The Norwegian Prednisolone in Early Psychosis Study

Study Overview
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Brief Summary
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Objective: The primary objective of this trial is to investigate whether prednisolone improves symptom severity as compared to placebo when given in addition to antipsychotic medication to patients with early-stage psychotic disorder. Secondary objectives include improvement of cognitive functioning and positive, negative and general psychopathological symptoms as well as general functioning. Study design: Randomized placebo-controlled double-blind trial. Study population: 90 men and women, with an age of 18 years and older, diagnosed with schizophrenia spectrum disorder. The time interval between the onset of psychosis and study entry should not exceed five years and CRP level should be at least 3.9 mg/L. Intervention: Patients will be randomized 1:1 to either prednisolone or placebo daily for a period of 6 weeks. Identical tablets will be administered. Prednisolone will be initiated at 40 mg for three days, after which it will be phased out within 6 weeks after start, following current treatment guidelines. Main study parameters/endpoints: Primary outcome is change in symptom severity, expressed as a change in total score on the Positive and Negative Symptom Scale (PANSS) from baseline to end of the 6-week treatment. Secondary outcomes are a 6-month follow-up assessment of PANSS, cognitive functioning (measured through a repeatable neurocognitive battery, change in GAF scores and the measurement of various immunological biomarkers. In post-hoc analyses, attempts will be made to identify baseline blood markers with predictive properties regarding improvement in the anti-inflammatory drug treatment arm. Expected benefits for consumers and care givers: A decrease in symptom severity is expected, as low grade brain inflammation may be associated with psychotic symptoms. The results may give raise to a new line of scientific research as well as treatment options for a disabling disorder.

Official Title
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The Norwegian Prednisolone in Early Psychosis Study - NorPEPS. The Role of Immune-modulating Strategies in the Treatment of Psychosis

Conditions
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Schizophrenia and Related Disorders, Immune Suppression, Psychosis, Cognitive Change

Intervention / Treatment
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* Drug: Prednisolone
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A DSM-IV-R diagnosis of: 295.x (schizophrenia, schizophreniform disorder, or schizoaffective disorder) or 298.9 (psychosis NOS) Onset of psychosis no longer than 5 years ago Minimum total PANSS score of 60 Age 18 -70 years. Patients are treated with antipsychotic medication Written informed consent is obtained Female patients of childbearing potential need to utilize a proper method of contraception (the pill, vaginal ring, hormonal patch, intrauterine device, cervical cap, condom, contraceptive injection, diaphragm) in case of sexual intercourse during the study. Exclusion Criteria: Presence of any of the contra-indications of prednisolone as reported in the SPC. These include hypersensitivity to any ingredients in the formulation, systemic infections unless specific anti-infective therapy is employed, patients with ocular herpes simplex due to the possibility of perforation, recent vaccination with live or weakened virus or bacteria. Also the following special warnings in the SPC will represent exclusion criteria: Existing or previous history of severe affective disorders in themselves or in their first degree relatives, including depressive or bipolar disorders or previous steroid psychosis, glaucoma or family history of glaucoma, hypertension or heart failure, liver impairment and/ or failure, epilepsy, osteoporosis, peptic ulceration, previous steroid myopathy, renal insufficiency, history of tuberculosis or x-ray changes characteristic of tuberculosis, recent myocardial infarction, chickenpox, measles. Presence of diabetes mellitus or random (non-fasting) glucose levels exceeding 11 mmol/L at screening, or family history of diabetes. Body Mass Index (BMI) of >30.0 Current or chronic use of systemic glucocorticosteroids (temporary use is permitted, if stopped before start of treatment trial) Chronic use of non-steroidal anti-inflammatory drugs, defined as daily use during more than 2 months. Intermittent use is permitted, if stopped at least 1 month before start of treatment trial. Pregnancy or breast-feeding. A urine pregnancy test will be performed at screening and then after 6 weeks of treatment and the event of treatment discontinuation. Concurrent use of certain types of medication: 1. liver enzyme inducing medication such as carbamazepine, riphampicine, primidone, barbiturates and phenytoine 2. HAART (both HIV protease inhibitors and (non)-nucleoside reverse transcriptase inhibitors), especially efavirenz, ritonavir and lopinavir. 3. telaprevir and boceprevir in treatment of Hepatitis C

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Placebo-controlled randomized 1:1 comparison.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prednisolone<br>Prednisolone tablets 5 mg | Drug: Prednisolone<br>* Prednisolone tablets initiated at 40 mg for three days, after which it will be phased out within 6 weeks after start<br>|
| Placebo Comparator: Placebo<br>Placebo tablets with identical appearance to the experimental drug. | Other: Placebo<br>* Placebo tablets initiated at 40 mg for three days, after which it will be phased out within 6 weeks after start<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement of overall symptom severity | Overall symptom severity measured by the Positive and Negative Syndrome Scale. 30 items rated between 1 (symptom not present) and 7 (symptom present in the most severe degree. The sum score constitutes the overall symptom severity, and ranges between 30 - 210 Points. | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement of overall symptom severity after 6 and 12 months | Overall symptom severity measured by the Positive and Negative Syndrome Scale. 30 items rated between 1 (symptom not present) and 7 (symptom present in the most severe degree. The sum score constitutes the overall symptom severity, and ranges between 30 - 210 Points. | 6 and 12 months | 
| Improvement of overall cognition | Cognitive functioning as measured by the Brief Assessment of Cognition in Schizophrenia (BACS). | 1 year | 
| Improvement of positive symptoms | The Positive subscale score as measured by the Positive and Negative Syndrome Scale. 7 items rated between 1 (symptom not present) and 7 (symptom present in the most severe degree. The range is between 7-49 points | 6 weeks, 6 months, 12 months | 
| Improvement of negative symptoms | The Negative subscale score as measured by the Positive and Negative Syndrome Scale. 7 items rated between 1 (symptom not present) and 7 (symptom present in the most severe degree. The range is between 7-49 points | 6 weeks, 6 months, 12 months | 
| Improvement of general psychopathology | The general psychopathology subscale as measured by the Positive and Negative Syndrome Scale. 16 items rated between 1 (symptom not present) and 7 (symptom present in the most severe degree. The range is between 16-112 points | 6 weeks, 6 months, 12 months | 
| Improvement og the Global Assessment of Functioning scale (GAF) | GAF is scored between 1 (lowest possible functioning) and 100 (best possible functioning). | 6 weeks, 6 months, 12 months | 
| Change of depressive symptoms | Severity of depression is assessed using the Calgary Depression Scale for Schizophrenia, which has 9 items scored as 0 (symptom not present), 1 (mild degree), 2 (moderate degree), or 3 (severe degree of symptom). This makes a possible sub score range between 0 and 27). | 6 weeks, 6 months, 12 months | 
| Number of participants with treatment-related adverse events as assessed by the UKU Side Effects Rating Scale | Occurrence and severity of severe adverse events and suspected unexpected severe adverse reaction as measured by the UKU Side Effects Rating Scale. | 12 months |