Back to resultsA Phase IV Study of Rebif ® 44mcg Administered Three Times Per Week by Subcutaneous Injection Compared With no Treatment in the Therapy of Relapsing Multiple Sclerosis After Mitoxantrone (REMAIN)
Primary Purpose
Multiple Sclerosis, Relapsing-Remitting
Status
Completed
Phase
Phase 4
Locations
Study Type
Interventional
Intervention
Interferon beta-1a (Rebif)
Sponsored by
About this trial
This is an interventional treatment trial for Multiple Sclerosis, Relapsing-Remitting focused on measuring Multiple sclerosis, Expanded Disability Status Scale, Multiple Sclerosis, Relapsing-Remitting, Rebif, Beta-1, interferon
Eligibility Criteria
Inclusion Criteria:
- Subject who had given written informed consent.
- Subjects with definite RRMS or SPMS with relapses
- Subjects with EDSS 1-6
- Subjects aged between 18-60 years
- Subjects who were escalated to mitoxantrone due to high relapse activity or MRI activity (not due to EDSS progression exclusively)
- Subjects who may not have a confirmed 1 point EDSS progression (0.5 points for EDSS >5.5) within the last 9 months
- Subjects free of relapses over the last 6 months
- Subjects with last mitoxantrone treatment between 1 and 6 months prior to screening
- Subjects treated with mitoxantrone for minimum 9 months and maximum 36 months, total cumulative dose being 40-120 mg/m^2
Female subjects who must be neither pregnant nor breast-feeding and must lack childbearing potential, as defined by either:
- Being post-menopausal or surgically sterile,or
- Using a hormonal contraceptive, intra-uterine device, diaphragm with spermicide or condom with spermicide for the duration of the study. Confirmation that the subject is not pregnant must be established by a negative serum or urinary human chorionic gonadotropin (hCG) test within 7 days prior to start of study treatment. A pregnancy test is not required if the subject is post menopausal or surgically sterile.
Exclusion Criteria:
- Subject who has received any cytokine or anti-cytokine therapy within the 3 months prior to study Day 1
- Subject who has been escalated to mitoxantrone due to EDSS progression
- Subject with an ongoing MS relapse
- Subject with PPMS
- Subject with SPMS without superimposed relapses
- Subject who has received immunomodulatory treatment other than IFN-beta or glatiramer acetate before mitoxantrone
- Subject who has previously received total lymphoid irradiation
- Subject who has received oral or systemic corticosteroids or adrenocorticotrophic hormone ACTH within 30 days of study Day 1
- Subject who has received intravenous immunoglobulins or underwent plasmapheresis within the 6 months prior to study day 1
- Subject who has received immunomodulatory or immunosuppressive therapy (including but not limited to cyclophosphamide, cyclosporin, methotrexate, azathioprine, linomide, teriflunomide, natalizumab, laquinimod, Campath) within the 12 months prior to study Day 1
- Subject who requires chronic or monthly pulse corticosteroids during the study
- Subject who has received any investigational drug or experimental procedure within 12 month of study Day 1
- Subject who has inadequate liver function, defined by a total bilirubin, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or alkaline phosphatase greater than 2.5 times the upper limit of the normal values.
- Subject who has inadequate bone marrow reserve, defined as a white blood cell count less than 0.5 times the lower limit of normal
- Subject who suffers from current autoimmune disease
- Subject with known allergy to IFN or the excipient(s)
- Subject who suffers from major medical or psychiatric illness that in the opinion of the investigator creates undue risk to the subject or could affect compliance with the study protocol
- Subject treated with drugs other than IFN-beta or glatiramer acetate within 2 years before mitoxantrone
- Subject with known cardiac or other systemic diseases
- Subjects who are pregnant.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
No Intervention
Arm Label
Rebif (3x44 mcg) Group
No treatment Group
Arm Description
Outcomes
Primary Outcome Measures
Time From Baseline to First Multiple Sclerosis Relapse (in Weeks)
A qualifying relapse was defined as a new or worsening neurological symptom, in the absence of fever, lasting for >= 48 hours, and accompanied by an objective change in the relevant (i.e. symptomatic) Kurtzke Functional Systems (KFS).
