Evaluation of Intensified Pharmacological Regimen with Clozapine and Drug Combination in Schizophrenia Patients Experiencing First-Line Treatment Failure

The primary objective of this study is to evaluate the **treatment response** in subjects with schizophrenia, schizoaffective disorder, or schizophreniform disorder who have experienced a first-time treatment failure on their first-line treatment. This is assessed by comparing changes in symptom severity from baseline to the end of a six-week treatment period using the Positive And Negative Syndrome Scale (PANSS). The study aims to determine the efficacy of an early-intensified pharmacological treatment compared to treatment as usual. This is clinically relevant as it may provide insights into optimizing treatment strategies for patients who do not respond to initial therapies.

Secondary objectives include:

• Comparing changes in PANSS subscale scores (positive, negative, and general) between the two treatment arms.
• Assessing changes in severity and improvement in global functioning using the Clinical Global Impression Scale (CGI).
• Evaluating changes in levels of depression and anxiety.
• Assessing changes in quality of life and functioning measures.
• Comparing changes in cognitive performance.
• Determining the proportion of subjects in symptomatic remission at visit 4.
• Comparing the presence of adverse events, both related and unrelated, between the treatment arms.
• Evaluating the use of concomitant medication.
• Assessing premature treatment discontinuation, including timing and reason.
• Comparing changes in suicidal ideation between the treatment arms.

The clinical trial involves a total of **108 participants** diagnosed with **schizophrenia**, schizoaffective disorder, or schizophreniform disorder. The study population includes both male and female subjects, aged between 18 and 70 years. Participants were selected based on their first-time treatment failure on a first-line pharmacotherapeutic agent for their primary DSM-5 diagnosis, with a requirement for a change in pharmacotherapeutic treatment. The trial includes both inpatients and outpatients who are willing and able to provide written informed consent, with the allowance for a legal guardian to cosign if necessary. Female participants of childbearing potential are required to use effective contraception and have a negative pregnancy test prior to randomization. The study population is characterized by a minimum symptom severity threshold and functional impairment, as measured by the Positive And Negative Syndrome Scale (PANSS) and the Sheehan Disability Scale (SDS), respectively. The trial does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **randomized, controlled** study to evaluate the efficacy of a six-week intensified pharmacological treatment for **schizophrenia**, schizoaffective disorder, and schizophreniform disorder compared to treatment as usual. The trial aims to assess changes in symptom severity using the Positive and Negative Syndrome Scale (PANSS) from baseline to the end of treatment. The study will involve adult participants aged 18 to 70 who have experienced a first-time treatment failure on their first-line treatment. The trial is expected to commence on January 1, 2024, and conclude by June 30, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit where eligibility criteria are confirmed, and informed consent is obtained. The baseline visit (visit 2) will involve randomization and initial assessments. Follow-up visits will occur throughout the six-week treatment period, with the primary endpoint being the mean change in PANSS total score at visit 4. Secondary endpoints include changes in PANSS subscale scores, Clinical Global Impression Scale scores, and quality of life measures. The end-of-study visit will evaluate the presence of symptomatic remission and any adverse events.

The expected duration of participant involvement is six weeks, with conditions for early termination including adverse events, withdrawal of consent, or non-compliance with study procedures. Participants will be monitored for concomitant medication use and any changes in the Columbia-Suicide Severity Rating Scale throughout the study. The trial will ensure that female participants of childbearing potential use effective contraception and have a negative pregnancy test before randomization. The study is not categorized as low intervention and involves authorized investigational medicinal products.

The clinical trial involves the administration of several **experimental medications** to evaluate their efficacy in treating schizophrenia, schizoaffective, or schizophreniform disorder. **Quetiapine** is administered orally in a pharmaceutical form coded as PHF00082MIG. The maximum daily dose is 800 mg, with a total maximum dose of 33,600 mg over a six-week period. **Sulpiride**, combined with **diazepam** and **pyridoxine hydrochloride**, is also administered orally, with a maximum daily dose of 1200 mg and a total maximum dose of 50,400 mg, using the pharmaceutical form PHF00006MIG.

**Cariprazine** is provided in an oral form, PHF00006MIG, with a maximum daily dose of 6 mg and a total maximum dose of 252 mg. **Levomepromazine hydrochloride** is administered orally in the form PHF00231MIG, with a maximum daily dose of 600 mg and a total maximum dose of 25,200 mg. **Asenapine** is administered sublingually, with a maximum daily dose of 20 mg and a total maximum dose of 840 mg, using the pharmaceutical form PHF00241MIG.

**Sertindole** is administered orally, with a maximum daily dose of 20 mg and a total maximum dose of 840 mg, in the form PHF00082MIG. **Chlorpromazine hydrochloride** is provided orally, with a maximum daily dose of 300 mg and a total maximum dose of 12,600 mg, using the form PHF00231MIG. **Aripiprazole** is administered orally, with a maximum daily dose of 30 mg and a total maximum dose of 1260 mg, in the form PHF00169MIG.

**Amisulpride** is administered orally, with a maximum daily dose of 800 mg and a total maximum dose of 33,600 mg, using the form PHF00082MIG. **Flupentixol decanoate** is provided orally, with a maximum daily dose of 40 mg and a total maximum dose of 1680 mg, in the form PHF00231MIG. **Brexpiprazole** is administered orally, with a maximum daily dose of 4 mg and a total maximum dose of 168 mg, using the form PHF00082MIG.

**Paliperidone** is administered orally, with a maximum daily dose of 12 mg and a total maximum dose of 504 mg, in the form PHF00212MIG. **Lurasidone** is provided orally, with a maximum daily dose of 148 mg and a total maximum dose of 6216 mg, using the form PHF00082MIG. **Fluphenazine decanoate** is administered intramuscularly, with a maximum daily dose of 100 mg and a total maximum dose of 300 mg, in the form PHF00231MIG.

**Perphenazine decanoate** is administered orally, with a maximum daily dose of 24 mg and a total maximum dose of 1008 mg, using the form PHF00231MIG. **Ziprasidone** is provided orally, with a maximum daily dose of 160 mg and a total maximum dose of 6720 mg, in the form PHF00170MIG. **Promazine hydrochloride** is administered orally, with a maximum daily dose of 400 mg and a total maximum dose of 16,800 mg, using the form PHF00009MIG.

**Clozapine** is administered orally, with a maximum daily dose of 900 mg and a total maximum dose of 37,800 mg, in the form PHF00245MIG. **Risperidone** is provided orally, with a maximum daily dose of 6 mg and a total maximum dose of 252 mg, using the form PHF00082MIG. **Fluoxetine hydrochloride** is administered orally, with a maximum daily dose of 20 mg and a total maximum dose of 840 mg, in the form PHF00082MIG.

All medications are administered over a six-week period, with compliance monitored through regular assessments. The trial includes a comparator group receiving standard-of-care therapy, allowing for a comprehensive evaluation of the experimental treatments' efficacy. The study aims to assess changes in symptom severity using the Positive And Negative Syndrome Scale (PANSS) to determine the effectiveness of the intensified pharmacological treatment compared to treatment as usual.

Efficacy in this clinical trial will be assessed primarily through the measurement of changes in symptom severity using the Positive and Negative Syndrome Scale (PANSS). The primary endpoint is the mean change from baseline in PANSS total score at six weeks, comparing the early-intensified pharmacological treatment (EIPT) group to the treatment as usual (TAU) group. Secondary endpoints include changes from baseline in PANSS subscale scores (positive, negative, and general), the Clinical Global Impression Scale (CGI) severity and improvement sub-scores, and the Hospital Anxiety and Depression Scale (HADS) total score and subscales. Additional assessments will include changes in quality of life and functioning measures, cognitive tests such as the Trail Making Test and the Digit Symbol Substitution Test, and the presence of symptomatic remission as defined by the PANSS modified Andreasen criteria.

Data collection will occur at specified timepoints, with baseline measurements taken at visit 2 and follow-up assessments at visit 4, which marks the end of the six-week treatment period. The trial will also monitor the presence of reported adverse events using the General Assessment of Side Effects Scale (GASE) and track concomitant medication use, premature treatment discontinuation, and changes on the Columbia-Suicide Severity Rating Scale (C-SSRS) throughout the study. These efficacy parameters will be analyzed to determine the comparative effectiveness of the EIPT versus TAU in subjects experiencing a first-time treatment failure on their first-line treatment for schizophrenia, schizoaffective, or schizophreniform disorder.