Efficacy of Composite Personalized Care with Calcium Folinate, Omega-3-Acid Ethyl Esters 90, Cyanocobalamin, and Acetylcysteine in Early Psychosis Patients

The primary objective of this study is to assess the **efficacy** of a composite personalised care (CPC) approach in patients with early psychosis, including those at ultra-high risk and experiencing a first episode of psychosis. This approach is based on biological tests and clinical profiles, involving the adaptation of add-on medications, cognitive reinforcement using digital applications, or a combination of both. The efficacy will be measured from baseline to 3 months, compared to treatment as usual (TAU), using the Personal and Social Performance (PSP) Scale to evaluate global functioning. This is clinically relevant as it aims to improve functional outcomes in early psychosis, potentially leading to better long-term prognosis and quality of life for patients.

Secondary objectives include: - Evaluating the persistence of efficacy on the PSP at V3. - Assessing the efficiency of CPC on clinical outcomes using psychopathological scales (PANSS, MADRS, CGI), clinical record textual notes, prosodic and linguistic markers, neurological soft signs, and cognitive performance at V3. - Investigating the effect of CPC on health-related quality of life (QoL) using SF-12 and EQ-5D-5L, and medication adherence measured by MARS. - Analyzing the influence of biological background and in vivo neuroimaging on outcomes. - Monitoring longitudinal epigenetic and seric changes associated with outcomes. - Conducting a cost-effectiveness analysis of CPC, including an incremental cost-effectiveness ratio in cost per quality-adjusted life-years. - Performing a budgetary impact analysis regarding costs and health gains associated with the generalization of CPC. - Evaluating acceptability and user satisfaction through the number of effective sessions and satisfaction scores (uMARS).

The clinical trial involves participants diagnosed with **Ultra High Risk of psychosis** and first episode psychosis. The study population consists of adolescents and young adults, both male and female, aged between 15 to 30 years. Participants are characterized according to the CAARMS criteria as being at ultra-high risk or experiencing a first episode of psychosis within the first year after diagnosis and care. The trial does not include a vulnerable population. Participants must have regular health insurance, excluding AME, and provide informed and written consent. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the efficacy of a **composite personalized care** (CPC) approach in patients with **early psychosis**, specifically those at ultra-high risk or experiencing a first episode of psychosis. This trial is structured as a **Prospective Randomised Open, Blinded End-point (PROBE) controlled trial**, with a focus on comparing the effects of biological add-on neuroprotective medication, such as vitamin supplementation, against digital cognitive reinforcement. The primary objective is to assess improvements in global functioning using the Personal and Social Performance (PSP) Scale over a period of three months.

Participants will be randomly assigned to one of the intervention groups or a control group receiving treatment as usual (TAU). The trial will span approximately 84 days, with the estimated recruitment start date set for December 15, 2023, and an anticipated end date of September 30, 2025. The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as age (15 to 30 years), diagnosis, and consent; regular follow-up visits to monitor progress and adherence to the intervention; and a final end-of-study visit to evaluate outcomes and collect data for analysis.

Participant involvement is expected to last for the full duration of the trial, approximately three months, unless specific conditions necessitate early termination. Such conditions may include withdrawal of consent, adverse events, or non-compliance with study protocols. The trial will ensure that all participants have regular health insurance, excluding those with AME, and will require informed and written consent prior to participation. The trial's primary endpoint is the assessment of global functioning, with no secondary endpoints specified. The trial is authorized in France, with the status currently marked as authorized following an evaluation period.

The clinical trial involves the administration of several experimental medications, each with specific characteristics and administration protocols. **FOLINORAL 25 mg**, a hard capsule containing **calcium folinate**, is administered via buccal use. The maximum daily dose is 50 mg, with a total treatment period of up to 84 days. This medication is produced by THERABEL LUCIEN PHARMA S.A. and is classified under the ATC code V03AF03. The active substance is of chemical origin.

**Omacor 1000 mg**, a soft capsule containing **omega-3-acid ethyl esters 90**, is also administered buccally. The maximum daily dose is 3000 mg, with a treatment duration of up to 84 days. Manufactured by BASF AS, this medication is categorized under the ATC code C10AX06. The active substance is a mixture.

**VITAMINE B12 GERDA 250 microgrammes**, a tablet containing **cyanocobalamin**, is administered via buccal use. The maximum daily dose is 500 micrograms, with a treatment period of up to 84 days. This product is produced by SUBSTIPHARM and falls under the ATC code B03BA01. The active substance is of chemical origin.

**MUCODRILL 600 mg SANS SUCRE**, an effervescent tablet containing **acetylcysteine**, is administered buccally. The maximum daily dose is 1800 mg, with a treatment period of up to 84 days. This medication is manufactured by ALPEX PHARMA (IRL) LIMITED and is classified under the ATC code R05CB01. The active substance is of chemical origin.

All medications are administered via the buccal route, and participant compliance is monitored throughout the trial. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The study aims to evaluate the efficacy of these medications in the context of early psychosis treatment.

The efficacy of the clinical trial will be assessed by evaluating the impact of a composite personalized care (CPC) approach on the functional outcomes of patients with early psychosis. The primary endpoint for efficacy assessment is the improvement in global functioning, which will be measured using the Personal and Social Performance (PSP) Scale. This scale will be used to compare the effects of CPC, which includes biological tests and clinical profile adaptations such as add-on medications and cognitive reinforcement through digital applications, against the standard Treatment as Usual (TAU).

The PSP Scale will be administered to participants at baseline and again 3 to 4 months after the initiation of the intervention to determine changes in global functioning. The trial is designed as a Prospective Randomised Controlled Trial, and the efficacy assessments will be conducted in a blinded manner to ensure objectivity. The trial aims to provide a comprehensive evaluation of the CPC's effectiveness in enhancing the functional outcomes of adolescents and young adults aged 15 to 30 years who are characterized as being at Ultra High Risk (UHR) or experiencing First Episode Psychosis (FEP) within the first year of diagnosis.