Evaluation of Dose Reduction Versus Maintenance Treatment in Schizophrenia Spectrum Disorder Using Pipotiazine and Drug Combination

The primary objective of this study is to assess whether an interaction exists between treatment strategy, specifically **Dose Reduction (DR)** versus Maintenance Treatment (MT), and psychotic phenotype, namely Cycloid Psychosis (CP) versus non-Cycloid Psychosis. The hypothesis posits that the benefit of the DR strategy compared to MT, in terms of functional remission, is larger in the CP arm than in the non-CP arm. This is aligned with personalized and precision medicine claims, which are clinically relevant as they may guide tailored treatment approaches for patients with schizophrenia spectrum disorder.

Secondary objectives include:

• Confirming a higher rate of functional remission (FR) in the CP-DR arm compared to the CP-MT arm, and a lower rate of FR in the non-CP-DR arm compared to the non-CP-MT arm, both related to treatment strategy.
• Confirming a higher rate of FR in CP compared to non-CP, related to phenotype characteristics.
• Evaluating the relapse rate across all arms.
• Assessing the rate of "successful DR" in CP and non-CP patients, defined by compliance to the DR schema, absence of significant relapse, and improvement in side effects, well-being, quality of life, or social functioning.
• Evaluating the therapeutic efficacy index and adherence to treatment in both DR and MT arms.
• Confirming the reduction of side effects with DR relative to MT, including cognition, negative symptoms, extrapyramidal side effects, metabolic syndrome, and well-being under antipsychotics.
• Evaluating the level of social and global functioning, including physical activity and leisure, and subjective well-being in all arms.
• Assessing whether expected arm differences are larger in patients with a history of psychotic episodes versus those with a first episode of psychosis.
• Identifying the individual minimal effective dose (i-MinED) of antipsychotics for CP and non-CP phenotypes.
• Confirming that the first step of the reduction (i.e., DM) is safe and desirable, regardless of phenotypes.
• Comparing the mean dosage of antipsychotics in all arms and confirming that the dose is lower in the DR than in the MT arms.

The clinical trial involves **participants** diagnosed with **schizophrenia spectrum disorder (SSD)**, including schizophrenia, schizophreniform, schizoaffective disorder, or brief psychotic episode as per DSM-5 criteria. The study population comprises both male and female subjects aged between 18 and 60 years, who are clinically stabilized for at least six months, indicated by a low intensity of positive symptoms. Participants are required to be treated with oral antipsychotics, either in mono or polytherapy, with second- or first-generation antipsychotics. The trial includes individuals with a Personal and Social Performance (PSP) score greater than 70 at baseline, who are outpatients followed by an ambulatory psychiatrist and have an identified caregiver. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants must be affiliated with health insurance and capable of understanding the research aims and risks, with informed consent obtained. The trial population was selected based on specific inclusion criteria, including the presence of either a cycloid psychosis phenotype or another psychotic phenotype, as determined by the By-CP score. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed as a **randomized**, controlled study to evaluate two treatment strategies for patients diagnosed with **schizophrenia spectrum disorder**. The trial aims to compare the efficacy of dose reduction of antipsychotics versus maintenance treatment, with a focus on the interaction between treatment strategy and psychotic phenotype. The study will involve a total duration of 24 months, with the primary endpoint being the percentage of patients achieving functional remission, as defined by a Personal and Social Performance (PSP) score greater than 70 at the end of the study period.

Participants will undergo a series of study visits, beginning with an inclusion visit to confirm eligibility based on criteria such as age, clinical stability, and diagnosis according to DSM-5. The inclusion visit will also involve obtaining informed consent. Follow-up visits will be scheduled at regular intervals to monitor clinical symptoms, treatment adherence, and side effects. These visits will include assessments using the PSP, PANSS-6, and other relevant scales. The end-of-study visit will evaluate the primary and secondary endpoints, including functional remission and quality of life measures.

The expected length of participant involvement is 24 months, with conditions for early termination including significant relapse, defined as new hospitalization, aggressive behavior, or suicidal attempt. Participants may also be withdrawn if they fail to adhere to the study protocol or if safety concerns arise. The trial will employ a double-blind approach for certain assessments, ensuring that the evaluation team remains unaware of the treatment arm to which participants are assigned. This methodology is intended to minimize bias and enhance the reliability of the study outcomes.

