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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT00731692




Registration number
NCT00731692
Ethics application status
Date submitted
7/08/2008
Date registered
11/08/2008
Date last updated
14/06/2017

Titles & IDs
Public title
This Was an Open-label, Single-arm Extension Study (CFTY720D2306E1) to a Double-blind, Randomized Multicenter, Placebo-controlled, Parallel-group Core Study (CFTY720D2306) in PPMS.
Scientific title
A Double-blind, Randomized, Multicenter, Placebo-controlled, Parallel-group Study Comparing the Efficacy and Safety of 0.5mg Fingolimod Administered Orally Once Daily Versus Placebo in Patients With Primary Progressive Multiple Sclerosis and An Open-label, Single-arm Extension Study to the Double-blind, Randomized, Multicenter, Placebo-controlled, Parallel-group Study Comparing the Efficacy and Safety of0.5 mg FTY720 Administered Orally Once Daily Versus Placebo in Patients With Primary Progressive Multiple Sclerosis
Secondary ID [1] 0 0
2007-002627-32
Secondary ID [2] 0 0
CFTY720D2306
Universal Trial Number (UTN)
Trial acronym
INFORMS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Primary Progressive Multiple Sclerosis 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - FTY720
Treatment: Drugs - Placebo

Experimental: FTY720D 0.5 mg - Cohort 2: The 0.5 mg group consists of patients who were directly randomized to fingolimod 0.5 mg (i.e. AFTER the amendment

Placebo comparator: Placebo - Cohort 1 and 2: Patients randomized to placebo continued on placebo after re-randomization

Experimental: FTY720D 1.25 mg switch to 0.5 mg - Cohort 1: fingolimod 1.25 group consists of patients who were initially randomized to fingolimod 1.25 mg and switched to fingolimod 0.5 mg after amendment on Nov 2009


Treatment: Drugs: FTY720
Fingolimod capsules at doses of 1.25 mg (prior to implementation of Amendment 5) and 0.5 mg (after Amendment 5) were administered orally once daily

Treatment: Drugs: Placebo
Matching placebo capsules were administered orally once daily
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Kaplan-Meier Estimate of the Risk of 3-month Confirmed Disability Progression Based on Composite Endpoint
Timepoint [1] 0 0
up to 36 months after the last patient was randomized
Secondary outcome [1] 0 0
Kaplan-Meier Estimate of the Risk of 3- Month Confirmed Disability Progression Based on Expanded Disability Status Scale (EDSS)
Timepoint [1] 0 0
up to 36 months after the last patient was randomized
Secondary outcome [2] 0 0
Percent Change From Baseline in Brain Volume at Month 36
Timepoint [2] 0 0
Baseline to month 36
Secondary outcome [3] 0 0
Kaplan Meier Estimate -Percentage of Participants With 3- Month Confirmed Disability Progression Based on 9-HPT.
Timepoint [3] 0 0
up to 36 months after the last patient was randomized
Secondary outcome [4] 0 0
Kaplan Meier Estimate -Percentage of Participants With 3- Month Confirmed Disability Progression Based on 25' TWT.
Timepoint [4] 0 0
up to 36 months after the last patient was randomized
Secondary outcome [5] 0 0
Number of New/Enlarging T2 Lesions Per Year Measured From Baseline to Month 36
Timepoint [5] 0 0
Baseline to 36 months
Secondary outcome [6] 0 0
Number of Gd-enhancing Lesions at Month 36
Timepoint [6] 0 0
Baseline to 36 months
Secondary outcome [7] 0 0
Percent Change in Total T2 Lesion Volume From Baseline to Month 36
Timepoint [7] 0 0
Baseline to month 36
Secondary outcome [8] 0 0
Change From Baseline in the Patient Reported Indices in Multiple Sclerosis (PRIMUS-QoL Score)
Timepoint [8] 0 0
Baseline, 36 months
Secondary outcome [9] 0 0
Change From Baseline in PRIMUS-Activities
Timepoint [9] 0 0
Baseline, 36 months
Secondary outcome [10] 0 0
Change From Baseline in Unidimensional Fatigue Impact (U-FIS) Score
Timepoint [10] 0 0
Baseline, 36 months
Secondary outcome [11] 0 0
Change From Baseline in European Quality of Life - 5 Dimensions (EQ-5D Score)
Timepoint [11] 0 0
Baseline, 36 months
Secondary outcome [12] 0 0
Change From Baseline in Multiple Sclerosis Walking Scale (MSWS-12 Score)
Timepoint [12] 0 0
Baseline, 36 months
Secondary outcome [13] 0 0
Blood Concentrations of Fingolimod and Fingolimod-phosphate
Timepoint [13] 0 0
Month 3 up to 36 months
Secondary outcome [14] 0 0
Change in MSFC Z-score and Subscale Scores From Baseline to Month 36
Timepoint [14] 0 0
Baseline to Month 36

Eligibility
Key inclusion criteria
General

1. sign written informed consent prior to participating in the study
2. 25 through 65 years of age inclusive
3. females of childbearing potential must:

* have a negative pregnancy test at Baseline (prior to randomization) and
* use simultaneously two forms of effective contraception during the treatment and 3-months after discontinuation of study medication

Primary Progressive Multiple sclerosis.

