Dapiglutide for the Treatment of Obesity (DREAM): a Randomised, Double-blind, Placebo-controlled, Investigator-initiated Trial
Phase: PHASE2
Conditions: Obesity, Inflammation
Sponsor: University Hospital, Gentofte, Copenhagen

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Dapiglutide for the treatment of obesity (DREAM): a randomised, 
double-blind, placebo-controlled, investigator-initiated trial 
 
Protocol code number: 
 
 
 
   The ‘DREAM’ trial 
EU Trial number:  
 
 
  
 
   2022-501649-54-00 
ClinicalTrials.gov identifier:  
 
 
   Currently N/A 
Investigational medicinal product: 
 
 
   Dapiglutide 10 mg/ml 
 
Principal investigator:  
Filip Krag Knop, MD PhD 
Co-investigators:  
Casper Kjærsgaard Nielsen, MSc 
 
Nicklas Järvelä Johansen, MD, PhD 
 
Sponsor-investigator:  
Center for Clinical Metabolic Research 
Herlev-Gentofte Hospital 
Gentofte Hospitalsvej 7, 3rd floor  
DK-2900 Hellerup 
Research location(s):  
Center for Clinical Metabolic Research 
Herlev-Gentofte Hospital 
Gentofte Hospitalsvej 7, 3rd floor  
DK-2900 Hellerup  
Gastroenterologist, Anne Haaber 
Mavespecialisten 
Jægersborg Allé 16, 2. sal 
DK-2920 Charlottenlund 
Monitor:  
The GCP-unit at Copenhagen University 
Frederiksberg Hospital 
Nordre Fasanvej 57, Skadestuevej 1 
DK-2000 Frederiksberg 
 
Date: 
Wednesday, 04 January 2023 

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_____________________________________________ 
 
 
 
 
     
 
                   
  Principal Investigator  
 
 
 
 
    Professor Filip Krag Knop, MD PhD 
 
 
 
 
 
_____________________________________________ 
 
 
 
 
     
 
                   
  Sponsor-Investigator 
 
 
 Filip Krag Knop, Center for Clinical Metabolic Research  
 
 
_____________________________________________ 
 
 
 
 
     
 
                   
  Co-Investigator 
 
 
  Casper Kjærsgaard Nielsen, MSc, PhD-stud 
 
 
 
 
 
 
 
 

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Table of Contents 
1. 
Introduction ............................................................................................................................... 6 
2. 
Aims of the study ...................................................................................................................... 7 
3. 
Hypothesis ................................................................................................................................. 7 
4. 
Methods ..................................................................................................................................... 8 
4.1 
Study design ...................................................................................................................... 8 
4.2 
Flowchart ......................................................................................................................... 10 
4.3 
Blinding and randomisation............................................................................................. 11 
5. 
Study population ..................................................................................................................... 12 
5.1 
Eligibility criteria ............................................................................................................. 12 
5.1.1 
Inclusion criteria ....................................................................................................... 12 
5.1.2 
Exclusion criteria ...................................................................................................... 12 
5.2 
Recruitment and informed consent procedure ................................................................. 14 
6. 
Endpoints ................................................................................................................................ 15 
7. 
Gastroduodenoscopies and biopsies ....................................................................................... 21 
8. 
Faecal samples ........................................................................................................................ 21 
9. 
Safety and AEs ........................................................................................................................ 21 
9.1 
Registration of AEs ......................................................................................................... 22 
9.2 
Definition of events ......................................................................................................... 22 
9.3 
Assessment of causality and severity .............................................................................. 23 
9.4 
Reporting of SAEs, SARs or SUSARs ............................................................................ 24 
10. The rationale for the study design and dose justification ....................................................... 25 
11. Pharmacokinetic parameters of dapiglutide ............................................................................ 25 
12. Trial assessment ...................................................................................................................... 26 

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12.1 
Risk assessment and ethical considerations ................................................................. 26 
12.2 
Benefit assessment ....................................................................................................... 26 
12.3 
Benefit-risk assessment ................................................................................................ 27 
13. Investigational medicinal products ......................................................................................... 27 
13.1 
Syringe for administration ........................................................................................... 27 
14. Identification of investigational medicinal product (IMP) ..................................................... 27 
15. Packaging and labelling .......................................................................................................... 27 
15.1 
Storage of IMP ............................................................................................................. 28 
15.2 
Drug accountability ...................................................................................................... 29 
16. Early termination of the study ................................................................................................. 29 
17. Statistical considerations and calculations .............................................................................. 30 
17.1 
General statistical considerations ................................................................................. 30 
17.2 
Baseline characteristics ................................................................................................ 30 
17.2.1 Primary analysis ....................................................................................................... 30 
17.3 
Intention-to-treat analysis ............................................................................................ 31 
17.4 
Secondary and exploratory analyses ............................................................................ 31 
17.4.1 Safety endpoints ....................................................................................................... 32 
17.5 
Missing data ................................................................................................................. 32 
17.6 
Sample size calculation ................................................................................................ 32 
17.6.1 Secondary endpoint power calculation .................................................................... 33 
18. Biological materials ................................................................................................................ 33 
19. Timeline .................................................................................................................................. 33 
20. Overview of milestones .......................................................................................................... 34 
21. Financial circumstances .......................................................................................................... 34 

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22. Funding ................................................................................................................................... 34 
23. Financial compensation to participants ................................................................................... 34 
24. Logistics .................................................................................................................................. 35 
25. Feasibility ................................................................................................................................ 35 
26. Insurance ................................................................................................................................. 35 
27. Registration ............................................................................................................................. 35 
28. Research biobank .................................................................................................................... 36 
29. Data ......................................................................................................................................... 36 
29.1 
Data location ................................................................................................................ 36 
30. Publication .............................................................................................................................. 37 
31. Study group ............................................................................................................................. 37 
32. References ............................................................................................................................... 38 
 
 
 

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1. Introduction 
Obesity has become a pandemic affecting more than a billion individuals globally1, and numbers 
are growing each year2. Moreover, obesity is the fifth leading cause of death worldwide3,4 and 
increases the risk of diseases such as type 2 diabetes, cancer, sleep apnoea, cardiovascular diseases 
and non-alcoholic fatty liver disease (NAFLD). Additionally, obesity is associated with 
psychological problems and reduced quality of life5–13.  
Obesity is a multi-factorial condition arising due to a positive energy balance resulting in excess 
storage of fat in adipose tissue as well as in other tissues (ectopic fat deposition)14,15. Excess storage 
of fat in insulin-sensitive tissues such as skeletal muscle, liver and adipose tissue results in insulin 
resistance as well as low-grade systemic inflammation, which in turn exacerbates insulin 
resistance16. Systemic low-grade inflammation and insulin resistance drive the development of 
many co-morbidities related to obesity. It has become clear that obesity is associated with reduced 
gut barrier function, i.e., a leaky gut, increasing translocation of microorganisms and their products, 
such as lipopolysaccharide (LPS), into the bloodstream17. This leaky gut seems to contribute 
importantly to obesity-related systemic low-grade inflammation and, thus, insulin resistance, 
fuelling the development of co-morbidities related to obesity, including type 2 diabetes, NAFLD 
with non-alcoholic steatohepatitis (NASH), atherosclerotic cardiovascular diseases and certain 
cancer forms18–20.  
Despite increasing awareness of obesity and its underlying complex pathophysiology, effective 
treatments, dually targeting calorie intake and low-grade systemic inflammation, are warranted. 
Glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2) are co-secreted from 
enteroendocrine L cells in response to nutrient ingestion. These peptide hormones act via their 
distinct receptors, the GLP-1 receptor (GLP-1R) and the GLP-2 receptor (GLP-2R). Besides its 
glucose-lowering effect, GLP-1 reduces appetite and induces satiety, translating to reduced energy 
intake. Presently, two GLP-1 receptor agonists (GLP-1RA), liraglutide and semaglutide, are 
approved for the treatment of obesity21,22; and both of these treatments result in loss of primarily 
body fat mass, translating to improved insulin sensitivity and lowering of the systemic low-grade 
inflammation originating from excess fat storage. GLP-2R agonism increases perfusion in 
mesenteric vessels and promotes regenerative function and proliferation of gut epithelial cells 
resulting in mucosal growth with increased crypt depth, villi height and barrier function23,24. Thus, 
GLP-2R agonism may restore gut barrier function in obesity and thereby diminish systemic low-
grade inflammation arising from obesity-associated leaky gut. Despite the obvious fit of GLP-1R 
and GLP-2R agonism in terms of addressing fundamental aspects of obesity pathophysiology, dual 
GLP-1R/GLP-2R agonism has yet to be explored as a strategy for the treatment of obesity.  
Dapiglutide is 33-amino acid peptide dual GLP-1R/GLP-2R agonist with a C18 acyl modification, 
which increases the half-life to approximately five days. Dapiglutide is administered 

