Efficacy and Safety of BIIB033 (Opicinumab) as an Add-on Therapy to Disease-Modifying Therapies (DMTs) in Relapsing Multiple Sclerosis (MS)

Phase 2TerminatedNCT03222973

Biogen263 enrolled

Overview

The primary objective of Part 1 of this study is to evaluate the effects of BIIB033 versus placebo on disability improvement over 72 weeks. The primary objective of Part 2 of this study is to evaluate the long-term safety profile of BIIB033 as an add-on therapy in participants with MS. The secondary objective of Part 1 is to evaluate the effects of BIIB033 versus placebo on additional measures of disability improvement. The secondary objective of Part 2 is to investigate long-term efficacy (disability improvement) and additional safety measures of BIIB033 as an add-on therapy in participants with MS.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

263

Conditions

Multiple Sclerosis

Interventions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 58 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: Part 1 * Baseline Expanded Disability Status Scale (EDSS) of 2.0 to 6.0, have a diagnosis of relapsing-remitting multiple sclerosis (RRMS) per the 2010 McDonald's criteria or onset of secondary progressive multiple sclerosis (SPMS) per the Lublin and Reingold criteria, and should have experienced their first MS symptom(s) within the previous 20 years. * Subjects must have experienced at least 1 of the following within 24 months prior to Day 1/Baseline: a clinical relapse (but not within 24 weeks prior to Day 1/Baseline), gadolinium-enhancing lesions on brain or spinal cord magnetic resonance imaging (MRI), or new T2 lesion(s) on brain or spinal cord MRI. * Subjects must be on a stable dose of a protocol-specified anti-inflammatory disease-modifying therapy (DMT) (IFNβ \[Avonex, Plegridy, Betaferon/Betaseron, or Rebif\], dimethyl fumarate (DMF) \[Tecfidera\], or natalizumab \[Tysabri\]) for at least 24 weeks prior to enrollment. * In addition, subjects must have met protocol-defined MRI characteristics using magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI) sequences at Screening/Baseline. Key Inclusion Criteria: Part 2 -Subjects who complete study treatment (BIIB033 or placebo) at Part 1/Week 72 Visit. Key Exclusion Criteria: Part 1 * Primary progressive MS * An MS relapse that has occurred within 24 weeks prior to Day 1/Baseline or the subject has not stabilized from a previous relapse at the time of Screening. * Treatment with any chemotherapeutic agents (e.g., mitoxantrone, cyclophosphamide, cladribine), cell-depleting monoclonal antibodies (mAbs) (e.g., rituximab, ocrelizumab, alemtuzumab), total lymphoid irradiation, T-cell or T-cell receptor vaccination, or teriflunomide within 1 year prior to Day 1/Baseline. * Treatment with other anti-inflammatory DMTs (e.g., GA, fingolimod, daclizumab) or plasmapheresis within 24 weeks prior to Day1/Baseline. * Treatment with Botox for limb spasticity within 24 weeks before Day 1/Baseline. * Contraindications to MRI, for example, presence of pacemakers or other implanted metal devices (excluding dental braces), an allergy to gadolinium renal impairment, or claustrophobia that cannot be medically managed. * History of human immunodeficiency virus or other immunodeficient conditions. * History of malignancy; however, subjects with a history of excised or treated basal cell carcinoma or fewer than 3 squamous cell carcinomas are eligible to participate in this study. Key Exclusion Criteria: Part 2 * Subjects who did not complete study treatment in Part 1/Week 72 Visit * Subjects who have a duration \>12 weeks between their Part 1/Week 72 Visit and Part 2/Day 1. * Contraindications to MRI, for example, presence of pacemakers or other implanted metal devices (excluding dental braces), an allergy to Gd, renal impairment, or claustrophobia that cannot be medically managed. * History of human immunodeficiency virus or other immunodeficient conditions not related to DMT treatment. * History of malignancy unless enrollment is approved by the Sponsor; subjects with a history of excised or treated basal cell carcinoma or fewer than 3 squamous cell carcinomas are eligible to participate in this study. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply

Locations (159)

Research Site

Cullman, Alabama, United States

Research Site

Gilbert, Arizona, United States

Research Site

Berkeley, California, United States

Research Site

Long Beach, California, United States

Research Site

Newport Beach, California, United States

Research Site

Outcomes

Primary Outcomes

Part 1: Overall Response Score

Overall Response Score is a multicomponent score based on 4 components: Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test in the dominant hand (9HPT-D), and 9HPT in the nondominant hand (9HPT-ND). Overall Score was sum of 4 components at each visit and ranges from +4 (improvement) to -4 (worsening). At each visit, each component is given a score relative to baseline (BL): -1 if threshold is met for worsening, 0 if no changes meet threshold criteria, or +1 if threshold is met for improvement. For T25FW and 9HPT improvement is ≥15% decrease in time from BL and worsening is ≥15% increase in time from BL. For EDSS, improvement is: ≥1.0-point decrease in EDSS from a BL score of ≤6.0, and worsening is defined as a ≥1-point increase from a BL score of ≤5.5 or a ≥0.5-point increase from a BL score equal to 6.0. Positive Overall Response Score indicated that there was improvement in more components than there was worsening.

