Relapsing Multiple Sclerosis
Conditions
Keywords
Biomarkers, Genetic markers
Brief summary
This study, REbif® vs Glatiramer acetate in relapsing multiple sclerosis (MS) disease - pharmacogenetic(s) (REGARD-PGx) is a single blood sampling exploratory pharmacogenetic study of the REGARD trial. The aim of this trial is to provide additional data on the factors influencing interferon (IFN) beta response. This is a Phase 4 trial involving subjects who previously participated in the REGARD trial. To address the trial objectives, a single visit follow-up trial will be performed during which a blood sample will be collected.
Interventions
OTHERBlood sampling
Subjects who had received Rebif® 44 microgram (mcg) three times a week for 96 weeks in study 24735 (NCT00078338) and not participated in the initial PGx sub-study will be enrolled in this retrospective cohort study wherein single blood sampling will be performed for pharmacogenetic markers analysis.
Sponsors
EMD Serono
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Was randomized in the REGARD 24735 study * Is willing and able to comply with the protocol * Has given written informed consent before performing any trial-related activities
Exclusion criteria
* Is unwilling or unable to participate in the study * Is already included in the initial REGARD 24735 PGx sub-study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | Day 1 of EMR200136_023 study | A responder was defined as a participant with no multiple sclerosis (MS) relapse and no Expanded Disability Status Scale (EDSS) progression during 96 weeks in 24735 (NCT00078338). All responders were categorized on the basis of following six SNP markers: SNP1, SNP2, SNP3, SNP4, SNP5, and SNP6. Two types of variables were possible for each SNP marker: two-level genotype-based or three-level allele-based association variables. For the two-level genotype-based SNP markers (SNP2, SNP4, and SNP6), the absence or presence of the genotype was analyzed as the dichotomous variable as 0 (absence of the genotype) and 1 (presence of the genotype). For the three-level allele-based association SNP markers (SNP1, SNP3, and SNP5), the analysis was based on the number of copies of the allele (0, 1 and 2). Percentage of responders segregated on the basis of SNP marker variable were reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Confirmed Expanded Disability Status Scale (EDSS) Progression as Defined by SNP2 Marker | Day 1 of EMR200136_023 study | 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. SNP2 is two-level genotype-based SNP marker. The absence or presence of the genotype was analyzed as the dichotomous variable as 0 (absence of the genotype) and 1 (presence of the genotype). Number of responders segregated on the basis of SNP2 marker variable were reported. |
| Change in Time Constant 1 Gadolinium (T1 Gd) Enhancing Lesion Volume as Defined by SNP3 and SNP4 Markers | Baseline (Day 1 of 24735 [NCT00078338] study) and Day 1 of EMR200136_023 study | Change in T1 Gd enhancing lesion volume was measured by using magnetic resonance imaging (MRI) scans. SNP4 is two-level genotype-based SNP marker. The absence or presence of the genotype was analyzed as the dichotomous variable as 0 (absence of the genotype) and 1 (presence of the genotype). SNP3 is a three-level allele-based association SNP markers. The analysis was based on the number of copies of the allele (0, 1 and 2). Change in T1 Gd enhancing lesion volume segregated on the basis of SNP3 and SNP4 marker variables were reported. |
| Change in Brain Volume as Defined by SNP2 Marker | Baseline (Day 1 of 24735 [NCT00078338] study) and Day 1 of EMR200136_023 study | Change in brain volume was measured as the brain parenchymal fraction using MRI scans. SNP2 is two-level genotype-based SNP marker. The absence or presence of the genotype was analyzed as the dichotomous variable as 0 (absence of the genotype) and 1 (presence of the genotype). Change in brain volume segregated on the basis of SNP2 marker variables were reported. |
| Mean Number of Time Constant 2 (T2) Active Lesions Per Subject Per Scan as Defined by SNP5 Marker | Day 1 of EMR200136_023 study | Mean number of T2 active lesions was measured by using MRI scans. SNP5 is a three-level allele-based association SNP markers. The analysis was based on the number of copies of the allele (0, 1 and 2). Mean number of T2 active lesions segregated on the basis of SNP5 marker variables were reported. |
Countries
United States
Participant flow
Pre-assignment details
Of the 758 participants randomized and treated in study 24735 (NCT00078338), 326 were enrolled in EMR200136\_023 (NCT01034579) out of which 2 participants, who had participated in initial pharmacogenetics (PGx) sub-study, were found to be ineligible and therefore, evaluable population for EMR200136\_023 (NCT01034579) comprised of 324 participants.
Participants by arm
| Arm | Count |
|---|---|
| Rebif® Cohort Participants who had received Rebif® 44 microgram (mcg) three times a week for 96 weeks in study 24735 (NCT00078338) and not participated in the initial pharmacogenetics (PGx) sub-study were enrolled in this retrospective cohort study wherein single blood sampling was performed for pharmacogenetic markers analysis. | 158 |
| Copaxone® Cohort Participants who had received Copaxone® (Glatiramer Acetate) 20 milligram once daily for 96 weeks in study 24735 (NCT00078338) and not participated in the initial PGx sub-study were enrolled in this retrospective cohort study wherein single blood sampling was performed for pharmacogenetic markers analysis. | 166 |
| Total | 324 |
Baseline characteristics
| Characteristic | Rebif® Cohort | Copaxone® Cohort | Total |
|---|---|---|---|
| Age, Continuous | 36.4 years STANDARD_DEVIATION 9.5 | 37.4 years STANDARD_DEVIATION 9.5 | 36.9 years STANDARD_DEVIATION 9.5 |
| Sex: Female, Male Female | 99 Participants | 119 Participants | 218 Participants |
| Sex: Female, Male Male | 59 Participants | 47 Participants | 106 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 158 | 0 / 166 |
Outcome results
Primary
Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers
A responder was defined as a participant with no multiple sclerosis (MS) relapse and no Expanded Disability Status Scale (EDSS) progression during 96 weeks in 24735 (NCT00078338). All responders were categorized on the basis of following six SNP markers: SNP1, SNP2, SNP3, SNP4, SNP5, and SNP6. Two types of variables were possible for each SNP marker: two-level genotype-based or three-level allele-based association variables. For the two-level genotype-based SNP markers (SNP2, SNP4, and SNP6), the absence or presence of the genotype was analyzed as the dichotomous variable as 0 (absence of the genotype) and 1 (presence of the genotype). For the three-level allele-based association SNP markers (SNP1, SNP3, and SNP5), the analysis was based on the number of copies of the allele (0, 1 and 2). Percentage of responders segregated on the basis of SNP marker variable were reported.
Time frame: Day 1 of EMR200136_023 study
Population: Evaluable population. Here, 'N' signifies number of participants who were evaluable for this outcome measure and 'n' signifies number of participants who were evaluable for the specified SNP categories.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rebif® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP2: Absent (n=29, 28) | 79.3 percentage of participants |
| Rebif® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP4: Present (n=73, 77) | 63.0 percentage of participants |
| Rebif® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP1: 1 copy (n=61, 73) | 65.6 percentage of participants |
| Rebif® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP4: Absent (n=62, 72) | 67.7 percentage of participants |
| Rebif® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP3: 0 copy (n=62, 72) | 67.7 percentage of participants |
| Rebif® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP5: 0 copy (n=58, 66) | 65.5 percentage of participants |
| Rebif® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP2: Present (n=106, 121) | 61.3 percentage of participants |
| Rebif® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP5: 1 copy (n=54, 67) | 64.8 percentage of participants |
| Rebif® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP3: 1 copy (n=64, 62) | 60.9 percentage of participants |
| Rebif® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP5: 2 copies (n=23, 16) | 65.2 percentage of participants |
| Rebif® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP1: 2 copies (n=11, 15) | 72.7 percentage of participants |
| Rebif® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP6: Present (n=18, 27) | 55.6 percentage of participants |
| Rebif® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP3: 2 copies (n=9, 15) | 77.8 percentage of participants |
| Rebif® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP6: Absent (n=117, 122) | 66.7 percentage of participants |
| Rebif® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP1: 0 copy (n=63, 61) | 63.5 percentage of participants |
| Copaxone® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP6: Absent (n=117, 122) | 63.1 percentage of participants |
| Copaxone® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP1: 0 copy (n=63, 61) | 63.9 percentage of participants |
| Copaxone® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP1: 1 copy (n=61, 73) | 60.3 percentage of participants |
| Copaxone® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP1: 2 copies (n=11, 15) | 73.3 percentage of participants |
| Copaxone® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP2: Present (n=106, 121) | 64.5 percentage of participants |
| Copaxone® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP2: Absent (n=29, 28) | 57.1 percentage of participants |
| Copaxone® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP3: 0 copy (n=62, 72) | 65.3 percentage of participants |
| Copaxone® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP3: 1 copy (n=64, 62) | 56.5 percentage of participants |
| Copaxone® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP3: 2 copies (n=9, 15) | 80.0 percentage of participants |
| Copaxone® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP4: Present (n=73, 77) | 61.0 percentage of participants |
| Copaxone® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP4: Absent (n=62, 72) | 65.3 percentage of participants |
| Copaxone® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP5: 0 copy (n=58, 66) | 60.6 percentage of participants |
| Copaxone® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP5: 1 copy (n=54, 67) | 67.2 percentage of participants |
| Copaxone® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP5: 2 copies (n=23, 16) | 56.3 percentage of participants |
| Copaxone® Cohort | Percentage of Responders as Defined by Single Nucleotide Polymorphism (SNP) Markers | SNP6: Present (n=18, 27) | 63.0 percentage of participants |
Secondary
Change in Brain Volume as Defined by SNP2 Marker
Change in brain volume was measured as the brain parenchymal fraction using MRI scans. SNP2 is two-level genotype-based SNP marker. The absence or presence of the genotype was analyzed as the dichotomous variable as 0 (absence of the genotype) and 1 (presence of the genotype). Change in brain volume segregated on the basis of SNP2 marker variables were reported.
