About this trial
The purpose of this trial is:
* To investigate whether the response to clozapine treatment can be enhanced by adding cannabidiol (CBD), compared to placebo, in treatment resistant psychosis patients. * To confirm the safety of CBD in people with psychosis.
The trial is a randomised, double-blind, placebo-controlled, multi-centre, international, clinical trial. Individuals with a diagnosis of treatment resistant psychosis in their illness who have had a suboptimal or no response to clozapine treatment will be recruited. These patients are randomised to treatment with oral CBD 500mg twice daily, or a matching placebo for 12 weeks, in addition to clozapine, which is standard care treatment for this population. By using a battery of clinical outcome assessments, the trial will assess several optional biomarkers to predict clinical outcomes and response to treatment with CBD. Biomarkers are being assessed as an exploratory outcome measure. Participants will be invited to provide additional blood samples, stool samples, and complete neuroimaging assessments.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
16 to 50 years of age (inclusive) who are willing and able to provide written informed consent/assent (country specific requirements apply).
The patient has been treated with clozapine for at least 8 weeks with a clozapine plasma concentration of at least 0.35 mg/L at screening. If a patient has a lower plasma concentration at screening, the patient can enter the trial at a later date once their plasma concentration is above the threshold*.
Within 10 years of first antipsychotic treatment prescribed for psychosis.
The patient meets DSM-5 criteria for schizophrenia, schizoaffective disorder or schizophreniform disorder, as confirmed through the SCID-5-RV. The patient does not meet modified Andreasen et al (2005) criteria for symptomatic remission cross-sectionally (time requirement does not apply), i.e., a severity rating score of no more than mild (score of </=3) on 8 specified Positive and Negative Syndrome Scale (PANSS) positive and negative symptom items: P1 - Delusions, P2 - Conceptual Disorganization, P3 - Hallucinatory Behaviour, N1 - Blunted Affect, N4 - Passive/Apathetic Social Withdrawal, N6 - Lack of Spontaneity and Flow of Conversation, G5 - Mannerisms and Posturing, G9 - Unusual Thought Content.
Disqualifiers
Current treatment with sodium valproate, valproate semisodium, or clobazam. In cases of current use of these medicines, participation is only permitted if they can and will be discontinued or switched to a suitable alternative medication prior to randomisation.
Hypersensitivity to the active substance, sesame oil, sesame seed or any of the excipients of the trial intervention.
Known hepatic insufficiency and/or transaminase elevations levels exceeding the upper limit of normal 2 times or more and bilirubin greater than 1.5 times the upper limit of normal.
Previous neurosurgery or neurological disorder, including epilepsy, which may affect the trial procedures*.
Trial design
Parallel
Treatments tested in this trial
CBD 100 mg/mL Oral Solution
DrugDaily dose 1000mg, taken as 500mg (5ml) b.i.d for 6 weeks. For participants with a weight lower than 50 kg, the dose is to be adjusted to 20 mg/kg/day divided over 2 intakes of 10 mg/kg/day, for a period of 12 weeks
Placeb
Drug5ml b.i.d for 6 weeks; For participants with a weight lower than 50 kg, the dose is to be adjusted to 20 mg/kg/day divided over 2 intakes of 10 mg/kg/day, for a period of 12 weeks
Treatment groups
Trial outcomes
Primary outcomes
Change in Positive and Negative Syndrome Scale (PANSS) total score
Change in Positive and Negative Syndrome Scale (PANSS) total score from baseline to 12 weeks. The minimum value is 1 and the maximum value is 7 for each item of the scale. 1. A patient meets remission criteria if none of the following items score a 4 or higher: P1, P2, P3, N1, N4, N6, G5 and G9. 2. A patient does not meet remission criteria if one or more of these items score a 4 or higher.
Secondary outcomes
Change in symptoms (sub-scale scores)
Change in scores on the Positive and Negative Syndrome Scale (PANSS) positive, negative and general symptom subscales from baseline to 12 weeks. Total PANSS score: Minimum: 30 (all items scored 1); Maximum: 210 (all items scored 7). Subscale ranges: Positive Scale: 7-49; Negative Scale: 7-49; General Psychopathology Scale: 16-112. Higher PANSS scores = worse outcome; Indicate greater symptom severity. Lower PANSS scores = better outcome; Indicate fewer or less severe symptoms.
Symptomatic remission
Symptomatic remission after 12 weeks as measured using the Positive and Negative Syndrome Scale (PANSS), defined using Andreasen (2005) remission criteria. Remission is based on the following PANSS: Positive symptoms: P1, P2, P3. Negative symptoms: N1, N4, N6. General psychopathology: G5, G9.Minimum score: 1 (absent); Maximum score: 7 (extreme). Lower scores are better outcome; Higher scores are worse outcome. Andreasen, N. C., Carpenter, W. T., Jr, Kane, J. M., Lasser, R. A., Marder, S. R., \& Weinberger, D. R. (2005). Remission in schizophrenia: proposed criteria and rationale for consensus. The American journal of psychiatry, 162(3), 441-449. https://doi.org/10.1176/appi.ajp.162.3.441
Change in overall clinical impression
Change in overall clinical impression, assessed through Clinical Global Impression of Improvement and Severity (CGI-I/S) scales from baseline to 12 weeks. Clinical Global Impression of Severity (CGI-S) is rated from 1 (normal, not at all ill) to 7 (among the most extremely ill), with lower scores indicating lower illness severity. Clinical Global Impression of Improvement (CGI-I) is rated from 1 (very much improved) to 7 (very much worse), with lower scores indicating greater clinical improvement.
Change in functioning
Change in functioning, assessed through Social and Occupational Function Scale (SOFAS) from baseline to 12 weeks. Score range 1-100, the higher score means the better function
Other outcomes
Change in overall patient impression of severity and improvement
Change in overall patient impression, assessed through Patient Global Impression of Improvement and Severity (PGI-I/S) scales from baseline to 12 weeks. The Patient Global Impression of Improvement (PGI-I) is a single question asking the patient to rate how their psychotic symptoms is now compared to the previous study visit on a scale of 1. very much better to 7. very much worse. The lower score is better in symptoms' improvement. The Patient Global Impression of Severity (PGI-S) is a single question asking the patient to rate how their psychotic symptoms is now on a scale of 1. not present to 7. very severe. The lower score is better in symptoms.
Sponsors and contacts
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University of Oxford
Lead sponsor
Wellcome Trust
Collaborator
Cambridge Cognition Ltd
Collaborator
Cambridgeshire and Peterborough NHS Foundation Trust
Collaborator
Oxford Health NHS Foundation Trust
Collaborator
West London NHS Trust
Collaborator
Charite University, Berlin, Germany
Collaborator
University of Cologne
Collaborator
Ludwig-Maximilians - University of Munich
Collaborator
University Hospital Frankfurt, Department of Psychiatry, Psychosomatic Medicine and Psychotherapy
Collaborator
The Sheba Fund for Health Services and Research
Collaborator
Shalvata Mental Health Center
Collaborator
Geha Mental Health Center
Collaborator
Amsterdam University Medical Center
Collaborator
National and Kapodistrian University of Athens
Collaborator
Hospital General Universitario Gregorio Marañon
Collaborator
Hospitales Universitarios Virgen del Rocío
Collaborator
University of Campania Luigi Vanvitelli
Collaborator
Psychiatric University Hospital, Zurich
Collaborator
Douglas Hospital Research Centre
Collaborator
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