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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT00404352




Registration number
NCT00404352
Ethics application status
Date submitted
27/11/2006
Date registered
28/11/2006
Date last updated
24/01/2014

Titles & IDs
Public title
REbif FLEXible Dosing in Early Multiple Sclerosis (MS)
Scientific title
A Phase III, Randomized, Double-blind, Placebo-controlled, Multicenter Clinical Trial of Rebif New Formulation (44 Microgram [Mcg] Three Times Weekly [Tiw] and 44 Mcg Once Weekly [ow]) in Subjects at High Risk of Converting to Multiple Sclerosis (REFLEX)
Secondary ID [1] 0 0
2006-002982-38
Secondary ID [2] 0 0
IMP27025
Universal Trial Number (UTN)
Trial acronym
REFLEX
Linked study record

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

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

Active Comparator: RNF 44 mcg three times weekly -

Active Comparator: RNF 44 mcg once weekly and placebo twice weekly for blinding -

Placebo Comparator: Placebo three times weekly -


Treatment: Drugs: RNF
Single dose of RNF administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 microgram (mcg) for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 24 months, or 36 months for patients enrolled in the OL extension.

Treatment: Drugs: RNF
Single dose of RNF administered subcutaneously once weekly at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 24 months.

Treatment: Drugs: Placebo
Placebo was supplied as a transparent, sterile solution for injection in pre-filled syringes matching the RNF pre-filled syringes, each containing 0.5 mL.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Time to Conversion to Multiple Sclerosis (MS) According to the McDonald Criteria (2005) - The McDonald criteria use dissemination in time and space established by magnetic resonance image (MRI) findings to provide a clinical diagnosis for MS. Dissemination in time is established by a new time constant 2 (T2) or gadolinium-enhancing (Gd+) lesion found on a repeat MRI. Dissemination in space is established by the presence of any 3 of the following: 1 Gd+ lesion or 9 T2 bright lesions if there is no enhancement; greater than or equal to 1 infratentorial lesion; greater than or equal to 1 juxtacortical lesion; greater than or equal to 3 periventricular lesions.
Timepoint [1] 0 0
Various time points from randomization up to 24 months
Primary outcome [2] 0 0
Time to Conversion to Multiple Sclerosis (MS) According to the McDonald Criteria (2005) - The McDonald criteria use dissemination in time and space established by MRI findings to provide a clinical diagnosis for MS. Dissemination in time is established by a T2 or Gd+ lesion found on a repeat MRI. Dissemination in space is established by the presence of any 3 of the following: 1 Gd+ lesion or 9 T2 bright lesions if there is no enhancement; greater than or equal to 1 infratentorial lesion; greater than or equal to 1 juxtacortical lesion; greater than or equal to 3 periventricular lesions.
Timepoint [2] 0 0
Various time points from randomization up to 36 months
Secondary outcome [1] 0 0
Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) Defined by Either a Second Attack or a 3-Month Sustained Increase (Greater Than or Equal to 1.5 Points) in the Expanded Disability Status Scale (EDSS) Score - CDMS was defined by the occurrence of a second exacerbation or relapse over 24 months in participants who presented with first clinical demyelinating event (FCDE) accompanied by an abnormal MRI scan. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated.
Timepoint [1] 0 0
Various time points from randomization up to 24 months
Secondary outcome [2] 0 0
Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) Defined by Either a Second Attack or a 3-Month Sustained Increase (Greater Than or Equal to 1.5 Points) in the Expanded Disability Status Scale (EDSS) Score - CDMS was defined by the occurrence of a second exacerbation or relapse over 36 months in participants who presented with FCDE accompanied by an abnormal MRI scan. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated.
Timepoint [2] 0 0
Various time points from randomization up to 36 months
Secondary outcome [3] 0 0
Mean Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, Gadolinium Enhanced (Gd+) Lesions and New Time Constant 1 (T1) Hypointense Lesions Per Participant Per Scan - Number of CUA lesions, new T2 lesions, Gd+ lesions and new T1 hypointense lesions were measured by using MRI scans.
Timepoint [3] 0 0
Month 24 up to Month 36
Secondary outcome [4] 0 0
Change From Baseline in Time Constant 2 (T2) Lesion Volume , Time Constant 1 (T1) Hypointense Lesion Volume and Gadolinium Enhanced (Gd+) Lesion Volume at Month 36 - Change from baseline in lesion volume was measured by using MRI scans for T2 lesions, T1 hypointense lesions and (Gd+) lesions.
Timepoint [4] 0 0
Baseline, Month 36
Secondary outcome [5] 0 0
Change From Baseline in Expanded Disability Status Score (EDSS) Score at Month 36 - EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. The change in EDSS at Month 36 was calculated as EDSS at Month 36 minus EDSS at baseline.
Timepoint [5] 0 0
Baseline, Month 36

Eligibility
Key inclusion criteria
- Single, first clinical event suggestive of MS within 60 days prior to study Day 1,
which is the day of randomization (clock starts 24 hours after onset). The event must
be a new neurological abnormality present for at least 24 hours, either mono- or
polysymptomatic, other than a paresthesia, vegetative or cerebral dysfunction

