Efficacy and Safety Study of Satralizumab (SA237) as Monotherapy to Treat Participants With Neuromyelitis Optica (NMO) and Neuromyelitis Optica Spectrum Disorder (NMOSD)

Study Overview
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Brief Summary
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The objectives of this study are to evaluate the efficacy, safety, pharmacodynamic, pharmacokinetic and immunogenic profiles of satralizumab in participants with NMO and NMOSD.

Official Title
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A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Satralizumab (SA237) as Monotherapy in Patients With Neuromyelitis Optica (NMO) and Neuromyelitis Optica Spectrum Disorder (NMOSD)

Conditions
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Neuromyelitis Optica (NMO), NMO Spectrum Disorder (NMOSD)

Intervention / Treatment
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* Drug: Satralizumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be diagnosed as having either neuromyelitis optica (NMO) or NMO spectrum disorder (NMOSD), defined as the following: NMO as defined by Wingerchuk et al. 2006 criteria (requires all of the following 3 criteria: I. Optic neuritis, II. Acute myelitis, III. At least two of three supportive criteria: Contiguous spinal cord lesion identified on a magnetic resonance imaging [MRI] scan extending over 3 vertebral segments; Brain MRI not meeting diagnostic criteria for multiple sclerosis [MS]; NMO-IgG seropositive status) NMOSD as defined by either of following criteria with anti-aquaporin-4 (AQP4) antibody seropositive status at screening: i. Idiopathic single or recurrent events of longitudinally extensive myelitis (≥3 vertebral segment spinal cord MRI lesion); ii. Optic neuritis, single, recurrent or simultaneous bilateral Clinical evidence of at least 1 documented relapse (including first attack) in last 12 months prior to screening Expanded Disability Status Scale (EDSS) score from 0 to 6.5 inclusive at screening Age 18 to 74 years, inclusive at the time of informed consent Ability and willingness to provide written informed consent and to comply with the requirements of the protocol Exclusion Criteria: Clinical relapse onset (including first attack) within 30 days prior to baseline Exclusion Criteria Related to Previous or Concomitant Therapy: Any previous treatment with interleukin 6 (IL-6) inhibitory therapy (e.g., tocilizumab), alemtuzumab, total body irradiation or bone marrow transplantation at any time Any previous treatment with anti-CD20, eculizumab, anti-BLyS monoclonal antibody (e.g., belimumab), any other treatment for prevention of multiple sclerosis (MS) relapse (e.g., interferon, natalizumab, glatiramer acetate, fingolimod, teriflunomide or dimethyl fumarate) within 6 months prior to baseline Any previous treatment with anti-CD4, cladribine, cyclophosphamide or mitoxantrone within 2 years prior to baseline Treatment with any investigational agent within 3 months prior to baseline Exclusions for General Safety: Pregnancy or lactation. For participants of reproductive potential, a positive result from a serum pregnancy test at screening, or not willing to use reliable means of contraception (physical barrier [participants or partner] in conjunction with a spermicidal product, contraceptive pill, patch, injectables, intrauterine device or intrauterine system) during the treatment period and for at least 3 months after the last dose of study drug Any surgical procedure (except for minor surgeries) within 4 weeks prior to baseline Evidence of other demyelinating disease or progressive multifocal leukoencephalopathy (PML) Evidence of serious uncontrolled concomitant diseases that may preclude participant participation, as described; Other nervous system disease, cardiovascular disease, hematologic/hematopoiesis disease, respiratory disease, muscular disease, endocrine disease, renal/urologic disease, digestive system disease, congenital or acquired severe immunodeficiency Known active infection (excluding fungal infections of nail beds or caries dentium) within 4 weeks prior to baseline Evidence of chronic active hepatitis B or C History of drug or alcohol abuse within 1 year prior to baseline History of diverticulitis that, in the Investigator's opinion, may lead to increased risk of complications such as lower gastrointestinal perforation Evidence of active tuberculosis (excluding participants receiving chemoprophylaxis for latent tuberculosis infection) Evidence of active interstitial lung disease Receipt of any live or live attenuated vaccine within 6 weeks prior to baseline History of malignancy within the last 5 years, including solid tumors, hematologic malignancies and in situ carcinoma (except basal cell and squamous cell carcinomas of the skin, or in situ carcinoma of the cervix uteri that have been completely excised and cured) History of severe allergic reaction to a biologic agent (e.g., shock, anaphylactic reactions) Active suicidal ideation within 6 months prior to screening, or history of suicide attempt within 3 years prior to screening History of Stevens-Johnson syndrome Following laboratory abnormalities at screening*. White blood cells <3.0 x10^3/microliter (μL) Absolute neutrophil count <2.0 x 10^3 /μL Absolute lymphocyte count <0.5 x 10^3 /μL Platelet count <10 x 10^4 /μL Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 times the upper limit of normal. If retest is conducted, the last value of retest before randomization must meet study criteria.