Long-Term Extension Study in Participants With Multiple Sclerosis Who Have Completed Study 205MS301 (NCT01064401) to Evaluate the Safety and Efficacy of BIIB019

Phase 3

Terminated

Conditions: Multiple Sclerosis
Relapsing-Remitting Multiple Sclerosis

Interventions: Drug: BIIB019 (Daclizumab)

Registration Number: NCT01797965

Lead Sponsor: Biogen

Brief Summary: The primary objective of the study is to assess the safety and tolerability of long-term treatment with BIIB019 (Daclizumab High Yield Process; DAC HYP) monotherapy in participants with relapsing remitting multiple sclerosis (RRMS) who completed Study 205MS301 (NCT01064401), Study 205MS203 (NCT01051349) or Study 205MS302 (NCT01462318).

Secondary objectives of this study in this study population are as follows:

To describe MS-related outcomes, including MS relapse, disability progression, MS lesion formation, and participant-reported impact of MS, following long-term treatment with DAC HYP To assess the long-term immunogenicity of DAC HYP administered by prefilled syringe (PFS) To assess the safety, tolerability, and efficacy of switching to DAC HYP in participants previously on long-term treatment with interferon β-1a (Avonex) in Study 205MS301(NCT01064401).

Detailed Description: Enrollment will include up to 1600 Participants, this includes approximately 1200 Participants who completed Study 205MS301 (NCT01064401). Additionally, approximately 400 Participants from the other BIIB019 extension studies 205MS203 (NCT01051349) and 205MS302 (NCT01462318) will be eligible to enter Study 205MS303 at Week 144 of Study 205MS303 \[Study 205MS301 (NCT01064401), study 205MS203 (NCT01051349) and study 205MS302 (NCT01462318) have been referred to as parent studies in the protocol\]. All Participants will receive the same dose of DAC HYP as received in the parent studies; i.e., 150 mg by an SC injection every 4 weeks.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 1501

Inclusion Criteria

Must be a subject currently participating in Study 205MS301 (NCT01064401), or subject currently participating in Study 205MS203 (NCT01051349) or Study 205MS302 (NCT01462318) who has completed End of Study Visit (Week 96 or later).
Women of childbearing potential must practice effective contraception during the study and be willing and able to continue contraception for 4 months after their last dose of study treatment.

Key

Exclusion Criteria

Any subject who permanently discontinued study treatment in Study 205MS301 (NCT01064401), Study 205MS203 (NCT01051349) or Study 205MS302 (NCT01462318) prior to the end of the study treatment period, or had an Early Termination visit in Study 205MS301, Study 205MS203 (NCT01051349) or Study 205MS302 (NCT01462318).
Any significant change in the subject's medical history that would preclude administration of BIIB019, including laboratory tests or a current clinically significant condition that, in the opinion of the Investigator, would have excluded the subject's participation in Study 205MS301 (NCT01064401), Study 205MS203 (NCT01051349) or Study 205MS302 (NCT01462318).

The Investigator must re review the subject's medical fitness for participation and consider any factors that would preclude treatment in this Study 205MS303.

NOTE: Other protocol-defined inclusion/exclusion criteria may apply.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
BIIB019	BIIB019 (Daclizumab)	BIIB019 150 mg subcutaneous (SC) every 4 weeks

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	First dose of study drug in Study 303 to within 180 days of last dose (up to approximately 5.5 years)	An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product; it does not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product. A SAE is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria.