- At least two clinically silent lesions on the T2-weighted MRI scan, with a size of at
least 3 millimeter (mm), at least one of which is ovoid or periventricular or
infratentorial

- EDSS 0 - 5.0 at least one time point during the screening period before start of
treatment

- 18 and 50 years old, inclusive

- Willing to follow study procedures

- Written informed consent

- If female, subject must:

- be neither pregnant nor breast-feeding nor attempting to conceive

- use a highly effective method of contraception. A highly effective method of
contraception is defined as those which result in a low failure rate (that is
[i.e.] less than 1 percent [%] per year) when used consistently and correctly
such as implants, injectables, combined oral contraceptives, some intrauterine
devices (IUDs), sexual abstinence or vasectomised partner
Minimum age
18 Years
Maximum age
50 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Diagnosis of MS (per McDonald criteria 2005)

- Any other disease that could better explain the subject's signs and symptoms

- Complete transverse myelitis or bilateral optic neuritis

- Subject uses or has used any other approved MS disease-modifying drug (DMD)

- Any investigational drug or undergone an experimental procedure within 12 weeks prior
to study Day 1

- Oral or systemic corticosteroids or adrenocorticotropic hormone (ACTH) within 30 days
prior to study Day 1

- Total bilirubin greater than 2.5 times upper limit of normal (ULN)

- Subject has total aspartate aminotransferase (AST) or alanine aminotransferase (ALT)
or alkaline phosphatase (ALP) greater than 2.5 times the ULN

- Inadequate bone marrow reserve, defined as a total white blood cell count less than
3.0 x 109 per liter (/L), platelet count less than 75 x 109/L, hemoglobin less than
100 gram per liter (g/L)

- Current autoimmune disease

- Major medical or psychiatric illness (including history of or current severe
depressive disorders and/or suicidal ideation) that in the opinion of the investigator
creates undue risk to the subject or could affect compliance with the study protocol

- History of seizures not adequately controlled by treatment

- Cardiac disease, such as angina, congestive heart failure or arrhythmia

- Known allergy to IFN-beta or the excipient(s) of the study medication

- Any condition that could interfere with the MRI evaluation;

- Known allergy to gadolinium-diethylene triamine pentaacetic acid (DTPA)

- Previously participated in this study

- Participated in any clinical trial within the past 6 months

- Any immunomodulatory or immunosuppressive therapy at any time prior to enrollment,
including, but not limited to, the following products: any IFN, glatiramer acetate
(Copolymer I), cyclophosphamide, cyclosporine, methotrexate, linomide, azathioprine,
mitoxantrone, teriflunomide, laquinimod, cladribine, total lymphoid irradiation,
anti-lymphocyte monoclonal antibody treatment (e.g. natalizumab, alemtuzumab/Campath,
anti-cluster of differentiation 4 [CD4]), intravenous, immunoglobulins (Igs),
cytokines or anti-cytokine therapy

- Any experimental MS treatment prior to trial entry, including, but not limited to, any
statins (if given to prevent MS) and pentoxyfylline

- History of alcohol or drug abuse

- Intolerance or any contraindication to both paracetamol (acetaminophen) and ibuprofen

