N-MOmentum: A Clinical Research Study of Inebilizumab in Neuromyelitis Optica Spectrum Disorders

Study Overview
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Brief Summary
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To compare the efficacy of inebilizumab (MEDI-551) versus placebo in reducing the risk of an neuromyelitis optica/neuromyelitis optica- spectrum disorders (NMO/NMOSD) attack in participants with NMO/NMOSD.

Detailed Description
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Inebilizumab is a genetically engineered humanized monoclonal antibody that binds to the B cell specific surface antigen cluster of differentiation (CD19) resulting in the depletion of B cells. Inebilizumab depletes antibody-secreting plasmablasts and some plasma cells, which are generally CD19 positive and CD20 negative. The main objective of this study is to determine whether inebilizumab compare to placebo decreases the risk of an attack in participants with NMO/NMOSD. This is a multicenter, multinational, randomized, double-masked, placebo controlled study with an open-label extension period to evaluate the efficacy and safety of intravenous (IV) inebilizumab in adult participants with NMO/NMOSD. After a screening period, eligible participants will enter a randomized-controlled period (RCP) of maximum 197 days where they will be randomized in a 3:1 ratio to receive either IV inebilizumab or placebo. NMO/NMOSD attacks will be evaluated by the investigator and confirmed against the attack criteria by an independent Adjudication Committee (AC). Participants for whom the attack was confirmed by the AC will be given the option to enroll into an open label period (OLP) with inebilizumab treatment. Participants who complete the RCP without experiencing an attack will be given the option to enroll into an OLP with inebilizumab treatment. The OLP will continue for a minimum of 1 year and a maximum of 3 years after the last participant enter the OLP. All participants who discontinue from the RCP or the OLP will continue in a Safety Follow-up for a total of 12 months from last dose to evaluate the long-term safety of the investigational product.

Official Title
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A Double-masked, Placebo-controlled Study With Open-label Period to Evaluate the Efficacy and Safety of MEDI-551 in Adult Subjects With Neuromyelitis Optica and Neuromyelitis Optica Spectrum Disorders.

Conditions
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Neuromyelitis Optica and Neuromyelitis Optica Spectrum Disorders

Intervention / Treatment
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* Drug: Inebilizumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women 18 years or older with diagnosis of NMO/NMOSD Confirmation of NMO/NMOSD status: AQP4-IgG sero-positive NMO/NMOSD with at least one attack requiring rescue therapy in the last year or two attacks requiring rescue therapy in the last 2 years AQP4-IgG sero-negative NMO with at least one attack requiring rescue therapy in the last year or two attacks requiring rescue therapy in the last 2 years Able and willing to give written informed consent and comply with the requirements of the study protocol. EDSS <= 7.5 (8 in special circumstances) Men and women of reproductive potential must agree to use a highly effective method of birth control from screening to 6 months after final dose of the investigational product. Exclusion Criteria: Lactating and pregnant females Treatment with any investigational agent within 4 weeks of screening Known history of a severe allergy or reaction to any component of the investigational product formulation or history of anaphylaxis following any biologic therapy. Known active severe bacterial, viral, or other infection or any major episode of infection requiring hospitalization. History of alcohol, drug, or chemical abuse, or a recent history of such abuse < 1 year prior to randomization Receipt of the following at any time prior to randomization: Alemtuzumab Total lymphoid irradiation Bone marrow transplant T-cell vaccination therapy Receipt of rituximab or any experimental B-cell depleting agent within 6 months prior screening and B-cells below the lower limit of normal. Receipt of intravenous immunoglobulin (IVIG) within 1 month prior to randomization. Receipt of any of the following within 3 months prior to randomization: Natalizumab (Tysabri®). Cyclosporin Methotrexate Mitoxantrone Cyclophosphamide Tocilizumab Eculizumab History of Hepatitis B and/or Hepatitis C (Hep B/C at screening) Known history of a primary immunodeficiency (congenital or acquired) or an underlying condition such as human immunodeficiency virus (HIV) infection History of malignancies, apart from squamous cell or basal cell carcinoma of the skin treated with documented success of curative therapy > 3 months prior to randomization Any concomitant disease other than NMO/NMOSD that required treatment with oral or intravenous steroids at doses over 20 mg a day for over 21 days

