A Study of Immune Phenotype Biomarkers in Patients With Relapsing Multiple Sclerosis (RMS) After Treatment With 0.5mg Fingolimod

Phase 4

Completed

Conditions: Relapsing Multiple Sclerosis

Interventions: Drug: Fingolimod

Registration Number: NCT03257358

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: A study of immune phenotype biomarkers in patients with Relapsing Multiple Sclerosis (RMS) after treatment with 0.5mg fingolimod

Detailed Description: This study used a 2-cohort, nonrandomized, open-label, multicenter design. Cohort 1: The first cohort was to be comprised of approximately 200 patients with RMS, who were newly prescribed commercially available fingolimod 0.5 mg/day. Cohort 2: The second cohort was to be comprised of approximately 200 RMS patients who had been on commercially available fingolimod 0.5 mg/day continuously without interruption of treatment for at least ≥ 2 years. Patients from both cohorts were recruited simultaneously from up to 125 MS centers in the United States. Both cohorts ran concurrently. The study consisted of 2 periods: Screening (up to 4 weeks) and Treatment period from Baseline (end of screening period considered as Day 1) up to 12 months with visits conducted at 3,6 and 12 months with a 14 day follow-up post treatment..

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 382

Inclusion Criteria

Diagnosis of relapsing forms of Multiple Sclerosis
Patients who started commercially prescribed fingolimod therapy 0.5mg per day OR patients already on commercially prescribed fingolimod 0.5mg per day continuously for ≥ 2 years

Exclusion Criteria (per USPI):

Patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, transient ischemic stroke, decompensated heart failure requiring hospitalization or Class III/IV heart failure
History or presence of Mobitz Type II second-degree or third-degree atrioventricular block or sick sinus syndrome, unless patient had a functioning pacemaker
Baseline QTc interval ≥ 500 msec
Treatment with Class Ia or Class III anti-arrhythmic drugs
Patients who had a hypersensitivity reaction to fingolimod or any of the excipients

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 1	Fingolimod	RMS patients who were newly prescribed commercially available fingolimod 0.5mg per day
Cohort 2	Fingolimod	RMS patients who had been on commercially available fingolimod 0.5mg per day continuously for ≥ 2 years

