Stratification and Treatment in Early Psychosis Study -ASSIST (STEP-ASSIST)

Full Title: Cannabidiol Augmentation of Clozapine in Treatment Resistant Psychosis: a Double-blind, Randomised Controlled 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.

Study Overview

• Status: Not yet recruiting
• Conditions: Psychosis; Treatment Resistant Psychosis
• Intervention / Treatment: Drug: CBD 100 mg/mL Oral Solution; Drug: Placeb

• Study Type: Interventional
• Enrollment (Estimated): 250
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Susan Zhao; Email: steptrials@phc.ox.ac.uk
• Study Contact Backup: Name: Jared Robinson; Email: steptrials@phc.ox.ac.uk

Study Locations

• Germany
  • Berlin, Germany
    • Charite Universitatsmedizin
  • Cologne, Germany
    • University Hospital Cologne
  • Munich, Germany
    • Ludwig-Maximilian-University Munich
• Greece
  • Athens, Greece
    • National and Kapodistrian University of Athens
• Israel
  • Hod HaSharon, Israel
    • Shalvata Mental Health Center
  • Petah Tikva, Israel
    • Geha Mental Health Center
  • Ramat Gan, Israel
    • Sheba Medical Centre
• Italy
  • Napoli, Italy
    • University of Campania 'Luigi Vanvitelli'
• Netherlands
  • Amsterdam, Netherlands
    • Stichting Amsterdam UMC
• Spain
  • Madrid, Spain
    • Hospital General Universitario Gregorio Marañon
  • Seville, Spain
    • Hospital Universitario Virgen del Rocio
• Switzerland
  • Zurich, Switzerland
    • Psychiatric University Hospital (PUK), Zurich
• United Kingdom
  • Cambridge, United Kingdom
    • Cambridgeshire and Peterborough NHS Foundation Trust
  • London, United Kingdom
    • West London NHS Trust
  • Oxford, United Kingdom
    • Oxford Health NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

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 exclusion criteria. Rescreening is permitted where the relevant circumstances may have changed.

1. 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.
2. Hypersensitivity to the active substance, sesame oil, sesame seed or any of the excipients of the trial intervention.
3. 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.
4. Previous neurosurgery or neurological disorder, including epilepsy, which may affect the trial procedures*.
5. IQ <70 as measured by a validated IQ test e.g. Wechsler Abbreviated Scale of Intelligence (WASI), Wechsler Adult Intelligence Scale (WAIS), and Wechsler Intelligence Scale for Children (WISC), as approved for local languages and appropriate for the participant's age.
6. Pregnancy or breastfeeding.
7. The patient has a current diagnosis of 'Substance or medication induced psychotic disorder' or 'Psychotic disorder due to another medical condition' as determined through the SCID-5-RV.
8. Current active suicidal ideation within the last 2 weeks, defined as a score of 1 or higher on CDSS question 8, followed by an assessment by the treating clinician who determines it is not safe for the patient to participate in the trial**
9. The participant meeting DSM-5 criteria for substance use disorder, with the exception of nicotine use disorder (mild, moderate, and severe allowed). Mild cannabis use disorder is allowed (i.e. can meet up to but no more than 3 criteria on the SCID) as long as the subject has not consumed cannabis on average more than three times a week in the past 30 days. Mild alcohol use disorder is also allowed.
10. Patient has participated in another clinical trial in which the participant received an experimental or investigational drug or agent <3 months before Visit 0. Participants who have participated in Type A studies (e.g. trials of standard and within-label treatments including antipsychotic medication) or non CTIMPs (e.g. studies of exercise therapy) must have completed the intervention.
11. The participant refuses any mandatory safety checks during the trial, specifically, refusal of: urine pregnancy test (those of child-bearing potential only); safety blood test; reporting of adverse events; and assessment of suicidality.

12. Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant's ability to participate in the trial.

    • Minor neurological disorders such as migraine, other minor headache disorders, sleep disorders or nerve palsies which are unlikely to affect trial outcomes including neuroimaging measures can be permitted.

      • The decision to include the patient is at clinician's discretion. The clinician can conclude that it is safe for the patient to participate after the patient is evaluated, in which case this exclusion criterion does not apply and the patient can participate. Either way, the treating clinician needs to record his/her evaluation of suicidal risk in the source documentation or medical file, including his/her considerations, and notify the site PI of the decision.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental: Cannobidiol; Participants in this arm will receive Cannabidiol (CBD) for 12 weeks.	Drug: CBD 100 mg/mL Oral Solution; 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
Placebo Comparator: Placebo; Participants in this arm will receive placebo for 12weeks.	Drug: Placeb; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.; 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.; A patient does not meet remission criteria if one or more of these items score a 4 or higher.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From baseline to 12 weeks
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	12 weeks
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.	From baseline to 12 weeks
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	from baseline to 12 weeks
Change in cognitive functioning	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).	from baseline to 12 weeks
Change in cognitive functioning	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 Rapid Visual Information Processing (RVP): key measures including RVP A' (score range 0-1; higher is better) and RVP median response latency(ms) (score range 100-1900; lower is better).	from baseline to 12 weeks
Change in cognitive functioning	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: Emotion Recognition Task (ERT): key measures including ERT overall median reaction time (ms) (score range 100-00; lower is better) and ERT total hits (score range 0-48; higher is better).	from baseline to 12 weeks
Change in quality of life	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.	from baseline to 12 weeks
Change in quality of life	Change in quality of life, assessed using the World Health Organization Quality-of-Life Scale (WHOQOL-BREF) from baseline to 12 weeks. The WHOQOL-BREF is a 26-item instrument consisting of four domains: physical health (7 items), psychological health (6 items), social relationships (3 items), and environmental health (8 items); it also contains QOL and general health items. Each individual item of the WHOQOL-BREF is scored from 1 to 5 on a response scale, which is stipulated as a five-point ordinal scale.	from baseline to 12 weeks
Acceptability of CBD treatment	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.	12 weeks
Incidence of adverse events	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.	12 weeks and 30 days post treatment
Changes in measuring the severity of anxiety and depression symptoms	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.	from baseline to 12 weeks
Changes in measuring the severity of anxiety and depression symptoms	Measure the severity of anxiety symptoms via the Overall Anxiety Severity and Impairment Scale (OASIS) from baseline to 12 weeks. It consists of five items that measure the frequency and severity of anxiety, as well as level of avoidance, work/school/home interference, and social interference associated with anxiety. Respondents select among five different response options for each item, which are coded 0-4 and summed to obtain a total score. Score range is 0-20. The lower score is better in symptoms.	from baseline to 12 weeks
Changes in measuring the depression symptoms	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.	from baseline to 12 weeks
Changes in biomarkers that occur in relation to symptomatic improvement with adjunctive cannabidiol compared to placebo.	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	baseline and 12 weeks
Changes in biomarkers that occur in relation to symptomatic improvement with adjunctive cannabidiol compared to placebo.	Measure the microbiome samples from baseline to 12 weeks if participant consents to it. The gut-microbiome (the microorganisms e.g. bacteria, normally found in participant's gut) is likely to be at play in determining whether participant respond or experience side effects from CBD. Two tubes of stool samples to be collected at two time points(baseline and week 12) if participant consent to it.	baseline and 12 weekds
Changes in biomarkers that occur in relation to symptomatic improvement with adjunctive cannabidiol compared to placebo.	Measure the blood samples for central lab assessment including (Epi)genetics, proteomics, inflammation, metabolomics, Redox markers from baseline to 12 weeks if participant consents to it.	from baseline to 12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	from baseline to 12 weeks

Collaborators and Investigators

• Sponsor: University of Oxford
• Collaborators: Hospital General Universitario Gregorio Marañon; Charite University, Berlin, Germany; Wellcome Trust; University of Cologne; National and Kapodistrian University of Athens; University Hospital Frankfurt, Department of Psychiatry, Psychosomatic Medicine and Psychotherapy; Hospitales Universitarios Virgen del Rocío; Psychiatric University Hospital, Zurich; Shalvata Mental Health Center; Cambridgeshire and Peterborough NHS Foundation Trust; Cambridge Cognition Ltd; Geha Mental Health Center; Oxford Health NHS Foundation Trust; Douglas Hospital Research Centre; Amsterdam University Medical Center; Ludwig Maximilian university of Munich; University of Campania Luigi Vanvitelli; West London NHS Trust; The Sheba Fund for Health Services and Research

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): September 1, 2029

Study Registration Dates

• First Submitted: December 4, 2025
• First Submitted That Met QC Criteria: December 23, 2025
• First Posted (Actual): January 8, 2026

Study Record Updates

• Last Update Posted (Actual): January 8, 2026
• Last Update Submitted That Met QC Criteria: December 23, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Psychotic Disorders; Pharmaceutical Preparations; Solutions
• Other Study ID Numbers: PID-18894; 1007007 (Other Identifier: UK-HRA IRAS)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Please contact the sponsor, who will provide instructions for submitting a data request. All data can be requested, regardless of the location of the requesting party.
• IPD Sharing Time Frame: Data and supporting documents will become available once the primary papers are available in the scientific domain.
• IPD Sharing Access Criteria: These will be provided by the sponsor to the requesting party.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No