PASSOS: A 3-year Multi-center Study to Describe Changes of OCT Parameters Under Treatment With Gilenya®

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01705236
• Collaborator: (none)
• Enrollment: 87
• Locations: 10
• Arm: 1
• Actual Duration (Months): 78
• Patients Per Site: 8.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This was a 3-year, prospective, multi-center, open-label study to describe the long term changes of optical coherence tomography (OCT) parameters in RRMS patients under treatment with Fingolimod. It was designed to longitudinally study the degeneration of retinal axons by measuring change in RNFL thickness by latest OCT-technology.

Condition or Disease	Intervention/Treatment	Phase
Relapsing Remitting Multiple Sclerosis RRMS	Drug: Fingolimod	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 87 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: A 3-year Multi-center Study to Describe the Long Term Changes of Optical Coherence Tomography (OCT) Parameters in Patients Under Treatment With Gilenya®
• Actual Study Start Date: Aug 20, 2012
• Actual Primary Completion Date: Feb 18, 2019
• Actual Study Completion Date: Feb 18, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Fingolimod - Longitudinal Assessment No study drug was provided. Fingolimod was to be prescribed according to local label. The decision to prescribe fingolimod had to be made independent of this study.	Drug: Fingolimod; All subjects received an oral dose of 0.5 mg fingolimod (FTY720) per capsule (hard gelatin capsules) once daily according to local label for the treatment of their MS.; Other Names: FTY720

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Month 36 in Average Retinal Nerve Fiber Layer Thickness (RNFLT) [Baseline, month 36]

   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).

Secondary Outcome Measures

1. Change From Baseline to Month 12 and 24 in Average Retinal Nerve Fiber Layer Thickness (RNFLT) [Baseline, month 12, month 24]

   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).

2. Change From Baseline to Month 12, 24 and 36 in Average Quadrant Retinal Nerve Fiber Layer Thickness (RNFLT) [Baseline, month 12, month 24, month 36]

   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.

3. Change From Baseline to Month 12, 24 and 36 in Total Macular Volume (TMV) [12, 24 and 36 months]

   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).

4. Change From Baseline to Month 12, 24 and 36 in Ganglion Cell Inner Plexiform (GCIP) [Baseline, month 12, month 24, month 36]

   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.

5. Number of Participants With Adverse Events [36 months]

   Number of participants with adverse events and specifically macular edema.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

Patients eligible for inclusion in this study have to fulfill all of the following criteria:

1. Written informed consent must be obtained before any assessment is performed.

2. Male or female subjects aged 18-65 years.

3. Subjects with relapsing remitting MS defined by 2010 revised McDonald criteria (see Appendix 4).

4. Patients with Expanded Disability Status Scale (EDSS) score of 0-6.0 inclusive (see Appendix 6).

5. Patients stable on immunomodulatory treatment with fingolimod for at least 1 month and at most 4 months prior to screening according to local label

6. Neurologically stable with no evidence of relapse within 30 days prior to inclusion date

7. Sufficient ability to read, write, communicate and understand

Exclusion Criteria

Patients fulfilling any of the following criteria are not eligible for inclusion in this study:

1. Patients who have been treated with:

• systemic corticosteroids or immunoglobulins within 1 month prior to screening;

• immunosuppressive medications such as azathioprine, cyclophosphamide, or methotrexate within 3 months prior to screening;

• monoclonal antibodies (including natalizumab) within 3 months prior to screening;

• mitoxantrone within 6 months prior to screening

• cladribine at any time.

1. Patients with any medically unstable condition, as assessed by the primary treating physician at each site.

2. Patients with any of the following cardiovascular conditions :

• history of myocardial infarction or with current unstable ischemic heart disease;

• Heart failure (NYHA III-IV) or any severe cardiac disease as determined by the Investigator (see Appendix 5);

• history or presence of a second-degree AV block, Type II or a third-degree AV block

• patients receiving Class Ia (ajmaline, disopyramide, procainamide, quinidine) or III antiarrhythmic drugs (e.g., amiodarone, bretylium, sotalol, ibulitide, azimilide, dofelitide);

• proven history of sick sinus syndrome;

• uncontrolled hypertension

1. Patients with severe respiratory disease, pulmonary fibrosis, or chronic obstructive pulmonary disease (Class III-IV).

2. Patients with history of specific MRI findings (tumor, subdural haematoma, post-contusional changes, territorial stroke, neurodegenerative disorders, aneurysm/arteriovenous malformation, evidence of past macroscopic haemorrhage, or other relevant MRI findings that would interfere with evaluation)

3. Any severe disability or clinical impairment that can prevent the patient to meet all study requirements at the investigator's discretion

4. History of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin

5. Patients who have received an investigational drug (excluding fingolimod) or therapy within 90 days or 5 half-lives of screening, whichever is longer.

6. 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 hCG test (serum)

7. Patients with any ophthalmologic reason for RNFL pathology other than MS, such as: optic neuropathy, active advanced glaucoma, injury of the optic nerve based on the ophthalmologist's clinical judgment

8. history or presence of severe myopia

9. in patients who have not had refractive surgery, a refractive error of greater than 6.00 diopters

10. pathologic fundus changes of high myopia, such as retinal pigmentary atrophy, besides peripapillary atrophy (atrophy involving the macula) or a staphyloma

11. in patients that have had previous refractive surgery, an axial eye length of greater than 26 mm

12. Acute optic neuritis within the past 6 months before screening

13. Evidence of advanced, non-proliferative or proliferative diabetic retinopathy

14. Presence of retinal conditions associated with edema, subretinal fluid, cysts, etc.

15. Concomitant use of drugs that may directly affect retinal structure and function (e.g.

chronic systemic corticosteroids [>30 consecutive days; doses higher than Cushing threshold e.g. prednisone 7.5mg/d], intraocular anti-angiogenic drugs [ranibizumab, bevacizumab], intraocular steroids etc.)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Bochum		Germany	44791
2	Novartis Investigative Site	Bonn		Germany	53105
3	Novartis Investigative Site	Dresden		Germany	01307
4	Novartis Investigative Site	Duesseldorf		Germany	40225
5	Novartis Investigative Site	Hannover		Germany	30625
6	Novartis Investigative Site	Heidelberg		Germany	69120
7	Novartis Investigative Site	Leipzig		Germany	04103
8	Novartis Investigative Site	Rostock		Germany	18057
9	Novartis Investigative Site	Ulm		Germany	89081
10	Novartis Investigative Site	Zuerich		Switzerland	8091

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Statistical Analysis Plan - Mar 26, 2019
• Study Protocol - Jul 26, 2016

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01705236
• Other Study ID Numbers: CFTY720DDE15TS
• First Posted: Oct 12, 2012
• Last Update Posted: Mar 2, 2020
• Last Verified: Feb 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Multiple sclerosis (MS); MS
• Additional relevant MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis; Fingolimod Hydrochloride

Study Results

Participant Flow

Recruitment Details	Subjects were screened at 10 study centers in Germany (9 centers) and Switzerland (1 center).
Pre-assignment Detail	Subjects who passed the screening were enrolled in the trial.

Arm/Group Title	Fingolimod - Longitudinal Assessment
Arm/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.
Period Title: Overall Study
STARTED	87
COMPLETED	60
NOT COMPLETED	27

Baseline Characteristics

Arm/Group Title	Fingolimod - Longitudinal Assessment
Arm/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.
Overall Participants	87
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	35.9 (9.5)
Sex: Female, Male (Count of Participants)
Female	55 63.2%
Male	32 36.8%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	84 96.6%
Other	3 3.4%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Month 36 in Average Retinal Nerve Fiber Layer Thickness (RNFLT)
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).
Time Frame	Baseline, month 36

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS). The FAS consisted of all subjects treated with fingolimod who had at least one post-baseline efficacy assessment.

Arm/Group Title	Fingolimod - Longitudinal Assessment
Arm/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.
Measure Participants	72
Mean (Standard Deviation) [micrometer]	-1.5 (2.7)

2. Secondary Outcome

Title	Change From Baseline to Month 12 and 24 in Average Retinal Nerve Fiber Layer Thickness (RNFLT)
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).
Time Frame	Baseline, month 12, month 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS). The FAS consisted of all subjects treated with fingolimod who had at least one post-baseline efficacy assessment.

Arm/Group Title	Fingolimod - Longitudinal Assessment
Arm/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.
Measure Participants	72
Change from baseline to month 12	-0.8 (2.4)
Change from baseline to month 24	-1.1 (2.4)

3. Secondary Outcome

Title	Change From Baseline to Month 12, 24 and 36 in Average Quadrant Retinal Nerve Fiber Layer Thickness (RNFLT)
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.
Time Frame	Baseline, month 12, month 24, month 36

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS). The FAS consisted of all subjects treated with fingolimod who had at least one post-baseline efficacy assessment.

Arm/Group Title	Fingolimod - Longitudinal Assessment
Arm/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.
Measure Participants	72
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)

4. Secondary Outcome

Title	Change From Baseline to Month 12, 24 and 36 in Total Macular Volume (TMV)
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).
Time Frame	12, 24 and 36 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS). The FAS consisted of all subjects treated with fingolimod who had at least one post-baseline efficacy assessment.

Arm/Group Title	Fingolimod - Longitudinal Assessment
Arm/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.
Measure Participants	72
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)

5. Secondary Outcome

Title	Change From Baseline to Month 12, 24 and 36 in Ganglion Cell Inner Plexiform (GCIP)
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.
Time Frame	Baseline, month 12, month 24, month 36

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS). The FAS consisted of all subjects treated with fingolimod who had at least one post-baseline efficacy assessment.

Arm/Group Title	Fingolimod - Longitudinal Assessment
Arm/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.
Measure Participants	72
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)

6. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	Number of participants with adverse events and specifically macular edema.
Time Frame	36 months

Outcome Measure Data

Analysis Population Description

Safety Population (SAF). The SAF consisted of all subjects treated with fingolimod for whom safety information had been collected.

Arm/Group Title	Fingolimod - Longitudinal Assessment
Arm/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.
Measure Participants	87
No. of subjects with any AE	80 92%
No. of subjects with macular edema	0 0%

Adverse Events

Time Frame	Adverse events were collected from first dose of study treatment until end of study treatment up to maximum duration of 36 months
Arm/Group Title	Fingolimod - Longitudinal Assessment
Arm/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.
All Cause Mortality
	Fingolimod - Longitudinal Assessment
	Affected / at Risk (%)	# Events
Total	0/87 (0%)
Serious Adverse Events
	Fingolimod - Longitudinal Assessment
	Affected / at Risk (%)	# Events
Total	11/87 (12.6%)
Cardiac disorders
AORTIC VALVE INCOMPETENCE	1/87 (1.1%)
Infections and infestations
ERYSIPELAS	1/87 (1.1%)
GASTROENTERITIS VIRAL	1/87 (1.1%)
OPHTHALMIC HERPES ZOSTER	1/87 (1.1%)
WOUND INFECTION	1/87 (1.1%)
Injury, poisoning and procedural complications
LOWER LIMB FRACTURE	1/87 (1.1%)
RADIUS FRACTURE	1/87 (1.1%)
SUTURE RELATED COMPLICATION	1/87 (1.1%)
Musculoskeletal and connective tissue disorders
INTERVERTEBRAL DISC PROTRUSION	1/87 (1.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
CERVIX CARCINOMA STAGE 0	1/87 (1.1%)
NASAL NEOPLASM	1/87 (1.1%)
UTERINE LEIOMYOMA	1/87 (1.1%)
Nervous system disorders
MULTIPLE SCLEROSIS RELAPSE	2/87 (2.3%)
NEURALGIC AMYOTROPHY	1/87 (1.1%)
UHTHOFF'S PHENOMENON	1/87 (1.1%)
Reproductive system and breast disorders
CERVICAL DYSPLASIA	1/87 (1.1%)
Other (Not Including Serious) Adverse Events
	Fingolimod - Longitudinal Assessment
	Affected / at Risk (%)	# Events
Total	68/87 (78.2%)
Blood and lymphatic system disorders
LYMPHOPENIA	9/87 (10.3%)
Gastrointestinal disorders
DIARRHOEA	6/87 (6.9%)
Infections and infestations
BRONCHITIS	6/87 (6.9%)
CONJUNCTIVITIS	5/87 (5.7%)
NASOPHARYNGITIS	41/87 (47.1%)
SINUSITIS	6/87 (6.9%)
UPPER RESPIRATORY TRACT INFECTION	7/87 (8%)
URINARY TRACT INFECTION	7/87 (8%)
Metabolism and nutrition disorders
VITAMIN D DEFICIENCY	8/87 (9.2%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	5/87 (5.7%)
BACK PAIN	7/87 (8%)
Nervous system disorders
DIZZINESS	5/87 (5.7%)
HEADACHE	10/87 (11.5%)
MULTIPLE SCLEROSIS RELAPSE	21/87 (24.1%)
PARAESTHESIA	5/87 (5.7%)
Psychiatric disorders
DEPRESSION	5/87 (5.7%)
Respiratory, thoracic and mediastinal disorders
COUGH	6/87 (6.9%)
Skin and subcutaneous tissue disorders
ALOPECIA	5/87 (5.7%)
Vascular disorders
HYPERTENSION	12/87 (13.8%)

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.