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subcutaneously once weekly and is currently under clinical development. In a recently completed 
phase I trial in normal-weight individuals, 3.5 mg dapiglutide administered once weekly caused a 
mean 4.3 ± 1.4% body weight reduction following 4 weeks of treatment compared to placebo. 
Moreover, dapiglutide at various doses ranging from 1.0 to 6.0 mg exhibited a tolerable safety 
profile, with adverse events (AEs) comprising mild to moderate in intensity and transient in 
duration. The most frequently observed AEs were nausea and decreased appetite as normally 
observed with GLP-1RAs25. 
The present protocol is designed to explore the effect of 12-week treatment with once-weekly 
dapiglutide (4 mg and 6 mg) as compared to placebo, on body weight in individuals with obesity. 
2. Aims of the study 
This randomised placebo-controlled study will investigate the efficacy of once-weekly 
subcutaneously administered dapiglutide in obese individuals during a 12-week treatment period.  
The primary aim is to evaluate the effects of 4 mg and 6 mg dapiglutide on change in body weight 
(%).  
Secondary and exploratory aims include evaluating the effects of 4 mg and 6 mg dapiglutide on: 
• Gut barrier function and blood microbiome 
• Systemic inflammation 
• Safety and tolerability 
• Lean body mass, fat mass, and visceral fat mass 
• Patient-reported outcomes (PROs) 
3. Hypothesis 
We hypothesise that: 
1) 6 mg dapiglutide treatment for 12 weeks is superior to placebo treatment for 12 weeks in 
reducing body weight relative to baseline 
2) 4 mg dapiglutide treatment for 12 weeks is superior to placebo treatment for 12 weeks in 
reducing body weight relative to baseline 
3) 6 mg dapiglutide treatment for 12 weeks is superior to 4 mg of dapiglutide treatment for 12 
weeks in reducing body weight relative to baseline 

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4) Dapiglutide will improve gut barrier function (as assessed by circulating levels of LPS-
binding protein (LBP)) 
 
 
5) Daspiglutide will reduce low-grade systemic inflammation (as assessed by circulating 
levels of high-sensitivity C-reactive protein (hs-CRP) and interleukin (IL)-6) 
4. Methods 
4.1 
Study design 
This study is an investigator-initiated, proof-of-concept, randomised, double-blind, placebo-
controlled, parallel-group, single-centre clinical trial investigating the body weight loss potential 
of dapiglutide, a dual GLP-1R/GLP-2R agonist, administered subcutaneously once weekly. 
Eligible subjects are randomised to one of three treatment arms as illustrated in Table 1: 
 
Treatment 
arm 
IMPs 
Dose 
Pharmaceutical 
dosage form 
Route of 
administration 
Administration 
frequency 
#1 
Dapiglutide (10 mg/ml) 
4 mg 
1 ml solution for 
injection in vial 
Subcutaneously 
Once weekly 
#2 
Dapiglutide (10 mg/ml) 
6 mg 
#3 
Placebo (n/a) 
4 mg 
6 mg 
Table 1 Overview of treatment arms, dose, usage, route- and frequency of IMP administration. 
 
In total, 54 obese participants with a body mass index (BMI) of ≥ 30 kg/m² are randomised to either 
treatment with the investigational medicinal product (IMP), being either dapiglutide 4 mg, 
dapiglutide 6 mg, or placebo for 12 weeks. To ensure blinding, the placebo arm is split between 4 
mg and 6 mg placebo, making the randomisation sequence 2:2:1:1. The trial encompasses a 3-week 
screening period containing a screening visit (V1) to assess eligibility, followed by a randomisation 
visit (V2) and subsequently a 12-week treatment period concluded with a 4-week follow-up period. 
The IMP is subcutaneously administered in the abdomen once weekly from week 0 (V2) until week 
12 (V14) (Table 2). The IMP is initiated at 2 mg once-weekly and up-titrated every third week 
with 2 mg until the respective trial doses are reached in each arm (Figure 1). Hereafter, the 
participants are kept at the dose level for the remainder of the trial (from week 3 and week 6 for 
the 4 mg and 6 mg doses, respectively). To reduce dropout in cases of low tolerability of the IMP, 
the investigator can postpone up-titration or down-titrate if judged necessary for participant 
retention or safety. The trial schedule will consist of five on-site visits, including screening, 

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randomisation and a safety follow-up visit (four weeks after end of treatment (EOT)), in addition 
to a minimum of 10 telephone consultations. Therefore, the maximum trial duration is 16 weeks. 
For exploratory purposes, participants are invited to participate in a gastroduodenoscopy sub-study 
obtaining gastric and duodenal biopsies before and after treatment with IMP. A maximum of 7 
participants from each treatment arm (total n=21) can participate in this sub-study.  
 
Figure 1. Illustration of the randomised (2:2:1:1) parallel-group, double-blind, placebo-controlled study design in which 54 
individuals with obesity will receive either 1) dapiglutide 2/4/6 mg, 2) dapiglutide 2/4 mg, 3) placebo 2/4/6 mg, or 4) placebo 2/4 
mg for a period of 12 weeks. 
 
 

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4.2 
Flowchart 
Screening 
Randomisation 
Dose escalation and treatment period 
End of treatment 
(EOT) 
End of trial 
(follow-up visit) 
Visit 
V1 
V2 
P3 
P4 
P5 
P6 
P7 
V8 
P9 P10 P11 P12 P13 
V14 
V15 
Time (weeks) 
-3 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
16 
Visit window (days) 
-21 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±5 
General 
Informed consent 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Assessment of eligibility criteria 
x 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
Demography 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical history  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Smoking/alcohol 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Assessment of childbearing potential 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Attend visit fasting 
 
x 
  
  
  
  
  
x 
  
  
  
  
  
x 
  
Gastroduodenoscopy and biopsiesI 
  
(x) 
  
  
  
  
  
  
  
  
  
  
  
(x) 
  
Drug dispensing 
  
x 
  
  
  
  
  
x 
  
  
  
  
  
  
  
Drug accountability 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
Drug handling instruction 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Drug dosingII 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Clinical assessment 
Body height 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
ECG 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
x 
Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
x 
x 
  
 
 
 
  
x 
  
 
 
 
 
x 
x 
Bioimpedance  
 
x 
  
  
  
  
  
x 
  
  
  
  
  
x 
x 
FibroScan® 
 
x 
  
  
  
  
  
x 
  
  
  
  
  
x  
x 
Waist circumference 
 
x 
  
  
  
  
  
x 
  
  
  
  
  
x 
x 
Blood pressure (systolic and diastolic) 
 
x 
  
  
  
  
  
x 
  
  
  
  
  
x 
x 
Heart rate 
 
x 
  
  
  
  
  
x 
  
  
  
  
  
x 
x 
BiosamplesIII 
 
x 
  
  
  
  
  
x 
  
  
  
  
  
x 
x 
Gut permeability biomarkers 
 
x 
  
  
  
  
  
x 
  
  
  
  
  
x 
x 
Inflammatory biomarkers 
 
x 
  
  
  
  
  
x 
  
  
  
  
  
x 
x 
Leukocytes 
 
x 
  
  
  
  
  
x 
  
  
  
  
  
x 
x 
Lipids 
 
x 
  
  
  
  
  
x 
  
  
  
  
  
x 
x 
Oxidative stress 
 
x 
  
  
  
  
  
x 
  
  
  
  
  
x 
x 

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Islet function and incretin 
 
x 
  
  
  
  
  
x 
  
  
  
  
  
x 
x 
Bone biomarkers 
 
x 
  
  
  
  
  
x 
  
  
  
  
  
x 
x 
Plasma PK sample 
 
 
  
  
  
  
  
x 
  
  
  
  
  
x 
x 
Blood microbiome 
 
x 
  
  
  
  
  
x 
  
  
  
  
  
x 
x 
Additional blood tests 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
x 
ADA 
 
x  
  
  
  
  
  
x 
  
  
  
  
  
 x 
x 
Faecal collection 
  
x 
  
  
  
  
  
  
  
  
  
  
  
x 
  
AEs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Patient-reported outcomes 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
SF-36 
 
x 
  
 
 
 
  
 
  
 
 
 
  
x 
  
IWQOL-Lite-CT26 
 
x 
  
 
 
 
  
 
  
 
 
 
  
x 
  
 
Table 2. ADA, anti-drug antibodies; AEs, adverse events; ECG, electrocardiogram; IWQOL-Lite-CT, The Impact of Weight on 
Quality of Life-Lite Clinical Trials Version; PK, pharmacokinetic; SF-36, The 36-Item Short Form Survey. 
I Not mandatory for study participation, i.e., optional (provided acceptance from the participant). For feasibility purposes, the 
gastroduodenoscopy can be conducted up to four days before V2 and V14. 
II Dosing of IMP occurs supervised either by physical presence at the research center or virtually during the phone visits 
III All biosamples (i.e. ADA, PK etc.) are collected prior to dosing during V2, V8. If IMP is dosed on the day of the sampling visit, 
ADA and PK samples are collected before dosing. Samples collected at V14 are approximately one week after the last dosing 
4.3 
Blinding and randomisation 
A total of 54 participants are randomised into three treatment arms (2:2:1:1) (Figure 1). A clinical 
assistant not otherwise affiliated with the study and with experience in producing randomisation 
lists will generate the randomisation list using https://www.sealedenvelope.com. The placebo arm 
is divided into two subgroups (4 mg and 6 mg volume-matched placebo) to ensure the double-blind 
procedure. The randomisation will employ blocks of randomised stratification with respect to sex, 
thereby securing balanced numbers of males and females in each treatment group (placebo, 4 mg 
or 6 mg of dapiglutide)27. 
A person not otherwise affiliated with the study is responsible for the treatment allocation and sub-
study and has access to the electronic randomisation key and sealed code-break envelopes in case 
of any medical emergencies. All clinical personnel affiliated with the study have access to sealed 
emergency envelopes. In such an event, the person breaking the code must complete, sign and date 
a Code Break notification, reporting the reason for unblinding. If the code is broken, the participant 
is automatically discontinued from the treatment and the study. Unblinding may be carried out at 
any time per investigator’s discretion.  
Participants will always be able to contact study personnel, ensuring contact with the principal 
investigator in case of an emergency requiring unblinding.  

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Zealand Pharma A/S will provide IMP (placebo and dapiglutide 10 mg/ml) in indistinguishable 
vials/cartons. 
5. Study population 
Fifty-four participants with obesity (BMI of ≥ 30 kg/m²) are included in the study. Dropouts will 
only be replaced if the dropout rate surpasses 25% in one of the treatment arms. The recruitment 
process is described in detail in Section 5.2. 
5.1 
Eligibility criteria 
5.1.1 Inclusion criteria 
• Age 18–75 years 
• BMI ≥ 30 kg/m²  
• History of at least one attempt to lose body weight 
5.1.2 Exclusion criteria 
• A self-reported change in body weight ≥ 5% within the last 90 days prior to the screening 
visit 
• Treatment with any therapy, including endoscopic procedures and/or medication (e.g. 
liraglutide, bupropion/naltrexone and orlistat), intended for weight management within 90 
days prior to screening 
• Previous, current, or planned (during the trial period) obesity treatment with surgery or a 
weight loss device < 1 year prior to screening 
• Glycated haemoglobin (HbA1c) ≥ 48 mmol/mol 
• History of type 1 diabetes or type 2 diabetes 
• Treatment with glucose-lowering agents within 90 days prior to screening 
• Compromised kidney function (estimated glomerular filtration rate (eGFR) < 60 
ml/min/1.73 m2) at screening 
• Known liver disease (except for non-alcoholic fatty liver disease) and/or elevated plasma 
alanine aminotransferase (ALT) > three times the upper limit of normal at screening 

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• History of acute and/or chronic pancreatitis 
• History and/or family history of medullary carcinoma and/or multiple endocrine neoplasia 
syndrome 
• Inflammatory bowel disease 
• Any history of colon cancer or intestinal polyps 
• Any history of intestinal stenosis 
• History of any other cancers (except margin-free resected cutaneous basal or squamous cell 
carcinoma or adequately treated in situ cervical cancer) unless disease-free state for at least 
five years 
• Uncontrolled thyroid disease as per discretion of the investigators 
• Any of the following: myocardial infarction, stroke, hospitalisation for angina and transient 
ischaemic attack within the last 60 days prior to screening 
• Class IV heart failure according to the New York Heart Association 
• Any concomitant disease or treatment that, at the discretion of the investigators, might 
jeopardise the participant’s safety during the trial 
• Alcohol/drug abuse as per discretion of the investigators 
• Known or suspected hypersensitivity to the trial product or related products 
• Previous treatment with the trial product 
• Administration of an investigational drug within 90 days prior to screening 
• Simultaneous participation in any other clinical intervention trial 
• Mental incapacity or language barriers that preclude adequate understanding or 
cooperation, or unwillingness to comply with trial requirements 
• Use of GLP-1RA, GLP-2RA, dipeptidyl peptidase 4 (DPP) inhibitors, human growth 
hormone, somatostatin, or analogues thereof, within three months prior to screening  
• Known radiation enteritis or significant villous atrophy, e.g., due to active coeliac disease 
or inflammatory bowel disease 
• Regarding fertile men and women:  
o Women who are pregnant, breastfeeding, intend to become pregnant or are of 
childbearing potential will not be included in the study 
o Sterilised or postmenopausal women (> 12 months amenorrhoea or females ≥ 60 
years of age) can be included 

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o The following contraceptive methods are considered adequate for study enrolment 
of male participants: Surgically sterilised or willing to refrain from sexual 
intercourse from screening and until completion of the follow-up visit, or, if 
sexually active, condom usage and partner-practised contraception during the trial, 
i.e., from screening to the last visit 
5.2 
Recruitment and informed consent procedure 
Participants are recruited via advertisement in newspapers and on the internet (including social 
media, www.forsøgsperson.dk and www.forskningnu.dk), via general practitioners in the Capital 
Region of Denmark and Region Zealand, and from registries of previous research participants who 
have agreed to be approached for other studies. Advertisement on social media is in accordance 
with GDPR, meaning that comments are turned off, and inquiries of study participation from 
potential participants will be carried out through direct e-mail to the investigator or/and via a link 
to www.forsøgsperson.dk and www.forskningnu.dk. The recruitment will take place at the 
Department of Medicine at Gentofte Hospital with recruitment assistance from study group 
personnel affiliated with different hospital sites in Denmark. Potential participants from the 
outpatient clinics are asked about their interest in the study and be contacted by telephone or e-
mail. According to their preferences, potential participants from previous studies are contacted by 
telephone or e-mail.  
Written information about the study is sent to potential participants, including information about 
the study, eligibility criteria, legal rights during participation in a biomedical research project and 
contact information of the principal investigator. Within a week after receiving the written 
information, potential participants are contacted by telephone to clarify and elaborate on the study 
information. The telephone call includes details on the purpose of the study and study conduct, 
potential benefits and risks, reimbursement, protocol compliance, and an estimation of the 
timeframe of study participation. If the potential participant is still interested in participating, a 
screening visit (V1) is scheduled. The subject is informed about the right to bring an assessor to 
the screening visit (V1) and all other trial visits. The screening visit will take place at Center for 
Clinical Metabolic Research at Gentofte Hospital – in a closed room without any disturbances. 
Trial information is given only by delegated GCP-trained study personnel. A physician performs 
the interview and collection of the informed consent during the screening visit. During the 
screening visit, it will be made clear that the purpose of the meeting is to inquire about potential 
participation in the study and that written and oral consent to study participation can be withdrawn 
at any time without further explanation. Trial information is given in terms understandable to the 
individual participant and will include more details on the purpose of the study, study conduct, 
potential benefits and risks, reimbursement, protocol compliance and an estimation of the 
timeframe of study participation. In addition to the trial information, the subject is reminded to 

