Hydroxychloroquine in progressive MS

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Varsinais-Suomen hyvinvointialue

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

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

Decision date (initial)

2025-11-20

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 assess whether change in microglial activation over twelve months is different in HCQ-treated patients vs. placebo-treated patients with MS

Secondary objectives 18

1. To assess the effct of HCQ on safety and tolerability of HCQ in the study population for the duration of the study
2. To assess the effect of HCQ on disease progression as measured with Timed 25 Foot Walk (T25FW)
3. To assess the effect of HCQ on hand dexterity as measured with the 9-Hole Peg Test (9HPT)
4. To assess the effect of HCQ on cognition as measured with symbol digit modalities test (SDMT)
5. To assess the effect of HCQ on health-related quality of life, as measured with the RAND 36-Item Health Survey (RAND-36) and Multiple Sclerosis Impact Scale (MSIS-29) questionnaires
6. To assess the effect of HCQ on fatigue, as measured with the Modified Fatigue Impact Scale (MFIS) and Fatigue Severity Scale (FSS) questionnaires
7. To assess the effect of HCQ on MRI volumetric measures in the brain regions of interest
8. To assess the effect of HCQ on T1 and T2 lesion burden using MRI
9. To assess the effect of HCQ on number of TSPO-PET-measurable chronic active lesions
10. To assess the effect of HCQ on proportion of TSPO-PET-detectable active voxels at the rim of chronic lesions (change in proportion of active voxels)
11. To assess the effect of HCQ on proportion of TSPO-PET-detectable active voxels in the NAWM (change in proportion of active voxels)
12. To assess the effect of HCQ on TSPO-PET signal (DVR, distribution volume ratio) at the edges of chronic lesions
13. To assess the effect of HCQ on TSPO-PET signal (DVR) in the NAWM
14. To assess the effect of HCQ on axonal damage as measured by serum neurofilament light chain (NfL) levels in blood
15. To assess the effect of HCQ on astroglial damage as measured by serum glial fibrillary acidic protein (GFAP) levels in blood
16. To assess the effect of HCQ on number of Quantitative susceptibility mapping (QSM)-positive iron rim lesions
17. To assess the effect of HCQ on neuroaxonal damage as measured by diffusion tensor imaging (DTI)-MRI parameters (fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD))
18. To assess the effect of HCQ on disease progression as measured with Expanded Disability Status Scale (EDSS)

Conditions and MedDRA coding

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 18-70 years of age at time of consent
3. Patients with PPMS based on the current diagnostic criteria or non-relapsing SPMS (with no relapses in the last 2 years). MS patients whose disease is still classified as RRMS in the clinic, but who have had no evidence of relapse activity in the last 24 months (including new T2 lesions), and who demonstrated signs of disease progression. Disease progression during the last 24 months is determined as follows: increased EDSS score or increase in points in Kurzke’s Functional Systems evaluation, or enlarging T1 lesions in brain MRI during the previous two years determined by visual inspection by the treating neurologist or clinical neuroradiologist or other indication of clinical worsening determined both by the patient and the experienced treating neurologist, indicating an insufficient control of disease progression.
4. Screening Expanded Disability Status Scale (EDSS) score between 3.0 and 7.5 at screening
5. Worsening of MS symptoms or enlarging of T1 lesions in brain MRI during the previous 2 years The worsening of MS symptoms can be indicated as an increase in total EDSS, or as an increase in points in Kurzke’s functional system evaluation over the last two years, or other indication of clinical worsening determined both by the patient and the experienced treating neurologist, indicating an insufficient treatment response. 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 26

