Multiple Sclerosis
Conditions
Keywords
Clinically Definite Multiple Sclerosis, Clinically Isolated Syndrome, Multiple Sclerosis
Brief summary
The primary objective is to assess the effect of treatment with glatiramer acetate (GA) compared to placebo on the time to conversion to CDMS, as determined by Poser criteria (the occurrence of the second clinical attack) during the double-blind period. The secondary objective is to assess, within the time frame of the up to 3-year double-blind, placebo-controlled study period, the effect of GA on clinical and Magnetic Resonance Imaging (MRI) parameters. The long-term objectives of the study (exploratory in nature) are to assess, within the time frame of 5 years, the neuroprotective effect of early versus delayed treatment with GA as reflected by clinical and MRI parameters measuring the accumulated irreversible brain tissue damage. A pre-planned interim analysis was performed on all efficacy and safety data accumulated in the database up to October 14, 2007, i.e. when 81% of exposure to treatment in the double-blind, placebo-controlled period had been collected. Upon review of the interim analysis results, the Data Monitoring Committee (DMC) recommended that the double-blind portion of the study be stopped and that subjects be switched to the 2-year Open-label period, during which time they would have the option of receiving GA therapy. The sponsor (Teva) adopted the DMC recommendations and took the necessary action towards its implementation.
Interventions
DRUGGlatiramer Acetate (DB)
Double blind period (DB): glatiramer acetate (GA) by subcutaneous injection, 20mg, once daily, for up to 36 months or until conversion to clinically definite multiple sclerosis (CDMS).
DRUGPlacebo
Double blind period (DB): subcutaneous injection of placebo, once daily, for up to 36 months or until conversion to CDMS
DRUGGlatiramer Acetate (OL)
Open label period (OL): glatiramer acetate (GA), 20 mg, subcutaneous injection, once daily, given for up to an additional 24 months.
Sponsors
Teva Branded Pharmaceutical Products R&D, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
1. The subject must have undergone a single clinical attack. 2. The subject must have a unifocal clinical presentation. 3. The subject should be enrolled within the period of 90 days after onset of a single unifocal clinical attack (index attack). 4. There must be 2 or more cerebral lesions highly suspicious of multiple sclerosis (MS) on the screening Magnetic Resonance Imaging (MRI), measuring 6mm or more in diameter. 5. Subjects must be between the ages of 18 and 45 years inclusive. 6. Subjects must not have taken corticosteroids within the 30 days prior to the MRI at the baseline visit. 7. Subjects may be male or female. Women of child-bearing potential must practice a medically acceptable method of birth control. Acceptable methods include oral contraceptive, contraceptive patch, long-acting injectable contraceptive, or double-barrier method (condom or intrauterine device with spermicide). 8. The subjects must be willing and able to give written informed consent, prior to entering the study.
Exclusion criteria
1. Multifocal clinical presentation. 2. Diseases other than MS responsible for the clinical/MRI presentation. The following laboratory tests must be part of the subject's medical history for differential diagnosis of clinically isolated syndrome (CIS): erythrocyte sedimentation rate (ESR), antinuclear antibody (ANA), complement (C3, C4) and anticardiolipin IgG - IgM. In the event that the results of these tests are inconclusive, the following additional tests may be requested by the Eligibility Evaluation Committee: syphilis screening, vitamin B12 and folic acid. In the case of spinal cord CIS presentation, a spinal cord MRI is required for confirmation of diagnosis in the medical history of the subject. 3. Use of experimental or investigational drugs, including IV immunoglobulin, and/or participation in an investigational drug study within 6 months prior to study entry. 4. Use of interferon agents within 6 months prior to the screening visit. 5. Chronic corticosteroid treatment (more than 30 consecutive days) in the 6 months prior to study entry. 6. Pregnancy or breast feeding. 7. Subjects who experience a relapse between the screening (month -1) and baseline (month 0) visits. 8. Life-threatening or other clinically significant disease. 9. A medical or psychiatric condition that affects the subject's ability to give informed consent, or to complete the study, or if the subject is considered by the treating neurologist/physician to be, for any other reason, an unsuitable candidate for this study. 10. A known history of sensitivity to mannitol. 11. A known history of sensitivity to gadolinium. 12. Inability to successfully undergo MRI scanning.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Clinically Definite Multiple Sclerosis (CDMS) Conversion | up to 3 years | Data from interim analysis with database lock on October 14, 2007. The time from randomization to conversion to CDMS as determined by the occurrence of a second clinical attack during the double-blind period. Poser criteria are: Two relapses and clinical evidence of two separate lesions; clinical evidence of one lesion and paraclinical evidence of another separate lesion. The two relapses must involve different parts of Central Nervous System and must be separated by a period of at least one month. Lesions are determined by Magnetic Resonance Imaging (MRI). |