Secondary Outcome Measures
Number of Relapse-free Participants
A qualifying relapse was defined as a new or worsening neurological symptom, in the absence of fever, lasting for >= 48 hours, and accompanied by an objective change in the relevant (i.e. symptomatic) Kurtzke Functional Systems (KFS).
Absolute Changes in the Number of T1 Lesions From Baseline to Week 24, 48, 72 and 96
Analysis of T1 lesions was done using magnetic resonance imaging (MRI) scans.
Absolute Changes in the Number of T1-Gadolinium (T1-Gd) Lesions From Baseline to Week 24, 48, 72 and 96
Analysis of T1-Gadolinium enhancing lesions was done using magnetic resonance imaging (MRI) scans.
Absolute Changes in the Number of T2 Lesions From Baseline to Week 24, 48, 72 and 96
Analysis of T2 lesions was done using magnetic resonance imaging (MRI) scans.
Mean Changes in Expanded Disability Status Scale (EDSS) Score From Baseline to Week 12, 24, 36, 48, 60, 72, 84, and 96
EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. EDSS progression was defined as increase by at least 1 point if last value of EDSS was equal to 5.5, and by at least 0.5 points if last EDSS was more than 5.5.
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
AE: any new untoward medical occurrence/worsening of pre-existing medical condition, whether or not related to study drug. SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was a medically important condition.
Full Information
NCT ID
NCT01142466
First Posted
June 10, 2010
Last Updated
January 26, 2014
Sponsor
Merck KGaA, Darmstadt, Germany
Collaborators
Gesellschaft für Therapieforschung mbH
1. Study Identification
Unique Protocol Identification Number
NCT01142466
Brief Title
A Phase IV Study of Rebif ® 44mcg Administered Three Times Per Week by Subcutaneous Injection Compared With no Treatment in the Therapy of Relapsing Multiple Sclerosis After Mitoxantrone
Acronym
REMAIN
Official Title
Phase IV, Multicenter, Open Label, Randomized Study of Rebif® 44mcg Administered Three Times Per Week by Subcutaneous Injection Compared With no Treatment in the Therapy of Relapsing Multiple Sclerosis After Mitoxantrone
Study Type
Interventional
2. Study Status
Record Verification Date
January 2014
Overall Recruitment Status
Completed
Study Start Date
December 2005 (undefined)
Primary Completion Date
December 2009 (Actual)
Study Completion Date
January 2010 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Merck KGaA, Darmstadt, Germany
Collaborators
Gesellschaft für Therapieforschung mbH
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
In the course of therapy escalation, the multiple sclerosis (MS) subjects with high activity of disease receive mainly mitoxantrone. The duration of therapy is limited because of a cumulative dose for life (140 mg/m^2 body surface area). In practice lower doses of mitoxantrone (60-120 mg/m^2 body surface area) are being used. The specific reason for this limited total dose are potential cardiotoxic side effects of mitoxantrone. Once this cumulative dose of mitoxantrone is reached and the subject becomes stable, there is the question for subsequent therapy. A possibility at this time, is the so-called "de-escalation", therefore reducing the subject back to immunomodulating basic treatment.
The target of this open-label, randomised, multicentric, comparative, parallel-group study was to inquire systematically into the use and course of basic therapy with Rebif 44 mcg thrice weekly (tiw) for a larger number of subjects.
Detailed Description
Multiple sclerosis is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) and is one of the most common causes of neurological disability in young adults. It is characterised by multi-focal recurrent attacks of neurological symptoms and signs with variable recovery. Eventually, the majority of subjects develop a progressive clinical course. The exact cause of MS is unknown, although an autoimmune process has been implicated. Genetic susceptibility plays a role in disease initiation but unidentified environmental factors may also be involved. Three clinical forms of MS are recognized: primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS) and relapsing remitting multiple sclerosis (RRMS). Primary progressive subjects are characterised by slow and steady accumulation of neurological deficits from onset without superimposed attacks. Subjects with RRMS have exacerbations or relapses with subsequent variable recovery (remission). Secondary progressive multiple sclerosis is characterised by the steady accumulation of significant and persistent neurological deficit with or without superimposed relapses.
