Muscle Strength and -Mass After Bariatric Surgery - a Possible Effect of Testosterone Replacement Therapy? Randomized, Placebo-controlled and Double-blinded Study
Phase: PHASE4
Conditions: Bariatric Surgery Candidate, Male Hypogonadism, Muscle Loss
Sponsor: Esbjerg Hospital - University Hospital of Southern Denmark

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
1 
Protocol 
Testosterone in bariatric patients 
 
 
 
 
 
Title 
Muscle strength and -mass after bariatric surgery - a possible effect of 
testosterone replacement therapy?  
Randomized, placebo-controlled and double-blinded study 
 
 
 
 
 
Research group 
Hospital of Southwest Jutland and Odense University Hospital, the Endocrinology units:  
Line Velling Magnussen 
Hospital of Southwest Jutland, the Endocrinology unit and bariatric team:  
Alin Andries, Claus Juhl and Bibi Gram 
Odense University Hospital, the Endocrinology unit:  
Jeppe Gram, Marianne Andersen, Dorte Glintborg and René Støving 
 
 

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
2 
TABLE OF CONTENTS 
 
1. GENERAL INFORMATION……………………………………………………………………. 3 
2. INTRODUCTION………………………………………………………………………………... 5 
3. TRIAL PLAN AND DESIGN…………………………………………………………………… 7  
4. STUDY POPULATION………………………………………………………………………….. 9  
5. TREATMENT OF PATIENTS…………………………………………………………………. 10 
6. EVALUATION OF EFFECT…………………………………………………………………... 13 
7. SAFETY……………………………………………………………………………………….... 16  
8. STATISTICS……………………………………………………………………………………. 17 
9. SOURCE DATA………………………………………………………………………………... 18 
10. QUALITY CONTROL AND QUALITY ASSURANCE…………………………………….. 18 
11. ETHICAL QUESTIONS………………………………………………………………………. 18 
12. HANDLING AND ARCHIVING DATA……………………………………………………... 19 
13. BIO BANK…………………………………………………………………………………….. 20 
14. FINANCING AND INSURANCE……………………………………………………………. 20   
15. GUIDELINES FOR PUBLICATION……………………………………………………….… 20 
16. SUMMARY AND APPENDICES……………………………………………………………. 20 
17. LITERATURE REFERENCES……………………………………………………………….. 21 
APPENDIX…………………………………………………………………………………………24 
 
 

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
3 
1. General information 
Sponsor, primary, practical and coordinating investigator:  
Line Velling Magnussen, MD, PhD 
Phone: 29787835 
E-mail: line.velling.magnussen@rsyd.dk 
 
Investigators:  
Hospital of Southwest Jutland (SVS) and Odense University Hospital (OUH), the Endocrinology 
units:  
Line Velling Magnussen 
Hospital of Southwest Jutland, the Endocrinology unit and bariatric team 
Haraldsgade 7F, 6700 Esbjerg: 
Alin Andries, Claus Juhl and Bibi Gram 
Odense University Hospital, the Endocrinology unit 
Kløvervænget 6, 5000 Odense:  
Jeppe Gram, Marianne Andersen, Dorte Glintborg and René Støving 
 
The trial will be monitored in accordance with GCP, and the local GCP unit will help establish the 
extent of the monitoring to ensure that the trial comply with GCP and applicable law. The trial will 
be conducted according to this protocol. The study protocol will be submitted to The Danish 
Medicines Agency and the Regional Ethics Committee, notified to the Danish Data Protection 
Agency and registered at ClinicalTrials.gov. The investigations are conducted as part of a post.doc 
position at the University of Southern Denmark. 
Collaborators:  
 
KBA at SVS and OUH (biochemistry)  
 
 
Institute of Regional Health Research/Centre of Southwest Jutland (muscle strength 
 
and VO2max) 
 
Physical Therapy section (exercise counseling) 
 
The GCP-section at Odense University Hospital 
 
OPEN (randomization and eCRF) 
 
Pharmacy at OUH (handling of study medicine) 

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
4 
 
Time schedule:  
Estimated August 2018 – January 2021  
 
Sponsor, primary, practical and coordinating investigator: 
Line Velling Magnussen, MD, PhD  
Hospital of Southwest Jutland and Odense University Hospital, the Endocrinology units.  
Phone: 29 78 78 35. 
E-mail: Line.velling.magnussen@rsyd.dk 
 
                                             
______________________________________  
Date             Signature                                                                                    
 
 
 

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
5 
2. Introduction 
Obesity, poor physical fitness and low muscular strength are associated with all-cause mortality [1-
5]. Loss of bodyweight is commonly achieved by diet with or without exercise intervention. 
However, both diet and diet+exercise programs are often followed by weight regain and it is 
generally difficult to achieve long-term weight loss [6].  
There are many challenges associated with the counselling of obese and sedentary individuals in 
order to increase their physical activity (PA), and there may be a need for a tight schematic 
counselling to achieve positive results [7]. Additionally, promoting PA among patients that have 
undergone bariatric surgery has also shown to be challenging [8, 9] even though PA may be of a 
great importance regarding several postoperative outcomes [9-12]. Lifestyle changes following 
bariatric surgery may be important for the overall effect of the BS in the long term. Therefore, it is 
vital to find an appropriate and well-suited setting to improve PA among these patients. When 
structuring PA counselling, the five A´s (Assess, Advise, Agree, Assist, Arrange) might be a helpful 
tool and it is considered important to engage the patients in PA counselling both before and after the 
surgery [9, 13]. 
Loss of bodyweight reduces morbidity and mortality [14]. Bariatric surgery is the most effective 
method to treat severe obesity and type 2 diabetes mellitus achieving high remission rates [15]. 
However, weight loss also decreases skeletal muscle mass [16, 17] which might counterbalance the 
positive effects of a bariatric surgery since low lean body mass is linked to increased mortality 
under various circumstances (i.e., heart disease, cancer, burn injuries) [18]. Furthermore, a 
substantial loss of bone mass is seen after bariatric surgery [19, 20] despite weight stability in the 
second-year post-operative [19], which could have important clinical implications for long-term 
skeletal health with increased fracture risk [19, 21]. On the other hand, the loss of muscle and bone 
mass could merely be a natural adaptation to a lower weight after bariatric surgery. Studies trying to 
establish whether the loss of muscle mass is disproportionately in patients following bariatric 
surgery compared to BMI-matched controls are conflicting, showing lower muscle mass in both 
sexes after surgery compared with their respective matched controls assessed by magnetic 
resonance imaging in one study [22] whereas another study has shown comparable fat-free mass 24 
months post-operative assessed by bioelectric impedance [23]. Currently, there are no effective 
approaches to prevent the immense loss of muscle and bone mass following bariatric surgery [18] 
although several approaches can be considered, e.g. exercise and dietary intervention [24].  

