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. All participants who complete the 26 weeks of intervention, will be invited for a follow up visit 1.5 yeras after study completion. 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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
104
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.
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.
Psychosis Research Unit, Aarhus University Hospital, Psychiatry,
Aarhus, Denmark
Psychiatric Centre Copenhagen, Rigshospitalet
Copenhagen, Denmark
Psychiatric Centre Nordsjaelland, Hillerød
Hillerød, Denmark
The primary endpoint is the change from baseline in glycated haemoglobin A1c (HbA1c).
Time frame: 26 weeks
Body weight (Kg)
Time frame: 26 weeks
Hip and Waist circumference (Cm)
Time frame: 26 weeks
Incretin hormones (Blood sampling)
GLP-1, GLP-2 and GIP
Time frame: 26 weeks
Bone Markers (Blood sampling)
Calcitonin, Vit-D, Ca, Phosphate, Mg, PTH, PINP, CTX, OC
Time frame: 26 weeks
Lipid Profile (Blood sampling)
LDL, HDL, triglycerider, total kolesterol,
Time frame: 26 weeks
Hormones (blood sampling)
Insulin, glucagon and C-peptide
Time frame: 26 weeks
Visceral fat
DXA scanning
Time frame: 26 weeks
Android to Gynoid fat ratio
DXA scanning
Time frame: 26 weeks
Total body fat
DXA scanning
Time frame: 26 weeks
Bone density
DXA scanning
Time frame: 26 weeks
Psychopathology
PANSS-6 interview
Time frame: 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
Time frame: 26 weeks
Reward value of sweet and fatty candy
Clicker test
Time frame: 26 weeks
Alcohol use
Questionnaires: AUDIT
Time frame: 26 weeks
Tobacco use
Questionnaires: FNTD
Time frame: 26 weeks
Drug use
Questionnaires: DUDIT
Time frame: 26 weeks
Schizophrenia quality of life scale
Questionnaire: SQLS
Time frame: 26 weeks
Psychosocial disability
Rating GAPD
Time frame: 26 weeks
Liver function (blood sampling)
ALT, ALP, AST, trombocytes and bilirubin
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 26 weeks
Vitals
Blood pressure and pulse
Time frame: 26 weeks
Insulin sensitivity and beta cell function
evaluated by homeostatic model assessment
Time frame: 26 weeks
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