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Clinical Trial Results:
A 3-year multi-center study to describe the long term changes of optical coherence tomography (OCT) parameters in patients under treatment with Gilenya®

Summary
EudraCT number	2012-000674-31
Trial protocol	DE
Global end of trial date	18 Feb 2019

Results information
Results version number	v1(current)
This version publication date	01 Mar 2020
First version publication date	01 Mar 2020
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

CFTY720DDE15TS

ISRCTN number

US NCT number

NCT01705236

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

18 Feb 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

18 Feb 2019

Was the trial ended prematurely?

Main objective of the trial

To evaluate the change in average RNFL thickness (RNFLT) in RRMS subjects treated with fingolimod over 36 months as assessed by OCT.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

20 Aug 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 77

Country: Number of subjects enrolled

Switzerland: 10

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects were screened at 10 study centers in Germany (9 centers) and Switzerland (1 center).

Screening details

Subjects who passed the screening were enrolled in the trial.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Fingolimod - Longitudinal Assessment

Arm description

No study drug was provided. Fingolimod was to be prescribed according to local label. The decision to prescribe fingolimod was to be made independent of this study.

Arm type

Experimental

Investigational medicinal product name

Fingolimod

Investigational medicinal product code

FTY720

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Fingolimod was to be prescribed according to local label. The decision to prescribe fingolimod was to be made independent of this study.

Number of subjects in period 1	Fingolimod - Longitudinal Assessment
Started	87
Completed	60
Not completed	27
Abnormal laboratory value(s)	4
Consent withdrawn by subject	5
Adverse event, non-fatal	5
Unsatisfactory therapeutic effect	3
Administrative problems	2
Lost to follow-up	1
Abnormal test procedure result(s)	4
Protocol deviation	3

Baseline characteristics

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Reporting group title

Fingolimod - Longitudinal Assessment

Reporting group description

No study drug was provided. Fingolimod was to be prescribed according to local label. The decision to prescribe fingolimod was to be made independent of this study.

Reporting group values	Fingolimod - Longitudinal Assessment	Total
Number of subjects	87	87
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	87	87
From 65-84 years	0	0
85 years and over	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	35.9 ± 9.5	-
Sex: Female, Male
Units: Participants
Female	55	55
Male	32	32
Race/Ethnicity, Customized
Units: Subjects
Caucasian	84	84
Other	3	3

End points

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Reporting group title

Fingolimod - Longitudinal Assessment

Reporting group description

No study drug was provided. Fingolimod was to be prescribed according to local label. The decision to prescribe fingolimod was to be made independent of this study.

Primary: Change from baseline to month 36 in average Retinal Nerve Fiber Layer Thickness (RNFLT)

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End point title

Change from baseline to month 36 in average Retinal Nerve Fiber Layer Thickness (RNFLT) ^[1]

End point description

The primary endpoint was the change, i.e. the absolute difference, in average RNFL thickness from baseline to month 36 (or last values in case of missing data) in the Full Analysis Set (FAS). Average RNFL thickness was the average of valid measurements of the right and left eye and assessed by optical coherence tomography (OCT).

End point type

Primary

End point timeframe

Baseline, month 36

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: single arm trial.

End point values	Fingolimod - Longitudinal Assessment
Number of subjects analysed	72
Units: micrometer
arithmetic mean (standard deviation)	-1.5 ± 2.7

No statistical analyses for this end point

Secondary: Change from baseline to month 12 and 24 in average Retinal Nerve Fiber Layer Thickness (RNFLT)

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End point title

Change from baseline to month 12 and 24 in average Retinal Nerve Fiber Layer Thickness (RNFLT)

End point description

Change from baseline in average RNFL thickness to months 12 and 24 (or last values in case of missing data) in the Full Analysis Set (FAS). Average RNFL thickness was the average of valid measurements of the right and left eye and assessed by optical coherence tomography (OCT).