1. diagnosis of primary progressive multiple sclerosis (according to the 2005 Revised McDonald criteria):
2. time since first reported symptoms between 2 and 10 years
3. evidence of clinical disability progression in the 2 years prior to Screening
4. disability status at Screening

* EDSS score of 3.5-6.0 inclusive
* pyramidal functional system score of 2 or more
* 25'TWT less than 30 seconds

Extension study Inclusion criteria

* Patients initially randomized to fingolimod 1.25 mg or placebo as part of the first study cohort, were to have completed at least 3 years on study drug treatment at the time of extension study initiation.
* Patients initially randomized to fingolimod 0.5 mg or placebo as part of the second study cohort, were to have continued on study drug treatment until such time as the last ongoing patient enrolled in the study had reached 3 years in study
Minimum age
25 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
PPMS specific:

* History of relapses/attacks
* Progressive neurological disorder other than PPMS
* Pure cerebellar syndrome or pure visual progressive syndrome or pure
* cognitive progressive syndrome
* Presence of spinal cord compression at screening MRI
* Relevant history of vitamin B12 deficit
* Evidence of syphilis or borreliosis at Screening

Cardiovascular conditions:

* Myocardial infarction within the past 6 months or current unstable ischemic heart disease
* History of angina pectoris due to coronary spasm or history of Raynaud's phenomenon
* Severe cardiac failure or cardiac arrest
* History of symptomatic bradycardia
* Resting pulse <55 bpm pre-dose
* History of sick sinus syndrome or sino-atrial heart block
* History or presence of second and third degree AV block or an increase QT interval (QTc>440 ms)
* Arrythmia requiring treatment with class III antiarrythmic drugs
* History of positive tilt test from workout of vasovagal syncope
* Hypertension, not controlled with medication

Pulmonary:

* Severe respiratory disease or pulmonary fibrosis
* TB
* Abnormal X-ray, suggestive of active pulmonary disease
* Abnormal PFT: <70% of predicted for FEV1 and FVC; <60% for DLCO
* Patients receiving chronic (daily) therapies for asthma

Hepatic:

* Known history of alcohol abuse, chronic liver or biliary disease
* Total or conjugated Brb >ULN, unless in context of Gilbert's syndrome
* AP >1.5xULN; ALT/AST >2xULN; GGT>3xULN

Other:

* History of chronic disease of the immune system other than MS
* Malignancy (other than successfully treated SCC or BCC)
* Diabetes Mellitus
* Macular Edema present at screening
* HIV, Hepatitis C or B, other active infection
* History of total lymphoid irradiation or bone marrow transplantation
* Serum creatinine >1.7 mg/dl
* WBC <3500 cells/mm3
* Lymphocyte count <800 cells/mm3
* History of substance abuse or any other factor that may interfere with subject ability to cooperate and comply with the study procedures
* Unable to undergo MRI scans
* Participation in any therapeutical clinical research study in the 6 months prior to randomization
* Pregnant or lactating women
* Drugs requiring wash-out period:

3 months:
* Systemic corticosteroids or ACTH
* INF-beta

6 months:
* Immunosuppressive medication
* Immunoglobulins
* Monoclonal antibodies
* Drugs that exclude participation in the study:
* Cladribine
* Cyclophosphamide
* Mitoxantrone (except: patients who received a cumulative dose of no more than 60mg/m2 more than 5 years ago could enter the study)

Extension study Exclusion criteria

-Patients were not eligible for enrollment in the extension study if they had any of the following key exclusion criteria at the extension study Baseline visit: active chronic immune system disease other than MS (or stable disease treated with immune therapy); known immunodeficiency syndrome; active infection; uncontrolled diabetes mellitus; macularedema; treatment with Class Ia or III antiarrhythmic drugs; any of the specified cardiac, pulmonary, or hepatic conditions; or any medically unstable condition

