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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

University Of Turku

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20], Diseases [C] - Nervous System Diseases [C10]

Trial duration

31 Mar 2025 → ongoing

Decision date (initial)

2024-11-15

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

International Progressive MS Alliance

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To study the change in the proportion of active voxels (DVR > 1.56) in cerebral WM (excluding T1 lesions) in the end-of-treatment TSPO-PET images vs. baseline TSPO-PET images in patients with progressive MS treated with istradefylline compared to patients on placebo.

Secondary objectives 17

1. To assess the effect of istradefylline on the number of TSPO-PET–measurable chronic active lesions compared to the placebo group
2. To assess the effect of istradefylline on the proportion of TSPO-PET–detectable active voxels at the rim of chronic lesions compared to the placebo group (change in proportion of active voxels)
3. To assess the effect of istradefylline on the proportion of TSPO-PET–detectable active voxels in the NAWM compared to the placebo group (change in proportion of active voxels)
4. To assess the effect of istradefylline on TSPO-PET signal (DVR, distribution volume ratio) at the rim of chronic lesions compared to the placebo group
5. To assess the effect of istradefylline on TSPO-PET signal (DVR, distribution volume ratio) in the NAWM compared to the placebo group
6. To assess the effect of istradefylline on the number of QSM-positive iron rim lesions compared to the placebo group
7. To assess the effect of istradefylline on MRI volumetric measures in the brain regions of interest compared to the placebo group
8. To assess the effect of istradefylline on T1 and T2 lesion burden using MRI compared to the placebo group
9. To assess the effect of istradefylline on neuroaxonal damage measured by DTI-MRI parameters (FA, MD, AD, and RD) compared to the placebo group.
10. To assess the safety and tolerability of istradefylline in the study population for the duration of the study
11. To assess the effect of istradefylline on disease worsening measured using the T25FW compared to the placebo group
12. To assess the effect of istradefylline on hand dexterity measured using the 9HPT compared to the placebo group
13. To assess the effect of istradefylline on Functional Systems and EDSS
14. To assess the effect of istradefylline on cognition measured using the neuropsychological evaluation compared to the placebo group
15. To assess the effect of istradefylline on health-related quality of life measured using the RAND 36-Item Health Survey (RAND-36) and Multiple Sclerosis Impact Scale (MSIS-29) questionnaires compared to the placebo group
16. To assess the effect of istradefylline on fatigue measured using the Modified Fatigue Impact Scale (MFIS) and Fatigue Severity Scale (FSS) questionnaires compared to the placebo group
17. To assess the effect of istradefylline on blood serum neurofilament light chain and glial fibrillary acdic protein levels

Conditions and MedDRA coding

Progressive multiple sclerosis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Written informed consent obtained
2. Men and women who are 18-67 years of age at time of consent
3. 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)
4. Screening Expanded Disability Status Scale (EDSS) score between 3.5 and 7.5 at screening
5. 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
6. 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
7. Patients must be fluent in the Finnish language

Exclusion criteria 21

1. 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
2. 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
3. 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
4. Any suicidal behavior in the past 1-year period prior to screening or during the screening period
5. Patients whose screening MRI scan shows gadolinium-enhancing lesions
6. Patients with moderate or severe renal insufficiency, defined as an eGFR < 60 mL/min/1.73 m2 at the screening visit
7. Patients with plasma ALT level > 3× ULN at the screening visit, or total plasma bilirubin > 2 × ULN
8. Active infection with hepatitis B or C virus
9. 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
10. Patients with known allergy or other intolerability to istradefylline or to gadolinium MRI contrast agent
11. Patients with claustrophobia or a history of moderate-to-severe anxiety disorder or panic attacks
12. 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.
13. Exposure to more than 10 mSv doses of ionizing radiation, in addition to that obtained from natural sources, in the past 12 months
14. Patients with intolerance to previous PET scans
15. 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
16. 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
17. 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)
18. 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
19. 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
20. 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
21. Concomitant use of strong inhibitors (e.g. itraconazole, ketoconazole, clarithromycin) or inducers (e.g. carbamazepine, rifampin, phenytoin, St. John’s wort) of CYP3A4

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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

Secondary endpoints 16

1. Change in number of TSPO-PET–measurable chronic active lesions
2. Change in proportion of TSPO-PET–detectable active voxels at the rim of chronic lesions (change in proportion of active voxels)
3. Change in proportion of TSPO-PET–detectable active voxels in the NAWM (change in proportion of active voxels)
4. Change in TSPO-PET signal (DVR, distribution volume ratio) at the rim of chronic lesions
5. Change in DVR in the NAWM
6. Change in QSM-positive iron rim lesions
7. Change in MRI volumetric measures in the brain regions of interest
8. Change in T1 and T2 lesion burden using MRI
9. Change in neuroaxonal damage measured by DTI-MRI parameters
10. Change in disease worsening measured using the Timed 25 Foot Walk
11. Change in hand dexterity measured using the 9-Hole Peg Test
12. Change in functional Systems and Expanded Disability Status Scale
13. Change in cognition measured using neuropsychological evaluation
14. Change in health-related quality of life measured using the RAND 36-Item Health Survey and Multiple Sclerosis Impact Scale questionnaires
15. Change in fatigue measured using the Modified Fatigue Impact Scale and Fatigue Severity Scale questionnaires
16. Change in blood serum neurofilament light chain and glial fibrillary acdic protein levels

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

University Of Turku

Sponsor organisation

University Of Turku

Address

P. O. Box 52

City

Turku

Postcode

20521

Country

Finland

Scientific contact point

Organisation

University Of Turku

Contact name

Laura Airas

Public contact point

Organisation

University Of Turku

Contact name

Laura Airas

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 14 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications