phase 1 drug-drug interaction (DDI) study (Q-21125) where a single 
dose of metoprolol was added to tesofensine administered for 2 weeks to study PK of both drugs 
when administered together.  Secondly, a 90 days Phase 2 study in obese and overweight patients 
with T2DM (TM001) designed to provide the proof-of-concept data that addition of metoprolol 
mitigates the tesofensine-induced increase in HR and BP.  In both studies (both completed), the 
co-administration of the drugs was generally well tolerated.  No new or unexpected safety 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 35 of 97 
14 June 2018 
 
findings have been observed in the study compared to previous studies with tesofensine alone.  
Third, the clinical part of a Phase 1 study (TM003) with the new fixed-dose combination multi-
layer tablet of Tesomet has just been completed.  Currently, there is an ongoing Phase 2 study in 
patients with Prader-Willi syndrome (TM002). 
1.3. 
Risk-benefit Assessment 
For details regarding safety data of tesofensine refer to the IB [3].  For details regarding safety 
data of metoprolol refer to SPC of metoprolol ER tablets [4]. 
Most probably, there will be no direct health benefit for the subjects from receipt of the 
Investigational medicinal product (IMP).  Only subjects with overweight will be included and a 
decrease in body weight may occur after tesofensine treatment.  However, due short duration of 
tesofensine dosing, more than slight to moderate decreases in body weight are unlikely to occur.   
The protocol has been designed to minimize the risk to participating subjects:  strict in- and 
exclusion criteria are implemented to minimize potential risks and subjects will be monitored to 
detect AEs during the study and followed appropriately to ensure resolution of AEs.  Metoprolol 
has already been approved for years, therefore side effects are well known.  Obese but otherwise 
healthy subjects will be eligible for the study only, if they do not meet any contraindications or 
the listed special warnings from metoprolol SPC.  Additionally, subjects will only be eligible to 
participate if they don’t have comorbidities typical for obesity such as hypertension, diabetes or 
any cardiovascular conditions.  Therefore it is acceptable to also include subjects with Grade 2 
obesity who are otherwise healthy. 
Tesofensine and metoprolol have been co-administered in 2 completed clinical studies:  in the 
DDI study as well as in the study with T2DM.  In both studies, the co-administration of the drugs 
was generally well tolerated.  Steady state levels of tesofensine had no major influence on the PK 
of metoprolol (Study Q-21125).  Increases in HR and BP may occur due to tesofensine dosing 
and decreases in HR and BP may occur due metoprolol dosing.  Subjects with hyper- or 
hypotension will not be eligible for the study and vital signs will be measured at all visits.  
Subjects will be in-house on all metoprolol dosing days and on the days of the administration of 
the loading doses of tesofensine and they will be closely monitored.  If needed remedial therapy 
would be immediately available.  Specific stopping criteria have been employed.   
Psychiatric AEs appeared to be associated with high single doses or forced titration of 
tesofensine and, importantly, in an age group (elderly) and populations (patients with 
Parkinson´s or Alzheimer´s disease) different from the population of this study.  Insomnia 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 36 of 97 
14 June 2018 
 
occurred as most prominent psychiatric event but only at higher loading doses.  Psychotic events 
seen in healthy volunteers were associated either with a single dose treatment with more than 
> 6 mg of tesofensine, or with multiple doses of more than 2 mg/day of tesofensine.  The 
maintenance doses planned for this study will be below these higher doses and the loading doses 
chosen will not exceed 2 mg/day. 
In obese patients (TIPO-1), 1 dose ranging study of 24 weeks’ duration was conducted including 
203 obese patients, with 151 of them exposed to 0.25 to 1.0 mg tesofensine.  The most frequent 
AEs in these studies were insomnia, dry mouth, dizziness, and constipation.  These events were 
dose-dependent and categorized as expected for drugs belonging to same pharmacological class.  
Cardiovascular AEs were most frequently reported in the elderly population, which was 
characterized by significant comorbidities, including cardiovascular conditions.  Serious 
cardiovascular AEs were reported only in PD/DAT patients, in 2% of the subjects in the 
tesofensine group and in 4% in the placebo group.  No clear dose-dependency was observed for 
any of the cardiovascular events reported in any target population.  No serious or severe 
cardiovascular AEs have been reported to date. 
Psychiatric tests (Patient Health Questionnaire-9 [PHQ-9] and Generalized Anxiety Disorder 
Assessment [GAD-7]) will be performed at Screening to exclude subjects with any psychiatric 
conditions or history of psychiatric conditions like anxiety disorders and or depression.  
Taken together, data from the clinical studies do not suggest that tesofensine 0.25 mg and 0.5 mg 
once daily in obese patients or up to 2 mg/day (for 7 days) in healthy volunteers will be 
associated with a clinically significant undesirable psychiatric adverse effect profile.   
Also, no additional risks are expected by the co-administration compared to those known for 
dosing of tesofensine and metoprolol alone. 
Please refer to the IB of Tesofensine [3] for further details.  


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 37 of 97 
14 June 2018 
 
2. 
STUDY OBJECTIVES 
The objectives of this study are as follows: 
2.1. 
Primary Objective 
• To determine the optimal dose of metoprolol to mitigate the effect of tesofensine on HR 
2.2. 
Secondary Objectives 
• To confirm that addition of metoprolol mitigates the effect of tesofensine on HR 
• To examine the concentration-response relationship between tesofensine and metoprolol on 
HR and BP 
• Assess the time dependence of tesofensine effect on HR by comparing HR data under 
tesofensine alone  
• Safety and tolerability of tesofensine alone and co-administration of tesofensine and 
metoprolol 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 38 of 97 
14 June 2018 
 
3. 
OVERALL DESIGN AND PLAN OF THE STUDY 
3.1. 
Overview 
This is a randomized, open-label for tesofensine and single-blind for metoprolol, parallel-arm 
study in 60 male and female subjects who meet the inclusion and none of the exclusion criteria 
for the study. 
Each subject will participate in a Screening Period (Day -28 to Day -3), a Baseline Period 
(Day -2 to Day -1) and a Treatment Period (Day 1 to Day 24) and will have 2 Follow-up phone 
calls (Day 30 and Day 50).   
The Treatment Period will comprise: 
• In Cohorts 1 and 2, an initial in-house stay (Day -2 to Day 3) until the last loading dose of 
tesofensine has been administered on Day 3  
 
or 
In Cohort 3, an initial in-house stay until the third loading dose tesofensine has been 
administered on Day 3 
• In Cohorts 1 and 2, a home-dosing period (Day 4 to Day 12, once daily dosing to achieve 
steady state of tesofensine with an ambulatory visit in the clinical unit on Day 7)  
or 
In Cohort 3, 2 ambulatory visits on Days 4 and 5 with administration of the 4th and 5th 
loading dose, followed by a home-dosing period (Day 6 to Day 12, once daily dosing to 
achieve steady state of tesofensine with an ambulatory visit in the clinical unit on Day 7)  
 
and  
• A second in-house stay (Day 13 to Day 24).  Safety evaluations will be performed on Day 30 
and Day 50 (end-of-study [EoS]) after last dosing over the phone.  A study overview is 
provided in Figure 1 and Figure 2. 
A total of 60 subjects will be randomly assigned to one of the following treatment cohorts: 
• Cohort 1 (20 subjects): tesofensine 0.25 mg once daily for 23 days (loading dose of 1.0 mg 
for the first 3 days)  
• Cohort 2 (20 subjects): tesofensine 0.50 mg once daily for 23 days (loading dose of 2.0 mg 
for the first 3 days)  


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 39 of 97 
14 June 2018 
 
• Cohort 3 (20 subjects): tesofensine 0.75 mg (0.25 mg + 0.50 mg) once daily for 23 days 
(loading dose of 2.0 mg [4 tablets of 0.50 mg] for the first 5 days)  
Dosing of tesofensine will be performed approximately 30 minutes after start of breakfast.  
Timing and quantity of meals will be consistent on PK and pharmacodynamic (PD) days, i.e., on 
Day -1, Day 13, Day 14, Day 15, Day 17, Day 18, Day 20, Day 21 and Day 23. 
In addition, each subject will receive a single dose of 25 mg, 50 mg or 100 mg metoprolol ER in 
random order in the morning of Day 15, Day 18 and Day 21, respectively, approximately 
30 minutes after start of a standard breakfast and together with the tesofensine dose. 
For each subject assessments (24-hour ECG, blood sampling for PK of metoprolol and 
tesofensine [Day 15, Day 18 and Day 21 only], blood sampling for PK of tesofensine [Day 13, 
Day 14 and Day 23 only] and 12-lead ECG, BP and pulse before each blood sampling for PK) 
will be performed to examine the dose-response relationship in combination of tesofensine and 
metoprolol:  
• On the day before start of IMP dosing (on Day -1); Holter-ECG recording will be checked 
prior to dosing on Day 1 to confirm that at least 22 hours are evaluable for HR.  If the 
Day - 1 Holter-ECG is not fully evaluable, it can be repeated (and the subject would be dosed 
later) 
At tesofensine steady state  
• On Day 14 and 15 (before and after the 1st metoprolol dose) 
• On Day 17 and 18 (before and after the 2nd metoprolol dose) 
• On Day 20 and 21 (before and after the 3rd metoprolol dose) 
• And on Day 23 (tesofensine alone) 
In addition, safety assessments will be performed throughout the study.  Day 16, Day 19 and 
Day 22 will be wash-out days for metoprolol. 
At each dosing of metoprolol, a metoprolol placebo tablet will be administered in addition to the 
metoprolol tablet in order to mask the dose level of metoprolol. 
On in-house days (i.e., Day 1 to Day 3, Day 7 and Day 13 to Day 23 and, in addition in Cohort 3, 
Day 4 and Day 5), the Investigator or a designee will administer the IMP(s), i.e., tesofensine, 
metoprolol and placebo, to the subjects approximately 30 minutes after start of the breakfast.  
From Day 4 to Day 6 (Cohorts 1 and 2) or on Day 6 (Cohort 3) and from Day 8 to Day 12 (all 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 40 of 97 
14 June 2018 
 
cohorts), subject will self-administer a single dose of tesofensine approximately 30 minutes after 
start of breakfast. 
For each of the treatment groups, blood samples will be collected pre-dose and at designated 
time points post dosing.  PD assessments (24-hour Holter-ECG, 12-lead ECG, BP and pulse) will 
be performed pre-dose and at designated time points post dosing.  Subjects will be discharged 
from the clinical unit after the 48 hours post-dose assessments have been completed on Day 3.  
Subjects will have a home-dosing period (from Day 4 to Day 6 [Cohorts 1 and 2] or on Day 6 
[Cohort 3] and from Day 8 to Day 12 [all cohorts]) with once daily dosing to achieve steady state 
of tesofensine with an ambulatory visit in the clinical unit (on Day 7) and a second in-house stay 
(Day 13 to Day 24).  At the Safety Follow-up phone calls (on Day 30 and Day 50), subjects will 
be asked regarding AE, and concomitant medications. 
The total duration for each subject will be up to 78 days, including Screening and Follow-up 
period. 
 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 41 of 97 
14 June 2018 
 
Figure 1 
Study Flow Overview – Cohort 1 and Cohort 2 
 
 
 
BP = blood pressure; ECG = electrocardiogram, PK = pharmacokinetic 
 
 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 42 of 97 
14 June 2018 
 
Figure 2 
Study Flow Overview – Cohort 3 
 
 
 
BP = blood pressure; ECG = electrocardiogram, PK = pharmacokinetic 
 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 43 of 97 
14 June 2018 
 
Please refer to Table 5 and Table 6 for detailed lists of procedures performed on each study day 
and visit. 
3.2. 
Endpoints 
3.2.1. 
Primary Endpoint 
The dose of metoprolol which will result in no change in M24HR for each respective dose of 
tesofensine – this will be calculated from a dose-response relationship with the dose of 
metoprolol as independent variable and change in M24HR induced by various doses of 
metoprolol given to patients on steady-state dose of tesofensine as the dependent variable. The 
dose for no change in M24HR derived from above calculation and the corresponding 95% CI 
will be calculated for each dose of tesofensine. 
3.2.2. 
Secondary Endpoints 
• The difference in increase in M24HR caused by tesofensine alone (calculated as the 
difference between the M24HR at pre-tesofensine baseline and the mean of M24HR on Days 
14, 17, 20 and 23) and the reduction in M24HR following each of the 3 metoprolol doses 
(M24HR on Day 15, 18 or 21) 
• Mean and absolute change in M24HR between pre-tesofensine baseline (Day -1) and after 
tesofensine alone (Day 14, Day 17, Day 20 and Day 23) 
• Mean and absolute change in M24HR after tesofensine co-administered with metoprolol 
(Day 15, Day 18 and Day 21) 
• Maximum and minimum HR24 (HRmax and HRmin) values after tesofensine alone (Day 14, 
Day 17, Day 20 and Day 23)  
• HRmax and HRmin values after tesofensine co-administered with metoprolol (Day 15, Day 
18 and Day 21) 
• Time of HRmin and HRmax after tesofensine alone (Day 14, Day 17, Day 20 and Day 23)  
• Time of HRmin and HRmax after tesofensine co-administered with metoprolol (Day 15, 
Day 18 and Day 21) 
• Mean HR during a designated quiet hour and a designated period after tesofensine alone 
(Day 14, Day 17, Day 20 and Day 23) 
• Mean HR during a designated quiet hour and a designated period after tesofensine 
co-administered with metoprolol (Day 15, Day 18 and Day 21) 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 44 of 97 
14 June 2018 
 
• HR after at least 10 minutes rest before each PK sampling time point or the corresponding 
time point (Day -1, Day 13 [pre-dose only], Day 14, Day 15, Day 17, Day 18, Day 20, 
Day 21 and Day 23) 
• Systolic blood pressure (SBP) and diastolic blood pressure (DBP) values after at least 
10 minutes rest before each PK sampling time point or the corresponding time point (Day -1, 
Day 13 [pre-dose only], Day 14, Day 15, Day 17, Day 18, Day 20, Day 21 and Day 23) 
The following PK parameters will be determined: 
• Ctrough of tesofensine on Day 13, Day 14, Day 15, Day 18, Day 21 and Day 23 
• Cmax of metoprolol on Day 15, Day 18, and Day 21 
• Tmax of metoprolol on Day 15, Day 18, and Day 21 
• AUC0-24 of metoprolol on Day 15, Day 18, and Day 21 
• Relation between metoprolol concentration and HR will be explored by tesofensine dose 
• A PK-PD curve for each dose of tesofensine will be generated with PK parameters (AUC0-24 
and Cmax) of metoprolol on the X-axis and change in M24HR on the y-axis.  The X-axis 
intercept and the corresponding 95% CI will be calculated for each dose of tesofensine 
3.2.3. 
Safety Endpoints 
The following safety variables will be recorded at specified time points during the study: 
• Vital signs (supine BP, pulse and body temperature) 
• Twelve-lead ECG: HR PR interval, QRS interval, RR interval, QT interval and QT interval 
corrected for HR (QTc) (Bazett’s correction [QTcB] and Fridericia’s correction [QTcF]) 
• Clinical laboratory tests (hematology, clinical chemistry and urinalysis) 
• Adverse event assessments 
• Concomitant medication assessments 
• Physical examinations 
3.3. 
Justification of the Study Design 
The safety assessments included in the study are accepted measures for ensuring safety of 
subjects during a clinical study. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 45 of 97 
14 June 2018 
 
The PK sampling schedule is considered appropriate given the information available and the 
goals of this study.  This study evaluates the PK profiles of 3 different doses of tesofensine and 
3 different doses of metoprolol administered orally.  Safety and PK of tesofensine have already 
been evaluated in many other studies and, therefore, it is not considered necessary to investigate 
the PK profiles in more detail.  The proposed sampling time points are deemed satisfactory to 
investigate the PK/PD correlation within a dosing interval.  
A cross-over approach with intra-individual comparison of the PD and PK profiles of 3 different 
metoprolol doses was chosen to cover a broad range of HR response.  A wash-out period of 48 
hours between the metoprolol doses has been chosen because of the continuous release of 
metoprolol from the ER tablets for about 20 hours and the mean half-life of metoprolol of about 
3.5 hours.  This shall ensure that HR values return to baseline before the next dose of metoprolol 
is given and to avoid continuous stimulus on the adrenergic receptors which could potentially 
lead to a change in receptor expression and presentation over time.  
A parallel-group design was chosen for the tesofensine doses due to the long half-life of 
tesofensine.  
The major metabolic pathway of metoprolol is via CYP2D6, therefore poor and ultrarapid 
CYP2D6 metabolizers are excluded to reduce variability in metoprolol PK and PD data. 
Overweight and obese subjects up to a BMI of <40 kg/m2 will be included in order to investigate 
the effects in the target population.  This “real-life approach“ is deemed more appropriate to 
meet the objectives of the study and in order to better plan future projects than using a purely 
mechanistic approach in a different population where the results would need to be adapted or 
extrapolated to the target population.  The next (Phase 2) study is planned in obese subjects and 
the data collected in this study will guide the metoprolol dose for that planned study. 
The rationale for dose selection is discussed in Section 5.2. 
3.4. 
Stopping Criteria and Termination of the Clinical Study 
The following event shall result in an immediate stop to dosing of all subjects and a re-evaluation 
of the risk-benefit profile: 
• A serious adverse reaction (i.e., an SAE considered at least possibly related to the IMP 
administration) in one subject. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 46 of 97 
14 June 2018 
 
In the event of an SAE, in which a relation to the IMPs cannot be excluded, the study may be 
restarted only after review and approval by Independent Ethics Committee (IEC) and Competent 
Authority. 
Based on safety criteria, the study will be stopped in case of any of the following: 
• Adverse event stopping criteria: 
− 3 or more subjects experience a severe AE of related causality 
− The Principal Investigator (or his deputy) and the Sponsor consider that the number 
and/or severity of AEs justify discontinuation of the study 
Based on safety criteria, the study will be stopped, if 2 or more subjects in a cohort experience 
the same stopping criterion of the following: 
• Psychiatric stopping criteria: 
− Severe AE related to any classified psychiatric disorder. 
• Vital signs stopping criteria: 
− Symptomatic hypotension (SBP < 85 mmHg).  If symptomatic hypotension is 
observed during the study, then a minimum of 2 repeat BP measurements should be 
obtained within 30 minutes.  The mean of the 3 SBP measurements will be used to 
determine stopping criteria. 
− Tachycardia defined as HR > 120 bpm lasting longer than 30 minutes or with 
impaired consciousness. 
• Electrocardiogram stopping criteria: 
− QTcB or QTcF interval > 500 msec or increase of QTc interval > 60 msec compared 
to pre-tesofensine baseline (If a prolonged QTc interval is observed during the study, 
then a minimum of 2 repeat ECGs should be obtained within 30 minutes.  The mean 
of the 3 ECGs will be used to determine stopping criteria.) 
• Clinical laboratory stopping criteria: 
− Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≥ 3 times 
the upper limit of normal (ULN, confirmed by repeat)  
with 
a) bilirubin ≥ 2 times the ULN (confirmed by repeat) without simultaneous alkaline 
phosphatase (ALP) ≥ 2 times the ULN (confirmed by repeat)   


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 47 of 97 
14 June 2018 
 
or 
b) international normalized ratio (INR; will be assessed, if the above criteria are 
reached) > 1.5 times the ULN without simultaneous alkaline phosphatase (ALP) 
≥ 2 times the ULN (confirmed by repeat) 
or 
c) the appearance or worsening of symptoms felt by the Investigator to be potentially 
related to hepatic inflammation, e.g., fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash or eosinophilia in 2 consecutive measurements within 
24 hours. 
If the Principal Investigator or the Sponsor becomes aware of conditions or events that suggest a 
possible hazard to subjects if the clinical study continues, then the clinical study will be 
terminated after appropriate consultation among the involved parties.  The clinical study may be 
terminated at the Sponsor’s discretion also in the absence of such a finding. 
Conditions that may warrant termination of the clinical study include, but are not limited to: 
• The discovery of an unexpected, relevant or unacceptable risk to the subjects enrolled in the 
clinical study; 
• Failure to enroll subjects at the required rate; 
• A decision of the Sponsor to suspend or discontinue development of the IMP. 
Should the study be terminated and/or the site closed for whatever reason, all documentation 
pertaining to the study and IMPs must be returned to the Sponsor.  Any actions of PAREXEL 
required for assessing or maintaining subject safety will continue as required, despite termination 
of the study by the Sponsor. 
Subject withdrawal criteria for the individual are provided in Section 4.4. 
For definition of EoS refer to Section 7.4. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 48 of 97 
14 June 2018 
 
4. 
STUDY POPULATION 
The study population will consist of male and female volunteers.  Subjects must be able to 
provide written informed consent and meet all the inclusion criteria and none of the exclusion 
criteria.  In addition to subjects with overweight, subjects with obesity type I and II have been 
selected as an appropriate study population in order to translate the results to the intended target 
patient population.  Two long-term studies (12 weeks on tesofensine/metoprolol; up to 24 weeks 
(TIPO-1) and an additional 48 weeks (TIPO-4) on tesofensine) have been already conducted in 
individuals within BMI ranges up to 40 mg/kg2 with no major safety issues.  Strict inclusion and 
exclusion criteria applied in this study ensure that obese subjects do not suffer from 
comorbidities which could affect a subjects’ safety. 
4.1. 
Number of Subjects 
A total of 60 subjects are planned for enrollment in the clinical study (N=20 will be randomly 
assigned to each of the 3 cohorts) according to the inclusion/exclusion criteria.  Reasonable 
efforts will be made to achieve gender balance; at least 8 subjects of each gender will be 
included into each cohort.  Subjects withdrawn due to other reasons than IMP-related AEs may 
be replaced (up to 25% in the study) after mutual agreement between Principal Investigator and 
Sponsor.  Overweight and obese subjects, who are otherwise healthy, will be included in order to 
investigate the effects in the target population. 
4.2. 
Inclusion Criteria 
Subjects who meet the following criteria will be considered eligible to participate in the clinical 
study: 
1. Subject voluntarily agrees to participate in this study and signs an IEC-approved informed 
consent prior to performing any of the Screening procedures. 
2. Male and female subjects between 18 to 60 years of age, inclusive, at Screening. 
3. Overweight and obese subjects with a body mass index (BMI) between ≥ 27 and < 40 kg/m2 
at Screening but otherwise healthy. 
4. Non-smokers (or other nicotine use) as determined by history (no nicotine use over the past 
6 months) and by urine cotinine concentration (< 500 ng/mL) at Screening and admission. 
5. No clinically relevant deviation or finding in pre-study medical evaluation (medical history, 
physical examination, vital signs, 12-lead ECG and clinical laboratory evaluations). 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 49 of 97 
14 June 2018 
 