| Twenty-fifth Percentile (25%) Kaplan-Meier Estimates for Time From Randomization to Conversion to Clinically Definite Multiple Sclerosis (CDMS) During the Double-blind Period | up to 3 years | Data from interim analysis with database lock on October 14, 2007. Due to the number of participants in the glatiramer acetate group that converted to CDMS (see outcome #6), the 25th percentile was considered when running the Kaplan-Meier estimate for time to conversion to CDMS. Conversion to CDMS is determined by the occurrence of the second clinical attack. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of New T2 Brain Lesions Observed at the Last Observed Value (LOV) in the Double-blind Period | up to 3 years | Data from interim analysis with database lock on October 14, 2007. T2 lesions are brain lesions that show on magnetic resonance imaging (MRI) and are associated with multiple sclerosis. This outcome measures the number of new lesions at the last observed value. Last Observed Value (LOV) is defined as the last post baseline measurement taken on study drug but no more than 30 days after study drug cessation. |
| Change From Baseline to Last Observed Value (LOV) in T2 Brain Lesion Volume in the Double-blind Period | Day 0 (baseline), up to 3 years | Data from interim analysis with database lock on October 14, 2007. The difference in T2 brain lesion volume as observed in MRIs from baseline to the last observed value. Last Observed Value (LOV) is defined as the last post baseline measurement taken on study drug but no more than 30 days after study drug cessation. |
| Percentage Change in Brain Volume From Baseline to the Last Observed Value (LOV) During the Double-blind Period Using the Structural Image Evaluation of Normalized Atrophy (SIENA) Technique | Day 0 (baseline), up to 3 years | Data from interim analysis with database lock on October 14, 2007. Brain volume was measured annually by magnetic resonance imaging (MRI) during the Double-blind period. Brain atrophy was measured by comparing the change in brain volume from baseline to the Last Observed Value (LOV). LOV is defined as the last post baseline measurement taken on study drug but no more than 30 days after study drug cessation. SIENA is a fully automated method of analyzing longitudinal brain change. |
| Percentage of Participants Who Converted to Clinically Definite Multiple Sclerosis (CDMS) During the Double-blind Period | up to 3 years | Data from interim analysis with database lock on October 14, 2007. Conversion to CDMS as determined by the occurrence of a second clinical attack during the double-blind period. Poser criteria are: Two relapses and clinical evidence of two separate lesions; clinical evidence of one lesion and paraclinical evidence of another separate lesion. The two relapses must involve different parts of Central Nervous System and must be separated by a period of at least one month. Lesions are determined by Magnetic Resonance Imaging (MRI). |
Participant flow
Recruitment details
A clinically isolated syndrome (CIS) is a first neurological episode, lasting at least 24 hours, caused by inflammation/demyelination in one or more sites in the central nervous system (CNS.) Subjects were enrolled within 90 days of the event and randomized up to 32 days following screening.
Pre-assignment details
Six-hundred and nineteen (619) subjects were screened for this study; 138 subjects were screening failures, including one subject, randomized in error. This subject, who had a relapse between screening visit and baseline, never received any treatment, and is considered a screening failure.
Participants by arm
| Arm | Count |
|---|---|
| Glatiramer Acetate (Double-blind Period) Glatiramer acetate 20 mg once daily by subcutaneous injection during the double-blind period. | 243 |
| Placebo (Double-blind Period) Placebo matching GA once daily by subcutaneous injection during the double-blind period. | 238 |
| Total | 481 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-Blind | Adverse Event | 15 | 5 |
| Double-Blind | Death | 1 | 0 |
| Double-Blind | Lost to Follow-up | 2 | 2 |
| Double-Blind | Noncompliance | 1 | 0 |
| Double-Blind | Physician Decision | 0 | 3 |
| Double-Blind | Pregnancy | 3 | 2 |
| Double-Blind | Sponsor decision | 1 | 0 |
| Double-Blind | Undefined/Unknown | 4 | 1 |
| Double-Blind | Withdrawal by Subject | 18 | 14 |
| Open-Label | Adverse Event | 8 | 43 |
| Open-Label | Lost to Follow-up | 4 | 5 |
| Open-Label | Noncompliance | 2 | 1 |
| Open-Label | Physician Decision | 7 | 5 |
| Open-Label | Pregnancy | 1 | 5 |
| Open-Label | Undefined/Unknown | 1 | 1 |
| Open-Label | Withdrawal by Subject | 12 | 25 |
Baseline characteristics
| Characteristic | Glatiramer Acetate (Double-blind Period) | Placebo (Double-blind Period) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 243 Participants | 238 Participants | 481 Participants |
| Age Continuous | 31.5 years STANDARD_DEVIATION 6.9 | 30.8 years STANDARD_DEVIATION 7 | 31.2 years STANDARD_DEVIATION 6.9 |
