Schizoaffecitve Disorder, Schizophrenia and Schizoaffective Disorder, Schizophrenia and Predominant Negative Symptoms
Conditions
Keywords
Deferiprone, N-acetylcysteine, Schizophrenia, Clinical Trial, negative symptoms
Brief summary
In following guidelines for studying negative symptoms in schizophrenia, 60 patients aged 18-40, diagnosed with schizophrenia or schizoaffective disorder during the last ten years, will receive a combination of the iron chelator DFP plus NAC or a matching placebo plus NAC combination, as add-on to their maintenance antipsychotic drug (APD) treatment, for a duration of 36 weeks. Prior to initiation of treatment, all participants will undergo baseline MRI scan. A follow-up MRI will be conducted at the end of the 36-week study period, or upon early withdrawal if applicable, to evaluate the effect of the add-on treatment on iron dyshomeostasis and morphology.
Detailed description
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.
Interventions
This intervention has not been used before on Schizophrenia or Schizoaffective patients with predominant negative symptoms.
This drug is given to both groups.
Sponsors
Amit Lotan
Hadassah Medical Organization
Jerusalem Mental Health Center
Hebrew University of Jerusalem
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
1. Aged 18-55 years. 2. 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). 3. Adequate antipsychotic treatment for ≥ 4 months prior to screening (excluding clozapine use). 4. Stable dose of antipsychotic medication for ≥ 8 weeks prior to screening (excluding clozapine use). 5. When relevant, stable dose of antidepressants, mood stabilizers and benzodiazepines/Z-drugs for ≥ 8 weeks prior to screening. 6. Screening and baseline PANSS total score ranging from 60 to 120. 7. Sum ≥ 20 for the 7 items in the Negative Symptoms subscale of the PANSS. 8. At least two items in the PANSS Negative Symptoms subscale scored ≥ 4. 9. Sum \< 20 for the 7 items in the Positive Symptoms subscale of the PANSS. 10. Score ≤ 5 for each item in the Positive Symptoms subscale of the PANSS. 11. Calgary Depression Schizophrenia Scale (CDSS) score of ≤ 6. 12. Persistent and predominant negative symptoms for ≥ 6 months, in the opinion of the investigator 13. 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. 14. 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. 15. For males or postmenopausal women, either of the following: 1. Serum ferritin ≥30 ng/mL at screening. OR 2. 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. 16. For premenopausal women: Serum ferritin ≥15 ng/mL at screening. 17. Screening serum hemoglobin ≥ 13g/dL for males, ≥ 12g/dL for females 18. Use of contraceptives in women of childbearing age. 19. 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. 20. Ability to safely undergo MRI scanning, assessed by a non-study psychiatrist. 21. 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. 22. 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
1. Primary DSM-5 diagnosis other than schizophrenia or schizoaffective disorder in the 12 months prior to screening, according to SCID-5-CT. 2. Subjects diagnosed with Autistic Spectrum Disorder (ASD). 3. Subjects diagnosed with Intellectual Developmental Disorder. 4. Patients who received clozapine within the 6 months preceding the screening. 5. Patients with a history of relapsing neutropenia (Absolute Neutrophile Count (ANC) \< 1,500 cells/µL) 6. Screening ANC ≤ 2,000 cells/µL. 7. Non-compliance during run-in period (percent adherence ≤ 80%, as examined by pill count). 8. Improvement \> 20% in PANSS total score or PANSS negative subscale during the run-in period. 9. Suicide attempt or serious suicidal behavior within the past 12 months. 10. Risk for suicidal behavior during the study as determined by the investigator's clinical assessment and Columbia-Suicide Severity Rating Scale (C-SSRS). 