6. HbA1c < 6.5% at Screening. 
7. Subject is willing to adhere to the contraception requirements details in Section 7.5.2. 
4.3. 
Exclusion Criteria 
Subjects who meet one or more of the following criteria will not be considered eligible to 
participate in the clinical study: 
1. Subject has history or evidence of any clinically significant cardiovascular, gastrointestinal, 
endocrinologic, hematologic, hepatic, immunologic, metabolic (e.g., diabetes, metabolic 
acidosis), urologic, pulmonary (e.g., asthma or chronic obstructive pulmonary disease), 
neurologic, dermatologic, psychiatric, renal, and/or other major disease or malignancy as 
judged by the Investigator. 
2. Subject has any disorder that would interfere with the absorption, distribution, metabolism or 
excretion of drugs. 
3. Subject has a clinically significant abnormality following the Investigator’s review of the 
physical examination, ECG and clinical study protocol-defined clinical laboratory tests at 
Screening or admission to the clinical unit or has any concurrent disease or condition that, in 
the opinion of the Investigator, would make the subject unsuitable for participation in the 
clinical study.  One re-test is allowed, if (a) test result(s) is outside the limits. 
4. History or presence of liver disease or liver injury, as indicated by abnormal liver function 
tests including:  
• AST > 1.2 x ULN 
• ALT > 1.1 x ULN  
5. Subject has a pulse < 50 or > 90 bpm; SBP < 90 mmHg or > 140 mmHg; DBP < 50 mmHg 
or > 90 mmHg (using the mean of triplicate measurements) at Screening or admission.  One 
re-test is allowed, if (a) test result(s) is outside these limits. 
6. History of any clinically significant cardiac arrhythmia.  Subject has a corrected QT interval 
using Fridericia’s formula (QTcF) interval > 450 msec or 2nd or 3rd degree atrioventricular 
(AV) block, high-grade sinoatrial block or PQ interval > 0.24 seconds at Screening (using the 
mean of triplicate measurements).  If a mean ECG parameter of a triplicate ECG exceeds the 
limits above, an additional triplicate ECG may be taken.  If this also gives an abnormal 
result, the subject will be excluded.  Also the following cardiac conditions will lead to 
exclusion of the subjects: Untreated heart failure (pulmonary oedema, impaired blood flow or 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 50 of 97 
14 June 2018 
 
hypotension) and continuous or intermittent treatment leading to an increased contractility of 
the heart muscle (beta-receptor agonism); Sick sinus syndrome; cardiogenic shock; severe 
peripheral arterial circulatory disturbances.   
7. Has a creatinine value exceeding the ULN. 
8. Subject has positive test for hepatitis B surface antigen (HBsAg), or hepatitis B core antibody 
(indicative of active hepatitis B), hepatitis A virus antibodies (immunoglobulin M), 
hepatitis C virus (HCV) antibodies or human immunodeficiency virus (HIV) 1 and/or -2 
antibodies. 
9. Use of any prescribed or non-prescribed drugs (including vitamins, natural and herbal 
remedies, e.g., St. John’s Wort) in the 2 weeks prior to admission or 5 half-lives of the drug, 
whichever is longer, except for the occasional use of paracetamol (up to 2 g/day) or other 
non-steroidal anti-inflammatory drugs (NSAIDs) and hormonal contraception for female 
subjects. 
10. Subject has history of alcohol and/or illicit drug abuse within 2 years of entry. 
11. Subject has positive urine drug test (e.g., cocaine, amphetamines, barbiturates, opiates, 
benzodiazepines, cannabinoids) or alcohol test at Screening or at admission.  
12. History of drinking > 168 g (males) and > 84 g (females) pure alcohol per week (10 g pure 
alcohol = 259 mL of beer [5%] or 35 mL of spirits [35%] or 100 mL of wine [12%] within 
3 months prior to admission to the clinical unit. 
13. Subject consumes more than 600 mg caffeine per day (e.g., more than 3 cups of coffee 
containing 200 mg caffeine per cup) within the 4 weeks before admission or the subject is 
unwilling to avoid consumption of coffee and caffeine-containing beverages within 48 hours 
prior to admission until discharge from the clinical unit. 
14. Subject is unwilling to avoid use of alcohol or alcohol-containing foods, medications or 
beverages, within 48 hours prior to Screening and from admission until discharge from the 
clinical unit. 
15. Any significant blood loss, donated one unit (450 mL) of blood or more, or received a 
transfusion of any blood or blood products within 60 days, or donated plasma within 7 days 
prior to the admission to the clinical unit. 
16. Participation in any clinical study within 3 months or 5 half-lives of the drug, whichever is 
longer, prior to the expected date of IMP administration, or participation in more than 
3 clinical studies within 12 months. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 51 of 97 
14 June 2018 
 
17. Subject with a relevant history or with a present psychiatric disorder, including depression, 
suicidal ideation, or eating disorders (e.g., bulimia or anorexia nervosa).  Subjects with a 
medical history of relevant psychiatric disorders or known and relevant family history or 
evidence of anxiety disorders or depression as judged by the Investigator using the 
Generalized Anxiety Disorder Assessment (GAD-7) and Patient Health Questionnaire-9 
(PHQ-9) at Screening.  Any of the following will lead to exclusion of the subject: 
• Subject has a GAD-7 mood scale score ≥ 10 
• Subject has a score ≥ 10 on the PHQ-9 questionnaire 
• Subject selects a response of “1, 2 or 3” to question number 9 on the PHQ-9 
questionnaire regarding potential for suicidal thoughts or ideation (independent of the 
total score of the PHQ-9). 
18. Use of any agent used for weight loss within the last 3 months. 
19. More than 5% weight loss within the last 3 months. 
20. Hypo- or hyperthyroidism. 
21. Subject is pregnant or lactating. 
22. Subject is unwilling to abstain from vigorous exercise from 48 hours prior to admission until 
discharge. 
23. Subject has a history of hypersensitivity to the IMPs or any of the excipients or to medicinal 
products with similar chemical structures. 
24. Any contraindication for metoprolol, e.g. severe peripheral arterial disease, untreated 
pheochromocytoma, concomitant intravenous administration of calcium antagonists of 
verapamil and diltiazem, due to the risk of hypotension, AV conduction disturbances, or left 
ventricular insufficiency. 
25. Subject has lactose intolerance or a rare hereditary problem of fructose intolerance, glucose 
galactose malabsorption or sucrase isomaltase insufficiency. 
26. Subject is unable to understand and communicate in German language or to understand the 
protocol requirements, instructions and study-related restrictions, the nature, scope and 
possible consequences of the clinical study or is unlikely to comply with the study 
requirements; e.g., uncooperative attitude and improbability of completing the clinical study. 
27. Subject has previously been enrolled in this clinical study. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 52 of 97 
14 June 2018 
 
28. Vulnerable subjects defined as individuals whose willingness to volunteer in a clinical study 
may be unduly influenced by the expectation, whether justified or not, of benefits associated 
with participation, or of a retaliatory response from senior members of a hierarchy in case of 
refusal to participate (e.g., persons in detention, minors and those incapable of giving 
consent). 
29. Subject is the Investigator or any Sub-Investigator, research assistant, pharmacist, study 
coordinator, other staff or relative thereof directly involved in the conduct of the study or 
employee of the Sponsor or PAREXEL. 
30. Poor or ultrarapid CYP2D6 metabolizer. 
4.4. 
Subject Withdrawal and Replacement 
The Sponsor reserves the right to request the withdrawal of a subject due to protocol deviation, 
administrative or any other valid and ethical reason.  If an Investigator judges a subject to be at 
medical risk by complying with the protocol, he or she will discontinue the participation of the 
subject.  The circumstances surrounding the decision must be discussed with the Sponsor and 
recorded in the subject’s source documents and electronic source data report (eSDR). 
Subjects must be withdrawn by the Investigator under the following circumstances: 
• SAE 
• AE that is unacceptable for the subject or the Investigator 
• Protocol violation affecting subject safety or evaluability of the study data 
• The subject withdraws consent 
• Pregnancy or breastfeeding 
• Study discontinuation by the Sponsor 
• At the discretion of Investigator 
• Subject shows a hypertension with resting supine SBP above 200 mmHg and persisting for at 
least 10 minutes, confirmed by a repeat measurement 
• Subject shows an increase in BP (confirmed SBP >160 mmHg and/or DBP >100 mmHg) for 
≥ 3 consecutive days 
• Subject may not be dosed with metoprolol if pre-dose resting supine SBP < 90 mmHg), 
confirmed by a repeat measurement.  However, the subjects does not have to discontinue, if 
SBP < 90 mmHg after metoprolol administration without symptoms 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 53 of 97 
14 June 2018 
 
• Subject shows a 2nd or 3rd degree AV block, high-grade sinoatrial block, significant cardiac 
arrhythmias related to the IMP intake, e.g., atrial fibrillation or confirmed significant 
tachycardia >120 bpm.  Subject may not be dosed with metoprolol if pre-dose resting supine 
HR < 45 bpm.  However, the subjects does not have to discontinue, if HR < 45 bpm after 
metoprolol administration without symptoms 
• Subject shows an absolute QTcF of > 500 msec or QTcF change from pre-tesofensine 
baseline > 60 msec in 3 repeated measurements within at least a 1 hour interval 
• Subject has ALT or AST ≥ 3 × ULN ( confirmed by repeat) with  
 
a) Total bilirubin ≥ 2 × ULN without simultaneous ALP ≥ 2 times the ULN (confirmed by 
repeat) 
 
or  
b) INR (will be assessed, if the above criteria are reached) > 1.5 times the ULN without 
simultaneous ALP ≥ 2 times the ULN (confirmed by repeat) 
 
or 
c) the appearance or worsening of symptoms potentially related to hepatic inflammation, 
e.g., fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or 
eosinophilia in 2 consecutive measurements within 24 hours. 
• Subject shows dopaminergic side effects such as agitation, hallucinations, psychoses 
including delusion, paranoid ideation and depression of moderate to severe intensity, 
jeopardizing subject safety and requiring medical intervention and supervision 
The reason(s) for withdrawal will be recorded in ClinBase™. 
If a subject is withdrawn, or chooses to withdraw, from the clinical study for any reason, the 
Investigator must make every possible effort to perform the evaluations described for Day 24. 
A genuine effort must be made to determine the reason(s) why a subject fails to return for the 
necessary visits (if needed) or is discontinued from the study.  If the subject is unreachable by 
telephone, a registered letter, at the minimum, should be sent to the subject requesting him/her to 
contact the clinic. 
While subjects are encouraged to complete all study evaluations, they may withdraw from the 
study at any time and for any reason.  Reasonable effort will be made to determine why any 
subject withdraws from the study prematurely.  All subjects who withdraw from the study with 
an ongoing AE must be followed until the event is resolved or deemed stable.  If a subject 
withdraws prematurely after dosing, all data to be collected prior to discharge from the clinical 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 54 of 97 
14 June 2018 
 
unit should be collected at the time of premature discontinuation or at the scheduled discharge 
(see also Section 7.3). 
Enrollment will continue until a total of 60 subjects are randomized.  Subjects withdrawn due to 
other reasons than IMP-related AEs may be replaced (up to 25% in the study) after mutual 
agreement between Principal Investigator and Sponsor. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 55 of 97 
14 June 2018 
 
5. 
INVESTIGATIONAL MEDICINAL PRODUCT 
5.1. 
Identity of the Investigational Medicinal Products 
The products that will be used in this study are outlined in Table 1. 
Table 1 
Identity of Investigational Products 
Drug Name 
Formulation 
Strength 
Route 
Manufacturer 
Tesofensine 
Film-coated tablet 
0.25 mg tesofensine 
Oral 
Sponsor 
Tesofensine 
Film-coated tablet 
0.50 mg tesofensine 
Oral 
Sponsor 
Metoprololsuccinat 
”Orion”, depottabletter1 
ER tablet 
25 mg metoprolol 
Oral 
Orion Corporation 
(Finland) 
Metoprololsuccinat 
”Orion”, depottabletter2 
ER tablet 
50 mg metoprolol 
Oral 
Orion Corporation 
(Finland) 
Metoprololsuccinat 
”Orion”, depottabletter3 
ER tablet 
100 mg metoprolol 
Oral 
Orion Corporation 
(Finland) 
Metoprolol placebo tablet 
Film-coated tablet 
Not applicable 
Oral 
Solural Pharma ApS 
(Denmark) 
ER = extended release 
1 
contains 23.75 mg metoprolol succinate corresponding to 25 mg metoprolol tartrate 
2 
contains 47.5 mg metoprolol succinate corresponding to 50 mg metoprolol tartrate 
3 
contains 95 mg metoprolol succinate corresponding to 100 mg metoprolol tartrate 
5.2. 
Dose Rationale Including Time of Dosing 
The doses of tesofensine selected for this study are based on the previous clinical experience, 
particularly the tesofensine alone study TIPO-1 (0.25 to 1.0 mg of tesofensine once daily for up 
to 24 weeks) as well as the recently completed Phase 2 study with Tesomet TM001 (0.5 mg of 
tesofensine co-administered with 100 mg of metoprolol ER for 12 weeks).  In addition, 
tesofensine alone was administered to more than 1300 patients at doses up to 1.0 mg for up to 
48 weeks.  Tesofensine was well tolerated up to and including single oral doses of 6.75 mg.  
Based on the available data it is anticipated that the range of doses of tesofensine co-
administered with metoprolol might be between 0.25 to 0.75 mg once daily.  On the other side of 
the dose range, doses < 0.2 mg of tesofensine are unlikely to produce clinically meaningful 
efficacy.  For more information please see the Tesomet IB [2]. 
The doses of metoprolol selected for this study are based on the study TM001 mentioned above 
and also the vast amount of clinical experience with metoprolol and its SPCs [4].  From the 
results of TM001, it seems that the required doses of metoprolol to be used in Tesomet are 
≤100 mg ER.  On the low side, metoprolol ER is usually prescribed as 50 mg once daily, but it is 
possible that for the low end of tesofensine dose range 25 mg of metoprolol may be enough to 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 56 of 97 
14 June 2018 
 
mitigate the effects of tesofensine on HR.  For more information please the Tesomet IB [2] and 
metoprolol SPCs [4]. 
It is important to note that the doses for both compounds proposed for administration in this 
study have been extensively studied and have a solid tolerability and safety track record. 
Timing of dosing will be as follows: 
• Tesofensine, film-coated tablet, 0.25 mg: 
− Oral dose of 4 tablets once daily from Day 1 to Day 3, Cohort 1 only (loading dose of 
1.0 mg) 
− Oral dose of 1 tablet once daily from Day 4 to Day 23, Cohort 1only 
− Oral dose of 1 tablet once daily from Day 6 to Day 23, Cohort 3 only 
• Tesofensine, film-coated tablet, 0.50 mg: 
− Oral dose of 4 tablets once daily from Day 1 to Day 3, Cohort 2 only (loading dose of 
2.0 mg) 
− Oral dose of 4 tablets once daily from Day 1 to Day 5, Cohort 3 only (loading dose of 
2.0 mg) 
− Oral dose of 1 tablet once daily from Day 4 to Day 23, Cohort 2 only 
− Oral dose of 1 tablet once daily from Day 6 to Day 23, Cohort 3 only 
• Metoprolol, 25 mg ER tablet (Metoprololsuccinat “Orion” 25 mg, depottabletter; each tablet 
contains 23.75 mg metoprolol succinate equivalent to 25 mg metoprolol tartrate; 
manufacturer: Orion Corporation, [Finland]) 
− Single oral dose of 1 tablet in each subject of Cohort 1, Cohort 2 and Cohort 3, on 
Day 15, Day 18 or Day 21 
• Metoprolol, 50 mg ER tablet (Metoprololsuccinat “Orion” 50 mg, depottabletter; each tablet 
contains 47.5 mg metoprolol succinate equivalent to 50 mg metoprolol tartrate; 
manufacturer: Orion Corporation, [Finland]) 
− Single oral dose of 1 tablet in each subject of Cohort 1, Cohort 2 and Cohort 3, on 
Day 15, Day 18 or Day 21 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 57 of 97 
14 June 2018 
 
• Metoprolol, 100 mg ER tablet (Metoprololsuccinat “Orion” 100 mg, depottabletter; each 
tablet contains 95 mg metoprolol succinate equivalent to 100 mg metoprolol tartrate; 
manufacturer: Orion Corporation, [Finland]) 
− Single oral dose of 1 tablet in each subject of Cohort 1, Cohort 2 and Cohort 3, on 
Day 15, Day 18 or Day 21 
• Metoprolol placebo film-coated tablet; manufacturer: Solural Pharma ApS (Denmark) 
− Single oral dose of 1 tablet in each subject at each metoprolol dosing i.e., on Day 15, 
Day 18 and Day 21 
Each subject will receive tablets for all days with self-administration of tesofensine. Subjects in 
Cohort 1 will receive 0.25 mg tablets, subjects in Cohort 2 will receive 0.50 mg tablets and 
subjects in Cohort 3 will receive 2 containers: one with 0.25 mg tablets and one with 0.50 mg 
tablets. 
5.3. 
Supply, Packaging, Labeling and Storage 
Investigational medicinal products will be supplied by a third party (KLIFO A/S, Smedeland 36, 
Glostrup, 2600, Denmark) contracted by Saniona A/S.  Tesofensine tablets will be packaged, 
labeled and Qualified Person (QP)-certified according to applicable local and regulatory 
requirements by KLIFO A/S.  ClinBase™ barcode will be added by contract pharmacy Hubertus 
to the subject-specific tesofensine containers provided by KLIFO A/S.  Metoprolol and placebo 
tablets will be packaged and labeled according to applicable local and regulatory requirements 
by contract pharmacy Hubertus. 
All supplies of IMPs must be stored in accordance with the manufacturer’s instructions.  The 
IMPs will be stored in a securely locked area, accessible to authorized persons only, until needed 
for dosing. 
Tesofensine for home-dosing days will be dispenses to the subjects in appropriately labeled 
containers together with instructions of use. 
5.4. 
Drug Accountability, Dispensing and Destruction 
The Investigator or designee is responsible for maintaining accurate accountability records of the 
IMPs throughout the clinical study.  The drug accountability log includes information such as, 
random number, amount dispensed and amount returned to the pharmacy (if any).  Products 
returned to the Hubertus pharmacy will be stored under the same conditions as products not yet 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 58 of 97 
14 June 2018 
 
dispensed.  The returned products should be marked as ‘returned’ and kept separate from the 
products not yet dispensed. 
All dispensing and accountability records will be available for Sponsor review.  When the Study 
Monitor visits PAREXEL, he/she will reconcile the drug accountability log with the products 
stored in the contract pharmacy (Hubertus).  
The pharmacist (or designee under the direction of the pharmacist) will prepare the IMPs for 
each subject according to the randomization list and will ship the IMPs to the site.  
After receiving Sponsor approval in writing, PAREXEL is responsible for returning all unused or 
partially used IMPs to the Sponsor or designated third party or for preparing the IMPs for 
destruction via incineration by the contract pharmacy. 
5.5. 
Subject Identification and Randomization 
5.5.1. 
Screening Numbers 
Subjects will be assigned a RunIn number after the subject has signed the informed consent 
document (ICD).  A subject who was screened for the study on a previous occasion but who was 
not enrolled may be re-screened for eligibility again, if he/she was eligible but could not be 
enrolled due to logistical reasons or due to transient reasons for ineligibility (e.g., too short 
wash-out of previous medication).  The re-screened subject will then be assigned a new RunIn 
number after signing a new ICD.  
5.5.2. 
Randomization Numbers 
Prior to first dosing, subjects will be assigned a randomization number in accordance with the 
randomization code generated by PAREXEL International.  The randomization code will include 
3-digit subject numbers starting from the beginning of the list with 101 for male subjects and 
starting from the end of the list (number 160) for female subjects. 
Once a randomization number has been allocated to one subject, it may not be assigned to 
another subject.  If subjects withdraw prematurely from the study and are replaced under the 
direction of the Sponsor, then a replacement randomization number will be assigned.  A 
replacement randomization code will be generated such that replacement subjects are assigned to 
the same treatment as the discontinued subjects.  The replacement randomization code will differ 
only in randomization numbers, which will be 4-digit numbers starting with a leading 1.  For 
example, if Subject 145 withdraws and is replaced, then the randomization number for the 
replacement subject will be 1145. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 59 of 97 
14 June 2018 
 
5.5.3. 
Randomization 
There will be 20 subjects in each of the 3 cohorts.  Subjects will be randomly assigned to a 
cohort.  Within each cohort the subjects will be randomized to different sequences of metoprolol 
doses.  For 18 of the subjects within each cohort a 3 treatment Williams design will be used to 
determine the sequences.  The final 2 subjects will be randomized according to an incomplete 
3 treatment Latin Square.  Each metoprolol sequence will have at least one subject of each 
gender.  An additional 2 sequences will randomly be assigned to 2 sequences.  Thus there will be 
at least 8 subjects of each gender within each cohort. 
5.6. 
Administration of Investigational Medicinal Products 
On in-house dosing days (i.e., Day 1 to Day 3 [Cohort 1 and Cohort 2], Day 1 to Day 5 
[Cohort 3], Day 7 and Day 13 to Day 23), the Investigator or a designee will administer the 
IMP(s), i.e., tesofensine, metoprolol and placebo, with 240 mL water to the subjects as per 
randomization schedule approximately 30 minutes after start of a standard breakfast (all IMPs at 
the same time).  From Day 4 to Day 6 (Cohort 1 and 2) or on Day 6 (Cohort 3) and from Day 8 
to Day 12, subject will self-administer a single dose of tesofensine approximately 30 minutes 
after start of breakfast.  If more water is needed for the intake of the tablets, up to further 200 mL 
water may be taken.  All IMPs should be swallowed whole with water. 
A mouth check will be performed to ensure the entire dose was swallowed by the subject. 
5.7. 
Compliance 
When subjects are at the site, dosing will be performed by trained, qualified personnel designated 
by the Investigator.  The date and time of dosing will be documented.  On outpatient days, date 
and time of dosing will be documented in a diary.  Comments will be recorded if there are any 
deviations from the planned dosing procedures. 
5.8. 
Blinding and Breaking the Blind 
Tesofensine dosing will be performed open-label.   
Metoprolol dosing will be performed “single-blind”, i.e., subjects will be blinded, 
Investigator(s), designee(s) and Sponsor will be unblinded.  Since the 3 dose strengths of 
metoprolol tablets used in this study have different sizes, to mask the metoprolol dose level, a 
placebo tablet similar to the 50 mg metoprolol Orion tablet will be administered simultaneously 
at the time of each metoprolol dosing. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 60 of 97 
14 June 2018 
 
During the administration itself, subjects’ eyes will be covered as each IMP would otherwise be 
visually distinguishable from the others due to having a different size. 
All tablets of metoprolol are of the same shape, just the size differs.  Therefore, a placebo tablet 
of the same shape and color but of different size will be added to avoid unblinding of the 
subjects.  With these procedures in place, it is very unlikely that subjects would be able to tell 
which dose they were administered. 
Single blinding procedures for metoprolol dosing: 
Single blinding will be achieved by the following procedures: 
• The ICD will be carefully worded so as not to associate any metoprolol dose with a particular 
tablet size and will not mention how many of each will be administered.  It will only list the 
dosage for each of the study drugs.  
• The randomization list will be prepared by a statistician. 
• Randomization list will be provided to the pharmacist, the pharmacovigilance group the 
clinical team, data management and statistician.  A copy will be available at the site in the 
emergency binder. 
• The individual subject doses will be prepared for administration at the pharmacy and put into 
hard, non-transparent containers.  On metoprolol dosing days, the labels on the 
subject-specific containers and the documentation in ClinBase™ will contain all possible 
dose strengths of metoprolol, i.e., 25 mg, 50 mg or 100 mg, but not the allocated dose for the 
specific day.  
• Dose administrators will perform only visual cross-checking of the number of tablets against 
ClinBase™ (verbal readout of the metoprolol will include all possible dose strengths, i.e., 25 
mg, 50 mg or 100 mg). 
• Subjects will have their eyes covered by blindfolds at time of administration. 
• The study drugs will be administered by the site staff and maximum care will be taken so that 
the subjects never actually see or touch the study drugs. 
• The study drugs will be given to subjects with a glass of water (240 mL) and they will be 
instructed to swallow them immediately.  If more water is needed for the intake of the tablets, 
up to further 200 mL water may be taken.   
After removing of blindfold from subject, they will be given instructions to avoid discussion 
surrounding dosing procedures and study drug (i.e., taste, texture, number, etc.). 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 61 of 97 
14 June 2018 
 