End point type

Secondary

End point timeframe

Baseline, month 12, month 24

End point values	Fingolimod - Longitudinal Assessment
Number of subjects analysed	72
Units: micrometer
arithmetic mean (standard deviation)
Change from baseline to month 12	-0.8 ± 2.4
Change from baseline to month 24	-1.1 ± 2.4

No statistical analyses for this end point

Secondary: Change from baseline to month 12, 24 and 36 in average quadrant Retinal Nerve Fiber Layer Thickness (RNFLT)

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End point title

Change from baseline to month 12, 24 and 36 in average quadrant Retinal Nerve Fiber Layer Thickness (RNFLT)

End point description

Change from baseline in average quadrant RNFL thickness to months 12, 24 and 36 (or last values in case of missing data) in the Full Analysis Set (FAS). Average quadrant RNFL thickness was the average of valid measurements of the right and left eye and assessed by optical coherence tomography (OCT). Quadrant RNFL thickness were: Nasal-inferior; nasal-superior; temporal-inferior; temporal-superior.

End point type

Secondary

End point timeframe

Baseline, month 12, month 24, month 36

End point values	Fingolimod - Longitudinal Assessment
Number of subjects analysed	72
Units: micrometer
arithmetic mean (standard deviation)
Nasal-superior RNFL thickness: month 12	0.5 ± 4.0
Nasal-superior RNFL thickness: month 24	-0.4 ± 3.4
Nasal-superior RNFL thickness: month 36	-0.7 ± 3.9
Nasal-inferior RNFL thickness: month 12	-1.2 ± 4.9
Nasal-inferior RNFL thickness: month 24	-1.6 ± 5.1
Nasal-inferior RNFL thickness: month 36	-2.1 ± 5.2
Temporal-inferior RNFL thickness: month 12	-1.2 ± 2.5
Temporal-inferior RNFL thickness: month 24	-1.6 ± 3.1
Temporal-inferior RNFL thickness: month 36	-2.3 ± 4.1
Temporal-superior RNFL thickness: month 12	-0.5 ± 3.9
Temporal-superior RNFL thickness: month 24	-0.4 ± 3.4
Temporal-superior RNFL thickness: month 36	-1.1 ± 4.1

No statistical analyses for this end point

Secondary: Change from baseline to month 12, 24 and 36 in Total Macular Volume (TMV)

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End point title

Change from baseline to month 12, 24 and 36 in Total Macular Volume (TMV)

End point description

Change from baseline in TMV to months 12, 24 and 36 (or last values in case of missing data) in the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

12, 24 and 36 months

End point values	Fingolimod - Longitudinal Assessment
Number of subjects analysed	72
Units: Cubic millimeter
arithmetic mean (standard deviation)
Change from baseline to month 12	-0.03 ± 0.08
Change from baseline to month 24	-0.04 ± 0.08
Change from baseline to month 36	-0.06 ± 0.10

No statistical analyses for this end point

Secondary: Change from baseline to month 12, 24 and 36 in Ganglion Cell Inner Plexiform (GCIP)

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End point title

Change from baseline to month 12, 24 and 36 in Ganglion Cell Inner Plexiform (GCIP)

End point description

Change from baseline in GCIP to months 12, 24 and 36 (or last values in case of missing data) in the Full Analysis Set (FAS). The change in Ganglion cell layer thickness (GCLT) had been defined as secondary endpoint in the protocol, but OCT measured the GCIP instead. This was done because both layers were not clearly separable by OCT. GCIP was calculated as mean of the inner sectors (nasal, superior, temporal, and inferior) and declared as usual parameter instead. This change was introduced prior to data base lock, but the derivation of GCIP was corrected after data base lock.

End point type

Secondary

End point timeframe

Baseline, month 12, month 24, month 36

End point values	Fingolimod - Longitudinal Assessment
Number of subjects analysed	72
Units: micrometer
arithmetic mean (standard deviation)
Change from baseline to month 12	-0.49 ± 2.39
Change from baseline to month 24	-0.42 ± 2.74
Change from baseline to month 36	-0.46 ± 3.01

No statistical analyses for this end point

Secondary: Number of participants with adverse events

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End point title

Number of participants with adverse events

End point description

Number of participants with adverse events and specifically macular edema.