Time frame: Baseline (Day 1 of 24735 [NCT00078338] study) and Day 1 of EMR200136_023 study
Population: MRI evaluable population was defined to include all participants from the evaluable population who had at least one post-baseline MRI evaluation during study 24735. Here, 'N' signifies number of participants who were evaluable for this outcome measure and 'n' signifies number of participants who were evaluable for the specified SNP categories.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rebif® Cohort | Change in Brain Volume as Defined by SNP2 Marker | SNP2: Present (n=33, 38) | -1.51 cubic millimeter (mm^3) | Standard Deviation 1.6 |
| Rebif® Cohort | Change in Brain Volume as Defined by SNP2 Marker | SNP2: Absent (n=11, 6) | -0.57 cubic millimeter (mm^3) | Standard Deviation 1.25 |
| Copaxone® Cohort | Change in Brain Volume as Defined by SNP2 Marker | SNP2: Present (n=33, 38) | -1.10 cubic millimeter (mm^3) | Standard Deviation 1.16 |
| Copaxone® Cohort | Change in Brain Volume as Defined by SNP2 Marker | SNP2: Absent (n=11, 6) | -0.48 cubic millimeter (mm^3) | Standard Deviation 0.41 |
Secondary
Change in Time Constant 1 Gadolinium (T1 Gd) Enhancing Lesion Volume as Defined by SNP3 and SNP4 Markers
Change in T1 Gd enhancing lesion volume was measured by using magnetic resonance imaging (MRI) scans. SNP4 is two-level genotype-based SNP marker. The absence or presence of the genotype was analyzed as the dichotomous variable as 0 (absence of the genotype) and 1 (presence of the genotype). SNP3 is a three-level allele-based association SNP markers. The analysis was based on the number of copies of the allele (0, 1 and 2). Change in T1 Gd enhancing lesion volume segregated on the basis of SNP3 and SNP4 marker variables were reported.
Time frame: Baseline (Day 1 of 24735 [NCT00078338] study) and Day 1 of EMR200136_023 study
Population: MRI evaluable population was defined to include all participants from the evaluable population who had at least one post-baseline MRI evaluation during study 24735. Here, 'N' signifies number of participants who were evaluable for this outcome measure and 'n' signifies number of participants who were evaluable for the specified SNP categories.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rebif® Cohort | Change in Time Constant 1 Gadolinium (T1 Gd) Enhancing Lesion Volume as Defined by SNP3 and SNP4 Markers | SNP3: 1 copy (n=31, 22) | -106.97 cubic millimeter (mm^3) | Standard Deviation 152.22 |
| Rebif® Cohort | Change in Time Constant 1 Gadolinium (T1 Gd) Enhancing Lesion Volume as Defined by SNP3 and SNP4 Markers | SNP4: Present (n=35, 27) | -97.77 cubic millimeter (mm^3) | Standard Deviation 146.18 |
| Rebif® Cohort | Change in Time Constant 1 Gadolinium (T1 Gd) Enhancing Lesion Volume as Defined by SNP3 and SNP4 Markers | SNP3: 2 copies (n=4, 5) | -26.50 cubic millimeter (mm^3) | Standard Deviation 53 |
| Rebif® Cohort | Change in Time Constant 1 Gadolinium (T1 Gd) Enhancing Lesion Volume as Defined by SNP3 and SNP4 Markers | SNP4: Absent (n=30, 42) | -524.23 cubic millimeter (mm^3) | Standard Deviation 1481.03 |
| Rebif® Cohort | Change in Time Constant 1 Gadolinium (T1 Gd) Enhancing Lesion Volume as Defined by SNP3 and SNP4 Markers | SNP3: 0 copy (n=30, 42) | -524.23 cubic millimeter (mm^3) | Standard Deviation 1481.03 |
| Copaxone® Cohort | Change in Time Constant 1 Gadolinium (T1 Gd) Enhancing Lesion Volume as Defined by SNP3 and SNP4 Markers | SNP4: Absent (n=30, 42) | -203.71 cubic millimeter (mm^3) | Standard Deviation 687.59 |
| Copaxone® Cohort | Change in Time Constant 1 Gadolinium (T1 Gd) Enhancing Lesion Volume as Defined by SNP3 and SNP4 Markers | SNP3: 0 copy (n=30, 42) | -203.71 cubic millimeter (mm^3) | Standard Deviation 687.59 |
| Copaxone® Cohort | Change in Time Constant 1 Gadolinium (T1 Gd) Enhancing Lesion Volume as Defined by SNP3 and SNP4 Markers | SNP3: 1 copy (n=31, 22) | -61.95 cubic millimeter (mm^3) | Standard Deviation 232.25 |