5.9. 
Prior and Concomitant Medications 
Any medicinal product, prescribed or over-the-counter (OTC), including herbal and other 
nontraditional remedies, is considered a concomitant medication.  Prior and concomitant 
medication use will be recorded for the 30 days prior to Screening until the Safety Follow-up 
phone call.  Prior and concomitant medication use is not permitted from 2 weeks before 
admission until discharge (occasional use of paracetamol up to 2 g/day or other NSAIDs and 
hormonal contraception is permitted).  However, concomitant medication use may be warranted 
for the treatment of AEs, a list of prohibited medication is provided in Appendix 11.1, with 
emergencies being the exemption. 
5.10. Treatment of Overdose 
Overdose is unlikely to occur in this study.  Standard symptomatic support measures should be 
used in the case of excessive pharmacological effects or overdose.  No antidotes are available.  
At intoxication, symptomatic treatment with dopamine D2-receptor antagonist haloperidol 
should be considered. 
An overdose of tesofensine is defined in this study as 6 times of single dose and metoprolol as 
4 times of a daily dose with or without occurrence of clinical symptoms.  If a subject or any 
unintended other person not part of the study has an accidental or intentional overdose of the 
IMP, even if the consequences are not serious, the overdose must be reported to the Sponsor 
immediately (within 24 hours).  The procedure for reporting SAEs should be followed. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 62 of 97 
14 June 2018 
 
6. 
MEASUREMENTS AND METHODS OF ASSESSMENT 
For timing of assessments, refer to the Schedules of Assessments (Table 5 and Table 6). 
A Safety management plan (SMP) will be signed between the Sponsor and PAREXEL. 
6.1. 
Medical History, Demographic and Other Baseline Information 
The medical history comprises: 
• General medical history 
• Medication history 
• Family history of psychiatric disorders (focusing on psychosis, depression, suicidality or 
suicide) 
The following demographic information will be recorded: 
• Age 
• Gender 
• Ethnic origin (Hispanic/Latino or not Hispanic/not Latino) 
• Race (White, Black, Asian, Native Hawaiian or other Pacific Islands, American Indian or 
Alaska Native, Asian-Japanese, Asian-Korean, Other) 
• Height, without shoes (cm) 
• Body weight, without shoes (kg), waist circumference 
• BMI (kg/m2) 
Other baseline characteristics will be recorded as follows: 
• History of drug abuse 
• History of alcohol abuse 
• Smoking history 
• History of caffeine use (or other stimulating beverages) 
• Special diet (vegetarian) 
• History of blood or plasma donation 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 63 of 97 
14 June 2018 
 
6.2. 
Safety Variables 
6.2.1. 
Adverse Events 
Adverse event reporting will begin for each subject from the date the ICD is signed and will 
continue until the final Safety Follow-up phone call (EoS). 
6.2.1.1. 
Definitions 
6.2.1.1.1. 
Definition of Adverse Event 
Any untoward medical occurrence in a subject administered a pharmaceutical product and which 
does not necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
Other untoward events occurring in the framework of a clinical study will be recorded as AEs, 
e.g., those occurring during treatment-free periods (including Screening or post-treatment 
Follow-up periods), in association with study-related procedures and assessments.  
Concomitant illnesses, which existed prior to entry into the clinical study, will not be considered 
AEs unless they worsen during the Treatment Period.  Pre-existing conditions will be recorded as 
part of the subject’s medical history. 
6.2.1.1.2. 
Definition of Serious Adverse Event 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening; this means that the subject was at risk of death at the time of the event; it 
does not mean that the event hypothetically might have caused death if it were more severe 
• Requires inpatient hospitalization or prolongation in existing hospitalization 
• Results in persistent or significant disability/incapacity or substantial disruption of the ability 
to conduct normal life functions 
• Is a congenital anomaly/birth defect, or 
• Is another important medical event (see below) 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 64 of 97 
14 June 2018 
 
Important medical events that do not result in death, are not life-threatening or do not require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or in a physician’s office, blood dyscrasias 
or seizures that do not result in inpatient hospitalization, and the development of drug 
dependency or drug abuse. 
A distinction should be drawn between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria above.  For example, a mild degree of 
gastrointestinal bleeding requiring an overnight hospitalization for monitoring purposes would be 
considered an SAE, but is not necessarily severe.  Similarly, an AE that is severe in intensity is 
not necessarily an SAE.  For example, alopecia may be assessed as severe in intensity but would 
not be considered an SAE. 
Medical and scientific judgment should be exercised in deciding if an AE is serious and if 
expedited reporting is appropriate. 
6.2.1.2. 
Recording of Adverse Events 
Adverse events should be collected and recorded for each subject from the date the ICD is signed 
until the end of their participation in the study, i.e., the subject has discontinued or completed the 
study. 
Adverse events may be volunteered spontaneously by the subject, or discovered by the study 
staff during physical examinations or by asking an open, non-leading question such as ‘How 
have you been feeling since you were last asked?’ All AEs and any required remedial action will 
be recorded. The nature of AE, date (and time, if known) of AE onset, date (and time, if known) 
of AE outcome to date, severity and action taken of the AE will be documented together with the 
Investigator’s assessment of the seriousness of the AE and causal relationship to IMP (with 
causality being assessed separately for tesofensine and metoprolol) and/or study procedure.   
All AEs should be recorded individually unless, in the opinion of the Investigator, the AEs 
constitute components of a recognized condition, disease or syndrome.  In the latter case, the 
condition, disease or syndrome should be named rather than each individual symptom.  The AEs 
will subsequently be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 65 of 97 
14 June 2018 
 
6.2.1.3. 
Assessment of Adverse Events 
Each AE will be assessed by the Investigator with regard to the categories discussed in the 
following sections. 
6.2.1.3.1. 
Intensity 
The Principal Investigator or designee will assess all AEs for severity in accordance with the 
following standard ratings. 
• Mild: Ordinarily transient symptoms, does not influence performance of subject’s daily 
activities.  Treatment is not ordinarily indicated. 
• Moderate: Marked symptoms, sufficient to make the subject uncomfortable.  Moderate 
influence on performance of subject’s daily activities.  Treatment may be necessary. 
• Severe: Symptoms cause considerable discomfort. Substantial influence on subject’s daily 
activities.  May be unable to continue in the study and treatment may be necessary. 
When changes in the intensity of an AE occur, the maximum intensity for the event will be 
noted. 
6.2.1.3.2. 
Causality 
The Investigator will assess the causality/relationship between the IMPs and the AE.  The 
causality will be assessed separately for tesofensine and metoprolol.  One of the categories 
described in Table 2 should be selected based on medical judgment, considering the definitions 
below and all contributing factors. 
Table 2 
Assessment of Relationship of Adverse Events to Investigational Product 
Related 
A clinical event, including laboratory test abnormality, occurs in a plausible time 
relationship to treatment administration, and which concurrent disease or other drugs or 
chemicals cannot explain. 
Not related 
A clinical event, including laboratory test abnormality, with little or no temporal relationship 
with treatment administration or confirmed other cause (e.g., other medical condition).   
 
6.2.1.3.3. 
Seriousness 
Severity is a measure of intensity whereas seriousness is defined by the criteria in 
Section 6.2.1.1.2. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 66 of 97 
14 June 2018 
 
6.2.1.4. 
Reporting of Serious Adverse Events 
The Investigator will review each SAE and evaluate the intensity and the causal relationship of 
the event to IMP.  All SAEs will be recorded from signing of the ICD until the EoS, i.e., the final 
Safety Follow-up phone call.  Serious AEs occurring after the EoS and coming to the attention of 
the Investigator must be reported only if there is (in the opinion of the Investigator) reasonable 
causal relationship with the IMP. 
An SAE Report Form has to be completed and sent by email to: 
pharmacovigilance@klifo.com 
or 
fax: +45 39 209 045 
The Investigator is responsible for providing notification to the KLIFO Pharmacovigilance 
Service of any SAE, whether deemed IMP-related or not, that a subject experiences during their 
participation in study within 24 hours of becoming aware of the event. 
As a minimum requirement, the initial notification should provide the following information: 
• Study number 
• Subject number 
• Sex 
• Age 
• Name of Principal Investigator and full clinical unit address 
• Details of SAE 
• Criterion for classification as ‘serious’ 
• IMP name, or code and treatment start date 
• Date of SAE onset 
• Causality assessment (if sufficient information is available to make this classification) 
KLIFO will send a receipt confirmation to the Site (PAREXEL) within 1 working day, with a 
copy to the Sponsor. If required, KLIFO will request follow-up using a data clarification form. 
Request for follow-up will be sent to the Site/PAREXEL. The Principal Investigator or an 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 67 of 97 
14 June 2018 
 
authorized delegate is responsible for sending the requested information to KLIFO within 
24 hours of the Sponsor’s request. 
Initial reports of SAEs must be followed later with detailed descriptions, including clear 
photocopies of other documents as necessary (e.g., hospital reports, consultant reports, autopsy 
reports), with the subject’s personal identifiers removed.  All relevant information obtained by 
the Principal Investigator through review of these documents will be recorded and sent to the 
KLIFO within 24 hours of receipt of the information.  If a new SAE Report Form is sent, then 
the Investigator must sign and date the form.  KLIFO may also request additional information on 
the SAE, which the Principal Investigator or an authorized delegate must send to the KLIFO 
within 24 hours of the request. 
Details can be found in the SMP. 
6.2.1.5. 
Follow-up of Adverse Events 
All AEs experienced by a subject, irrespective of the suspected causality, will be monitored until 
the event has resolved, until any abnormal laboratory values have returned to baseline or 
stabilized at a level acceptable to the Principal Investigator, until there is a satisfactory 
explanation for the changes observed or until the subject is lost to follow-up. 
6.2.1.6. 
Pregnancy 
Any pregnancy that occurs in a female subject or the female partner of a male subject during 
trial participation until at least 8 weeks after the last administration of IMP must be reported 
on a pregnancy report form in the same manner as an SAE to KLIFO Pharmacovigilance 
Service (Section 6.2.1.4). 
The Investigator will arrange for the pregnant person to be counselled by a specialist to 
discuss the risks of continuing with the pregnancy and the possible effects on the foetus. 
Monitoring of the pregnant person should continue until the outcome of the pregnancy is 
known. 
The pregnancy must be followed up to determine outcome (including spontaneous 
miscarriage, elective termination, normal birth, or congenital abnormality) and status of 
mother and child, even if the subject was discontinued from the trial.  
All data related to pregnancy, pregnancy outcome, and SAE associated with pregnancy will also 
be recorded in a safety database maintained by KLIFO Pharmacovigilance Service. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 68 of 97 
14 June 2018 
 
Consent to report information regarding pregnancy outcomes has to be obtained from the mother 
and the (where possible) father. 
6.2.2. 
Clinical Laboratory Assessments 
Samples for clinical laboratory assessments will be collected at the time points detailed in the 
Schedules of Assessments (Table 5 and Table 6). 
Clinical laboratory tests will be performed by the laboratories mentioned in the List of Study 
Staff of this clinical study protocol.  Samples will be collected in appropriate tubes and handled 
according to standard procedures of the applicable laboratory. 
Clinical laboratory variables will be determined as outlined in Table 3. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 69 of 97 
14 June 2018 
 
Table 3 
Clinical Laboratory Assessments 
Hematology 
White blood cell (WBC) count 
Neutrophils (percentage and absolute count) 
Red blood cell (RBC) count 
Lymphocytes (percentage and absolute count)  
Hemoglobin (Hb) 
Monocytes (percentage and absolute count)  
Hematocrit (HCT) 
Eosinophils (percentage and absolute count)  
Mean corpuscular volume (MCV) 
Basophils (percentage and absolute count)  
Mean corpuscular hemoglobin (MCH) 
Platelet count 
Mean corpuscular hemoglobin concentration (MCHC) 
RBC distribution width  
HbA1c (at Screening only) 
Clinical Chemistry 
Alanine aminotransferase (ALT) 
Glucose 
Albumin 
Lactate dehydrogenase (LDH) 
Alkaline phosphatase (ALP) 
Phosphorus 
Aspartate aminotransferase (AST) 
Potassium 
Blood urea nitrogen (BUN) 
Sodium 
Calcium 
Total bilirubin 
Chloride 
Total protein 
Cholesterol 
Triglycerides 
Creatinine 
Thyroid-stimulating hormone (TSH) 
Creatine phosphokinase (CPK) 
Uric acid 
Gamma glutamyl transferase (GGT) 
Follicle-stimulating hormone (female subjects only, at 
Screening only) 
Urinalysis 
Bilirubin 
Blood 
Glucose 
pH and specific gravity 
Ketones 
Protein 
Leukocytes 
Urobilinogen 
Nitrite 
 
Upon a positive urine test from leucocytes, blood or protein, the Investigator may require further urine analysis, such 
as flow cytometry. Results of additional urine analyses will be included in the database. 
If the flow cytometry examination shows a different result than the urine stix, it will be checked by microscopy or 
full automated digital imaging, (e.g., leukocytes, erythrocytes, casts in urine will be analyzed). 
Viral Serology 
Hepatitis B core antibody (anti-HBc) 
Human immunodeficiency virus (HIV)  
(Types 1 and 2) antibodies 
Hepatitis B surface antigen (HBsAg) 
Hepatitis A virus antibodies (immunoglobulin M) 
Hepatitis C virus antibody (anti-HCV) 
Pregnancy Tests (in Female Subjects) 
β-human chorionic gonadotropin in serum (at Screening) 
β-human chorionic gonadotropin in urine (on each 
admission) 
Urine Drug Screening, Cotinine and Alcohol Test 
Amphetamines 
Cocaine 
Barbiturates 
Opiates 
Benzodiazepines 
Phencyclidine 
Cannabinoids 
Cotinine 
Alcohol 
Urinary creatinine (to exclude dilution effect) 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 70 of 97 
14 June 2018 
 
 
Any value outside the normal range will be flagged for the attention of the Principal Investigator 
or designee at the site.  The Principal Investigator or designee will indicate whether or not the 
value is of clinical significance.  If the result of any test (or repeat test, if done) from the samples 
taken during the Screening Period is indicated as clinically significant, the subject will not be 
allowed into the study.  Additional testing during the study may be done if medically indicated.  
If a clinically significant abnormality is found in the samples taken after dosing, during the 
study, and/or at discharge, it should be recorded as an AE and the subject will be followed until 
the test(s) has (have) normalized or stabilized, at the discretion of the Principal Investigator. 
6.2.3. 
Vital Signs 
Vital signs will be assessed at the time points detailed in the Schedules of Assessments (Table 5 
and Table 6).  The following vital signs will be measured in triplicates (i.e., 3 measurements 
at least 1 minute apart) with an appropriate cuff always at the same arm: 
• Blood pressure (systolic and diastolic [mmHg]) 
• Pulse (bpm) 
Recordings will be made after the subject has been supine and at rest ≥ 10 minutes.  At 
Screening and first admission the mean of the 3 measurements will be used to check eligibility. 
In addition, oral body temperature (°C) will be measured.   
6.2.4. 
Standard 12-lead Electrocardiograms 
Standard safety 12-lead ECGs will be performed at the time points detailed in the Schedules of 
Assessments (Table 5 and Table 6).  
The12-lead ECGs will be performed in triplicates (i.e., 3 recordings of 10 seconds each at least 
60 seconds apart) after the subject has been resting supine for ≥ 10 minutes.  The ECG will 
include all 12 standard leads and a Lead II rhythm strip on the bottom of the tracing.  The ECG 
will be recorded at a paper speed of 25 mm/sec.  The following ECG parameters will be 
collected: HR, PR interval, QRS interval, RR interval, QT interval and QTc interval (QTcB and 
QTcF) (QTcF will be used for clinical decisions).  The mean ECG parameters of the triplet will 
be used to determine subject eligibility. 
All ECGs must be evaluated by a qualified physician for the presence of abnormalities. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 71 of 97 
14 June 2018 
 
6.2.5. 
Physical Examinations 
Physical examinations will be performed at the time points detailed in the Schedules of 
Assessments (Table 5 and Table 6). 
Physical examination: 
An assessment of general appearance and a review of systems (dermatologic, head, eyes, ears, 
nose, mouth/throat/neck, thyroid, lymph nodes, respiratory, cardiovascular, gastrointestinal, 
extremities, musculoskeletal), including orientating neurologic examination. 
Other evaluations may be performed as deemed necessary by the Investigator.  This will be 
commented upon in the clinical study report (CSR), if performed. 
6.2.6. 
Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder 
Assessment (GAD-7) 
The Patient Health Questionnaire (PHQ) was developed and validated as a self-administered 
version of the Primary Care Evaluation of Mental Disorders (PRIME-MD).  The PHQ in general 
and the PHQ-9 depression scale in particular have gained increasing use in both research and 
practice for assessing and monitoring depression severity.  Though originally developed and 
validated to diagnose generalized anxiety disorder, the GAD-7 also proved to have good 
sensitivity and specificity as a screener for panic, social anxiety, and post-traumatic stress 
disorder.  
Each PHQ module can be used alone (e.g. the PHQ-9 if depression is the condition of interest), 
together with other modules, or as part of the full PHQ. 
Question No. 9 of the PHQ-9 serves as screener for suicidal ideation and self-harm.  A final 
decision about the actual risk of self-harm requires a clinical interview. 
The final question on the PHQ addresses patient-rated difficulty (“How difficult have these 
problems made it for you to do your work, take care of things at home, or get along with other 
people?”).  It is not used in calculating any PHQ score or diagnosis but rather represents the 
patient‘s global impression of symptom-related impairment.  It may be useful in decisions to be 
made by a health care professional or an Investigator in a clinical study. 
The severity scores are now used much more commonly than the provisional diagnoses.  A 
cutpoint of 10 or greater is considered a "yellow flag" on both measures (i.e., drawing attention 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 72 of 97 
14 June 2018 
 
to a possible clinically significant condition), while a cutpoint of 15 is a "red flag" on all 
3 measures (i.e., targeting individuals in whom active treatment is probably warranted). 
PHQ-9 Depression Severity.  This is calculated by assigning scores of 0, 1, 2, and 3, to the 
response categories of "not at all", "several days," "more than half the days", and "nearly every 
day", respectively. PHQ-9 total score for the 9 items ranges from 0 to 27.  Scores of 5, 10, 15, 
and 20 represent cutpoints for mild, moderate, moderately severe and severe depression, 
respectively [5].  Sensitivity to change has also been confirmed. 
GAD-7 Anxiety Severity.  This is calculated by assigning scores of 0, 1, 2, and 3, to the 
response categories of "not at all", "several days", "more than half the days", and "nearly every 
day", respectively.  GAD-7 total score for the 7 items ranges from 0 to 21.  Scores of 5, 10, and 
15 represent cutpoints for mild, moderate, and severe anxiety, respectively.  Though designed 
primarily as a screening and severity measure for generalized anxiety disorder, the GAD-7 also 
has moderately good operating characteristics for 3 other common anxiety disorders – panic 
disorder, social anxiety disorder, and post-traumatic stress disorder.  When screening for anxiety 
disorders, a recommended cutpoint for further evaluation is a score of 10 or greater. 
Subjects rating ≥ 1 on the suicidal ideation question of the PHQ-9 or whose ratings of ≥ 10 in 
PHQ-9 or GAD-7 indicate moderate or worse depressive or anxiety symptomatology, 
respectively, will not be included in the study. 
Please refer to the Instruction Manual [6] and the questionnaires [7] for further details. 
Severity of psychiatric AEs will be assessed by the Investigator. Life-threatening events should 
be reported as SAEs.  The subject must be referred to a mental health care professional for 
further assessment and/or treatment in case of psychiatric SAEs. The decision on whether the 
study treatment should be discontinued is to be taken by the Investigator in consultation with the 
mental health professional to whom the subject is referred. 
6.3. 
Pharmacokinetics Variables 
6.3.1. 
Blood Sample Collection 
Blood for the analysis of tesofensine and metoprolol will be collected at the time points detailed 
in the Schedules of Assessments (Table 5 and Table 6).  Analysis of tesofensine’s active 
metabolite will not be performed. 
Blood sample collection, processing and shipping details will be outlined in a separate laboratory 
manual.  In brief, blood will be processed and plasma analyzed using validated assays. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 73 of 97 
14 June 2018 
 
6.4. 
Pharmacodynamic Variables 
A 2-lead Holter-ECG device will be used for recording of 24-hour HR at the time periods 
detailed in the Schedules of Assessments (Table 5 and Table 6). 
With regard to HRmin and HRmax the minute in which the minimum and the minute in which 
the maximum HR occurred will be determined over the 24 hour period. 
In addition, the mean HR from a designated period (from 3 to 16 hours post-dose) and in a quiet 
hour (from 12 to 13 hours post-dose) will be extracted from the Holter-ECG.  During the quiet 
hour, subjects will have to rest, i.e., each subject will be asked to find a personally comfortable 
supine position with the head and whole body firmly supported.  The subjects will not be 
permitted to watch television or to listen to radio or music player.  They will not be permitted to 
read, to sleep or converse, and will be kept free from any external disturbance (e.g., personal 
media).  No electric equipment including mobile phones may be switched on in the room. 
In addition, 12-lead ECG, BP and pulse will be assessed after a rest of at least 10 minutes as 
detailed in the Schedules of Assessments (Table 5 and Table 6), in Section 6.2.3 and 
Section 6.2.4. 
6.5. 
Total Amount of Blood 
Each subject will have less than 500 mL of blood collected over the course of the entire study 
(from Screening to discharge, but not including repeat or additional tests ordered by the 
Investigator), which presents no undue risk to the subjects (see Table 4). 
Table 4 
Approximate Total Amount of Blood for Each Subject 
Assessment 
Sample Volume 
(mL) 
Number of Samples 
Total Blood Volume 
(mL) 
Pharmacokinetics (tesofensine, 
metoprolol or both) 
7.5 
21 
157.5 
Hematology and clinical chemistry1 
10.2 
4 
40.8 
Cytochrome (CYP)2D6 
2.7 
1 
2.7 
Total Blood Volume2 per Subject 
201.0 
1 
Viral serology and pregnancy test will be performed on the sample collected for hematology and clinical 
chemistry at Screening, as applicable.   
2 
Excluding repeat laboratory investigations. 
 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 74 of 97 
14 June 2018 
 
7. 
STUDY CONDUCT 
7.1. 
Schedule of Assessments 
The study consists of a Screening Visit (Day –28 to Day –3), admission (Day –2), a Baseline 
Period (Day -2 to Day -1) and a Treatment Period (Day 1 to Day 24) and will have 2 Follow-up 
phone calls (Day 30 and Day 50).  The Treatment Period will comprise an initial in-house stay 
(Day -2 to Day 3) until the last loading dose of tesofensine has been administered on Day 3 (see 
below), a home-dosing period (Day 4 to Day 12, once daily dosing to achieve steady state of 
tesofensine with an ambulatory visit in the clinical unit on Day 7) and a second in-house stay 
(Day 13 to Day 24).  Safety evaluations will be performed on Day 30 and Day 50 (EoS) after last 
dosing over the phone. 
Therefore, the maximal study duration for an individual subject will be up to 78 days, including 
Screening. 
Please see Table 5 and Table 6 for the Schedules of Assessments. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 75 of 97 
14 June 2018 
 
Table 5 
Schedule of Assessments for Cohort 1 and Cohort 2 
Evaluation 
Screening 
Base-
line 
Treatment Period 
Safety 
FU 
Phone 
Calls 
Day 
-28 to -3 
-2 
-1a 
1 
2 
3 
7 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
30 
50 
Admission 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
In-house stayb 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Ambulatory visits 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Body weight  
X 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Waist circumference 
X 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Height, calculation of BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling for CYP2D6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory tests (clinical 
chemistry, hematology and 
urinalysis) in fasted state 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
HBA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy testm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Urine pregnancy testm 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Xn 
Psychodiagnostic self-rating 
instruments (PHQ-9 and GAD-7) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen, cotinine and 
alcohol test 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
24-hours Holter ECGc 
 
 
Xa 
 
 
 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
12-lead ECGd,f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 76 of 97 
14 June 2018 
 
Evaluation 
Screening 
Base-
line 
Treatment Period 
Safety 
FU 
Phone 
Calls 
Day 
-28 to -3 
-2 
-1a 
1 
2 
3 
7 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
30 
50 
Supine blood pressure and pulsee,f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Body temperatureg 
X 
X 
X 
 
 
 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
A designated period from 3 to 
16 hours post-dose and a quiet hour 
from 12 to 13 hours post-dosef 
 
 
X 
 
 
 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
Randomizationh 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dosing of tesofensinei 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Dosing of metoprololj 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Blood sampling for PKk 
 
 
 
 
 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
Dispense of tesofensine container 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject returns tesofensine 
container to the clinical unit 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense of the diary and 
instructionsl 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of the diary 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE = adverse event; BMI = Body Mass Index; ECG = electrocardiogram; FU = Follow-up; PK = pharmacokinetics; GAD-7 = Generalized Anxiety Disorder 
Assessment; PHQ-9 = Patient Health Questionnaire-9  
a 
The 24-hours ECG recording at pre-tesofensine baseline may be repeated, if less recording time than 22 hours for comparison of the data is available for 
evaluation due to technical issues.  Then dosing and all subsequent assessments will be postponed by 1 day. 
 
b 
Subjects will be admitted in the morning of Day -2 and will leave the study center in the morning of Day 3 after dosing of the last loading dose and after 
completion of all study-related assessments. 
 