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
6 
Low testosterone levels have been associated with sarcopenia, insulin resistance, increased body fat, 
reduced quality of life and loss of libido and sexual function. Testosterone therapy increases lean 
body mass (i.e. muscle mass), improves bone density and decreases fat mass [25]. As up to 78.8% 
of patients undergoing bariatric surgery suffer from low testosterone levels [26-28], testosterone 
therapy prior to and after bariatric surgery may prevent or reduce the considerable loss of muscle 
mass during the weight loss period [29]. So far, no studies have evaluated the effect of testosterone 
therapy combined with exercise and diet counselling on body composition and quality of life in men 
undergoing bariatric surgery. 
 
Testosterone therapy and cardiovascular risk 
Studies on cardiovascular risk during testosterone therapy are conflicting. A study in old men with 
limitations in mobility showed significantly more cardiovascular events during testosterone therapy 
compared to placebo and the study was ended prematurely [30]. Low HDL levels are linked to an 
increased morbidity and mortality of cardiovascular disease. A significant small decrease in HDL 
cholesterol levels in men treated with testosterone was reported in a meta-analysis [31] and a 
systematic review [32]. However, a large observational study on pooled data in obese, hypogonadal 
diabetic men during six years of testosterone therapy reported a favorable change in lipid profile 
along with reduced pulse pressure and reduced arterial stiffness, which are independent risk factors 
for cardiovascular disease [33]. Another approach in clarifying the effect of testosterone therapy on 
cardiovascular disease risk is the evaluation of biomarkers for cardiovascular disease during 
therapy, i.e. soluble Klotho, a protein, which may function as a hormone [34]. Higher levels of 
soluble Klotho are independently associated with a lower likelihood of having cardiovascular 
disease [35]. To date, no reports on Klotho have been published in obese patients undergoing 
bariatric surgery during testosterone therapy. 
Few studies have addressed the influence of testosterone therapy on the haemostatic system. 
Thrombin generation (TG) measures are risk markers of cardiovascular disease and address the 
composite of multiple factors that influence blood coagulation [36]. One intervention study showed 
that i.m. testosterone treatment for one year in elderly men with low testosterone levels had no 
impact on thrombin generation measured at one year [37]. A significant number of patients 
sustaining venous thrombotic events after initiation of testosterone therapy often had inherited 
cardiovascular risk factors such as Factor V Leiden [38], and thrombotic events were primarily 

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
7 
observed within the first months of testosterone treatment, suggesting that testosterone therapy 
triggers cardiovascular events in thrombosis prone individuals. Thus, studies on both the short term 
and the long term impact of testosterone treatment on the haemostatic system are warranted [38, 
39].  
 
Pseudo-Cushing’s syndrome  
Central obesity results in a cluster of metabolic abnormalities contributing to premature death, so-
called Pseudo-Cushing’s syndrome [40]. Glucocorticoids regulate adipose-tissue differentiation, 
function and distribution, and in excess, cause central obesity. To our knowledge, no studies have 
reported results on levels of cortisol and testosterone before and after bariatric surgery. 
 
3. Trial plan and design  
General aim 
To investigate the effect and clinical relevance of testosterone therapy combined with exercise and 
diet counselling in hypogonadal men undergoing bariatric surgery. 
 
Objectives 
To evaluate the effect of testosterone therapy combined with exercise and diet counselling on 
muscle strength, body composition, hormones, components of the metabolic syndrome, 
inflammation, sexual function, and quality of life after weight loss in obese, hypogonadal men 
undergoing bariatric surgery. 
 
Perspective 
The study will investigate whether testosterone therapy can stabilize muscle function, prevent the 
substantial decrease in muscle mass (lean body mass), and improve components of the metabolic 
syndrome, inflammation and quality of life in patients after bariatric surgery. 
 
Study design 
A two centre, randomized, double-blind, placebo-controlled study on testosterone therapy combined 
with lifestyle intervention, in men eligible for bariatric surgery with low testosterone levels. Routine 

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
8 
bariatric procedure will be conducted between 3 and 6 months after inclusion. The end of the study 
is 52 weeks postoperatively.  
 
Study endpoints 
Primary outcome: 
- 
Maximal isometric muscle strength (N) in shoulder muscles (shoulder 
elevation. 
Secondary outcomes: 
- 
Regional body composition (DXA scan, BMI, Waist/hip-ratio) 
- 
Physical strength: maximal isometric muscle strength in lower extremities (hip 
extension, hip abduction), muscle strength in upper-extremities (shoulder 
abduction, shoulder adduction) 
- 
Physical function: performance-based measures of physical function (stair 
climb test) and maximal oxygen uptake (VO2max). 
- 
Glucose metabolism (HOMA-R, HbA1c, Fasting-P-Blood glucose) 
- 
Coagulation/fibrinolysis status (thrombin generation measures) 
- 
Adipokines and inflammation markers (leptin, adiponectin, hsCRP, IL-6, 
suPAR, lipid profile (HDL, LDL, triglycerides)) 
- 
Hormones and binding proteins (testosterone, SHBG, LH, FSH, prolactin, 
CBG, growth hormone-axis (IGF-I and IGF-II, IGFBPs, bioactive IGF-I), 
cortisol, aldosterone, Cortisol and cortisol metabolites) 
- 
Vascular markers (soluble Klotho, fibulin-1) 
- 
Bone markers and calcitropic hormones (osteocalcin, PINP, 1CTP, CTX, PTH, 
25OH-vitaminD, 1.25(OH)2-Vitamin-D) 
- 
Quality of life and sexual function (International Index of Erectile Function 
(IIEF-5), Major Depression Inventory (MDI), World Health Organization Well 
Being Index (WHO-5), Physical function component of Vitality scale of Short 
Form 36 (SF36) 
 
 

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
9 
Method  
A randomized, double-blind, placebo-controlled intervention study in men eligible for bariatric 
surgery and low testosterone levels (total testosterone < 12.0 nmol/l [41]). Routine bariatric 
procedure will be conducted between 3 and 6 months after inclusion. 
 
4. Study population 
Recruitment 
Patients will be recruited among bariatric patients at Hospital of Southwest Jutland and at Odense 
University Hospital. As part of a review of existing clinical practice in the Region of Southern 
Denmark, patients who are entitled to bariatric surgery are currently subject to an audit with the 
establishment of a quality and research database. As part of the audit, patients have had their 
testosterone levels in the blood measured. MD Line Velling Magnussen (LVM) may obtain these 
results from the journal, if there is a signed consent statement during the audit, where the patients 
also have agreed to be contacted for future projects, where their participation will be relevant. MD 
LVM may phone those patients with low testosterone levels and send the written information  
regarding the trial along with the booklets ”Før du beslutter dig” and ”Forsøgspersoners rettigheder 
i et sundhedsvidenskabeligt forskningsprojekt”, if agreed by the patients. Patients are informed that 
they are entitled to bring a bystander for the oral information. Those who may wish to participate, 
are contacted on the first day of the participation of the patient school at the Southwest Hospital of 
Jutland, Esbjerg (as part of the standard treatment procedure prior to bariatric surgery), where a MD 
from the research team, all of whom have experience within the field of bariatri and GCP 
experience, will provide oral information regarding the trial. The information is giving in a suitable 
room, ensuring that the conversation can take place without interference. After the oral information, 
the patient has minimum 24 hours to think about participation. Upon acceptance, time is given for 
visits, screening blood samples and obtaining written informed consent.  Inclusion will be in the 
beginning of the mandatory 8% weight loss period lasting 3-6 months.  
 