Rebif [recombinant interferon (IFN) beta-1a] has been tested in a series of studies in MS subjects at doses ranging from 22 mcg to 132 mcg weekly with a dose frequency ranging from weekly (qw) to tiw. Rebif has been found to be well tolerated in all clinical pharmacology studies, even at high doses (up to 66 mcg/m^2). In later phase trials, Rebif has been tested across a broad range of doses, for varying duration, and in different stages of MS disease. Dose testing has ranged from 22 mcg to 132 mcg weekly with frequency of administration being qw to tiw.
OBJECTIVES
Primary objective:
To asses if treatment with Rebif 44 mcg tiw compared with subjects not treated during 96 weeks can maintain or prolong clinical or magnetic resonance imaging (MRI) stability after previous treatment with mitoxantrone
Secondary objectives:
To compare the mean number of T2 active lesions, defined as new or enlarging T2 lesions, per subject per scan during 96 weeks of treatment with Rebif 44 mcg three times per week with subjects not treated
To assess the safety and efficacy of Rebif 44 mcg
This was an open-label, randomised, multicentric, comparative, parallel-group study with a neurologist blinded to treatment for performing neurologic exams and a neuro-radiologist blinded to treatment for assessing central MRI scans. The study was divided into a screening phase (up to 28 days before the start of IFN-beta-1a treatment), a treatment phase of 96 weeks as well as a follow-up period of 4 weeks for subjects with ongoing serious adverse events (SAEs) at week 96. The study consisted of 2 groups to compare the therapeutic effect of high dose, high frequency IFN beta-1a therapy (Rebif 44 mcg) to subjects who will not be treated with Rebif 44 mcg. Subjects of both groups were previously treated with mitoxantrone in the < 3 months prior to study inclusion. Subjects assigned to no treatment were switched to Rebif 44 mcg x 3 after reaching the primary endpoint or defined stopping criteria. The treatment period of this study begun with the completion of all baseline evaluations and the initiation of study drug treatment on Study Day 1 (baseline visit) and continues through until completion of the treatment period at the Week 96 visit.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Sclerosis, Relapsing-Remitting
Keywords
Multiple sclerosis, Expanded Disability Status Scale, Multiple Sclerosis, Relapsing-Remitting, Rebif, Beta-1, interferon
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
30 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Rebif (3x44 mcg) Group
Arm Type
Experimental
Arm Title
No treatment Group
Arm Type
No Intervention
Intervention Type
Drug
Intervention Name(s)
Interferon beta-1a (Rebif)
Other Intervention Name(s)
Rebif
Intervention Description
The dosage of IFN-beta-1a , following initial dose titration, was 44 mcg injected subcutaneously (s.c.) tiw. An auto-injector device, Rebiject, was available as an optional aid for the administration of IFN-beta-1a . IFN-beta-1a was administered, if possible, at the same time (preferably in the late afternoon or evening) on the same three days at least 48 hours apart each week.
Primary Outcome Measure Information:
Title
Time From Baseline to First Multiple Sclerosis Relapse (in Weeks)
Description
A qualifying relapse was defined as a new or worsening neurological symptom, in the absence of fever, lasting for >= 48 hours, and accompanied by an objective change in the relevant (i.e. symptomatic) Kurtzke Functional Systems (KFS).
Time Frame
Baseline through Week 96
Secondary Outcome Measure Information:
Title
Number of Relapse-free Participants
Description
A qualifying relapse was defined as a new or worsening neurological symptom, in the absence of fever, lasting for >= 48 hours, and accompanied by an objective change in the relevant (i.e. symptomatic) Kurtzke Functional Systems (KFS).
Time Frame
Baseline through Week 96
Title
Absolute Changes in the Number of T1 Lesions From Baseline to Week 24, 48, 72 and 96
Description
Analysis of T1 lesions was done using magnetic resonance imaging (MRI) scans.
Time Frame
Baseline to Week 24, 48, 72, and 96
Title
Absolute Changes in the Number of T1-Gadolinium (T1-Gd) Lesions From Baseline to Week 24, 48, 72 and 96
Description
Analysis of T1-Gadolinium enhancing lesions was done using magnetic resonance imaging (MRI) scans.