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
28/07/2008
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
22/06/2015
Sample size
Target
Accrual to date
Final
970
Recruitment in Australia
Recruitment state(s)
NSW,TAS,VIC
Recruitment hospital [1] 0 0
Novartis Investigative Site - Camperdown
Recruitment hospital [2] 0 0
Novartis Investigative Site - Liverpool
Recruitment hospital [3] 0 0
Novartis Investigative Site - Hobart
Recruitment hospital [4] 0 0
Novartis Investigative Site - Box Hill
Recruitment hospital [5] 0 0
Novartis Investigative Site - Heidelberg
Recruitment hospital [6] 0 0
Novartis Investigative Site - Parkville
Recruitment postcode(s) [1] 0 0
2050 - Camperdown
Recruitment postcode(s) [2] 0 0
2170 - Liverpool
Recruitment postcode(s) [3] 0 0
7000 - Hobart
Recruitment postcode(s) [4] 0 0
3128 - Box Hill
Recruitment postcode(s) [5] 0 0
3084 - Heidelberg
Recruitment postcode(s) [6] 0 0
3050 - Parkville
Recruitment outside Australia
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United States of America
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California
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Colorado
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Wisconsin
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Belgium
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Charleroi
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Edegem
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TO
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Amsterdam
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Lodz
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Lublin
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Spain
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Catalunya
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Comunidad Valenciana
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Madrid
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Pais Vasco
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Sweden
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Goeteborg
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Stockholm
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Basel
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Switzerland
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Bern
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Lausanne
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Lugano
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Switzerland
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Zuerich
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Turkey
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Ankara
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Atakum / Samsun
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Balcova / Izmir
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Istanbul
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Yenisehir / Izmir
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United Kingdom
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Manchester
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South Yorkshire
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Bristol
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London
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Newcastle Upon Tyne
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United Kingdom
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Norwich

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Novartis Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
The purpose of this study is to evaluate whether FTY720 is effective in delaying MS disability progression compared to placebo in patients with PPMS. This was an open-label, single-arm extension study to a double-blind, randomized multicenter, placebo-controlled, parallel-group core study. The core study completed and eligible patients enrolled into the extension study at the next scheduled or unscheduled core study visit. All patients, regardless of their treatment in the core study, received fingolimod 0.5 mg in the extension study. The extension study was terminated early after the results of the core study became available showing that the study did not meet its primary endpoint which was defined as confirmed disability progression in this population
Trial website
https://clinicaltrials.gov/study/NCT00731692
Trial related presentations / publications
Leppert D, Kropshofer H, Haring DA, Dahlke F, Patil A, Meinert R, Tomic D, Kappos L, Kuhle J. Blood Neurofilament Light in Progressive Multiple Sclerosis: Post Hoc Analysis of 2 Randomized Controlled Trials. Neurology. 2022 May 24;98(21):e2120-e2131. doi: 10.1212/WNL.0000000000200258. Epub 2022 Apr 4.
Koch MW, Mostert J, Repovic P, Bowen JD, Strijbis E, Uitdehaag B, Cutter G. Smoking, obesity, and disability worsening in PPMS: an analysis of the INFORMS original trial dataset. J Neurol. 2022 Mar;269(3):1663-1669. doi: 10.1007/s00415-021-10750-z. Epub 2021 Aug 15.
Koch MW, Mostert J, Zhang Y, Wolinsky JS, Lublin FD, Strijbis E, Cutter G. Association of Age With Contrast-Enhancing Lesions Across the Multiple Sclerosis Disease Spectrum. Neurology. 2021 Sep 28;97(13):e1334-e1342. doi: 10.1212/WNL.0000000000012603. Epub 2021 Aug 10.
Miller DH, Lublin FD, Sormani MP, Kappos L, Yaldizli O, Freedman MS, Cree BAC, Weiner HL, Lubetzki C, Hartung HP, Montalban X, Uitdehaag BMJ, MacManus DG, Yousry TA, Gandini Wheeler-Kingshott CAM, Li B, Putzki N, Merschhemke M, Haring DA, Wolinsky JS. Brain atrophy and disability worsening in primary progressive multiple sclerosis: insights from the INFORMS study. Ann Clin Transl Neurol. 2018 Jan 30;5(3):346-356. doi: 10.1002/acn3.534. eCollection 2018 Mar.
Lublin F, Miller DH, Freedman MS, Cree BAC, Wolinsky JS, Weiner H, Lubetzki C, Hartung HP, Montalban X, Uitdehaag BMJ, Merschhemke M, Li B, Putzki N, Liu FC, Haring DA, Kappos L; INFORMS study investigators. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2016 Mar 12;387(10023):1075-1084. doi: 10.1016/S0140-6736(15)01314-8. Epub 2016 Jan 28. Erratum In: Lancet. 2017 Jan 21;389(10066):254. doi: 10.1016/S0140-6736(17)30042-9.
Hartung HP, Aktas O. Bleak prospects for primary progressive multiple sclerosis therapy: downs and downs, but a glimmer of hope. Ann Neurol. 2009 Oct;66(4):429-32. doi: 10.1002/ana.21880. No abstract available.
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT00731692