Testing orismilast, alone or with semaglutide, for weight management in obesity

Who can take part

• Age 18-75
• BMI ≥ 30 kg/m²
• History of at least one attempt to lose body weight

Who cannot take part

• A self-reported change in body weight ≥ 5% within the last three months prior to the screening visit
• Suicidal behaviour three months prior to screening visit
• Any prior suicidal attempt
• 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
• Administration of any investigational drug within three months 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 three months prior to the screening visit
• Use of GLP-1RAs, glucagon-like peptide 2 receptor agonists, dipeptidyl peptidase 4 (DPP4) inhibitors, human growth hormone, somatostatin or analogues thereof, within three months prior to screening visit
• Treatment with antipsychotics known to modulate energy intake three months prior to screening visit
• Prolonged treatment (>1 week) with anti-inflammatory agents or any PDE4 inhibition within three months prior to the screening visit
• Any type of bariatric surgery
• Previous, current or planned (during the trial period) obesity treatment with surgery or a weight loss device < 12 months prior to the screening visit
• History of major cardiovascular events three months prior to screening visit, including myocardial infarction, stroke, hospitalisation for angina and transient ischaemic attack
• History of major depressive disorder within 2 years of screening
• Unstable severe psychiatric disorder (e.g. bipolar disorder or schizophrenia)
• Class IV heart failure, according to the New York Heart Association
• Known or suspected hypersensitivity to orismilast, semaglutide or related products
• History or evidence of hepatitis B virus infection
• Evidence of hepatitis C virus (HCV) infection. Confirmatory testing for HCV RNA will be conducted for participants who have a positive test result. Participants who have a negative result for HCV RNA will be eligible to participate in the trial
• Known human immunodeficiency virus (HIV) positive or evidence positive for HIV antibodies (HIV-1 or HIV-2)
• Uncontrolled thyroid disease as per the discretion of the investigators
• History of type 1 diabetes or type 2 diabetes
• History of acute or chronic pancreatitis
• History and/or family history of medullary carcinoma and/or multiple endocrine neoplasia syndrome
• 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
• Treatment with glucose-lowering agents within three months prior to the screening visit
• Glycated haemoglobin (HbA1c) ≥ 48 mmol/mol at the screening visit
• Compromised kidney function (estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2) at screening visit
• Known liver disease (except for MASLD) at screening visit. Elevated plasma alanine aminotransferase (ALT) > three times the upper limit of normal
• Positive urine human chorionic gonadotropin (hCG) (for fertile women). Regarding fertile men and women: Women who are pregnant, intend to become pregnant, or are breastfeeding will not be included in the study. Sterilised or postmenopausal women (> 12 months amenorrhoea or females ≥ 60 years of age) can be included without the hCG-testing during the trial period. Female of childbearing potential: To exclude pregnancy, urine hCG tests are performed every fourth week after V2 (Week 4, 8, 12, 16 and 20). The following contraceptive methods are considered adequate for study enrolment for females if maintained throughout the study duration: an intrauterine device, hormonal contraception (birth control pills, implant, patch, vaginal ring or injection), a monogamous relationship with a sterilized partner, or sexual abstinence
• Simultaneous participation in any other clinical intervention trial until completion of follow-up visit (V6)
• Mental incapacity or language barriers that preclude adequate understanding or cooperation or unwillingness to comply with trial requirements