Subject will take tesofensine at home once daily from Day 4 to Day 6 and from Day 8 to Day 12. 
 
On Day 7, subject will come to the study center for an ambulatory visit (including dosing). 
 
Subjects will be admitted in the morning of Day 13 and will leave the study center on Day 24 after completion of all study-related assessments. 
c 
2-lead Holter-ECG recordings will start in the morning before dosing (or at corresponding time at pre-tesofensine baseline) and will end approximately 
24 hours after respective dose.  


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 77 of 97 
14 June 2018 
 
d 
On Days -1, 14, 15, 17, 18, 20, 21 and Day 23: Triplicate measurement (i.e., 3 recordings of 10 seconds each, at least 60 seconds apart) within 10 minutes 
before each PK sampling and at corresponding time points (pre-dose and at 2, 4, 8, 12 and 24 hours post-dose).  
On other days and at Screening, also in triplicates: once daily in the morning (pre-dose on dosing days). 
e 
On Days -1, 14, 15, 17, 18, 20, 21 and Day 23: Triplicate measurement within 10 minutes before each PK sampling and at corresponding time points (pre-
dose and at 2, 4, 8, 12 and 24 hours post-dose).  
On other days and at Screening, also in triplicates: once daily in the morning (pre-dose on dosing days). 
f 
Subjects will have to rest during the quiet hour and for at least 10 minutes before 12-lead ECG recording and blood pressure and pulse measurements, i.e., 
each subject will be asked to find a personally comfortable supine position with the head and whole body firmly supported.  The subjects will not be 
permitted to watch television or to listen to radio or music player.  They will not be permitted to read, to sleep or converse, and will be kept free from any 
external disturbance (e.g., personal media).  No electric equipment including mobile phones may be switched on in the room. 
g 
Once daily, on in-house days in the morning.   
h 
Randomization will be performed pre-dose on Day 1. 
i 
Dosing of tesofensine will start in the morning of Day 1 and will be continued until the morning of Day 23, when the last dose of tesofensine will be given; 
subjects will be randomly assigned to any of the 3 tesofensine dose cohorts (Cohort 1, Cohort 2, Cohort 3). 
 
Cohort 1: 1.0 mg once daily for the first 3 days (loading dose), then 0.25 mg once daily. 
 
Cohort 2: 2.0 mg once daily for the first 3 days (loading dose), then 0.50 mg once daily. 
 
j 
Dosing of extended release metoprolol will be performed in the morning of Day 15, Day 18 and Day 21 approximately 30 minutes after start of a breakfast.  
Administration of single doses of 25 mg, 50 mg and 100 mg in random order. 
k 
Blood sampling for metoprolol: at pre-dose and at 2, 4, 8, 12 and 24 hours post-dose on Day 15, Day 18 and Day 21.  
 
Blood sampling for tesofensine: at pre-dose on Day 13, Day 14 and Day 15 to confirm steady state, at pre-dose on Day 18, Day 21 and Day 23 and at 8 hours 
post-dose on Day 15, Day 18 and Day 21.   
l 
On outpatient days, date and time of dosing, adverse events (if any) and use of concomitant medication (if any) will be documented in a diary. 
m Pregnancy tests will be performed whenever deemed necessary. 
n 
The pregnancy test on Day 50 will be performed at home and the result will be communicated during the safety FU phone call. 
 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 78 of 97 
14 June 2018 
 
Table 6 
Schedule of Assessments for Cohort 3 
Evaluation 
Scree-
ning 
Base-
line 
Treatment Period 
Safety 
FU 
Phone 
Calls 
Day 
-28 
to -3 
-2 
-1a 
1 
2 
3 
4 
5 
7 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
30 
50 
Admission 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
In-house stayb 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Ambulatory visits 
X 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Body weight  
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Waist circumference 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Height, calculation of BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling for CYP2D6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory tests (clinical 
chemistry, hematology and 
urinalysis) in fasted state 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Serum pregnancy testm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
Urine pregnancy testm 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Xn 
Psychodiagnostic self-rating 
instruments (PHQ-9 and GAD-7) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen, cotinine and 
alcohol test 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
24-hours Holter ECGc 
 
 
Xa 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
12-lead ECGd,f 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 79 of 97 
14 June 2018 
 
Evaluation 
Scree-
ning 
Base-
line 
Treatment Period 
Safety 
FU 
Phone 
Calls 
Day 
-28 
to -3 
-2 
-1a 
1 
2 
3 
4 
5 
7 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
30 
50 
Supine blood pressure and pulsee,f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Body temperatureg 
X 
X 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
A designated period from 3 to 
16 hours post-dose and a quiet hour 
from 12 to 13 hours post-dosef 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
Randomizationh 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dosing of tesofensinei 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Dosing of metoprololj 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Blood sampling for PKk 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
Dispense of tesofensine containers 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject returns tesofensine 
containers to the clinical unit 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense of the diary and 
instructionsl 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of the diary 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE = adverse event; BMI = Body Mass Index; ECG = electrocardiogram; FU = Follow-up; PK = pharmacokinetics; GAD-7 = Generalized Anxiety Disorder 
Assessment; PHQ-9 = Patient Health Questionnaire-9  
 
a 
The 24-hours ECG recording at pre-tesofensine baseline may be repeated, if less recording time than 22 hours for comparison of the data is available for 
evaluation due to technical issues.  Then dosing and all subsequent assessments will be postponed by 1 day. 
 
b 
Subjects will be admitted in the morning of Day -2 and will leave the study center in the morning of Day 3 after dosing of the last loading dose and after 
completion of all study-related assessments. 
 
Subjects will come to the study center for ambulatory visits and dosing of tesofensine on Days 4 and 5.  
Subjects will take tesofensine at home once daily on Day 6 and from Day 8 to Day 12. 
 
On Day 7, subject will come to the study center for an ambulatory visit (including dosing). 
 
Subjects will be admitted in the morning of Day 13 and will leave the study center on Day 24 after completion of all study-related assessments. 
c 
2-lead Holter-ECG recordings will start in the morning before dosing (or at corresponding time at pre-tesofensine baseline) and will end approximately 
24 hours after respective dose.   


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 80 of 97 
14 June 2018 
 
d 
On Days -1, 14, 15, 17, 18, 20, 21 and Day 23: Triplicate measurement (i.e., 3 recordings of 10 seconds each, at least 60 seconds apart) within 10 minutes 
before each PK sampling and at corresponding time points (pre-dose and at 2, 4, 8, 12 and 24 hours post-dose).  
On other days and at Screening, also in triplicates: once daily in the morning (pre-dose on dosing days). 
e 
On Days -1, 14, 15, 17, 18, 20, 21 and Day 23: Triplicate measurement within 10 minutes before each PK sampling and at corresponding time points (pre-
dose and at 2, 4, 8, 12 and 24 hours post-dose).  
On other days and at Screening, also in triplicates: once daily in the morning (pre-dose on dosing days). 
f 
Subjects will have to rest during the quiet hour and for at least 10 minutes before 12-lead ECG recording and blood pressure and pulse measurements, i.e., 
each subject will be asked to find a personally comfortable supine position with the head and whole body firmly supported.  The subjects will not be 
permitted to watch television or to listen to radio or music player.  They will not be permitted to read, to sleep or converse, and will be kept free from any 
external disturbance (e.g., personal media).  No electric equipment including mobile phones may be switched on in the room. 
g 
Once daily, on in-house days in the morning.   
h 
Randomization will be performed pre-dose on Day 1. 
i 
Dosing of tesofensine will start in the morning of Day 1 and will be continued until the morning of Day 23, when the last dose of tesofensine will be given; 
subjects will be randomly assigned to any of the 3 tesofensine dose cohorts (Cohort 1, Cohort 2, Cohort 3). 
 
Cohort 3: 2.0 mg once daily for the first 5 days (loading dose), then 0.75 mg once daily. 
j 
Dosing of extended release metoprolol will be performed in the morning of Day 15, Day 18 and Day 21 approximately 30 minutes after start of a breakfast.  
Administration of single doses of 25 mg, 50 mg and 100 mg in random order. 
k 
Blood sampling for metoprolol: at pre-dose and at 2, 4, 8, 12 and 24 hours post-dose on Day 15, Day 18 and Day 21.  
 
Blood sampling for tesofensine: at pre-dose on Day 13, Day 14 and Day 15 to confirm steady state, at pre-dose on Day 18, Day 21 and Day 23 and at 8 hours 
post-dose on Day 15, Day 18 and Day 21.   
  
l 
On outpatient days, date and time of dosing, adverse events (if any) and use of concomitant medication (if any) will be documented in a diary. 
m Pregnancy tests will be performed whenever deemed necessary. 
n 
The pregnancy test on Day 50 will be performed at home and the result will be communicated during the safety FU phone call. 
 
 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 81 of 97 
14 June 2018 
 
7.2. 
Order of Assessments 
The following order will be in effect when more than one assessment is required at a pre-dose 
(except for Screening and on admission) and post-dose time point, with PK blood sampling 
being performed nearest to the specified time: 
1. 12-lead ECG 
2. Vital signs 
3. PK blood sampling 
4. Blood sampling for safety assessments 
7.3. 
Early Termination 
If a subject withdraws prematurely after dosing, all data normally collected at discharge from the 
clinical unit should be collected at the time of premature discontinuation or at the scheduled 
discharge.  The subjects will have Safety Follow-up phone calls.  If deemed necessary by the 
Principal Investigator, the subject will be asked to return for a Follow-up visit. 
7.4. 
End-of-Study 
End-of-study is defined as completion of the final Follow-up phone call.  For those subjects that 
withdraw prematurely, EoS is defined as the time of the subject’s last data collection. 
7.5. 
Restrictions 
7.5.1. 
Dietary and Fluid Restrictions 
Caffeine: 
Xanthine containing products (coffee, tea, chocolate, cola, energy drinks) are 
prohibited from 48 hours before each admission until discharges from the clinical 
unit. 
Alcohol: 
Alcohol use is prohibited 48 hours prior to the Screening Visit.  Alcohol use is 
prohibited from 48 hours prior to first admission until discharge. 
 
Subjects may not drink > 168 g (males) and > 84 g (females) pure alcohol per 
week (10 g pure alcohol = 259 mL of beer [5%] or 35 mL of spirits [35%] or 100 
mL of wine [12%] within 3 months prior to first admission. 
Meals: 
No outside food or drink is permitted at the clinical unit.  All meals and snacks 
will be provided.  Subjects will receive standard meals and snacks at regimented 
times on PK and PD days. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 82 of 97 
14 June 2018 
 
7.5.2. 
Contraception Requirements 
Subjects should be informed of the potential risks associated with becoming pregnant or 
fathering a child while enrolled in the trial.  
Female subjects  
Women of childbearing potential must be using highly effective methods of birth control† 
(failure rate < 1% per year when used consistently and correctly) starting at least 4 weeks prior to 
Screening and continued until at least 8 weeks after the last administration of IMP.  The subjects 
should be using the same method for 3 months prior to the first dose of tesofensine.  In addition, 
a barrier method‡ must always be used concomitantly to the highly effective method. Double-
barrier is not considered a highly effective method.  
Abstinence is acceptable, if it is the subject’s usual lifestyle. Periodic abstinence (eg, calendar, 
ovulation, symptothermal, post-ovulation methods) is not an acceptable means of contraception.  
Female subjects are considered to be of non-childbearing potential, when they are either  
• surgically sterile (hysterectomy and/or bilateral oophorectomy and/or bilateral salpingectomy 
and/or bilateral tubal ligation), or  
• post-menopausal, i.e., 12 months of amenorrhoea with an appropriate clinical profile (e.g., 
age appropriate, history of vasomotor symptoms) or for women < 60 years the 
follicle-stimulating hormone (FSH) level is > 40 mIU/mL.  
†Highly effective methods of birth control are implants, injectables, combined oral 
contraceptives, and some intrauterine devices (Note: The intrauterine device (IUD) must have a 
failure rate < 1%).  
‡ Barrier methods of contraception include:  
− Condom (without spermicidal foam/gel/film/cream/suppository or fat- or oil-
containing lubricants)  
− Occlusive 
cap 
(diaphragm 
or 
cervical/vault 
caps) 
with 
spermicidal 
gel/film/cream/suppository 
Please note: The combination of a condom together with diaphragm/cervical cap with 
spermicidal foam/gel/film/cream/suppository is not considered as highly effective contraceptive 
method.  


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 83 of 97 
14 June 2018 
 
Male subjects  
Male subjects must use a condom without spermicide or oil-containing products (e.g., lubricants) 
during sexual activity with female partners of childbearing potential throughout the trial until at 
least 8 weeks after the last administration of IMP.  Female sexual partners of male subjects 
should be willing to avoid pregnancy according to the above described methods. 
7.5.3. 
Other Restrictions 
Nicotine: 
Smoking and other nicotine containing products are prohibited.  The study must 
enroll nonsmoking subjects. 
Activity: 
Strenuous physical activity is prohibited from 48 hours prior to first admission 
until Day 24.  After discharge, mild physical activity can be resumed.  Subjects 
will be required to rest at the times specified in Table 5 and Table 6. 
Medications: Use of prescription, herbal, OTC medication(s) or dietary supplements is 
prohibited within the 2 weeks prior to study Day -2 until the Safety Follow-up 
phone call.  Concomitant medication use is permitted if indicated by the 
Investigator for treatment of an AE.  Occasional use of paracetamol (up to 
2 g/day) or other NSAIDs and the use of hormonal contraceptives are permitted.  
A list of prohibited medication is provided in Appendix 11.1. 
Blood donation: Donation of one unit (450 mL) of blood or more is prohibited during the study 
and until 3 months after discharge. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 84 of 97 
14 June 2018 
 
8. 
STATISTICAL METHODS 
Before database lock, a statistical analysis plan (SAP) will be issued as a separate document, 
providing detailed methods for the analyses outlined below.  Any deviations from the planned 
analyses will be described in an SAP addendum and described and justified in the CSR. 
8.1. 
Study Population 
8.1.1. 
Analysis Populations 
Safety population: All subjects who received at least one dose of IMP.  Subjects will be included 
in the analysis according to the dose and IMP received.  The safety population will be used for 
all safety analysis and to list PK concentrations. 
PK population: All randomized subjects with at least one quantifiable tesofensine or metoprolol 
concentration and without major protocol deviations which could influence the PK.  Subjects 
will be included in the analysis according to the dose and IMP received.  The PK population will 
be used for all PK analysis. 
PD population: All randomized subjects with at least HR assessments on at least 2 days out of 
Baseline (Day -2 to -1), Day 15, Day 18 and Day 21 without any major protocol deviations 
which could influence the PD parameters.  Subjects will be included in the analysis according to 
the dose and IMP received.  The PD population will be used for all PD analysis. 
8.2. 
General Considerations 
Continuous data will be summarized by treatment group using descriptive statistics (number, 
mean, standard deviation [SD], minimum, median and maximum).  Categorical data will be 
summarized by treatment group using frequency tables (number and percentage). 
The individual subject concentration-time data will be listed and displayed graphically on the 
linear and log scales by analyte, treatment and overall, as applicable.  The concentration-time 
data will be summarized descriptively by analyte, treatment and overall in tabular and graphical 
formats (linear and log scales).  The non-compartmental PK parameters named in Section 3.2.2 
will be listed and summarized descriptively by analyte and treatment in tabular format.  
Summary statistics of the PK parameters will be presented by treatment and dose-normalized 
when relevant.   
If needed, selected individual vital signs and ECG parameters may be plotted against 
concentration data of tesofensine and/or metoprolol. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 85 of 97 
14 June 2018 
 
An SAP will be issued as a separate document, providing detailed methods for the analyses. 
8.3. 
Protocol Deviations 
Important protocol deviations will be listed by subject. 
Protocol deviations will be handled in accordance with PAREXEL standard operating 
procedures (SOPs). 
8.4. 
Subject Disposition 
The number and percentage of subjects entering and completing the clinical study will be 
presented by treatment. 
Subjects excluded from the safety, PK and PD analysis sets and data excluded from the PK and 
PD analysis sets will be listed including the reason for exclusion.  Subject disposition will be 
summarized and will include the following information: number of subjects randomized and 
dosed, number and percentage of subjects completing the study and the number and percentage 
of subjects who were withdrawn (including reasons for withdrawal).  Disposition data will be 
presented based on all subjects randomized. 
Subject discontinuations will be listed including the date of study exit, duration of treatment and 
reason for discontinuation.  A listing of informed consent response will also be presented. 
A randomization listing will be presented and include the following: each subject’s 
randomization number and the treatment to which the subject has been randomized. 
8.5. 
Demographic and Anthropometric Information and Baseline Characteristics 
Demographic and anthropometric variables (age, gender, ethnicity, race, height, weight and 
BMI) will be listed by subject.  Demographic characteristics (age, gender, ethnicity and race) and 
anthropometric characteristics (height, weight and BMI) will be summarized by treatment and 
for all subjects in the safety analysis set.  The denominator for percentages will be the number of 
subjects in the safety analysis set for each treatment or for all subjects as applicable. 
Medical history data will be listed by subject including visit, description of the 
disease/procedure, MedDRA system organ class (SOC), MedDRA preferred term (PT), start 
date, and stop date (or ongoing, if applicable). 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 86 of 97 
14 June 2018 
 
8.6. 
Prior and Concomitant Medication and Drug Administration 
Prior medications are those that started and stopped prior to the first dose of IMP.  Concomitant 
medications are those taken after first dosing (including medications that started prior to dosing 
and continued after). 
Prior and concomitant medication will be listed by subject and will include the following 
information: reported name, PT, the route of administration, dose, frequency, start date/time, 
duration and indication. 
Prior and concomitant medication will be coded according to the World Health Organization 
Drug Dictionary (WHO-DD) latest version. 
Drug administration dates and times will be listed for each subject. 
8.7. 
Exposure 
A listing of drug administration will be created and will include the date and time of 
administration. 
8.8. 
Safety Analyses 
8.8.1. 
Adverse Events 
All AEs will be listed.  The number and percent of subjects experiencing a treatment emergent 
AE (TEAE) will be tabulated by treatment for each SOC and PT.  The TEAEs will also be 
tabulated according to intensity and causality. 
Serious AEs will be listed separately. 
8.8.2. 
Clinical Laboratory Tests 
Individual data listings of laboratory results will be presented for each subject.  Flags will be 
attached to values outside of the laboratory’s reference limits along with the Investigator’s 
assessment.  Clinically significant laboratory test abnormalities that were considered AEs by the 
Investigator will be presented in the AE listings. 
Clinical laboratory tests (observed values) will be summarized descriptively in tabular format.  
Shift tables will be presented for select laboratory parameters. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 87 of 97 
14 June 2018 
 
8.8.3. 
Vital Signs 
Individual data listings of vital signs (observed and change from baseline) will be presented for 
each subject.  Individual clinically significant vital signs findings that were considered AEs by 
the Principal Investigator will be presented in the AE listings. 
Observed values as well as change from baseline data will be summarized descriptively in 
tabular format.  Graphical displays over time may be presented for individual and summarized 
data. 
8.8.4. 
Standard 12-lead Electrocardiogram 
Standard 12-lead ECG data (observed and change from baseline) will be listed for each subject 
and time point.  Observed values will be summarized descriptively in tabular format.  Change 
from baseline will be summarized descriptively for QTc data.  A categorical QTc analysis will 
also be performed.  Graphical displays over time may be presented for individual and 
summarized data. 
8.8.5. 
Physical Examination 
Abnormal physical examination findings will be listed. 
8.9. 
Pharmacokinetic Analyses 
PK parameters of metoprolol and tesofensine will be computed using standard 
non-compartmental methods using Phoenix®WinNonlin®6.3 (or higher) (Certara, L.P., 1699 
South Hanley Road, St Louis, Missouri 63144, United States of America). 
The PK parameters will be calculated using the actual sampling time relative to corresponding 
IMP administration for tesofensine and metoprolol. 
PK parameters computed for metoprolol will be: 
• Maximum observed plasma concentration (Cmax); 
• Observed time at Cmax (Tmax); 
• Area under the plasma concentration-time curve from time zero to 24-hour post-
administration of metoprolol (AUC0-24). 
PK parameters computed for tesofensine will be: 
• Trough concentration in a dosing period (Ctrough) 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 88 of 97 
14 June 2018 
 
Additional PK parameters may be calculated for exploratory purposes. 
PK data will be listed and summarized in tabular format by descriptive statistics as appropriate.  
Descriptive statistics will be applied and presented by treatment group.  No imputation of 
missing data will be performed.  Summary statistics of the PK parameters will be presented by 
treatment and dose-normalized when relevant.  PK data may also be displayed graphically as 
appropriate.  An SAP will be written as a separate document, providing detailed methods for the 
analyses. 
8.10. Pharmacodynamic Analyses 
• The mean and absolute change in M24HR after tesofensine alone will be calculated as the 
difference between the mean of the 3 pre-administration measurements on Day 14, Day 17 
and Day 20 and the post-administration measurement on Day 23 and pre-tesofensine baseline 
(Day -1) and summarized descriptively by treatment. 
• The mean and absolute change in M24HR after tesofensine co-administered with 3 different 
doses of metoprolol will be calculated as the difference between each mean of the 
3 metoprolol doses on Days 15, 18 and 21, and pre-tesofensine baseline (Day -1) and 
summarized descriptively by treatment. 
• The mean and absolute change in M24HR after tesofensine co-administered with 3 different 
doses of metoprolol relative to tesofensine alone will be calculated as the difference between 
each mean of the 3 metoprolol doses on Days 15, 18 and 21 and the mean of the 3 pre-
administration measurements on Day 14, Day 17 and Day 20 and the post-administration 
measurement on Day 23, and summarized descriptively by treatment. 
• The mean maximum and minimum HR24 values after tesofensine alone and when co-
administered with 3 different doses of metoprolol will be summarized descriptively by 
treatment. 
• The time of minimum heart rate (HRmin) and maximum heart rate (HRmax) after 
tesofensine alone and when co-administered with 3 different doses of metoprolol will be 
summarized descriptively by treatment. 
• Mean SBP and DBP values after tesofensine alone and when co-administered with 3 
different doses of metoprolol will be summarized descriptively by treatment.  
• Mean HR during a designated quite hour and a designated period will be summarized 
descriptively by treatment.  