Secondary Outcome Measures

Name	Time	Method
Annualized Relapse Rate (ARR) in the 205MS303 Treatment Period	Up to 4.6 years in the 303 study	Relapses are defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Study Neurologist. The unadjusted ARR was calculated by tabulating the total number of relapses experienced in the group divided by the number of days up to the end of study, and the ratio then multiplied by 365.25. Relapses that occurred after participants received alternative multiple sclerosis (MS) medications were excluded from the analyses. ARR was adjusted for relapse rate, IFN beta use, Expanded Disability Status Scale (EDSS) (\<=2.5 vs \>2.5) and age (\<=35 vs \>35) prior to start of study treatment in 205MS301, calculated using the negative binomial model.
Number of Participants With Sustained Disability Progression in the 205MS301-303 Combined Study Period	Up to 5.6 years combining 303 with the initial Study 301	Sustained disability progression is defined as at least a 1.0-point increase on the Expanded Disability Status Scale (EDSS) from 303 baseline EDSS ≥1.0 that is sustained for 24 weeks, or at least a 1.5-point increase on the EDSS from 303 baseline EDSS of 0, that is sustained for 24 weeks. The EDSS measures the disability status of people with multiple sclerosis on a scale that ranges from 0 to 10. The range of main categories include (0) =normal neurologic exam; to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to (10) = death due to MS. Higher scores indicate more disability.
Number of Participants With New T1 Hypointense Lesions in the 205MS301 Treatment Period	Baseline 301, Weeks 24, 96, 144 in Study 301	T1 hypointense lesions were evaluated by MRI and were analyzed by a central MRI reader. The number of participants with New T1 Hyperintense Lesions relative to the 301 Baseline in the 301 Treatment Period is reported .
Number of Participants With Relapse in the 205MS303 Treatment Period	Up to 4.6 years in the 303 study	Relapses are defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Study Neurologist.
Number of Participants With Relapse in the 205MS301-303 Combined Study Period	Up to 5.6 years combining 303 with the initial Study 301	Relapses are defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Study Neurologist.
Number of Participants With New or Newly Enlarging T2 Hyperintense Lesions in the 205MS303 Treatment Period	Baseline 303, Weeks 48, 96, 144, 192, 240 in Study 303	T2 Hyperintense Lesions were assessed by magnetic resonance imaging (MRI) and were analyzed by a central MRI reader. The number of participants with New or Newly Enlarging T2 Hyperintense Lesions relative to the 303 Baseline in the 303 Treatment Period is reported.
Change From Baseline in the Multiple Sclerosis Impact Scale 29 (MSIS 29) Physical and Psychological Scores in the 205MS303 Treatment Period	Baseline 303, Weeks 12, 24, 48, 96, 120 and 144	The 29-item MSIS-29 is a disease specific participant-reported outcome measure that has been developed and validated to examine the physical (coordination and mobility) and psychological (mental) impact of MS from a participant's perspective; it measures 20 physical items and 9 psychological items. The results for each of the physical and psychological scores are transformed to a score of 0 to 100 (worse state of health). A negative change from Baseline indicates improvement.
Direct Health Resource Utilization (HRU): Number of Unscheduled Site Visits in the 205MS303 Treatment Period	301-303: Baseline 303, Weeks 24, 48, 96, 144, 192, 240; 203-303 and 302-303: Baseline 303, Weeks 48, 96 in 303	Heath resource utilization was assessed by the number of hospitalizations, emergency room visits, and unscheduled neurologist visits for MS-related and non-MS-related visits.
ARR in the 205MS301-303 Combined Study Period and 205MS301 Treatment Period	Up to 5.6 years combining 303 with the initial Study 301; Up to 1 year in the 301 study	Relapses are defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Study Neurologist. The unadjusted ARR was calculated by tabulating the total number of relapses experienced in the group divided by the number of days up to the end of study, and the ratio then multiplied by 365.25. Relapses that occurred after participants received alternative MS medications were excluded from the analyses. ARR was adjusted for relapse rate, IFN beta use, EDSS (\<=2.5 vs \>2.5) and age (\<=35 vs \>35) prior to start of study treatment in 301, calculated using the negative binomial model.
Number of Participants With Sustained Disability Progression in the 205MS303 Treatment Period	Up to 4.6 years in Study 303	Sustained disability progression is defined as at least a 1.0-point increase on the Expanded Disability Status Scale (EDSS) from 303 baseline EDSS ≥1.0 that is sustained for 24 weeks, or at least a 1.5-point increase on the EDSS from 303 baseline EDSS of 0, that is sustained for 24 weeks. The EDSS measures the disability status of people with multiple sclerosis on a scale that ranges from 0 to 10. The range of main categories include (0) =normal neurologic exam; to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to (10) = death due to MS. Higher scores indicate more disability.
