Relapsing Remitting Multiple Sclerosis
Conditions
Keywords
Multiple Sclerosis, brain atrophy, Glatiramer Acetate, Copaxone, Steroids, Prednisone
Brief summary
This is a study evaluating the effect on brain volume of daily glatiramer acetate (GA) and add-on pulse steroids.
Detailed description
One interim analysis was planned for possible early termination due to proven efficacy when 75% of the preplanned 500 (approx. 375 patients) recruited patients completed the entire study duration or early discontinued. In addition to the stopping rule already given for proven efficacy, the sponsor was also interested in examining the data for futility (i.e., absence of the desired treatment effect) with the view to terminating the trial if an insufficient effect of the treatment is seen. The reasons why the need for futility arose were: 1. Recruitment difficulties 2. Increasing dropout rate 3. Budgetary constraints The primary efficacy measure is defined as the percent change from baseline to termination (Month 36 or Early Termination) in normalized brain volume (Brain Atrophy) measured according to the SIENA (Structural Imaging Evaluation using Normalization of Atrophy) method. However, since not many patients had completed the entire study at the time of futility analysis, it was the sponsor's decision that the futility analysis be performed on patients with MRI scans at months 24 or 36 or at early termination visits - the latest available. Based on the recalculation of study power (probability is unconditioned on the interim result and provide the real power of the study if designed anew), conditional power (based on the interim results) and risk assessment of a false negative, the Data Monitoring Committee agreed that the study should be terminated early.
Interventions
DRUGGlatiramer Acetate
20mg glatiramer acetate (GA) administered by daily subcutaneous injections
DRUGPlacebo
Placebo for prednisone given daily
DRUGPrednisone
Prednisone 1250 mg taken daily
Sponsors
Teva Branded Pharmaceutical Products R&D, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
1. Clinically definite multiple sclerosis (CDMS) according to Poser (Ann. Neurol. 1983) or McDonald (Ann. Neurol. 2001) 2. Subjects eligible for GA treatment based on the investigator's clinical assessment and according to the current indication. 3. Subjects must have a relapsing remitting disease course. 4. Subjects must have had at least 1 documented relapse within the last year prior to study entry. 5. Subjects may be male or female. Women of childbearing potential must practice an acceptable method of birth control. Acceptable methods include oral contraceptive, contraceptive patch, long-acting injectable contraceptive, double-barrier method (condom or intrauterine device \[IUD\] with spermicide), or partner's vasectomy. 6. Subjects must be between the ages of 18 and 55 years inclusive. 7. Subjects must be ambulatory, with a Kurtzke Expanded Disability Status Scale (EDSS) score between 0 and 5.0 inclusive. 8. Subjects must be willing and able to give written informed consent prior to entering the study.
Exclusion criteria
1. Long-term glatiramer acetate users who have been on therapy within 6 months of the baseline magnetic resonance imaging (MRI). New glatiramer acetate users who have initiated therapy for more than 6 weeks prior to the baseline MRI. 2. Previous use of cladribine. 3. Previous use of mitoxantrone. 4. Use of digitalis at study entry. 5. Previous use of immunosuppressive agents (such as azathioprine, cyclophosphamide or mycophenolate mofetil) in the last 6 months prior to screening. 6. Use of experimental or investigational drugs, including intravenous (IV) immunoglobulin within 6 months prior to screening. 7. Use of interferon agents within 1 month prior to the baseline MRI. 8. Use of corticosteroids (IV, intramuscular \[IM\] and/or by mouth \[PO\]) within 30 days prior to the baseline MRI. 9. Chronic corticosteroid (IV, IM and/or PO) treatment (more than 30 consecutive days) in the 6 months prior to the screening visit. 10. Subjects with diabetes. 11. Previous total body irradiation or total lymphoid irradiation. 12. Pregnancy or breast feeding. 13. Significant medical or psychiatric condition that affects the subject's ability to give informed consent, or to complete the study, or any condition which the investigator feels may interfere with participation in the study (e.g. alcohol or drug abuse). 14. Other diseases that can cause brain atrophy (ex. neurodegenerative disorder, cerebrovascular disease, history of alcohol abuse). 15. Bone density less than -2.5 standard deviations (SD) (osteoporosis). 16. A known history of sensitivity to mannitol. 17. Contraindication to, or known history of, sensitivity or severe reaction to steroids. 18. A known history of sensitivity to gadolinium. 19. Inability to successfully undergo MRI scanning. 20. Previous use of natalizumab.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline to Termination in Normalized Brain Volume Measured According to the SIENA (Structural Imaging Evaluation Using Normalization of Atrophy) Method | Day 0, latest scan at month 24, 36 or early termination visit | Results represent the database as of January 29, 2009. Brain volume was measured at baseline and at months 24, 36 and at early termination visits by magnetic resonance imaging (MRI). Brain atrophy was measured by comparing the change in brain volume from baseline to the latest scan at the three during study timeframes. SIENA is a fully automated method of analyzing longitudinal brain change. Adjusted (least square) mean values are presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Number of Enhancing Lesions at Months 12, 24 and 36 | Months 12, 24, and 36 | Results represent the database as of January 29, 2009. Enhancing lesions are lesions that show inflammation on an MRI and are assumed to be new lesions. The sum of enhancing lesions observed in MRIs taken at months 12, 24 and 36 are offered. |
| Change From Baseline to Month 36 or Early Termination Visit in Volume of T2-Lesions | Day 0, Month 36 or the early termination visit | Results represent the database as of January 29, 2009. The difference in T2 brain lesion volume as observed in MRIs from baseline to Month 36 or the early termination visit. T2 lesions are hyperintense lesions meaning that they appear as bright spots on the MRI image. These tend to show the total number of lesions and disease burden. |
| Change From Baseline to Month 36 or Early Termination Visit in Volume of Hypointense Lesions | Day 0, Month 36 or early termination visit | Results represent the database as of January 29, 2009. The difference in hypointense brain lesion volume as observed in MRIs from baseline to Month 36 or the early termination visit. Hypointense lesions display as dark areas on the MRI image, and represent areas of permanent axonal damage. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| GA + Placebo Glatiramer acetate (GA) 10mg as a subcutaneous injection daily, plus a placebo to mimic prednisone given daily. | 199 |
| GA + Prednisone Glatiramer acetate (GA) 20mg daily as a subcutaneous injection, plus 1250 mg of prednisone daily. | 209 |
| Total | 408 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 18 |
| Overall Study | Death | 1 | 2 |
| Overall Study | Lost to Follow-up | 11 | 5 |
| Overall Study | Non-compliance | 4 | 8 |
| Overall Study | Ongoing: in database - January 29, 2009 | 131 | 109 |
| Overall Study | Ongoing: not in database - Jan 29, 2009 | 5 | 1 |
| Overall Study | Other | 5 | 5 |
| Overall Study | Physician Decision | 8 | 7 |
| Overall Study | Pregnancy | 3 | 0 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Teva requested participant withdrawal | 1 | 1 |
| Overall Study | Withdrawal by Subject | 13 | 47 |
Baseline characteristics
| Characteristic | GA + Prednisone | GA + Placebo | Total |
|---|---|---|---|
| Age, Customized <=29 years | 40 participants | 32 participants | 72 participants |
| Age, Customized =30 and < 40 years | 68 participants | 61 participants | 129 participants |
| Age, Customized =40 and < 50 years | 70 participants | 70 participants | 140 participants |
| Age, Customized =50 and < 55 years | 29 participants | 35 participants | 64 participants |
| Age, Customized >= 55 years | 2 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized Asian / Oriental | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Black of African Heritage | 15 participants | 13 participants | 28 participants |
| Race/Ethnicity, Customized Caucasian | 179 participants | 171 participants | 350 participants |
| Race/Ethnicity, Customized Hispanic | 9 participants | 10 participants | 19 participants |
| Race/Ethnicity, Customized Other | 6 participants | 4 participants | 10 participants |
| Region of Enrollment Australia | 1 participants | 4 participants | 5 participants |
| Region of Enrollment Canada | 20 participants | 16 participants | 36 participants |
| Region of Enrollment United States | 188 participants | 179 participants | 367 participants |
| Sex: Female, Male Female | 157 Participants | 151 Participants | 308 Participants |
| Sex: Female, Male Male | 52 Participants | 48 Participants | 100 Participants |
| T1 Enhancing Lesions at Baseline | 1.86 lesions STANDARD_DEVIATION 9.91 | 1.05 lesions STANDARD_DEVIATION 2.77 | 1.43 lesions STANDARD_DEVIATION 7.12 |
| T1 Hypointense Lesions Volume at Baseline | 0.84 cm^3 STANDARD_DEVIATION 1.5 | 0.94 cm^3 STANDARD_DEVIATION 1.77 | 0.89 cm^3 STANDARD_DEVIATION 1.64 |
| T2 Lesions Volume at Baseline | 5.35 cm^3 STANDARD_DEVIATION 7.97 | 5.51 cm^3 STANDARD_DEVIATION 7.17 | 5.44 cm^3 STANDARD_DEVIATION 7.55 |
| Time from First Multiple Sclerosis (MS) Symptom | 76.7 months STANDARD_DEVIATION 75.5 | 89.8 months STANDARD_DEVIATION 104.5 | 83.1 months STANDARD_DEVIATION 91 |
| Time from MS Diagnosis | 42.1 months STANDARD_DEVIATION 62.9 | 40.5 months STANDARD_DEVIATION 71.4 | 41.3 months STANDARD_DEVIATION 67.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 131 / 199 | 151 / 209 |
| serious Total, serious adverse events | 16 / 199 | 13 / 209 |
Outcome results
Primary
Percent Change From Baseline to Termination in Normalized Brain Volume Measured According to the SIENA (Structural Imaging Evaluation Using Normalization of Atrophy) Method
Results represent the database as of January 29, 2009. Brain volume was measured at baseline and at months 24, 36 and at early termination visits by magnetic resonance imaging (MRI). Brain atrophy was measured by comparing the change in brain volume from baseline to the latest scan at the three during study timeframes. SIENA is a fully automated method of analyzing longitudinal brain change. Adjusted (least square) mean values are presented.
