Combination Therapy of Deferiprone and N-Acetylcysteine for Treating Negative Symptoms in Schizophrenia
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 80
- 试验地点
- 2
- 主要终点
- Change in Total PANSS Score
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 40 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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
- •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 ≥
- •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 ≤
- •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.
排除标准
- •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 ≥
- •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.
研究组 & 干预措施
Deferiprone + N-Acetylcysteine
干预措施: Deferiprone (DFP) (Drug)
Deferiprone + N-Acetylcysteine
干预措施: N-Acetyl Cysteine (NAC) (Drug)
Placebo + N-Acetylcysteine
干预措施: N-Acetyl Cysteine (NAC) (Drug)
结局指标
主要结局
Change in Total PANSS Score
时间窗: 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.
次要结局
- Blood pressure (mm Hg)(From enrollment to the end of treatment at 36 weeks)
- PANSS Marder Negative Symptom Factor Score(12, 24 and 36 weeks)
- PANSS Positive Subscale Score(12, 24 and 36 weeks)
- PANSS Negative Subscale Score(12, 24 and 36 weeks)
- PANSS General Psychopathological Subscale Score(12, 24 and 36 weeks)
- BNSS (Brief Negative Symptom Scale) Score(12, 24 and 36 weeks)
- BACS (Brief Cognitive Assessment in Schizophrenia) Score(12, 24 and 36 weeks)
- Reported adverse events (descriptive)(From enrollment to the end of treatment at 36 weeks)
- Weight (kg)(From enrollment to the end of treatment at 36 weeks)
- Height (cm)(From enrollment to the end of treatment at 36 weeks)
- BMI (Body Mass Index, kg/cm^2)(From enrollment to the end of treatment at 36 weeks)
- Heart rate (BPM)(From enrollment to the end of treatment at 36 weeks)
- Electrocardiogram (ECG)(From enrollment to the end of treatment at 36 weeks)
- Complete Blood Count (CBC)(From enrollment to the end of treatment at 36 weeks)
- Serum creatinine(From enrollment to the end of treatment at 36 weeks)
- Serum alanine transaminase(From enrollment to the end of treatment at 36 weeks)
- Serum ferritin(From enrollment to the end of treatment at 36 weeks)
- Simpson-Angus Extrapyramidal Rating Scale (SAS)(From enrollment to the end of treatment at 36 weeks)
- Barnes Akathisia Rating Scale (BARS)(From enrollment to the end of treatment at 36 weeks)
- Abnormal Involuntary Movement Scale (AIMS)(From enrollment to the end of treatment at 36 weeks)
- Columbia-Suicide Severity Rating Scale (C-SSRS)(From enrollment to the end of treatment at 36 weeks)
- Udvalg for Kliniske Undersøgelser Side Effect Rating Scale (UKU-SERS )(From enrollment to the end of treatment at 36 weeks)
- Discontinuation-Emergent Signs and Symptoms (DESS)(From enrollment to the end of treatment at 36 weeks)
- Quantitative MRI - Proton Density (PD)(baseline, 36 weeks)
- Quantitative MRI - R1 (Longitudinal Relaxation Rate)(Baseline, 36 weeks)
- Quantitative MRI - Magnetization Transfer (MT)(Baseline, 36 weeks)
- Quantitative MRI - R2*(Baseline, 36 weeks)
- Quantitative MRI - Quantitative Susceptibility Mapping (QSM)(Baseline, 36 weeks)
- Quantitative MRI - R2 (Transverse Relaxation Rate)(Baseline, 36 weeks)
- Quantitative MRI - R1-R2 Relaxivity(Baseline, 36 weeks)
- Quantitative MRI - Tissue Relaxivity (MTV Dependency)(Baseline, 36 weeks)
- Quantitative MRI - Diffusion MRI(Baseline, 36 weeks)
- Quantitative MRI - G-Ratio Mapping(Baseline, 36 weeks)
- Quantitative MRI - Macroscopic Morphometry(Baseline, 36 weeks)
- Quantitative MRI - Neuromelanin-Sensitive MRI (NM-MRI)(Baseline, 36 weeks)
- Magnetic Resonance Spectroscopy (MRS)(Baseline, 36 weeks)
研究者
Amit Lotan
Director, Department of Adult Psychiatry and the Biological Psychiatry Lab, Hadassah University Medical Center; Chair, Department of Psychiatry, Hebrew University Medical School
Hadassah Medical Organization