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maintain habitual diet and exercise patterns in conjunction with the recitation of the Danish health 
authorities' recommendation regarding diet and exercise: Eat plant-rich, varied and not too much 
and exercise (moderate intensity) for 30 minutes a day28. During this verbal information, the 
participant is encouraged to ask questions at any time. When all questions are answered and the 
participant has a full scope of the trial, the participants are given time to reflect. Reflection time is 
determined by the participant and can be up to one week. As a default, the subject is given a 
minimum of 5 minutes alone to reflect and/or discuss the content of the trial with the assessor. 
Hence, the screening visit cannot take place immediately after the oral information if the potential 
participant wishes time to reflect. All participants have the right to a minimum of 24 hours of 
consideration before consenting to trial participation. If the subject declines further reflection time 
and expresses interest in study participation, written informed consent and formal documents are 
signed by both parties. Hereafter, the clinical assessments needed for the evaluation of eligibility 
are conducted (body weight measurement, ECG, blood sample collection etc.). In case of study 
participation ineligibility, the subject is reminded of the predefined inclusion- and exclusion criteria 
determining study participation and is thanked for the interest shown in the trial. Throughout the 
study, any new personal health information obtained is shared with the participant. 
6. Endpoints 
Primary endpoint 
No. of 
endpoint 
Endpoint title 
Time frame 
Unit 
#1 
Change in body weight 
From week 0 
(baseline) to week 12 
(EOT) 
%-point 
 
Secondary endpoints 
No. of 
endpoint 
Endpoint title 
Time frame 
Unit 
#2 
Body weight reduction ≥ 5% 
At week 12 (EOT) 
Yes/No  
#3 
Body weight reduction ≥ 10%  
At week 12 (EOT) 
Yes/No 
#4 
Change in fasting serum/plasma 
concentrations of gut 
permeability biomarkers 
From week 0 
(baseline) to week 12 
(EOT) 
%-point 

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•  LPS-binding protein 
(LBP) 
#5 
Change in fasting serum/plasma 
concentrations of inflammation 
markers 
• hs-CRP 
• IL-6 
From week 0 
(baseline) to week 12 
(EOT) 
%-point 
#6 
Exploratory endpoints 
#7 
Body weight reduction ≥ 15% 
At week 12 (EOT) 
Yes/No 
#8 
Change in BMI (kg/m2) 
From week 0 
(baseline) to week 12 
(EOT) 
%-point 
#9 
Change in waist-hip ratio 
From week 0 
(baseline) to week 12 
(EOT) 
%-point 
#10 
Change in waist circumference 
(cm) 
From week 0 
(baseline) to week 12 
(EOT) 
%-point 
#11 
Change in systolic blood 
pressure (mmHg) 
From week 0 
(baseline) to week 12 
(EOT) 
%-point 
#12 
Change in diastolic blood 
pressure (mmHg) 
From week 0 
(baseline) to week 12 
(EOT) 
%-point 
#13 
Change in heart rate (beats per 
minute) 
From week 0 
(baseline) to week 12 
(EOT) 
%-point 
#14 
Change in fat-free mass as 
measured by bioimpedance 
From week 0 
(baseline) to week 12 
(EOT) 
%-point 
#15 
Change in total fat mass as 
measured by bioimpedance 
From week 0 
(baseline) to week 12 
(EOT) 
%-point 
#16 
Change in visceral fat mass 
rating as measured by 
bioimpedance 
From week 0 
(baseline) to week 12 
(EOT) 
%-point 

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#17 
Change in bone mass as 
measured by bioimpedance 
From week 0 
(baseline) to week 12 
(EOT) 
%-point 
#18 
Faecal microbiota composition  
From week 0 
(baseline) to week 12 
(EOT) 
%-point 
#19 
Change in fasting serum/plasma 
concentrations of inflammatory 
biomarkers 
• Fibrinogen 
• Serum amyloid A 
• Haptoglobin 
• Soluble cluster of 
differentiation 14 
• Lactate dehydrogenase 
• IL-1 receptor antagonist, 
IL-1β, IL-2, IL-8, IL-10, 
IL-12, IL-17, IL-18, IL-
22 
• Interferon γ  
• Resistin 
• Tumour necrosis factor 
α  
• Adiponectin 
From week 0 
(baseline) to week 12 
(EOT) 
%-point 
#20 
Change in fasting serum/plasma 
concentrations of leukocytes 
• Total leukocyte count 
• Neutrophil 
• Lymphocyte  
• Basophil  
• Eosinophil  
• Neutrophil:lymphocyte 
ratio 
From week 0 
(baseline) to week 12 
(EOT) 
%-point 
#21 
Change in fasting serum/plasma 
concentrations of lipid 
biomarkers 
• Low-density lipoprotein 
cholesterol 
From week 0 
(baseline) to week 12 
(EOT) 
%-point 

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• Very-low-density 
lipoprotein 
• High-density lipoprotein 
cholesterol 
• Triglycerides 
• Lipoprotein (a) 
• Apolipoprotein B  
• Apolipoprotein C3 
#22 
Change in fasting serum/plasma 
concentrations of islet function 
and incretin biomarkers 
• Glucose 
• HbA1c 
• Insulin 
• C-peptide 
• Insulin sensitivity as 
assessed by homeostasis 
model assessment 2 
• Glucagon 
• GLP-1 
• GLP-2  
• Glucose-dependent 
insulinotropic 
polypeptide 
From week 0 
(baseline) to week 12 
(EOT) 
%-point 
#23 
Change in fasting serum/plasma 
concentrations of bone 
biomarkers 
• C-terminal telopeptides 
of type I collagen 
• Amino-terminal 
propeptide of type I 
procollagen 
• 25-hydroxy-vitamin D 
• Parathyroid hormone 
• Phosphate 
• Serum calcium 
• Urinary calcium 
From week 0 
(baseline) to week 12 
(EOT) 
%-point 

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• Testosterone 
• Oestradiol 
#24 
Change in fasting serum/plasma 
concentrations of additional 
blood tests 
• Haemoglobin 
• Thrombocytes 
• Serum albumin 
• Potassium 
• Sodium 
• Creatinine 
• eGFR 
• Standard bicarbonate 
• ALT 
• Aspartate 
aminotransferase (AST) 
• Gamma-glutamyl 
transferase 
• Bilirubin 
• Amylase 
• Triacylglycerol lipase 
• Thyroid-stimulating 
hormone 
• Fibroblast growth factor 
19 
• Fibroblast growth factor 
21 
• α-hydroxy-4-cholesten-
3-one 
• Leptin 
• Lipocalin 2 
• Zonulin 
• Citrulline 
• LPS 
• D-lactate 
• Fatty acid-binding 
proteins 
From week 0 
(baseline) to week 12 
(EOT) 
%-point 

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#25 
Change in blood microbiome 
From week 0 
(baseline) to week 12 
(EOT) 
%-point 
#26 
Change in FibroScan®-assessed 
liver steatosis (dB/m) 
From week 0 
(baseline) to week 12 
(EOT) 
%-point 
#27 
Change in FibroScan®-assessed 
liver fibrosis (kPa) 
From week 0 
(baseline) to week 12 
(EOT) 
%-point 
#28 
Change in Fatty liver index 
score 
From week 0 
(baseline) to week 12 
(EOT) 
%-point 
#29 
Change in fibrosis 4 score 
From week 0 
(baseline) to week 12 
(EOT) 
%-point 
Patient-reported outcomes 
#30 
Change in the 36-Item Short 
Form Survey  
• Physical functioning  
• Role-physical 
• Bodily pain 
• General health 
• Vitality 
• Social functioning 
• Role-emotional 
• Mental health 
• Physical component 
summary 
• Mental component 
summary 
From week 0 
(baseline) to week 12 
(EOT) 
Score points 
#31 
Change in IWQOL-Lite-CT 
• Pain/discomfort domain 
score 
• Psychosocial domain 
score 
• Total score 
From week 0 
(baseline) to week 12 
(EOT) 
Score points 
Safety endpoints 

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#32 
Number of treatment-emergent 
AEs 
From signed consent 
form (week -3) to 
follow-up visit (week 
16) 
Counts of events 
#33 
Number of serious AEs (SAEs) 
From signed consent 
form (week -3) to 
follow-up visit (week 
16) 
Counts of events 
 
