Follow up Study of Patients on Fingolimod Who Were Enrolled in the Original Biobank Study (CFTY720DDE01)

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02720107
• Collaborator: (none)
• Enrollment: 133
• Locations: 26
• Arm: 1
• Actual Duration (Months): 6.1
• Patients Per Site: 5.1
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

The purpose of this single visit extension study is to explore immune status in RRMS patients treated for at least 48 months with fingolimod. Long-term changes in T cell counts will be compared to short-term changes in immune status (baseline to month 6) after treatment start with fingolimod as assessed in the original Biobank study (CFTY720DDE01).

Condition or Disease	Intervention/Treatment	Phase
Relapsing-remitting Multiple Sclerosis	Drug: fingolimod	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 133 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Long-term Follow up of Patients With Relapsing-remitting Multiple Sclerosis Enrolled in the Multicenter, Single-arm, Open-label Biobank Study (CFTY720DDE01), to Investigate Changes in Biomarkers After 48 Months of Treatment With 0.5 mg Fingolimod (FTY720)
• Actual Study Start Date: May 12, 2016
• Actual Primary Completion Date: Nov 14, 2016
• Actual Study Completion Date: Nov 14, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: fingolimod Patients did not receive any protocol specified treatment during this follow-up study. Patients remained on their current treatment regime (fingolimod), as determined by their regular treating physician (i.e. 0.5 mg fingolimod daily, single-arm).	Drug: fingolimod

Outcome Measures

Primary Outcome Measures

1. Change in T Cells Status (Decrease or Increase) at Month 48 (FAS) [Baseline up to approximately 48 months]

   Aim of trial was to was to show reduction of CD4+ and CD8+ naïve T cells (CCR7+CD45RA+), central memory T cells (CCR7+CD45RA-), central memory Th17 cells (CD4+ CCR4+ and CCR6+), and an elevation of 2 types of effector memory T cells TEM (CCR7- CD45RA-) and TEMRA (CCR7- CD45RA+) in peripheral venous blood. Changes from baseline to month 48 in biomarkers were analyzed for all patients in the FAS.

Secondary Outcome Measures

1. Percentage of Participants With Disability Progression as Measured by Expanded Disability Status Scale (EDSS) (FAS) [Baseline up to approximately 48 months]

   EDSS is a scale for assessing neurologic impairment in MS. It is a two-part system including (1) a series of scores in each of eight functional systems, and (2) the EDSS steps (ranging from 0 (normal) to 10 (death due to MS). The definition of disability progression was based on increases in EDSS from baseline and depended on the EDSS baseline value: Disability progression was defined as a 1.5 increase in EDSS from baseline in subjects with a baseline EDSS score between 0.0 and 0.5, as a 1.0 increase in EDSS from baseline in subjects with a baseline EDSS score between 1.0 and 5.0 inclusive and 0.5 increase from baseline in subjects with EDSS score > 5.0.

2. Change From Baseline in Disability Progression Assessed With the Expanded Disability Status Scale (EDSS) at Month 6 and Month 48 (FAS) [Baseline, month 6 up to approximately 48 months]

   EDSS is a scale for assessing neurologic impairment in MS. It is a two-part system including (1) a series of scores in each of eight functional systems, and (2) the EDSS steps (ranging from 0 (normal) to 10 (death due to MS). The definition of disability progression was based on increases in EDSS from baseline and depended on the EDSS baseline value: Disability progression was defined as a 1.5 increase in EDSS from baseline in subjects with a baseline EDSS score between 0.0 and 0.5, as a 1.0 increase in EDSS from baseline in subjects with a baseline EDSS score between 1.0 and 5.0 inclusive and 0.5 increase from baseline in subjects with EDSS score > 5.0.

3. Change in Immune Status of B Cells, Monocytes and Natural Killer Cells (NK) Cells (FAS) [Baseline up to approximately 48 months]

   Changes in immune status of B cells (CD19+, CD20+, CD69+), monocytes (CD14+) and NK cells (CD56+) were analyzed as a percentage of parent cell population (CD4+, CD8+ or total lymphocytes) by flow cytometry

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Written informed consent before any assessment was performed.

2. Randomized in study CFTY720DDE01 and received at least one dose of study drug (fingolimod) and completed the study.

3. Continuous intake of fingolimod after end of study CFTY720DDE01 with a maximum treatment interruption of 3 months in total before entering this study.

4. Parallel participation at study CFTY720DDE02 (Pangaea NIS) was allowed.

Exclusion criteriat:

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

2. Patients with onset of an acute relapse had to postpone their evaluation until deemed stable from relapse by treating physician, but at least for 1 month since end of relapse.