Time frame: Day 0, latest scan at month 24, 36 or early termination visit
Population: Treated population of participants who had both a baseline MRI and an MRI at least one of the three during study time frames. The latest MRI was used if more than one during study MRI was available.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| GA + Placebo | Percent Change From Baseline to Termination in Normalized Brain Volume Measured According to the SIENA (Structural Imaging Evaluation Using Normalization of Atrophy) Method | -0.46 percent change of baseline brain volume | Standard Error 0.088 |
| GA + Prednisone | Percent Change From Baseline to Termination in Normalized Brain Volume Measured According to the SIENA (Structural Imaging Evaluation Using Normalization of Atrophy) Method | -0.43 percent change of baseline brain volume | Standard Error 0.106 |
p-value: 0.802395% CI: [-0.26, 0.2]ANCOVA
Secondary
Change From Baseline to Month 36 or Early Termination Visit in Volume of Hypointense Lesions
Results represent the database as of January 29, 2009. The difference in hypointense brain lesion volume as observed in MRIs from baseline to Month 36 or the early termination visit. Hypointense lesions display as dark areas on the MRI image, and represent areas of permanent axonal damage.
Time frame: Day 0, Month 36 or early termination visit
Population: Treated population of participants with an MRI at the stated time frames.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GA + Placebo | Change From Baseline to Month 36 or Early Termination Visit in Volume of Hypointense Lesions | 0.43 cm^3 | Standard Deviation 1.6 |
| GA + Prednisone | Change From Baseline to Month 36 or Early Termination Visit in Volume of Hypointense Lesions | 0.17 cm^3 | Standard Deviation 0.86 |
Secondary
Change From Baseline to Month 36 or Early Termination Visit in Volume of T2-Lesions
Results represent the database as of January 29, 2009. The difference in T2 brain lesion volume as observed in MRIs from baseline to Month 36 or the early termination visit. T2 lesions are hyperintense lesions meaning that they appear as bright spots on the MRI image. These tend to show the total number of lesions and disease burden.
Time frame: Day 0, Month 36 or the early termination visit
Population: Treated population of participants with an MRI at the stated time frames.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GA + Placebo | Change From Baseline to Month 36 or Early Termination Visit in Volume of T2-Lesions | 0.07 cm^3 | Standard Deviation 3.21 |
| GA + Prednisone | Change From Baseline to Month 36 or Early Termination Visit in Volume of T2-Lesions | 0.09 cm^3 | Standard Deviation 2.93 |
Secondary
Cumulative Number of Enhancing Lesions at Months 12, 24 and 36
Results represent the database as of January 29, 2009. Enhancing lesions are lesions that show inflammation on an MRI and are assumed to be new lesions. The sum of enhancing lesions observed in MRIs taken at months 12, 24 and 36 are offered.
Time frame: Months 12, 24, and 36
Population: Treated population who had at least a 12 month MRI
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GA + Placebo | Cumulative Number of Enhancing Lesions at Months 12, 24 and 36 | 0.69 lesions | Standard Deviation 3.28 |
| GA + Prednisone | Cumulative Number of Enhancing Lesions at Months 12, 24 and 36 | 0.76 lesions | Standard Deviation 1.86 |