 

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
10 
Overview:  
 
Randomization 
After the baseline assessment, the patients will be randomly assigned to either testosterone or 
placebo. The randomization sequence will be created using OPEN Randomise, stratifying patients 
with a 1:1 allocation using random block sizes of 2, 4 and 6. The allocation sequence will be 
concealed from the researcher enrolling and OPEN Randomise will send an e-mail to an email 
address each time a randomization is performed. 
 
Inclusion criteria  
 
- 
Eligible for bariatric surgery according to the Danish national criteria (i.e. aged 18‒60 years, 
BMI >35 kg/m2 with specific secondary disease or BMI >40 kg/m2 with significant health 
issues assessed by the multidisciplinary bariatric team) [42] 
- 
Caucasian men 
- 
Total testosterone < 12.0 nmol/l 
- 
No contraindications for testosterone treatment 
 
Exclusion criteria  
 
- 
Previously diagnosed with prostate, mammae or liver cancer. Any other cancer within the 
last 5 years. 
- 
Hypersensitivity to the active substance or to any of the excipients in Nebido® 
- 
Symptomatic heart disease NYHA >2 
- 
Recently thromboembolic disease <3 months 
- 
PSA >4.0 ug/l or PSA>3.0 ug/l and lower urinary tract symptoms 
- 
Disability that severely affect the ability to perform exercise training 
- 
EVF > 52% 

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
11 
 
The following treatments are not allowed in the study 
- 
5-α-reductase inhibitors 
- 
Prednisolone >5mg/day 
 
5. Treatment of patients 
Treatment regimen 
- 
Inj. Testosterone undecanoat (Nebido®), 1000 mg im or placebo preoperative (baseline, 
weeks 6, 18 and 30 depending on time to surgery) and postoperative (weeks 4, 16, 28, 40) 
(Table 1). 
- 
Administration: deep and slow (over two minutes) intragluteal injection 
- 
Due to the risk of anaphylaxis, patients are observed at least 30 minutes on the test site after 
the first two injections 
 
Non-pharmacological intervention 
- 
Routine bariatric procedure (Roux en Y gastric bypass or sleeve gastrectomy). Surgery will 
be conducted between 3 and 6 months after inclusion.  
- 
Lifestyle intervention program: Routine instructions on diet and dietary precautions after 
surgery [43] and individual exercise counseling three times after surgery. 
 
Contraindications Testosteron undecanoate (ATC-code G03BA03)    
- 
previously diagnosed with prostate, mammae or liver cancer. Any other cancer within the 
last 5 years.   
- 
hypersensitivity to the active substance or to any of the excipients  
Caution in 
- 
cardiac insufficiency, especially known ischemic heart disease and hypertension 
- 
hepatic or renal insufficiency 
- 
clotting disorders / anti-coagulant treatment 
- 
known epilepsy and migraine  
- 
pre-existing sleep apnoea 
 

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
12 
Adverse reactions (see Appendix). 
 
Study medicine is administered at the departments of endocrinology at SVS or OUH. Study 
medicine is handled according to annex 13. 
Patients are treated with Testosterone Undecanoate 1000 mg/4 ml, intramuscular (i.m.) or placebo. 
Study medicine and placebo have been produced by Bayer Health Care. Packing, blinding, labeling 
and randomization of study medicine are done by the pharmacy of Odense University Hospital  
according to annex 13: Name of sponsor, route of administration, batch number, trial reference 
code, user manual for study medicine, storage of study medicine expiration date (a copy of the label 
is placed in the trial master file). 
The medicine (active and placebo) is delivered to the pharmacy from Bayer with no labels. Identical 
labels will be put on the ampules, with the exception of the randomization number. 
Study medicine can be used only in clinical trials. 
Sponsor is responsible for the destruction of surplus medicine. 
 
Medicine records  
All medicine is accounted for in total and for every patient. The records are kept in the trial master 
file. The randomization code is kept according to law. The procedure for code breakage: In case of 
a medical emergency an investigator is allowed to break code and inform whether testosterone or 
placebo is administered. Other members of the study group will remain blinded. The patient will be 
excluded from the study if the code is broken. Testosterone treatment is a registered treatment. It is 
not of clinical significance for further acute treatment to know within 24 hours if a patient is in 
active treatment or not. All the investigators who are medical doctors are affiliated with one the 
departments of endocrinology at SVS or OUH. At least one of these investigators has their cell 
phone open 24 hours a day, also during vacations. 
 
Discontinuation of study treatment 
Treatments stop: 
- 
Confirmed increase in serum PSA > 3 ug/l and clinical symptoms and at least 20% increase 
since baseline is followed by referral to urological evaluation  
- 
Suspicion of prostate cancer 

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
13 
- 
Hematocrit (EVF) > 0.52 and at least 20% increase since baseline 
- 
Serum ALAT >3 times upper normal limit and at least 20% increase since baseline  
- 
Patients can leave the study prior to end of study, due to safety issues (increased safety 
parameters), fulfillment of exclusion criterion, at own request or due to lack of compliance 
including failure to achieve 8% weight loss prior to operation. 
 
Pharmacokinetics 
Nebido® slowly releases testosterone after intramuscular injection with no first-pass effect. 
Testosterone is metabolized in the liver (CYP3A4) to active metabolites estradiol and 
dihydrotestosterone. An increase in serum levels of testosterone above basal values may be seen 
one day after administration, and has an average half-life time of 50-130 days. Steady-state 
conditions are expected to be achieved between the 3rd and the 5th administration with constant 
dosing interval of 10 weeks during the following administrations. The median intra- and inter-
individual variability (coefficient of variation, %) of Cmin values was 22 % (range: 9-28%) and 
34% (range: 25-48%), respectively. 
 
 
 
 

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
14 
6. Evaluation of effect 
Assessments according to visits: 
Table 1 
 
Pre-operative 
Per/Post-operative 
 
Baseline 
W 
6 
W 
18 
W 
30 
W 
0 
W 
4 
W 
16 
W 
28 
W 
40 
W 
52 
Testosterone injection* 
X 
X 
X 
X 
 
X** 
X 
X 
X 
 
Safety 
X 
X 
X 
 
X 
 
X 
X 
 
X 
Exercise and diet counseling 
X 
 
 
 
X 
 
 
X 
 
X 
Muscle strength and VO2max test 
X 
 
 
 
X 
 
 
X 
 
X 
Physical examination 
X 
 
 
 
X 
 
 
X 
 
X 
Blood samples 
X 
 
 
 
X 
 
 
X 
 
X 
Urine samples 
X 
 
 
 
X 
 
 
 
 
X 
Body composition (DEXA scan) 
X 
 
 
 
X 
 
 
X 
 
X 
Questionnaires 
X 
 
 
 
X 
 
 
X 
 
X 
Dexamethasone suppression test 
X 
 
 
 
X 
 
 
 
 
X 
W=weeks, W0= from one to seven days before operation. 
* Number of injections depends on time to achieve the mandatory 8% preoperative weight loss. The 
testosterone injection needs to be applied in the preoperative period at Weeks 6 and hereafter every 
12 weeks, correspondingly Weeks 18 and Weeks 30 if necessary. 
** The first time for injection in the postoperative period will be 12 weeks after the last injection 
during the preoperative period. Injection within 4 weeks before planned surgery is postponed to 
week 4 +/- 2 weeks postoperatively. 
 
Blood samples  
1) Hormones and binding proteins: Total testosterone, SHBG, LH, FSH, prolactin, CBG, growth 
hormone-axis (IGF-I and IGF-II, IGFBPs, bioactive IGF-I), cortisol, ACTH 
2) Adipokines and inflammation markers (leptin, adiponectin, hsCRP, IL-6, suPAR, YKL40, 
GDF15, sCD36, FGF23, phosphate, total-calcium, lipids) 

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
15 
3) Vascular markers (aldosterone, fibulin-1, soluble Klotho) 
4) Bone markers and calcitropic hormones (osteocalcin, PINP, 1CTP, CTX, PTH, 25OH-vitaminD) 
5) Glucose metabolism: s-insulin, HbA1c, Fasting-P-Blood glucose 
6) Safety parameters (hemoglobin, hematocrit, PSA, ALAT) 
7) Coagulation/fibrinolysis status (thrombin generation measures) 
 
Urine samples 
Diurnal U-Cortisol and cortisol metabolites 
 
Body composition  
Whole body composition, lumbar and hip bone mineral density and will be assessed using Dual x-
ray absorptiometry (DEXA) on Hologic Discovery devices (Waltham, MA, US). DXA scans will 
be performed at the Department of Endocrinology, SVS. 
 
Questionnaires 
The participants will be asked to fill in standardized and validated questionnaires regarding quality 
of life and sexuality: 
 
- 
Short Form 36 (SF-36) from Qualimetrics (qualimetrics.com) 
- 
IIEF5 –International Index of Erectile Function, copyright of Pfizer Danmark, Lautrupvang 
8, 2750 Ballerup 
- 
Major Depression Inventory (MDI) 
- 
World Health Organization Well Being Index (WHO-5) 
 
Dexamethasone suppression test  
The test is used in diagnosing Cushing's syndrome by measuring how cortisol levels change in 
response to 1 mg dexamethasone overnight.  
 
 
 

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
16 
Physical examination 
1) Body weight: will be measured on calibrates scales with patients only wearing their underwear 
(no shoes) 
2) Height: will be measured without shoes 
3) BMI will be calculated by the formula weight/height² (kg/m²) 
4) Waist: will be measured in the middle of the distance between the 12th rib and antero-superior 
iliac spine, while keeping the measuring tape parallel with the floor 
5) Hip: will be measured across the widest part of the hips while keeping the tape parallel to the 
floor 
5) Waist/hip ratio will be computed 
6) Blood pressure measures thrice while sitting (the participants are to be seated at least 5 minutes 
prior to the measurements). The mean of the last two measurements is registered 
7) Testicular volume will be assessed by using Prader orchid meter 
8) Changes in primary and secondary sex characteristics (breast size / gynecomastia and pubic hair) 
will be assessed by using the Tanner scale  
 
Muscle strength testing  
1) Muscle strength: Maximal isometric muscle strength will be measured with a Bofors MODEL 
dynamometer (Bofors Elektronik, Karlskoga, Sweden). Three maximal voluntary contractions 
(MVC) with 30 seconds of recovery between attempts will be conducted, and the highest value will 
be recorded. Maximal force and the corresponding moment arm will be registered [44]. 
2) VO2 max and functional capacity: Maximal oxygen uptake will be estimated from the relation 
between sub-maximal workload and stable heart rate obtained in Åstrand one-point sub-max test 
[45]. The bike test will be conducted by using Monark 939E electronic ergometer work test bike 
(939E) which is digitally controlled and has embedded protocol and calculation of max VO2 
(Astrand formula). The pedaling frequency will be adjusted at 60 rounds per minute and the initial 
workload is 450 kilopond meter/minute (corresponding to ~ 75 watt). 
3) Functional capacity will be estimated using stair-climb test. The outcome is the number of times 
the subjects are able to reach the stairs up and down for a period of one minute. 
 
 
 

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
17 
7. Safety evaluation 
Monitoring:  
- 
Physical examination (baseline, per/postoperative weeks 0, 28 and 52) (Table 1) 
- 
Biochemical examinations: 1. testosterone levels (baseline) 2. PSA, EVF, ALAT (baseline, 
preoperative weeks 6 and 18, postoperative weeks 0, 16, 28 and 52) 
- 
Clinical relevant abnormal measurements are repeated 
Safety parameters: 
- 
Measurements of hematocrit: testosterone therapy increases the hematocrit level and high 
levels of hematocrit leads to higher risks of venous thrombosis (Danish Urological Society 
(DUS) 2013). 
- 
In order to take into account the Danish Urology Cancer Group (DUCG) 2013 report on 
prostate cancer,  and the Danish Urological Society report on androgen substitution (2013) 
the exclusion criterion for PSA in the study is based on the above level. 
 
Registration and reporting of adverse events: 
An adverse event: Any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment.  
A serious adverse event: Any untoward medical occurrence or effect that at any dose results in 
death is life threatening, requires hospitalization or prolongation of existing hospitalization, results 
in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect. All 
serious adverse events are reported from investigator to sponsor within 24 hours of becoming 
aware. 
Adverse events are reported to Danish health and medicines authority and regional ethics committee 
according to current guidelines. Other investigators are informed.  
The sponsor ensures that all relevant information about suspected unexpected serious adverse 
reactions (SUSARs) that are fatal or life threatening is recorded and reported as soon as possible to 
the competent authorities and to the Ethics Committee no later than seven days after knowledge by 
the sponsor of such a case. Relevant follow-up information is subsequently communicated within 
an additional eight days.  