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 89 of 97 
14 June 2018 
 
• M24HR on Days 14, 17, 20 and 23 will be compared by means of analysis of variance 
(ANOVA) with random subjects nested under sequence.  In this analysis there will be no 
period effect and treatment effect (such as metoprolol dose) other than the fixed days. 
• Change from pre-tesofensine baseline (Day -1) of M24HR on Days 15, 18 and 21 will be 
compared by means of ANOVA with random subjects nested under sequence and fixed Day 
(Day 15, 18 and 21 will play the role of period in a conventional cross-over) and treatments. 
In this analysis the metoprolol dose will be distinguishing between treatments.  
• Boxplots will be made on M24HR for Days -1, 14, 15, 17, 18, 20, 21 and 23 and will be 
displayed using treatment and treatment plus visit (for tesofensine days). 
8.10.1. 
Regression Analysis 
A cross-over ANOVA model will be used to reduce change from baseline M24HR data to mean 
levels for each dose (adjusting for subject, day and treatment effects).  A straight line linear 
regression will be used to fit the means to log dose.  Based on the regression equation a dose for 
no effect will be estimated.  Confidence intervals will be determined using a bootstrap method. 
Details of the modelling will be provided in the SAP. 
In case the linear model linking Mean M24HR to log dose is clearly not satisfactory, an 
alternative strategy may be employed, for instance, by interpolation between 2 adjacent doses. 
The need and approaches for such analysis will be discussed after the initial analysis is finished. 
8.10.2. 
Pharmacokinetic-Pharmacodynamic Analysis 
The relation between metoprolol concentration and HR will be explored using plots of HR or 
time-matched change from baseline HR against concentration by tesofensine dose.  The plots 
will possibly be augmented with local regression lines and confidence intervals. 
A straight line regression will be used to fit change from baseline M24HR against PK parameters 
(AUC0-24 and Cmax) of metoprolol for each tesofensine dose.  Based on the regression equation a 
parameter value for no effect will be estimated.  Confidence intervals will be determined using a 
bootstrap method. 
Details of the analysis and/or additional approaches will be provided in the SAP. 
8.10.3. 
Pharmacokinetic-Pharmacodynamic Modelling 
A population PK-PD model may be developed if deemed appropriate on the data from this study 
with the final objective of describing relative contribution to the final effect of plasma exposure 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 90 of 97 
14 June 2018 
 
to tesofensine and metoprolol, simulating optimal dose regimen for multiple administration and 
evaluate effect of covariates (e.g., polymorphism of PK, body weight, gender) on the overall 
effect. 
Details of the analysis will be in case included in a separate Data Analysis plan and outcome of 
the modelling will be reported separately. 
8.11. Interim Analyses 
No formal interim analysis will be performed.  
However, after completion of approximately 20 evaluable subjects, M24HR obtained on 
Days 14, 17, 20, and 23 will be reviewed to confirm that the M24HR returned to steady state 
tesofensine conditions prior to each metoprolol dosing.  Appropriate statistical methods such as 
regression analysis and/or ANOVA may be applied to compare HR24 values across study Days 
14, 17, 20, 23.  If similar pre-metoprolol dosing conditions cannot be confirmed the study may 
be stopped for ethical and futility reasons, or amended appropriately, e.g. by adjusting the 
metoprolol wash-out period.  No other data will be evaluated during this interim look. 
8.12. Determination of Sample Size 
No formal sample size calculation has been performed.   
With a sample size of N=20 with 80% power assuming the same within-subject variability in HR 
as observed in the study TM001 (within-subject variability = 5%) a mean difference of 3.3 beats 
per minute can be detected within a tesofensine cohort.  This detectable difference is smaller than 
the increase in HR induced by all 3 studied doses of tesofensine in the study TIPO-1; thus, 
20 subjects per cohort should provide adequate sample size for the purpose of this Phase 1 study. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 91 of 97 
14 June 2018 
 
9. 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS 
9.1. 
Data Quality Assurance 
The Sponsor will supervise a study initiation visit to verify the qualifications of the Principal 
Investigator, inspect the facilities and inform the Principal Investigator of responsibilities and 
procedures for ensuring adequate and correct documentation. 
The Principal Investigator must prepare and maintain adequate and accurate records of all 
observations and other data pertinent to the clinical study for each study participant.  Frequent 
communication between the clinical unit and the Sponsor is essential to ensure that the safety of 
the study is monitored adequately.  The Principal Investigator will make all appropriate safety 
assessments on an ongoing basis.   
All aspects of the study will be carefully monitored with respect to Good Clinical Practice (GCP) 
and SOPs for compliance with applicable government regulations.  The Study Monitor will be an 
authorized individual designated by the Sponsor.  The Study Monitor will have access to all 
records necessary to ensure integrity of the data and will periodically review the progress of the 
study with the Principal Investigator. 
9.1.1. 
Data Collection 
PAREXEL’s ClinBase™ system (a Clinical Study Management System for source data capture 
and process control) will be utilized in this study.  Data from ClinBase™ can be exported 
to/prepared as an eSDR in PDF format.  The eSDR will follow the same design as the empty 
eSDR that is used for the database setup approval. 
PAREXEL ClinBase™ designer will design ClinBase™ to be completed for each subject who 
enters the study.  The entries will be checked by trained personnel.  Errors or inconsistencies will 
be corrected.  Any changes or corrections to ClinBase™ will be dated, initialed and explained (if 
necessary).  An explanation for the omission of any required data will appear on the appropriate 
page.  The Investigator will sign the completed ClinBase™, thereby taking responsibility for the 
accuracy of the data in the entire ClinBase™.  The Investigator will retain records of the changes 
and corrections.  
Source data will be defined as such in the Source Document Agreement.  The clinical unit’s 
ClinBase™ system will be used to capture certain safety data - this will be indicated on the 
Source Document Agreement. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 92 of 97 
14 June 2018 
 
Paper-based data will be subject to data entry in ClinBase™.  For electronic source data, no data 
entry will be performed. 
The responsible Study Monitor will check data at the monitoring visits to the clinical unit.  The 
Investigator will ensure that the data collected are accurate, complete and legible. 
All clinical work conducted under this clinical study protocol is subjected to GCP regulations. 
This includes an inspection by the Sponsor and Competent Authority representatives at any time.  
The Investigator will agree to the inspection of study-related records by Competent Authority 
representatives and the audits of the Sponsor or third parties named by the Sponsor. 
9.1.2. 
Data Management 
Data management of all data documented will be performed under the responsibility of the Head 
of the Department of Data Management, PAREXEL Early Phase and in accordance with the 
SOPs for data management. 
The Data management plan (DMP) will be provided to the Sponsor describing the work and data 
flow within this clinical study. Versions for the computer systems, coding and reconciliation of 
data will be defined in the DMP.  The DMP will be sent to the Sponsor for review and approval. 
The DMP must be finalized in accordance with PAREXEL SOP. 
9.2. 
Access to Source Data/Documents 
PAREXEL will use an electronic data capture system to manage data collection during this 
study.  The electronic data capture system (ClinBaseTM) is a software tool designed to ensure 
quality assurance and facilitate data capture during clinical studies.  Through a system regulated 
workflow that includes barcode scanning and interfaces to medical equipment to avoid manual 
data entry, study operations performance is controlled and captured in real time.  The system is 
fully Code of Federal Regulations (CFR) 21 part 11 compliant. 
The Principal Investigator will ensure the accuracy, completeness and timeliness of the data 
reported to the Sponsor.  Data collection processes and procedures will be reviewed and 
validated to ensure completeness, accuracy, reliability and consistency.  A complete audit trail 
will be maintained of all data changes.  The Principal Investigator or designee will cooperate 
with the Sponsor’s representative(s) for the periodic review of study documents to ensure the 
accuracy and completeness of the data capture system at each scheduled monitoring visit. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 93 of 97 
14 June 2018 
 
Electronic consistency checks and manual review will be used to identify any errors or 
inconsistencies in the data.  This information will be provided to the respective study sites by 
means of electronic or manual queries. 
The Principal Investigator or designee will prepare and maintain adequate and accurate study 
documents (e.g., medical records, ECGs, AE and concomitant medication reporting, raw data 
collection forms, etc.) designed to record all observations and other pertinent data for each 
subject receiving IMP. 
The Principal Investigator will allow Sponsor representatives, contract designees, authorized 
regulatory authority inspectors and the IEC to have direct access to all documents pertaining to 
the study. 
9.3. 
Archiving Study Documents 
According to International Council for Harmonisation (ICH) guidelines, essential documents 
should be retained for a minimum of 2 years after the last approval of a marketing application in 
an ICH region and until there are no pending or contemplated marketing applications in an ICH 
region or at least 2 years have elapsed since the formal discontinuation of clinical development 
of the IMP.  However, these documents should be retained for a longer period if required by the 
applicable legal requirements. 
9.4. 
Good Clinical Practice 
The procedures set out in this clinical study protocol are designed to ensure that the Sponsor and 
the Principal Investigator abide by the principles of the ICH guidelines on GCP.  The clinical 
study also will be carried out in keeping with national and local legal requirements and with 
ethical principles that have their origins in the Declaration of Helsinki (Version 1996). 
9.5. 
Informed Consent 
Before each subject is enrolled in the clinical study, written informed consent will be obtained 
from the subject according to the regulatory and legal requirements of the participating country.  
As part of this procedure, the Principal Investigator must explain orally and in writing the nature, 
duration and purpose of the study and the action of the drug in such a manner that the subject is 
aware of the potential risks, inconveniences or AEs that may occur.  The subject should be 
informed that he is free to withdraw from the study at any time.  He will receive all information 
that is required by federal regulations and ICH guidelines.  The Principal Investigator or 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 94 of 97 
14 June 2018 
 
designee will provide the Sponsor with a copy of the IEC-approved ICD prior to the start of the 
study. 
The ICD must be signed and dated; one copy will be handed to the subject, and the Principal 
Investigator will retain a copy as part of the clinical study records.  The Principal Investigator 
will not undertake any investigation specifically required for the clinical study until written 
consent has been obtained.  The terms of the consent and when it was obtained must also be 
documented. 
If a protocol amendment is required, then the ICD may need to be revised to reflect the changes 
to the protocol.  If the ICD is revised, it must be reviewed and approved by the responsible IEC, 
and signed by all subjects subsequently enrolled in the clinical study as well as those currently 
enrolled in the clinical study. 
9.6. 
Protocol Approval and Amendment(s) 
Before the start of the clinical study, the clinical study protocol and other relevant documents 
will be approved by the RA (regulatory authority) and IEC, in accordance with local legal 
requirements.  The Sponsor must ensure that all ethical and legal requirements have been met 
before the first subject is enrolled in the clinical study. 
This protocol is to be followed exactly.  To alter the protocol, amendments must be written, 
which must be released by the responsible staff and receive RA and IEC approval prior to 
implementation (as appropriate).  
Administrative changes may be made without the need for a formal amendment, but will also be 
mentioned in the integrated CSR.  All amendments will be distributed to all study protocol 
recipients, with appropriate instructions. 
9.7. 
Insurance and Indemnity 
Every subject participating in the study is insured in accordance with local law against injuries to 
health, which may occur during the clinical study.  Any injury to health, which might have 
occurred as a result of participating in the study, must be reported by the subject to the 
Investigator without delay.  In all cases the Investigator is obliged to make a report to the 
Sponsor and the insurer.  The Investigator is responsible for dispensing the study medication 
according to this protocol, and for its secure storage and safe handling throughout the study.  
Additional insurance details will be provided in the Insurance Policy.  The subject insurance will 
be arranged by Saniona. 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 95 of 97 
14 June 2018 
 
9.8. 
Confidentiality Data Protection 
All clinical study findings and documents will be regarded as confidential.  Study documents 
(protocols, IBs and other material) will be stored appropriately to ensure their confidentiality.  
The Principal Investigator and members of his/her research team (including the IEC) must not 
disclose such information without prior written approval from the Sponsor, except to the extent 
necessary to obtain informed consent from subjects who wish to participate in the study or to 
comply with regulatory requirements. 
The anonymity of participating subjects must be maintained.  Subjects will be specified on study 
documents by their randomization number, year of birth, not by name.  Documents that identify 
the subject (e.g., the signed ICD) must be maintained in confidence by the Principal Investigator. 
9.9. 
Publication Policy 
By signing the clinical study protocol, the Principal Investigator agrees with the use of results of 
the clinical study for the purposes of national and international registration, publication and 
information for medical and pharmaceutical professionals.  If necessary, the regulatory 
authorities will be notified of the Principal Investigator’s name, address, qualifications and extent 
of involvement. 
A Principal Investigator shall not publish any data (poster, abstract, paper, etc.) without 
obtaining prior written permission from the Sponsor. 
PAREXEL will prepare a CSR after the completion of the study. The Sponsor representative will 
sign the final study report intended to be submitted to regulatory authorities. 
The results of this study may be published or presented at scientific meetings.  The Sponsor will 
be responsible for publication of all the data generated in this study.   


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 96 of 97 
14 June 2018 
 
10. 
REFERENCE LIST 
1. Colman E. Food and Drug Administration’s Obesity Drug Guidance Document: A Short 
History. Circulation 2012;125(17):2156-2164 
2. Investigator's Brochure of Tesomet. Version 1.0, Final, 11 September 2017 
3. Investigator's Brochure of tesofensine. Version 14.0, Final, 02 June 2018 
4. SPC of metoprolol ER tablets.  Metoprololsuccinat ”Orion”, depottabletter, Orion 
Corporation (Finland), SPC dated 16. November 2015 
5. Spitzer RL, Kroenke K, Williams JB (1999). Validation and utility of a self-report version of 
PRIME-MD: the PHQ primary care study. JAMA. Nov 10; 282(18): 1737–44 
6. INSTRUCTION MANUAL Instructions for Patient Health Questionnaire (PHQ) and GAD-7 
Measures. 
https://phqscreeners.pfizer.edrupalgardens.com/sites/g/files/g10016261/f/201412/instructions
.pdf 
7. Patient Health Questionnaire (PHQ) Screeners: http://www.phqscreeners.com/select-
screener/ [on-line; accessed 11 JUN 2018] 
 
 


Saniona A/S 
Clinical Study Protocol 
TM004 
CONFIDENTIAL 
 
Final 2.0 
Page 97 of 97 
14 June 2018 
 
11. 
APPENDICES 
11.1. Appendix 1 - List of Prohibited Medication 
Drug Class 
Episodic 
Use 
Chronic 
Use 
Comment 
Antiarrhythmic (Amiodarone, quinidine) 
N 
N 
Strong inhibitor of CYP2D6 
Antiretroviral (Ritonavir) 
N 
N 
Strong inhibitor of CYP2D6 
Anorectic agents 
N 
N 
Antiandrogens (abiraterone, cyproterone acetate, 
finasteride) 
N 
N 
Antihistamines 
Y 
N 
Topical antihistamines – always approved 
Antiepileptic drugs 
N 
N 
Antidepressant drugs 
N 
N 
Anti-anxiety drugs 
N 
N 
Anti-Parkinsonian drugs  
N 
N 
Anti-Dementia drugs donepezil and galantamin 
N 
N 
Antifungal (terbinafine) 
N 
N 
Moderate inhibitor of  CYP2D6 
Muscarinreceptor blocker darifenacin 
N 
N 
Moderate inhibitor of  CYP2D6 
Barbiturates 
N 
N 
Benzodiazepines 
N 
N 
Beta- blockers 
N 
N 
Per protocol 
Buproprion (non-SSRI antidepressant) 
N 
N 
Strong inhibitor of  CYP2D6 
Calcium channel blockers 
N 
N 
Per protocol 
Carbonic anhydrase inhibitors (e.g., 
acetazolamide, dichlorphenamide, dorzolamide, 
methazolamide) 
N 
N 
Cinacalcet (calcimimetic) 
N 
N 
Strong inhibitor of  CYP2D6 
Dopamine reuptake inhibitors (e.g., bupropion) 
N 
N 
Glucocorticoids 
Y 
N 
Hypnotic sedative (glutethimide) 
N 
N 
Strong inducer of  CYP2D6 
H2-receptor antagonist (cimetidine) 
N 
N 
Weak inhibitor of  CYP2D6 
Immunosuppressives 
N 
N 
Insulin and/or other injectable anti-diabetic 
medications, or thiazolidinediones (TZDs) 
N 
N 
Per protocol 
Lithium 
N 
N 
Monoamine oxidase (MAO) inhibitors 
N 
N 
Opioids, cannabinidiols 
N 
N 
Oral hypoglycemic 
- 
- 
Per protocol 
Orlistat 
N 
N 
Phenothiazines 
N 
N 
Selective serotonin reuptake inhibitors (SSRIs) 
N 
N 
Serotonin and norepinephrine reuptake inhibitors 
(SNRIs) 
N 
N 
 

SAP_001.pdf: 
PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 1 of 54 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
TM004 
 
A Phase 1 Study to Examine Pharmacodynamic Interaction Between Tesofensine and Metoprolol on 
24-hours Mean Heart Rate 
 
 
 
 
 
Version:  Final 1.0 
Date: 05/Jul/2019 
REVISION HISTORY 
Version 
Version Date 
Author 
Summary of Changes Made 
Draft 1.0 
19/Sep/2018 
Kees Duineveld 
New Document 
Draft 2.0 
19/Nov/2018 
Kees Duineveld 
Comments by sponsor 
Draft 3.0 
26/Apr/2019 
Kees Duineveld 
Comments by sponsor corrected. 
Added analysis for specialist assessment. 
Draft 4.0 
07/Jun/2019 
Kees Duineveld 
Updates after sponsor review 
Final 1.0 
08/Jul/2019 
Kees Duineveld 
finalized 
 
 






PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 4 of 54 
TABLE OF CONTENTS 
REVISION HISTORY .................................................................................................................... 1 
SIGNATURE PAGE – SANIONA A/S ......................................................................................... 2 
SIGNATURE PAGE - PAREXEL ................................................................................................. 3 
TABLE OF CONTENTS ................................................................................................................ 4 
LIST OF TABLES .......................................................................................................................... 7 
ABBREVIATION AND ACRONYM LIST .................................................................................. 8 
STATISTICAL ANALYSIS PLAN ............................................................................................. 10 
1. 
STUDY OBJECTIVES.................................................................................................... 10 
1.1 
Primary Objective ............................................................................................... 10 
1.2 
Secondary Objectives ......................................................................................... 10 
2. 
STUDY DESIGN ............................................................................................................ 10 
3. 
ENDPOINTS ................................................................................................................... 12 
3.1 
Primary Endpoint ................................................................................................ 12 
3.2 
Secondary Endpoints .......................................................................................... 12 
3.3 
Safety Endpoints ................................................................................................. 13 
4. 
STUDY POPULATION .................................................................................................. 14 
5. 
STATISTICAL BASIS FOR SAMPLE SIZE ................................................................. 14 
6. 
RANDOMIZATION ....................................................................................................... 14 
7. 
STATISTICAL ANALYSIS CONVENTIONS .............................................................. 14 
7.1 
Analysis Variables .............................................................................................. 14 
7.1.1 
Demographic and Background Variables ........................................................14 
7.1.2 
Safety Variables ..............................................................................................15 
7.1.2.1 
Adverse Events ................................................................................15 
7.1.2.2 
Clinical Laboratory Tests .................................................................16 
7.1.2.3 
Vital Signs ........................................................................................18 
7.1.2.4 
Safety Electrocardiograms (ECG) ...................................................18 
7.1.2.5 
Physical Examination .......................................................................18 
7.1.2.6 
Concomitant Medication ..................................................................19 
7.1.2.7 
Patient Health Questionnaire-9 and (PHQ-9) and Generalized Anxiety 
Disorder Assessment (GAD-7) ........................................................19 
7.1.2.8 
Additional assessments based on BfArM’s request .........................19 
7.1.3 
Pharmacokinetic Variables ..............................................................................19 
7.1.3.1 
Pharmacokinetic Parameter Calculation Methods ...........................20 
7.1.4 
Pharmacodynamic Variables ...........................................................................21 
7.2 
Analysis Populations .......................................................................................... 21 
7.2.1 
Safety Population ............................................................................................21 
7.2.2 
Pharmacokinetic Population ............................................................................21 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 5 of 54 
7.2.3 
Pharmacodynamic Population .........................................................................22 
7.3 
Statistical Analysis Methods .............................................................................. 22 
7.3.1 
Listings and Descriptive Statistics ..................................................................22 
7.3.1.1 
Treatments in outputs .......................................................................23 
7.3.1.2 
Analysis periods ...............................................................................24 
7.3.2 
Baseline ...........................................................................................................24 
7.3.3 
Statistical Significance Level ..........................................................................25 
7.3.4 
Software ..........................................................................................................25 
7.3.5 
Missing Data ...................................................................................................25 
7.3.6 
Interim Analysis ..............................................................................................25 
7.3.7 
Protocol Deviations .........................................................................................25 
7.3.8 
Demographic Data ...........................................................................................26 
7.3.9 
Concomitant Medication .................................................................................26 
7.3.10 
Exposure to the Investigational Medicinal Product .........................................26 
7.3.11 
Pharmacokinetic Concentrations and Variables ..............................................26 
7.3.11.1 Handling of Values Below the Limit of Quantification (BLQ) in 
Concentration Summaries and Listings ...........................................27 
7.3.12 
Pharmacodynamic Variables ...........................................................................27 
7.3.12.1 Analysis to check M24HR assumptions on Tesofensine days .........29 
7.3.12.2 Statistical Analysis for mitigating dose ...........................................30 
7.3.12.3 Sensitivity Analysis .........................................................................32 
7.3.13 
Pharmacokinetic/Pharmacodynamic Analysis ................................................32 
7.3.13.1 Analysis of PD against metoprolol in plasma ..................................32 
7.3.13.2 Analysis of PD against metoprolol PK parameters ..........................33 
7.3.13.3 Population modelling .......................................................................34 
7.3.14 
Safety Analysis ................................................................................................34 
7.3.14.1 Adverse Events ................................................................................34 
7.3.14.2 Clinical Safety Laboratory Tests (hematology, clinical chemistry and 
urinalysis) .........................................................................................35 
7.3.14.3 Vital Signs ........................................................................................36 
7.3.14.4 Twelve-Lead Electrocardiogram ......................................................36 
7.3.14.5 Physical Examination .......................................................................36 
7.3.14.6 Patient Health Questionnaire-9 and (PHQ-9) and Generalized Anxiety 
Disorder Assessment (GAD-7) ........................................................36 
7.3.14.7 Additional assessments based on BfArM’s request .........................37 
8. 
REFERENCES ................................................................................................................ 38 
9. 
SCHEDULE OF ASSESSMENTS .................................................................................. 39 
9.1 
Schedule of Assessments for Cohort 1 and Cohort 2 ......................................... 39 
9.2 
Schedule of Assessments for Cohort 3 ............................................................... 43 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 6 of 54 
10. 
TABLES AND LISTINGS TO BE INCLUDED IN SECTION 14 OF THE CLINICAL 
STUDY REPORT ............................................................................................................ 46 
11. 
FIGURES ......................................................................................................................... 49 
12. 
LISTINGS TO BE INCLUDED IN SECTION 16 OF THE CLINICAL STUDY REPORT
 ......................................................................................................................................... 51 
13. 
DOCUMENTATION OF STATISTICAL METHODS.................................................. 54 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 7 of 54 
LIST OF TABLES 
Table 1 Clinical Laboratory Assessments ..................................................................................... 16 
 