- Inability to administer subcutaneous injections either by self or by caregiver

- Moderate to severe renal impairment

Study design
Purpose of the study
Prevention
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
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Research Site - Sydney
Recruitment postcode(s) [1] 0 0
- Sydney
Recruitment outside Australia
Country [1] 0 0
Argentina
State/province [1] 0 0
Mendoza
Country [2] 0 0
Austria
State/province [2] 0 0
Graz
Country [3] 0 0
Austria
State/province [3] 0 0
Innsbruck
Country [4] 0 0
Belgium
State/province [4] 0 0
B-Leuven
Country [5] 0 0
Belgium
State/province [5] 0 0
Brugge
Country [6] 0 0
Bulgaria
State/province [6] 0 0
Pleven
Country [7] 0 0
Bulgaria
State/province [7] 0 0
Rousse
Country [8] 0 0
Bulgaria
State/province [8] 0 0
Shumen
Country [9] 0 0
Bulgaria
State/province [9] 0 0
Sofia
Country [10] 0 0
Bulgaria
State/province [10] 0 0
Varna
Country [11] 0 0
Canada
State/province [11] 0 0
Montreal, Quebec
Country [12] 0 0
Canada
State/province [12] 0 0
Ontario
Country [13] 0 0
Canada
State/province [13] 0 0
Victoria British Columbia
Country [14] 0 0
Croatia
State/province [14] 0 0
Karlovac
Country [15] 0 0
Croatia
State/province [15] 0 0
Osijek
Country [16] 0 0
Croatia
State/province [16] 0 0
Rijeka
Country [17] 0 0
Croatia
State/province [17] 0 0
Split
Country [18] 0 0
Croatia
State/province [18] 0 0
Zagreb
Country [19] 0 0
Czech Republic
State/province [19] 0 0
Hradec Kralove
Country [20] 0 0
Czech Republic
State/province [20] 0 0
Olomouc
Country [21] 0 0
Czech Republic
State/province [21] 0 0
Prague
Country [22] 0 0
Estonia
State/province [22] 0 0
Tallinn
Country [23] 0 0
Estonia
State/province [23] 0 0
Tartu
Country [24] 0 0
Finland
State/province [24] 0 0
OYS
Country [25] 0 0
Finland
State/province [25] 0 0
Vantaa
Country [26] 0 0
France
State/province [26] 0 0
Paris
Country [27] 0 0
France
State/province [27] 0 0
Poissy Cedex
Country [28] 0 0
Germany
State/province [28] 0 0
Hannover
Country [29] 0 0
Germany
State/province [29] 0 0
Henningsdorf
Country [30] 0 0
Germany
State/province [30] 0 0
Munich
Country [31] 0 0
Greece
State/province [31] 0 0
Athens
Country [32] 0 0
Israel
State/province [32] 0 0
Ness Ziona
Country [33] 0 0
Israel
State/province [33] 0 0
Safed
Country [34] 0 0
Israel
State/province [34] 0 0
Tel-Hashomer
Country [35] 0 0
Italy
State/province [35] 0 0
Catania
Country [36] 0 0
Italy
State/province [36] 0 0
Milano
Country [37] 0 0
Italy
State/province [37] 0 0
Padova
Country [38] 0 0
Italy
State/province [38] 0 0
Roma
Country [39] 0 0
Latvia
State/province [39] 0 0
Riga
Country [40] 0 0
Lebanon
State/province [40] 0 0
Beirut
Country [41] 0 0
Morocco
State/province [41] 0 0
Rabat
Country [42] 0 0
Poland
State/province [42] 0 0
Bialystok
Country [43] 0 0
Poland
State/province [43] 0 0
Lodz
Country [44] 0 0
Poland
State/province [44] 0 0
Warsaw
Country [45] 0 0
Poland
State/province [45] 0 0
Wroclaw
Country [46] 0 0
Portugal
State/province [46] 0 0
Lisboa
Country [47] 0 0
Romania
State/province [47] 0 0
Bucharest
Country [48] 0 0
Romania
State/province [48] 0 0
Iasi
Country [49] 0 0
Romania
State/province [49] 0 0
Targu-Mures
Country [50] 0 0
Romania
State/province [50] 0 0
Timisoara
Country [51] 0 0
Russian Federation
State/province [51] 0 0
Ekaterinburg
Country [52] 0 0
Russian Federation
State/province [52] 0 0
Moscow
Country [53] 0 0
Russian Federation
State/province [53] 0 0
Nizhny Novgorod
Country [54] 0 0
Russian Federation
State/province [54] 0 0
Novosibirsk
Country [55] 0 0
Russian Federation
State/province [55] 0 0
Saint-Petersburg
Country [56] 0 0
Russian Federation
State/province [56] 0 0
Samara
Country [57] 0 0
Russian Federation
State/province [57] 0 0
Saratov
Country [58] 0 0
Saudi Arabia
State/province [58] 0 0
Riyadh
Country [59] 0 0
Serbia
State/province [59] 0 0
Belgrade
Country [60] 0 0
Serbia
State/province [60] 0 0
Nis
Country [61] 0 0
Slovakia
State/province [61] 0 0
Presov
Country [62] 0 0
Spain
State/province [62] 0 0
Barcelona
Country [63] 0 0
Spain
State/province [63] 0 0
Bilbao
Country [64] 0 0
Spain
State/province [64] 0 0
Madrid
Country [65] 0 0
Spain
State/province [65] 0 0
Sevilla
Country [66] 0 0
Turkey
State/province [66] 0 0
Istanbul

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Merck KGaA, Darmstadt, Germany
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
The study is a 24 months randomized, double-blind, Placebo-controlled, multi-center clinical
trial with an optional 12 months open label extension.

The primary objective of the study is to evaluate the effect of fetal bovine serum
[FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN] beta-1a (RNF) 44
microgram (three times weekly and once weekly) versus placebo on the time to conversion to
McDonald multiple sclerosis (MS) criteria (2005) in subjects with a first clinical
demyelinating event at high risk of converting to MS.

The main secondary objective of study is to evaluate the effect of RNF 44 microgram (three
times weekly and once weekly) versus placebo on the "Time to conversion to clinically
definite MS (CDMS)" in subjects with a first clinical demyelinating event at high risk of
converting to MS.

At the end of 24 month double-blind core REFLEX trial, subjects who will not convert to CDMS
and decide to receive open-label (OL) treatment will be enrolled into an open-label, 12 month
extension period to evaluate the effect of RNF 44 mcg three times weekly treatment on the
time to conversion to McDonald MS and time to conversion to CDMS.
Trial website
https://clinicaltrials.gov/show/NCT00404352
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Bettina M. Stubinski, MD
Address 0 0
Merck Serono S.A., Geneva
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
Other publications