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

A 3-year Multi-center Study to Describe the Long Term Changes of Optical Coherence Tomography (OCT) Parameters in Patients Under Treatment With Gilenya®

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.

Study Overview

• Status: Completed
• Conditions: Relapsing Remitting Multiple Sclerosis RRMS
• Intervention / Treatment: Drug: Fingolimod

• Study Type: Interventional
• Enrollment (Actual): 87
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Bochum, Germany, 44791
    • Novartis Investigative Site
  • Bonn, Germany, 53105
    • Novartis Investigative Site
  • Dresden, Germany, 01307
    • Novartis Investigative Site
  • Duesseldorf, Germany, 40225
    • Novartis Investigative Site
  • Hannover, Germany, 30625
    • Novartis Investigative Site
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Leipzig, Germany, 04103
    • Novartis Investigative Site
  • Rostock, Germany, 18057
    • Novartis Investigative Site
  • Ulm, Germany, 89081
    • Novartis Investigative Site
• Switzerland
  • Zuerich, Switzerland, 8091
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

3. 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
4. Patients with severe respiratory disease, pulmonary fibrosis, or chronic obstructive pulmonary disease (Class III-IV).
5. 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)
6. Any severe disability or clinical impairment that can prevent the patient to meet all study requirements at the investigator's discretion
7. 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
8. Patients who have received an investigational drug (excluding fingolimod) or therapy within 90 days or 5 half-lives of screening, whichever is longer.
9. 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)
10. 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

11. history or presence of severe myopia

    1. in patients who have not had refractive surgery, a refractive error of greater than 6.00 diopters
    2. pathologic fundus changes of high myopia, such as retinal pigmentary atrophy, besides peripapillary atrophy (atrophy involving the macula) or a staphyloma
    3. 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.)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Month 12 and 24 in Average Retinal Nerve Fiber Layer Thickness (RNFLT)	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).	Baseline, month 12, month 24
Change From Baseline to Month 12, 24 and 36 in Average Quadrant Retinal Nerve Fiber Layer Thickness (RNFLT)	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.	Baseline, month 12, month 24, month 36
Change From Baseline to Month 12, 24 and 36 in Total Macular Volume (TMV)	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).	12, 24 and 36 months
Change From Baseline to Month 12, 24 and 36 in Ganglion Cell Inner Plexiform (GCIP)	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.	Baseline, month 12, month 24, month 36
Number of Participants With Adverse Events	Number of participants with adverse events and specifically macular edema.	36 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 20, 2012
• Primary Completion (ACTUAL): February 18, 2019
• Study Completion (ACTUAL): February 18, 2019

Study Registration Dates

• First Submitted: August 13, 2012
• First Submitted That Met QC Criteria: October 11, 2012
• First Posted (ESTIMATE): October 12, 2012

Study Record Updates

• Last Update Posted (ACTUAL): March 2, 2020
• Last Update Submitted That Met QC Criteria: February 14, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Multiple sclerosis (MS); MS
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Sphingosine 1 Phosphate Receptor Modulators; Fingolimod Hydrochloride
• Other Study ID Numbers: CFTY720DDE15TS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

Drug and device information, study documents

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