REbif FLEXible Dosing in Early Multiple Sclerosis (MS)

Multiple Sclerosis Clinical Trial

— REFLEX  

Official 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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00404352
• Other study ID #: IMP27025
• Secondary ID: 2006-002982-38
• Status: Completed
• Phase: Phase 3
• First received: November 27, 2006
• Last updated: December 18, 2013
• Start date: November 2006
• Est. completion date: July 2011

Study information

• Verified date: December 2013
• Source: Merck KGaA
• Contact: n/a
• Is FDA regulated: No
• Health authority: Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia MedicaAustralia: Department of Health and Ageing Therapeutic Goods AdministrationAustralia: Human Research Ethics CommitteeAustria: Agency for Health and Food SafetyAustria: EthikkommissionBelgium: The Federal Public Service (FPS) Health, Food Chain Safety and EnvironmentBulgaria: Bulgarian Drug AgencyBulgaria: Ministry of HealthCanada: Canadian Institutes of Health ResearchCroatia: Ministry of Health and Social CareCzech Republic: Ethics CommitteeCzech Republic: State Institute for Drug ControlDenmark: Danish Dataprotection AgencyDenmark: Danish Medicines AgencyDenmark: Ethics CommitteeEstonia: The State Agency of MedicineFinland: Ethics CommitteeFinland: Finnish Medicines AgencyFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)France: Ministry of HealthFrance: National Consultative Ethics Committee for Health and Life SciencesGermany: Federal Institute for Drugs and Medical DevicesGermany: Ministry of HealthGreece: Ministry of Health and WelfareHungary: National Institute of PharmacyIsrael: Ministry of HealthItaly: Ethics CommitteeLatvia: State Agency of MedicinesLithuania: Bioethics CommitteeLithuania: State Medicine Control Agency - Ministry of HealthMacedonia: Ethics CommitteeMorocco: Ministry of Public HealthNetherlands: The Central Committee on Research Involving Human Subjects (CCMO)Poland: Ministry of HealthPoland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsRomania: Ministry of Public HealthRomania: National Medicines AgencyRussia: Ethics CommitteeRussia: Ministry of Health of the Russian FederationSerbia and Montenegro: Agency for Drugs and Medicinal DevicesSerbia: Ethics CommitteeSlovakia: State Institute for Drug ControlSpain: Comité Ético de Investigación ClínicaSpain: Ministry of HealthSwitzerland: EthikkommissionSwitzerland: SwissmedicTurkey: Ethics CommitteeTurkey: Ministry of Health
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 517
• Est. completion date: July 2011
• Est. primary completion date: August 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 50 Years

Eligibility

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

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

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Multiple Sclerosis
• Sclerosis

Intervention

Drug:
• 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.
• 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.
• 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.

Locations

Country	Name	City	State
Argentina	Research Site	Mendoza
Australia	Research Site	Sydney
Austria	Research Site	Graz
Austria	Research Site	Innsbruck
Belgium	Research Site	B-Leuven
Belgium	Research Site	Brugge
Bulgaria	Research Site	Pleven
Bulgaria	Research Site	Rousse
Bulgaria	Research Site	Shumen
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Varna
Canada	Research Site	Montreal, Quebec
Canada	Research Site	Ontario
Canada	Research Site	Victoria British Columbia
Croatia	Research Site	Karlovac
Croatia	Research Site	Osijek
Croatia	Research Site	Rijeka
Croatia	Research Site	Split
Croatia	Research Site	Zagreb
Czech Republic	Research Site	Hradec Kralove
Czech Republic	Research Site	Olomouc
Czech Republic	Research Site	Prague
Estonia	Research Site	Tallinn
Estonia	Research Site	Tartu
Finland	Research Site	OYS
Finland	Research Site	Vantaa
France	Research Site	Paris
France	Research Site	Poissy Cedex
Germany	Research Site	Hannover
Germany	Research Site	Henningsdorf
Germany	Research Site	Munich
Greece	Research Site	Athens
Israel	Research Site	Ness Ziona
Israel	Research Site	Safed
Israel	Research Site	Tel-Hashomer
Italy	Research Site	Catania
Italy	Research Site	Milano
Italy	Research Site	Padova
Italy	Research Site	Roma
Latvia	Research Site	Riga
Lebanon	Research Site	Beirut
Morocco	Research Site	Rabat
Poland	Research Site	Bialystok
Poland	Research Site	Lodz
Poland	Research Site	Warsaw
Poland	Research Site	Wroclaw
Portugal	Research Site	Lisboa
Romania	Research Site	Bucharest
Romania	Research Site	Iasi
Romania	Research Site	Targu-Mures
Romania	Research Site	Timisoara
Russian Federation	Research Site	Ekaterinburg
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Nizhny Novgorod
Russian Federation	Research Site	Novosibirsk
Russian Federation	Research Site	Saint-Petersburg
Russian Federation	Research Site	Samara
Russian Federation	Research Site	Saratov
Saudi Arabia	Research Site	Riyadh
Serbia	Research Site	Belgrade
Serbia	Research Site	Nis
Slovakia	Research Site	Presov
Spain	Research Site	Barcelona
Spain	Research Site	Bilbao
Spain	Research Site	Madrid
Spain	Research Site	Sevilla
Turkey	Research Site	Istanbul

Sponsors (1)

Lead Sponsor	Collaborator
Merck KGaA

Countries where clinical trial is conducted

Argentina,  Australia,  Austria,  Belgium,  Bulgaria,  Canada,  Croatia,  Czech Republic,  Estonia,  Finland,  France,  Germany,  Greece,  Israel,  Italy,  Latvia,  Lebanon,  Morocco,  Poland,  Portugal,  Romania,  Russian Federation,  Saudi Arabia,  Serbia,  Slovakia,  Spain,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Various time points from randomization up to 24 months	No
Primary	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.	Various time points from randomization up to 36 months	No
Secondary	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.	Various time points from randomization up to 24 months	No
Secondary	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.	Various time points from randomization up to 36 months	No
Secondary	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.	Month 24 up to Month 36	No
Secondary	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.	Baseline, Month 36	No
Secondary	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.	Baseline, Month 36	No

External Links

•   Full FDA approved prescribing information can be found here