dapiglutide for the treatment of obesity

Conditions: Obesity; Inflammation

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.

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.

Eligibility criteria:
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

Keywords: gut barrier function