1. Patients undergoing treatment with other antimalarial drugs, amiodarone, dapsone or digoxin, other drugs associated with a significant risk for QT prolongation (see Appendix H), systemic glucocorticoids, or immunorupressing drugs mitoxantrone, cyclophosphamide, natalizumab, alemtuzumab or cladribine
2. Patients with other neurodegenerative disease or other 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. Suicidal ideation type 5 in the C-SSRS (i.e. active suicidal thought with plan and intent) in the past 6 months prior to screening or during the screening period; patients with suicidal ideation type 4 in the C-SSRS (i.e. active suicidal thought with intent but without specific plan) in the past 6 months prior to screening or during the screening period may only be included in the study if assessed and documented by a licensed mental health professional that there is no immediate risk of suicide
6. Positive urine test result for drugs of abuse at the screening or baseline visit, unless explained in a manner acceptable by the investigator by the patient’s medical history and concomitant medications
7. Patients whose screening ophthalmological examination shows retinopathy
8. Patients whose screening MRI scan shows gadolinium enhancing lesions
9. Patients with significant abnormal findings other than MS-related in the screening MRI
10. Patients with moderate or severe renal insufficiency, defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 at the screening visit
11. Patients with indication of liver disease, defined as either plasma alanine transferase (ALT) level > 3 x upper limit normal (ULN) at the screening visit, or total plasma bilirubin > 2 x ULN
12. Active infection with hepatitis B or C virus
13. Patients with known porphyria or psoriasis
14. Patients with known allergy or other intolerability to HCQ, or to gadolinium MRI contrast agent
15. Patients who are unable or unwilling to undergo gadolinium enhanced MRI scans
16. Patients with claustrophobia, or a history of moderate-to-severe anxiety disorder or panic attacks
17. Pregnant or breast-feeding women, and women of child-bearing potential (WOCBP) 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 a period of at least 60 days after last trial drug intake.
18. Exposure to more than 10 mSv doses of ionizing radiation, in addition to that obtained from natural sources, in the past 12 months
19. Patients with intolerance to previous PET scans
20. Participation in another investigational drug trial in the 3 months prior to baseline, or within 4 elimination half-lives of the trial medication, whichever is longer
21. Patients who are using systemically acting glucocorticoids during the study period; use of topical formulations (ointments, nasal sprays, eye drops etc.) is allowed
22. 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
23. Evidence of an immune system that is compromised; including, but not limited to, a diagnosis of HIV; or the participant has been splenectomised or has received an organ transplant (corneal transplants excluded)
24. Diagnosis of cancer (haematological or solid tumour) 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 tumours, such as basal or squamous cell carcinoma, may be included
25. 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), 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 withdrawal from study medication for more than 2 weeks during the study period
26. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change in proportion of active voxels in supratentorial cerebral white matter (excluding T1 lesions) in the end-of-treatment TSPO-PET images vs. baseline TSPO-PET images in participants with progressive MS treated with HCQ vs. placebo

Secondary endpoints 18

1. Change in disease progression as measured with Timed 25 Foot Walk (T25FW)
2. Change in hand dexterity as measured with the 9-Hole Peg Test (9HPT)
3. Change in cognition as measured with symbol digit modalities test (SDMT)
4. Change in health-related quality of life, as measured with the RAND 36-Item Health Survey (RAND-36) and Multiple Sclerosis Impact Scale (MSIS-29) questionnaires
5. Change in fatigue, as measured with the Modified Fatigue Impact Scale (MFIS) and Fatigue Severity Scale (FSS) questionnaires
6. Change in MRI volumetric measures in the brain regions of interest
7. Change in T1 and T2 lesion burden using MRI
8. Change in number of TSPO-PET-measurable chronic active lesions
9. Change in proportion of TSPO-PET-detectable active voxels at the rim of chronic lesions (change in proportion of active voxels)
10. Change in proportion of TSPO-PET-detectable active voxels in the NAWM (change in proportion of active voxels)
11. Change in TSPO-PET signal (DVR, distribution volume ratio) at the edges of chronic lesions
12. Change in TSPO-PET signal (DVR) in the NAWM
13. Change in axonal damage as measured by serum neurofilament light chain (NfL) levels in blood
14. Change in astroglial damage as measured by serum glial fibrillary acidic protein (GFAP) levels in blood
15. Change in number of Quantitative susceptibility mapping (QSM)-positive iron rim lesions
16. Change in neuroaxonal damage as measured by diffusion tensor imaging (DTI)-MRI parameters
17. Change in disease progression as measured with Expanded Disability Status Scale (EDSS)
18. Number of Serious Adverse Events

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Varsinais-Suomen hyvinvointialue

Sponsor organisation

Varsinais-Suomen hyvinvointialue

Address

Kiinamyllynkatu 4-8

City

Turku

Postcode

20520

Country

Finland

Scientific contact point

Organisation

Varsinais-Suomen hyvinvointialue

Contact name

Laura Airas

Public contact point

Organisation

Varsinais-Suomen hyvinvointialue

Contact name

Laura Airas

Third parties 1

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Results and documents

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

Documents 11 files

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

Application history

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