End point type

Secondary

End point timeframe

36 months

End point values	Fingolimod - Longitudinal Assessment
Number of subjects analysed	87
Units: Participants
No. of subjects with any AE	80
No. of subjects with macular edema	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events were collected from first dose of study Treatment until end of study treatment up to maximum duration of 36 months.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

Total

Reporting group description

Total

Serious adverse events	Total
Total subjects affected by serious adverse events
subjects affected / exposed	11 / 87 (12.64%)
number of deaths (all causes)	0
number of deaths resulting from adverse events	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
CERVIX CARCINOMA STAGE 0
subjects affected / exposed	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
NASAL NEOPLASM
subjects affected / exposed	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
UTERINE LEIOMYOMA
subjects affected / exposed	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Injury, poisoning and procedural complications
LOWER LIMB FRACTURE
subjects affected / exposed	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
RADIUS FRACTURE
subjects affected / exposed	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
SUTURE RELATED COMPLICATION
subjects affected / exposed	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Cardiac disorders
AORTIC VALVE INCOMPETENCE
subjects affected / exposed	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Nervous system disorders
MULTIPLE SCLEROSIS RELAPSE
subjects affected / exposed	2 / 87 (2.30%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
NEURALGIC AMYOTROPHY
subjects affected / exposed	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
UHTHOFF'S PHENOMENON
subjects affected / exposed	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Reproductive system and breast disorders
CERVICAL DYSPLASIA
subjects affected / exposed	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Musculoskeletal and connective tissue disorders
INTERVERTEBRAL DISC PROTRUSION
subjects affected / exposed	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Infections and infestations
ERYSIPELAS
subjects affected / exposed	1 / 87 (1.15%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
GASTROENTERITIS VIRAL
subjects affected / exposed	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
OPHTHALMIC HERPES ZOSTER
subjects affected / exposed	1 / 87 (1.15%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
WOUND INFECTION
subjects affected / exposed	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Total
Total subjects affected by non serious adverse events
subjects affected / exposed	68 / 87 (78.16%)
Vascular disorders
HYPERTENSION
subjects affected / exposed	12 / 87 (13.79%)
occurrences all number	12
Nervous system disorders
DIZZINESS
subjects affected / exposed	5 / 87 (5.75%)
occurrences all number	5
HEADACHE
subjects affected / exposed	10 / 87 (11.49%)
occurrences all number	10
MULTIPLE SCLEROSIS RELAPSE
subjects affected / exposed	21 / 87 (24.14%)
occurrences all number	31
PARAESTHESIA
subjects affected / exposed	5 / 87 (5.75%)
occurrences all number	5
Blood and lymphatic system disorders
LYMPHOPENIA
subjects affected / exposed	9 / 87 (10.34%)
occurrences all number	10
Gastrointestinal disorders
DIARRHOEA
subjects affected / exposed	6 / 87 (6.90%)
occurrences all number	8
Respiratory, thoracic and mediastinal disorders
COUGH
subjects affected / exposed	6 / 87 (6.90%)
occurrences all number	7
Skin and subcutaneous tissue disorders
ALOPECIA
subjects affected / exposed	5 / 87 (5.75%)
occurrences all number	5
Psychiatric disorders
DEPRESSION
subjects affected / exposed	5 / 87 (5.75%)
occurrences all number	5
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	5 / 87 (5.75%)
occurrences all number	5
BACK PAIN
subjects affected / exposed	7 / 87 (8.05%)
occurrences all number	10
Infections and infestations
BRONCHITIS
subjects affected / exposed	6 / 87 (6.90%)
occurrences all number	8
CONJUNCTIVITIS
subjects affected / exposed	5 / 87 (5.75%)
occurrences all number	7
NASOPHARYNGITIS
subjects affected / exposed	41 / 87 (47.13%)
occurrences all number	68
SINUSITIS
subjects affected / exposed	6 / 87 (6.90%)
occurrences all number	9
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	7 / 87 (8.05%)
occurrences all number	13
URINARY TRACT INFECTION
subjects affected / exposed	7 / 87 (8.05%)
occurrences all number	12
Metabolism and nutrition disorders
VITAMIN D DEFICIENCY
subjects affected / exposed	8 / 87 (9.20%)
occurrences all number	8

More information

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Were there any global substantial amendments to the protocol? Yes

06 Feb 2013

Implementation of an update of the Gilenya® (fingolimod) label providing refined guidance on when existing first dose monitoring procedures should be repeated after treatment interruption or after pharmacological intervention during first dose monitoring.

