Multiple Sclerosis
Conditions
Keywords
Multiple Sclerosis, Relapsing forms of multiple sclerosis
Brief summary
The primary objective of the study is to compare the immunogenicity of the new fetal bovine serum (FBS)-free/human serum albumin (HSA)-free Rebif® formulation (RNF) to historical data.
Detailed description
As has been seen with other recombinant protein molecules, the use of injectable recombinant proteins may result in the development of neutralising antibodies (NAbs). Antibodies are considered neutralising by their ability to inhibit the biological effect of interferon in a bioassay system. EMD Serono has actively pursued improvements in the formulation of interferon (IFN) beta-1a to reduce aggregate levels and to develop a formulation that is HSA-free. Reducing aggregates should reduce antigenicity of the product while removal of HSA may have an unpredictable effect on antigenicity. EMD Serono will conduct a study to assess the immunogenicity and safety of the new HSA-free formulation, manufactured using IFN-ß-1a drug substance produced by a new clone from the FBS-free process.
Interventions
BIOLOGICALInterferon-beta-1a FBS-free/HSA-free
Pre-filled syringes 44mcg/injected subcutaneous 3x per week. Total study period is 96 weeks.
Sponsors
Pfizer
EMD Serono
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Participant has a relapsing form of Multiple Sclerosis (MS); diagnosis of MS is in accordance with the McDonald criteria * Participant is eligible for interferon therapy * Participant is between 18 and 60 years old * Participant has an Expanded Disability Status Scale (EDSS) \< 6.0. * Participant is willing to follow study procedures * Participant has given written informed consent * Female participants 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 participant is not pregnant must be established by a negative serum or urinary hCG test within 7 days prior to start of study treatment. A pregnancy test is not required if the participant is post-menopausal or surgically sterile.
Exclusion criteria
* Participant has a Clinically Isolated Syndrome (CIS), Primary Progressive MS, or Secondary Progressive MS without superimposed relapses. * Participant had any prior interferon beta therapy (either beta-1b or beta-1a) * Participant has an ongoing MS relapse. * Participant received any other approved disease modifying therapy for MS (e.g. glatiramer acetate) or any cytokine or anti-cytokine therapy within the 3 months prior to Study Day 1(SD1). * Participant had prior use of cladribine or has previously received total lymphoid irradiation. * Participant received oral or systemic corticosteroids or adrenocorticotropic hormone (ACTH) within 30 days of SD1. * Participant received intravenous immunoglobulins or underwent plasmapheresis within the 6 months prior to SD1. * Participant received immunomodulatory or immunosuppressive therapy (including but not limited to cyclophosphamide, cyclosporin, methotrexate, azathioprine, linomide, mitoxantrone, teriflunomide, natalizumab, laquinimod, Campath) within the 12 months prior to SD1. * Participant requires chronic or monthly pulse corticosteroids during the study. * Participant received any investigational drug or experimental procedure within 12 weeks of SD1. * Participant has inadequate liver function, defined by a total bilirubin, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or alkaline phosphatase \> 2.5 times the upper limit of the normal values. * Participant has inadequate bone marrow reserve, defined as a white blood cell count less than 0.5 x lower limit of normal. * Participant suffers from current autoimmune disease. * Participant 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. * Participant has a known allergy to IFN or the excipients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Were Neutralising Antibody (NAb) Positive at the Week 96 Visit. | 96 weeks | The NAb positive value was defined as NAb value greater or equal to 20 NU/mL. NAbs were detected using a viral cytopathic assay. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Were Neutralising Antibody (NAb) Positive at Anytime During the Study | 96 weeks | The NAb positive value was defined as NAb value greater or equal to 20 NU/mL. NAbs were detected using a viral cytopathic assay. |
| Number of Participants With Binding Antibodies (BAb) at Week 96 | 96 weeks | Presence of BAbs. BAbs were measured by ELISA (Enzyme-linked immunosorbent assay). |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled from 25 Jan 2005 and attended the last visit on 16 April 2007. Two hundred and eighty two participants were screened for enrollment and 260 were enrolled.
Pre-assignment details
Screening phase of up to 28 days before the start of interferon-beta-1a treatment. There were 47 centres in: Argentina (5), Australia (4),Canada (1), Denmark (1),Ireland (2), Israel (2), Lithuania(2), Russia (10), Spain (4), Sweden (1), UK (5) and US (10). 1 additional centre in Australia screened 1 participant who was not enrolled into the trial.
Participants by arm
| Arm | Count |
|---|---|
| Rebif New Formulation (RNF) Cohort Interferon-beta-1a FBS-free/HSA-free Pre-filled syringes 44mcg/injected subcutaneous 3x per week | 260 |
| Total | 260 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Administration of plasmapheresis | 1 |
| Overall Study | Adverse Event | 15 |
| Overall Study | Decided not to continue treatment | 1 |
| Overall Study | Initiated mitoxantrone therapy | 1 |
| Overall Study | Lack of Efficacy | 1 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Participation in MS vaccine study | 1 |
| Overall Study | Patient is to be administered copaxone | 1 |
| Overall Study | Patient non-compliance | 1 |
| Overall Study | Patient refused to come back | 1 |
| Overall Study | Patient refused to continue | 1 |
| Overall Study | Patient refused to participate | 1 |
| Overall Study | Patient's decision | 1 |
| Overall Study | Patient will | 1 |
| Overall Study | Pregnancy | 1 |
| Overall Study | Pregnancy (Protocol violation) | 2 |
| Overall Study | Protocol Violation | 2 |
| Overall Study | The patient has refused | 2 |
| Overall Study | The patient has refused to visit site | 1 |
Baseline characteristics
| Characteristic | Rebif New Formulation (RNF) Cohort |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 260 Participants |
| Age, Continuous | 34.9 years STANDARD_DEVIATION 9.5 |
| Region of Enrollment Argentina | 14 participants |
| Region of Enrollment Australia | 10 participants |
| Region of Enrollment Canada | 4 participants |
| Region of Enrollment Denmark | 4 participants |
| Region of Enrollment Ireland | 4 participants |
| Region of Enrollment Israel | 4 participants |
| Region of Enrollment Lithuania | 20 participants |
| Region of Enrollment Russian Federation | 134 participants |
| Region of Enrollment Spain | 13 participants |
| Region of Enrollment Sweden | 5 participants |
| Region of Enrollment United Kingdom | 23 participants |
| Region of Enrollment United States | 25 participants |
| Sex: Female, Male Female | 186 Participants |
| Sex: Female, Male Male | 74 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 247 / 260 |
| serious Total, serious adverse events | 15 / 260 |
Outcome results
Primary
Number of Participants Who Were Neutralising Antibody (NAb) Positive at the Week 96 Visit.
The NAb positive value was defined as NAb value greater or equal to 20 NU/mL. NAbs were detected using a viral cytopathic assay.
Time frame: 96 weeks
Population: ITT (One participant did not have any post-baseline NAb assessments). LOCF imputation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rebif New Formulation (RNF) Cohort | Number of Participants Who Were Neutralising Antibody (NAb) Positive at the Week 96 Visit. | 45 participants |
Secondary
Number of Participants Who Were Neutralising Antibody (NAb) Positive at Anytime During the Study
The NAb positive value was defined as NAb value greater or equal to 20 NU/mL. NAbs were detected using a viral cytopathic assay.
Time frame: 96 weeks
Population: ITT (One participant did not have any post-baseline NAb assessments). LOCF imputation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rebif New Formulation (RNF) Cohort | Number of Participants Who Were Neutralising Antibody (NAb) Positive at Anytime During the Study | 49 participants |
Secondary
Number of Participants With Binding Antibodies (BAb) at Week 96
Presence of BAbs. BAbs were measured by ELISA (Enzyme-linked immunosorbent assay).
Time frame: 96 weeks
Population: ITT (One participant did not have any post-baseline NAb assessments) LOCF imputation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rebif New Formulation (RNF) Cohort | Number of Participants With Binding Antibodies (BAb) at Week 96 | 74 Participants |