11. The subject has a history of substance use disorder or any illicit drug use (other than nicotine) within the past 3 years. 12. Positive urine drug screen for drugs of abuse (cocaine, methadone, amphetamines, cannabinoids, opiates, and barbiturates). 13. Risk of violent behavior in the opinion of the Investigator. 14. Known hypersensitivity to deferiprone or N-Acetylcysteine. 15. Pregnancy or intention to become pregnant during the study duration. 16. Female patients who are lactating. 17. ECT treatment within 18 weeks prior to screening and study entry. 18. Patient with substantially confounding extrapyramidal symptoms (according to screening SAS, BARS, AIMS score). 19. Conditions that are not suitable for partaking in an MRI scan, including metal implants and incompatible devices. 20. Subjects with BMI ≤ 18 or ≥ 40. 21. Participation in another clinical trial involving investigational drugs within 3 months prior to screening. 22. Clinically significant general medical conditions (neurological, cardiovascular, respiratory, gastrointestinal, renal, hepatic, hematologic, oncologic) that could interfere with participation. 23. Major active contagious disease. 24. 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. 25. Any condition that, in the investigator's judgment, may compromise subject safety or interfere with study assessments.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Total PANSS Score | 36 Weeks (LOCF) | Change from Baseline to Week 36 in the PANSS (Positive and Negative Syndrome Scale) total score. PANSS total score range: 30 to 210 (30 items, each rated 1-7, so minimum 30 and maximum 210). Higher scores indicate more severe symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PANSS Marder Negative Symptom Factor Score | 12, 24 and 36 weeks | Change from Baseline in the PANSS Marder Negative Symptom Factor Score (NSF) |
| PANSS Positive Subscale Score | 12, 24 and 36 weeks | Change from Baseline in the PANSS Positive sub-scale score |
| PANSS Negative Subscale Score | 12, 24 and 36 weeks | Change from Baseline in the PANSS Negative sub-scale score |
| PANSS General Psychopathological Subscale Score | 12, 24 and 36 weeks | Change from Baseline in the PANSS General Psychopathological sub-scale score |
| BNSS (Brief Negative Symptom Scale) Score | 12, 24 and 36 weeks | Change from Baseline in the BNSS (Brief Negative Symptom Scale) score |
| BACS (Brief Cognitive Assessment in Schizophrenia) Score | 12, 24 and 36 weeks | Change from Baseline in the BACS (Brief Cognitive Assessment in Schizophrenia) score |
| Reported adverse events (descriptive) | From enrollment to the end of treatment at 36 weeks | Safety and tolerability assessment |
| Weight (kg) | From enrollment to the end of treatment at 36 weeks | Safety and tolerability assessment |
| Height (cm) | From enrollment to the end of treatment at 36 weeks | Safety and tolerability assessment |
| BMI (Body Mass Index, kg/cm^2) | From enrollment to the end of treatment at 36 weeks | Safety and tolerability assessment |
| Blood pressure (mm Hg) | From enrollment to the end of treatment at 36 weeks | Safety and tolerability assessment |
| Heart rate (BPM) | From enrollment to the end of treatment at 36 weeks | Safety and tolerability assessment |
| Electrocardiogram (ECG) | From enrollment to the end of treatment at 36 weeks | Safety and tolerability assessment |
| Complete Blood Count (CBC) | From enrollment to the end of treatment at 36 weeks | Safety and tolerability assessment |
| Serum creatinine | From enrollment to the end of treatment at 36 weeks | kidney function test, mg/dL, Safety and tolerability assessment |
| Serum alanine transaminase | From enrollment to the end of treatment at 36 weeks | ALT, liver function test, U/L, Safety and tolerability assessment |