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Satralizumab<br>Participants randomized to this arm for the double-blind period will receive satralizumab monotherapy. The double-blind period for the participant ends either when the participant experiences a Clinical Endpoint Committee (CEC) confirmed protocol-defined relapse, the total number of CEC confirmed protocol-defined relapses reaches 44, or 1.5 years after the last patient was randomized. In the open-label extension period, the participant will receive satralizumab SC injection at Weeks 0, 2, and 4, and Q4W thereafter, up to the end of the study. | Drug: Satralizumab<br>* Satralizumab will be administered subcutaneously (SC) at Weeks 0, 2, and 4, and thereafter once every 4 weeks (Q4W).<br>* Other names: RG6168;|
| Placebo Comparator: Placebo<br>Participants randomized to this arm for the double-blind period will receive placebo monotherapy. The double-blind period for the participant ends either when the participant experiences a Clinical Endpoint Committee (CEC) confirmed protocol-defined relapse, the total number of CEC confirmed protocol-defined relapses reaches 44, or 1.5 years after the last patient was randomized.. In the open-label extension period, the participant will receive satralizumab SC injection at Weeks 0, 2, and 4, and Q4W thereafter, up to the end of the study. | Drug: Satralizumab<br>* Satralizumab will be administered subcutaneously (SC) at Weeks 0, 2, and 4, and thereafter once every 4 weeks (Q4W).<br>* Other names: RG6168;Drug: Placebo<br>* Placebo will be administered subcutaneously (SC) at Weeks 0, 2, and 4, and thereafter once every 4 weeks (Q4W).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Protocol-Defined Relapse (TFR) During the Double-Blind (DB) Period | TFR was defined as time from randomization to first occurrence of relapse in the DB period. Protocol-defined relapse was occurrence of new or worsening neurological symptoms attributable to neurological neuromyelitis optica (NMO) or neuromyelitis optica spectrum disorder (NMOSD). Symptoms had to persist for >24 hours and not be attributable to confounding clinical factors (e.g., fever, infection, injury, change in mood, adverse reactions to medications). New or worsening neurological symptoms that occurred < 31 days following onset of a protocol-defined relapse were considered part of same relapse (i.e., if 2 relapses had onset days that were 30 days of one another, they were counted only as 1 relapse), and onset date used in analysis was the date of first relapse. | Up to Week 216 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 24 in Visual Analogue Scale (VAS) for Pain During the DB Period | The VAS is a subjective measure of pain consisting of a 100 mm line with two endpoints representing 0 = no pain and 100 = pain as bad as it could be. Participants rated their pain by placing a mark on the line corresponding to their current level of pain. The distance along the line from the no pain marker was measured with a ruler giving a pain score out of 100. A higher score indicated more pain and lower scores reflected a better health state. A negative change from baseline indicates an improvement. ANCOVA was used for analysis to report the adjusted mean and standard error (SE). | Baseline, Week 24 | 
| Change From Baseline to Week 24 in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale During the DB Period | The FACIT Fatigue scale is a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function over the past 7 days. As each of the 13 items of the scale ranges from 0-4, the range of possible scores was computed using FACIT scoring algorithm as 0-52, where 0 is the worst possible score and 52 the best which indicated less fatigue. A positive change from baseline indicates an improvement. | Baseline, Week 24 | 
| Relapse-Free Rate During the DB Period | Protocol-defined relapse was occurrence of new or worsening neurological symptoms attributable to neurological neuromyelitis optica (NMO) or neuromyelitis optica spectrum disorder (NMOSD). Symptoms had to persist for >24 hours and not be attributable to confounding clinical factors (e.g., fever, infection, injury, change in mood, adverse reactions to medications). New or worsening neurological symptoms that occurred < 31 days following onset of a protocol-defined relapse were considered part of same relapse (i.e., if 2 relapses had onsets within 30 days of one another, they were counted as 1), and onset date used in analysis was the date of first relapse. | Up to Week 216 | 
| Annualized Relapse Rate (ARR) During the DB Period | The ARR is calculated as the total number of participants with adjudicated PDRs experienced divided by the patient-years at risk. Protocol-defined relapse was occurrence of new or worsening neurological symptoms attributable to neurological NMO or NMOSD. Symptoms had to persist for >24 hours and not be attributable to confounding clinical factors (e.g., fever, infection, injury, change in mood, adverse reactions to medications). New or worsening neurological symptoms that occurred < 31 days following onset of a protocol-defined relapse were considered part of same relapse (2 relapses with onset days in 30 days of one another was counted as 1 relapse), onset date used in analysis was the date of first relapse. | Up to Week 216 | 