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
18 
All other suspected serious unexpected adverse reactions will be reported to the Danish health and 
medicines authority (DKMA) and to the Ethics Committee concerned as soon as possible but within 
a maximum of 15 days of first knowledge by the sponsor. The sponsor is obliged to inform all 
investigators. 
A definition of a suspected unexpected serious adverse reaction (SAR) is as follows: An adverse 
reaction, the nature or severity of which is not consistent with the applicable product information as 
not being according to the summary of product characteristics of Nebido®. The reference document 
used is the specified product summary for Nebido® (section 4.8 of the summary), when assessing 
whether a SAR is unexpected/expected, thus possibly becoming a SUSAR. 
SUSARs are reported electronically (e-blanket) to DKMA. 
All adverse events are registered. Sponsor is obliged to report a list of serious adverse events to 
DKMA and the regional ethics committee annually.  
Sponsor will forward serious adverse events and suspected unexpected serious adverse reaction to 
Bayer within 24 hours of becoming aware. 
 
Treatment of complications and follow-up: 
- 
Patients will be referred to the relevant specialist department for further control and possible 
treatment. 
Criteria for end of study:  
- 
The study will end after 52 weeks of testosterone therapy postoperatively. The patients will 
be offered a visit in the clinic six months after end of study. 
- 
Patients can leave the study prior to this due to safety issues (increased safety parameters), 
fulfillment of exclusion criterion, at own request or due to lack of compliance including 
failure to achieve 8% weight loss prior to operation. 
 
8. Statistics 
Sample size: The power and sample size calculation is based on the primary outcome maximal 
voluntary isometric contraction in shoulder muscles (shoulder elevation) after the intervention. To 
detect a minimal relevant difference between (MIREDIF) of 14% [46] the groups with a two-sided 
significance level of 0.05 assuming a SD of 34 N [46], and to obtain a power 80%, it is required to 

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
19 
enroll 18 patients in the ITT-population. We will include 25 participants in each group to account 
for drop outs. 
Statistical analyses: All data being collected, primary and secondary outcomes will be analyzed 
according to the ITT principle. Missing data were handled by multiple imputations, assuming 
missing values were randomly distributed. Baseline demographic and clinical characteristics will be 
reported descriptively for all patients in the full analysis set. For assessments of change from 
baseline, analyses of covariance (ANCOVA) will be applied, with treatment assignment serving as 
the main factor and the baseline value as covariate. Unless stated otherwise, results will be 
expressed as the difference between the group means with 95% confidence interval. P values will 
be reported if appropriate. Significance level: 5%. Additionally to the ITT analyses per protocol 
analyses will be conducted. 
 
9. Source data 
Source data includes patient journals and laboratory/scan reports using eCRF in REDCap through 
OPEN. Direct access to source data is allowed in monitoring of the study, audit and inspection from 
ethics committee, Danish health and medicines authority, the Danish data protection agency and 
other relevant health authorities. This is accepted by participants in a written authorization. 
 
10. Quality control and quality assurance 
Quality control and securing of quality is done according to §§ 3 and 4 in the GCP–guidelines, 
annex 3 and GCP guidelines section 1.46 and 1.47. 
 
 
11. Ethical questions 
An increasing number of patients become obese. Bariatric surgery is an effective method in the 
treatment of severe obesity and T2D achieving high remission rates. However, weight loss also 
decreases skeletal muscle mass. Obesity together with poor physical fitness and low muscular 
strength is associated to all-cause mortality. As many patients undergoing bariatric surgery suffer 
from low testosterone levels, testosterone therapy may prevent the immense loss of muscle mass 
together with physical and diet counselling in these patients. So far, no other treatment has 
prevented this loss of muscle mass. Hence a study like this is needed to investigate if testosterone 
therapy in these patients will be beneficial.  

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
20 
Nebido® is registered in Denmark. Injection with testosterone or placebo can be uncomfortable for 
some. The drug is administered in the gluteal muscle and local swelling and redness of the skin can 
be observed. This is temporary and safe. The study is in accordance with the Helsinki II declaration 
and is reported to the regional ethics committee and the Danish health and medicines authority. 
Individuals found eligible to bariatric surgery and who accept to undergo the operation will be 
included in the study at the beginning of the mandatory 8% preoperative 6 month’s weight loss 
period. Individuals will be recruited among patients referred to bariatric surgery at Hospital of 
Southwest Jutland and at Odense University Hospital. Patients will be asked at their first attendance 
at the clinic if they would like to consider participation in the study and if so they will receive 
written information regarding the study and they will be contacted by MD Line Velling Magnussen. 
It will be emphasized that participation is voluntary and that the consent can be withdrawn at any 
time and that this will not have any relevance further treatment. The written information concerning 
the trial will follow guidelines regarding information and consent requirements. All patients will be 
provided written information material (see appendix). For oral information, this will include an 
explanation of the written information and a further description of the study. Information relating to 
patients is protected by the law on the processing of personal data and the law on patients' legal 
status. 
In this trial, half of the patients are treated with Nebido®, which is an approved and marketed 
testosterone product. The other half will receive injection with placebo. Placebo is necessary during 
this double-blinded study for methodological reasons. It could affect the results of the trial, if the 
patients or healthcare staff know in advance whether active treatment is given or not. As always, in 
clinical trials, unknown effects or complications might occur. Patients cannot be guaranteed effect 
of treatment, but it is highly probable that: The patients randomized to Nebido® experience an 
improvement in their muscle mass and muscle strength, as well as improved quality of life and 
reduced symptoms associated with low testosterone levels. The patients randomized to placebo will 
receive counseling in relation to exercise before and after bariatric surgery compared to standard 
procedure. As standard treatment is used as comparative treatment, no one is treated differently or 
worse compared to the normal treatment procedure, including standard follow-up by physician, 
dietitians and nurses in the clinic. The knowledge gained through the experiment will contribute 
with significant scientific information of importance to the future treatment of men undergoing 
bariatric surgery. Thus, it is the opinion of the investigators that the trial is relevant and ethical. 

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
21 
The DXA scans in the study program give rise to a radiation dose of 1 mSV, which corresponds to 
1/7 of the background radiation per year in Denmark. Exposure for 1 mSv increases the risk of 
dying of cancer by 0.005%. The background risk of dying of cancer in Denmark is 25%. 
Participation in the project will mean exposure to ionizing radiation for patients, which will give 
rise to a risk increase from 25% to 25.00125%. This does not affect current or future health. 
The patients will be offered a visit in the clinic six months after end of study including a physical 
examination and control of androgen status. 
 
12. Handling and archiving data 
Data is handled and filed according to EMEA guidelines for Good Clinical Practice section 5.5. 
Data is collected and analyzed electronically (OPEN) and no unauthorized access to data is allowed. 
Original data is filed according to one participant number. 
The study is reported to the Danish Data Protection Agency (joint report from the Region of 
Southern Denmark) and will be handled according to the regulations of the Act on Processing of 
Personal Data. Data will be stored for 10 years. 
This is a privately initiated trial and hence sponsor is responsible for data. Information on 
concomitant medication and patient history from the medical journal will be given to the 
investigator as part of the inclusion procedure to secure that the exclusion criteria are met and later 
on for the evaluation of the effect of testosterone therapy in patients undergoing bariatric surgery. In 
the latter case referring to data observed during the study: physical examination (weight, height, hip 
goal, waist circumference, breast development, blood pressure), blood tests and urine tests.     
 