| Serum ferritin | From enrollment to the end of treatment at 36 weeks | iron store index, ng/mL, Safety and tolerability assessment |
| Simpson-Angus Extrapyramidal Rating Scale (SAS) | From enrollment to the end of treatment at 36 weeks | 10 items, each 0-4, Safety and tolerability assessment |
| Barnes Akathisia Rating Scale (BARS) | From enrollment to the end of treatment at 36 weeks | Global clinical assessment of akathisia (0-5), Safety and tolerability assessment |
| Abnormal Involuntary Movement Scale (AIMS) | From enrollment to the end of treatment at 36 weeks | Items counted: 7, Per-item range: 0-4, Total (sum) range: 0-28, Safety and tolerability assessment |
| Columbia-Suicide Severity Rating Scale (C-SSRS) | From enrollment to the end of treatment at 36 weeks | Ideation severity: 0-5, Ideation intensity (sum): 0-25, Behavior: categorical (yes/no; counts), Safety and tolerability assessment |
| Udvalg for Kliniske Undersøgelser Side Effect Rating Scale (UKU-SERS ) | From enrollment to the end of treatment at 36 weeks | Per item range: 0-3 (0 = none, 1 = mild, 2 = moderate, 3 = marked/severe), Safety and tolerability assessment |
| Discontinuation-Emergent Signs and Symptoms (DESS) | From enrollment to the end of treatment at 36 weeks | 43-item checklist: each symptom is scored 0/1 (absent/present), total range 0-43; Safety and tolerability assessment |
| Quantitative MRI - Proton Density (PD) | baseline, 36 weeks | PD is normalized to derive the water fraction (WF); WF yields the Macromolecular Tissue Volume (MTV). These reflect the ratio of water to non water tissue and act as biomarkers of atrophy or density |
| Quantitative MRI - R1 (Longitudinal Relaxation Rate) | Baseline, 36 weeks | R1 is sensitive to myelin, iron and water content. R1 and MTV are acquired using the same variable flip angle or/and MP2RAGE sequences, which can also include MT and multi echo acquisitions for R2\* and QSM |
| Quantitative MRI - Magnetization Transfer (MT) | Baseline, 36 weeks | MT modeling estimates the macromolecular contribution to R1, yielding MTsat. Combined with R1 and MTV, this enables R1sat and MTVsat estimation, providing contrast related to saturated vs. unsaturated water pools |
| Quantitative MRI - R2* | Baseline, 36 weeks | R2\* is influenced by magnetic field inhomogeneities and is sensitive to iron deposition and other sources |
| Quantitative MRI - Quantitative Susceptibility Mapping (QSM) | Baseline, 36 weeks | QSM estimates tissue magnetic susceptibility from R2\* data and is sensitive to iron, calcium and related tissue properties |
| Quantitative MRI - R2 (Transverse Relaxation Rate) | Baseline, 36 weeks | R2 reflects tissue integrity and is influenced by myelin and iron. Multi-component fitting allows estimation of Myelin Water Fraction (MWF) |
| Quantitative MRI - R1-R2 Relaxivity | Baseline, 36 weeks | The voxel-wise slope of R1 vs. R2\* within an ROI (R1-R2\* relaxivity) can reflect specific iron forms |
| Quantitative MRI - Tissue Relaxivity (MTV Dependency) | Baseline, 36 weeks | Parameter-MTV slope (MDM: Multidimensional Dependency on MTV) reflects lipid and macromolecular composition |
| Quantitative MRI - Diffusion MRI | Baseline, 36 weeks | Mean Diffusivity (MD) |
| Quantitative MRI - G-Ratio Mapping | Baseline, 36 weeks | Combines diffusion (axon density) and qMRI (myelin) data to estimate the g-ratio: the ratio of axon to fiber diameter |
| Quantitative MRI - Macroscopic Morphometry | Baseline, 36 weeks | Cortical volume |
| Quantitative MRI - Neuromelanin-Sensitive MRI (NM-MRI) | Baseline, 36 weeks | T1-weighted or MT-enhanced sequences detect neuromelanin in the substantia nigra and locus coeruleus; used to assess catecholaminergic neuron integrity |
| Magnetic Resonance Spectroscopy (MRS) | Baseline, 36 weeks | Estimates concentrations of brain metabolites |
Countries
Israel
Contacts
CONTACTAmit Lotan
Outcome results
None listed