A Study to Evaluate Rebif® New Formulation (Interferon-beta-1a) in Relapsing Remitting Multiple Sclerosis (IMPROVE)

• ClinicalTrials.gov Identifier: NCT00441103
• Recruitment Status: Completed
• First Posted: February 28, 2007
• Results First Posted: July 5, 2010
• Last Update Posted: July 9, 2014
• Sponsor: Merck KGaA, Darmstadt, Germany
• Information provided by (Responsible Party): Merck KGaA, Darmstadt, Germany

Study Description

Brief Summary:

General Note: throughout this record, "Rebif® New Formulation" is used for historical and consistency purposes.

Objectives:

Primary: To evaluate the efficacy of Rebif® New Formulation (Interferon-beta-1a [IFN-beta-1a], RNF), compared to placebo, in subjects with Relapsing Remitting Multiple Sclerosis and active disease by means of Magnetic Resonance Imaging (MRI) at the end of 16 weeks of treatment Secondary: To evaluate the efficacy of RNF by comparing the mean number of combined unique (CU) lesions per scan per subject between the initial 16 weeks of placebo treatment and 24 weeks of RNF treatment in the same subjects, originally randomized to placebo.

Primary Endpoints: The primary endpoint is the difference between the number of CU active MRI lesions at Week 16 in the RNF group (Group 1) versus the placebo group (Group 2).

Secondary Endpoints: The secondary endpoint is the difference in the mean number of CU active MRI lesions per scan per subject over the following treatment periods: Study Day 1 - Week 16 versus Weeks 17 - 40 for the subjects randomized to Group 2.

Condition or disease	Intervention/treatment	Phase
Multiple Sclerosis, Relapsing-Remitting	Drug: Rebif® New Formulation (IFN-beta-1a, RNF); Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 180 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Two-arm, Randomized, Double-blind, Control Group-compared, Multicenter, Phase IIIb Study With Monthly MRI and Biomarker Assessments to Evaluate the Efficacy, Safety, and Tolerability of Rebif® New Formulation (IFN Beta-1a) in Subjects With Relapsing Remitting Multiple Sclerosis
• Study Start Date: December 2006
• Actual Primary Completion Date: November 2008
• Actual Study Completion Date: February 2009

Arms and Interventions

Arm	Intervention/treatment
Experimental: Rebif® New Formulation (IFN-beta-1a, RNF)	Drug: Rebif® New Formulation (IFN-beta-1a, RNF); RNF will be administered at a dose of 44 mcg subcutaneously three times a week for 40 weeks.; Other Name: IFN-beta-1a
Placebo Comparator: Placebo/RNF	Drug: Placebo; Matching placebo will be administered subcutaneously three times a week for 16 weeks.; Drug: Rebif® New Formulation (IFN-beta-1a, RNF); RNF will be administered at a dose of 44 mcg subcutaneously three times a week from Week 17 to Week 40.; Other Name: IFN-beta-1a

Outcome Measures

Primary Outcome Measures :

1. Number of Combined Unique (CU) Active Magnetic Resonance Imaging (MRI) Lesions at Week 16 [ Time Frame: 16 Weeks ]
   CU active lesions were defined as a unique newly active or persistently active lesion on the protocol density/time constant 2 (PD/T2) scan or the gadolinium (Gd-) enhanced time constant 1 (T1) scan (with a method to avoid double counting).
2. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to Week 40 ]
   An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. AEs were categorized based upon the treatment period during which they occurred, that is, double-blind period (up to Week 16) and rater-blind period (Week 17 up to Week 40).

Secondary Outcome Measures :

1. Mean Number of CU Lesions Per Scan Between the Initial 16 Weeks of Placebo Treatment and 24 Weeks of RNF Treatment in the Same Participants, Originally Randomized to Placebo. [ Time Frame: Day 1 up to Week 16 and Week 17 up to Week 40 ]
   CU active lesions were defined as a unique newly active or persistently active lesion on the PD/T2 scan or the gadolinium enhanced T1 scan (with a method to avoid double counting). Only "Placebo Followed by RNF" arm was evaluable for this outcome measure.
2. Number of CU Active MRI Lesions [ Time Frame: Up to Week 40 ]
   CU active lesions were defined as a unique newly active or persistently active lesion on the PD/T2 scan or the gadolinium enhanced T1 scan (with a method to avoid double counting).

