Clinical trial NCT04892199: Does GLP-1RA Prevent Deterioration of Metabolic State in Prediabetic and Diabetic Patients Treated With Antipsychotic Medication?
Official title: 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?
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Metabolic Disturbance
Schizophrenia
Type 2 Diabetes
Clozapine
GLP-1
Olanzapine
Lead sponsor: Psychiatric Centre Rigshospitalet
Sponsor class: OTHER
First posted: 2021-05-19
Enrollment: 104
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomised, Double-blinded, Parallel, Placebo-controlled, clinical trial
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

1. Informed oral and written consent
2. 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)
3. Initiating current treatment with clozapine or olanzapine within 60 months (not PRN ordinations)
4. Age 18 years to 65 years (both included)
5. Body mass index (BMI) ≥25 kg/m2
6. 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:

1. Acute worsening of psychosis based on a clinical evaluation (score of 6 or 7 on the CGI-S scale)
2. Coercive measures
3. Females of child-bearing potential who are pregnant, breast-feeding or have intention of becoming pregnant.
4. Women who are not willing to use adequate contraceptive during the full length of the study
5. Patients treated with corticosteroids or other hormone therapy (except oestrogens)
6. Any active substance abuse or dependence for the past six months (except for nicotine)
7. Impaired hepatic function (plasma liver transaminases \>3 times upper normal limit)
8. Impaired renal function (serum creatinine \>150 μmol/l and/or macroalbuminuria)
9. Impaired pancreatic function (acute or chronic pancreatitis and/or plasma amylase \>2 times upper normal limit)
10. Cardiac problems defined as decompensated heart failure (NYHA class III/IV), unstable angina pectoris and/or myocardial infarction within the last 12 months
11. Hypertension with systolic blood pressure \>180 mmHg or diastolic blood pressure \>100 mmHg
12. Any condition that the investigator feels would interfere with trial participation
13. Receiving any experimental or pre-marketing drug within the last 3 months
14. Use of weight-lowering pharmacotherapy within the preceding 3 month
15. Known type 1 diabetes
16. 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.
17. 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.
18. Any known contraindication towards the treatment with semaglutide.

Primary outcomes:
measure: The primary endpoint is the change from baseline in glycated haemoglobin A1c (HbA1c).
timeFrame: 26 weeks
Secondary outcomes:
measure: Body weight (Kg)
timeFrame: 26 weeks
measure: Hip and Waist circumference (Cm)
timeFrame: 26 weeks
measure: Incretin hormones (Blood sampling)
timeFrame: 26 weeks
measure: Bone Markers (Blood sampling)
timeFrame: 26 weeks
measure: Lipid Profile (Blood sampling)
timeFrame: 26 weeks
measure: Hormones (blood sampling)
timeFrame: 26 weeks
measure: Visceral fat
timeFrame: 26 weeks
measure: Android to Gynoid fat ratio
timeFrame: 26 weeks
measure: Total body fat
timeFrame: 26 weeks
measure: Bone density
timeFrame: 26 weeks
measure: Psychopathology
timeFrame: 26 weeks
measure: Registration of body movements/level of activity with a sensor
timeFrame: 26 weeks
measure: Reward value of sweet and fatty candy
timeFrame: 26 weeks
measure: Alcohol use
timeFrame: 26 weeks
measure: Tobacco use
timeFrame: 26 weeks
measure: Drug use
timeFrame: 26 weeks
measure: Schizophrenia quality of life scale
timeFrame: 26 weeks
measure: Psychosocial disability
timeFrame: 26 weeks
measure: Liver function (blood sampling)
timeFrame: 26 weeks
measure: Proteomic analyses (Blood sampling)
timeFrame: 26 weeks
measure: Proteomic analyses (Urine sampling)
timeFrame: 26 weeks
measure: FIB-4 score
timeFrame: 26 weeks
measure: Vitals
timeFrame: 26 weeks
measure: Insulin sensitivity and beta cell function
timeFrame: 26 weeks
Other outcomes:
Locations:
city: Aarhus
country: Denmark
facility: Psychosis Research Unit, Aarhus University Hospital, Psychiatry,
city: Copenhagen
country: Denmark
facility: Psychiatric Centre Copenhagen, Rigshospitalet
city: Hillerød
country: Denmark
facility: Psychiatric Centre Nordsjaelland, Hillerød
Study officials:
affiliation: Psychiatric Centre Copenhagen
name: Anders Fink-Jensen, MD
role: PRINCIPAL_INVESTIGATOR
References: