ISTRADEFYLLINE for Progressive multiple sclerosis

Inclusion criteria

• {"criterion_text":"- Written informed consent obtained\n- Men and women who are 18-67 years of age at time of consent\n- 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)\n- Screening Expanded Disability Status Scale (EDSS) score between 3.5 and 7.5 at screening\n- 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\n- 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\n- Patients must be fluent in the Finnish language"}

Exclusion criteria

• {"criterion_text":"- 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\n- Patients with known allergy or other intolerability to istradefylline or to gadolinium MRI contrast agent\n- Patients with claustrophobia or a history of moderate-to-severe anxiety disorder or panic attacks\n- 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.\n- Exposure to more than 10 mSv doses of ionizing radiation, in addition to that obtained from natural sources, in the past 12 months\n- Patients with intolerance to previous PET scans\n- 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\n- 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\n- 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.\tEvidence 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)\n- 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\n- Any of the following, according to the judgment of the investigator: a)\tClinically 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)\tSymptomatic/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)\tSignificant or unstable physical condition that may require change to concomitant medication or hospitalization that would impact the assessments of the trial d)\tPlanned major surgery requiring\n- 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\n- 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\n- Concomitant use of strong inhibitors (e.g. itraconazole, ketoconazole, clarithromycin) or inducers (e.g. carbamazepine, rifampin, phenytoin, St. John’s wort) of CYP3A4\n- 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\n- Any suicidal behavior in the past 1-year period prior to screening or during the screening period\n- Patients whose screening MRI scan shows gadolinium-enhancing lesions\n- Patients with moderate or severe renal insufficiency, defined as an eGFR < 60 mL/min/1.73 m2 at the screening visit\n- Patients with plasma ALT level > 3× ULN at the screening visit, or total plasma bilirubin > 2 × ULN\n- Active infection with hepatitis B or C virus\n- 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"}

Primary endpoints

• {"endpoint_text":"- The change in proportion of active voxels in supratentorial cerebral white matter in the end-of-treatment TSPO-PET images vs. baseline TSPO-PET images in participants with progressive MS treated with istradefylline vs. placebo","definition_or_measurement_approach":"Measured by TSPO-PET imaging assessing proportion of active voxels (DVR > 1.56) in supratentorial cerebral white matter (excluding T1 lesions) comparing end-of-treatment vs baseline scans between istradefylline and placebo groups."}

Secondary endpoints

• {"endpoint_text":"- Change in number of TSPO-PET–measurable chronic active lesions","definition_or_measurement_approach":"Measured by TSPO-PET lesion counting on PET imaging."}
• {"endpoint_text":"- Change in proportion of TSPO-PET–detectable active voxels at the rim of chronic lesions (change in proportion of active voxels)","definition_or_measurement_approach":"Measured by TSPO-PET assessing proportion of active voxels at lesion rims (change from baseline)."}
• {"endpoint_text":"- Change in proportion of TSPO-PET–detectable active voxels in the NAWM (change in proportion of active voxels)","definition_or_measurement_approach":"Measured by TSPO-PET assessing proportion of active voxels in normal-appearing white matter (NAWM)."}
• {"endpoint_text":"- Change in TSPO-PET signal (DVR, distribution volume ratio) at the rim of chronic lesions","definition_or_measurement_approach":"Measured by TSPO-PET DVR quantification at lesion rims."}
• {"endpoint_text":"- Change in DVR in the NAWM","definition_or_measurement_approach":"Measured by TSPO-PET DVR quantification in NAWM."}
• {"endpoint_text":"- Change in QSM-positive iron rim lesions","definition_or_measurement_approach":"Measured by MRI QSM sequences to identify and count iron rim lesions."}
• {"endpoint_text":"- Change in MRI volumetric measures in the brain regions of interest","definition_or_measurement_approach":"Measured by MRI volumetric analysis of predefined brain ROIs."}
• {"endpoint_text":"- Change in T1 and T2 lesion burden using MRI","definition_or_measurement_approach":"Measured by MRI assessment of T1 and T2 lesion volumes/burden."}
• {"endpoint_text":"- Change in neuroaxonal damage measured by DTI-MRI parameters","definition_or_measurement_approach":"Measured using DTI-MRI parameters (FA, MD, AD, RD) to assess neuroaxonal integrity."}
• {"endpoint_text":"- Change in disease worsening measured using the Timed 25 Foot Walk","definition_or_measurement_approach":"Measured by Timed 25-Foot Walk (T25FW) performance change from baseline."}
• {"endpoint_text":"- Change in hand dexterity measured using the 9-Hole Peg Test","definition_or_measurement_approach":"Measured by 9-Hole Peg Test (9HPT) performance change from baseline."}
• {"endpoint_text":"- Change in functional Systems and Expanded Disability Status Scale","definition_or_measurement_approach":"Measured by changes in functional system scores and EDSS."}
• {"endpoint_text":"- Change in cognition measured using neuropsychological evaluation","definition_or_measurement_approach":"Measured by predefined neuropsychological test battery comparing baseline and follow-up scores."}
• {"endpoint_text":"- Change in health-related quality of life measured using the RAND 36-Item Health Survey and Multiple Sclerosis Impact Scale questionnaires","definition_or_measurement_approach":"Measured by RAND-36 and MSIS-29 questionnaire scores."}
• {"endpoint_text":"- Change in fatigue measured using the Modified Fatigue Impact Scale and Fatigue Severity Scale questionnaires","definition_or_measurement_approach":"Measured by MFIS and FSS questionnaire scores."}
• {"endpoint_text":"- Change in blood serum neurofilament light chain and glial fibrillary acdic protein levels","definition_or_measurement_approach":"Measured by blood serum assays for neurofilament light chain (NfL) and GFAP levels."}

Methods

• Site-based recruitment at participating hospitals/clinical research facilities in Finland (Turku sites listed).
• Recruitment leaflet (document: K2_Recruitment leaflet_FI_public) — Finnish language material.
• Recruitment material for social media (document: K3_Recruitment material_social media_FI) — Finnish social media materials.
• Recruitment arrangements document (document: K1_Recruitment arrangements).

Finland

Earliest CTIS Part Ii Submission Date

29-10-2024

Latest Decision Or Authorization Date

15-11-2024

Processing Time Days

17

Number Of Sites

3

Number Of Participants

34

Primary sponsor

Full Name

University Of Turku

Organisation Type

Educational Institution

Country Of Registered Address

Finland

Third parties

• {"country":"","full_name":"International Progressive MS Alliance","duties_or_roles":"Monetary support","organisation_type":""}