3. Patients that received immunomodulating or immunosuppressive MS treatments other than fingolimod since completion of study CFTY720DDE01 as for example: Natalizumab,Alemtuzumab, Dimethyl fumarate, Teriflunomide, intravenous Immunoglobulins,Mitoxantrone, Methotrexate, Azathioprine or experimental immunomodulating-immunosuppressive therapies.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Ostfildern	Baden-Wuerttemberg	Germany	73760
2	Novartis Investigative Site	Altenholz-Stift		Germany	24161
3	Novartis Investigative Site	Aschaffenburg		Germany	63739
4	Novartis Investigative Site	Berlin		Germany	10713
5	Novartis Investigative Site	Berlin		Germany	12163
6	Novartis Investigative Site	Berlin		Germany	13347
7	Novartis Investigative Site	Boblingen		Germany	71032
8	Novartis Investigative Site	Celle		Germany	29223
9	Novartis Investigative Site	Dortmund		Germany	44137
10	Novartis Investigative Site	Dresden		Germany	01307
11	Novartis Investigative Site	Erbach		Germany	64711
12	Novartis Investigative Site	Frankfurt		Germany	60313
13	Novartis Investigative Site	Göttingen		Germany	37073
14	Novartis Investigative Site	Jena		Germany	07740
15	Novartis Investigative Site	Kiel		Germany	24105
16	Novartis Investigative Site	Klingenmünster		Germany	76889
17	Novartis Investigative Site	Lappersdorf		Germany	93138
18	Novartis Investigative Site	Leverkusen		Germany	51375
19	Novartis Investigative Site	Mönchengladbach		Germany	41239
20	Novartis Investigative Site	München		Germany	81829
21	Novartis Investigative Site	Neuburg an der Donau		Germany	86633
22	Novartis Investigative Site	Siegen		Germany	57076
23	Novartis Investigative Site	Singen		Germany	78224
24	Novartis Investigative Site	Troisdorf		Germany	53844
25	Novartis Investigative Site	Ulm		Germany	89073
26	Novartis Investigative Site	Unterhaching		Germany	82008

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02720107
• Other Study ID Numbers: CFTY720DDE01E1
• First Posted: Mar 25, 2016
• Last Update Posted: Feb 8, 2019
• Last Verified: Sep 1, 2018

• Keywords provided by Novartis Pharmaceuticals: fingolimod; Biomarker; Multiple sclerosis; Relapsing-remitting multiple sclerosis
• Additional relevant MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis; Fingolimod Hydrochloride

Study Results

Participant Flow

Pre-assignment Detail	There were 133 patients enrolled in the study but only 130 received drug

Arm/Group Title	Fingolimod
Arm/Group Description	Patients did not receive any protocol specified treatment during this follow-up study. Patients remained on their current treatment regime (fingolimod), as determined by their regular treating physician (i.e. 0.5 mg fingolimod daily, single-arm).
Period Title: Overall Study
STARTED	130
COMPLETED	130
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Fingolimod
Arm/Group Description	Patients did not receive any protocol specified treatment during this follow-up study. Patients remained on their current treatment regime (fingolimod), as determined by their regular treating physician (i.e. 0.5 mg fingolimod daily, single-arm).
Overall Participants	130
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.1 (8.54)
Sex: Female, Male (Count of Participants)
Female	83 63.8%
Male	47 36.2%
Multiple Sclerosis History at screening of CFTY720DDE01 (Core) (years) [Mean (Standard Deviation) ]
Difference of first symptons and diagnosis	2.4 (3.56)
Difference of dagnosis and tx start in Core	8.6 (6.23)

Outcome Measures

1. Primary Outcome

Title	Change in T Cells Status (Decrease or Increase) at Month 48 (FAS)
Description	Aim of trial was to was to show reduction of CD4+ and CD8+ naïve T cells (CCR7+CD45RA+), central memory T cells (CCR7+CD45RA-), central memory Th17 cells (CD4+ CCR4+ and CCR6+), and an elevation of 2 types of effector memory T cells TEM (CCR7- CD45RA-) and TEMRA (CCR7- CD45RA+) in peripheral venous blood. Changes from baseline to month 48 in biomarkers were analyzed for all patients in the FAS.
Time Frame	Baseline up to approximately 48 months

Outcome Measure Data

Analysis Population Description

required baseline and month 48 visit measurement of the respective cell count

Arm/Group Title	Fingolimod
Arm/Group Description	Patients did not receive any protocol specified treatment during this follow-up study. Patients remained on their current treatment regime (fingolimod), as determined by their regular treating physician (i.e. 0.5 mg fingolimod daily, single-arm).
Measure Participants	130
CD4+ Naïve T cells	-23.7 (0.62)
CD4+Central memory T cells	-1.2 (0.59)
CD4+ Effector memory T cells	22.2 (2.37)
CD8+ Naïve T cells	-37.2 (0.38)
CD8+ Central memory T cells	-1.6 (0.07)
CD8+ Effector memory T cells	-12.9 (1.59)
TH17 central memory cells	-0.6 (0.03)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fingolimod
	Comments	CD4+ Naïve T cells
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments	The ANCOVA model included the covariates center, baseline of corresponding cell counts from Core study, sex and duration of disease until start of Core study
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fingolimod
	Comments	CD4+ Central memory T cells
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0493
	Comments	The ANCOVA model included the covariates center, baseline of corresponding cell counts from study Core study, sex and duration of disease until start of Core study
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Fingolimod
	Comments	CD4+ Effector memory T cells
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments	The ANCOVA model included the covariates center, baseline of corresponding cell counts from Core study, sex and duration of disease until start of Core study
	Method	ANCOVA
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Fingolimod
	Comments	CD8+ Naïve T cells
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments	The ANCOVA model included the covariates center, baseline of corresponding cell counts from Core study, sex and duration of disease until start of Core study
	Method	ANCOVA
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Fingolimod
	Comments	CD8+ Central memory T cells
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments	The ANCOVA model included the covariates center, baseline of corresponding cell counts from Core study, sex and duration of disease until start of Core study
	Method	ANCOVA
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Fingolimod
	Comments	CD8+ Effector memory T cells
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments	The ANCOVA model included the covariates center, baseline of corresponding cell counts from Core study, sex and duration of disease until start of Core study
	Method	ANCOVA
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Fingolimod
	Comments	TH17 central memory cells
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments	The ANCOVA model included the covariates center, baseline of corresponding cell counts from Core study, sex and duration of disease until start of Core study
	Method	ANCOVA
	Comments