Primary Outcome Measures

Name	Time	Method
Change From Baseline to Month 6 in CD4+ Effector Memory T Cells (CCR7-CD45RA-CD45RO+)	Baseline to Month 6	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 6 in CD4+ Th2 Cells (CCR4+)	Baseline to Month 6	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 6 in CD4+ Th17 Cells (CCR6+)	Baseline to Month 6	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 6 in NK Cells (CD56+)	Baseline to Month 6	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 6 in CD4+ Naive T Cells (CCR7+ CD45RA+)	Baseline to Month 6	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 6 in CD8+ Central Memory T Cells (CCR7+CD45RA-CD45RO+)	Baseline to Month 6	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 6 in CD4+ Central Memory T Cells (CCR7+CD45RA-CD45RO+)	Baseline to Month 6	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 6 in CD4+ Th1 Cells (CXCR3+)	Baseline to Month 6	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 6 in CD8+ Naive T Cells (CCR7+CD45RA+)	Baseline to Month 6	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 6 in CD8+ Effector Memory T Cells (CCR7-CD45RA-CD45RO+)	Baseline to Month 6	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 6 in Memory B Lymphocytes (CD19+CD27+)	Baseline to Month 6	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 6 in Naive B Lymphocytes (CD19+CD27-)	Baseline to Month 6	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 6 in Regulatory B Lymphocytes (CD19+CD24+CD38+)	Baseline to Month 6	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 6 in Monocytes (CD14+)	Baseline to Month 6	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 6 in Neutrophils (CD16+)	Baseline to Month 6	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 6 in Total CD4+ Absolute Cell Count	Baseline to Month 6	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 6 in Total CD4+ Differential Cell Count	Baseline to Month 6	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 6 in Total CD8+ Differential Cell Counts (%)	Baseline to Month 6	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 6 in Total CD8+ Absolute Cell Count	Baseline to Month 6	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 6 in Total CD19+ Absolute Cell Count	Baseline to Month 6	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 6 in Total CD19+ Differential Cell Count (%)	Baseline to Month 6	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline to Month 12 in CD4+ Naive T Cells (CCR7+CD45RA+)	Baseline to Month 12	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 12 in CD4+ Th17 Cells (CCR6+)	Baseline to Month 12	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 12 in CD8+ Naive T Cells (CCR7+CD45RA+)	Baseline to Month 12	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 12 in CD8+ Effector Memory T Cells (CCR7-CD45RA-CD45RO+)	Baseline to Month 12	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 12 in Naive B Lymphocytes (CD19+CD27-)	Baseline to Month 12	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 12 in Memory B Lymphocytes (CD19+CD27+)	Baseline to Month 12	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 12 in Regulatory B Lymphocytes (CD19+CD24+CD38+)	Baseline to Month 12	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 12 in Monocytes (CD14+)	Baseline to Month 12	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 12 in CD4+ Effector Memory T Cells (CCR7-CD45RA-CD45RO+)	Baseline to Month 12	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 12 in Neutrophils (CD16+)	Baseline to Month 12	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 12 in NK Cells (CD56+)	Baseline to Month 12	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 12 in Total CD4+ Absolute Cell Count	Baseline to Month 12	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Months 6 and 12 in the Anti-JCV Antibody Index (Index/Value)	Baseline to Month 6 and 12
Change From Baseline to Month 12 in Total CD8+ Absolute Cell Count	Baseline to Month 12	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 12 in Total CD19+ Absolute Cell Count	Baseline to Month 12	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Number of Participants Who Received Steroid Treatment for MS Relapses During Treatment	Baseline to Month 12	A relapse is defined as the appearance of a new neurological abnormality or worsening of previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. The abnormality must be present for at least 24 hours and occur in the absence of fever (\<37.5°C) or infection.
Change From Baseline in Patient Determined Disease Steps (PDDS)	Baseline to Month 12	PDDS scoring ranges 0 to 8. 0 = Normal; 1 = Mild disability; 2 = Moderate disability; 3 = Gait disability; 4 = Early cane; 5 = Late cane; 6 = Bilateral support; 7 = Wheelchair/scooter; 8 = Bedridden.
Change From Baseline to Month 12 in CD4+ Central Memory T Cells (CCR7+CD45RA-CD45RO+)	Baseline to Month 12	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 12 in CD4+ Th1 Cells (CXCR3+)	Baseline to Month 12	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 12 in CD4+ Th2 Cells (CCR4+)	Baseline to Month 12	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 12 in CD8+ Central Memory T Cells (CCR7+CD45RA-CD45RO+)	Baseline to Month 12	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 12 in Total CD4+ Differential Cell Count (%)	Baseline to Month 12	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline to Month 12 in Total CD8+ Differential Cell Counts (%)	Baseline to Month 12	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Multiple Sclerosis (MS) Relapses During Treatment	Baseline to Month 12	A relapse is defined as the appearance of a new neurological abnormality or worsening of previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. The abnormality must be present for at least 24 hours and occur in the absence of fever (\<37.5°C) or infection.
Change From Baseline in T2 Lesion Burden	Baseline to Month 12
Change From Baseline to Month 12 in Total CD19+ Differential Cell Count (%)	Baseline to Month 12	Blood samples (approximately 60-80 ml) were collected at specifiied visits for biomarker and hematology assessments. In Cohort 1 patients it was critical that the blood sample was collected prior to administration of fingolimod, first dose observation (FDO). A central laboratory was used for analysis of all specimens collected.
Change From Baseline for New Gd-Enhancing T1 Lesion Count	Baseline to Month 12