Relapsing-Remitting Multiple Sclerosis
Conditions
Keywords
MS, multiple sclerosis
Brief summary
The primary objective of this study is to determine whether DAC HYP, when compared to placebo, is effective in reducing the rate of relapses between baseline and Week 52. The secondary objectives are to determine whether DAC HYP is effective in reducing the number of new gadolinium (Gd)-enhancing lesions, reducing the number of new or newly-enlarging T2 hyperintense lesions, reducing the proportion of participants with relapses, and improving quality of life.
Interventions
BIOLOGICALBIIB019 (Daclizumab High Yield Process)
SC injection
DRUGPlacebo
Placebo SC injection
Sponsors
AbbVie
Biogen
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 55 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Multiple Sclerosis (MS) subjects who have a confirmed diagnosis of relapsing-remitting MS according to McDonald criteria #1-4 and a baseline Expanded Disability Status Scale (EDSS) between 0.0 and 5.0, inclusive, who meet either of the following 2 criteria: * Have experienced at least 1 relapse within the 12 months prior to randomization, with a cranial magnetic resonance imaging (MRI) demonstrating lesion(s) consistent with MS , OR * Show evidence of gadolinium-enhancing lesions of the brain on an MRI performed within the 6 weeks prior to randomization. Key
Exclusion criteria
* Diagnosis of primary progressive, secondary progressive, or progressive relapsing MS * History of malignancy * History of severe allergic or anaphylactic reactions or known drug hypersensitivity * History of abnormal laboratory results based on investigator judgment * History of human immunodeficiency virus (HIV) or other immunodeficient conditions * History of drug or alcohol abuse within the 2 years prior to randomization * An MS relapse that has occurred within the 50 days prior to randomization AND/OR the subject has not stabilized from a previous relapse prior to randomization * Positive screening for active infection with Hepatitis B virus or Hepatitis C virus * Varicella or herpes zoster virus infection or any severe viral infection within 6 weeks before Screening * Exposure to varicella zoster virus within 21 days before Screening. * Abnormal blood tests at Screening: Hemoglobin ≤9.0 g/dL, Platelets ≤100 × 10\^9/L, Lymphocytes ≤1.0 × 10\^9/L, Neutrophils ≤1.5 × 10\^9/L, alanine aminotransferase/serum glutamate pyruvate transaminase (ALT/SGPT), aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT), or gamma-glutamyl-transferase \>2 times the upper limit of normal (ULN) and serum creatinine \>ULN. NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Annualized Relapse Rate Between Baseline and Week 52 | Baseline through Week 52 | Relapses are defined as new or recurrent neurologic symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the examining neurologist. The annualized relapse rate was calculated as the total number of relapses that occurred during the study divided by the total number of subject-years followed in the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Number of New Gadolinium (Gd)-Enhancing Lesions Between Week 8 and Week 24 | Week 8 through Week 24 | Gd-enhancing lesions are detected when Gd leaks into a perivascular space due to local breakdown of the blood-brain barrier, indicating the presence of active inflammation. For participants with missing data the last valid nonbaseline measurement was carried forward if the participant was missing only 1 or 2 consecutive postbaseline scans. Otherwise the mean based on treatment group and visit was used as the imputed value. Estimated from a negative binomial model adjusted for the baseline number of Gd-enhancing lesions. |
| Adjusted Mean Number of New or Newly-enlarging T2 Hyperintense Lesions at Week 52 | Week 52 | Lesions detected on T2-weighted sequences represent a range of histopathology related to MS, including edema, inflammation, demyelination, gliosis, and axon loss. |
| Proportion of Participants Who Relapsed at Week 52 | Week 52 | Estimated cumulative proportion of participants relapsed at Week 52, based on the Kaplan-Meier product limit method. Only relapses confirmed by the Independent Neurology Evaluation Committee were included in the analysis. |