7. Gastroduodenoscopies and biopsies 
At visit V2 and V14, a maximum of seven participants from each treatment arm are biopsied from 
the upper small intestine and the gastric ventricle during a gastroduodenoscopy procedure. Six 
biopsies are collected from prespecified locations in the duodenum and two biopsies from the 
gastric ventricle near the pyloric antrum. During the gastroduodenoscopies, luminal fluids will also 
be collected (approximately 2 ml per visit). The analysis of biopsies and luminal fluid samples will 
include a combination of full- and single cell transcriptomics, microbiome, proteomics, and 
metabolomics analysis. Also, histological analysis, including villus height, crypt depth and villus 
height:crypt depth ratio, as well as relevant immunohistochemistry, is performed.  
8. Faecal samples 
Faecal samples from a private home setting before and after treatment are shipped in envelopes to 
the lab by the participants. The faecal samples are collected in DNA genotek buffers which enable 
the samples to be stored at room temperature for 60 days. Faecal samples are analysed by shotgun 
sequencing enabling species and potential strain identification.  
9. Safety and AEs 
The IMP supplier (Zealand Pharma A/S) will receive a monthly report of all AEs regardless of 
seriousness, severity, or presumed relationship to the trial product from time of signing informed 
consent until the end of the trial. Participants with AEs will receive relevant monitoring, 
counselling, clinical assessment, laboratory examinations, and/or treatment at investigator’s 
discretion. All AEs are followed-up until the participant is stabilised/recovered.  

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9.1 
Registration of AEs 
The investigator is responsible for detection, documentation, recording, and follow-up of all AEs. 
All AEs occurring after signed informed consent (V1) until completion of the study period are 
registered (V15), as illustrated in Table 1. The participants are instructed to record AEs in a diary 
in between site visits, and study staff will enquire about AEs in an open-ended and non-leading 
way during weekly phone visits. All AEs are evaluated for severity and relationship to IMP by the 
investigator. All types of AEs are recorded in the electronic case report form (eCRF).  
9.2 
Definition of events 
The study complies with the following definitions of events: 
• AE: Any unwanted medical occurrence in a participant administered the medicinal product, 
which does not necessarily have a causal relationship with the treatment. An AE can 
therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or 
not considered related to the product 
• Adverse reaction (AR): Any harmful and unwanted reaction to a medicinal product 
regardless of the dose (causality is mandatory) 
• SAE or serious AR (SAR): An AE or AR that, regardless of dose, results in death, is life-
threatening, requires hospitalisation or prolongation of existing hospitalisation, results in 
persistent or significant disability or incapacity, or leads to a congenital defect or 
abnormality (planned hospitalisation is not regarded as an SAE) (the principal investigator 
is responsible for evaluating the causality of all SAEs; in the case of an SAE, the principal 
investigator is to actively interview the participant regarding this issue) 
• Suspected unexpected SAR (SUSAR): A SAR that is unexpected (not consistent with the 
applicable reference safety information) the expectedness is based on the Reference Safety 
Information in the current investigator brochure (IB), which means that all SAEs assessed 
as being related to the trial drug, are considered unexpected and is reported as SUSARs 
For this trial, the following events are to be regarded as AEs of special interest (AESI) with data 
collected under a specific eCRF form and within 24 hours of the investigator’s knowledge: 
• Liver injury: Suspicion of liver injury defined as ALT or AST >3 × upper normal limit 
(UNL) and total bilirubin >2 × UNL, where no alternative aetiology exists (Hy’s law); due 
to the severity of these events, they should always be reported as a SAEs 
• Acute gallbladder disease: The occurrence of acute gallbladder disease (i.e., gallstones or 
cholecystitis) 

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• Acute pancreatitis: The onset of acute pancreatitis is defined based on two of the following 
features 
o Serum lipase and/or amylase activity ≥3 × UNL 
o Abdominal pain (onset severe, persistent epigastric pain typically radiating to the 
back) 
o Acute pancreatitis characteristics as determined by imaging 
• Neoplasms: Any event with the confirmation of malignant or non-malignant neoplasm  
• Medication error, misuse and/or abuse: Any unintended erroneous IMP treatment 
leading to harm or potential harm of the participant (e.g., wrong unique dispensing number 
(DUN), wrong administration route, or accidentally higher dose administered than 
instructed)  
• Suspicion of transmission of infectious agents via the IMP 
• Overdose of the IMP (defined as administration of a dose and /or frequency and/or duration 
of dosing higher than the recommended dose, frequency and duration in the protocol) 
• Inadvertent or accidental exposure to the IMP 
9.3 
Assessment of causality and severity 
When assessing the causality and severity of an AE, the following definitions are used: 
Causality: 
• Probably: Good reason and sufficient documentation to assume a causal relationship 
• Possibly: A causal relationship is conceivable and cannot be dismissed 
• Unlikely: The event is most likely related to aetiology other than the product 
Severity: 
• Mild: No or transient symptoms, no interference with the participant’s daily activities 
• Moderate: Marked symptoms, moderate interference with the participant’s daily activities 
• Severe: Considerable interference with the participant’s daily activities, which the 
participant finds unacceptable. A severe reaction does not necessarily deem the AE as 
serious, and an SAE are not always severe in nature 
The investigator must determine the most appropriate outcome of the AE. 

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Final outcome: 
• Recovered/resolved: The participant has fully recovered, or by medical or surgical 
treatment, the condition has returned to the level observed at the first trial-related activity 
after the participant signed the informed consent 
• Recovering/resolving: The condition is improving, and the participant is expected to 
recover from the event. This term is only applicable if the participant has completed the 
trial or has died from another AE. This term is, for example, applicable in events of chronic 
ongoing illness (e.g. cancer) 
• Recovered/resolved with sequelae: The participant has recovered from the condition but 
with lasting effect due to a disease, injury, treatment, or procedure. If a sequela meets an 
SAE criterion, the AE must be reported as an SAE 
• Not recovered/not resolved: The condition of the participant has not improved, and the 
symptoms are unchanged, or the outcome is not known 
• Fatal: This term is only applicable if the participant died from a condition related to the 
reported AE. Outcomes of other reported AEs in a participant before he/she died should be 
assessed as “recovered/resolved”, “recovering/resolving”, “recovered/resolved with 
sequelae”, or “not recovered/not resolved”. An AE with a fatal outcome must be reported 
as an SAE 
• Unknown: This term is only applicable if the participant is lost to follow-up 
9.4 
Reporting of SAEs, SARs or SUSARs 
As soon as possible: All SAEs, SARs and SUSARs are reported by the sponsor-investigator as 
soon as possible (preferably within 24 hours and no later than 7 days) to Zealand Pharma A/S and 
the database EudraVigilance. Before being reported, all SARs and SUSARs are unblinded by a 
clinical assistant who is not otherwise involved in the study.  
Within 7 days: A life-threatening or a fatal SUSAR is reported by the sponsor-investigator in the 
database EudraVigilance as soon as possible and no later than seven calendar days after the first 
knowledge of the life-threatening or fatal SUSAR. Further relevant information must be provided 
by the sponsor-investigator in the database EudraVigilance within an additional calendar eight days 
after the initial report.  
Within 15 days: In case of a life-threatening or a fatal SUSAR, the investigator is obligated to 
supply the database EudraVigilance with complementary and relevant information regarding the 
follow-up actions made by the investigator. All other SUSARs (non-life-threatening or non-fatal) 

