Investigating the Effect of Diroximel Fumarate on Glutathione in Schizophrenia

Обзор

Schizophrenia is a condition that causes symptoms like delusions, hallucinations, reduced motivation and muddled thinking. It is a common, severe and disabling psychiatric illness affecting about 1/100 (1%) of people. It is ranked the third most disabling illness worldwide. Six in seven patients do not recover from the illness in 6-12 months and continue to experience psychotic symptoms. Therefore, there is a strong unmet need for new evidence-based treatments to target the neurobiology underlying schizophrenia. There is increasing evidence to indicate that glutathione (GSH), the main brain antioxidant, is abnormal in schizophrenia and may provide a new treatment target. In this study, the investigators plan to determine whether Diroximel Fumarate (DRF) (currently a treatment for a brain disorder called multiple sclerosis) can increase GSH in the brain of patients with schizophrenia using a brain scan (MRI) and explore whether changes in GSH are related to other brain measures (measured with MRI and EEG- which measures electrical activity in the brain), blood markers of GSH, and symptoms. During this study 30 people with schizophrenia will be recruited. Participants will take the drug DRF for two weeks, a computer will then decide randomly whether each person will continue to take DRF or a placebo/dummy pill for another two weeks. During this part of the study neither the patients nor the researchers will know which type of drug the patient is taking. Brain GSH and the other measures described will be assessed before and after taking the DRF and placebo/dummy pill. At the end of the study (2027), the investigators will see if taking DRF alters the brain chemical (GSH) in people with schizophrenia and whether this is linked to other measures and symptoms. It will also give researchers information about the best way to design future studies for patients with schizophrenia using this drug.

Подробное описание

Study Objectives: To determine if the level of GSH in the ACC, as indexed by 1HMRS, will increase after treatment with DRF compared to baseline in patients with schizophrenia.

Study Design: Participants will take DRF as open label for 2 weeks (231mg for 7 days, then increase to 462mg for another 7 days), then participants will have the option to participate in the second phase of the study, where participants will be randomly allocated to either DRF for further 2 weeks or placebo. Allocation will be double-blinded. Participants will have baseline blood tests, schizophrenia rating scales, EEG and MRI, and these will be repeated after the open label and once again after the randomised phase.

30 patients with schizophrenia will be recruited from mental health teams.

Inclusion Criteria:

* 18-65 years * diagnosis of schizophrenia (Diagnostic and Statistical Manual of Mental Disorders-5 (SCID) (DSM-5) * stable antipsychotic dose (no change for 1 month) * currently stable in mental state with no evidence of relapse within the last 2 months prior to study enrolment * minimum score of 60 Positive and Negative Syndrome Scale (PANSS) * capacity to provide informed consent

Exclusion criteria (https://www.medicines.org.uk/emc/product/13087/smpc):

* history of significant co-morbid medical or neurological disorder including but not limited to HIV, malignancies, Systemic Lupus Erythematosus, sarcoidosis, autoimmune vasculitis, bone marrow transplantation * current use of medication that is known to interact with DRF, live vaccines given within the period of DRF treatment, nephrotoxic medication (including but not limited to aminoglycosides, diuretics, non-steroidal anti-inflammatory drugs, Lithium) * contraindications to DRF (pregnancy, women of childbearing potential not currently using effective contraception (combined pill (oestrogen \& progesterone), progesterone -only with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner, sexual abstinence), breast feeding, severe hepatic impairment, moderate renal impairment, severe active gastrointestinal disease, lymphocyte count - below the Lower Limit of Normal (LLN) for the local laboratory (e.g 1.30 x109/L LLN for Viapath Kings College London), suspected or confirmed progressive multifocal leukoencephalopathy (PML), presence of risk factors for PML (previous and/or current immunosuppressant or immunomodulatory treatment (including natalizumab, other fumaric esters including Dimethyl Fumarate (DMF) (topical or systemic)), serious infection, current or recent herpes virus infection) * substance dependence/abuse other than to cigarettes * current high suicide risk * participation in a clinical study of unlicensed medicines within the previous 30 days * presence/history of other acute or chronic illness that would make participating unsafe or unsuitable, any contraindication to MRI scanning (e.g. claustrophobia, metallic implants, pacemaker, vascular clips, metal in eyes, pregnancy) * allergies to any of DRFs ingredients * taking part in a research study involving an unlicensed medicine within the last 30 days

Вмешательства

• Препарат Diroximel fumarate (DRF)
  Diroximel fumarate is an immunomodulating drug licensed for use in multiple sclerosis. It has been found to cross the blood brain barrier and increase brain glutathione levels.
• Препарат Placebo
  A placebo pill given to participants.

Первичные конечные точки

• MRS glutathione (GSH) levels in ACC [Срок оценки: Within one year of conclusion of the Research]

Вторичные конечные точки (1)

• MMN Amplitude [Срок оценки: Within one year of conclusion of the Research]

Критерии участия

Критерии включения

• 18 -65 years, diagnosis of schizophrenia (Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5)
• Stable antipsychotic dose (no change for 1 month)
• Currently stable with no evidence of relapse within the last 2 months prior to study enrolment
• Minimum of 60 on the Positive and Negative Syndrome Scale (PANSS)
• Capacity to provide informed consent

Критерии исключения

• History of significant co-morbid medical or neurological disorder including but not limited to HIV, malignancies, Systemic Lupus Erythematosus, sarcoidosis, autoimmune vasculitis, bone marrow transplantation
• Current use of medication that is known to interact with DRF, live vaccines given within the period of DRF treatment, nephrotoxic medication (including but not limited to aminoglycosides, diuretics, non-steroidal anti-inflammatory drugs, Lithium)
• Contraindications to DRF (pregnancy, women of childbearing potential not currently using effective contraception (combined pill (oestrogen \& progesterone), progesterone -only with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner, sexual abstinence), breast feeding, severe hepatic impairment, moderate renal impairment, severe active gastrointestinal disease, lymphocyte count - below the Lower Limit of Normal (LLN) for the local laboratory (e.g 1.30 x109/L LLN for Viapath King's College London), suspected or confirmed progressive multifocal leukoencephalopathy (PML), presence of risk factors for PML (previous and/or current immunosuppressant or immunomodulatory treatment (including natalizumab, other fumaric esters including Dimethyl Fumarate (DMF) (topical or systemic)), serious infection, current or recent herpes virus infection)
• Substance dependence/abuse other than to cigarettes
• Current high suicide risk
• Participation in a clinical study of unlicensed medicines within the previous 30 days
• Presence/history of other acute or chronic illness that would make participating unsafe or unsuitable, any contraindication to MRI scanning (e.g. claustrophobia, metallic implants, pacemaker, vascular clips, metal in eyes, pregnancy)
• Allergies to any of DRFs ingredients
• Taking part in a research study involving an unlicensed medicine within the last 30 days

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Перекрёстный дизайн

Маскирование

Тройное слепое

Основная цель

Фундаментальное исследование

Центры проведения

Великобритания · 3 центра

• South London and Maudsley NHS Foundation Trust — London
• Department of Computer Science, Faculty of Engineering Science, University College London — London
• School of Psychology, University of birmingham — Birmingham

Публикации

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• Raffa M, Mechri A, Othman LB, Fendri C, Gaha L, Kerkeni A. Decreased glutathione levels and antioxidant enzyme activities in untreated and treated schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry. 2009 Oct 1;33(7):1178-83. doi: 10.1016/j.pnpbp.2009.06.018. Epub 2009 Jul 2. PMID 19576938
• Owjfard M, Karimi F, Mallahzadeh A, Nabavizadeh SA, Namavar MR, Saadi MI, Hooshmandi E, Salehi MS, Zafarmand SS, Bayat M, Karimlou S, Borhani-Haghighi A. Mechanism of action and therapeutic potential of dimethyl fumarate in ischemic stroke. J Neurosci Res. 2023 Sep;101(9):1433-1446. doi: 10.1002/jnr.25202. Epub 2023 May 14. PMID 37183360
• Linker RA, Lee DH, Ryan S, van Dam AM, Conrad R, Bista P, Zeng W, Hronowsky X, Buko A, Chollate S, Ellrichmann G, Bruck W, Dawson K, Goelz S, Wiese S, Scannevin RH, Lukashev M, Gold R. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain. 2011 Mar;134(Pt 3):678-92. doi: 10.1093/brain/awq386. PMID 21354971
• Jauhar S, Veronese M, Nour MM, Rogdaki M, Hathway P, Turkheimer FE, Stone J, Egerton A, McGuire P, Kapur S, Howes OD. Determinants of treatment response in first-episode psychosis: an 18F-DOPA PET study. Mol Psychiatry. 2019 Oct;24(10):1502-1512. doi: 10.1038/s41380-018-0042-4. Epub 2018 Apr 20. PMID 29679071
• Jaaskelainen E, Juola P, Hirvonen N, McGrath JJ, Saha S, Isohanni M, Veijola J, Miettunen J. A systematic review and meta-analysis of recovery in schizophrenia. Schizophr Bull. 2013 Nov;39(6):1296-306. doi: 10.1093/schbul/sbs130. Epub 2012 Nov 20. PMID 23172003
• Halstead S, Siskind D, Amft M, Wagner E, Yakimov V, Shih-Jung Liu Z, Walder K, Warren N. Alteration patterns of peripheral concentrations of cytokines and associated inflammatory proteins in acute and chronic stages of schizophrenia: a systematic review and network meta-analysis. Lancet Psychiatry. 2023 Apr;10(4):260-271. doi: 10.1016/S2215-0366(23)00025-1. Epub 2023 Feb 27. PMID 36863384

Идентификаторы

NCT: NCT06957808 · 331465

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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