Effect of Fingolimod on Neurodegeneration

Effect of Fingolimod on Neurodegeneration, Brain Atrophy and Cognitive Impairment in Relapsing Remitting Multiple Sclerosis Patients

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.

Study Overview

• Status: Terminated
• Conditions: Cognition; Brain Volume Loss
• Intervention / Treatment: Drug: 0,5 mg Fingolimod

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 4

Contacts and Locations

Study Locations

• Turkey
  • Bursa, Turkey, 16059
    • Novartis Investigative Site
  • Kocaeli, Turkey, 41380
    • Novartis Investigative Site
  • Kutahya, Turkey, 43000
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

  4. 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:

    1. Corticosteroids or adrenocorticotropic hormone (ACTH) during the last 1 month
    2. Immunosuppressive medications such as azathioprine or methotrexate etc.
    3. Immunoglobulin treatment during the last 3 months
    4. Cladribine, cyclophosphamide, mitoxantrone, natalizumab at any time

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Fingolimod arm; 0.5 mg p.o fingolimod daily	Drug: 0,5 mg Fingolimod; 0.5 mg p.o fingolimod daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) Battery Test at 12 Months	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).	baseline , month 12.
Change From Baseline in The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) Battery Test at 24 Months	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).	baseline and month 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in PASAT Test	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.	baseline ,months 6, month 12 and month 24
Change From Baseline in Stroop Test	The Stroop Color and Word Test assesses cognitive processing and provides valuable diagnostic information on brain dysfunction, cognition, and psychopathology	baseline, month 6, month 12 and month 24
Change From Baseline in Brain Gray Matter Atrophy and Thalamic Atrophy	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.	baseline, month 6, month 12, month 18 and month 24
Change From Baseline in Serum Levels of 24S-hydroxycholesterol (24OHC) , Osteopontin and Matrix Metalloproteinases (and Also MMPI's)	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).	baseline, month 6, month , month 12 and month 24
the Correlation Between Effect of Fingolimod on Cognitive Performances and Brain Atrophy (Gray Matter Atrophy and Thalamic Atrophy) by Comparing Baseline and Month 24.	Correlation between effect of fingolimod on cognitive performances based on cognitive tests and brain atrophy based on MRI assessments will be explored.	baseline, month 24

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 16, 2016
• Primary Completion (ACTUAL): January 27, 2017
• Study Completion (ACTUAL): January 27, 2017

Study Registration Dates

• First Submitted: October 12, 2015
• First Submitted That Met QC Criteria: October 12, 2015
• First Posted (ESTIMATE): October 14, 2015

Study Record Updates

• Last Update Posted (ACTUAL): February 27, 2019
• Last Update Submitted That Met QC Criteria: October 17, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: biomarkers,; Multiple Sclerosis,; RRMS,; Cognition,; brain,; Fingolimod,; neurodegeneration,; Brain atrophy,; gray matter atrophy,; thalamic atrophy,; BICAMS Battery,
• Additional Relevant MeSH Terms: Pathologic Processes; Nerve Degeneration; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Sphingosine 1 Phosphate Receptor Modulators; Fingolimod Hydrochloride
• Other Study ID Numbers: CFTY720DTR05

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No