13. Bio bank 
A research bio bank will be established for blood (approximately 200 ml) and urine (approximately 
300 ml) per participant. The purpose is to analyze blood and urine according to section 6 as part of 
this trial. Some of the analyses will be conducted during the trial due to evaluation of “safety”, lack 
of resistance to freezing or as part of everyday analyses, whereas other analyses will be performed 
after end of trial due to economic and/or methodological reasons. If the research group wishes to 
carry out other analyzes than those approved in the current project material, the Regional Ethics 
Committee must be requested for permission. After the study is finished, the remaining material 
will be fully anonymized and kept for 10 years and then destroyed. 

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
22 
 
14. Financing and insurance 
Investigator initiated research project. Funding is obtained from Hospital of Southwest Jutland, 
Odense University Hospital and Region of Southern Denmark. The investigators and the 
departments of endocrinology have no financial gain regarding the study and no conflict of interest 
that could be perceived as prejudicing the impartiality of this study. The patients will not receive 
payment. The placebo and Nebido have been donated by Bayer. There will be applied for additional 
research grants. 
The study is conducted under the insurance of the department of endocrinology, SVS. 
The grant from the Region of Southern Denmark has been placed on a project account by Deputy 
Head in “økonomi og planlægning” Morten Lyhne Jørgensen at the Hospital of Southwest Jutland. 
Sted no. 101 123 190 123. Account 138 61 633 04. 
 
Budget 
 
 
15. Guidelines for publication  

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
23 
The study is registered at clinicaltrials.gov and publication is according to the Vancouver 
regulation. 
The study group is obliged to publish positive, inconclusive as well as negative results. Sponsor 
will inform the Danish medicines agency no later than 90 days after study end and 1 year after 
study end report study outcomes to the Danish medicines agency (lov om lægemidler § 89, stk. 2, 
nr. 4). In summarized form: number of treated patients, used doses, results and adverse events. The 
Danish medicines agency can ask for the full study report. 
 
16. Summary and appendices.  
Resume 
Bariatric surgery is an effective method in the treatment of severe obesity and type 2 diabetes 
mellitus achieving high remission rates. However, weight loss also causes loss of skeletal muscle 
and bone mass which at least partly could be prevented by exercise and dietary intervention 
although the counselling of obese and sedentary individuals in order to increase their physical 
activity presents a challenge. As up to 78.8% of men undergoing bariatric surgery have low levels 
of testosterone, testosterone therapy could be considered an attractive alternative or supplement to 
prevent the immense loss of muscle mass during weight loss. Furthermore, low testosterone levels 
are associated with sarcopenia, insulin resistance, increased body fat, reduced quality of life, loss of 
libido and reduced sexual function. The study is a long-term randomized, placebo-controlled trial 
investigating the effects of testosterone therapy combined with exercise and diet counselling on 
body composition, components of the metabolic syndrome, hormones, inflammation, sexual 
function and quality of life before and after weight loss in obese, hypogonadal men undergoing 
bariatric surgery. 
 
17. Literature references 
1. 
Ruiz JR, Sui X, Lobelo F, Morrow JR, Jr., Jackson AW, Sjostrom M, Blair SN: Association between 
muscular strength and mortality in men: prospective cohort study. BMJ (Clinical research ed) 
2008, 337:a439. 
2. 
Laukkanen JA, Rauramaa R, Salonen JT, Kurl S: The predictive value of cardiorespiratory fitness 
combined with coronary risk evaluation and the risk of cardiovascular and all-cause death. J 
Intern Med 2007, 262(2):263-272. 
3. 
Laukkanen JA, Rauramaa R, Kurl S: Exercise workload, coronary risk evaluation and the risk of 
cardiovascular and all-cause death in middle-aged men. European journal of cardiovascular 
prevention and rehabilitation : official journal of the European Society of Cardiology, Working 

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
24 
Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology 2008, 
15(3):285-292. 
4. 
Blair SN, Kohl HW, 3rd, Paffenbarger RS, Jr., Clark DG, Cooper KH, Gibbons LW: Physical fitness and 
all-cause mortality. A prospective study of healthy men and women. JAMA : the journal of the 
American Medical Association 1989, 262(17):2395-2401. 
5. 
Blair SN, Kampert JB, Kohl HW, 3rd, Barlow CE, Macera CA, Paffenbarger RS, Jr., Gibbons LW: 
Influences of cardiorespiratory fitness and other precursors on cardiovascular disease and all-
cause mortality in men and women. JAMA : the journal of the American Medical Association 1996, 
276(3):205-210. 
6. 
Wu T, Gao X, Chen M, van Dam RM: Long-term effectiveness of diet-plus-exercise interventions 
vs. diet-only interventions for weight loss: a meta-analysis. Obesity reviews : an official journal of 
the International Association for the Study of Obesity 2009, 10(3):313-323. 
7. 
Creel DB, Schuh LM, Reed CA, Gomez AR, Hurst LA, Stote J, Cacucci BM: A randomized trial 
comparing two interventions to increase physical activity among patients undergoing bariatric 
surgery. Obesity (Silver Spring) 2016, 24(8):1660-1668. 
8. 
Crisp AH, Verlengia R, Ravelli MN, Junior IR, de Oliveira MRM: Changes in Physical Activities and 
Body Composition after Roux-Y Gastric Bypass Surgery. Obes Surg 2017. 
9. 
King WC, Bond DS: The importance of preoperative and postoperative physical activity counseling 
in bariatric surgery. Exercise and sport sciences reviews 2013, 41(1):26-35. 
10. 
Mundbjerg LH, Stolberg CR, Cecere S, Bladbjerg EM, Funch-Jensen P, Gram B, Juhl CB: Supervised 
Physical Training Improves Weight Loss After Roux-en-Y Gastric Bypass Surgery: A Randomized 
Controlled Trial. Obesity (Silver Spring, Md) 2018, 26(5):828-837. 
11. 
Stolberg CR, Mundbjerg LH, Funch-Jensen P, Gram B, Bladbjerg EM, Juhl CB: Effects of gastric 
bypass surgery followed by supervised physical training on inflammation and endothelial 
function: A randomized controlled trial. Atherosclerosis 2018, 273:37-44. 
12. 
Stolberg CR, Mundbjerg LH, Funch-Jensen P, Gram B, Juhl CB, Bladbjerg EM: Effects of gastric 
bypass followed by a randomized study of physical training on markers of coagulation activation, 
fibrin clot properties, and fibrinolysis. Surg Obes Relat Dis 2018. 
13. 
Whitlock EP, Orleans CT, Pender N, Allan J: Evaluating primary care behavioral counseling 
interventions: an evidence-based approach. Am J Prev Med 2002, 22(4):267-284. 
14. 
Flegal KM, Kit BK, Orpana H, Graubard BI: Association of all-cause mortality with overweight and 
obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA 
: the journal of the American Medical Association 2013, 309(1):71-82. 
15. 
Lee WJ, Chong K, Chen JC, Ser KH, Lee YC, Tsou JJ, Chen SC: Predictors of diabetes remission after 
bariatric surgery in Asia. Asian J Surg 2012, 35(2):67-73. 
16. 
Chaston TB, Dixon JB, O'Brien PE: Changes in fat-free mass during significant weight loss: a 
systematic review. Int J Obes (Lond) 2007, 31(5):743-750. 
17. 
Carey DG, Pliego GJ, Raymond RL, Skau KB: Body composition and metabolic changes following 
bariatric surgery: effects on fat mass, lean mass and basal metabolic rate. Obesity surgery 2006, 
16(4):469-477. 
18. 
Katsanos CS, Madura JA, 2nd, Roust LR: Essential amino acid ingestion as an efficient nutritional 
strategy for the preservation of muscle mass following gastric bypass surgery. Nutrition (Burbank, 
Los Angeles County, Calif) 2016, 32(1):9-13. 
19. 
Yu EW, Bouxsein ML, Putman MS, Monis EL, Roy AE, Pratt JS, Butsch WS, Finkelstein JS: Two-year 
changes in bone density after Roux-en-Y gastric bypass surgery. The Journal of clinical 
endocrinology and metabolism 2015, 100(4):1452-1459. 
20. 
Fleischer J, Stein EM, Bessler M, Della Badia M, Restuccia N, Olivero-Rivera L, McMahon DJ, 
Silverberg SJ: The decline in hip bone density after gastric bypass surgery is associated with 

