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

Phase 3CompletedNCT02028884

Hoffmann-La Roche85 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Neuromyelitis Optica (NMO)NMO Spectrum Disorder (NMOSD)

Interventions

SatralizumabDRUG

Satralizumab will be administered subcutaneously (SC) at Weeks 0, 2, and 4, and thereafter once every 4 weeks (Q4W).

PlaceboDRUG

Placebo will be administered subcutaneously (SC) at Weeks 0, 2, and 4, and thereafter once every 4 weeks (Q4W).

Baseline TreatmentDRUG

As specified in the protocol, one of the following drugs at a stable dose is required as monotherapy for baseline treatment during the double-blind period: azathioprine (AZA); mycophenolate mofetil (MMF); or oral corticosteroids (CS). For participants aged 12 to 17 years at the time of informed consent, baseline treatment with AZA or MMF in combination with oral CS is also permitted. Change or termination of baseline treatment is only permitted during the open-label extension period.

Eligibility

Sex: ALLMin age: 12 YearsMax age: 74 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Patients must be diagnosed as having either neuromyelitis optica (NMO) or NMO spectrum disorder (NMOSD), defined as the following: 1. 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) 2. 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 2. 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 3. EDSS score from 0 to 6.5 inclusive at screening 4. Age 12 to 74 years, inclusive at the time of informed consent 5. 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 6. 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: 1. Any previous treatment with IL-6 inhibitory therapy (e.g. tocilizumab), alemtuzumab, total body irradiation or bone marrow transplantation at any time 2. Any previous treatment with anti-CD20, eculizumab, belimumab, interferon, natalizumab, glatiramer acetate, fingolimod, teriflunomide or dimethyl fumarate within 6 months prior to baseline 3. Any previous treatment with anti-CD4, cladribine or mitoxantrone within 2 years prior to baseline 4. Treatment with any investigational agent within 3 months prior to baseline Exclusions for general safety: 5. Pregnancy or lactation 6. 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 7. Any surgical procedure (except for minor surgeries) within 4 weeks prior to baseline 8. Evidence of other demyelinating disease or progressive multifocal leukoencephalopathy (PML) 9. 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 10. Known active infection (excluding fungal infections of nail beds or caries dentium) within 4 weeks prior to baseline 11. Evidence of chronic active hepatitis B or C 12. History of drug or alcohol abuse within 1 year prior to baseline 13. History of diverticulitis that, in the Investigator's opinion, may lead to increased risk of complications such as lower gastrointestinal perforation 14. Evidence of active tuberculosis (TB; excluding patients receiving chemoprophylaxis for latent TB infection) 15. Evidence of active interstitial lung disease 16. Receipt of any live or live attenuated vaccine within 6 weeks prior to baseline 17. 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) 18. History of severe allergic reaction to a biologic agent (e.g. shock, anaphylactic reactions) 19. Active suicidal ideation within 6 months prior to screening, or history of suicide attempt within 3 years prior to screening 20. Following laboratory abnormalities at screening\*. 1. White blood cells (WBC) \<3.0 x10\^3/microliter (μL) 2. Absolute neutrophil count (ANC) \<2.0 x10\^3/μL 3. Absolute lymphocyte count \<0.5 x10\^3/μL 4. Platelet count \<10 x 10\^4/μL 5. 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

Locations (40)

Outcomes

Primary Outcomes

Time to First Protocol-Defined Relapse (TFR) in the Double-Blind 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) 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.

Time frame: Up to Week 224

Secondary Outcomes

Change From Baseline at Week 24 in the Visual Analogue Scale (VAS) Score 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).

Time frame: Baseline, Week 24

Change From Baseline at Week 24 in the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Score 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. ANCOVA was used for analysis to report the adjusted mean and SE.

Data from ClinicalTrials.gov

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Children's Hospital of Alabama

Birmingham, Alabama, United States

Hopital de Hautepierre CHRU de Strasbourg

Strasbourg, France

NeuroCure Clinical Research Center (NCRC)

Berlin, Germany

St. Josef-Hospital, Klinik für Neurologie

Bochum, Germany

Heinrich-Heine Universitätsklinik Düsseldorf

Düsseldorf, Germany

Jahn Ferenc Dél-Pesti Kórház

Budapest, Hungary

Azienda Ospedaliera Sant'Andrea-Universitr di Roma La Sapien

Rome, Lazio, Italy

Ospedale San Raffaele

Milan, Lombardy, Italy

PO G.Rodolico, AOU Policlinico-Vittorio Emanuele Catania

Catania, Sicily, Italy

Fond. Ist. S. Raffaele - giglio

Cefalù, Sicily, Italy

...and 30 more locations

Time frame: 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.

Time frame: Up to Week 216

Annualized Relapse Rate (ARR) During the DB Period

The ARR is calculated as the total number of participants with relapses 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.

Time frame: 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.