A Multicenter, Randomized, Addition to Baseline Treatment, Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Satralizumab (SA237) in Patients With Neuromyelitis Optica (NMO) and NMO Spectrum Disorder (NMOSD)
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 85
- Locations
- 40
- Primary Endpoint
- Time to First Protocol-Defined Relapse (TFR) in the Double-Blind Period
Study Overview
Brief Summary
The objective of this study is to evaluate the efficacy, safety, pharmacodynamic, pharmacokinetic, and immunogenic profiles of satralizumab, compared with placebo, in addition to baseline immunosuppressive treatment in participants with NMO and NMOSD.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Double (Participant, Investigator)
Eligibility Criteria
- Ages
- 12 Years to 74 Years (Child, Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Patients 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 the following Wingerchuk 2007 criteria with anti-AQP4 antibody (Ab) seropositive status at screening (i. Idiopathic single or recurrent events of longitudinally extensive myelitis [≥3 vertebral segment spinal cord MRI lesion]; ii. Optic neuritis: recurrent or simultaneous bilateral); For patients aged 12 to 17 years, a minimum of 4 patients should be positive for anti-AQP4Ab status at screening
- •Clinical evidence of at least 2 documented relapses (including first attack) in the last 2 years prior to screening, at least one of which has occurred in the 12 months prior to screening
- •EDSS score from 0 to 6.5 inclusive at screening
- •Age 12 to 74 years, inclusive at the time of informed consent
- •One of the following baseline treatments must be at stable dose as a monotherapy for 8 weeks prior to baseline: Azathioprine; Mycophenolate mofetil; Oral corticosteroids. For participants aged 12 to 17 years, either of the following baseline treatments for relapse prevention can be allowed: Azathioprine + oral corticosteroids; Mycophenolate mofetil + oral corticosteroids
- •Ability and willingness to provide written informed consent and to comply with the requirements of the protocol
- •For adolescents who may be enrolled after the end of the double-blind period, the inclusion criterion 2 is as follows (other criteria are same): Clinical evidence of at least 2 documented relapses (including first attack) prior to screening.
Exclusion Criteria
- •Exclusion criteria related to previous or concomitant therapy:
- •Any previous treatment with 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, belimumab, interferon, natalizumab, glatiramer acetate, fingolimod, teriflunomide or dimethyl fumarate within 6 months prior to baseline
- •Any previous treatment with anti-CD4, cladribine 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 patients of reproductive potential, a positive result from a serum pregnancy test at screening, or not willing to use reliable means of contraception (physical barrier [patient 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 patient participation, such as: 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 (TB; excluding patients receiving chemoprophylaxis for latent TB 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
- •Following laboratory abnormalities at screening*.
- •White blood cells (WBC) <3.0 x10^3/microliter (μL)
- •Absolute neutrophil count (ANC) <2.0 x10^3/μL
- •Absolute lymphocyte count <0.5 x10^3/μL
- •Platelet count <10 x 10^4/μL
- •Aspartate aminotransferase (AST) or alanine aminotranferase (ALT) >1.5 times the upper limit of normal (ULN) * If retest is conducted, the last value of retest before randomization must meet study criteria.
- •For adolescents who may be enrolled after the end of the double-blind period, the annotation in the exclusion criterion 20 is as follows (other criteria are same): * If retest is conducted, the last value of retest before baseline must meet study criteria
Arms & Interventions
Satralizumab + Baseline Treatment
Participants randomized to this arm for the double-blind period will receive satralizumab in addition to baseline treatment. The double-blind period ends when either the participant has a treated relapse or the total number of protocol-defined relapses confirmed by the Clinical Endpoint Committee (CEC) reaches 26. In the open-label extension period, the participant will receive (with or without baseline treatment) an SC injection of satralizumab at Weeks 0, 2, and 4, and Q4W thereafter, with the last study drug administration on or before 31 December 2021.
Intervention: Satralizumab (Drug)
Satralizumab + Baseline Treatment
Participants randomized to this arm for the double-blind period will receive satralizumab in addition to baseline treatment. The double-blind period ends when either the participant has a treated relapse or the total number of protocol-defined relapses confirmed by the Clinical Endpoint Committee (CEC) reaches 26. In the open-label extension period, the participant will receive (with or without baseline treatment) an SC injection of satralizumab at Weeks 0, 2, and 4, and Q4W thereafter, with the last study drug administration on or before 31 December 2021.
Intervention: Baseline Treatment (Drug)
Placebo + Baseline Treatment
Participants randomized to this arm for the double-blind period will receive placebo in addition to baseline treatment.The double-blind period ends when either the participant has a treated relapse or the total number of protocol-defined relapses confirmed by the Clinical Endpoint Committee (CEC) reaches 26. In the open-label extension period, the participant will receive (with or without baseline treatment) an SC injection of satralizumab at Weeks 0, 2, and 4, and Q4W thereafter, with the last study drug administration on or before 31 December 2021.
