Evaluation of Istradefylline for Reducing Microglial Activation in Progressive Multiple Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial
- Trial ID
- 2024-517336-21-00
- Sponsor
- University Of Turku
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the change in the proportion of active **voxels** (DVR > 1.56) in cerebral white matter (excluding T1 lesions) in end-of-treatment TSPO-PET images compared to baseline TSPO-PET images in patients with progressive **multiple sclerosis** treated with istradefylline versus those receiving a placebo. This objective is clinically relevant as it aims to assess the potential of istradefylline in reducing microglial activation, which is a key factor in the progression of multiple sclerosis.
Secondary objectives include:
- Assessing the effect of istradefylline on the number of TSPO-PET–measurable chronic active lesions and the proportion of TSPO-PET–detectable active voxels at the rim of chronic lesions and in the normal-appearing white matter (NAWM).
- Evaluating the TSPO-PET signal (DVR) at the rim of chronic lesions and in the NAWM.
- Determining the effect on the number of QSM-positive iron rim lesions and MRI volumetric measures in brain regions of interest.
- Assessing T1 and T2 lesion burden using MRI and neuroaxonal damage measured by DTI-MRI parameters.
- Evaluating safety and tolerability, disease worsening using the T25FW, hand dexterity using the 9HPT, and changes in Functional Systems and EDSS.
- Assessing cognitive function, health-related quality of life, and fatigue using various scales and questionnaires.
- Measuring blood serum neurofilament light chain and glial fibrillary acidic protein levels.
Participants
The clinical trial focuses on individuals diagnosed with **progressive multiple sclerosis**, specifically targeting both men and women aged 18 to 67 years. The study population includes those with either Primary Progressive Multiple Sclerosis or non-active Secondary Progressive Multiple Sclerosis, as per current diagnostic criteria. Participants are required to have a Screening Expanded Disability Status Scale (EDSS) score between 3.5 and 7.5 and must have shown disease progression or enlarging T1 lesions in brain MRI over the past two years. The trial does not involve a vulnerable population, and participants must be fluent in Finnish. The sponsor has not provided information regarding the total number of participants. Selection criteria emphasize the ability to comply with protocol procedures, requiring participants to have sufficient vision, hearing, and a minimum educational achievement of the 8th grade. Lifestyle factors such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy of oral **istradefylline** in reducing microglial activation in the brain of patients with **progressive multiple sclerosis**. The trial will be conducted at a single center and will involve a comparative analysis between the active treatment group receiving istradefylline and a placebo group. The primary objective is to assess the change in the proportion of active voxels in cerebral white matter using TSPO-PET imaging from baseline to the end of treatment. The trial is expected to commence recruitment on November 1, 2024, and conclude by November 30, 2026, with a maximum treatment period of six months for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of primary or non-active secondary progressive multiple sclerosis, and language proficiency. Following successful screening, participants will be randomized to receive either istradefylline or placebo. Regular follow-up visits will be scheduled to monitor safety, adherence, and efficacy outcomes, including imaging assessments and clinical evaluations. The end-of-study visit will involve final assessments to evaluate the primary and secondary endpoints, such as changes in TSPO-PET measurable lesions and MRI volumetric measures.
The expected length of participant involvement is approximately six months, with conditions for early termination including withdrawal of consent, adverse events, or non-compliance with study procedures. The trial will adhere to rigorous methodological standards to ensure the validity and reliability of the findings, contributing valuable insights into the management of progressive multiple sclerosis.
Treatment
The clinical trial involves the administration of **ISTRADEFYLLINE**, an experimental medication, which is an antagonist of the A2A receptor. The pharmaceutical form of Istradefylline is a tablet, and it is administered orally. The dosage for this trial is set at 40 mg once daily. The maximum daily dose is 40 mg, with a total maximum dose of 7200 mg over the course of the treatment period, which spans up to 6 months. The active substance in Istradefylline is chemically derived, and the medication is not formulated for pediatric use. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.
The study also includes a **placebo** as a non-experimental treatment to serve as a comparator. The placebo tablets are white, round, flat, scored, and 9 mm in diameter. These tablets are sourced from Yliopiston Apteekki. The placebo is administered orally, mirroring the administration route of the experimental medication, to maintain the double-blind nature of the trial. The placebo is used to evaluate the efficacy of Istradefylline by comparing the outcomes between the treatment and control groups. Compliance with placebo administration will be similarly monitored to ensure the integrity of the trial results.
Efficacy
Efficacy in this clinical trial will be assessed by evaluating the change in the proportion of active voxels in supratentorial cerebral white matter using TSPO-PET imaging. The primary endpoint is the change in the proportion of active voxels in the end-of-treatment TSPO-PET images compared to baseline images in patients with progressive **Multiple Sclerosis** (MS) treated with istradefylline versus placebo. Secondary endpoints include changes in the number of TSPO-PET–measurable chronic active lesions, the proportion of TSPO-PET–detectable active voxels at the rim of chronic lesions, and the TSPO-PET signal (DVR, distribution volume ratio) at the rim of chronic lesions. Additional secondary endpoints involve changes in MRI volumetric measures, T1 and T2 lesion burden, neuroaxonal damage measured by DTI-MRI parameters, and disease worsening measured using the Timed 25 Foot Walk. Other assessments include changes in hand dexterity using the 9-Hole Peg Test, functional systems and Expanded Disability Status Scale, cognition through neuropsychological evaluation, and health-related quality of life using the RAND 36-Item Health Survey and Multiple Sclerosis Impact Scale questionnaires. Fatigue will be measured using the Modified Fatigue Impact Scale and Fatigue Severity Scale questionnaires, and changes in blood serum neurofilament light chain and glial fibrillary acidic protein levels will also be evaluated. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial to determine the impact of istradefylline on patients with progressive MS.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Written informed consent obtained
- Men and women who are 18-67 years of age at time of consent
- With Primary Progressive Multiple Sclerosis, according to current diagnostic criteria or a clinical diagnosis of non-active Secondary Progressive Multiple Sclerosis (nSPMS, with no relapses in the last 2 years)
- Screening Expanded Disability Status Scale (EDSS) score between 3.5 and 7.5 at screening
- Disease progression during the last two years (by evaluation of the treating physician in the clinic), or they have had enlarging of T1 lesions in brain MRI during the previous two years. Enlargement of T1 lesions is determined by visual inspection by the treating neurologist or clinical neuroradiologist
- Patients must, in the investigator’s opinion, exhibit reliability and physiologic capability (e.g., sufficient vision, hearing, etc.) to comply with all protocol procedures, and have attained an educational achievement of minimum 8th grade
- Patients must be fluent in the Finnish language
Exclusion Criteria
- Patients undergoing treatment with systemic glucocorticoids or mitoxantrone, cyclophosphamide, cladribine, natalizumab or alemtuzumab; use of topical corticosteroid formulations (ointments, nasal sprays, eye drops, etc.) is allowed
- Patients with another neurodegenerative disease or another significant neurological disease than MS (including epilepsy); patients with any generalized seizures within one year of screening are also excluded
- Patients with major psychiatric illness in the past 3 years prior to screening (including, but not limited to schizophrenia, bipolar disorder, schizoaffective psychosis, and major depressive disorder); patients with mild depression may be included at the investigator’s discretion
- Any suicidal behavior in the past 1-year period prior to screening or during the screening period
- Patients whose screening MRI scan shows gadolinium-enhancing lesions
- Patients with moderate or severe renal insufficiency, defined as an eGFR < 60 mL/min/1.73 m2 at the screening visit
- Patients with plasma ALT level > 3× ULN at the screening visit, or total plasma bilirubin > 2 × ULN
- Active infection with hepatitis B or C virus
- Patients with known active infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus within the last 35 days prior to the baseline visit
- Patients with known allergy or other intolerability to istradefylline or to gadolinium MRI contrast agent
- Patients with claustrophobia or a history of moderate-to-severe anxiety disorder or panic attacks
- Pregnant or breast-feeding women, and women of child-bearing potential with heterosexual relationships who are not capable or willing to use highly effective birth control measures according to ICH M3 (R2) guidance, with an annual failure rate of < 1%. Such methods should be used throughout the trial and for at least 60 days after the last trial drug intake.
- Exposure to more than 10 mSv doses of ionizing radiation, in addition to that obtained from natural sources, in the past 12 months
- Patients with intolerance to previous PET scans
- Participation in another investigational drug trial in the three months prior to baseline or within 4 elimination half-lives of the trial medication, whichever is longer
- Evidence of current or history of any significant autoimmune disease that, in the opinion of the investigator, could interfere with evaluation of the study results or constitute a health hazard for the participant
- Evidence of an immune system that is compromised; including, but not limited to, a diagnosis of human immunodeficiency virus (HIV); or the participant has been splenectomized or has received an organ transplant (corneal transplants excluded) 17. Evidence of an immune system that is compromised; including, but not limited to, a diagnosis of human immunodeficiency virus; or the participant has been splenectomized or has received an organ transplant (corneal transplants excluded)
- Diagnosis of cancer (hematological or solid tumor) for which the participant is currently being treated, or for which there is evidence of active disease. Participants with local prostate cancer or local dermatological tumors, such as basal or squamous cell carcinoma, may be included
- Any of the following, according to the judgment of the investigator: a) Clinically significant abnormal finding of the physical examination, vital signs (including blood pressure and heart rate), electrocardiogram (ECG), or laboratory value that would jeopardize the patient’s safety while participating in the trial or capability to participate in the trial, or confound the assessments of the trial b) Symptomatic/uncontrolled/unstable or clinically relevant concomitant disease or any other clinical condition that would jeopardize the patient’s safety while participating in the trial or capability to participate in the trial, or confound the assessments of the trial c) Significant or unstable physical condition that may require change to concomitant medication or hospitalization that would impact the assessments of the trial d) Planned major surgery requiring
- Patients with artificial cardiac pacemaker or other metal implants that might interfere with the MRI procedures; patients with tattoos, history as metal workers or history of metallic foreign objects in the body need to be evaluated by the investigator for MRI-related risks before inclusion in the study
- Concomitant use of strong inhibitors (e.g. itraconazole, ketoconazole, clarithromycin) or inducers (e.g. carbamazepine, rifampin, phenytoin, St. John’s wort) of CYP3A4
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Finland | Recruiting | 01 Nov 2024 | 34 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Placebo tablets will be white, round, flat, scored tablet, 9 mm in diameter sourced from Yliopiston Apteekki | Placebo | N/A | — | — | — | N/A |
ISTRADEFYLLINE | Test | — | ORAL | 40 | 6 | SUB126676 |