Time Frame
Baseline to Week 24, 48, 72, and 96
Title
Absolute Changes in the Number of T2 Lesions From Baseline to Week 24, 48, 72 and 96
Description
Analysis of T2 lesions was done using magnetic resonance imaging (MRI) scans.
Time Frame
Baseline to Week 24, 48, 72, and 96
Title
Mean Changes in Expanded Disability Status Scale (EDSS) Score From Baseline to Week 12, 24, 36, 48, 60, 72, 84, and 96
Description
EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. EDSS progression was defined as increase by at least 1 point if last value of EDSS was equal to 5.5, and by at least 0.5 points if last EDSS was more than 5.5.
Time Frame
Baseline to Week 12, 24, 36, 48, 60, 72, 84, and 96
Title
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
Description
AE: any new untoward medical occurrence/worsening of pre-existing medical condition, whether or not related to study drug. SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was a medically important condition.
Time Frame
Baseline to Week 96
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Subject who had given written informed consent.
Subjects with definite RRMS or SPMS with relapses
Subjects with EDSS 1-6
Subjects aged between 18-60 years
Subjects who were escalated to mitoxantrone due to high relapse activity or MRI activity (not due to EDSS progression exclusively)
Subjects who may not have a confirmed 1 point EDSS progression (0.5 points for EDSS >5.5) within the last 9 months
Subjects free of relapses over the last 6 months
Subjects with last mitoxantrone treatment between 1 and 6 months prior to screening
Subjects treated with mitoxantrone for minimum 9 months and maximum 36 months, total cumulative dose being 40-120 mg/m^2
Female subjects who must be neither pregnant nor breast-feeding and must lack childbearing potential, as defined by either:
Being post-menopausal or surgically sterile,or
Using a hormonal contraceptive, intra-uterine device, diaphragm with spermicide or condom with spermicide for the duration of the study. Confirmation that the subject is not pregnant must be established by a negative serum or urinary human chorionic gonadotropin (hCG) test within 7 days prior to start of study treatment. A pregnancy test is not required if the subject is post menopausal or surgically sterile.
Exclusion Criteria:
Subject who has received any cytokine or anti-cytokine therapy within the 3 months prior to study Day 1
Subject who has been escalated to mitoxantrone due to EDSS progression
Subject with an ongoing MS relapse
Subject with PPMS
Subject with SPMS without superimposed relapses
Subject who has received immunomodulatory treatment other than IFN-beta or glatiramer acetate before mitoxantrone
Subject who has previously received total lymphoid irradiation
Subject who has received oral or systemic corticosteroids or adrenocorticotrophic hormone ACTH within 30 days of study Day 1
Subject who has received intravenous immunoglobulins or underwent plasmapheresis within the 6 months prior to study day 1
Subject who has received immunomodulatory or immunosuppressive therapy (including but not limited to cyclophosphamide, cyclosporin, methotrexate, azathioprine, linomide, teriflunomide, natalizumab, laquinimod, Campath) within the 12 months prior to study Day 1
Subject who requires chronic or monthly pulse corticosteroids during the study
Subject who has received any investigational drug or experimental procedure within 12 month of study Day 1
Subject who has inadequate liver function, defined by a total bilirubin, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or alkaline phosphatase greater than 2.5 times the upper limit of the normal values.
Subject who has inadequate bone marrow reserve, defined as a white blood cell count less than 0.5 times the lower limit of normal
Subject who suffers from current autoimmune disease
Subject with known allergy to IFN or the excipient(s)
Subject who suffers from major medical or psychiatric illness that in the opinion of the investigator creates undue risk to the subject or could affect compliance with the study protocol
Subject treated with drugs other than IFN-beta or glatiramer acetate within 2 years before mitoxantrone
Subject with known cardiac or other systemic diseases
Subjects who are pregnant.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sigbert Jahn, PD Dr. med
Organizational Affiliation
Merck Serono GmbH, Germany
Official's Role
Study Director
12. IPD Sharing Statement
Learn more about this trial
A Phase IV Study of Rebif ® 44mcg Administered Three Times Per Week by Subcutaneous Injection Compared With no Treatment in the Therapy of Relapsing Multiple Sclerosis After Mitoxantrone
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