Time frame: Part 1: Baseline to Week 72

Part 2: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs)

An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can 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, whether or not related to the medicinal (investigational) product. A SAE is any untoward medical occurrence that at any dose results in death, life-threatening event, requires inpatient hospitalization, significant disability/incapacity or congenital anomaly.

Time frame: Part 2: Baseline to Week 169

Secondary Outcomes

Part 1: Percentage of Participants With 12-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND

EDSS measures disability status over time in MS on a scale ranging from 0 to 10, with higher scores indicating more disability. For EDSS, improvement is defined as a ≥1.0-point decrease in EDSS from a BL score of ≤6.0. T25FW is a quantitative mobility and leg function performance test based on a timed walk over 25 feet that is averaged between two completed trials. Longer time indicates slower walking. The 9HPT is a quantitative test of upper extremity function that measures the time it takes to place 9 pegs into 9 holes and then remove the pegs. Longer time indicates poorer upper limb function. For T25FW and 9HPT ≥15% decrease in time from BL indicates improvement.

Time frame: Part 1: Baseline to Week 72

Part 1: Percentage of Participants With 12-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, 9HPT-ND, or 3-Second Paced Auditory Serial Addition Test (PASAT-3)

EDSS measures disability status over time in MS (scale range: 0-10), higher scores=more disability and improvement defined as ≥1.0-point decrease in EDSS from BL score ≤6.0. T25FW is quantitative mobility and leg function performance test, where timed walk over 25 feet that is averaged between two completed trials. Longer time=slower walking. 9HPT is quantitative test of upper extremity function, measures time to place 9 pegs into 9 holes and then remove pegs. Longer time=poorer upper limb function. PASAT assesses auditory information processing speed. In 3-second PASAT, numbers are presented at a rate of 1 every 3 seconds with scores (range 0-120), higher scores=better working memory. For T25FW and 9HPT ≥15% decrease in time from BL is improvement. For PASAT ≥15% increase from BL is improvement.

Time frame: Part 1: Baseline to Week 72

Part 1: Percentage of Participants With 12-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND, and Without Confirmed Worsening in Any of the 4 Assessments During the 72 Weeks of the Study

EDSS measures disability status over time in MS on a scale ranging from 0 to 10, with higher scores indicating more disability. For EDSS, improvement is defined as a ≥1.0-point decrease in EDSS from a BL score of ≤6.0, and worsening is defined as a ≥1-point increase from a BL score of ≤5.5 or a ≥0.5-point increase from a BL score equal to 6.0. T25FW is a quantitative mobility and leg function performance test based on a timed walk over 25 feet that is averaged between two completed trials. Longer time indicates slower walking. The 9HPT is a quantitative test of upper extremity function that measures the time it takes to place 9 pegs into 9 holes and then remove the pegs. Longer time indicates poorer upper limb function. For T25FW and 9HPT ≥15% decrease in time from BL indicates improvement and ≥15% increase in time from BL indicates worsening.

Time frame: Part 1: Baseline to Week 72

Part 1: Percentage of Participants With 12-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, 9HPT-ND, and Symbol Digit Modalities Test (SDMT)

EDSS measures disability status over time in MS on a scale (range 0-10), higher scores=more disability. For EDSS, improvement is: a ≥1.0-point decrease in EDSS from a BL score of ≤6.0. T25FW is a quantitative mobility and leg function performance test based on a timed walk over 25 feet that is averaged between two completed trials. Longer time=slower walking. 9HPT is quantitative test of upper extremity function that measures time it takes to place 9 pegs into 9 holes and then remove pegs. Longer time=poorer upper limb function. For T25FW and 9HPT ≥15% decrease in time from BL indicates improvement. The SDMT measures time to pair abstract geometric symbols with specific numbers. The score is the number of correctly coded items (range 0-110) in 90 seconds, higher scores=better outcome. Improvement is: ≥4-point increase from BL.