Number of Participants With New or Newly Enlarging T2 Hyperintense Lesions in the 205MS301 Treatment Period	Baseline 301, Weeks 24, 96, 144 in Study 301	T2 Hyperintense Lesions were assessed by MRI and were analyzed by a central MRI reader. The number of participants with New or Newly Enlarging T2 Hyperintense Lesions relative to the 301 Baseline in the 301 Treatment Period is reported.
Number of Participants With Gadolinium-enhancing (Gd+) Lesions in the 205MS301 Treatment Period	Baseline 301, Weeks 24, 96 and 144	Gd+ lesions were evaluated by MRI and were analyzed by a central MRI reader.
Percent Change in Brain Volume From the 205MS303 Baseline	Baseline 303, Weeks 48, 96, 144, 192, 240 in Study 303	To assess brain atrophy, total brain volume was measured by MRI and was analyzed by a central MRI reader. A negative percent change from baseline indicates improvement.
Treatment Satisfaction as Assessed by the Participant in the 205MS303 Treatment Period	Baseline 303, Weeks 12, 24, 48, 72, 96, 120 in Study 303	Participants answered the question: "How satisfied or dissatisfied are you with the ability of the medication to prevent or treat the condition?" using the following scale: Dissatisfied (Extremely dissatisfied, Very dissatisfied, Dissatisfied) or Satisfied (Somewhat satisfied, Satisfied, Very Satisfied and Extremely satisfied). The number of participants in the Dissatisfied and Satisfied categories is reported.
HRPQ: Hours of Work Missed Due to MS or Its Treatment in the 205MS303 Treatment Period	301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240; 203-303 and 302-303: Baseline 303, Weeks 24, 48, 72, 96 in Study 303	The HRPQ was used by the participant to assess the impact of MS or its treatments on employment. The participant recorded the hours they missed work due to MS or its treatments. Data is reported by part time or full time employment.
Number of Participants With New T1 Hypointense Lesions in the 205MS303 Treatment Period	Baseline 303, Weeks 48, 96, 144, 192, 240 in Study 303	T1 hypointense lesions were evaluated by MRI and were analyzed by a central MRI reader. The number of participants with New T1 Hyperintense Lesions relative to the 303 Baseline in the 303 Treatment Period is reported.
Percent Change in Brain Volume From 205MS301 Baseline	Baseline 301, Weeks 48, 96, 144, 192, 240 in Study 303	To assess brain atrophy, total brain volume was measured by MRI and was analyzed by a central MRI reader. A negative percent change from baseline indicates improvement.
Change From Baseline in the Multiple Sclerosis Functional Composite (MSFC) Score in the 205MS303 Treatment Period	Baseline 303, Weeks 12, 24 and 48 in Study 303	MSFC is a three-part, standardized, quantitative, assessment instrument consisting of (Timed 25-Foot Walk, Nine-Hole Peg Test (9HPT) and Paced Auditory Serial Addition Test (PASAT-3"). 2 timed 25-foot walk scores are averaged. 4 trials of the Peg Test (2 for each hand) are converted to the reciprocals and averaged. The number correct of the PASAT-3 is used. The composite Z-score is calculated by: Z(25-foot walk) + Z (HPT) + Z(PASAT)/3. A positive change from baseline indicates improvement.
Change From 205MS301 Baseline in the MSFC Score in the 205MS301-303 Combined Study Period	Baseline 301, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156 in the 301 study, Baseline 303, Weeks 12, 24, 48 in the 303 study	MSFC is a three-part, standardized, quantitative, assessment instrument consisting of (Timed 25-Foot Walk, Nine-Hole Peg Test (9HPT) and Paced Auditory Serial Addition Test (PASAT-3"). 2 timed 25-foot walk scores are averaged. 4 trials of the Peg Test (2 for each hand) are converted to the reciprocals and averaged. The number correct of the PASAT-3 is used. The composite Z-score is calculated by: Z(25-foot walk) + Z (HPT) + Z(PASAT)/3. A positive change from baseline indicates improvement.
Number of Participants With Gadolinium-enhancing (Gd+) Lesions in the 205MS303 Treatment Period	301-303: Baseline 303, Weeks 48, 96, 144, 192, 240; 203-303 and 302-303: Week 96	Gd+ lesions were evaluated by MRI and were analyzed by a central MRI reader.
Change From Baseline in the Expanded Disability Status Scale (EDSS) Score in the 205MS303 Treatment Period	301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, 260; 203-303 and 302-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 116 in Study 303	The EDSS measures the disability status of people with multiple sclerosis as assessed by the Study Neurologist based on 8 functional systems that ranges from 0=normal neurologic exam; to 5=ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to 10=death due to MS. Higher scores indicate more disability. A negative change from Baseline indicates improvement.
