Combination Therapy of Deferiprone and N-Acetylcysteine for Treating Negative Symptoms in Schizophrenia

The present study is designed as an interventional trial over a 36-week period per patient. The target populThe present study is designed as an interventional trial over a 36-week period per patient. The target population consists of patients with schizophrenia (age 18-40 years), up to ten years since onset of positive symptoms. The overall objective of the study is to assess the safety and efficacy of DFP-NAC combination add-on in patients with schizophrenia, compared to NAC-only add-on (control group). This study is designed to test the hypothesis that, in patients with prominent negative symptoms, adjunctive treatment with DFP-NAC combination will demonstrate a favorable safety profile and produce clinical improvements in negative and cognitive domains of schizophrenia beyond those offered by addition of NAC alone.ation consists of patients with schizophrenia (age 18-40 years), up to ten years since onset of positive symptoms. The overall objective of the study is to assess the safety and efficacy of DFP-NAC combination add-on in patients with schizophrenia, compared to NAC-only add-on (control group). This study is designed to test the hypothesis that, in patients with prominent negative symptoms, adjunctive treatment with DFP-NAC combination will demonstrate a favorable safety profile and produce clinical improvements in negative and cognitive domains of schizophrenia beyond those offered by addition of NAC alone.

Inclusion criteria

• Aged 18-55 years.
• Diagnosis of schizophrenia/schizoaffective disorder according to the Diagnostic and Statistical Manual of Mental Disorders- Fifth Edition (DSM-5) criteria. The diagnostic assessment will be conducted using the Structured Clinical Interview for DSM-5 Clinical Trials Version (SCID-5-CT).
• Adequate antipsychotic treatment for ≥ 4 months prior to screening (excluding clozapine use).
• Stable dose of antipsychotic medication for ≥ 8 weeks prior to screening (excluding clozapine use).
• When relevant, stable dose of antidepressants, mood stabilizers and benzodiazepines/Z-drugs for ≥ 8 weeks prior to screening.
• Screening and baseline PANSS total score ranging from 60 to 120.
• Sum ≥ 20 for the 7 items in the Negative Symptoms subscale of the PANSS.
• At least two items in the PANSS Negative Symptoms subscale scored ≥ 4.
• Sum < 20 for the 7 items in the Positive Symptoms subscale of the PANSS.
• Score ≤ 5 for each item in the Positive Symptoms subscale of the PANSS.
• Calgary Depression Schizophrenia Scale (CDSS) score of ≤ 6.
• Persistent and predominant negative symptoms for ≥ 6 months, in the opinion of the investigator
• The subject exhibits clinical stability in both positive and negative symptoms of schizophrenia over the past 6 months, as assessed by the treating psychiatrist and supported by documentation in the medical record.
• No incarceration in prison or acute crisis intervention due to symptom exacerbation within 6 months of screening. The subject must be considered psychiatrically stable in the opinion of the investigator.
• For males or postmenopausal women, either of the following:

• Serum ferritin ≥30 ng/mL at screening. OR
• Serum ferritin 15-29 ng/mL at screening, provided that:

i. An evaluation of potential underlying causes as well as potentially comorbid deficiencies has been completed, including assessment of folate, vitamin B12, celiac antibodies and H. pylori infection, and, in patients over 40 years old or with positive family history of colorectal cancer, also an appropriate colorectal screening test, alongside other tests deemed as relevant by the investigator; ii. Identified clinically significant causes have been appropriately managed; iii. Repeated ferritin assessment prior to randomization remains within the range of 15-29 ng/mL; and iv. Oral iron supplementation is initiated according to the study protocol.

• For premenopausal women: Serum ferritin ≥15 ng/mL at screening.
• Screening serum hemoglobin ≥ 13g/dL for males, ≥ 12g/dL for females
• Use of contraceptives in women of childbearing age.
• Ability to provide informed consent, confirmed by a non-study psychiatrist. When a subject is under guardianship, both patient assent and guardian consent are required. Obtaining written informed consent, dated and signed, is mandatory prior to the initiation of any procedures related to the clinical trial.
• Ability to safely undergo MRI scanning, assessed by a non-study psychiatrist.
• In the Investigator's opinion, the subject can understand the nature of the trial, comply with study drug administration and protocol procedures or has a guardian able to assist.
• Availability of a reliable caregiver or other responsible person (e.g., family member, social worker, nurse) to support treatment adherence and provide collateral information for rating scales.

Exclusion criteria

• Primary DSM-5 diagnosis other than schizophrenia or schizoaffective disorder in the 12 months prior to screening, according to SCID-5-CT.
• Subjects diagnosed with Autistic Spectrum Disorder (ASD).
• Subjects diagnosed with Intellectual Developmental Disorder.
• Patients who received clozapine within the 6 months preceding the screening.
• Patients with a history of relapsing neutropenia (Absolute Neutrophile Count (ANC) < 1,500 cells/µL)
• Screening ANC ≤ 2,000 cells/µL.
• Non-compliance during run-in period (percent adherence ≤ 80%, as examined by pill count).
• Improvement > 20% in PANSS total score or PANSS negative subscale during the run-in period.
• Suicide attempt or serious suicidal behavior within the past 12 months.
• Risk for suicidal behavior during the study as determined by the investigator's clinical assessment and Columbia-Suicide Severity Rating Scale (C-SSRS).
• The subject has a history of substance use disorder or any illicit drug use (other than nicotine) within the past 3 years.
• Positive urine drug screen for drugs of abuse (cocaine, methadone, amphetamines, cannabinoids, opiates, and barbiturates).
• Risk of violent behavior in the opinion of the Investigator.
• Known hypersensitivity to deferiprone or N-Acetylcysteine.
• Pregnancy or intention to become pregnant during the study duration.
• Female patients who are lactating.
• ECT treatment within 18 weeks prior to screening and study entry.
• Patient with substantially confounding extrapyramidal symptoms (according to screening SAS, BARS, AIMS score).
• Conditions that are not suitable for partaking in an MRI scan, including metal implants and incompatible devices.
• Subjects with BMI ≤ 18 or ≥ 40.
• Participation in another clinical trial involving investigational drugs within 3 months prior to screening.
• Clinically significant general medical conditions (neurological, cardiovascular, respiratory, gastrointestinal, renal, hepatic, hematologic, oncologic) that could interfere with participation.
• Major active contagious disease.
• Patients with clinically significant abnormalities in hematology, blood chemistry, ECG or physical examination, not resolved by the Baseline visit, that can interfere with study participation.
• Any condition that, in the investigator's judgment, may compromise subject safety or interfere with study assessments.