Efficacy and Safety Evaluation of Aripiprazole vs. Paliperidone/Risperidone in First Episode Psychosis Using Multi-omics Data

The primary objective of this clinical trial is to identify a set of **biomarkers** using multi-omics techniques to predict the therapeutic response of aripiprazole or paliperidone after 3 months of treatment in patients experiencing a first psychotic episode within the schizophrenia spectrum. This is clinically relevant as it aims to enhance personalized treatment strategies, potentially improving outcomes by tailoring therapy based on individual biomarker profiles. Additionally, the study seeks to assess the efficacy of these medications at 3 months in reducing psychotic symptoms, defining "responder" status using the PANSS and CGI-S scales. The trial also evaluates the short-term effectiveness through the proportion of discontinuation of the first antipsychotic received within the first 3 months, and the long-term effectiveness through the time to discontinuation during the first year of treatment.

Secondary objectives include: - Assessing the efficacy of aripiprazole paliperidone at 3 and 12 months in reducing positive and negative psychotic symptoms using the PANSS scale, and negative symptoms using the SANS scale, as well as depressive symptoms using the CDSS scale. - Evaluating improvements in social functionality using the PSP scale and quality of life using the EuroQoL scale. - Comparing the tolerability profile by quantifying side effects with the UKU scale. - Comparing changes in anthropometric measurements, cardiovascular, and laboratory tests at 3 and 12 months.

The clinical trial involves **patients with a first psychotic episode** within the schizophrenia spectrum, including conditions such as **schizophrenia** and treatment-resistant schizophrenia. The study population comprises individuals aged between 15 and 40 years, encompassing both male and female participants. The trial does not focus on a vulnerable population. Participants were selected based on their diagnosis according to DSM-5 criteria, which include schizophreniform disorder, schizophrenia, schizoaffective disorder, brief psychotic disorder, or psychotic disorder not otherwise specified. Additionally, participants are required to reside within the area of influence of the study site. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

This clinical trial is a **randomized**, open-label, dose-flexible, multicenter, Phase IV study designed to evaluate the efficacy and safety of **aripiprazole** versus paliperidone/risperidone in patients experiencing a first psychotic episode within the schizophrenia spectrum. The trial aims to identify biomarkers using multi-omics techniques to predict therapeutic response after three months of treatment and assess the efficacy of the medications in reducing psychotic symptoms. The study will also evaluate the short-term and long-term effectiveness of the treatments through the proportion of discontinuation and time to discontinuation of the first antipsychotic received during the first year of treatment.

The trial is expected to commence recruitment on November 1, 2023, and conclude by December 31, 2025. Participants will be involved in the study for a maximum treatment period of 12 months. The trial includes several key visits: an initial **screening** visit to determine eligibility based on criteria such as age (15-40 years) and diagnosis according to DSM-5, followed by regular follow-up visits at 3 and 12 months to assess changes in symptoms and side effects using scales like PANSS, SANS, and UKU. The end-of-study visit will evaluate the overall treatment response and any long-term effects.

Participants may be withdrawn from the study if they experience significant adverse effects, fail to adhere to the study protocol, or if the investigator deems it necessary for their safety. The primary endpoint is the therapeutic response to aripiprazole or paliperidone, while secondary endpoints include changes in psychotic symptoms, depressive symptoms, functionality, quality of life, and side effects at 3 and 12 months. The study is classified as low-intervention due to the established safety profile of the investigational drugs, which are already marketed for treating schizophrenia in adults and adolescents aged 15 years and older.

The clinical trial involves the administration of **Abilify Maintena**, a pharmaceutical product containing the active substance **aripiprazole**. This medication is provided as a **powder and solvent for prolonged-release suspension for injection**. The formulation is designed for **parenteral** administration. The dosage regimen includes a maximum daily dose of 300 mg, with a total maximum dose of 400 mg. The treatment period is set for a maximum of 12 months. The product is manufactured by Otsuka Pharmaceutical Netherlands B.V. and is authorized under the marketing authorization number EU/1/13/882/001. The administration of the drug is monitored to ensure compliance with the dosing schedule.

Another treatment used in the study is **Xeplion**, which is available in two dosages: 150 mg and 100 mg. This medication is also a **prolonged-release suspension for injection** and is administered via the **parenteral** route. The maximum daily dose for Xeplion is 50 mg, with a total maximum dose of 150 mg. The treatment duration is similarly capped at 12 months. Xeplion is produced by Janssen-Cilag International NV and holds the marketing authorization number EU/1/11/672/006. As with Abilify Maintena, participant compliance with the dosing schedule is closely monitored throughout the trial.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the **therapeutic response** to aripiprazole or paliperidone. Secondary endpoints include changes in positive and negative psychotic symptoms, depressive symptoms, functionality, quality of life, and side effects, all measured at 3 and 12 months. These will be evaluated using validated scales such as the Positive and Negative Syndrome Scale (PANSS), the Scale for the Assessment of Negative Symptoms (SANS), the Calgary Depression Scale (CDS), the Personal and Social Performance Scale (PSP), and the EuroQoL visual-analog scale. Side effects will be assessed using the UKU Side Effect Rating Scale.

Additionally, changes in anthropometric measurements, cardiovascular parameters, and laboratory tests will be monitored at the same intervals. The trial aims to identify biomarkers predictive of therapeutic response using multi-omics techniques after 3 months of treatment. The effectiveness of the treatments will also be evaluated by the proportion of discontinuation of the first antipsychotic received within the first 3 months and the time to discontinuation during the first year. Data collection will occur at specified timepoints, including baseline, 3 months, and 12 months, to ensure comprehensive analysis of the efficacy parameters.