27 Mar 2014

Further definition of blood biomarker sampling was added and the period of one month was defined as 28 days. Furthermore, the specifications for contraception and for elevated liver function tests were adjusted and some inconsistencies within the protocol were corrected.

20 May 2015

Blood biomarker sampling was removed from the protocol and a responsible person for OCT quality control was added.

26 Jul 2016

Clarification that the minimum pre-treatment with fingolimod was 28 days and adaption of the visit schedule to the recommended visit schedule in the fingolimod product information which recommends visits every 3 months of treatment. Therefore, one month during the observational period of this study was re-defined as 28–31 days depending on the actual length of the respective month. The definition of one month as 28 days was removed.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
A 3-year multi-center study to describe the long term changes of optical coherence tomography (OCT) parameters in patients under treatment with Gilenya®

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from baseline to month 36 in average Retinal Nerve Fiber Layer Thickness (RNFLT)

Primary: Change from baseline to month 36 in average Retinal Nerve Fiber Layer Thickness (RNFLT)

Secondary: Change from baseline to month 12 and 24 in average Retinal Nerve Fiber Layer Thickness (RNFLT)

Secondary: Change from baseline to month 12 and 24 in average Retinal Nerve Fiber Layer Thickness (RNFLT)

Secondary: Change from baseline to month 12, 24 and 36 in average quadrant Retinal Nerve Fiber Layer Thickness (RNFLT)

Secondary: Change from baseline to month 12, 24 and 36 in average quadrant Retinal Nerve Fiber Layer Thickness (RNFLT)

Secondary: Change from baseline to month 12, 24 and 36 in Total Macular Volume (TMV)

Secondary: Change from baseline to month 12, 24 and 36 in Total Macular Volume (TMV)

Secondary: Change from baseline to month 12, 24 and 36 in Ganglion Cell Inner Plexiform (GCIP)

Secondary: Change from baseline to month 12, 24 and 36 in Ganglion Cell Inner Plexiform (GCIP)

Secondary: Number of participants with adverse events

Secondary: Number of participants with adverse events

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A 3-year multi-center study to describe the long term changes of optical coherence tomography (OCT) parameters in patients under treatment with Gilenya®

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from baseline to month 36 in average Retinal Nerve Fiber Layer Thickness (RNFLT)

Primary: Change from baseline to month 36 in average Retinal Nerve Fiber Layer Thickness (RNFLT)

Secondary: Change from baseline to month 12 and 24 in average Retinal Nerve Fiber Layer Thickness (RNFLT)

Secondary: Change from baseline to month 12 and 24 in average Retinal Nerve Fiber Layer Thickness (RNFLT)

Secondary: Change from baseline to month 12, 24 and 36 in average quadrant Retinal Nerve Fiber Layer Thickness (RNFLT)

Secondary: Change from baseline to month 12, 24 and 36 in average quadrant Retinal Nerve Fiber Layer Thickness (RNFLT)

Secondary: Change from baseline to month 12, 24 and 36 in Total Macular Volume (TMV)

Secondary: Change from baseline to month 12, 24 and 36 in Total Macular Volume (TMV)

Secondary: Change from baseline to month 12, 24 and 36 in Ganglion Cell Inner Plexiform (GCIP)

Secondary: Change from baseline to month 12, 24 and 36 in Ganglion Cell Inner Plexiform (GCIP)

Secondary: Number of participants with adverse events

Secondary: Number of participants with adverse events

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A 3-year multi-center study to describe the long term changes of optical coherence tomography (OCT) parameters in patients under treatment with Gilenya®