Number of Participants Who Are Free From Disease Activity in the 205MS303 Treatment Period	Up to 4.6 years in Study 303	Participants without clinical or radiological activity are defined as disease-free. Clinical activity includes assessment of relapses and of disease progression. Radiological activity includes assessments of Gd+ lesions and new or enlarging T2 lesions.
Change From Baseline in Quality of Life as Assessed by the European Quality of Life, 5 Dimensions (EQ 5D) Health Scores in the 205MS303 Treatment Period	301-303: Baseline 303, Weeks 12, 24, 48, 96, 120, 144, 192, 240; 203-303 and 302-303: Baseline 303, Weeks 48 and 96 in Study 303	The EQ-5D is a self-administered questionnaire consisting of 5 domains pertaining to specific health state profile : mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The participants recorded their level of current health for each domain where: 1=no problems, 2=some problem and 3=severe problems. The health score is derived from the individual scores for each of the 5 domains transformed to a score of 0=worst health state to 1=perfect health state. A positive change from Baseline indicates improvement.
Change From Baseline in Quality of Life as Assessed by the European Quality of Life, Visual Analog Scale (EQ VAS) in the 205MS303 Treatment Period	301-303: Baseline 303, Weeks 12, 24, 48, 96, 120, 44, 192, 240; 203-303 and 302-303: Baseline 303, Weeks 48 and 96 in Study 303	The participant rated their current heath state using the EQ VAS 20-centimeter horizontal line from 0 (worst imaginable health state) to 100 (best imaginable health state). A positive change from baseline indicates improvement.
HRPQ: Number of Participants Where MS or Its Treatments Resulted in Missed Work in the 205MS303 Treatment Period	301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240; 203-303 and 302-303: Baseline 303, Weeks 24, 48, 72, 96 in Study 303	The HRPQ was used by the participant to assess the impact of MS or its treatments on employment. The participant recorded whether their MS or its treatments caused them to miss work. Data is reported by part time or full time employment.
HRPQ: Percent Impact on Performing Household Chores in the 205MS303 Treatment Period	301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240; 203-303 and 302-303: Baseline 303, Weeks 24, 48, 72, 96 in Study 303	The HRPQ was used by the participant to assess the impact of MS or its treatments on performing household chores. The participant assessed the percent impact of MS and its treatments on how much they accomplished using a VAS where 0= MS or its treatments had no impact on how much I accomplished to 100=MS or its treatments kept me from accomplishing anything.
Total Volume of T2 Hyperintense Lesions in the 205MS303 Treatment Period	Baseline 303, Weeks 48, 96, 144, 192, 240 in Study 303; 203-303 and 302-303: Week 96	Volume of T2 hyperintense Lesions was evaluated by MRI and was analyzed by a central MRI reader.
Health Related Productivity Questionnaire (HRPQ): Scheduled Work Hours in the 205MS303 Treatment Period	301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240; 203-303 and 302-303: Baseline 303, Weeks 24, 48, 72, 96 in Study 303	The HRPQ was used by the participant to assess the impact of MS or its treatments on employment. The participant recorded their scheduled work hours. Data is reported by part time or full time employment.
HRPQ: Hours of Household Chores Planned to Perform in the 205MS303 Treatment Period	301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240; 203-303 and 302-303: Baseline 303, Weeks 24, 48, 72, 96 in Study 303	The HRPQ was used by the participant to assess the impact of MS or its treatments on performing household chores. The participant recorded their planned hours for household chores.
Number of Participants in Local Tolerability Clinician Injection Site Assessment Categories	After the first and fourth injections in 303, approximately Week 0 and Week 12	The investigator assessed the injection site after the first dose and before the fourth dose for the presence of erythema (None, Mild, Moderate, Severe), pigmentation (None, Hypo, Hyper), Induration (None, Mild, Moderate, Severe), Tenderness (None, Mild, Moderate, Severe) and Temperature (Normal, Warm, Hot). The number of participants in each grade is reported.
Change From Baseline in 3-Second Paced Auditory Serial Addition Test (PASAT 3) Score in the 205MS303 Treatment Period	Baseline 303, Weeks 12, 24, 48, 120, 144, 168, 192, 216, 240 in 303	The PASAT 3 assesses auditory information processing speed. A random series of numbers from 1 to 9, inclusive, are presented and the participant is instructed to consecutively add pairs of numbers so that each number is added to the one that immediately preceded it. In the 3- second PASAT, numbers are presented at a rate of 1 every 3 seconds. The total possible score is the number of correct responses from 0 to 60 (best). A positive change from baseline indicates improvement.