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
25 
extent of weight loss. The Journal of clinical endocrinology and metabolism 2008, 93(10):3735-
3740. 
21. 
Shanbhogue VV, Stoving RK, Frederiksen KH, Hanson S, Brixen K, Gram J, Jorgensen NR, Hansen S: 
Bone structural changes after gastric bypass surgery evaluated by HR-pQCT: a two-year 
longitudinal study. European journal of endocrinology / European Federation of Endocrine Societies 
2017, 176(6):685-693. 
22. 
Korner J, Punyanitya M, Taveras C, McMahon DJ, Kim HJ, Inabnet W, Bessler M, Gallagher D: Sex 
differences in visceral adipose tissue post-bariatric surgery compared to matched non-surgical 
controls. Int J Body Compos Res 2008, 6(3):93-99. 
23. 
Strain GW, Ebel F, Honohan J, Gagner M, Dakin GF, Pomp A, Gallagher D: Fat-free mass is not lower 
24 months postbariatric surgery than nonoperated matched controls. Surg Obes Relat Dis 2017, 
13(1):65-69. 
24. 
Srinivas-Shankar U, Roberts SA, Connolly MJ, O'Connell MD, Adams JE, Oldham JA, Wu FC: Effects 
of testosterone on muscle strength, physical function, body composition, and quality of life in 
intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. 
The Journal of clinical endocrinology and metabolism 2010, 95(2):639-650. 
25. 
Isidori AM, Giannetta E, Greco EA, Gianfrilli D, Bonifacio V, Isidori A, Lenzi A, Fabbri A: Effects of 
testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: 
a meta-analysis. Clinical endocrinology 2005, 63(3):280-293. 
26. 
Luconi M, Samavat J, Seghieri G, Iannuzzi G, Lucchese M, Rotella C, Forti G, Maggi M, Mannucci E: 
Determinants of testosterone recovery after bariatric surgery: is it only a matter of reduction of 
body mass index? Fertility and sterility 2013, 99(7):1872-1879 e1871. 
27. 
Pellitero S, Olaizola I, Alastrue A, Martinez E, Granada ML, Balibrea JM, Moreno P, Serra A, Navarro-
Diaz M, Romero R et al: Hypogonadotropic hypogonadism in morbidly obese males is reversed 
after bariatric surgery. Obes Surg 2012, 22(12):1835-1842. 
28. 
Boonchaya-Anant P, Laichuthai N, Suwannasrisuk P, Houngngam N, Udomsawaengsup S, Snabboon 
T: Changes in Testosterone Levels and Sex Hormone-Binding Globulin Levels in Extremely Obese 
Men after Bariatric Surgery. International journal of endocrinology 2016, 2016:1416503. 
29. 
Ng Tang Fui M, Prendergast LA, Dupuis P, Raval M, Strauss BJ, Zajac JD, Grossmann M: Effects of 
testosterone treatment on body fat and lean mass in obese men on a hypocaloric diet: a 
randomised controlled trial. BMC medicine 2016, 14(1):153. 
30. 
Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM, Eder R, Tennstedt S, Ulloor J, 
Zhang A et al: Adverse events associated with testosterone administration. The New England 
journal of medicine 2010, 363(2):109-122. 
31. 
Whitsel EA, Boyko EJ, Matsumoto AM, Anawalt BD, Siscovick DS: Intramuscular testosterone esters 
and plasma lipids in hypogonadal men: a meta-analysis. The American journal of medicine 2001, 
111(4):261-269. 
32. 
Fernandez-Balsells MM, Murad MH, Lane M, Lampropulos JF, Albuquerque F, Mullan RJ, Agrwal N, 
Elamin MB, Gallegos-Orozco JF, Wang AT et al: Clinical review 1: Adverse effects of testosterone 
therapy in adult men: a systematic review and meta-analysis. The Journal of clinical endocrinology 
and metabolism 2010, 95(6):2560-2575. 
33. 
Haider A, Yassin A, Doros G, Saad F: Effects of long-term testosterone therapy on patients with 
"diabesity": results of observational studies of pooled analyses in obese hypogonadal men with 
type 2 diabetes. International journal of endocrinology 2014, 2014:683515. 
34. 
Xu Y, Sun Z: Molecular basis of Klotho: from gene to function in aging. Endocr Rev 2015, 36(2):174-
193. 