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Males and females between 18 and 60 years of age
• Female subjects must be neither pregnant nor breast-feeding and must lack child-bearing potential, as defined by either: post-menopausal or surgically sterile or use an effective method of contraception for the duration of the study
• Have Relapsing Remitting Multiple Sclerosis (RRMS) according to the revised McDonald criteria 2005
• Have brain and/or spinal MRI with findings typical of Multiple Sclerosis (MS)
• Have disease duration for more than 12 months
• Have disease activity characterized by at least one clinical event and one or more Gadolinium-enhancing MRI lesions within the 6 months prior to randomization
• Have score of <=5.5 on the Expanded Disability Status Scale (EDSS)
• Be willing and able to comply with the protocol for the duration of the study
• Have given written informed consent prior to any study-related procedure not part of the normal medical practice

Exclusion Criteria:

• Have any disease other than MS that could better explain his/her signs and symptoms
• Have complete transverse myelitis or bilateral optic neuritis
• Have received or have used anytime monoclonal antibodies, mitoxantrone, cytotoxic or immunosuppressive therapy (excluding systemic steroids and adrenocorticotrophic hormone [ACTH]), or total lymphoid irradiation
• Have received within 3 months prior to baseline any approved disease-modifying therapy for MS, cytokine or anti-cytokine therapy, intravenous immunoglobulin, plasmapheresis, any investigational drug, or experimental procedure
• Have received within 30 days prior to baseline oral or systemic corticosteroids or ACTH
• Other protocol defined exclusion criteria could apply

Contacts and Locations

Sponsors and Collaborators

Merck KGaA, Darmstadt, Germany

Investigators

• Study Director: Bettina Stubinski, MD; Merck Serono SA - Geneva, an affiliate of Merck KGaA Darmstadt, Germany

More Information

Additional Information:

Full FDA approved prescribing information can be found here 

Publications of Results:

De Stefano N, Curtin F, Stubinski B, Blevins G, Drulovic J, Issard D, Shotekov P, Gasperini C; IMPROVE Study Investigators. Rapid benefits of a new formulation of subcutaneous interferon beta-1a in relapsing-remitting multiple sclerosis. Mult Scler. 2010 Jul;16(7):888-92. doi: 10.1177/1352458510362442. Epub 2010 Mar 3.

De Stefano N, Sormani MP, Stubinski B, Blevins G, Drulovic JS, Issard D, Shotekov P, Gasperini C. Efficacy and safety of subcutaneous interferon beta-1a in relapsing-remitting multiple sclerosis: further outcomes from the IMPROVE study. J Neurol Sci. 2012 Jan 15;312(1-2):97-101. doi: 10.1016/j.jns.2011.08.013. Epub 2011 Aug 31.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Giorgio A, Battaglini M, Gentile G, Stromillo ML, Gasperini C, Visconti A, Paolillo A, De Stefano N. Mapping the Progressive Treatment-Related Reduction of Active MRI Lesions in Multiple Sclerosis. Front Neurol. 2020 Nov 20;11:585296. doi: 10.3389/fneur.2020.585296. eCollection 2020.

• Responsible Party: Merck KGaA, Darmstadt, Germany
• ClinicalTrials.gov Identifier: NCT00441103
• Other Study ID Numbers: 27178; 2006-003037-32
• First Posted: February 28, 2007
• Results First Posted: July 5, 2010
• Last Update Posted: July 9, 2014
• Last Verified: June 2014

Keywords provided by Merck KGaA, Darmstadt, Germany:

Subjects with relapsing remitting multiple sclerosis

Additional relevant MeSH terms:

Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis; Pathologic Processes; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Interferon beta-1a; Interferon-beta; Adjuvants, Immunologic; Immunologic Factors; Physiological Effects of Drugs; Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents