Relapsing Remitting Multiple Sclerosis (RRMS)
Conditions
Brief summary
To evaluate the tolerability of a new formulation of rebif and Betaseron in subjects with relapsing-remitting multiple sclerosis (RRMS) by comparing the mean change in injection site pain scores from pre-injection to 30 minutes post therapy administration.
Interventions
DRUGNew Formulation of rebif - human interferon beta-1a
New Formulation of rebif- 44 mcg, SC (sub-cutaneous) thrice weekly (tiw) injection.
DRUGInterferon beta -1b
Betaseron - 250 mcg, SC (sub-cutaneous) every other day injection.
Sponsors
Pfizer
EMD Serono
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
1. Subject with diagnosis of RRMS according to McDonald criteria or Poser 2. Subject is between 18 and 60 years old inclusive 3. Subject is willing to follow study procedures 4. Subject has given written informed consent 5. Female subjects 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.
Exclusion criteria
1. Subject has Clinically Isolated Syndrome (CIS), Primary Progressive MS, or Secondary Progressive MS without superimposed relapses. 2. Subject has had any prior interferon beta therapy (either beta-1b or beta-1a) prior to study Day 1. 3. Subject received any other approved disease modifying therapy for MS (glatiramer acetate) or any cytokine or anti-cytokine therapy within the 3 months prior to Study Day 1. 4. Subject received immunomodulatory or immunosuppressive therapy (including but not limited to cyclophosphamide, cyclosporin, methotrexate, azathioprine, linomide, mitoxantrone, teriflunomide, natalizumab, laquinimod, Campath and cladribine) within the 12 months prior to Study Day 1. 5. Subject had prior use of Cladribine or has previously received total lymphoid irradiation. 6. Subject has known allergy to natural or recombinant interferon or any other component of formulation excipient(s) of Rebif® or Betaseron®: Mannitol, Poloxamer 188, Methionine, Benzyl alcohol or Albumin (human). 7. Use of any other injectable medications on a regular basis during the week prior to the screening period or during the screening or treatment periods. Receiving a single injection for treatment or prophylaxis of a condition unrelated to the subject's multiple sclerosis or the subject's Rebif® or Betaseron® therapy (e.g. receiving a influenza or pneumococcus vaccination) is acceptable. 8. History of any chronic pain syndrome. 9. Subject has any other disease apart from MS that could better explain the subjects signs and symptoms. 10. Subject has complete transverse myelitis or bilateral optic neuritis. 11. Subjects who used any investigational drug or experimental procedure within 12 weeks prior to visit 1. 12. Subject 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. 13. Subject has inadequate bone marrow reserve, defined as a white blood cell count less than 0.5 x lower limit of normal. 14. Subject suffers from current autoimmune disease (other than RRMS). 15. Subject 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 16. Subject is pregnant or attempting to conceive 17. Visual or physical impairment that precludes completion of diaries and questionnaires. 18. Subject received oral or systemic corticosteroids or ACTH within 30 days of visit 1.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Visual Analog Scale (VAS) of Patient Reported Pain: Change in Mean VAS for the 21 Full-dose Injections at Pre-injection and 30 Minutes Post-injection Timepoints | From pre-injection to 30 minutes post injection of the VAS pain scores across the first 21 injections of full dose therapy of a new formulation of rebif and Betaseron | Subject reported perception of pain on the VAS where the slash drawn by the patient represents pain of increasing intensity from 0 (no pain) to 100 (worse possible pain), measured in millimeters. Mean VAS of 21 injections for each patient at pre-injection compared to mean VAS of 21 injections for each patient 30 minutes post-injection |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean VAS for the 21 Full-dose Injections at Pre-injection and Immediately After Injection Timepoints | Pre-Injection to Immediately after Injection | A visual analog scale (VAS) ranging from 0 to 100 mm on which subjects rate pain from no pain (0 mm) to worst possible pain (100 mm) was used. Mean VAS of 21 injections for each patient at pre-injection compared to mean VAS of 21 injections for each patient immediately after injection. |
| Change in Mean VAS for the 21 Full-dose Injections at Pre-injection and 10 Minutes Post-injection Timepoints | Pre-injection to 10 minutes post-injection | A visual analog scale (VAS) ranging from 0 to 100 mm on which subjects rate pain from no pain (0 mm) to worst possible pain (100 mm) was used. Mean VAS of 21 injections for each patient at pre-injection compared to mean VAS of 21 injections for each patient 10 minutes post injection. |
| Number of Pain Free Patients at 30 Minutes Post-injection | 30 minutes post injection | A visual analog scale (VAS) ranging from 0 to 100 mm on which subjects rate pain from no pain (0 mm) to worst possible pain (100 mm) was used. Pain-free was defined as a VAS score of 0 for all 21 full-dose injections for the Intent-to-Treat (ITT) population. |
| Diameter of Injection Site Redness | 1-72 hours post injection over the first 12 weeks including the titration period | Blinded assessment of mean change in diameter of redness (in mm) at an injection site following an injection |
Other
| Measure | Time frame | Description |
|---|---|---|
| Secondary Outcome - Extension Phase: Change in Mean (mm) VAS for Pre-injection and Immediately After Injection Timepoints | Pre-injection and immediately after injection | A visual analog scale (VAS) ranging from 0 to 100 mm on which subjects rate pain from no pain (0 mm) to worst possible pain (100 mm) was used. Mean VAS of 21 injections for each patient at pre-injection compared to mean VAS of 21 injections for each patient immediately after injection. |
| Secondary Outcome - Extension Phase: Change in Mean VAS at Pre-injection and 10 Minutes Post Injection | Pre-injection and 10 minutes post injection | — |
| Secondary Outcome - Extension Phase: Number of Pain Free Patients at 30 Minutes Post Injection | Pain free patients at 30 minutes post injection | — |
| Secondary Outcome - Extension Phase: Diameter in Injection Site Redness | 1 to 72 hours post injection | — |
| Primary Outcome - Extension Phase: Visual Analog Scale (VAS) of Patients Reported Pain; Change in Mean VAS at Pre-injection and 30 Minutes Post Injection | Pre-injection and 30 minutes post injection | — |
Countries
United States
Participant flow
Recruitment details
129 subjects were recruited from 27 Multiple Sclerosis (MS) Clinics in the US from December 2006 through August 2007.
Pre-assignment details
Subjects had a pre-study evaluation period (screening) within 14 days of Study Day 1 which consisted of informed consent, medical/disease history, physical exam and laboratory assessments.
Participants by arm
| Arm | Count |
|---|---|
| New Formulation of Rebif Human interferon beta 1a, (new formulation of rebif) 44 mcg, subcutaneous injection, three times a week | 65 |
| Betaseron Human interferon beta-1b, Betaseron 250 mcg, subcutaneous injection, every other day | 64 |
| Total | 129 |
Baseline characteristics
| Characteristic | New Formulation of Rebif | Betaseron | Total |
|---|---|---|---|
| Age Continuous | 40.26 years STANDARD_DEVIATION 9.8 | 40.78 years STANDARD_DEVIATION 9.56 | 40.52 years STANDARD_DEVIATION 9.68 |
| Region of Enrollment United States | 65 participants | 64 participants | 129 participants |
| Sex: Female, Male Female | 46 Participants | 44 Participants | 90 Participants |
| Sex: Female, Male Male | 19 Participants | 20 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 62 / 65 | 57 / 64 |
| serious Total, serious adverse events | 4 / 65 | 5 / 64 |
Outcome results
Primary
Visual Analog Scale (VAS) of Patient Reported Pain: Change in Mean VAS for the 21 Full-dose Injections at Pre-injection and 30 Minutes Post-injection Timepoints
Subject reported perception of pain on the VAS where the slash drawn by the patient represents pain of increasing intensity from 0 (no pain) to 100 (worse possible pain), measured in millimeters. Mean VAS of 21 injections for each patient at pre-injection compared to mean VAS of 21 injections for each patient 30 minutes post-injection
Time frame: From pre-injection to 30 minutes post injection of the VAS pain scores across the first 21 injections of full dose therapy of a new formulation of rebif and Betaseron
Population: One subject from the new formulation of rebif group discontinued due to pregnancy therefore, data for the Full Dose Calculation 30min Mean Change was not calculated
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| New Formulation of Rebif | Visual Analog Scale (VAS) of Patient Reported Pain: Change in Mean VAS for the 21 Full-dose Injections at Pre-injection and 30 Minutes Post-injection Timepoints | Mean Pre-Injection VAS Score | 0.43 mm | Full Range 2.06 |
| New Formulation of Rebif | Visual Analog Scale (VAS) of Patient Reported Pain: Change in Mean VAS for the 21 Full-dose Injections at Pre-injection and 30 Minutes Post-injection Timepoints | Mean VAS at 30 minutes Post-Injection | 1.10 mm | Full Range 4.24 |
| New Formulation of Rebif | Visual Analog Scale (VAS) of Patient Reported Pain: Change in Mean VAS for the 21 Full-dose Injections at Pre-injection and 30 Minutes Post-injection Timepoints | Mean Change to 30 Minutes Post-Injection | 0.67 mm | Full Range 2.32 |
| Betaseron | Visual Analog Scale (VAS) of Patient Reported Pain: Change in Mean VAS for the 21 Full-dose Injections at Pre-injection and 30 Minutes Post-injection Timepoints | Mean Pre-Injection VAS Score | 0.40 mm | Full Range 1.64 |
| Betaseron | Visual Analog Scale (VAS) of Patient Reported Pain: Change in Mean VAS for the 21 Full-dose Injections at Pre-injection and 30 Minutes Post-injection Timepoints | Mean VAS at 30 minutes Post-Injection | 1.54 mm | Full Range 5.19 |
| Betaseron | Visual Analog Scale (VAS) of Patient Reported Pain: Change in Mean VAS for the 21 Full-dose Injections at Pre-injection and 30 Minutes Post-injection Timepoints | Mean Change to 30 Minutes Post-Injection | 1.14 mm | Full Range 4.81 |
Comparison: The primary efficacy endpoint was analyzed by using a two-way ANOVA model on ranked data including treatment group and site as fixed effect.p-value: 0.524ANOVA
Secondary
Change in Mean VAS for the 21 Full-dose Injections at Pre-injection and 10 Minutes Post-injection Timepoints
A visual analog scale (VAS) ranging from 0 to 100 mm on which subjects rate pain from no pain (0 mm) to worst possible pain (100 mm) was used. Mean VAS of 21 injections for each patient at pre-injection compared to mean VAS of 21 injections for each patient 10 minutes post injection.
Time frame: Pre-injection to 10 minutes post-injection
Population: One subject from the new formulation of Rebif group discontinued due to pregnancy
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| New Formulation of Rebif | Change in Mean VAS for the 21 Full-dose Injections at Pre-injection and 10 Minutes Post-injection Timepoints | 0.70 Millimeters | Full Range 1.89 |
| Betaseron | Change in Mean VAS for the 21 Full-dose Injections at Pre-injection and 10 Minutes Post-injection Timepoints | 1.89 Millimeters | Full Range 5.45 |
p-value: 0.838ANOVA
Secondary
Change in Mean VAS for the 21 Full-dose Injections at Pre-injection and Immediately After Injection Timepoints
A visual analog scale (VAS) ranging from 0 to 100 mm on which subjects rate pain from no pain (0 mm) to worst possible pain (100 mm) was used. Mean VAS of 21 injections for each patient at pre-injection compared to mean VAS of 21 injections for each patient immediately after injection.
Time frame: Pre-Injection to Immediately after Injection
Population: One subject from the new formulation of rebif group discontinued due to pregnancy
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| New Formulation of Rebif | Change in Mean VAS for the 21 Full-dose Injections at Pre-injection and Immediately After Injection Timepoints | 1.46 millimeters | Full Range 2.93 |
| Betaseron | Change in Mean VAS for the 21 Full-dose Injections at Pre-injection and Immediately After Injection Timepoints | 4.63 millimeters | Full Range 10.02 |
p-value: 0.484ANOVA
Secondary
Diameter of Injection Site Redness
Blinded assessment of mean change in diameter of redness (in mm) at an injection site following an injection
Time frame: 1-72 hours post injection over the first 12 weeks including the titration period
Population: One subject from the new formulation of rebif group discontinued due to pregnancy
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| New Formulation of Rebif | Diameter of Injection Site Redness | 8.28 mm | Standard Deviation 9.51 |
| Betaseron | Diameter of Injection Site Redness | 6.87 mm | Standard Deviation 7.67 |
p-value: 0.338ANOVA
Secondary
Number of Pain Free Patients at 30 Minutes Post-injection
A visual analog scale (VAS) ranging from 0 to 100 mm on which subjects rate pain from no pain (0 mm) to worst possible pain (100 mm) was used. Pain-free was defined as a VAS score of 0 for all 21 full-dose injections for the Intent-to-Treat (ITT) population.
Time frame: 30 minutes post injection
Population: One subject from the new formulation of rebif group discontinued due to pregnancy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| New Formulation of Rebif | Number of Pain Free Patients at 30 Minutes Post-injection | 31 Participants |
| Betaseron | Number of Pain Free Patients at 30 Minutes Post-injection | 28 Participants |
p-value: 0.451Cochran-Mantel-Haenszel
Other Pre-specified
Primary Outcome - Extension Phase: Visual Analog Scale (VAS) of Patients Reported Pain; Change in Mean VAS at Pre-injection and 30 Minutes Post Injection
Time frame: Pre-injection and 30 minutes post injection
Population: 3 subjects discontinued and withdrew consent from the Betaseron to the new formulation of rebif group in the Extension Phase
| Arm | Measure | Value (MEAN) |
|---|---|---|
| New Formulation of Rebif | Primary Outcome - Extension Phase: Visual Analog Scale (VAS) of Patients Reported Pain; Change in Mean VAS at Pre-injection and 30 Minutes Post Injection | 0.34 Millimeters |
| Betaseron | Primary Outcome - Extension Phase: Visual Analog Scale (VAS) of Patients Reported Pain; Change in Mean VAS at Pre-injection and 30 Minutes Post Injection | 0.42 Millimeters |
Other Pre-specified
Secondary Outcome - Extension Phase: Change in Mean (mm) VAS for Pre-injection and Immediately After Injection Timepoints
A visual analog scale (VAS) ranging from 0 to 100 mm on which subjects rate pain from no pain (0 mm) to worst possible pain (100 mm) was used. Mean VAS of 21 injections for each patient at pre-injection compared to mean VAS of 21 injections for each patient immediately after injection.
Time frame: Pre-injection and immediately after injection
Population: 3 subjects discontinued and withdrew consent from the Betaseron to the new formulation of rebif group in the Extension Phase
| Arm | Measure | Value (MEAN) |
|---|---|---|
| New Formulation of Rebif | Secondary Outcome - Extension Phase: Change in Mean (mm) VAS for Pre-injection and Immediately After Injection Timepoints | 1.67 millimeters |
| Betaseron | Secondary Outcome - Extension Phase: Change in Mean (mm) VAS for Pre-injection and Immediately After Injection Timepoints | 2.50 millimeters |
Other Pre-specified
Secondary Outcome - Extension Phase: Change in Mean VAS at Pre-injection and 10 Minutes Post Injection
Time frame: Pre-injection and 10 minutes post injection
Population: 3 subjects discontinued and withdrew consent from the Betaseron to the new formulation of rebif group in the Extension Phase
| Arm | Measure | Value (MEAN) |
|---|---|---|
| New Formulation of Rebif | Secondary Outcome - Extension Phase: Change in Mean VAS at Pre-injection and 10 Minutes Post Injection | 0.40 Millimeters |
| Betaseron | Secondary Outcome - Extension Phase: Change in Mean VAS at Pre-injection and 10 Minutes Post Injection | 0.91 Millimeters |
Other Pre-specified
Secondary Outcome - Extension Phase: Diameter in Injection Site Redness
Time frame: 1 to 72 hours post injection
Population: 3 subjects discontinued and withdrew consent from the Betaseron to Rebif New Formulation Group in the Extension Phase
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| New Formulation of Rebif | Secondary Outcome - Extension Phase: Diameter in Injection Site Redness | 10.79 Millimeters | Standard Deviation 13.89 |
| Betaseron | Secondary Outcome - Extension Phase: Diameter in Injection Site Redness | 7.46 Millimeters | Standard Deviation 10.57 |
Other Pre-specified
Secondary Outcome - Extension Phase: Number of Pain Free Patients at 30 Minutes Post Injection
Time frame: Pain free patients at 30 minutes post injection
Population: 3 subjects discontinued and withdrew consent from the Betaseron to the new formulation of rebif group in the Extension Phase
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| New Formulation of Rebif | Secondary Outcome - Extension Phase: Number of Pain Free Patients at 30 Minutes Post Injection | 30 Participants |
| Betaseron | Secondary Outcome - Extension Phase: Number of Pain Free Patients at 30 Minutes Post Injection | 36 Participants |