 
 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 8 of 54 
ABBREVIATION AND ACRONYM LIST  
Abbreviation / Acronym 
Definition / Expansion 
AE 
Adverse event 
AN(C)OVA 
analysis of (co-)variance 
ATC 
Anatomical therapeutic chemical 
AUC 
Area under the concentration-time curve 
AUC0-24  
AUC from time zero to 24 hours 
BfArM 
Bundesinstitut für Arzneimittel und Medizinprodukte 
BLQ 
Below the lower limit of quantification 
BMI 
Body Mass Index 
BP 
Blood Pressure 
Bpm 
Beats per minute 
CI 
Confidence interval 
CSP 
Clinical Study Protocol 
Cmax 
Maximum observed concentration 
CS 
Clinically significant 
Ctrough 
Trough concentration in a dosing period 
CV% 
Coefficient of variation 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
EoS 
End-of-study 
GAD-7 
Generalized Anxiety Disorder Assessment 
gCV% 
Geometric CV% 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
HRmax 
Maximum HR over 24 hours 
HRmin 
Minimum HR over 24 hours 
HR24 
Heart rate over 24 hours 
IMP 
Investigational Medicinal Product 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 9 of 54 
Abbreviation / Acronym 
Definition / Expansion 
LLOQ 
Lower limit of quantification 
MAD 
Multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
M24HR 
Mean HR over 24 hours 
NCS 
Not clinically significant 
NK 
Not known 
PD 
Pharmacodynamic 
PHQ-9 
Patient Health Questionnaire-9 
PK 
Pharmacokinetic 
QCD 
Quantitative Clinical Development 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation  
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
TLFs 
Tables, Listings and Figures 
tmax 
Time corresponding to occurrence of Cmax 
WHO-DD 
World Health Organisation - Drug Dictionary 
WNL 
WinNonlin 
 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 10 of 54 
STATISTICAL ANALYSIS PLAN 
The Statistical Analysis Plan (SAP) details the statistical methodology to be used in analyzing study data 
and outlines the statistical programming specifications for the Tables, Listings and Figures (TLFs). It 
describes the variables and populations, anticipated data transformations and manipulations and other 
details of the analyses not provided in the Clinical Study Protocol (CSP). 
The analyses described are based on the final CSP, 2.0 that incorporates Amendment No. 1, 
dated,  14/Jun/2018.  
The SAP will be finalized prior to database lock and describes the statistical analysis as it is foreseen 
when the study is being planned. If circumstances should arise during the study rendering this analysis 
inappropriate, or if improved methods of analysis should arise, updates to the analyses may be made. 
Any deviations from the SAP after database lock, reasons for such deviations and all alternative or 
additional statistical analyses that may be performed, will be described in a SAP Addendum. 
1. 
STUDY OBJECTIVES 
1.1 
Primary Objective 
• To determine the optimal dose of metoprolol to mitigate the effect of tesofensine on Heart Rate 
(HR) 
1.2 
Secondary Objectives 
• To confirm that addition of metoprolol mitigates the effect of tesofensine on HR 
• To examine the concentration-response relationship between tesofensine and metoprolol on HR 
and blood pressure (BP) 
• Assess the time dependence of tesofensine effect on HR by comparing HR data under tesofensine 
alone 
• Safety and tolerability of tesofensine alone and co-administration of tesofensine and metoprolol 
2. 
STUDY DESIGN 
This is a randomized, open-label for tesofensine and single-blind for metoprolol, parallel-arm study in 
60 male and female subjects. 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 11 of 54 
Each subject will participate in a Screening Period (Day -28 to Day -3), a Baseline Period (Day -2 to Day 
-1) and a Treatment Period (Day 1 to Day 24) and will have 2 Follow-up phone calls (Day 30 and Day 
50). 
The Treatment Period will comprise: 
• An initial in-house stay consisting of loading dose of tesofensine followed by a home dosing-
period to Day 12 
o In Cohorts 1 and 2 the initial in-house stay is until the last loading dose of tesofensine has 
been administered on Day 3  
o In Cohort 3 the initial in-house stay until the third loading dose tesofensine has been 
administered on Day 3, followed by ambulatory visits on Days 4 and 5 with administration 
of the 4th and 5th loading dose with an ambulatory visit in the clinical unit on Day 7 
• A second in-house stay (Day 13 to Day 24). Safety evaluations will be performed on Day 30 and 
Day 50 (end-of-study [EoS]) after last dosing over the phone. 
A total of 60 subjects will be randomly assigned to one of the following treatment cohorts: 
• Cohort 1 (20 subjects): tesofensine 0.25 mg once daily for 23 days (loading dose of 1.0 mg for 
the first 3 days) 
• Cohort 2 (20 subjects): tesofensine 0.50 mg once daily for 23 days (loading dose of 2.0 mg for 
the first 3 days) 
• Cohort 3 (20 subjects): tesofensine 0.75 mg (0.25 mg + 0.50 mg) once daily for 23 days (loading 
dose of 2.0 mg [4 tablets of 0.50 mg] for the first 5 days) 
In addition, each subject will receive a single dose of 25 mg, 50 mg or 100 mg metoprolol ER in random 
order in the morning of Day 15, Day 18 and Day 21, respectively, within 30 minutes after start of a 
standard breakfast and together with the tesofensine dose, according to a Williams design. 
Additional details can be found the CSP. 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 12 of 54 
3. 
ENDPOINTS 
3.1 
Primary Endpoint 
The dose of metoprolol which will result in no change relative to baseline in Mean HR over 24 hours 
(M24HR) for each respective dose of tesofensine – this will be calculated from a dose response 
relationship with the log-dose of metoprolol as independent variable and change in M24HR induced by 
various doses of metoprolol given to patients on steady-state dose of tesofensine as the dependent 
variable. The dose for no change in M24HR derived from above calculation and the corresponding 95% 
Confidence Interval (CI) will be calculated for each dose of tesofensine. 
3.2 
Secondary Endpoints 
• The difference in increase in M24HR caused by tesofensine alone (calculated as the difference 
between the M24HR at pre-tesofensine baseline and the mean of M24HR on Days 14, 17, 20 and 
23) and the reduction in M24HR following each of the 3 metoprolol doses (change from baseline 
in M24HR on Day 15, 18 or 21). 
• Absolute values and Change in M24HR between pre-tesofensine baseline (Day -1) and after 
tesofensine alone (Day 14, Day 17, Day 20 and Day 23) 
• Absolute values and Change in M24HR after tesofensine co-administered with metoprolol (Day 
15, Day 18 and Day 21) 
• Maximum and minimum HR over 24 hours (HR24) (HRmax and HRmin) values after tesofensine 
alone (Day 14, Day 17, Day 20 and Day 23) 
• HRmax and HRmin values after tesofensine co-administered with metoprolol (Day 15, Day 18 
and Day 21) 
• Time of HRmin and HRmax after tesofensine alone (Day 14, Day 17, Day 20 and Day 23) 
• Time of HRmin and HRmax after tesofensine co-administered with metoprolol (Day 15, Day 18 
and Day 21) 
• Mean HR during a designated quiet hour and a designated period after tesofensine alone (Day 14, 
Day 17, Day 20 and Day 23) 
• Mean HR during a designated quiet hour and a designated period after tesofensine co-
administered with metoprolol (Day 15, Day 18 and Day 21) 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 13 of 54 
• HR after at least 10 minutes rest before each PK sampling time point or the corresponding time 
point (Day -1, Day 13 [pre-dose only], Day 14, Day 15, Day 17, Day 18, Day 20, Day 21 and 
Day 23) 
• Systolic blood pressure (SBP) and diastolic blood pressure (DBP) values after at least 10 minutes 
rest before each PK sampling time point or the corresponding time point (Day -1, Day 13 [pre-
dose only], Day 14, Day 15, Day 17, Day 18, Day 20, Day 21 and Day 23) 
• The following PK parameters will be determined: 
• Ctrough of tesofensine on Day 13, Day 14, Day 15, Day 18, Day 21 and Day 23 
• Cmax of metoprolol on Day 15, Day 18, and Day 21 
• Tmax of metoprolol on Day 15, Day 18, and Day 21 
• AUC0-24 of metoprolol on Day 15, Day 18, and Day 21 
• Relation between metoprolol concentration and HR will be explored by tesofensine dose 
• A linear PK-PD curve for each dose of tesofensine will be generated with log value of metoprolol 
PK parameters (AUC0-24 and Cmax) on the X-axis and change in M24HR on the Y-axis. The X-
axis intercept and the corresponding 95% CI will be calculated for each dose of tesofensine 
3.3 
Safety Endpoints 
The following safety variables will be recorded at specified time points during the study: 
• Vital signs (supine BP, pulse and body temperature) 
• Twelve-lead ECG: HR PR interval, QRS interval, RR interval, QT interval and QT interval 
corrected for HR (QTc) (Bazett’s correction [QTcB] and Fridericia’s correction [QTcF]) 
• Clinical laboratory tests (hematology, clinical chemistry and urinalysis) 
• Adverse event assessments 
• Concomitant medication assessments  
• Physical examinations 
Upon request of Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) additional assessments 
by cardiologist, neurologist and psychiatrist were added for safety following the early termination of the 
study. 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 14 of 54 
4. 
STUDY POPULATION 
The study population will consist of 60 adult subjects. 
Detailed lists of inclusion and exclusion criteria are shown in Sections 4.2 and 4.3 of the CSP. 
5. 
STATISTICAL BASIS FOR SAMPLE SIZE 
No formal sample size calculation has been performed. 
With a sample size of N=20 with 80% power assuming the same within-subject variability in HR as 
observed in the study TM001 (within-subject variability = 5%) a mean difference of 3.3 beats per minute 
can be detected within a tesofensine cohort. This detectable difference is smaller than the increase in HR 
induced by all 3 studied doses of tesofensine in the study TIPO-1; thus, 20 subjects per cohort should 
provide adequate sample size for the purpose of this Phase 1 study. 
6. 
RANDOMIZATION 
There will be 20 subjects in each of the 3 cohorts. Subjects will be randomly assigned to a cohort. Within 
each cohort the subjects will be randomized to different sequences of metoprolol doses. For 18 of the 
subjects within each cohort a 3 treatment Williams design will be used to determine the sequences (all 
six possible sequences needed). The final 2 subjects will be randomized according to parts of an extra 3 
treatment Latin Square. Each metoprolol sequence will have at least one subject of each gender. To obtain 
the required 8 subjects for each gender, an additional 2 sequences will randomly be assigned to 2 subjects 
from each gender. 
7. 
STATISTICAL ANALYSIS CONVENTIONS 
7.1 
Analysis Variables 
7.1.1 
Demographic and Background Variables 
The following demographic and anthropometric information will be recorded as given in Section 9: 
• Date of informed consent 
• Medical history (including previous and current medical conditions and medications) 
• Drug, alcohol and smoking history 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 15 of 54 
• Age as provided in the database. 
• Gender 
• Ethnic origin 
• Race 
• Height, without shoes (cm) 
• Body weight (kg) 
• Body mass index (BMI) calculated as [weight/height2] (kg/m2) 
• Waist Circumference 
• Special Diet (vegetarian) 
• History of blood or plasma donation 
All medical history will be coded using Version 20.1 of the Medical Dictionary for Regulatory Activities 
(MedDRA). 
7.1.2 
Safety Variables 
7.1.2.1 
Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
All AEs will be coded using Version 20.1 of the MedDRA. 
A treatment-emergent adverse event (TEAE) is defined as an AE that begins or that worsens in severity 
after at least one dose of the study drug has been administered. 
Any AEs with incomplete start and end dates/times will be treated as follows: 
• Adverse events with unknown start and/or end times (but where the date is known) will be 
imputed with a time of 00:00 h for the tabulations but will be shown as NK:NK in the listings 
(where NK = Not Known). 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 16 of 54 
• Adverse events with completely unknown start dates will be considered as treatment-emergent 
for the tabulations and will be shown as NK in the listings, unless it is clear from supporting 
information that the AE is not treatment-emergent. 
The following assignment to a specific treatment will be made: 
• An AE is assigned to the last treatment prior to the AE 
• In case of missing start dates or times and taking into account supporting information (such as 
end date times) then the following rules will apply.  
− If an AE can occur on either after tesofensine or tesofensine plus metoprolol, then it will be 
assigned to tesofensine plus metoprolol 
− if an AE can occur at two different doses of metoprolol then the lower dose will be chosen. 
(e.g. if an AE can be either attributed to Tesofensine + 25 mg Metoprolol or Tesofensine + 
100 mg Metoprolol, then Tesofensine + 25 mg Metoprolol will be chosen, [a day between 
those with just Tesofensine will not be used because of the previous rule]).  
7.1.2.2 
Clinical Laboratory Tests 
The safety laboratory parameters in Table 1 will be measured according to the schedules in Section 9: 
Table 1 Clinical Laboratory Assessments 
Hematology 
White blood cell (WBC) count 
Neutrophils (percentage and absolute count) 
Red blood cell (RBC) count 
Lymphocytes (percentage and absolute count)  
Hemoglobin (Hb) 
Monocytes (percentage and absolute count)  
Hematocrit (HCT) 
Eosinophils (percentage and absolute count)  
Mean corpuscular volume (MCV) 
Basophils (percentage and absolute count)  
Mean corpuscular hemoglobin (MCH) 
Platelet count 
Mean corpuscular hemoglobin concentration (MCHC) 
RBC distribution width  
 
HbA1c (at Screening only) 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 17 of 54 
Table 1 Clinical Laboratory Assessments 
Clinical Chemistry 
Alanine aminotransferase (ALT) 
Glucose 
Albumin 
Lactate dehydrogenase (LDH) 
Alkaline phosphatase (ALP) 
Phosphorus 
Aspartate aminotransferase (AST) 
Potassium 
Blood urea nitrogen (BUN) 
Sodium 
Calcium 
Total bilirubin 
Chloride 
Total protein 
Cholesterol 
Triglycerides 
Creatinine 
Thyroid-stimulating hormone (TSH) 
Creatine phosphokinase (CPK) 
Uric acid 
Gamma glutamyl transferase (GGT) 
Follicle-stimulating hormone (female subjects only, at 
Screening only) 
Urinalysis 
Bilirubin 
Blood 
Glucose 
pH and specific gravity 
Ketones 
Protein 
Leukocytes 
Urobilinogen 
Nitrite 
 
Upon a positive urine test from leucocytes, blood or protein, the Investigator may require further urine analysis, such 
as flow cytometry. Results of additional urine analyses will be included in the database. 
If the flow cytometry examination shows a different result than the urine stix, it will be checked by microscopy or full 
automated digital imaging, (e.g., leukocytes, erythrocytes, casts in urine will be analyzed). 
Viral Serology 
Hepatitis B core antibody (anti-HBc) 
Human immunodeficiency virus (HIV)  
(Types 1 and 2) antibodies 
Hepatitis B surface antigen (HBsAg) 
Hepatitis A virus antibodies (immunoglobulin M) 
Hepatitis C virus antibody (anti-HCV) 
Pregnancy Tests (in Female Subjects) 
β-human chorionic gonadotropin in serum (at Screening) 
β-human chorionic gonadotropin in urine (on each 
admission) 
Urine Drug Screening, Cotinine and Alcohol Test 
Amphetamines 
Cocaine 
Barbiturates 
Opiates 
Benzodiazepines 
Phencyclidine 
Cannabinoids 
Cotinine 
Alcohol 
Urinary creatinine (to exclude dilution effect) 
 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 18 of 54 
7.1.2.3 
Vital Signs 
The vital signs measurements will be obtained according to the schedules in Section 9. In case of triplicate 
measurements the original three measurements will be listed, while the mean will be listed and used for further 
analysis. The following measurements will be obtained. 
• 
Systolic blood pressure (SBP) [mmHg] 
• 
Diastolic blood pressure (DBP) [mmHg] 
• 
Pulse rate (bpm) 
• 
Body temperature (oral) [°C] 
• 
Interpretation 
7.1.2.4 
Safety Electrocardiograms (ECG) 
The standard safety 12-lead ECG parameters will be recorded according to the schedules in Section 9. In case 
of triplicate measurements the original three measurements will be listed, while the mean will be listed and used 
for further analysis. The following measurements will be obtained. 
• 
RR-interval (msec) 
• 
PR-interval (msec) 
• 
QRS-interval (msec) 
• 
QT-interval (msec) 
• 
QT-interval corrected using the Bazett correction formula (QTcB) (msec) 
• 
QT-interval corrected using the Fridericia correction formula (QTcF) (msec) 
• 
Heart rate (HR) (beats per minute [bpm]) 
The ECG will be evaluated by the Investigator as ‘Normal’, ‘Abnormal, Not Clinically Significant (NCS)’ or 
‘Abnormal, Clinically Significant (CS)’. 
7.1.2.5 
Physical Examination 
Physical Examination will be performed according to the schedules in Section 9. 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 19 of 54 
7.1.2.6 
Concomitant Medication 
Prior and concomitant medication will be coded using the World Health Organisation-Drug Dictionary 
(WHO-DD) (Version Sep 2017) and will be classified by Anatomical Therapeutic Chemical (ATC) 
categories. 
7.1.2.7 
Patient Health Questionnaire-9 and (PHQ-9) and Generalized Anxiety Disorder Assessment 
(GAD-7) 
The Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder Assessment (GAD-7) 
[Ref: Instruction Manual] will be performed according to the schedules in Section 9.  
PHQ-9 Depression Severity.  
This is calculated by assigning scores of 0, 1, 2, and 3, to the response categories of "not at all", "several 
days," "more than half the days", and "nearly every day", respectively. PHQ-9 total score for the 9 items 
ranges from 0 to 27. Scores of 5, 10, 15, and 20 represent cut points for mild, moderate, moderately 
severe and severe depression, respectively. Sensitivity to change has also been confirmed. 
GAD-7 Anxiety Severity.  
This is calculated by assigning scores of 0, 1, 2, and 3, to the response categories of "not at all", "several 
days", "more than half the days", and "nearly every day", respectively. GAD-7 total score for the 7 items 
ranges from 0 to 21. Scores of 5, 10, and 15 represent cut points for mild, moderate, and severe anxiety, 
respectively. 
7.1.2.8 
Additional assessments based on BfArM’s request 
Additional evaluations by cardiologist, neurologist and psychiatrist will be displayed for 
normal/abnormal result, including description of abnormality, clinical significance and further action. 
Associated AE and Concomitant medication will be added in the database. 
7.1.3 
Pharmacokinetic Variables 
Unless otherwise stated, derivation of tesofenesine and metoprolol PK parameters will be the 
responsibility of Early Phase, Quantitative Clinical Development (QCD), PAREXEL International.: 
At a minimum, following PK parameters will be computed for metoprolol on Day 15, 18 and 21. 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 20 of 54 
• Maximum observed plasma concentration (Cmax) 
• Observed time at Cmax (Tmax) 
• Area under the plasma concentration time curve (AUC) from time zero to 24-hour post-
administration of metoprolol (AUC0-24). 
PK parameters computed for tesofensine will be: 
• Trough concentration of the day. On days when 0 and 8 hour blood samples are drawn, the lower 
concentration will be considered the trough concentration, Ctrough, of the day. On days when only 
0 hour sample is drawn, that concentration will be considered Ctrough. 
7.1.3.1 
Pharmacokinetic Parameter Calculation Methods 
Metoprolol PK parameters will be calculated by non-compartmental analysis methods from the 
concentration-time data using Phoenix® WinNonlin (WNL) Professional (Version 6.3 or higher) or 
SAS (Version 9.3 or later) following these guidelines: 
• Actual sampling times relative to dosing rather than nominal times will be used in the calculation 
of all derived PK parameters. 
• There will be no imputation of missing data.  
• Any subjects with missing concentration data will be included in the PK analysis set provided 
that at least Cmax or AUC0-24 of metoprolol can be reliably calculated as determined by the 
pharmacokineticist. 
• For calculation of PK parameters, all BLQ values will be treated as missing, except for first dose 
pre-dose sample where it will be substituted with zero before the first quantifiable concentration.  
PK parameters will be estimated according to the following guidelines: 
• Cmax will be obtained directly from the concentration-time data. 
• tmax is the time at which Cmax is observed. 
• 
AUC0-24 will be calculated as follows: 
AUC0-24 = AUC0-tlast + AUCt-24. AUC0-tlast will be computed using trapezoidal up and log-
trapezoidal down method to the last measurable concentration, Clast. AUCt-24 will be estimated by 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 21 of 54 
integrating Ct*exp(-lambda*s) between t and 24h, where lambda is the terminal elimination rate. 
If concentrations are not BLQ at 24 hr, no extrapolation is needed.  
7.1.4 
Pharmacodynamic Variables 
A Holter-ECG device will be used for recording of 24-hour HR at the time periods detailed in the 
Schedules of Assessments (Section 9).  
The following PD parameters will be extracted from the Holger-ECG 
• Primary endpoint M24HR is the mean HR over 24 Hours  
• Minimum and maximum HR in the 24 hour period, HRmin and HRmax, also time of HRmin and 
HRmax 
• Mean HR from a designated period (from 3 to 16 hours post-dose) 
• Mean HR in a quiet hour (from 12 to 13 hours post-dose)  
During the quiet hour, subjects will have to rest, i.e., each subject will be asked to find a 
personally comfortable supine position with the head and whole body firmly supported.  The 
subjects will not be permitted to watch television or to listen to radio or music player.  They will 
not be permitted to read, to sleep or converse, and will be kept free from any external disturbance 
(e.g., personal media).  No electric equipment including mobile phones may be switched on in 
the room. 
In addition, Heart Rate from 12-lead ECG, BP and pulse will be assessed after a rest of at least 10 minutes 
as detailed in the Schedules of Assessments (Section 9). 
7.2 
Analysis Populations 
7.2.1 
Safety Population 
All subjects who received at least one dose of tesofensine.  Subjects will be included in the analysis 
according to the dose of tesofensine/metoprolol received in the actual period of interest.  The safety 
population will be used for all safety analysis, disposition, demographics and to list PK concentrations. 
7.2.2 
Pharmacokinetic Population 
All randomized subjects with at least one quantifiable tesofensine or metoprolol concentration and 
without major protocol deviations which could influence the PK.  Subjects will be included in the analysis 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 22 of 54 
according to the dose of tesofensine/metoprolol received.  The PK population will be used for all PK 
analysis. 
Data may/will be excluded (depending on the protocol and compound under study) from PK analysis 
(concentrations listed only) if any of the following criteria are fulfilled: 
• Concomitant medication, which could render the plasma concentration-time profile unreliable  
• The pre-dose concentration is greater than 5% of the corresponding Cmax in any given treatment 
period. 
• Subject vomits within 2 x the reported median t max for the analyte. 
• Subject has moderate or severe diarrhea within 2 x the reported median tmax for the analyte. 
Any data excluded will be discussed in the CSR.  
7.2.3 
Pharmacodynamic Population 
All randomized subjects with at least HR assessments (24 Hour Holter) on Baseline (Day -2 to -1) and 
on at least 2 Visits out of, Day 15, Day 18 and Day 21 without any major protocol deviations which could 
influence the PD parameters.  Additional subjects may be included during the data review meeting for 
purpose of PD analysis, however, these will not be included in the primary analysis.  Subjects will be 
included in the analysis according to the dose and IMP received.  The PD population will be used for all 
PD analysis. 
7.3 
Statistical Analysis Methods 
7.3.1 
Listings and Descriptive Statistics 
All original and derived parameters as well as population characteristics will be listed and described 
using summary statistics. Frequency counts (number of subjects [n] and percentages) will be made for 
each qualitative variable. Descriptive statistics (n, mean, standard deviation [SD], median, minimum and 
maximum) will be calculated for each quantitative variable (unless otherwise stated). For descriptive 
statistics of PK variables see Section 7.3.11. All listings will include repeated and unscheduled 
measurements. 
In case of triplicate measurements, the original three measurements will be listed together with the means, 
while the means will be used for summaries and baseline (see Section 7.3.2).  


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 23 of 54 
The following rules will apply to any repeated measurements: 
• If the repeated measurement occurs prior to the first dose of study drug then the last obtained 
value of any repeated measurement will be used in the descriptive statistics 
• If the repeated measurement occurs after the first dose of study drug then the original value of 
any repeated measurements will be used in the descriptive statistics 
• If a triplicate is whole or partly repeated prior to the first dose of study drug, then mean of the 
last (part) triplicate will be used in descriptive statistics and analyses 
• If a triplicate is whole or partly repeated after the first dose of study drug then the original mean 
value of any repeated measurements will be used in the descriptive statistics and analyses 
• if more than three measurements are made in a triplicate, then all will be used 
7.3.1.1 
Treatments in outputs 
In listings the outputs will be sorted by visit and time point. Unless otherwise described, in tables, the 
outputs will be sorted by treatment and time point. Summaries before any dosing and after the treatment 
period (screening and follow up) will be displayed without treatment. Treatments without metoprolol 
will be summarized by cohort, treatment (tesofensine dose), visit and time point. Treatments with 
metoprolol will be summarized by cohort, treatment and time point, without visit. 
In particular, pre-dosing safety assessments on metoprolol dosing dates will be assigned to the dosing of 
the previous day, the 24 hour post dose assessment will be assigned to the Metoprolol treatment. 
For PK concentration samples, see Section 7.3.11.  
The following treatments will be used: 
Cohort 1 
• Tesofensine 0.25 mg 
• Tesofensine 0.25 mg, Metoprolol 25 mg 
• Tesofensine 0.25 mg, Metoprolol 50 mg 
• Tesofensine 0.25 mg, Metoprolol 100 mg 
Cohort 2 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 24 of 54 
• Tesofensine 0.5 mg 
• Tesofensine 0.5 mg, Metoprolol 25 mg 
• Tesofensine 0.5 mg, Metoprolol 50 mg 
• Tesofensine 0.5 mg, Metoprolol 100 mg 
Cohort 3 
• Tesofensine 0.75 mg 
• Tesofensine 0.75 mg, Metoprolol 25 mg 
• Tesofensine 0.75 mg, Metoprolol 50 mg 
• Tesofensine 0.75 mg, Metoprolol 100 mg. 
7.3.1.2 
Analysis periods 
During the treatment period the following periods will be recognized: 
1. Baseline Period Tesofensine (Day -1) 
2. Steady dose of Tesofensine (Day 1 to Day 14) 
3. Tesofensine plus Metoprolol (Day 15) 
4. Steady dose of Tesofensine (Day 16, 17) 
5. Tesofensine plus Metoprolol (Day 18) 
6. Steady dose of Tesofensine (Day 19, 20) 
7. Tesofensine plus Metoprolol (Day 21) 
8. Steady dose of Tesofensine (Day 22, 23) 
7.3.2 
Baseline 
The baseline for all measurements (where applicable) will be the last pre-dose measurement, with 
exception for the PK/PD analysis, where time matched baseline will be used (see Section 7.3.13).  
If a repeated measurement is the last measurement prior to the first dose of study drug, then it will be 
used to calculate change from baseline as applicable. 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 25 of 54 
In case of triplicate measurements, the baseline and change from baseline will be obtained from the 
triplicate within each time point. In case of missing data within a triplicate, the remaining data will be 
used for the baseline. Following the rules above, if a triplicate prior to dosing is partly or fully repeated, 
then mean or the repeat will be used as baseline. 
7.3.3 
Statistical Significance Level 
All statistical tests will be two-sided and will be performed at the 5% level of significance. Confidence 
intervals will be two-sided and be at 95% level of significance. 
7.3.4 
Software 
All statistical analyses will be performed using Statistical Analysis Software (SAS®) Version 9.3 or later. 
The PK analysis will be performed using Phoenix WinNonlin Professional Software Version 6.3 or later 
or SAS Version 9.3 or later. 
7.3.5 
Missing Data 
There will be no imputation of missing data, except for the calculation of PK parameters, see 
Section 7.1.3.1 and 7.3.11.1.  
7.3.6 
Interim Analysis 
No formal interim analysis will be performed.  
However, after completion of approximately 20 evaluable subjects, MHR24 obtained on Days -1, 14, 15, 
17, 18, 20, 21 and 23 will be reviewed on an individual basis to confirm that the M24HR returned to 
baseline conditions are maintained prior to each metoprolol dosing.  No summaries of these data will be 
created nor will any other data be evaluated during this interim look. 
7.3.7 
Protocol Deviations 
All protocol deviations will be recorded by the Investigator and will be listed by subject. All protocol 
deviations will be discussed between PAREXEL (physician, Data Manager, Biostatistician, PK 
Scientist/Analyst and Medical Writer) and also the Sponsor during the clean file meeting before database 
lock in order to determine whether these may warrant exclusion of a subject from the pre-defined analysis 
populations or selected samples/measurements from the analysis. 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 26 of 54 
7.3.8 
Demographic Data 
All demographic data will be presented using the safety population. Demographic data will be 
summarized by cohort and overall. 
7.3.9 
Concomitant Medication 
Prior and concomitant medication will be listed by subject and will include the following information: 
reported name, PT, the route of administration, dose, frequency, start date/time, duration and indication. 
Prior medications are those that started and stopped prior to the first dose of IMP. Concomitant 
medications are those taken after first dosing (including medications that started prior to dosing and 
continued after). 
7.3.10 
Exposure to the Investigational Medicinal Product 
The actual doses received by subjects will be displayed in a listing.  
7.3.11 
Pharmacokinetic Concentrations and Variables 
The analysis of the PK data will be based on the PK population. 
Concentrations below the Lower limit of quantification (LLOQ) will be indicated by ‘Below the lower 
limit of quantification’ (BLQ) in the listings.  
Pharmacokinetic concentration data will be listed by subject including actual sampling times relative to 
dosing. Plasma concentrations of metoprolol will be summarized by cohort, treatment and time point, 
the pre-dose concentration will be assigned to the treatment which will follow (tesofensine plus 
metoprolol). Plasma concentrations of tesofensine will be summarized by cohort and day. In addition the 
tesofensine concentrations on Days 15, 18 and 21 (pre-dose and 8 h post dose) will be summarized by 
cohort, treatment and time point, in this summary the pre-dose sample will be assigned to the treatment 
which will follow (tesofensine plus metoprolol). The following descriptive statistics will be presented 
for plasma concentrations obtained at each nominal time point: n, n below LLOQ (with %) arithmetic 
mean, SD, CV%, geometric mean, geometric CV% (calculated as: gCV% =SQRT(es²-1)*100; where s is 
the standard deviation of the log-transformed values), median, minimum and maximum values. 
Pharmacokinetic parameters will be listed by subject for both tesofensine and metoprolol. 
Pharmacokinetic parameters of metoprolol will be summarized by cohort and treatment.  


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 27 of 54 
Descriptive statistics for calculated PK parameters will include: n, arithmetic mean, SD, gCV%, 
geometric mean, median, minimum and maximum values. For tmax, only median, minimum and 
maximum values will be presented.  
No descriptive statistics will be determined when fewer than three individual PK parameters are 
available. 
Individual plasma concentration versus actual times of metoprolol will be plotted by cohort and treatment 
on linear and semi-logarithmic scale. Mean plasma concentrations of metoprolol versus nominal times 
will also be presented in linear and semi-logarithmic scale. Two layouts will be used, all treatments 
overlaid on the same plot by cohort and all cohorts overlaid by metoprolol dose. Plots for metoprolol will 
have an approximately 24 hour time axis, from pre-dose to 24 hours post dose. 
Individual plasma concentration versus actual times from first dose of tesofensine will be plotted by 
cohort on linear and semi-logarithmic scale. Mean plasma concentrations of tesofensine vs nominal times 
will also be presented in linear and semi-logarithmic scale. Plots for tesofensine will have a 10 day time 
axis, Day 13 till Day 23, dosing of tesofensine will be shown in plot annotations.  
7.3.11.1 
Handling of Values Below the Limit of Quantification (BLQ) in Concentration Summaries 
and Listings 
Handling of values below the limit of quantification (BLQ) in listings and for the calculation of descriptive 
statistics at each time point: 
All BLQ concentrations or missing concentrations will be labeled as such in the concentration data 
listings. Missing samples will be reported as no sample ("NS") and excluded from analysis. Values that 
are BLQ will be substituted with BLQ/2 for the calculation of descriptive statistics of concentration by 
time point.   
Graphical presentation: 
Any BLQ values prior to the first quantifiable concentration will be plotted at zero for individual 
linear/linear graphs and excluded from log/linear graphs.  
For graphs of arithmetic and geometric means concentrations will follow the rules of summary statistics.   
7.3.12 
Pharmacodynamic Variables 
The analysis of the PD data will be based on the PD population.  


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 28 of 54 
The baseline for PD parameters will be the Day -1 measurement. A second baseline will be derived using 
a matched Day; Days 14, 17, 20 and -1 are baseline for Day 15, 18, 21 and 23 respectively. 
In this section the name ‘Tesofensine days’ will be used to indicate the days on which only tesofensine 
was dosed, these are days 14, 17, 20 and post dose-administration on day 23. These tesofensine days are 
typically summarized by treatment and day and in addition all days are combined, giving summaries 
where each subject by protocol contributes four measurements.  
Some PD variables (Pulse, SBP, DBP, HR) are also safety variables and will be listed as part of the safety 
assessments. They will be listed again, together with the Holter derived PD parameters (M24HR, 
maximum and minimum HR24, mean HR from designated period and mean HR in quiet hour) by cohort, 
subject and Day, and will include Day, absolute values, changes from baseline and change from matched 
day as applicable.  
Times of HRmin and HRmax will be listed by cohort, subject and Day, including time relative to dosing. 
For Baseline (Day -1), a fictive datetime of dosing will be used, this will be 24 hours before Dosing on 
Day 1. 
PD variable summaries of all PD parameters except times of HRmin and HRmax will contain n, mean, 
SD, median, minimum, maximum. Times of HRmin and HRmax will be summarized categorically. 
A pairwise summary will show PD results by tesofensine dose (0.25, 0.50 and 0.75 mg) including change 
from Baseline and change from Matched day (metoprolol dose).  
• Baseline (Day -1) and Day 23. 
• Pairs of Day 14 with 15, 17 with 18 and 20 with 21 by metoprolol dose. 
o Metoprolol 25 mg, Day before Metoprolol 25 mg 
o Metoprolol 50 mg, Day before Metoprolol 50 mg 
o Metoprolol 100 mg, Day before Metoprolol 100 mg 
The M24HR data will be shown in two box plots. One plot with all days showing observed data, a second 
box plot showing change from Matched Day. 
These same pairs of days will be used to create a pairwise frequency count of relative times of HRmin 
and HRmax per hour after dosing. 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 29 of 54 
The absolute values and the change from Baseline in M24HR on Tesofensine days will be summarized 
descriptively by tesofensine dose and Day. This summary will include a summary of Day -1 (providing 
summary of baseline data) and a mean combining Day 14, 17, 20 and 23.  
7.3.12.1 
Analysis to check M24HR assumptions on Tesofensine days 
This concerns three analyses, comparing days, carry over effect of metoprolol and equality of M24HR 
prior to metoprolol. Observation of significant effects in these analyses will not be taken into 
consideration in the selection of mitigating dose.  
Values of M24HR on Days 14, 17, 20 and 23 will be compared by means of analysis of variance 
(ANOVA) with random subjects nested under sequence by cohort.  Means, differences between means 
and CI of differences will be presented. In this analysis there will be no period effect and treatment effect 
(such as metoprolol dose) other than the fixed days. The following code will be used as basis for the 
analysis. 
PROC MIXED; 
BY cohort; 
CLASS sequence day subject; 
MODEL M24HR=day sequence; 
RANDOM subject (sequence); 
LSMEANS day / CL alpha=0.05 diff; 
 
ODS OUTPUT LSMEANS=ls_means; 
QUIT; 
Carry over of metoprolol will be analyzed using data of Days 17, 20 and 23. In this model the M24HR will be 
compared using the metoprolol dose of previous days (Day 15, 18 and 21) respectively. The model will be an 
analysis of variance (ANOVA) with random subjects nested under sequence by cohort.  Means, 
differences between means and CI of differences will be presented. The following code will be used as 
basis for the analysis. 
PROC MIXED; 
BY cohort; 
CLASS sequence day subject treatment; 
MODEL M24HR=treatment day sequence; 
RANDOM subject (sequence); 
LSMEANS treatment / CL alpha=0.05 diff; 
 
ODS OUTPUT LSMEANS=ls_means; 
QUIT; 
Differences in M24HR before dosing will be analysis using data of Days 14, 17 and 20. In this model 
the M24HR will be compared using the metoprolol dose of the subsequent days (15, 18 and 21). The 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 30 of 54 
model will be an analysis of variance (ANOVA) with random subjects nested under sequence by cohort.  
Means, differences between means and CI of differences will be presented. The following code will be 
used as basis for the analysis. 
PROC MIXED; 
BY cohort; 
CLASS sequence day subject treatment; 
MODEL m24hr=treatment day sequence; 
RANDOM subject (sequence); 
LSMEANS treatment / CL alpha=0.05 diff; 
 
ODS OUTPUT LSMEANS=ls_means; 
QUIT; 
7.3.12.2 
Statistical Analysis for mitigating dose  
Mitigating dose is estimated using a linear regression modelling mean change from pre-tesofensine 
baseline (Day -1) of M24HR as a function of the log metoprolol dose. Based on the regression equation 
a dose for no effect will be estimated. The final estimate and CI will be obtained using bootstrapping.  
As a first step, change from pre-tesofensine baseline (Day -1) of M24HR on Days 15, 18 and 21 will be 
compared by means of cross-over ANOVA with random subjects nested under sequence and fixed Day 
(Day 15, 18 and 21 will play the role of period in a conventional cross-over), treatments and baseline by 
cohort. Means, differences between means and CI of differences will be presented. In this analysis the 
metoprolol dose will be distinguishing between treatments.  
PROC MIXED; 
 
BY cohort; 
 
CLASS treatment day sequence subject; 
 
MODEL cfb_m24hr=treatment sequence day baseline; 
RANDOM subject(sequence); 
 
LSMEANS treatment / CL ALPHA=0.05 DIFF; 
 
ODS OUTPUT LSMEANS=ls_means; 
QUIT; 
In the final analysis, bootstrapping will be used. The bootstrap samples will be obtained by random 
selection of subjects in each bootstrap sample. At least 5000 samples will be taken, though more may be 
used by judgement of the statistician, important consideration for increasing the number of samples will 
be shape and smoothness of the distribution curve of the final parameter. The ANOVA model above will 
be used to obtain mean levels for each metoprolol dose.  A straight line linear regression will be used to 
fit the means to log metoprolol dose and the mitigating dose for the sample computed. Mitigating dose 
will be estimated as mean of bootstrap sample estimates.  Confidence intervals will be determined using 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 31 of 54 
the percentiles of the bootstrap estimates.  A density plot of the bootstrap estimates for the mitigating 
dose and for the estimated slopes will be provided. The following code will be used as basis for the 
estimation. 
PROC MIXED; 
 
BY cohort bootstrap_sample; 
 
CLASS treatment day sequence subject; 
 
MODEL cfb_m24hr=treatment sequence day baseline; 
RANDOM subject(sequence); 
 
LSMEANS treatment / CL ALPHA=0.05; 
 
ODS OUTPUT LSMEANS=ls_means; 
QUIT; 
 
PROC REG OUTTEST=outtest; 
 
BY cohort bootstrap_sample; 
MODEL ls_means=log_metoprolol_dose; 
RUN; 
 
DATA result; 
SET outtest; 
log_est=-intercept/slope_of_log_metoprolol_dose; 
est=EXP(log_est); 
RUN; 
Bootstrap samples will be removed before summary, for either of the following reasons: 
1. Intercept and/or slope could not be estimated 
2. Slope is positive (medically implausible) 
In case more than 10% of samples are excluded for any reason, the results will not be displayed. If the 
percentage of samples discarded due to the first reason is too high (e.g. brings the total to over 10%) in 
the judgment of the statistician, the statistician may decide to simplify the model regarding regression or 
covariance structure.  
The final model will be displayed in a footnote in all relevant outputs. The summary tables will display 
number and percentage of removed samples by reason for removal, as well as the bootstrap estimates 
with CIs. 
If the sample size is small, it is expected that the bootstrap samples can include slopes very close to zero. 
This would lead to implausibly high estimates for the mitigating dose. To evaluate the potential influence 
the following will be part of the raw statistical output of the model: histogram of the mitigating dose over 
the bootstrap samples and comparison of median estimate vs mean estimate. 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 32 of 54 
In case the linear model linking Mean M24HR to log dose is clearly not satisfactory, an alternative 
strategy may be employed, for instance, by interpolation between 2 adjacent doses. The need and 
approaches for such analysis will be discussed after the initial analysis is finished and will be described 
in an addendum if alternative analysis will be performed. 
7.3.12.3 
Sensitivity Analysis 
For each Cohort, a sensitivity analysis will be calculated using Fieller CI (Hirschberg and Lye, Beyene 
and Moineddin). For this calculation a linear relation between CfB M24HR and metoprolol dose will be 
calculated directly in PROC MIXED. Based on the PROC MIXED the CI are calculated using the 
following formulas: 
𝜃̂ + (
𝑘
1 −𝑘) (θ̂ + 𝑉12
𝑉22
) ±
𝑧𝛼/2
𝛽̂(1 −𝑘) √{𝑉11 + 2𝜃̂𝑉12 + 𝜃̂2𝑉22 −𝑘(𝑉11 −𝑉12
2
𝑉22
)}  
Using: 
𝑘= 𝑧𝛼2
⁄
2
𝑉22
𝛽̂2  
𝜃̂ = 𝛼̂/𝛽̂ 
With 𝛼̂ and 𝛽̂ the regression estimates and V their Variance-Covariance matrix  
The following SAS code will be used as basis for the PROC MIXED calculation: 
PROC MIXED; 
CLASS subject day sequence; 
MODEL cfb_m24hr = log_dose  sequence   day  / covb; 
RANDOM subject(sequence); 
ESTIMATE 'intercept' intercept 1 log_dose 0; 
ESTIMATE 'slope' intercept 0 log_dose 1; 
ODS OUTPUT Estimates=estimates covb=covb; 
RUN; 
7.3.13 
Pharmacokinetic/Pharmacodynamic Analysis 
7.3.13.1 
Analysis of PD against metoprolol in plasma 
In this analysis, a time matched change from baseline for the HR will be employed. In particular this 
means that baseline will be the HR on time points corresponding to PK measurement points on Day -1. 
(pre-dose and 2, 4, 8, 12 and 24 hour post dose on Days 15, 18, 21 with 24, 22, 20, 12 and 0 hours 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 33 of 54 
pre-dose as baseline). These are triplicate measurements; in this analysis the mean of the triplicates will 
be used, the original three measurements of the triplicates will not be displayed in this section, they will 
be part of the safety listings. If one or two of the triplicate measurements are missing, then the remaining 
data will be used to obtain the mean. If all three are missing then the observation will be missing. If all 
three are missing on day -1 for a subject, then the change from baseline for the complete time point will 
be missing for the subject.  
A listing will be provided showing mean of triplicate HR, time matched change from baseline HR, and 
metoprolol plasma concentration by cohort and nominal time point. This listing will include Day -1 
(where only HR will be listed).  Plots will be provided showing time matched change from baseline 
against metoprolol plasma concentration by cohort.   
7.3.13.2 
Analysis of PD against metoprolol PK parameters 
This analysis is the equivalent of the analysis in Section 7.3.12.2. However rather than log metoprolol 
dose the log PK parameters will be used. Hence an additional step is introduced, calculation of mean log 
PK parameters. For this a cross over mixed model using fixed treatment day and sequence with random 
subjects nested under sequence will be used. The following code will be used as basis for the analysis.  
PROC MIXED; 
 
BY cohort bootstrap_sample; 
 
CLASS treatment day sequence subject; 
 
MODEL cfb_m24hr=treatment sequence day baseline; 
RANDOM subject(sequence); 
 
LSMEANS treatment / CL ALPHA=0.05; 
 
ODS OUTPUT LSMEANS=ls_means_m24hr; 
QUIT; 
 
PROC MIXED; 
 
BY cohort bootstrap_sample; 
 
CLASS treatment day sequence subject; 
 
MODEL log_pkparam=treatment sequence day; 
RANDOM subject(sequence); 
 
LSMEANS treatment / CL ALPHA=0.05; 
 
ODS OUTPUT LSMEANS=ls_means_log_pkparam; 
QUIT; 
 
PROC REG OUTTEST=outtest; 
 
BY cohort bootstrap_sample; 
MODEL ls_means_m24hr=ls_means_log_pkparam; 
RUN; 
 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 34 of 54 
DATA result; 
SET outtest; 
log_est=-intercept/slope_of_log_pkparam; 
est=EXP(log_est); 
RUN; 
A straight line regression will be used to fit change from baseline M24HR against log PK parameters 
(AUC0-24 and Cmax) of metoprolol for each tesofensine dose.  Based on the regression equation a 
parameter value for no effect will be estimated.  Confidence intervals of the no effect parameter value 
will be determined using a bootstrap method, again using at least 5000 bootstrap samples. The bootstrap 
samples will be obtained by random selection of subjects. Plots of change from M24HR as a function of 
log PK parameter will be displayed by cohort and will include the regression line.  
7.3.13.3 
Population modelling 
A population PK-PD model may be developed if deemed appropriate on the data from this study with 
the final objective of describing relative contribution to the final effect of plasma exposure to tesofensine 
and metoprolol, simulating optimal dose regimen for multiple administration and evaluate effect of 
covariates (e.g., polymorphism of PK, body weight, gender) on the overall effect. 
Details of the analysis will be included in a separate Data Analysis plan and outcome of the modelling 
will be reported separately, if population PK-PD modeling is conducted. 
7.3.14 
Safety Analysis 
The analysis of the safety variables will be based on the safety population. 
7.3.14.1 
Adverse Events 
The following listings will be produced: 
• All pre-treatment AEs and TEAEs (by subject). 
• Withdrawals due to AEs (if applicable). 
• Serious Adverse Events (SAEs) (if applicable). 
• Serious Adverse Events Leading to Death (if applicable). 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 35 of 54 
The following information will be included in the listings: AE number, reported term, System Organ 
Class (SOC), Preferred Term (PT), start and end date/time, intensity, causality, action taken, outcome, 
classified as serious and treatment emergence. 
Numbers of TEAEs will be summarized by treatment, SOC, PT, and also by treatment, SOC, PT and 
severity and also by treatment, SOC, PT and causality to treatment. In addition serious TEAES will be 
summarized by treatment, SOC and PT.  
For all summaries of TEAEs the treatments of Section 7.3.1 will be used. In addition the summaries for 
the following combined treatments will be created: 
• Cohort 1  
• Cohort 2 
• Cohort 3 
• Tesofensine without Metoprolol (all doses) 
• Metoprolol 25 mg (Combining all Tesofensine doses) 
• Metoprolol 50 mg (Combining all Tesofensine doses) 
• Metoprolol 100 mg (Combining all Tesofensine dose) 
• Tesofensine and Metoprolol (combining all doses) 
• All TEAE combined 
7.3.14.2 
Clinical Safety Laboratory Tests (hematology, clinical chemistry and urinalysis) 
Laboratory values (hematology, clinical chemistry and urinalysis) will be listed by subject and study time 
point including changes from baseline (with the exception of urinalysis). The baseline for the laboratory 
values will be the results obtained on Day -2. 
All values outside the clinical reference ranges will be flagged in the data listings. The abnormal values 
will be flagged with ‘L’ for values below the lower limit of the clinical reference range and ‘H’ for values 
above the upper limit of the clinical reference range and included in the listings. The Investigator will 
assess whether the values outside the clinical reference range are clinically significant and these will be 
reported as abnormal NCS or abnormal CS. Clinically significant laboratory values will be recorded by 
the Investigator as AEs. 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 36 of 54 
Descriptive statistics (for non-categorical data including hematology and clinical chemistry) will be 
presented by Cohort, visit and treatment for both individual values (N, mean, SD, median, minimum, 
maximum) and changes from baseline. 
Shift tables for hematology and clinical chemistry will be presented by Cohort, visit and treatment. 
7.3.14.3 
Vital Signs 
Vital signs data will be listed by subject including changes from baseline. The baseline for the vital signs 
measurements will be the pre-dose measurement on Day 1. Baseline for Body weight and waist 
circumference will be Day -2. 
Triplicate measurements of vital signs will be listed with both the original measurements and the mean 
for the time point. For triplicate measurements the mean within a time point will be used for summaries, 
baseline and change from baseline as applicable.  
Descriptive statistics (n, mean, SD, median, minimum, maximum) for absolute values and changes from 
baseline will be presented by treatment and time point or treatment, visit and time point for days where 
only tesofensine is dosed. 
7.3.14.4 
Twelve-Lead Electrocardiogram 
All ECG parameters obtained from the ECG measurement will be listed by subject for each treatment 
and time point including changes from baseline. The baseline for the ECG measurements will be pre-
dose measurement obtained on Day 1. 
Descriptive statistics (n, mean, SD, median, minimum, maximum) for absolute values and changes from 
baseline will be presented by treatment and time point. 
7.3.14.5 
Physical Examination 
The results of the physical examination will be listed by subject and time-point. 
7.3.14.6 
Patient Health Questionnaire-9 and (PHQ-9) and Generalized Anxiety Disorder 
Assessment (GAD-7) 
Results of the questionnaires will be listed by subject. Sum scores of PHQ-9 and GAD-7 will summarized 
by cohort and overall using the safety population. 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 37 of 54 
7.3.14.7 
Additional assessments based on BfArM’s request 
Additional assessments will be listed, including further actions recommended and performed and 
references to AEs and concomitant medications added. 
 