| Copaxone® Cohort | Change in Time Constant 1 Gadolinium (T1 Gd) Enhancing Lesion Volume as Defined by SNP3 and SNP4 Markers | SNP3: 2 copies (n=4, 5) | -22.80 cubic millimeter (mm^3) | Standard Deviation 34.27 |
| Copaxone® Cohort | Change in Time Constant 1 Gadolinium (T1 Gd) Enhancing Lesion Volume as Defined by SNP3 and SNP4 Markers | SNP4: Present (n=35, 27) | -54.70 cubic millimeter (mm^3) | Standard Deviation 209.73 |
Secondary
Mean Number of Time Constant 2 (T2) Active Lesions Per Subject Per Scan as Defined by SNP5 Marker
Mean number of T2 active lesions was measured by using MRI scans. SNP5 is a three-level allele-based association SNP markers. The analysis was based on the number of copies of the allele (0, 1 and 2). Mean number of T2 active lesions segregated on the basis of SNP5 marker variables were reported.
Time frame: Day 1 of EMR200136_023 study
Population: MRI evaluable population was defined to include all participants from the evaluable population who had at least one post-baseline MRI evaluation during study 24735. Here, 'N' signifies number of participants who were evaluable for this outcome measure and 'n' signifies number of participants who were evaluable for the specified SNP categories.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rebif® Cohort | Mean Number of Time Constant 2 (T2) Active Lesions Per Subject Per Scan as Defined by SNP5 Marker | SNP5: 0 copy (n=31, 42) | 0.72 T2 lesions | Standard Deviation 1.5 |
| Rebif® Cohort | Mean Number of Time Constant 2 (T2) Active Lesions Per Subject Per Scan as Defined by SNP5 Marker | SNP5: 1 copy (n=36, 34) | 0.53 T2 lesions | Standard Deviation 1.41 |
| Rebif® Cohort | Mean Number of Time Constant 2 (T2) Active Lesions Per Subject Per Scan as Defined by SNP5 Marker | SNP5: 2 copies (n=11, 7) | 0.30 T2 lesions | Standard Deviation 0.4 |
| Copaxone® Cohort | Mean Number of Time Constant 2 (T2) Active Lesions Per Subject Per Scan as Defined by SNP5 Marker | SNP5: 0 copy (n=31, 42) | 1.05 T2 lesions | Standard Deviation 1.32 |
| Copaxone® Cohort | Mean Number of Time Constant 2 (T2) Active Lesions Per Subject Per Scan as Defined by SNP5 Marker | SNP5: 1 copy (n=36, 34) | 0.55 T2 lesions | Standard Deviation 1.19 |
| Copaxone® Cohort | Mean Number of Time Constant 2 (T2) Active Lesions Per Subject Per Scan as Defined by SNP5 Marker | SNP5: 2 copies (n=11, 7) | 0.18 T2 lesions | Standard Deviation 0.37 |
Secondary
Number of Participants With Confirmed Expanded Disability Status Scale (EDSS) Progression as Defined by SNP2 Marker
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. SNP2 is two-level genotype-based SNP marker. The absence or presence of the genotype was analyzed as the dichotomous variable as 0 (absence of the genotype) and 1 (presence of the genotype). Number of responders segregated on the basis of SNP2 marker variable were reported.
Time frame: Day 1 of EMR200136_023 study
Population: Evaluable population. Here, 'N' signifies number of participants who were evaluable for this outcome measure and 'n' signifies number of participants who were evaluable for the specified SNP categories.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rebif® Cohort | Number of Participants With Confirmed Expanded Disability Status Scale (EDSS) Progression as Defined by SNP2 Marker | SNP2: Present (n=106, 123) | 16 participants |
| Rebif® Cohort | Number of Participants With Confirmed Expanded Disability Status Scale (EDSS) Progression as Defined by SNP2 Marker | SNP2: Absent (n=29, 28) | 3 participants |
| Copaxone® Cohort | Number of Participants With Confirmed Expanded Disability Status Scale (EDSS) Progression as Defined by SNP2 Marker | SNP2: Present (n=106, 123) | 16 participants |
| Copaxone® Cohort | Number of Participants With Confirmed Expanded Disability Status Scale (EDSS) Progression as Defined by SNP2 Marker | SNP2: Absent (n=29, 28) | 0 participants |