| Change From Baseline in Short Form Generic Health Survey (SF-36) Bodily Pain Domain Scores at 24 Week Intervals During the DB Period | The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health component summary measures and a preference-based health utility index. The domain scores were transformed to a 0-100 scale, where higher scores indicate better quality of life. A positive change from baseline indicates an improvement. | Baseline up to Week 216 | 
| Change From Baseline in SF-36 General Health Domain Scores at 24 Week Intervals During the DB Period | The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health component summary measures and a preference-based health utility index. The domain scores were transformed to a 0-100 scale, where higher scores indicate better quality of life. A positive change from baseline indicates an improvement. | Baseline up to Week 216 | 
| Change From Baseline in SF-36 Mental Health Domain Scores at 24 Week Intervals During the DB Period | The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health component summary measures and a preference-based health utility index. The domain scores were transformed to a 0-100 scale, where higher scores indicate better quality of life. A positive change from baseline indicates an improvement. | Baseline up to Week 216 | 
| Change From Baseline in SF-36 Physical Functioning Domain Scores at 24 Week Intervals During the DB Period | The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health component summary measures and a preference-based health utility index. The domain scores were transformed to a 0-100 scale, where higher scores indicate better quality of life. A positive change from baseline indicates an improvement. | Baseline up to Week 216 | 
| Change From Baseline in SF-36 Role-Emotional Domain Scores at 24 Week Intervals During the DB Period | The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health component summary measures and a preference-based health utility index. The domain scores were transformed to a 0-100 scale, where higher scores indicate better quality of life. A positive change from baseline indicates an improvement. | Baseline up to Week 216 | 
| Change From Baseline in SF-36 Role-Physical Domain Scores at 24 Week Intervals During the DB Period | The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health component summary measures and a preference-based health utility index. The domain scores were transformed to a 0-100 scale, where higher scores indicate better quality of life. A positive change from baseline indicates an improvement. | Baseline up to Week 216 | 
| Change From Baseline in SF-36 Social Role Functioning Domain Scores at 24 Week Intervals During the DB Period | The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health component summary measures and a preference-based health utility index. The domain scores were transformed to a 0-100 scale, where higher scores indicate better quality of life. A positive change from baseline indicates an improvement. | Baseline up to Week 216 | 
| Change From Baseline in SF-36 Vitality Domain Scores at 24 Week Intervals During the DB Period | The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health component summary measures and a preference-based health utility index. The domain scores were transformed to a 0-100 scale, where higher scores indicate better quality of life. A positive change from baseline indicates an improvement. | Baseline up to Week 216 | 
| Change From Baseline in SF-36 Mental Component Summary Scores at 24 Week Intervals During the DB Period | The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health summary measures and a preference-based health utility index. The component scores were transformed to a 0-100 scale, where higher score indicates better quality of life. A positive change from baseline indicates an improvement. | Baseline up to Week 216 | 
| Change From Baseline in SF-36 Physical Component Summary Scores at 24 Week Intervals During the DB Period | The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health summary measures and a preference-based health utility index. The component scores were transformed to a 0-100 scale, where higher score indicates better quality of life. A positive change from baseline indicates an improvement. | Baseline up to Week 216 | 
| Change From Baseline in EuroQoL-5 Dimensions (EQ-5D) Index Scores at 24 Week Intervals During the DB Period | The EQ-5D is a participant-answered questionnaire measuring 5 dimensions of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression with 3 possible response categories: 1) no problems; 2) some problems; 3) severe problems. The scores from 5 dimensions are used as input to generate EQ-5D index score using scoring algorithm. The EQ-5D index score is scored on a scale of -0.2 to 1. A higher score reflects a better health state. A positive change from baseline indicates an improvement | Baseline up to Week 216 | 
| Change From Baseline in Speed of Timed 25-Foot Walk (T25W) at 24 Week Intervals During the DB Period | The T25W is an assessment of walking ability. The time (in seconds) that the participant took to walk 25 feet was measured. Speed is calculated as 1/Timed 25-Foot Walk where time is measured in seconds. A positive change from baseline indicates an improvement. | Baseline up to Week 216 | 
