Inflammation, Obesity
Conditions
Keywords
Gut barrier function
Brief summary
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. The study will investigate the efficacy of once-weekly subcutaneously administered of 4 mg and 6 mg dapiglutide versus placebo in 54 obese individuals (BMI \>30 kg/m2) during a 12-week treatment period.
Detailed description
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). 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. 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, 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) participate in this sub-study.
Interventions
DRUGDapiglutide
GLP-1/GLP-2 receptor agonism
DRUGPlacebo
Placebo
Sponsors
Zealand Pharma
University Hospital, Gentofte, Copenhagen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
To ensure blinding, the placebo arm is split between 4 mg and 6 mg placebo, making the randomisation sequence 2:2:1:1 (e.i. 2x 4 mg dapiglutide, 2x 6 mg dapiglutide, 1x 4 mg placebo and 1x 6 mg placebo
Intervention model description
Three arms: 12 weeks of 4 mg and 6 mg dapiglutide and placebo
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Age 18-75 years * BMI ≥ 30 kg/m² * History of at least one attempt to lose body weight
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 * 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: * Women who are pregnant, breastfeeding, intend to become pregnant or are of childbearing potential will not be included in the study * Sterilised or postmenopausal women (\> 12 months amenorrhoea or females ≥ 60 years of age) can be included * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage change in body weight (kg) | From week 0 (baseline) to week 12 (end of treatment) | %-point |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Body weight reduction ≥ 5% | From week 0 (baseline) to week 12 (end of treatment) | count (yes/no) |
| Body weight reduction ≥ 10% | From week 0 (baseline) to week 12 (end of treatment) | count (yes/no) |
| Change in fasting serum/plasma concentrations of gut permeability biomarker (LPS-binding protein (LBP)) | From week 0 (baseline) to week 12 (end of treatment) | %-point |
| Change in fasting serum/plasma concentrations of inflammation markers (hs-CRP and IL-6) | From week 0 (baseline) to week 12 (end of treatment) | %-point |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in body composition as measured by bioimpedance | From week 0 (baseline) to week 12 (end of treatment) | %-point |
| Change in FibroScan®-assessed liver steatosis (dB/m) | From week 0 (baseline) to week 12 (end of treatment) | %-point |
| Change in FibroScan®-assessed liver fibrosis (kPa) | From week 0 (baseline) to week 12 (end of treatment) | %-point |
| Change in Fatty liver index score (FLI) | From week 0 (baseline) to week 12 (end of treatment) | %-point (FLI score: Range interval 0-100, \< 30 negative likelihood of fatty liver and \>60 positive likelihood of fatty liver) |
| Body weight reduction ≥ 15% | From week 0 (baseline) to week 12 (end of treatment) | count (yes/no) |
| Change in the 36-Item Short Form Survey | From week 0 (baseline) to week 12 (end of treatment) | Score points |
| Change in IWQOL-Lite-CT | From week 0 (baseline) to week 12 (end of treatment) | Score points |
| Number of treatment-emergent AEs | From signed consent form (week -3) to follow-up visit (week 16) | Counts of events |
| Number of serious AEs (SAEs) | From signed consent form (week -3) to follow-up visit (week 16) | Counts of events |
| Change in fibrosis 4 score (FIB-4) | From week 0 (baseline) to week 12 (end of treatment) | %-point (score of \<1.30 = low risk; 1.30-2.67 = intermediate risk; \>2.67 = high risk of advanced fibrosis) |
| Change in BMI (kg/m2) | From week 0 (baseline) to week 12 (end of treatment) | %-point |
| Change in systolic blood pressure (mmHg) | From week 0 (baseline) to week 12 (end of treatment) | %-point |
| Change in diastolic blood pressure (mmHg) | From week 0 (baseline) to week 12 (end of treatment) | %-point |
| Change in resting heart rate (beats per minute) | From week 0 (baseline) to week 12 (end of treatment) | %-point |
Countries
Denmark
Outcome results
None listed