Lifestyle Changes, Mushroom Supplementation, and Bupropion to Reduce Adiposity and Cardiometabolic Risk

This is a 12-month, multicenter, randomized, parallel-group, open-label, controlled trial investigating the effects of lifestyle changes, lyophilized powder from edible mushrooms, and bupropion treatment on adiposity and cardiometabolic risk in people with overweight. The study includes five parallel treatment arms: 1.Control; 2. Lifestyle; 3. Lifestyle + Dietary supplement; 4. Lifestyle + Pharmacological treatment; 5.Lifestyle + Dietary supplement + Pharmacological treatment.

250 subjects will be enrolled and randomized in five parallel groups with 50 subjects in each treatment arm. Randomization will be performed in four strata, defined by sex (male or female) and cardiometabolic risk factors (presence or absence of hypertension, hyperlipidemia, or prediabetes). The randomization for each stratum will be done within balanced blocks to ensure approximately equal numbers of subjects across the treatment arms within each stratum. The study population will be composed such that each level of the stratification factors is represented by at least 30% of participants, i.e., at least 30% men and 30% women, and at least 30% with and 30% without cardiometabolic risk factors.

Participants in treatment arm 4 and 5 receiving the pharmacological treatment will undergo re-randomization after 6 months (visit 4) in a 1:1 ratio to either discontinue the medication or continue at a maintenance dose.

The study comprises eight physical visits: enrolment visit (Visit 1), randomization visit (Visit 2), four follow-up visits conducted during the treatment period (Visit 3-6), and two follow-up visits conducted after the treatment period at 24 and 36 months after inclusion in the study (Visits 8, and 9). In addition, one follow-up assessment will be conducted via telephone 18 months after inclusion (Visit 7).

Long-term follow-up of the participants will be performed through national registers. Such data may be obtained for five years before and up to 20 years after inclusion in the study and will be assessed in relation to baseline data and data collected during the physical visits and telephone follow-up.

Inclusion criteria

• Men and women aged 18-55 years.
• BMI of 25.0 - 34.9 kg/m2.
• Signed informed consent.
• Have a mobile phone, tablet, or computer with internet access.
• Cardiometabolic risk factors: a) None of the following diagnoses: hypertension, hyperlipidemia, or prediabetes according to WHO classification (Stratum A); b) One or several of the following diagnoses: hypertension, hyperlipidemia, or prediabetes according to WHO classification (Stratum B).
• For women of childbearing potential: use of a highly effective birth control method

Exclusion criteria

• Present food intolerances and/or allergies of relevance to the interventions, such as celiac disease and allergy to edible mushrooms or fungal spores.
• Contraindication to bupropion, or any unacceptable risk with either treatment as assessed by the investigator. Specifically, and not covered elsewhere:

• History of epilepsy or lowered seizure threshold;
• History of bulimia or anorexia nervosa;
• Central nervous system tumor;
• Hypersensitivity to bupropion;
• History of bipolar disorder;
• Known or suspected Brugada syndrome;
• Current or recent adherence to a low-calorie diet, receipt of pharmacological treatment for weight loss, and/or weight loss of > 3 kg within the past 3 months.
• Previous or planned bariatric surgery
• Diagnosed diabetes, coronary heart disease, heart failure, stroke, liver failure or kidney disease (eGFR<60 ml/min/1.73m2) as well as other ongoing serious conditions with short life expectancy or conditions affecting participation in the study.
• Any condition, as judged by the investigator, that suggests that the participant will be non-compliant or otherwise unsuitable to study medication or study participation. For example, serious psychiatric, eating, alcohol or substance abuse disorders.
• Use of the following medications within indicated time frames:

• Other bupropion-containing products (last 2 weeks);
• Other weight lowering-drugs: orlistat, phentermine-topiramate, sodium-glucose transporter 2 inhibitors (SGLT2i), GLP-1 receptor agonists (last 3 months);
• Antipsychotics, mirtazapine, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors (last 3 months);
• MAOIs (last 2 weeks);
• Systemic glucocorticoids (last 3 months);
• Testosterone, anabolic steroids (last 6 months);
• Medications not listed above that are metabolized by CYP2D6;
• Medications that affect CYP2B6;
• Be pregnant or intend to become pregnant during the study period.
• Involvement in the planning and/or conduct of the study.
• Ongoing participation in another interventional clinical trial.