2. Secondary Outcome

Title	Percentage of Participants With Disability Progression as Measured by Expanded Disability Status Scale (EDSS) (FAS)
Description	EDSS is a scale for assessing neurologic impairment in MS. It is a two-part system including (1) a series of scores in each of eight functional systems, and (2) the EDSS steps (ranging from 0 (normal) to 10 (death due to MS). The definition of disability progression was based on increases in EDSS from baseline and depended on the EDSS baseline value: Disability progression was defined as a 1.5 increase in EDSS from baseline in subjects with a baseline EDSS score between 0.0 and 0.5, as a 1.0 increase in EDSS from baseline in subjects with a baseline EDSS score between 1.0 and 5.0 inclusive and 0.5 increase from baseline in subjects with EDSS score > 5.0.
Time Frame	Baseline up to approximately 48 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fingolimod
Arm/Group Description	Patients did not receive any protocol specified treatment during this follow-up study. Patients remained on their current treatment regime (fingolimod), as determined by their regular treating physician (i.e. 0.5 mg fingolimod daily, single-arm).
Measure Participants	130
Number [percentage of participants]	21.54 16.6%

3. Secondary Outcome

Title	Change From Baseline in Disability Progression Assessed With the Expanded Disability Status Scale (EDSS) at Month 6 and Month 48 (FAS)
Description	EDSS is a scale for assessing neurologic impairment in MS. It is a two-part system including (1) a series of scores in each of eight functional systems, and (2) the EDSS steps (ranging from 0 (normal) to 10 (death due to MS). The definition of disability progression was based on increases in EDSS from baseline and depended on the EDSS baseline value: Disability progression was defined as a 1.5 increase in EDSS from baseline in subjects with a baseline EDSS score between 0.0 and 0.5, as a 1.0 increase in EDSS from baseline in subjects with a baseline EDSS score between 1.0 and 5.0 inclusive and 0.5 increase from baseline in subjects with EDSS score > 5.0.
Time Frame	Baseline, month 6 up to approximately 48 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fingolimod
Arm/Group Description	Patients did not receive any protocol specified treatment during this follow-up study. Patients remained on their current treatment regime (fingolimod), as determined by their regular treating physician (i.e. 0.5 mg fingolimod daily, single-arm).
Measure Participants	130
Baseline	2.7 (1.17)
Month 6	2.6 (1.38)
Month 48	2.7 (1.52)
Change from baseline to month 6	-0.1 (0.69)
Change from month 6 to month 48	0.2 (1.18)
Change from baseline to month 48	0.0 (1.19)

4. Secondary Outcome

Title	Change in Immune Status of B Cells, Monocytes and Natural Killer Cells (NK) Cells (FAS)
Description	Changes in immune status of B cells (CD19+, CD20+, CD69+), monocytes (CD14+) and NK cells (CD56+) were analyzed as a percentage of parent cell population (CD4+, CD8+ or total lymphocytes) by flow cytometry
Time Frame	Baseline up to approximately 48 months

Outcome Measure Data

Analysis Population Description

analysis required valid samples for baseline and month 48

Arm/Group Title	Fingolimod
Arm/Group Description	Patients did not receive any protocol specified treatment during this follow-up study. Patients remained on their current treatment regime (fingolimod), as determined by their regular treating physician (i.e. 0.5 mg fingolimod daily, single-arm).
Measure Participants	130
B cells	-7.2 (0.42)
Monocytes	42.3 (2.03)
Natural Killer cells	28.0 (2.09)

Adverse Events

Time Frame	(Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.(approximately 48 months)
Arm/Group Title	Fingolimod 0.5 mg
Arm/Group Description	fingolimod 0.5 mg
All Cause Mortality
	Fingolimod 0.5 mg
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Fingolimod 0.5 mg
	Affected / at Risk (%)	# Events
Total	0/130 (0%)
Other (Not Including Serious) Adverse Events
	Fingolimod 0.5 mg
	Affected / at Risk (%)	# Events
Total	1/130 (0.8%)
Investigations
Blood immunoglobulin M decreased	1/130 (0.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.