Psychosis, Treatment Resistant Psychosis
Conditions
Brief summary
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.
Interventions
Daily 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
DRUGPlaceb
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
Sponsors
Wellcome Trust
Cambridge Cognition Ltd
Cambridgeshire and Peterborough NHS Foundation Trust
Oxford Health NHS Foundation Trust
West London NHS Trust
Charite University, Berlin, Germany
University of Cologne
Ludwig Maximilian university of Munich
University Hospital Frankfurt, Department of Psychiatry, Psychosomatic Medicine and Psychotherapy
The Sheba Fund for Health Services and Research
Shalvata Mental Health Center
Geha Mental Health Center
Amsterdam University Medical Center
National and Kapodistrian University of Athens
Hospital General Universitario Gregorio Marañon
Hospitales Universitarios Virgen del Rocío
University of Campania Luigi Vanvitelli
Psychiatric University Hospital, Zurich
Douglas Hospital Research Centre
University of Oxford
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double blind - CBD and placebo will have an identical appearance, taste and texture.
Intervention model description
Randomized, double-blind, placebo-controlled
Eligibility
Sex/Gender
ALL
Age
16 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
Participation in the trial requires meeting all of the following inclusion criteria: 1. 16 to 50 years of age (inclusive) who are willing and able to provide written informed consent/assent (country specific requirements apply). 2. 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\*. 3. Within 10 years of first antipsychotic treatment prescribed for psychosis. 4. 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. 5. Patients of child-bearing potential\*\* must be willing to ensure that they use highly effective contraception during the trial and as per the requirements in the protocol\*\*\*. 6. In the Investigator's opinion, is able and willing to comply with all trial requirements. 7. Willing to allow their General Practitioner and/or consultant, if required by local guidelines/regulations, to be notified of participation in the trial. 8. For patients who take part in the optional MRI scans: they must be eligible for MRI scanning as per local requirements, for example concerning e.g. implants, braces etc. There is inadequate information on the effects of cannabidiol on the foetus in humans. Participants of child-bearing potential\*\* should use a highly effective method of contraception3 for the duration of the trial and for 3 months after the last time the trial intervention was used. There is no special requirement for male participants to use highly effective contraception as there are no known safety concerns in males, such as sperm toxicity, as per the Investigator's Brochure. This trial will also not be collecting pregnancy data from partners of male participants. \*Clozapine levels can be up to 4 weeks old if the clozapine dose remained within 25 mg of the dose used at the time of blood draw. \*\*A person is considered of child-bearing potential, i.e. fertile, following menarche and until becoming post-menopausal (no menses for 12 months without an alternative medical cause) unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. \*\*\*Methods that can achieve a failure rate of less than 1% per year when used consistently and correctly are considered as highly effective birth control methods. Such methods include: 1) combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral; intravaginal; transdermal); 2) progestogen-only hormonal contraception associated with inhibition of ovulation (oral; injectable; implantable); 3) intrauterine device (IUD); 4) intrauterine hormone-releasing system (IUS); 5) bilateral tubal occlusion; 6) vasectomised partner; 7) sexual abstinence (abstinence should only be used as a contraceptive method if it is in line with the subjects' usual and preferred lifestyle). Periodic abstinence (calendar, symptothermal, post-ovulation methods) is not an acceptable method of contraception. The participant agrees to use an acceptable method of contraception\*\* for the duration of the trial and for 3 months after any trial intervention administration, unless surgically sterile or postmenopausal. The age range for eligibility has been applied as this corresponds to the usual age range for treatment resistant psychosis; individual cases outside of this age range may have a different aetiology and/or prognosis which could impact on the trial outcomes.
Exclusion criteria
Individuals are excluded from participation in the trial if they meet one or more of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Positive and Negative Syndrome Scale (PANSS) total score | 12 weeks | 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
| Measure | Time frame | Description |
|---|---|---|
| Change in symptoms (sub-scale scores) | From baseline to 12 weeks | 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 | 12 weeks | 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 | From baseline to 12 weeks | 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 | from baseline to 12 weeks | 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 |
| Change in cognitive functioning | from baseline to 12 weeks | Change in cognitive functioning as assessed through the PsyCog battery from baseline to 12 weeks. PsyCog comprises the tests that were chosen from the larger CANTAB battery to assess the key cognitive deficits associated with psychosis, including: o Paired Associates Learning (PAL): key measures including PAL total errors adjusted (score range 0-70; lower is better) and PAL first attempt memory score (score range 0-20; higher is better). |
| Acceptability of CBD treatment | 12 weeks | Acceptability of CBD treatment, measured through Clinician rating scale (CRS) to assess adherence to trial medication (Kemp et al., 1998) and all-cause discontinuation over 12 weeks. Clinical rating scale score range: Minimum: 1; Maximum: 7. Higher scores are better outcome; Indicate greater adherence to trial medication. Lower scores are worse outcome; Indicate poor or absent adherence. |
| Incidence of adverse events | 12 weeks and 30 days post treatment | Incidence of adverse events, measured through Glasgow Antipsychotic Side-effect Scale (GASS) over 12 weeks. Spontaneous adverse event reporting is until 30 days after the study intervention has been discontinued. |
| Changes in measuring the severity of anxiety and depression symptoms | from baseline to 12 weeks | Measure the severity of anxiety symptoms via Hamilton Anxiety Scale (HAM-A) from baseline to 12 weeks. Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where \<17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. |
| Changes in measuring the depression symptoms | from baseline to 12 weeks | Measure the depression in schizophrenia without overlap with negative symptoms and extrapyramidal symptoms by using the Calgary Depression Scale for schizophrenia (CDSS) from baseline to 12 weeks. it includes 9 items in the scale. All ratings of the items are defined according to operational criteria from 0-3. The CDSS depression score is obtained by adding each of the item scores. Score range is 0-27, which is the lower score is better. |
| Changes in biomarkers that occur in relation to symptomatic improvement with adjunctive cannabidiol compared to placebo. | baseline and 12 weeks | Measure the neuroimaging (Magnetic resonance imaging (MRI)) from baseline to 12 weeks if participant consents to it. The Magnetic resonance imaging (MRI) scan includes: T1 - brain structure T2 FLAIR - brain structure / clinical reporting Neuromelanin sensitive MRI - neuromelanin content of substantial nigra (proxy of dopamine activity) Magnetic Resonance Spectroscopy of the anterior cingulate cortex - metabolites e.g. glutamate Resting state fMRI - bold activation during rest or free mind wandering |
| Change in quality of life | from baseline to 12 weeks | Change in quality of life, assessed using the EuroQol 5-Dimension, 3-Level Questionnaire (EQ-5D-3L) from baseline to 12 weeks. It includes five dimensions-MOBILITY, SELF-CARE, USUAL ACTIVITIES, PAIN /DISCOMFORT and ANXIETY / DEPRESSION. Each dimension has three levels: no problems, some problems, extreme problems (labelled1-3). The respondent is asked to indicate his / her health state by checking the box against the most appropriate statement in each of the five dimensions. The EQ VAS records the respondent's self-rated health on a vertical VAS where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. This information can be used as a quantitative measure of health outcome as judged by the individual respondents. Score range: Minimum: 0 (worst imaginable health); Maximum: 100 (best imaginable health). Higher scores indicate better health; Lower scores indicate worse health. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in overall patient impression of severity and improvement | from baseline to 12 weeks | 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. |
Countries
Germany, Greece, Israel, Italy, Netherlands, Spain, Switzerland, United Kingdom
Contacts
Primary ContactJared Robinson
Backup ContactSusan Zhao
Outcome results
None listed