Direct Health Resource Utilization (HRU): Number of Unscheduled Site Visits in the 205MS301 Treatment Period	Baseline 301, Weeks 24, 48, 72, 96, 120 and 144 in 301	Heath resource utilization was assessed by the number of hospitalizations, emergency room visits, and unscheduled neurologist visits for MS-related and non-MS-related visits.
HRPQ: Hours Not Performing Household Chores Due to MS or Its Treatment in 205MS303 Treatment Period	301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240; 203-303 and 302-303: Baseline 303, Weeks 24, 48, 72, 96 in Study 303	The HRPQ was used by the participant to assess the impact of MS or its treatments on performing household chores. The participant recorded the hours where they were not able to perform household chores due to MS or its treatments.
Number of Participants With Anti-BIIB019 Neutralizing Antibodies (Nabs) in the 205MS303 Treatment Period	Up to 4.6 years in the 303 Treatment Period	Blood samples were collected for NAbs and were analyzed using a laboratory test. The number of participants NAb positive at any post-baseline timepoint is reported.
Change From 205MS303 Baseline in the Symbol Digit Modalities Test (SDMT) Score in the 205MS303 Treatment Period	Baseline 303, Weeks 144, 168, 192, 240 in 303	SDMT is a screening test for cognitive impairment. Participants are given 90 seconds in which to pair specific numbers with given geometric figures using a key. Scores range from 0 to 110 (best). A positive change from baseline indicates improvement.
Change From 205MS301 Baseline in the SDMT Score in the 205MS301-303 Combined Study Period	Baseline 301, Weeks 24, 48, 72, 96, 120, 144 in 301; Weeks 144, 168, 192, 216, 240 in 303	SDMT is a screening test for cognitive impairment. Participants are given 90 seconds in which to pair specific numbers with given geometric figures using a key. Scores range from 0 to 110 (best). A positive change from baseline indicates improvement.
HRPQ: Percent Impact on Employment in the 205MS303 Treatment Period	301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240; 203-303 and 302-303: Baseline 303, Weeks 24, 48, 72, 96 in Study 303	The HRPQ was used by the participant to assess the impact of MS or its treatments on employment. The participants assessed the percent impact of MS and its treatments on their work output using a VAS where 0= MS or its treatments had no impact on how much I accomplished to 100=MS or its treatments kept me from accomplishing anything. Data is reported for part time or full time employment.
Number of Participants With Clinically Significant Changes From Baseline in Clinical Laboratory Assessments in the 205MS303 Treatment Period	Up to 4.6 years in 303	Clinical Laboratory assessments included tests of hematology, blood chemistry, renal function, and thyroid function. The investigator determined if the results were clinically significant.
HRPQ: Number of Participants Where MS or Its Treatments Kept the Participant From Completing Chores in the 205MS303 Treatment Period	301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240; 203-303 and 302-303: Baseline 303, Weeks 24, 48, 72, 96 in Study 303	The HRPQ was used by the participant to assess the impact of MS or its treatments on performing household chores. The participant recorded whether MS or its treatments kept them from completing household chores.
Local Tolerability as Assessed by Participant-reported Injection Site Pain VAS	After the first and fourth injections in 303, approximately Week 0 and Week 12	The VAS is a 10 cm-long horizontal line labeled with 2 extremes of pain at either end: 0 =no pain on the left and 100=very painful on the right. The participant rates their perceived pain of each injection by placing a vertical mark on the line to indicate the level of pain.
Number of Participants With Anti-BIIB019 Binding Antibodies (ADAbs) in the 205MS303 Treatment Period	Up to 4.6 years in the 303 Treatment Period	Blood samples were collected for ADAbs and were analyzed using a laboratory test. The number of participants ADAb positive at any post-baseline timepoint is reported.
Change From Baseline in 3-Second Paced Auditory Serial Addition Test (PASAT 3) Score in the 205MS301-303 Combined Study Period	Baseline 301, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156 in the 301 study, Baseline 303, Weeks 12, 24, 48, 120, 144,168, 192, 216, 240 in 303 study	The PASAT 3 assesses auditory information processing speed. A random series of numbers from 1 to 9, inclusive, are presented and the participant is instructed to consecutively add pairs of numbers so that each number is added to the one that immediately preceded it. In the 3- second PASAT, numbers are presented at a rate of 1 every 3 seconds. The total possible score is the number of correct responses from 0 to 60 (best). A positive change from baseline indicates improvement.