The DREAM trial – protocol V3.0 
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are reported by the investigator within 15 days after the investigator’s first information about the 
event. 
Within 90 days (after study completion): All SAEs, SARs, and SUSARs are submitted to CTIS 
in yearly reports, and a list of all AEs and ARs are provided in a final report to CTIS within one 
year after study completion. Sponsor-investigator submits a yearly list that summarises any SARs 
and SUSARs as well as a report regarding the safety of study participants in the CTIS system. 
10. The rationale for the study design and dose justification 
Dapiglutide is currently in phase II development and has previously been administered in healthy 
volunteers with mean BMI of 24.8 kg/m2 (19.9−27.9), with the highest doses being one weekly 
dose of 3.5 mg and 3 once-weekly doses of 6.0 mg. The mean body weight loss was 4.27% at the 
end of the fourth week of treatment, while it was 0.20% in the pooled placebo group. Mean body 
weight loss following four once-weekly doses of 3.5 mg was 2.35%. 
No AEs leading to withdrawal, severe AEs, SAEs, deaths, or AESI occurred. Approximately 60% 
(17 of 28) of participants dosed with dapiglutide reported a total of 90 AEs, of which the majority 
were mild (74 events), and the rest were moderate (16 events). Approximately 40% (5 of 12) of 
participants dosed with placebo reported a total of 5 AEs, which were all mild. All events (except 
for one event in a placebo participant) were resolved at the end of the trial. 
The incidence of treatment-emergent AEs was similar across dose groups for multiple doses of 1.0, 
2.25, and 3.5 mg dapiglutide and just slightly higher than with placebo but increased in the highest 
dose group after escalation to 6.0 mg dapiglutide from the first dose of 3.5 mg. The most common 
dapiglutide-related AEs across all dose groups were nausea, abdominal distension, dyspepsia, and 
decreased appetite. All drug-related AEs were recovered/resolved at the end of the trial.  
In order to reduce the number of AEs observed with the multiple 6 mg doses, an up-titration cycle 
every third week by 2 mg is employed in the present trial. Furthermore, 2 mg dose increments and 
three weeks at each dose level prior to dose escalation are planned. Dose titration has been used 
previously with other marketed GLP-1R agonists to make higher doses more tolerable. 
11. Pharmacokinetic parameters of dapiglutide 
In the single ascending dose trial, ZP7570-18144, the pharmacokinetics displayed dose 
proportionality with a good dose-response relationship for maximal concentration (Cmax) and area 
under the curve (AUC)0-168h. Low inter-subject variability was seen. Maximum dapiglutide 
concentration was reached after a median of 20 to 24 hours, and the half-life was approximately 
five days. 

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In the multiple ascending dose trial, ZP7570-18145, dapiglutide exposure of each dose group 
linearly increased with dose. Peak concentration (Tmax) occurred around 24 h after dosing, and 
concentrations declined thereafter. Similar-shaped profiles were obtained from the dose groups. 
The variability of Cmax and AUCtau was low within each dose group. Steady-state was reached after 
the fourth dose in all groups, and the terminal half-life was approximately five days, which is 
suitable for once-weekly dosing.  
12. Trial assessment 
12.1 Risk assessment and ethical considerations 
A complete list of possible undesirable effects of dapiglutide is provided in the IB25. The most 
frequent undesirable side effects of dapiglutide reported in the human single-dose and multiple-
dose study are gastrointestinal-related; nausea, vomiting, abdominal distension, dyspepsia, and 
decreased appetite25. Injection site reactions, including itching and skin rashes, are observed in 
most studies involving injectable peptides25. It is unknown whether the frequency or intensity of 
the injection site reaction is different with dapiglutide administration. Dapiglutide was not a local 
irritant at the injection site in studies involving rats and dogs25. Headache has been reported in 
GLP-1RA studies but not in GLP-2RA studies25. In clinical trials, headaches are commonly 
observed in connection with nausea and vomiting.  
There is an inherent risk of inducing an ADA response in studies involving modified peptide 
administration. In the 4-week and 13-week toxicity studies in rats and dogs, immunogenicity was 
investigated25. The studies showed that ADA formation was not associated with altered 
pharmacokinetics or pharmacodynamic effects. The long half-life of dapiglutide may increase the 
risk of ADA, but no ADA has so far been detected in human studies with dapiglutide, comprising 
up to four weeks of dosing.  
12.2 Benefit assessment 
GLP-1RA therapy has been demonstrated to reduce body weight in obese individuals in several 
clinical studies22. GLP-2RA therapy has been shown to reduce gastrointestinal transit time and 
gastric secretions and increase absorption of water and nutrients in humans while decreasing 
inflammatory mediators in diet-obese rodents, indicating that GLP-2RA therapy could work as an 
anti-inflammatory agent in obesity. After the follow-up visit, all participants are invited to a diet 
and exercise group counselling. Therefore, it is believed that all participants benefit from trial 
participation in terms of improving weight-related health. Furthermore, all participants will receive 
thorough medical assessments, including testing for liver steatosis, ECG, and blood sampling.  

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12.3 Benefit-risk assessment 
The potential benefits from trial participation mentioned above are anticipated to outweigh any 
risks and/or discomfort associated with trial procedures and administration of dapiglutide. All 
participants will receive the trial product free of charge. A permanent weight loss after trial 
participation is not expected. 
13. Investigational medicinal products 
The investigator is responsible for dispensing the trial product according to the dosage scheme as 
planned in Table 1. The trial products will only be handled by delegated study personnel and trial 
participants (after careful instruction of administration and handling). A telephone consultation is 
conducted on the agreed days of dose escalation to ensure correct escalation.  
Zealand Pharma A/S will supply - in hard copy - a trial-specific Instructions For Use (IFU) in local 
language. 
The investigator is obligated to document that thorough instructions for the use of IMP are given 
to the participants in writing and verbally. The investigator will monitor the first administration at 
the investigation site and subsequently repeat and recap directions for use verbally prior to 
administration in the participant’s home environment and during the telephone consultations. The 
dose escalations occur three (P5) and six (V8) weeks after randomisation, as illustrated in Figure 
1. Thereby, 4 mg or 6 mg constitutes a steady-state phase of six weeks from week 6 to week 12. 
Participants are instructed to return all dispensed vials and cartons to the clinical trial site.  
13.1 Syringe for administration 
The syringe and needle used is a BD Plastipak™ 1 ml Syringe with detached BD Microlance™ 3 
Needle 26 G /13 mm (BD, Holdredge, US). 
14. Identification of investigational medicinal product (IMP) 
The IMPs listed in Table 1 are used in this trial. All IMPs are for single-use and are administered by 
using a single-use syringe with needle. The IMP is supplied by Zealand Pharma A/S. The investigator 
is responsible for the supply of appropriate syringes with needle and sharps containers for used syringes. 
15. Packaging and labelling 
The IMP is packaged, labelled and supplied by Zealand Pharma A/S.  

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The IMP is packaged and labelled in the local language. Labelling is performed according to Annex 
VI and Good Manufacturing Practice guidelines of the European Commission, International 
Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, and local laws and 
regulations.  
Dapiglutide and placebo vials are packed and labelled blinded without revealing the treatment 
allocation. The labels contain no information about the participants. Each dispensing unit (one 
carton with three vials) will have a trial unique DUN to be used for drug allocation, accountability, 
and traceability.  
Enough IMP for the scheduled number of participants, including a buffer volume, is packed and 
supplied.  
The IMP allocated to the present trial may not be relabelled or reassigned for use outside the trial.  
Please see the Trial Material Manual provided by Zealand Pharma A/S for information on the 
handling of the IMP. 
15.1 Storage of IMP 
Dapiglutide and placebo must be stored refrigerated at 2-8°C. Storage conditions for the IMP are 
detailed on the label. The investigator must ensure the availability of proper storage conditions at 
the site in a secure area with restricted access. The temperature should be monitored by recording 
the actual, minimum, and maximum temperatures using a calibrated thermometer or by continuous 
recording using a qualified temperature monitoring system with an alarm function. The temperature 
should be evaluated and documented weekly on a temperature log.  
The investigator will contact Zealand Pharma A/S in case of temperature deviations outside the 
acceptable range and must have the capacity to ensure correct storage capacity. IMP that has been 
stored improperly must be set into quarantine and is not be dispensed to any participant before it 
has been evaluated and approved for further use. The Investigator must take appropriate action to 
ensure correct storage. The participants receive verbal and written (the IFU) instructions on how 
to properly handle and store the IMP. 
IMP returned from participants can be stored in a dedicated area at room temperature without 
temperature monitoring.  

