A clinical proof-of-concept study to reduce smoldering inflammation in progressive MS

Prior treatment

• 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
• 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 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)
• Concomitant use of strong inhibitors (e.g. itraconazole, ketoconazole, clarithromycin) or inducers (e.g. carbamazepine, rifampin, phenytoin, St. John’s wort) of CYP3A4
• 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 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

Other illness

• 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.
• 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
• 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
• 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 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
• Active infection with hepatitis B or C virus

Lab values

• 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 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

Other

• Patients whose screening MRI scan shows gadolinium-enhancing lesions

• 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