| Mean Change From Baseline in Multiple Sclerosis Impact Scale (MSIS)-29 Physical Impact Score at Week 52 | Baseline and Week 52 | The 29-item Multiple Sclerosis Impact Scale (MSIS-29) is a disease specific patient-reported outcome measure that has been developed and validated to examine the physical and psychological impact of MS from a patient's perspective; it measures 20 physical items and 9 psychological items. Responses use a 5 point Likert scale range from 1 to 5. All questions are to be answered. The total score is the sum of points for all 29 questions, with a minimum score of 29, and a maximum score of 145. A lower total score indicates less physically-related impact while a higher total score indicates greater physically-related impact on a subject's functioning. |
Countries
Czechia, Germany, Hungary, India, Poland, Russia, Ukraine, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo administered as 3 SC injections every 4 weeks for up to 52 weeks | 204 |
| 150 mg DAC HYP 150 mg DAC HYP administered as 3 SC injections every 4 weeks for up to 52 weeks | 208 |
| 300 mg DAC HYP 300 mg DAC HYP administered as 3 SC injections every 4 weeks for up to 52 weeks | 209 |
| Total | 621 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 4 | 3 |
| Overall Study | Investigator Decision | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 3 | 0 |
| Overall Study | Other | 3 | 4 | 2 |
| Overall Study | Subject Non-compliance | 1 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 13 | 9 | 7 |
Baseline characteristics
| Characteristic | Placebo | 150 mg DAC HYP | 300 mg DAC HYP | Total |
|---|---|---|---|---|
| Age, Continuous | 36.6 years STANDARD_DEVIATION 9.02 | 35.3 years STANDARD_DEVIATION 8.94 | 35.2 years STANDARD_DEVIATION 8.67 | 35.7 years STANDARD_DEVIATION 8.88 |
| Age, Customized 18 to 19 years | 1 participants | 4 participants | 5 participants | 10 participants |
| Age, Customized 20 to 29 years | 46 participants | 55 participants | 53 participants | 154 participants |
| Age, Customized 30 to 39 years | 79 participants | 73 participants | 90 participants | 242 participants |
| Age, Customized 40 to 49 years | 60 participants | 67 participants | 49 participants | 176 participants |
| Age, Customized 50 to 55 years | 18 participants | 9 participants | 12 participants | 39 participants |
| Sex: Female, Male Female | 128 Participants | 140 Participants | 134 Participants | 402 Participants |
| Sex: Female, Male Male | 76 Participants | 68 Participants | 75 Participants | 219 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 128 / 204 | 109 / 208 | 111 / 209 | 220 / 417 |
| serious Total, serious adverse events | 53 / 204 | 32 / 208 | 36 / 209 | 68 / 417 |
Outcome results
Primary
Adjusted Annualized Relapse Rate Between Baseline and Week 52
Relapses are defined as new or recurrent neurologic symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the examining neurologist. The annualized relapse rate was calculated as the total number of relapses that occurred during the study divided by the total number of subject-years followed in the study.
Time frame: Baseline through Week 52
Population: Intent to treat population: all randomized participants who received at least 1 dose of study medication (excluding 21 participants from a single site due to a protocol violation in dosing).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Adjusted Annualized Relapse Rate Between Baseline and Week 52 | 0.458 relapses per person-years |
| 150 mg DAC HYP | Adjusted Annualized Relapse Rate Between Baseline and Week 52 | 0.211 relapses per person-years |
| 300 mg DAC HYP | Adjusted Annualized Relapse Rate Between Baseline and Week 52 | 0.230 relapses per person-years |
p-value: <0.000195% CI: [0.318, 0.668]Negative Binomial Regression
p-value: 0.000295% CI: [0.352, 0.721]Negative Binomial Regression
Secondary
Adjusted Mean Number of New Gadolinium (Gd)-Enhancing Lesions Between Week 8 and Week 24
Gd-enhancing lesions are detected when Gd leaks into a perivascular space due to local breakdown of the blood-brain barrier, indicating the presence of active inflammation. For participants with missing data the last valid nonbaseline measurement was carried forward if the participant was missing only 1 or 2 consecutive postbaseline scans. Otherwise the mean based on treatment group and visit was used as the imputed value. Estimated from a negative binomial model adjusted for the baseline number of Gd-enhancing lesions.