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15.2 Drug accountability 
The investigator must maintain adequate records showing the receipt, dispensing, return, or other 
disposition of the trial product, including the date, quantity, batch number and Dispensing Unit 
Number, and identification of the participant (ID number) who received the IMP.  
Any destruction of used/unused IMP must only take place after prior final reconciliation of trial 
product and written approval by Zealand Pharma A/S.  
16. Early termination of the study 
For the individual participant, study participation is terminated if  
• The informed consent is withdrawn 
• In case continued study participation imposes a health risk for the participant as deemed by 
the investigator 
• The event of exceptional circumstances (e.g. some types of SAEs), making it impossible to 
complete the study 
Participants are thoroughly informed about the decision and underlying causes in all cases. In case 
of early study termination, the participant will still be invited to a follow-up visit four weeks after 
being discontinued from study participation. Data collected until the point of early study 
termination are included in the final data analysis. 
The Sponsor/Investigator, Zealand Pharma, or a pertinent regulatory authority may decide to 
terminate the trial or part of the trial at any time if deemed needed.  
Conditions that will warrant termination of the clinical trial include, but are not limited to: 
• Unacceptable Risk/Benefit-profile 
• Administrative reasons 
• The discovery of an unexpected, important, or unacceptable risk to the subjects enrolled in 
the clinical trial 
• A decision of Zealand Pharma or Sponsor/investigator to suspend or discontinue 
investigation of the IMP 
• A fatal or life-threatening SUSAR 
If a trial is prematurely terminated or suspended, the sponsor/investigator should promptly inform 
the subjects and assure appropriate therapy and follow-up. Furthermore, the Sponsor/investigator 
should promptly inform the IEC and Zealand Pharma and provide a detailed written explanation. 

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If the benefit/risk analysis has changed after the termination of the trial, the new evaluation should 
be provided to the IEC in case it impacts the planned follow-up of the subjects who have 
participated in the trial. Necessary actions needed to protect the subjects will be described. 
 
17. Statistical considerations and calculations 
17.1 
General statistical considerations 
Statistical comparisons are made pairwise between all three treatments. The two placebo arms are 
pooled when analysed. In this small-scale proof of concept study, the primary, secondary, and 
exploratory analyses target an efficacy estimand corresponding to the hypothetical treatment 
difference found if everyone in the target population had completed the treatments. In particular, 
study participants completing < 75% of their assigned treatment are considered as non-completers, 
and their outcomes at follow-up are treated as missing data. For comparability with other obesity 
trials, the primary analysis is supplemented with an intention-to-treat analysis which targets the 
treatment policy estimand, i.e. the de facto treatment difference that is found in a target population 
where some are able to complete the treatment while other fail due to side effects and lack of effect 
(Section 17.3). 
17.2 
Baseline characteristics 
Baseline characteristics are summarised as number (%) for categorical data, mean +/- SD for 
normally distributed data, and median (interquartile range (IQR)) for non-normally distributed 
numerical data. 
17.2.1 Primary analysis 
The primary endpoint, % change in body weight from baseline to 12 weeks, is analysed using an 
ANCOVA model including baseline weight, gender, and treatment arm as covariates. Estimated 
treatment differences are reported as baseline- and gender-adjusted mean differences with 95% 
confidence intervals. 
To control the familywise error rate at the 5%-level, the treatment differences are tested 
hierarchically in the following order: 
1) 6 mg dapiglutide treatment for 12 weeks is superior to placebo treatment for 12 weeks in 
reducing body weight relative to baseline 

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2) 4 mg dapiglutide treatment for 12 weeks is superior to placebo treatment for 12 weeks in 
reducing body weight relative to baseline 
3) 6 mg dapiglutide treatment for 12 weeks is superior to 4 mg of dapiglutide treatment for 12 
weeks in reducing body weight relative to baseline 
Thus, superiority of 4 mg dapiglutide compared to placebo will only be tested if superiority of 6 
mg dapiglutide has previously been concluded and superiority of 6 mg dapiglutide compared to 4 
mg dapiglutide is only tested if superiority of 4 mg dapiglutide compared to placebo has previously 
been concluded. A treatment is considered superior to another if the two-sided 95% confidence 
interval indicates a ratio effect >1 in the appropriate direction. 
17.3 Intention-to-treat analysis 
For comparability with other obesity trials, the primary analysis is supplemented by an intention-
to-treat analysis in which data from all study participants is included regardless of treatment 
completion. Genuine missing data from dropouts is handled by placebo imputations assuming that 
dropouts will have similar outcomes as had they received placebo treatment. Besides the different 
handling of non-completers and dropouts, the %-point change in body weight from baseline to 12 
weeks is analysed using an ANCOVA model similar to the primary analysis. Estimated treatment 
differences are reported as baseline- and gender-adjusted mean differences with 95% confidence 
intervals. 
17.4 
Secondary and exploratory analyses 
Outcomes for which %-point changes are targeted are assumed to be approximately log-normally 
distributed and are analysed using a constrained (i.e., baseline-adjusted) linear mixed model with 
log-transformed outcome as dependent variable, including gender, visit and the constrained visit-
treatment interaction as fixed effects, and assuming an unstructured covariance pattern to account 
for repeated measurements on each study participant. Estimated treatment differences are back-
transformed and reported as baseline-adjusted ratio differences in geometric mean bodyweight with 
95% confidence intervals. Other continuous scale outcomes are assumed to be normally distributed 
and are analysed using the same constrained linear mixed model only without the logarithmic 
transformation. Estimated treatment differences are reported as baseline-adjusted mean differences 
with 95% confidence intervals. Binary outcomes are analysed with the chi-square test and reported 
with risk differences and 95% confidence intervals. In case event counts are low, Fisher’s exact 
test is used in place.  
Categorical outcomes obtained from the PROs are summarised in frequency tables and evaluated 
by a Pearson’s chi-squared test. In case event counts are low, Fisher’s exact test is used in place. 

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Scores from the PROs are analysed using a constrained linear mixed model similar to that for the 
normally distributed outcomes. The scoring of the PROs included in the present study is in 
accordance with published instructions. A minimal clinically important difference (MCID) is 
defined as29 
𝑀𝐶𝐼𝐷= 0.2 × 𝑆𝐷𝑃𝑟𝑒𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 
To guard against false positives, the p-values from the secondary and exploratory analyses are 
adjusted separately and for each treatment comparison, in turn, using the method of Benjamini and 
Hochberg30, which controls the false discovery rate. An adjusted p-value <0.05 is considered 
statistically significant. 
17.4.1 Safety endpoints 
AEs, SAEs, SARs, SUSARs and AESIs are reported in numbers and percentages. All events are 
reported regardles of treatment adherence and dropout. No formal statistical tests are performed 
due to presumed lack of power. 
17.5 
Missing data 
Numbers and reasons for dropout are tabulated for each treatment arm, and descriptive tables are 
made to compare the characteristics between the dropouts and the completers. Based on similar 
studies31, we aim at having a dropout rate of 10% or less. Missing data in the primary analysis is 
handled by standard multiple imputations. Missing data in the intention-to-treat analysis is handled 
by placebo imputations. In case of larger than expected or differential dropout, sensitivity analyses 
based on best case – worst case scenarios are performed for the primary efficacy analysis and the 
supplementary intention to treat analyses. Missing data in continuous outcomes from the secondary 
and exploratory analysis are handled implicitly by maximum likelihood estimation in the 
constrained linear mixed model. Missing data in binary and categorical outcomes is omitted from 
analyses. In case of larger than expected or differential dropout, sensitivity analyses based on best 
case – worsts case scenarios are performed for the secondary binary outcomes. 
17.6 
Sample size calculation 
To detect a 5% loss of body weight after 12 weeks of treatment with dapiglutide and with a 
significance level of 2.5% using a two-sided t-test (unpaired) and with an estimated standard 
deviation of 4.0% and assuming a dropout rate of 25%, the study requires 54 participants (3 arms 
× 14 participants + 12 dropouts). The sample size calculation is based on data from a randomised 
clinical trial evaluating semaglutide vs liraglutide therapy for the treatment of obesity.22 

The DREAM trial – protocol V3.0 
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Detectable 
difference 
Standard 
deviation 
Significance 
level 
Power 
Subjects per 
arm 
Subjects pr arm 
(with 25% 
dropouts) 
5% 
3.6% 
2.5% 
80% 
12 
15 
5% 
3.6% 
2.5% 
90% 
15 
19 
5% 
4% 
2.5% 
80% 
14 
18 
5% 
4% 
2.5% 
90% 
18 
23 
Table 3. Power for sample size with a 2.5% significance level 
17.6.1 Secondary endpoint power calculation 
Considering the key secondary endpoint, body weight reduction ≥ 5%, after 12 weeks of treatment, 
n=14 completers in each arm will ensure a power of 83% to detect a 50% difference in success rate 
in favour of dapiglutide compared to placebo based on the two-sided Pearson Chi-square test, 
assuming a success rate of at most 10% with placebo and a significance level of 5%. 
18. Biological materials 
Approximately 20-60 ml of blood is collected during fasting visits (V1, V2, V8 and V14), 
accumulating a total blood withdrawal of 160 to 240 ml over 19 weeks.  
In total, a maximum of 300 ml of blood is collected during the trial period (19 weeks), which is 
considered a non-substantial amount compared to a donation of blood (450 ml at one time). 
Faecal samples are collected before- and after treatment 
Six biopsies are taken from prespecified locations in the duodenum and two biopsies from the 
gastric ventricle near the pyloric antrum. 
19. Timeline 
First participant first visit (FPFV) is expected in Q4 2022. Last participant last visit (LPLV) is 
expected in Q4 2023. If the study is prematurely terminated, the investigator will promptly inform 
the study participants and ensure appropriate therapy and follow-up. The sponsor/investigator will 
further inform the Danish Medicine Agency (DMA), the Danish Medical Research Ethics 
Committees and Zealand Pharma A/S. 
 