| Change From Baseline in Modified Rankin Scale (mRS) Scores at 24 Week Intervals During the DB Period | The mRS is a 7-point disability scale that assesses the degree of disability in participants with neurological impairment. Possible scores range from 0 (no symptoms at all) up to 6 (death). Higher scores reflect increased disability. A negative change from baseline indicates an improvement. | Baseline up to Week 216 | 
| Change From Baseline in Zarit Burden Interview (ZBI) Scores at 24 Week Intervals During the DB Period | The ZBI is the measurement to assess caregiver burden. The 22 items ask for the strain caregivers perceive. Responses range from 0 (never) to 4 (nearly always). The overall ZBI score ranges from 0 to 88. The higher the total score, the heavier the perceived burden. A negative change from baseline indicates an improvement. | Baseline up to Week 120 | 
| Change From Baseline in Expanded Disability Status Scale (EDSS) Scores at 24 Week Intervals During the DB Period | The EDSS is an ordinal scale with values from 0 points (normal neurological examination) to 10 points (death) increasing in half-point increments once an EDSS of 1.0 has been reached. Higher scores represent increased disability. A negative change from baseline indicates an improvement. | Baseline up to Week 216 | 
| Change From Baseline in Visual Acuity (Snellen Chart) at 24 Week Intervals During the DB Period | Visual acuity was measured using Snellen 20-foot wall chart and then converted to logMAR visual acuity scoring. Lower values indicate better visual acuity. Data are reported for right eye (OD) and left eye (OS). A negative change from baseline indicates an improvement. | Baseline up to Week 216 | 
| Change From Baseline in Visual Function (Low-Contrast Sloan Letter Chart [LCSLC]) Scores at 24 Week Intervals During the DB Period | The LCSLC evaluates the visual function and captures the minimum size at which individuals can perceive letters of a particular contrast level. The change in binocular visual acuity, as assessed by the number of letters read correctly from a distance of 2 meters on 100%, 2.5% and 1.25% contrast level Sloan letter charts, was analyzed. The LCSLC is scored on a scale of 0-60. Higher scores indicate better visual function. A positive change from baseline indicates an improvement. | Baseline up to Week 216 | 
| Number of Participants With at Least One Adverse Event in the DB Period | An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Pre-existing conditions which worsen during a study are also considered as adverse events. | Up to Week 216 | 
| Number of Participants With at Least One Serious Adverse Event in the DB Period | A serious adverse event is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is medically significant or requires intervention to prevent one or other of the outcomes listed above. | Up to Week 216 | 
| Number of Participants With Non-Serious Adverse Events of Special Interest in the DB Period | Non-serious adverse events of special interest for this study included: 1) cases of an elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) in combination with either an elevated bilirubin or clinical jaundice, 2) suspected transmission of an infectious agent by the study treatment. | Up to Week 216 | 
| Number of Participants With Selected Adverse Events in the DB Period | Selected adverse events for this study included: 1) all infections, 2) serious infections, 3) potential opportunistic infections, 4) injection-related reactions (IRRs; an AE which occured within 24 hours after study treatment injection except where the event was not considered an allergic reaction), 5) psychiatric disorders and 6) anaphylaxis (an acute allergic/hypersensitivity reaction). | Up to Week 216 | 
| Number of Participants With Suicidal Behaviors and Ideations Collected by Columbia-Suicide Severity Rating Scale in the DB Period | The Columbia-Suicide Severity Rating Scale (C-SSRS) is an assessment tool to evaluate suicidal ideation and behavior. Categories have binary responses (yes/no) and include: Wish to be Dead; Non-specific Active Suicidal Thoughts; Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act; Active Suicidal Ideation with Some Intent to Act, without Specific Plan; Active Suicidal Ideation with Specific Plan and Intent, Preparatory Acts and Behavior; Aborted Attempt; Interrupted Attempt; Actual Attempt (non-fatal); Completed Suicide. Suicidal ideation or behavior is indicated by a yes answer to any of the listed categories. A score of 0 is assigned if no suicide risk is present. A score of 1 or higher indicates suicidal ideation or behavior. | Baseline and Post-Baseline (up to Week 216) | 
| Serum Satralizumab Concentration During the DB Period |  | Baseline, Weeks 2, 4, 5, 6, 8, and every 4 weeks thereafter up to Week 204 | 
| Serum Interleukin-6 (IL-6) Concentration During the DB Period |  | Baseline, Weeks 2, 4, and every 4 weeks thereafter up to Week 216 | 
| Serum Soluble IL-6 Receptor (sIL-6R) Concentration During the DB Period |  | Baseline, Weeks 2, 4, and every 4 weeks thereafter up to Week 216 | 
| Serum High Sensitivity C-Reactive Protein (hsCRP) Concentration During the DB Period |  | Baseline, Weeks 2, 4, and every 4 weeks thereafter up to Week 216 | 
| Percentage of Participants With Anti-Drug Antibodies to Satralizumab in the DB Period | Reported here is the percentage of participants with at least one positive anti-drug antibody measurement during the DB period. | Up to approximately Week 216 |