 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 38 of 54 
8. 
REFERENCES 
1. SAS® Version 9.2 of the SAS System for Personal Computers. Copyright © 2002-2003. SAS Institute 
Inc. SAS and all other SAS Institute Inc. product or service names are registered trademarks or 
trademarks of SAS Institute Inc., Cary, NC, USA. 
2. Pharsight® WinNonlin Professional Software Version 6.3. http://www.pharsight.com 
3. INSTRUCTION MANUAL Instructions for Patient Health Questionnaire (PHQ) and GAD-7 
Measures. 
https://phqscreeners.pfizer.edrupalgardens.com/sites/g/files/g10016261/f/201412/instructions.pdf 
4. Hirschberg J, Lye J. A Geometric Comparison of the Delta and Fieller Confidence Intervals. The 
American Statistician, August 2010, 234-241.  
5. Beyene J, Moineddin R. Methods for confidence inerval estimation of a raio parameter with 
application to location quotients MBC Medical Research Methodology 2005, 5:32. 
 
 
 
 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 39 of 54 
9. 
SCHEDULE OF ASSESSMENTS 
9.1 
Schedule of Assessments for Cohort 1 and Cohort 2 
Evaluation 
Screening 
Base-
line 
Treatment Period 
Safety 
FU 
Phone 
Calls 
Day 
-28 to -3 
-2 
-1a 
1 
2 
3 
7 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
30 
50 
Admission 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
In-house stayb 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Ambulatory visits 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Body weight  
X 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Waist circumference 
X 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Height, calculation of BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling for CYP2D6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory tests (clinical 
chemistry, hematology and 
urinalysis) in fasted state 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
HBA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy testm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 40 of 54 
Evaluation 
Screening 
Base-
line 
Treatment Period 
Safety 
FU 
Phone 
Calls 
Day 
-28 to -3 
-2 
-1a 
1 
2 
3 
7 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
30 
50 
Urine pregnancy testm 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Xn 
Psychodiagnostic self-rating 
instruments (PHQ-9 and GAD-7) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen, cotinine and 
alcohol test 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
24-hours Holter ECGc 
 
 
Xa 
 
 
 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
12-lead ECGd,f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Supine blood pressure and pulsee,f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Body temperatureg 
X 
X 
X 
 
 
 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
A designated period from 3 to 
16 hours post-dose and a quiet hour 
from 12 to 13 hours post-dosef 
 
 
X 
 
 
 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
Randomizationh 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dosing of tesofensinei 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Dosing of metoprololj 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Blood sampling for PKk 
 
 
 
 
 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
Dispense of tesofensine container 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject returns tesofensine 
container to the clinical unit 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense of the diary and 
instructionsl 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of the diary 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 41 of 54 
Evaluation 
Screening 
Base-
line 
Treatment Period 
Safety 
FU 
Phone 
Calls 
Day 
-28 to -3 
-2 
-1a 
1 
2 
3 
7 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
30 
50 
AE monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE = adverse event; BMI = Body Mass Index; ECG = electrocardiogram; FU = Follow-up; PK = pharmacokinetics 
a 
The 24-hours ECG recording at pre-tesofensine baseline may be repeated, if less recording time than 22 hours for comparison of the data is available for evaluation 
due to technical issues.  Then dosing and all subsequent assessments will be postponed by 1 day. 
 
b 
Subjects will be admitted in the morning of Day -2 and will leave the study center in the morning of Day 3 after dosing of the last loading dose and after completion 
of all study-related assessments. 
 
Subject will take tesofensine at home once daily from Day 4 to Day 6 and from Day 8 to Day 12. 
 
On Day 7, subject will come to the study center for an ambulatory visit (including dosing).  
Subjects will be admitted in the morning of Day 13 and will leave the study center on Day 24 after completion of all study-related assessments. 
c 
2-lead Holter-ECG recordings will start in the morning before dosing (or at corresponding time at pre-tesofensine baseline) and will end 24 hours after respective 
dose.   
d 
On Days -1, 14, 15, 17, 18, 20, 21 and Day 23: Triplicate measurement (i.e., 3 recordings of 10 seconds each, at least 60 seconds apart) within 10 minutes before each 
PK sampling and at corresponding time points (pre-dose and at 2, 4, 8, 12 and 24 hours post-dose).  
 
On other days and at Screening, also in triplicates: once daily in the morning (pre-dose on dosing days). 
e 
On Days -1, 14, 15, 17, 18, 20, 21 and Day 23: Triplicate measurement within 10 minutes before each PK sampling and at corresponding time points (pre-dose and at 2, 4, 8, 
12 and 24 hours post-dose).  
 
On other days and at Screening, also in triplicates: once daily in the morning (pre-dose on dosing days). 
f 
Subjects will have to rest during the quiet hour and for at least 10 minutes before 12-lead ECG recording and blood pressure and pulse measurements, i.e., each subject 
will be asked to find a personally comfortable supine position with the head and whole body firmly supported.  The subjects will not be permitted to watch television 
or to listen to radio or music player.  They will not be permitted to read, to sleep or converse, and will be kept free from any external disturbance (e.g., personal media).  
No electric equipment including mobile phones may be switched on in the room. 
g 
Once daily, on in-house days in the morning.   
h 
Randomization will be performed pre-dose on Day 1. 
i 
Dosing of tesofensine will start in the morning of Day 1 and will be continued until the morning of Day 23, when the last dose of tesofensine will be given; subjects 
will be randomly assigned to any of the 3 tesofensine dose cohorts (Cohort 1, Cohort 2, Cohort 3). 
 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 42 of 54 
Cohort 1: 1.0 mg once daily for the first 3 days (loading dose), then 0.25 mg once daily. 
 
Cohort 2: 2.0 mg once daily for the first 3 days (loading dose), then 0.50 mg once daily. 
 
j 
Dosing of extended release metoprolol will be performed in the morning of Day 15, Day 18 and Day 21 within 30 minutes after start of a breakfast. 
 
Administration of single doses of 25 mg, 50 mg and 100 mg in random order. 
k 
Blood sampling for metoprolol: at pre-dose and at 2, 4, 8, 12 and 24 hours post-dose on Day 15, Day 18 and Day 21.   
Blood sampling for tesofensine: at pre-dose on Day 13, Day 14 and Day 15 to confirm steady state, at pre-dose on Day 18, Day 21 and Day 23 and at 8 hours post-
dose on Day 15, Day 18 and Day 21.   
l 
On outpatient days, date and time of dosing, adverse events (if any) and use of concomitant medication (if any) will be documented in a diary. 
m 
Pregnancy tests will be performed whenever deemed necessary. 
n 
The pregnancy test on Day 50 will be performed at home and the result will be communicated during the safety FU phone call. 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 43 of 54 
9.2 
Schedule of Assessments for Cohort 3 
Evaluation 
Scree-
ning 
Base-
line 
Treatment Period 
Safety 
FU 
Phone 
Calls 
Day 
-28 
to -3 
-2 
-1a 
1 
2 
3 
4 
5 
7 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
30 
50 
Admission 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
In-house stayb 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Ambulatory visits 
X 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Body weight  
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Waist circumference 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Height, calculation of BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling for CYP2D6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory tests (clinical 
chemistry, hematology and 
urinalysis) in fasted state 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Serum pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Urine pregnancy test 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Xn 
Psychodiagnostic self-rating 
instruments (PHQ-9 and GAD-7) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 44 of 54 
Evaluation 
Scree-
ning 
Base-
line 
Treatment Period 
Safety 
FU 
Phone 
Calls 
Day 
-28 
to -3 
-2 
-1a 
1 
2 
3 
4 
5 
7 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
30 
50 
Urine drug screen, cotinine and 
alcohol test 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
24-hours Holter ECGc 
 
 
Xa 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
12-lead ECGd,f 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Supine blood pressure and pulsee,f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Body temperatureg 
X 
X 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
A designated period from 3 to 
16 hours post-dose and a quiet hour 
from 12 to 13 hours post-dosef 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
Randomizationh 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dosing of tesofensinei 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Dosing of metoprololj 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Blood sampling for PKk 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
Dispense of tesofensine containers 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject returns tesofensine 
containers to the clinical unit 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense of the diary and 
instructionsl 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of the diary 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE = adverse event; BMI = Body Mass Index; ECG = electrocardiogram; FU = Follow-up; PK = pharmacokinetics 
a 
The 24-hours ECG recording at pre-tesofensine baseline may be repeated, if less recording time than 22 hours for comparison of the data is available for evaluation 
due to technical issues.  Then dosing and all subsequent assessments will be postponed by 1 day. 
 
b 
Subjects will be admitted in the morning of Day -2 and will leave the study center in the morning of Day 3 after dosing of the last loading dose and after completion 
of all study-related assessments. 
 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 45 of 54 
Subjects will come to the study center for ambulatory visits and dosing of tesofensine on Days 4 and 5. 
 
Subjects will take tesofensine at home once daily on Day 6 and from Day 8 to Day 12. 
 
On Day 7, subject will come to the study center for an ambulatory visit (including dosing).  
Subjects will be admitted in the morning of Day 13 and will leave the study center on Day 24 after completion of all study-related assessments. 
c 
2-lead Holter-ECG recordings will start in the morning before dosing (or at corresponding time at pre-tesofensine baseline) and will end 24 hours after respective 
dose.   
d 
On Days -1, 14, 15, 17, 18, 20, 21 and Day 23: Triplicate measurement (i.e., 3 recordings of 10 seconds each, at least 60 seconds apart) within 10 minutes before each PK 
sampling and at corresponding time points (pre-dose and at 2, 4, 8, 12 and 24 hours post-dose).  
 
On other days and at Screening, also in triplicates: once daily in the morning (pre-dose on dosing days). 
e 
On Days -1, 14, 15, 17, 18, 20, 21 and Day 23: Triplicate measurement within 10 minutes before each PK sampling and at corresponding time points (pre-dose and at 2, 4, 8, 
12 and 24 hours post-dose).  
 
On other days and at Screening, also in triplicates: once daily in the morning (pre-dose on dosing days). 
f 
Subjects will have to rest during the quiet hour and for at least 10 minutes before 12-lead ECG recording and blood pressure and pulse measurements, i.e., each subject 
will be asked to find a personally comfortable supine position with the head and whole body firmly supported.  The subjects will not be permitted to watch television 
or to listen to radio or music player.  They will not be permitted to read, to sleep or converse, and will be kept free from any external disturbance (e.g., personal media).  
No electric equipment including mobile phones may be switched on in the room. 
g 
Once daily, on in-house days in the morning.   
h 
Randomization will be performed pre-dose on Day 1. 
i 
Dosing of tesofensine will start in the morning of Day 1 and will be continued until the morning of Day 23, when the last dose of tesofensine will be given; subjects 
will be randomly assigned to any of the 3 tesofensine dose cohorts (Cohort 1, Cohort 2, Cohort 3). 
 
Cohort 3: 2.0 mg once daily for the first 5 days (loading dose), then 0.75 mg once daily. 
j 
Dosing of extended release metoprolol will be performed in the morning of Day 15, Day 18 and Day 21 within 30 minutes after start of a breakfast. 
 
Administration of single doses of 25 mg, 50 mg and 100 mg in random order. 
k 
Blood sampling for metoprolol: at pre-dose and at 2, 4, 8, 12 and 24 hours post-dose on Day 15, Day 18 and Day 21.   
Blood sampling for tesofensine: at pre-dose on Day 13, Day 14 and Day 15 to confirm steady state, at pre-dose on Day 18, Day 21 and Day 23 and at 8 hours post-
dose on Day 15, Day 18 and Day 21.     
l 
On outpatient days, date and time of dosing, adverse events (if any) and use of concomitant medication (if any) will be documented in a diary.  
m Pregnancy tests will be performed whenever deemed necessary. 
n  
The pregnancy test on Day 50 will be performed at home and the result will be communicated during the safety FU phone call. 
 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 46 of 54 
10. 
TABLES AND LISTINGS TO BE INCLUDED IN SECTION 14 OF THE 
CLINICAL STUDY REPORT 
 
Subject Disposition 
Table 14.1.1 
Subject Disposition (Safety Population) 
Table 14.1.2 
Subject Disposition by Cohort (Safety Population) 
 
 
Baseline and Demographic Data 
Table 14.1.3 
Subject Demographics by Cohort (Safety Population) 
 
 
Pharmacokinetic and pharmacodynamic Data 
Table 14.2.1 
Summary of Plasma Concentrations of Tesofensine versus Nominal Sampling 
Times by Tesofensine Dose (PK Population) 
Table 14.2.2 
Summary of Plasma Concentrations of Metoprolol versus Nominal Sampling 
Times by Metoprolol Dose and Cohort (PK Population) 
Table 14.2.3 
Summary of Pharmacokinetic Parameters of Tesofensine by Tesofensine Dose 
and Visit (PK Population) 
Table 14.2.4 
Summary of Pharmacokinetic Parameters of Metoprolol by Metoprolol Dose and 
Cohort (PK Population) 
Table 14.2.5 
Summary of Pharmacodynamic Parameters (PD Population) 
Table 14.2.6 
Frequency of Times of Minimum and Maximum Heart Rate by Hour (PD 
Population) 
Table 14.2.7 
Summary of M24HR by Metoprolol Dose (PD Population) 
Table 14.2.8 
Comparison of M24HR on Tesofensine Days by Day (PD Population) 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 47 of 54 
Table 14.2.9 
Comparison of M24HR of Days 17, 20 and 23 by preceding Metoprolol dose (PD 
Population) 
Table 14.2.10 
Comparison of M24HR of Days 14, 17 and 20 by subsequent Metoprolol dose 
(PD Population) 
Table 14.2.11 
Comparison of Change from Baseline M24HR by Metoprolol dose (PD 
Population) 
Table 14.2.12 
Relation between Change from Baseline M24HR and Metoprolol Dose (PD 
Population) 
Table 14.2.13 
Fieller Intervals of Relation between Change from Baseline M24HR and 
Metoprolol Dose (PD Population) 
 
 
Pharmacokinetic/Pharmacodynamic Analysis 
Table 14.2.14 
Relation between Change from Baseline M24HR and Metoprolol PK parameters 
(PK Population) 
 
 
Safety Data 
 
Table 14.3.1.1 
Summary of Treatment Emergent Adverse Events (Safety Population) 
Table 14.3.1.2 
Treatment-Emergent Adverse Events by Treatment, System Organ Class and 
Preferred Term (Safety Population) 
Table 14.3.1.3 
Treatment-Emergent Adverse Events by Treatment, System Organ Class, 
Preferred Term and Causality (Safety Population) 
Table 14.3.1.4 
Treatment-Emergent Adverse Events by Treatment, System Organ Class, 
Preferred Term and Severity (Safety Population) 
Table 14.3.1.5 
Serious Treatment-Emergent Adverse Events by Treatment, System Organ Class 
and Preferred Term (Safety Population) 
Listing 14.3.2.1 
Serious Adverse Events Leading to Death (Safety Population) 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 48 of 54 
Listing 14.3.2.2 
Serious Adverse Events (Safety Population) 
Listing 14.3.2.3 
Adverse Events Leading to Discontinuation (Safety Population) 
Listing 14.3.4.1 
Abnormal Clinical Chemistry Values (Safety Population) 
Listing 14.3.4.2 
Abnormal Hematology Values (Safety Population) 
Listing 14.3.4.3 
Abnormal Urinalysis Values (Safety Population) 
Table 14.3.5.1 
Clinical Chemistry (Safety Population) 
Table 14.3.5.2 
Hematology (Safety Population) 
Table 14.3.5.3 
Clinical Chemistry Shift Table (Safety Population) 
Table 14.3.5.4 
Hematology Shift Table (Safety Population) 
Table 14.3.6.1 
Vital Signs (Safety Population) 
Table 14.3.6.2 
Electrocardiograms (Safety Population) 
Table 14.3.6.3 
Patient Health Questionnaire-9 and (PHQ-9) and Generalized Anxiety Disorder 
Assessment (GAD-7) (Safety Population) 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 49 of 54 
11. 
FIGURES 
Figure 14.2.1 
Subject Profiles for Metoprolol Plasma Concentration Time Data (Linear Scale) 
(Safety Population) 
Figure 14.2.2 
Subject Profiles for Metoprolol Plasma Concentration Time Data (Semi-
logarithmic Scale) (Safety Population) 
Figure 14.2.3 
Subject Profiles for Tesofensine Plasma Concentration Time Data (Linear Scale) 
(Safety Population) 
Figure 14.2.4 
Subject Profiles for Tesofensine Plasma Concentration Time Data (Semi-
logarithmic Scale) (Safety Population) 
Figure 14.2.5 
Mean (± Standard Deviation) Profiles for Metoprolol Plasma Concentration Time 
Data (Linear Scale) (PK Population) 
Figure 14.2.6 
Mean Profiles for Metoprolol Plasma Concentration Time Data (Semi-
logarithmic Scale) (PK Population) 
Figure 14.2.7 
Mean (± Standard Deviation) Profiles for Tesofensine Plasma Concentration 
Time Data (Linear Scale) (PK Population) 
Figure 14.2.8 
Mean Profiles for Tesofensine Plasma Concentration Time Data (Semi-
logarithmic Scale) (PK Population) 
Figure 14.2.9 
Individual M24HR vs Treatment (PD Population) 
Figure 14.2.10 
Combined Individual M24HR vs Treatment by Tesofensine Dose (PD Population) 
Figure 14.2.11 
Box Plot of M24HR vs. Metoprolol dose by Tesofensine Dose (PD Population) 
Figure 14.2.12 
Box Plot of Change from Matched Day M24HR vs. Metoprolol Dose by 
Tesofensine Dose (PD Population) 
Figure 14.2.13 
Display of Bootstrap Results by Tesofensine Dose (PD Population) 
Figure 14.2.14 
Combined Display of Bootstrap Results (PD Population) 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 50 of 54 
Figure 14.2.15 
Density Plot for Estimated Metoprolol Dose to Compensate M24HR by 
Tesofensine Dose (PD Population) 
Figure 14.2.16 
Time Matched Change from Baseline HR against Metoprolol Plasma 
Concentration (PK Population) 
Figure 14.2.17 
Density Plot for Estimated PK Parameter to Compensate M24HR by Tesofensine 
Dose (PD Population) 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 51 of 54 
12. 
LISTINGS TO BE INCLUDED IN SECTION 16 OF THE CLINICAL 
STUDY REPORT 
Subject Disposition 
Listing 16.2.1.1 
Withdrawals from the Study (Safety Population) 
Listing 16.2.1.2 
Informed Consent (Safety Population) 
Listing 16.2.1.3 
Study Visits (Safety Population) 
Listing 16.2.1.4 
Failed Inclusion and Exclusion Criteria (Safety Population) 
Listing 16.2.2 
Protocol Deviations (Safety Population) 
Listing 16.2.3 
Assignment to Analysis Populations (Safety Population) 
 
 
Baseline and Demographic Data 
Listing 16.2.4.1 
Subject Demographics (Safety Population) 
Listing 16.2.4.2 
Medical History (Safety Population) 
Listing 16.2.4.3 
Subject Habits (Safety Population) 
 
 
Concomitant Medication 
Listing 16.2.4.4 
Prior and Concomitant Medications (Safety Population) 
 
 
Exposure 
Listing 16.2.5.1 
Exposure to Study Drug (Safety Population) 
Listing 16.2.5.2 
Individual Blood Sampling Times and Concentrations (Safety Population) 
 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 52 of 54 
Pharmacokinetic Data 
Listing 16.2.6.1 
Pharmacokinetic Parameters of Metoprolol (PK Population) 
Listing 16.2.6.2 
Pharmacokinetic Parameters of Tesofensine (PK Population) 
 
 
Pharmacodynamic Data 
Listing 16.2.6.3 
Pharmacodynamic Variables and Change from Baseline (PD Population) 
Listing 16.2.6.4 
Times of HRmin and HRmax including times relative to dosing (PD Population) 
Listing 16.2.6.5 
Heart Rate with time matched change from baseline (PD Population) 
 
 
Safety Variables 
Listing 16.2.7 
Adverse Events (Safety Population) 
Listing 16.2.8.1 
Clinical Chemistry (Safety Population) 
Listing 16.2.8.2 
Hematology (Safety Population) 
Listing 16.2.8.3 
Urinalysis (Safety Population) 
Listing 16.2.8.4 
Serology (Safety Population) 
Listing 16.2.8.5 
Drugs of Abuse (Safety Population) 
Listing 16.2.8.6 
Other Clinical Laboratory (Safety Population) 
Listing 16.2.9.1 
Vital Signs (Safety Population) 
Listing 16.2.9.2 
Electrocardiogram Parameters (Safety Population) 
Listing 16.2.9.3 
Physical Examination (Safety Population) 
Listing 16.2.9.4 
Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder 
Assessment (GAD-7) (Safety Population) 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 53 of 54 
Listing 16.2.9.5 
Safety Assessments based on BfArM’s Request (Safety Population) 


PAREXEL International 
Statistical Analysis Plan 
Saniona A/S 
 
Final 1.0 
TM004 
 
08/Jul/2019 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 54 of 54 
13. 
DOCUMENTATION OF STATISTICAL METHODS 
Appendix 16.1.9.2.1 
Comparison of M24HR on Tesofensine Days by Day (PD Population) 
Appendix 16.1.9.2.2 
Comparison of M24HR of Days 14, 17 and 20 by subsequent Metoprolol dose 
(Pharmacodynamic Population) 
Appendix 16.1.9.2.3 
Comparison of M24HR of Days 17, 20 and 23 by preceding Metoprolol dose 
(Pharmacodynamic Population) 
Appendix 16.1.9.2.4 
Comparison of Change from Baseline M24HR by Metoprolol dose (PD 
Population) 
Appendix 16.1.9.2.5 
WinNonLin Outputs