Does GLP-1RA Prevent Deterioration of Metabolic State in Prediabetic and Diabetic Patients Treated With Antipsychotic Medication?

Study Overview
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Brief Summary
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Background and objective: Clozapine and olanzapine are some of the most effective antipsychotic drugs, but unfortunately, both drugs induce weight gain and conveys a high degree of metabolic disturbances. The antipsychotic-induced side-effects cause a major clinical problem among patients diagnosed with schizophrenia receiving antipsychotic treatment. Limited effects have been demonstrated for counteracting the side-effects by the switch of antipsychotic therapy, non-pharmacological/behavioural interventions or adjunct pharmacological treatments. Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA,) is approved for the treatment of type 2 diabetes worldwide. The objective of the study is to investigate effects of semaglutide once-weekly vs. semaglutide placebo once-weekly on the metabolic state in prediabetic or diabetic patients with schizophrenia, who have initiated treatment with clozapine or olanzapine. Methods and analysis: Trial design, intervention and participants: The study is a 26-week, double-blinded, randomized, parallel-group, placebo-controlled, good clinical practice (GCP)-monitored, clinical trial. 104 prediabetic or diabetic patients diagnosed with a schizophrenia, age 18 years and 65 years, who have initiated of clozapine- or olanzapine-treatment within 5 years will be included in the study. The patients will be randomized to receive blinded treatment in one of the two study arms; semaglutide once-weekly vs. semaglutide placebo. The primary endpoint is the change from baseline in glycated haemoglobin A1c (HbA1c). Secondary endpoints include change in body weight, hip and waist circumference, vitals, and plasma levels of insulin, glucose, C-peptid, insulin sensitivity, beta cell function, glucagon, liver function, lipid profile, incretin hormones, lipid profile, bone makers, body composition, bone density and proteomic analyses. Additional endpoints include alcohol, tobacco and drug use, food preferences, psychopathology, activity and quality of life.

Official Title
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Does the Glucagon-like Peptide-1 Receptor Agonist Semaglutide Prevent Deterioration of Metabolic State in Prediabetic or Diabetic Patients With Schizophrenia Treated With the Antipsychotic Compounds Clozapine or Olanzapine?

Conditions
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GLP-1, Metabolic Disturbance, Schizophrenia, Type 2 Diabetes, Clozapine, Olanzapine