The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Pipotiazine** is administered in the form of a film-coated tablet, with a maximum daily dose of 30 mg and a total maximum dose of 21.9 g over a 24-week period. The route of administration is oral. **Pipotiazine Palmitate** is provided as a solution for injection, with a maximum daily dose of 14 mg and a total maximum dose of 10.22 g, administered intramuscularly over the same period.

**Levomepromazine** is administered orally in a pharmaceutical form coded as PHF00231MIG, with a maximum daily dose of 400 mg and a total maximum dose of 292 g over 24 weeks. **Quetiapine** is also administered orally, with a maximum daily dose of 800 mg and a total maximum dose of 584 g, using the pharmaceutical form PHF00082MIG. **Olanzapine** is provided in the same pharmaceutical form as Levomepromazine, with a maximum daily dose of 20 mg and a total maximum dose of 14.60 g.

**Flupentixol** is administered orally with a maximum daily dose of 400 mg and a total maximum dose of 292 g. **Flupentixol Decanoate** is administered as a solution for intramuscular injection, with a maximum daily dose of 21 mg and a total maximum dose of 15.33 g. **Aripiprazole** is administered orally in the form PHF00245MIG, with a maximum daily dose of 30 mg and a total maximum dose of 21.9 g.

**Amisulpride** is administered orally with a maximum daily dose of 1200 mg and a total maximum dose of 876 g. **Haloperidol Decanoate** is administered orally, with a maximum daily dose of 20 mg and a total maximum dose of 14.6 g. **Chlorpromazine Hydrochloride** is administered orally with a maximum daily dose of 600 mg and a total maximum dose of 438 g.

**Risperidone** is administered orally with a maximum daily dose of 16 mg and a total maximum dose of 12 g. **Loxapine** is administered orally with a maximum daily dose of 600 mg and a total maximum dose of 438 g. **Zuclopenthixol** is administered orally with a maximum daily dose of 50 mg and a total maximum dose of 36.5 g.

Participant compliance with the dosing schedule is monitored throughout the trial period. The trial aims to evaluate the efficacy of dose reduction versus maintenance treatment strategies in patients with schizophrenia spectrum disorder, stratified by psychotic phenotype. The study does not include any pediatric formulations, and all medications are administered according to the specified dosing schedules and routes.

The efficacy of the clinical trial will be assessed primarily through the evaluation of functional remission in patients with schizophrenia spectrum disorder. The primary endpoint is defined as the percentage of patients achieving functional remission, indicated by a Personal and Social Performance (PSP) Scale score greater than 70 at the 24-month follow-up. This assessment will be conducted by the Dreams-Phen evaluation team, who will remain blind to the patients' treatment arms. The evaluation will be based on the patient's functioning during the month preceding the assessment and will be conducted via a web meeting with the patient and their caregiver.

Secondary endpoints include various measures of clinical symptoms and treatment efficacy. Clinical symptoms will be assessed using the short form of the Positive and Negative Syndrome Scale (PANSS-6) and the Clinical Global Impression (CGI) scale. Relapse will be identified by new hospitalizations due to symptom exacerbation, aggressive behavior, or suicidal attempts. A structured interview will be conducted at the end of the study to confirm relapse presence or absence. The therapeutic efficacy index will be evaluated using the CGI-difference, and adherence to treatment will be assessed with the Medication Adherence Rating Scale (MARS) and the Brief Adherence Rating Scale (BARS). Additionally, drug monitoring will be implemented to ensure compliance with the treatment arm.

Treatment side effects will be evaluated using the Abnormal Involuntary Movement Scale (AIMS), the Simpson & Angus Scale (SAS), body mass index, and biological measures for metabolic syndrome. Cognitive functioning will be assessed with subjective scales such as SSTICS and cognitive tests completed online using Millisecond software. Subjective well-being under antipsychotics will be measured using the Subjective Well-being under Neuroleptics Scale (SWN-SF). Global and social functioning will be assessed using the Global Assessment of Functioning (GAF), the PSP total score, and the Evaluation of Personal and Household Performance (EPHP) rated by caregivers. Quality of life will be measured using the S-QoL and the EQ-5D-5L (EuroQoL-5D), and the recovery process will be evaluated with the Questionnaire about the Process of Recovery (QPR).