Intervention: Placebo (Drug)
Placebo + Baseline Treatment
Participants randomized to this arm for the double-blind period will receive placebo in addition to baseline treatment.The double-blind period ends when either the participant has a treated relapse or the total number of protocol-defined relapses confirmed by the Clinical Endpoint Committee (CEC) reaches 26. In the open-label extension period, the participant will receive (with or without baseline treatment) an SC injection of satralizumab at Weeks 0, 2, and 4, and Q4W thereafter, with the last study drug administration on or before 31 December 2021.
Intervention: Baseline Treatment (Drug)
Outcomes
Primary Outcomes
Time to First Protocol-Defined Relapse (TFR) in the Double-Blind Period
Time Frame: Up to Week 224
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) as adjudicated by an independent clinical endpoint committee (CEC). 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.
Secondary Outcomes
- Change From Baseline at Week 24 in the Visual Analogue Scale (VAS) Score for Pain During the DB Period(Baseline, Week 24)
- Change From Baseline in Expanded Disability Status Scale (EDSS) Scores at 24 Week Intervals During the DB Period(Baseline up to Week 216)
- Change From Baseline at Week 24 in the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Score During the DB Period(Baseline, Week 24)
- Relapse-Free Rate During the DB Period(Up to Week 216)
- Annualized Relapse Rate (ARR) During the DB Period(Up to Week 216)
- Change From Baseline in Modified Rankin Scale (mRS) Scores at 24 Week Intervals During the DB Period(Baseline up to Week 216)
- Change From Baseline in Zarit Burden Interview (ZBI) Scores at 24 Week Intervals During the DB Period(Baseline up to Week 168)
- Change From Baseline in SF-36 General Health Domain Scores at 24 Week Intervals During the DB Period(Baseline up to Week 216)
- Change From Baseline in SF-36 Mental Health Domain Scores at 24 Week Intervals During the DB Period(Baseline up to Week 216)
- Change From Baseline in Visual Acuity (Snellen Chart) at 24 Week Intervals During the DB Period(Baseline up to Week 216)
- Change From Baseline in Short Form Generic Health Survey (SF-36) Mental Component Summary Scores at 24 Week Intervals During the DB Period(Baseline up to Week 216)
- Change From Baseline in SF-36 Physical Component Summary Scores at 24 Week Intervals During the DB Period(Baseline up to Week 216)
- Change From Baseline in SF-36 Bodily Pain Domain Scores at 24 Week Intervals During the DB Period(Baseline up to Week 216)
- Change From Baseline in SF-36 Physical Functioning Domain Scores at 24 Week Intervals During the DB Period(Baseline up to Week 216)
- Change From Baseline in SF-36 Role-Emotional Domain Scores at 24 Week Intervals During the DB Period(Baseline up to Week 216)
- Change From Baseline in SF-36 Role-Physical Domain Scores at 24 Week Intervals During the DB Period(Baseline up to Week 216)
- Change From Baseline in SF-36 Social Role Functioning Domain Scores at 24 Week Intervals During the DB Period(Baseline up to Week 216)
- Change From Baseline in SF-36 Vitality Domain Scores at 24 Week Intervals During the DB Period(Baseline up to Week 216)
- Change From Baseline in EuroQoL-5 Dimensions (EQ-5D) Index Scores at 24 Week Intervals During the DB Period(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 224)
- Serum Soluble IL-6 Receptor (sIL-6R) Concentration During the DB Period(Baseline, Weeks 2, 4, and every 4 weeks thereafter up to Week 224)
- Serum High Sensitivity C-Reactive Protein (hsCRP) Concentration During the DB Period(Baseline, Weeks 2, 4, and every 4 weeks thereafter up to Week 224)
- Serum Interleukin-6 (IL-6) Concentration During the DB Period(Baseline, Weeks 2, 4, and every 4 weeks thereafter up to Week 224)
- Number of Participants With at Least One Adverse Event in the DB Period(Up to Week 224)
- Number of Participants With at Least One Serious Adverse Event in the DB Period(Up to Week 224)
- Number of Participants With Non-Serious Adverse Events of Special Interest in the DB Period(Up to Week 224)
- Number of Participants With Selected Adverse Events in the DB Period(Up to Week 224)
- Number of Participants With Suicidal Behaviors and Ideations Collected by Columbia-Suicide Severity Rating Scale in the DB Period(Baseline and Post-Baseline (up to Week 224))
- Percentage of Participants With Anti-Drug Antibodies to Satralizumab in the DB Period(Up to approximately Week 224)
- Percentage of Participants With Anti-Drug Antibodies to Satralizumab Overall S237 Period(Up to approximately Week 368)