| Participants Who Used Corticosteroids for Initial Attack Did not use corticosteroids | 94 participants | 79 participants | 173 participants |
| Participants Who Used Corticosteroids for Initial Attack Used corticosteroids | 149 participants | 159 participants | 308 participants |
| Race/Ethnicity, Customized Asian / Oriental | 2 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized Black or African American | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Caucasian | 233 participants | 229 participants | 462 participants |
| Race/Ethnicity, Customized Hispanic | 3 participants | 2 participants | 5 participants |
| Race/Ethnicity, Customized Other (not specified) | 4 participants | 5 participants | 9 participants |
| Region of Enrollment Argentina | 7 participants | 6 participants | 13 participants |
| Region of Enrollment Australia | 7 participants | 6 participants | 13 participants |
| Region of Enrollment Austria | 5 participants | 6 participants | 11 participants |
| Region of Enrollment Denmark | 5 participants | 6 participants | 11 participants |
| Region of Enrollment Finland | 10 participants | 10 participants | 20 participants |
| Region of Enrollment France | 11 participants | 11 participants | 22 participants |
| Region of Enrollment Germany | 32 participants | 31 participants | 63 participants |
| Region of Enrollment Hungary | 16 participants | 15 participants | 31 participants |
| Region of Enrollment Italy | 56 participants | 57 participants | 113 participants |
| Region of Enrollment New Zealand | 4 participants | 3 participants | 7 participants |
| Region of Enrollment Norway | 2 participants | 2 participants | 4 participants |
| Region of Enrollment Romania | 28 participants | 30 participants | 58 participants |
| Region of Enrollment Spain | 23 participants | 22 participants | 45 participants |
| Region of Enrollment Sweden | 2 participants | 0 participants | 2 participants |
| Region of Enrollment United Kingdom | 15 participants | 12 participants | 27 participants |
| Region of Enrollment United States | 20 participants | 21 participants | 41 participants |
| Sex: Female, Male Female | 159 Participants | 163 Participants | 322 Participants |
| Sex: Female, Male Male | 84 Participants | 75 Participants | 159 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 165 / 238 | 191 / 243 | 352 / 454 |
| serious Total, serious adverse events | 19 / 238 | 11 / 243 | 44 / 454 |
Outcome results
Primary
Time to Clinically Definite Multiple Sclerosis (CDMS) Conversion
Data from interim analysis with database lock on October 14, 2007. The time from randomization to conversion to CDMS as determined by the occurrence of a second clinical attack during the double-blind period. Poser criteria are: Two relapses and clinical evidence of two separate lesions; clinical evidence of one lesion and paraclinical evidence of another separate lesion. The two relapses must involve different parts of Central Nervous System and must be separated by a period of at least one month. Lesions are determined by Magnetic Resonance Imaging (MRI).
Time frame: up to 3 years
Population: Intent-to-Treat (ITT) analysis set. The ITT consists of all participants who have been randomized and received at least one dose of glatiramer acetate or placebo.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glatiramer Acetate (Double-blind Period) | Time to Clinically Definite Multiple Sclerosis (CDMS) Conversion | 657.85 days | Standard Deviation 349.3 |
| Placebo (Double-blind Period) | Time to Clinically Definite Multiple Sclerosis (CDMS) Conversion | 590.54 days | Standard Deviation 340.2 |
p-value: 0.000595% CI: [0.4, 0.77]Regression, Cox
Primary
Twenty-fifth Percentile (25%) Kaplan-Meier Estimates for Time From Randomization to Conversion to Clinically Definite Multiple Sclerosis (CDMS) During the Double-blind Period
Data from interim analysis with database lock on October 14, 2007. Due to the number of participants in the glatiramer acetate group that converted to CDMS (see outcome #6), the 25th percentile was considered when running the Kaplan-Meier estimate for time to conversion to CDMS. Conversion to CDMS is determined by the occurrence of the second clinical attack.
Time frame: up to 3 years
Population: Intent-to-Treat (ITT) analysis set. The ITT consists of all participants who have been randomized and received at least one dose of glatiramer acetate or placebo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Glatiramer Acetate (Double-blind Period) | Twenty-fifth Percentile (25%) Kaplan-Meier Estimates for Time From Randomization to Conversion to Clinically Definite Multiple Sclerosis (CDMS) During the Double-blind Period | 722 days |
| Placebo (Double-blind Period) | Twenty-fifth Percentile (25%) Kaplan-Meier Estimates for Time From Randomization to Conversion to Clinically Definite Multiple Sclerosis (CDMS) During the Double-blind Period | 336 days |
Secondary
Change From Baseline to Last Observed Value (LOV) in T2 Brain Lesion Volume in the Double-blind Period
Data from interim analysis with database lock on October 14, 2007. The difference in T2 brain lesion volume as observed in MRIs from baseline to the last observed value. Last Observed Value (LOV) is defined as the last post baseline measurement taken on study drug but no more than 30 days after study drug cessation.