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
26 
35. 
Semba RD, Cappola AR, Sun K, Bandinelli S, Dalal M, Crasto C, Guralnik JM, Ferrucci L: Plasma 
klotho and mortality risk in older community-dwelling adults. The journals of gerontology Series 
A, Biological sciences and medical sciences 2011, 66(7):794-800. 
36. 
Glintborg D, Sidelmann JJ, Altinok ML, Mumm H, Andersen M: Increased thrombin generation in 
women with polycystic ovary syndrome: A pilot study on the effect of metformin and oral 
contraceptives. Metabolism: clinical and experimental 2015, 64(10):1272-1278. 
37. 
Agledahl I, Brodin E, Svartberg J, Hansen JB: Impact of long-term testosterone treatment on 
plasma levels of free TFPI and TF-induced thrombin generation ex vivo in elderly men with low 
testosterone levels. Thromb Haemost 2009, 102(5):945-950. 
38. 
Glueck CJ, Wang P: Testosterone therapy, thrombosis, thrombophilia, cardiovascular events. 
Metabolism: clinical and experimental 2014, 63(8):989-994. 
39. 
Brodin E, Vikan T, Hansen JB, Svartberg J: Testosterone, hemostasis, and cardiovascular diseases 
in men. Semin Thromb Hemost 2011, 37(1):87-94. 
40. 
Bujalska IJ, Kumar S, Stewart PM: Does central obesity reflect "Cushing's disease of the 
omentum"? Lancet 1997, 349(9060):1210-1213. 
41. 
Nielsen TL, Hagen C, Wraae K, Brixen K, Petersen PH, Haug E, Larsen R, Andersen M: Visceral and 
subcutaneous adipose tissue assessed by magnetic resonance imaging in relation to circulating 
androgens, sex hormone-binding globulin, and luteinizing hormone in young men. The Journal of 
clinical endocrinology and metabolism 2007, 92(7):2696-2705. 
42. 
Sundhedsstyrelsen: National Klinisk Retningslinje for Fedmekirurgi. 2017. 
43. 
Mechanick JI, Youdim A, Jones DB, Garvey WT, Hurley DL, McMahon MM, Heinberg LJ, Kushner R, 
Adams TD, Shikora S et al: Clinical practice guidelines for the perioperative nutritional, metabolic, 
and nonsurgical support of the bariatric surgery patient--2013 update: cosponsored by American 
Association of Clinical Endocrinologists, the Obesity Society, and American Society for Metabolic 
& Bariatric Surgery. Endocrine practice : official journal of the American College of Endocrinology 
and the American Association of Clinical Endocrinologists 2013, 19(2):337-372. 
44. 
Essendrop M SB, Hansen K: Reliability of isometric muscle strength tests for the trunk, hands and 
shoulders. Int J Ind Ergonomics 2001, 28(6):379-387. 
45. 
Astrand PO RI: A nomogram for calculation of aerobic capacity (physical fitness) from pulse rate 
during submaximal work. J Appl Physiol 1954, 7(2):218–221. 
46. 
Kvorning T, Christensen LL, Madsen K, Nielsen JL, Gejl KD, Brixen K, Andersen M: Mechanical 
muscle function and lean body mass during supervised strength training and testosterone 
therapy in aging men with low-normal testosterone levels. Journal of the American Geriatrics 
Society 2013, 61(6):957-962. 
 
 
APPENDIX 
Adverse reactions/side effects, testosterone. 
System Organ Class 
Common  
(≥ 1/100 to < 1/10) 
Uncommon 
(≥ 1/1,000 to <1/100) 
Rare 
(≥ 1/10,000 to < 
1/1,000) 

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
27 
Blood and lymphatic 
system disorders 
Polycythaemia 
Haematocrit increased 
Red blood cell count 
increased 
Haemoglobin increased 
Immune system 
disorders 
Hypersensibility 
Metabolism and 
nutrition disorders 
Weight increased 
Increased appetite 
Glycosylated 
haemoglobin increased 
Hypercholesterolaemia 
Blood triglycerides 
increased 
Blood cholesterol 
increased 
Psychiatric disorders 
Depression 
Emotional disorder 
Insomnia 
Restlessness 
Aggression 
Irritability 
Nervous system 
disorders 
Headache 
Migraine 
Tremor 
Vascular disorders 
Hot flush 
Cardiovascular disorder 
Hypertension 
Dizziness 
Respiratory, thoracic 
and mediastinal 
disorders 
Bronchitis 
Sinusitis 
Cough 
Dyspnoea 

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
28 
Snoring 
Dysphonia 
Gastrointestinal 
disorders 
Diarrhoea 
Nausea 
Hepatobiliary disorders 
Liver function test 
abnormal 
Aspartate 
aminotransferase 
increased 
Skin and subcutaneous 
tissue disorders 
Acne 
Alopecia 
Erythema 
Rash 
Pruritus 
Dry skin 
Musculoskeletal and 
connective tissue 
disorders 
Arthralgia 
Myalgia 
Pain in extremity 
Musculoskeletal 
stiffness 
Blood creatine 
phosphokinase 
increased 
Renal and urinary 
disorders 
Urine flow decreased 
Urinary retention 
Urinary tract disorder 
Nocturia 
Dysuria 
Reproductive system 
and breast disorders 
Prostate specific antigen 
increased 
Prostatic intraepithelial 
neoplasia 

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
29 
Prostate examination 
abnormal 
Benign prostate 
hyperplasia 
Prostate induration 
Prostatitis 
Prostatic disorder 
Libido changes 
Testicular pain 
Breast induration 
Breast pain 
Gynaecomastia 
Oestradiol increased 
Testosterone increased 
General disorders and 
administration site 
conditions 
Various kinds of 
injection site reactions1 
Fatigue 
Asthenia 
Hyperhidrosis 
Night sweats 
Injury, poisoning and 
procedural 
complications 
Pulmonary oil 
microembolism2 
1 - Various kinds of injection site reaction: Injection site pain, Injection site discomfort, Injection 
site pruritus, Injection site erythema, Injection site haematoma, Injection site irritation, Injection site 
reaction 
2 - can in rare cases lead to signs and symptoms such as cough, dyspnoea, malaise, hyperhidrosis, 
chest pain, dizziness, paraesthesia, or syncope. These reactions may occur during or immediately 
after the injections and are reversible. 
 
Other: nervousness, hostility, sleep apnoea, various skin reactions including seborrhea, increased 
hair growth, increased frequency of erections and in very rare cases jaundice have been reported 
under treatment with testosterone containing preparations. 
Therapy with high doses of testosterone preparations commonly reversibly interrupts or reduces 
spermatogenesis, thereby reducing the size of the testicles; testosterone replacement therapy of 
hypogonadism can in rare cases cause persistent, painful erections (priapism). High-dosed or long-

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
30 
term administration of testosterone occasionally increases the occurrences of water retention and 
edema. 
See SPC for complete safety reference information 
(https://www.medicines.org.uk/emc/product/3873/smpc) 
 
 
 
 

Version 5  
EudraCT:  2018-002365-19 
 
27TH of August 2018 
Godkendt VEK: ______ Projekt ID: S-20180074  
Godkendt LMS: _______ Journal nr: 2018061692 
 
31 
Counselling intervention 
The overall aim with the counselling is to prevent significant decrease in muscle strength as a 
consequence of Bariatric surgery. The partial aims are, through counselling, to make the patients 
aware of the importance of maintaining physical function to increase motivation and PA levels. 
The Counselling: 
The patients will be offered counselling four times during the study period; one exercise 
counselling before the surgery and three times exercise counselling post-surgery (Table 1). 
The structure of the counselling will be based on the five A’s (Assess, Advise, Agree, Assist, 
Arrange) however, specific emphasis will be on motivational interviewing, goal setting, individual 
tailored PA programs, and instructions in the provided programs. 
 
PDF with test protocol (double-click to open)