Time frame: Week 8 through Week 24
Population: Magnetic Resonance Imaging (MRI) Intensive Population: a protocol-defined subset of participants consisting of the first 307 participants enrolled in the study with non-missing baseline values.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Adjusted Mean Number of New Gadolinium (Gd)-Enhancing Lesions Between Week 8 and Week 24 | 4.79 lesions |
| 150 mg DAC HYP | Adjusted Mean Number of New Gadolinium (Gd)-Enhancing Lesions Between Week 8 and Week 24 | 1.46 lesions |
| 300 mg DAC HYP | Adjusted Mean Number of New Gadolinium (Gd)-Enhancing Lesions Between Week 8 and Week 24 | 1.03 lesions |
Comparison: For each of the secondary endpoints, a sequential closed testing procedure was used, with the first comparison (the DAC HYP 300 mg group versus placebo) and the second comparison (the DAC HYP 150 mg group versus placebo). Secondary endpoints were rank prioritized, in the order presented. If statistical significance was not achieved for an endpoint, all endpoints(s) of a lower rank were not considered statistically significant.p-value: <0.000195% CI: [65.97, 86.35]Negative Binomial Regression
Comparison: For each of the secondary endpoints, a sequential closed testing procedure was used, with the first comparison (the DAC HYP 300 mg group versus placebo) and the second comparison (the DAC HYP 150 mg group versus placebo). Secondary endpoints were rank prioritized, in the order presented. If statistical significance was not achieved for an endpoint, all endpoints(s) of a lower rank were not considered statistically significant.p-value: <0.000195% CI: [52.4, 80.41]Negative Binomial Regression
Secondary
Adjusted Mean Number of New or Newly-enlarging T2 Hyperintense Lesions at Week 52
Lesions detected on T2-weighted sequences represent a range of histopathology related to MS, including edema, inflammation, demyelination, gliosis, and axon loss.
Time frame: Week 52
Population: Intent to treat population: all randomized subjects who received at least 1 dose of study medication (excluding 21 subjects from a single site due to a protocol violation in dosing) with a non-missing value at baseline.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Adjusted Mean Number of New or Newly-enlarging T2 Hyperintense Lesions at Week 52 | 8.13 lesions |
| 150 mg DAC HYP | Adjusted Mean Number of New or Newly-enlarging T2 Hyperintense Lesions at Week 52 | 2.42 lesions |
| 300 mg DAC HYP | Adjusted Mean Number of New or Newly-enlarging T2 Hyperintense Lesions at Week 52 | 1.73 lesions |
Comparison: For each of the secondary endpoints, a sequential closed testing procedure was used, with the first comparison (the DAC HYP 300 mg group versus placebo) and the second comparison (the DAC HYP 150 mg group versus placebo). Secondary endpoints were rank prioritized, in the order presented. If statistical significance was not achieved for an endpoint, all endpoints(s) of a lower rank were not considered statistically significant.p-value: <0.000195% CI: [71.33, 84.22]Negative Binomial Regression
Comparison: For each of the secondary endpoints, a sequential closed testing procedure was used, with the first comparison (the DAC HYP 300 mg group versus placebo) and the second comparison (the DAC HYP 150 mg group versus placebo). Secondary endpoints were rank prioritized, in the order presented. If statistical significance was not achieved for an endpoint, all endpoints(s) of a lower rank were not considered statistically significant.p-value: <0.000195% CI: [59.94, 77.88]Negative Binomial Regression
Secondary
Mean Change From Baseline in Multiple Sclerosis Impact Scale (MSIS)-29 Physical Impact Score at Week 52
The 29-item Multiple Sclerosis Impact Scale (MSIS-29) is a disease specific patient-reported outcome measure that has been developed and validated to examine the physical and psychological impact of MS from a patient's perspective; it measures 20 physical items and 9 psychological items. Responses use a 5 point Likert scale range from 1 to 5. All questions are to be answered. The total score is the sum of points for all 29 questions, with a minimum score of 29, and a maximum score of 145. A lower total score indicates less physically-related impact while a higher total score indicates greater physically-related impact on a subject's functioning.
Time frame: Baseline and Week 52
Population: Intent to treat population: all randomized subjects who received at least 1 dose of study medication (excluding 21 subjects from a single site due to a protocol violation in dosing).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline in Multiple Sclerosis Impact Scale (MSIS)-29 Physical Impact Score at Week 52 | 3.0 units on a scale | Standard Deviation 13.52 |
| 150 mg DAC HYP | Mean Change From Baseline in Multiple Sclerosis Impact Scale (MSIS)-29 Physical Impact Score at Week 52 | -1.0 units on a scale | Standard Deviation 11.8 |
| 300 mg DAC HYP | Mean Change From Baseline in Multiple Sclerosis Impact Scale (MSIS)-29 Physical Impact Score at Week 52 | 1.4 units on a scale | Standard Deviation 13.53 |
Comparison: For each of the secondary endpoints, a sequential closed testing procedure was used, with the first comparison (the DAC HYP 300 mg group versus placebo) and the second comparison (the DAC HYP 150 mg group versus placebo). Secondary endpoints were rank prioritized, in the order presented. If statistical significance was not achieved for an endpoint, all endpoints(s) of a lower rank were not considered statistically significant.p-value: 0.128495% CI: [-4.42, 0.56]Analysis of Variance
Comparison: For each of the secondary endpoints, a sequential closed testing procedure was used, with the first comparison (the DAC HYP 300 mg group versus placebo) and the second comparison (the DAC HYP 150 mg group versus placebo). Secondary endpoints were rank prioritized, in the order presented. If statistical significance was not achieved for an endpoint, all endpoints(s) of a lower rank were not considered statistically significant.p-value: 0.000895% CI: [-6.76, -1.78]Analysis of Variance
Secondary
Proportion of Participants Who Relapsed at Week 52
Estimated cumulative proportion of participants relapsed at Week 52, based on the Kaplan-Meier product limit method. Only relapses confirmed by the Independent Neurology Evaluation Committee were included in the analysis.
Time frame: Week 52
Population: Intent to treat population: all randomized subjects who received at least 1 dose of study medication (excluding 21 subjects from a single site due to a protocol violation in dosing). Participants who did not experience a relapse prior to switching to alternative MS medications or withdrawal from study were censored.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Proportion of Participants Who Relapsed at Week 52 | 0.36 proportion of participants |
| 150 mg DAC HYP | Proportion of Participants Who Relapsed at Week 52 | 0.19 proportion of participants |
| 300 mg DAC HYP | Proportion of Participants Who Relapsed at Week 52 | 0.20 proportion of participants |
Comparison: For each of the secondary endpoints, a sequential closed testing procedure was used, with the first comparison (the DAC HYP 300 mg group versus placebo) and the second comparison (the DAC HYP 150 mg group versus placebo). Secondary endpoints were rank prioritized, in the order presented. If statistical significance was not achieved for an endpoint, all endpoints(s) of a lower rank were not considered statistically significant.p-value: 0.000395% CI: [0.33, 0.72]Cox Proportional Hazard
Comparison: For each of the secondary endpoints, a sequential closed testing procedure was used, with the first comparison (the DAC HYP 300 mg group versus placebo) and the second comparison (the DAC HYP 150 mg group versus placebo). Secondary endpoints were rank prioritized, in the order presented. If statistical significance was not achieved for an endpoint, all endpoints(s) of a lower rank were not considered statistically significant.p-value: <0.000195% CI: [0.3, 0.67]Cox Proportional Hazard