Time frame: Part 1: Baseline to Week 72

Part 1: Percentage of Participants With 12-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND (20% Thresholds for T25FW and 9HPT)

Time frame: Part 1: Baseline to Week 72

Part 2: Overall Response Score

Time frame: Part 2: Baseline to Week 96

Part 2: Percentage of Participants With 24-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND

Time frame: Part 2: Baseline to Week 108

Part 2: Percentage of Participants With 24-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, 9HPT-ND, or PASAT-3

Time frame: Part 2: Baseline to Week 108

Part 2: Percentage of Participants With 24-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND, and Without Confirmed Worsening in Any of the 4 Assessments During the 96 Weeks of the Study

Time frame: Part 2: Baseline to Week 96

Part 2: Percentage of Participants With 24-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, 9HPT-ND, and SDMT

Time frame: Part 2: Baseline to Week 108

Part 2: Percentage of Participants With 24-week Confirmed Improvement in at Least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND (20% Thresholds for T25FW and 9HPT)

Time frame: Part 2: Baseline to Week 108

Part 2: Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values

Laboratory assessments including hematology and blood chemistry were evaluated for safety. Criteria for abnormality: In 10\^9/liter (L) \[white blood cells \<3.0/\>16, neutrophils \<1.5/ \>13.5, lymphocytes \<0.8/ \>12, monocytes \>2.5, eosinophils \>1.6, basophils \>1.6, platelets \<=75/ \>=700\], hemoglobin \<=95 \[female (F)\] or \<=115 \[male (M)\] or \>=175 (F) or \>=190 (M) gram per liter (g/L), hematocrit \<=32 (F) or \<=37 (M) or \>=54 (F) or \>=60 (M) percentage (%), red blood cells \<=3.5/ \>=6.4 10\^12/L, in millimoles per liter (mmol/L) \[sodium \<=126/ \>=156, potassium \<=3/ \>=6, chloride \<=90/ \>=118, bicarbonate \<=16/ \>=35, calcium \<=2/ \>=3, phosphorous \<=0.5491/ \>=1.7119, glucose (non-fasting) \<=2.2/\>=13.75\], AST/SGOT \>=3x upper limit of normal (ULN), ALT/SGPT \>=3xULN, alkaline phosphatase \>=3xULN, creatinine \>=1.5xULN, total bilirubin \>=1.5xULN, total protein \<=45/ \>=100 g/L, albumin \<=25 g/L, uric acid \>=501.5 (F)/\>=619.5 (M) micromole (umol)/L

Time frame: Part 2: Baseline to Week 96

Part 2: Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Values

The ECG result was classified as "normal", "abnormal", "abnormal, not adverse event", or "abnormal, adverse event". Shift to 'abnormal, not adverse event' included shift from normal or unknown to 'abnormal, not adverse event'. Shift to 'abnormal, adverse event' included shift from normal or unknown to 'abnormal, adverse event'.

Time frame: Part 2: Baseline to Week 96

Part 2: Percentage of Participants With Potentially Clinically Significant Abnormal Vital Signs Values

Vital sign measurements including temperature, pulse rate (supine), systolic blood pressure (BP) and diastolic (supine) BP were evaluated for safety. Criteria for abnormalities: Temperature: \>38 degree celsius (◦C) or \>=1 ◦C increase from baseline (BL); Pulse: \[\>100 beats per minute (bpm) or increase from BL of \>30 bpm\] or (\<40 bpm or decrease from BL of \>20 bpm); Systolic BP: \[\>160 millimeters of mercury (mmHg)/increase from BL of \>40 mmHg\] or (\<90 mmHg/decrease from BL of \>30 mmHg); Diastolic BP: (\>100 mmHg/increase from BL of \>30 mmHg) or (\<45 mmHg/decrease from BL of \>20 mmHg).

Time frame: Part 2: Baseline to Week 96

Part 2: Percentage of Participants With Potentially Clinically Significant Abnormal Weight Values

Criteria for abnormality was defined as a \>7% increase or decrease in weight at the specified time point.

Time frame: Part 2: Baseline, Week 12, 24, 36, 48, 72 and 96

Part 2: Number of Participants With Columbia Suicide Severity Rating Scale (C-SSRS) Score at Any Post-Baseline Visit

C-SSRS systematically assess suicidal ideation and behavior rating scale. It rates an individual's degree of suicidal ideation on a scale, ranging from "wish to be dead" to "active suicidal ideation with specific plan and intent and behaviors". The scale identifies specific behaviors ranging from "preparatory acts or behavior" to "suicide" which may be indicative of an individual's intent to complete suicide.

Time frame: Part 2: Baseline to Week 96