Intervention / Treatment
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* Drug: Semaglutide, 1.34 mg/mL
* Drug: Semaglutide-placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed oral and written consent Diagnosed with schizophrenia according to the criteria of ICD-10 (International Classification of Diseases, World Health Organization (WHO)) or the DSM-V (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, the American Psychiatric Association) Initiating current treatment with clozapine or olanzapine within 60 months (not PRN ordinations) Age 18 years to 65 years (both included) Body mass index (BMI) ≥25 kg/m2 Diagnosed with prediabetes or type 2 diabetes, after initiation of current treatment with clozapine- or olanzapine, with the following plasma levels: Prediabetes: HbA1c 35-47 mmol/mol or fasting plasma glucose (FPG) 5.6-6.9 mM or 2-h during 75 mg OGGT 7.8-11.0 mM. The test result has to be confirmed on a different day. Type 2 diabetes: HbA1c 48-57 mmol/mol or fasting plasma glucose (FPG) 6.9-9.9 mM or 2h OGTT > 11 mM (although FPG and HbA1c might still be under the diagnostic range). The test result has to be confirmed on a different day. Exclusion Criteria: Acute worsening of psychosis based on a clinical evaluation (score of 6 or 7 on the CGI-S scale) Coercive measures Females of child-bearing potential who are pregnant, breast-feeding or have intention of becoming pregnant. Women who are not willing to use adequate contraceptive during the full length of the study Patients treated with corticosteroids or other hormone therapy (except oestrogens) Any active substance abuse or dependence for the past six months (except for nicotine) Impaired hepatic function (plasma liver transaminases >3 times upper normal limit) Impaired renal function (serum creatinine >150 μmol/l and/or macroalbuminuria) Impaired pancreatic function (acute or chronic pancreatitis and/or plasma amylase >2 times upper normal limit) Cardiac problems defined as decompensated heart failure (NYHA class III/IV), unstable angina pectoris and/or myocardial infarction within the last 12 months Hypertension with systolic blood pressure >180 mmHg or diastolic blood pressure >100 mmHg Any condition that the investigator feels would interfere with trial participation Receiving any experimental or pre-marketing drug within the last 3 months Use of weight-lowering pharmacotherapy within the preceding 3 month Known type 1 diabetes Suicidal behavior as judged by the investigator and based on clinical evaluation. At all contact with patient attendance possible suicidality will be evaluated according to the guidelines. If the patient is evaluated as suicidal, the person will be excluded from the study and evaluated by a senior consultant in psychiatry, who will take further action. Plasma HbA1c > 57 mmol/mol (tested twice) in which case the patient will be excluded from the study and transferred to general practitioner or hospital for diabetic treatment. No diabetic medication is allowed except for the trial medicin. Any known contraindication towards the treatment with semaglutide.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomised, Double-blinded, Parallel, Placebo-controlled, clinical trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Semaglutide injection once-weekly<br> | Drug: Semaglutide, 1.34 mg/mL<br>* Semaglutide 1.34 mg/ml, 1.5 ml pre-filled pen-injector is supplied in pens for injection containing 2.0 mg of the GLP-1RA semaglutide in 1.5 ml sterile water with disodiumphosphate and propylenglycol, and phenol for conservation (pH 8.15). Direction for use will be given together with trial products.The possible doses of semaglutide are 0.25 mg, 0.50 mg and 1.0 mg. The initial weekly dose will be 0.25 mg for four weeks, then 0.5 mg for four weeks and then 1.0 mg for the remaining treatment period. Patients who, due to adverse events, do not tolerate up-titration to 1.0 mg semaglutide will remain on 0.5 mg once-weekly. The injection is administered subcutaneously once-weekly.<br>|
| Placebo Comparator: Semaglutide-Placebo injection once-weekly<br> | Drug: Semaglutide-placebo<br>* The semaglutide placebo pens contain XX-vehicle (no active drug) and are administered in the same way and volume as semaglutide. The semaglutide placebo is specially packed for this study and will be used in the study only. The initial weekly dose will be 0.25 mg for four weeks, then 0.5 mg for four weeks and then 1.0 mg for the remaining treatment period. Patients who, due to adverse events, do not tolerate up-titration to 1.0 mg semaglutide placebo will remain on 0.5 mg once-weekly. The injection is administered once-weekly. If the lowest tolerated dose is less than 0.5 mg of semaglutide placebo once-weekly, the patient will be excluded from the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary endpoint is the change from baseline in glycated haemoglobin A1c (HbA1c). |  | 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body weight (Kg) |  | 26 weeks | 
| Hip and Waist circumference (Cm) |  | 26 weeks | 
| Incretin hormones (Blood sampling) | GLP-1, GLP-2 and GIP | 26 weeks | 
| Bone Markers (Blood sampling) | Calcitonin, Vit-D, Ca, Phosphate, Mg, PTH, PINP, CTX, OC | 26 weeks | 
| Lipid Profile (Blood sampling) | LDL, HDL, triglycerider, total kolesterol, | 26 weeks | 
| Hormones (blood sampling) | Insulin, glucagon and C-peptide | 26 weeks | 
| Visceral fat | DXA scanning | 26 weeks | 
| Android to Gynoid fat ratio | DXA scanning | 26 weeks | 
| Total body fat | DXA scanning | 26 weeks | 
| Bone density | DXA scanning | 26 weeks | 
| Psychopathology | PANSS-6 interview | 26 weeks | 
| Registration of body movements/level of activity with a sensor | Activity measurements (approximate for sleep, inactivity, energy expenditure and steps taken by the patient) will be collected continuously by the use of a wearable activity device worn by the patient for 1 week from inclusion day and 1 week at the end of the study | 26 weeks | 
| Reward value of sweet and fatty candy | Clicker test | 26 weeks | 
| Alcohol use | Questionnaires: AUDIT | 26 weeks | 
| Tobacco use | Questionnaires: FNTD | 26 weeks | 
| Drug use | Questionnaires: DUDIT | 26 weeks | 
| Schizophrenia quality of life scale | Questionnaire: SQLS | 26 weeks | 
| Psychosocial disability | Rating GAPD | 26 weeks | 
| Liver function (blood sampling) | ALT, ALP, AST, trombocytes and bilirubin | 26 weeks | 
| Proteomic analyses (Blood sampling) | Inflammatory biomarkers and cytokines: IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, MDA, plasma antioxidants uric acid and, vitaminC | 26 weeks | 
| Proteomic analyses (Urine sampling) | biomarkers for measurement of systemic oxidative stress on DNA and RNA: 8-oxo-7,8-dihydro2´-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo | 26 weeks | 
| FIB-4 score | A non-invasive scoring system for Liver Fibrosis is a non-invasive scoring system based on several laboratory tests (ALT, AST, trombocytes) and age | 26 weeks | 
| Vitals | Blood pressure and pulse | 26 weeks | 
| Insulin sensitivity and beta cell function | evaluated by homeostatic model assessment | 26 weeks |