Time frame: Day 0 (baseline), up to 3 years
Population: Intent to treat population for which data at both timepoints are available
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glatiramer Acetate (Double-blind Period) | Change From Baseline to Last Observed Value (LOV) in T2 Brain Lesion Volume in the Double-blind Period | 1.2 ml | Standard Deviation 2.6 |
| Placebo (Double-blind Period) | Change From Baseline to Last Observed Value (LOV) in T2 Brain Lesion Volume in the Double-blind Period | 2.6 ml | Standard Deviation 3.9 |
p-value: 0.001395% CI: [0.79, 0.95]ANCOVA
Secondary
Number of New T2 Brain Lesions Observed at the Last Observed Value (LOV) in the Double-blind Period
Data from interim analysis with database lock on October 14, 2007. T2 lesions are brain lesions that show on magnetic resonance imaging (MRI) and are associated with multiple sclerosis. This outcome measures the number of new lesions at the last observed value. Last Observed Value (LOV) is defined as the last post baseline measurement taken on study drug but no more than 30 days after study drug cessation.
Time frame: up to 3 years
Population: Intent-to-Treat (ITT) analysis set. The ITT consists of all participants who have been randomized and received at least one dose of glatiramer acetate or placebo.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glatiramer Acetate (Double-blind Period) | Number of New T2 Brain Lesions Observed at the Last Observed Value (LOV) in the Double-blind Period | 0.7 new T2 lesions | Standard Deviation 1.7 |
| Placebo (Double-blind Period) | Number of New T2 Brain Lesions Observed at the Last Observed Value (LOV) in the Double-blind Period | 1.8 new T2 lesions | Standard Deviation 3.6 |
p-value: <0.000195% CI: [0.29, 0.61]Quasi-Likelihood NB* Regression
Secondary
Percentage Change in Brain Volume From Baseline to the Last Observed Value (LOV) During the Double-blind Period Using the Structural Image Evaluation of Normalized Atrophy (SIENA) Technique
Data from interim analysis with database lock on October 14, 2007. Brain volume was measured annually by magnetic resonance imaging (MRI) during the Double-blind period. Brain atrophy was measured by comparing the change in brain volume from baseline to the Last Observed Value (LOV). LOV is defined as the last post baseline measurement taken on study drug but no more than 30 days after study drug cessation. SIENA is a fully automated method of analyzing longitudinal brain change.
Time frame: Day 0 (baseline), up to 3 years
Population: Intent to treat population of participants with both baseline and last observed values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glatiramer Acetate (Double-blind Period) | Percentage Change in Brain Volume From Baseline to the Last Observed Value (LOV) During the Double-blind Period Using the Structural Image Evaluation of Normalized Atrophy (SIENA) Technique | -0.3 percent change | Standard Deviation 0.6 |
| Placebo (Double-blind Period) | Percentage Change in Brain Volume From Baseline to the Last Observed Value (LOV) During the Double-blind Period Using the Structural Image Evaluation of Normalized Atrophy (SIENA) Technique | -0.4 percent change | Standard Deviation 0.7 |
Secondary
Percentage of Participants Who Converted to Clinically Definite Multiple Sclerosis (CDMS) During the Double-blind Period
Data from interim analysis with database lock on October 14, 2007. Conversion to CDMS as determined by the occurrence of a second clinical attack during the double-blind period. Poser criteria are: Two relapses and clinical evidence of two separate lesions; clinical evidence of one lesion and paraclinical evidence of another separate lesion. The two relapses must involve different parts of Central Nervous System and must be separated by a period of at least one month. Lesions are determined by Magnetic Resonance Imaging (MRI).
Time frame: up to 3 years
Population: Intent-to-Treat (ITT) analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Glatiramer Acetate (Double-blind Period) | Percentage of Participants Who Converted to Clinically Definite Multiple Sclerosis (CDMS) During the Double-blind Period | 24.7 percentage of total participants |
| Placebo (Double-blind Period) | Percentage of Participants Who Converted to Clinically Definite Multiple Sclerosis (CDMS) During the Double-blind Period | 42.9 percentage of total participants |
p-value: <0.000195% CI: [0.27, 0.61]Regression, Logistic