A phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial of Rebif New Formulation (44 mcg tiw and 44 mcg ow) in subjects at high risk of converting to Multiple Sclerosis - Rebif FLEXible dosing in early Multiple Sclerosis (REFLEX)

• Register: EUCTR
• Last refreshed on: 3 December 2012
• Main ID: EUCTR2006-002982-38-DE
• Date of registration: 10/10/2006
• Prospective Registration: Yes
• Primary sponsor: Merck Serono S.A. - Geneva, an affiliate of Merck KGaA Darmstadt, Germany
• Public title: A phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial of Rebif New Formulation (44 mcg tiw and 44 mcg ow) in subjects at high risk of converting to Multiple Sclerosis - Rebif FLEXible dosing in early Multiple Sclerosis (REFLEX)
• Scientific title: A phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial of Rebif New Formulation (44 mcg tiw and 44 mcg ow) in subjects at high risk of converting to Multiple Sclerosis - Rebif FLEXible dosing in early Multiple Sclerosis (REFLEX)
• Date of first enrolment: 16/03/2007
• Target sample size: 480
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2006-002982-38
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Austria, Belgium, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Italy, Lithuania, Portugal, Spain

Key inclusion & exclusion criteria

Inclusion criteria:
· Subject with a single, first clinical event suggestive of MS within the last 60 days prior to SD1, which is the day of randomisation (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;
· Subject has at least two clinically silent lesions on the T2-weighted MRI scan, with a size of at least 3 mm, at least one of which is ovoid or periventricular or infratentorial;
· EDSS 0 - 5.0 at at least one time point during the screening period before start of treatment;
· Subject is between 18 and 50 years old, inclusive;
· Subject is willing to follow study procedures;
· Subject has given written informed consent;
· If female, subject must:
a) be neither pregnant nor breast-feeding nor attempting to conceive
b) use a highly effective method of contraception. A highly effective method of contraception is defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence or vasectomised partner.*

*Note for subjects using a hormonal contraceptive method: No formal drug interaction studies have been carried out with IFN-beta-1a or HSA free IFN beta 1a. As interferons have been reported to exert an inhibitory activity on hepatic microsomal enzymes, it is unlikely that the clearance of oral contraceptives would be increased and result in decreased efficacy. In over 10,000 patient-years of clinical trial experience with Rebif®, there has never been any indication of an interaction with oral contraceptives.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
· Subject has a diagnosis of Multiple Sclerosis (per McDonald criteria 2005);
· Subject has any other disease that could better explain the patient’s signs and symptoms;
· Subject has complete transverse myelitis or bilateral optic neuritis;
· Subject uses or has used any other approved MS DMD;
· Subject has used any investigational drug or undergone an experimental procedure within 12 weeks prior to SD1;
· Subject received oral or systemic corticosteroids or ACTH within 30 days prior to SD1;
· Subject has total bilirubin > 2.5x upper limit of normal,
· Subject has total aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or alkaline phosphatase > 2.5 times the upper limit of normal values;
· Subject has inadequate bone marrow reserve, defined as a total white blood cell count < 3.0 x 109/L, platelet count < 75 x 109/L, haemoglobin < 100 g/L.
· Subject suffers from current autoimmune disease;
· Subject suffers from major medical or psychiatric illness (including history of 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;
· Subject has a history of seizures not adequately controlled by treatment;
· Subject has cardiac disease, such as angina, congestive heart failure or arrhythmia;
· Subject has a known allergy to IFN-beta or the excipient(s) of the study medication;
· Subject has any condition that could interfere with the MRI evaluation;
· Subject has a known allergy to gadolinium-DTPA;
· Subject has previously participated in this study;
· Subject has participated in any clinical trial within the past 6 months prior to SD1;
· Subject has received any immunomodulatory or immunosuppressive therapy at any time prior to SD1, including, but not limited to, the following products: any interferon, 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-CD4), IvIg, cytokines or anti-cytokine therapy;· Subject has received any experimental MS treatment prior to SD1, including, but not limited to, any statins (if given to prevent MS) and pentoxyfilline;
· Subject has a history of alcohol or drug abuse;
· Subject has intolerance or any contraindication to both paracetamol (acetaminophen) and ibuprofen;
· Inability to administer subcutanteous injections either by self or by caregiver;
· Subject has moderate to severe renal impairment.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Subjects at high risk of converting to Multiple Sclerosis
MedDRA version: 9.0 Level: PT Classification code 10028245

Intervention(s)

Trade Name: Rebif
Product Name: Interferon-beta 1a FBS-free/HSA free, RNF
Product Code: Not Applicable
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Interferon-beta 1a
CAS Number: NA
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 44-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

Main Objective: The primary objective of the study is to evaluate the effect of Rebif New Formulation 44 mcg (tiw and ow) versus placebo on the "Time to conversion to McDonald MS" in subjects with a first clinical demyelinating event at high risk of converting to MS.

Primary end point(s): The primary endpoint is the time to conversion to MS (from randomization), according to the revised McDonald criteria (2005). Patients who do not convert are considered as censored for analysis.

Secondary Objective: The secondary objectives of the study include the assessment of secondary efficacy endpoints and safety:

The main secondary objective is to assess:
· The time to conversion to CDMS

Other secondary objectives are:
· Number of combined unique active MRI lesions
· Number of new T2 lesions
· Number of new T1 lesions
· Number of new Gd-enhancing lesions
· T2 lesion volume
· T1 hypointensive lesion volume
· T1 Gd-enhancing lesion volume
· Cognition by means of PASAT
· Relapse rate
· EDSS
· MSFC
· Development of BAbs and NAbs
· Safety, including AEs, SAEs and laboratory parameters

Secondary ID(s)

27025

2006-002982-38-BE