Effect of Fingolimod on Neurodegeneration

Phase 4

Terminated

• Conditions: Cognition; Brain Volume Loss
• Interventions: Drug: 0,5 mg Fingolimod

• Registration Number: NCT02575365
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

This was a 24-month, open-label, multicenter study with a single treatment arm design.

Primary objective of this study was:

-To investigate the effects of Fingolimod on cognitive performance in highly active relapsing remitting multiple sclerosis patients

Secondary objectives of this study were:

* To investigate the correlation between the effect of fingolimod on cognitive performances and MRI data.

* To evaluate the effect of fingolimod on biomarkers (24 hydroxy cholesterol, osteopontin and matrix metalloproteinases) related to neurodegeneration

* To investigate the effect of fingolimod on brain gray matter atrophy and thalamic atrophy.

Polulation The hope was to recruit a minimum of 80 relapsing remitting MS (RRMS) patients according to the McDonald criteria.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2015-10-12
• Study First Submitted QC: 2015-10-12
• Study First Posted: 2015-10-14
• Study Start: 2016-02-16
• Primary Completion: 2017-01-27
• Study Completion: 2017-01-27
• Results First Submitted: 2018-01-25
• Status Verified: 2018-10
• Results First Submitted QC: 2018-10-17
• Last Update Submitted: 2018-10-17
• Results First Posted: 2019-02-27
• Last Update Posted: 2019-02-27

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 4

Inclusion Criteria

1. Diagnosed with RRMS as described in 2010 McDonald criteria (36)

2. Provided written informed consent prior to any intervention

3. Unresponsive to treatment with a beta interferon or glatiramer acetate for a minimum of one year at and at adequate dose and with high disease activity .

   (Unresponsive patients: patients with no changes in relapses, increased relapses, severer relapses with one-year treatment or those who had had at least one relapse during the past one year under previous treatments and one or multiple contrast enhancing lesions in cranial MRI or increased T2 lesions in successive MRIs)

4. EDSS score below 5.5 at screening

Exclusion Criteria

• 1. Patients with primary or secondary progressive or progressive relapsing MS. 2. Patients with known contraindications for fingolimod treatment. 3. Other coexistent autoimmune diseases including Hashimoto thyroiditis, systemic lupus erythematosus, rheumatoid anthiritis, psoriasis etc.

  2. Patients with any of the following cardiovascular conditions:

  • Resting heart rate < 45 bpm/min

  • Cardiac failure at any time during the first study visit (Class III as per NYHA classification) or significant heart disease as judged by the physician

  • Myocardial infarction during the last 6 months

  • History of Mobitz Type II grade 2 AV block

  • Past or current grade 3 AV block

  • Confirmed history of sick sinus syndrome or sino-atrial heart block

  • arrhythmia requiring current treatment with Class Ia drugs (ajmaline, disopyramid, procainamide, quinidine)

  • hypertension uncontrolled with medication 5. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.

    6. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, detected by urinalysis and confirmed by a positive hCG laboratory test.

    7. Negative for varicella-zoster virus IgG antibodies at screening. Patients who have negative results for varicella-zoster virus IgG antibodies can be included in the study after vaccination for varicella-zoster virus.

    8. Active systemic bacterial, viral or fungal infections, or diagnosis of AIDS, Hepatitis B, Hepatitis C infection defined as a positive HIV antibody, Hepatitis B surface antigen or Hepatitis C antibody tests, respectively 9. History of previous fingolimod therapy 10. Patient who received any of the treatments below:

    9. Corticosteroids or adrenocorticotropic hormone (ACTH) during the last 1 month

    10. Immunosuppressive medications such as azathioprine or methotrexate etc.

    11. Immunoglobulin treatment during the last 3 months

    12. Cladribine, cyclophosphamide, mitoxantrone, natalizumab at any time

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Fingolimod arm	0,5 mg Fingolimod	0.5 mg p.o fingolimod daily

Primary Outcome Measures

Name	Time	Method
Change From Baseline in The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) Battery Test at 12 Months	baseline , month 12.	The Brief International Cognitive Assessment for MS ( BICAMS Battery ) includes 3 cognitive tests, 1-Symbol Digit Modalities Test (SDMT, 2-the second edition of the California Verbal Learning Test (CVLT2) and 3-the revised Brief Visuospatial Memory Test (BVMTR).
Change From Baseline in The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) Battery Test at 24 Months	baseline and month 24	The Brief International Cognitive Assessment for MS (BICAMS Battery) includes 3 cognitive tests, 1-Symbol Digit Modalities Test (SDMT, 2-the second edition of the California Verbal Learning Test (CVLT2) and 3-the revised Brief Visuospatial Memory Test (BVMTR).

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in PASAT Test	baseline ,months 6, month 12 and month 24	The Paced Auditory Serial Addition Test (PASAT) has been widely used in MS trials and it is considered to be a measure of sustained attention, divided attention, concentration, and information processing speed.
Change From Baseline in Serum Levels of 24S-hydroxycholesterol (24OHC) , Osteopontin and Matrix Metalloproteinases (and Also MMPI's)	baseline, month 6, month , month 12 and month 24	Serum samples will be collected at baseline and at months 6, 12 and 24 from each participant after evaluation for inclusion and exclusion criteria for measurement of 24 hydroxy cholesterol, osteopontin and matrix metalloproteinases (including MMPI's).
the Correlation Between Effect of Fingolimod on Cognitive Performances and Brain Atrophy (Gray Matter Atrophy and Thalamic Atrophy) by Comparing Baseline and Month 24.	baseline, month 24	Correlation between effect of fingolimod on cognitive performances based on cognitive tests and brain atrophy based on MRI assessments will be explored.
Change From Baseline in Stroop Test	baseline, month 6, month 12 and month 24	The Stroop Color and Word Test assesses cognitive processing and provides valuable diagnostic information on brain dysfunction, cognition, and psychopathology
Change From Baseline in Brain Gray Matter Atrophy and Thalamic Atrophy	baseline, month 6, month 12, month 18 and month 24	MRI scans will be obtained by using 1,5T MRI for measuring gray matter atrophy and thalamic atrophy and a standard scanning protocol will be used for MRI in all centers.

Trial Locations

Locations (1)

Novartis Investigative Site; 🇹🇷 Kutahya, Turkey