A Randomized, Double-Blind, Placebo-Controlled Trial of Cannabidiol as an Adjunct to Antipsychotic Therapy in Remitted Early Phase Schizophrenia

The primary objective of this clinical trial is to evaluate the **efficacy** of cannabidiol compared to placebo as an add-on to state-of-the-art antipsychotic maintenance treatment in individuals with remitted early phase schizophrenia. This is clinically relevant as it aims to determine whether cannabidiol can enhance the therapeutic outcomes of standard antipsychotic treatments, potentially offering a novel adjunctive therapy for improving patient recovery and quality of life.

Secondary objectives include:

• Evaluating improvements in psychopathology, social, and occupational functioning.
• Analyzing changes in neurocognition.
• Assessing the safety and drug-drug interaction of cannabidiol in long-term treatment.
• Comparing changes in the cumulative dose of concomitant and rescue medication.
• Evaluating alterations in endocannabinoid levels and lipidomic profiles.
• Determining whether aberrations in oral microbial community structure and function accompany schizophrenia.
• Quantifying the incidence of extrapyramidal side-effects and weight gain.

The clinical trial focuses on individuals diagnosed with **remitted early phase schizophrenia**. The study population includes both male and female participants aged between 18 and 65 years. Participants are required to be in generally stable health, as indicated by a Body Mass Index (BMI) between 18 and 40, although those with a BMI over 40 may be considered if no further medical conditions suggest a metabolic syndrome. The trial does not involve a vulnerable population. Participants must be fluent in either German or English. The selection criteria include a stable oral dose of specific antipsychotic medications for at least two weeks prior to inclusion, ensuring the maximal effect of previous medication. The trial sponsor has not provided information regarding the total number of participants. Key lifestyle considerations include the requirement for female participants of childbearing potential to use a proper method of contraception. The trial population was selected based on these criteria to evaluate the efficacy of cannabidiol as an add-on treatment to standard antipsychotic maintenance therapy.

The clinical trial is designed to evaluate the efficacy of **cannabidiol** as an add-on treatment to standard antipsychotic therapy in patients with remitted early phase schizophrenia. This is a multi-center, two-arm, double-blind, randomized controlled trial comparing cannabidiol capsules to a placebo. The trial is set to run until December 31, 2025, with an estimated recruitment start date of November 9, 2017. Participants will be randomly assigned to receive either cannabidiol or a placebo, both administered orally in hard capsule form. The maximum daily dose of cannabidiol is 800 mg, with a total treatment period of up to 195 days.

Study visits are structured to ensure comprehensive monitoring and data collection. The initial inclusion visit involves screening participants to confirm eligibility based on criteria such as age, diagnosis, and medication stability. Follow-up visits are scheduled to assess treatment adherence, symptom progression, and any adverse events. The primary endpoint is all-cause discontinuation within 12 months post-randomization, which includes conditions such as symptom worsening or non-compliance with medication. Secondary endpoints include improvements in psychopathology, social functioning, and quality of life, as well as changes in neurocognition and biomarkers.

Participants are expected to be involved in the study for the entire duration unless early termination is warranted. Conditions for early termination include significant symptom exacerbation, non-adherence to medication for over 14 consecutive days, or failure to attend scheduled appointments for more than six weeks. Withdrawal of informed consent or clinical reasons as determined by the investigator may also lead to early termination. The trial aims to provide valuable insights into the potential benefits of cannabidiol as an adjunctive treatment in schizophrenia, with rigorous safety and efficacy assessments conducted throughout the study period.

The clinical trial involves the administration of **Cannabidiol Capsules** as the experimental medication. These capsules are in a hard pharmaceutical form and are administered orally. The active substance in the capsules is **cannabidiol**, a chemical compound. The maximum daily dose of cannabidiol is 800 mg, with a total maximum dose of 151.6 g over the treatment period. The treatment period is set for a maximum of 195 days. The cannabidiol capsules are not formulated for pediatric use. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

The study also includes a placebo group, which receives **Füllstoffmischung DAC** in hardshell gelatin capsules, size 1. This placebo consists of 99.5% mannitol and 0.5% silloidal silicon dioxide (Aerosil®). The placebo is designed to match the experimental medication in appearance to maintain the double-blind nature of the trial. The placebo does not contain any active pharmaceutical ingredients and serves as a control to evaluate the efficacy of the cannabidiol treatment. Participants in the placebo group will follow the same administration schedule as those receiving the experimental medication.

The efficacy of cannabidiol as an add-on treatment for schizophrenia will be assessed in a multi-center, two-arm, double-blind, randomized clinical trial. The primary endpoint for evaluating efficacy is the **all-cause discontinuation** within 12 months following randomization. This includes conditions such as relevant worsening of symptoms, non-adherence to medication for more than 14 consecutive days, failure to attend scheduled appointments for over six weeks, inability to trace the participant despite extensive efforts, withdrawal of informed consent, and termination of treatment upon the investigator's request due to clinical reasons.

Secondary endpoints include improvements in psychopathology from baseline using the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression (CGI), Brief Symptom Inventory (BSI-53), and Freiburg Psychosis Evaluation Scale (FROGS). Additionally, social and occupational functioning will be measured using the Global Assessment of Functioning (GAF) and Personal and Social Performance (PSP) scales, while quality of life will be assessed with the WHO Quality of Life-BREF (WHOQUOL-Bref) and Lancashire Quality of Life Profile (LQLP). Changes from baseline in the Calgary Depression Scale for Schizophrenia (CDSS), neurocognition, and self-reported treatment adherence using the Drug Attitude Inventory (DAI) will also be evaluated. Other assessments include changes in biomarkers, such as endogenous cannabinoids and lipidomic profiling, and changes from baseline in the UKU Side Effect Rating Scale, Abnormal Involuntary Movement Scale (AIMS), and evaluation of extrapyramidal symptoms (EPS). The Columbia Suicidality Severity Rating Scale (C-SSRS) will be used to assess suicidality severity. Safety and tolerability will be monitored through adverse events, physical examinations, body mass index (BMI), vital signs, ECG, neurological functioning assessments, and detailed laboratory tests.