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20. Overview of milestones 
2022  
Q2 
 
Writing protocol  
Q3 
 
Submission of clinical trial application to authorities 
Study site initiation, including delivery of study drug 
Advertisement / pre-screening 
Q4 
 
FPFV 
Q4 
 
Trial conduct 
2023  
Q1-Q3  
Trial conduct / first participant last visit 
Q4 
 
LPLV / trial conduct   
2024 
Q1 
 
Trial conduct / LPLV 
Q2-Q3  
Data analysis / write-up 
Q2-Q3  
Reporting, presentation and publication 
21. Financial circumstances 
This is an investigator-initiated trial initiated by members of the study group who have no financial 
interest or gains from the results of this study. 
22. Funding 
This study is an investigator-initiated trial initiated by the Center of Clinical Metabolic Research. 
In addition to the IMP provided free of charge, a grant of DKK 6.077.820 from Zealand Pharma 
A/S funds the entire study. The grant is received as pure support without any kind of obligation to 
Zealand Pharma A/S. The grant covers the study’s entire expenses, including the investigator's 
salaries, utensils, blood sample analysis, conduction of visits, etc. The value of the grant is 
transferred to Center of Clinical Metabolic Research, Gentofte Hospital Denmark. The study group 
members have no financial connection to Zealand Pharma A/S and will have the opportunity to 
publish and present the results without interference from Zealand Pharma A/S. By contract 
agreement, Zealand Pharma is notified a minimum of 30 days before submission for publication 
and can delay by up to 90 days before such submission to ensure against inadvertent disclosure of 
unprotected trial drug discoveries or confidential information. 
23. Financial compensation to participants 
The participants are remunerated for documented travel expenses. Likewise, participants are 
financially compensated for the inconvenience following study participation with DKK 2,000 due 
to general labour-heavy trial participation. Additionally, the participants receive DKK 2,500 per 

The DREAM trial – protocol V3.0 
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gastroduodenoscopy completed. The participants receive remuneration of DKK 1000 if the 
participants resign from study participation or are discontinued per the principal investigator’s 
initiative. 
24. Logistics 
With the exception of the gastroduodenoscopies, all visits are conducted at Center for Clinical 
Metabolic Research, Herlev-Gentofte Hospital, at Gentofte Hospital Denmark (Sponsor-
investigator and Research Site), which accommodates all the practical necessities to carry out the 
experimental procedures and storage of IMP before dispensing to participants. The 
gastroduodenoscopies are performed by affiliated gastroenterologist Anne Haaber, MD, who is co-
investigator of the trial. 
25. Feasibility 
The site staff at Center for Clinical Metabolic Research at Gentofte Hospital, University of 
Copenhagen, has experience from several clinical studies involving treatment and/or investigation 
of obesity. Moreover, we have a track record in mechanistic research involving GLP-1 and GLP-2 
and are experienced in conducting clinical proof-of-concept studies in the field 32–34.  
26. Insurance 
All participants are covered by the general patient compensation applicable to public institutions 
(‘Patienterstatningen’). 
27. Registration 
The trial is conducted in compliance with the protocol. The trial is registered with 
ClinicalTrials.gov and CTIS and approved by the Danish Medical Research Ethics Committees, 
the Danish Medicines Authority and the Data Protection Agency. It is carried out under the 
surveillance and guidance of the GCP unit, University of Copenhagen, Copenhagen, Denmark, in 
accordance with the International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH)-GCP guidelines, as well as EU Regulation 
No 536-2014 - Annex I. Data, are collected and stored on an approved and secured server of the 
Capital Region and Region Zealand via an electronic case report file in REDCap (database 
program). Data are processed in compliance with the General Data Protection Regulation (GDPR) 
and the Danish Data Protection Act. Results are presented at national and international scientific 
meetings and synthesised in one or more scientific manuscripts for publication per the CONSORT 

The DREAM trial – protocol V3.0 
Page 36 of 40 
2010 statement in international, peer-reviewed scientific journals. Positive, negative, and 
inconclusive results together with the statistical method, are published as soon as scientifically 
justifiable. The summary of the clinical trial results will be made available in CTIS no later than a 
year after end of trial.  
28. Research biobank 
Centrifuged blood samples (serum/plasma), faecal material and gastroduodenoscopy biopsies are 
stored in a biobank (-20°C and -80°C freezers) during the study until the expected termination of 
the study in January 2028. The biobank is equipped with an alarm, and unique identification is 
needed to access the freezers. Excess biological material are stored in the same biobank. In the case 
of future research, the biological material is stored in the biobank after study termination (January 
2028). If the biological material is used in future research projects, a new application is formulated 
to the Region Ethics Committee before conducting the new study. As a default, new consent from 
participants is requisitioned. However, the Region Ethics Committee can give dispensation in this 
matter. All samples in the biobank are fully anonymised, and all data protection rules are still 
followed in this period. ADA samples are analysed at the Charles River Laboratories Edinburgh 
Ltd, Great Britian and dapiglutide concentrations are determined at York Bioanalytical Solutions 
Limited, Cedar House Northminster Business Park Upper Poppleton, York YO26 6QR. Collection 
and processing of data in Great Britain will happen in accordance with chapter V of the Regulation 
(EU) 2016/67 
Biobank location: Center for Clinical Metabolic Research, Herlev-Gentofte Hospital.  
29. Data 
All data are pseudonymised as all participants are given a unique ID number. Registries with unique 
social security identification number tied to each individual are kept on a safe and secure server. 
Data in paper are locked behind double-locks and/or electronic case report files using REDCap or 
in a closed folder at a secure ‘L:drive’ and ‘P:drive’ at Herlev-Gentofte Hospital. Blinded and 
pseudonymised data can be shared with Zealand Pharma A/S. 
29.1 Data location 
Data registries are under the supervision of the Danish Data Protection Agency. Data collected 
during the trials - such as biological material, ECG readings etc. - are archived for a period 
maximum of 25 years. Furthermore, the investigator allows direct access to source data and 
documents (including medical records) when monitoring, auditions, and/or inspections of the GCP-
unit and/or the Danish Medicines Agency. 

The DREAM trial – protocol V3.0 
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30. Publication 
The results derived from this study are submitted for publication as one or several manuscripts in 
relevant high-impact journals. Positive, negative and/or inconclusive results are published, and 
results shall be uploaded to CTIS as soon as possible after LPLV. The investigator reserves the 
right to publish all findings related to the study. However, the investigator is obligated to notify 
Zealand Pharma A/S of any such publication at least 30 days prior to submission for publication to 
ensure against inadvertent disclosure of unprotected trial drug discoveries or confidential 
information. In case of a patent application, Zealand Pharma A/S can require a delay of any 
publication for up to 90 days. 
31. Study group 
Per 29th of June 2022: 
Casper Kjærsgaard Nielsen, MSc, Clinical Metabolic Research, Herlev-Gentofte Hospital, 
Gentofte 
Nicklas Järvelä Johansen, MD, PhD, Clinical Metabolic Research, Herlev-Gentofte Hospital, 
Gentofte 
Professor Filip Krag Knop, MD PhD, Clinical Metabolic Research, Herlev-Gentofte Hospital, 
Gentofte  
 
 

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