Ages Eligible for Study
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Minimum Age: 18 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo/Inebilizumab<br>Aquaporin-4-antibody (AQP4-IgG) sero positive and sero negative participants will receive IV dose of placebo matched to inebilizumab on Day 1 and Day 15 of the RCP. The participants who enter OLP will receive IV inebilizumab 300 mg on both Day 1 and Day 15, followed by a single IV dose of inebilizumab 300 mg every 6 months until maximum of 3 years after the last participant enters the OLP. Participants will have choice to enter in the SFP at any point during RCP or OLP and will be free to pursue other treatment options otherwise prohibited during the RCP and OLP. Participants will continue in the SFP for 12 months from last dose of study drug. | Drug: Inebilizumab<br>* Participants will receive IV inebilizumab 300 mg.<br>* Other names: MEDI-551;Other: Placebo<br>* Participants will receive IV placebo matched to inebilizumab.<br>|
| Experimental: Inebilizumab/Inebilizumab<br>AQP4-IgG sero positive and sero negative participants will IV dose of inebilizumab 300 mg on Day 1 and Day 15 of RCP. The participants who enter OLP will receive IV inebilizumab 300 mg on Day 1 and matching placebo on Day 15, followed by a single IV dose of inebilizumab 300 mg every 6 months until maximum of 3 years after the last participant enters the OLP. Participants will have choice to enter in the SFP at any point during RCP or OLP and will be free to pursue other treatment options otherwise prohibited during the RCP and OLP. Participants will continue in the SFP for 12 months from last dose of study drug. | Drug: Inebilizumab<br>* Participants will receive IV inebilizumab 300 mg.<br>* Other names: MEDI-551;Other: Placebo<br>* Participants will receive IV placebo matched to inebilizumab.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Adjudication Committee (AC)-Determined Neuromyelitis Optica Spectrum Disorder (NMOSD) Attack During RCP | The NMOSD attack is defined as the presence of new or worsening symptom(s) related to NMOSD that meet at least one of the 18 protocol-defined attack criteria. These criteria were developed in conjunction with a panel of disease experts and with Food and Drug Administration input, and were intended to be clinically meaningful, objective, quantifiable, and able to be used worldwide. Only attacks positively adjudicated by the AC were used for the primary analysis. | Day 1 (Baseline) through Day 197 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Worsening in Expanded Disability Severity Scale (EDSS) Score From Baseline to the Last Visit of RCP | EDSS and its associated functional system (FS) score provide a system for quantifying disability and monitoring changes in the level of disability over time. EDSS is a scale for assessing neurologic impairment in multiple sclerosis (MS). It consists of 7 FS (visual FS, brainstem FS, pyramidal FS, cerebellar FS, sensory FS, bowel and bladder FS, and cerebral FS) which are used to derive EDSS score ranging from 0 (normal neurological exam) to 10 (death from MS). A negative change from baseline indicates improvement. A participant was considered to have a worsening in overall EDSS score of at least 2 if baseline EDSS score was 0, or at least 1 point if baseline EDSS score is 1 to 5, or at least 0.5 point if baseline EDSS score is 5.5 or more. | Day 1 (Baseline) through Day 197 | 
| Change From Baseline in Low-Contrast Visual Acuity Binocular Score to the Last Visit of RCP | Low-contrast visual acuity test is used to determine the number of letters that can be read on a standardized low-contrast Landolt C Broken Rings Chart held at a distance of 3 meters. Binocular score is the number of letters read correctly on an eye chart using both eyes simultaneously. The total score ranges from 0-70. Higher score indicates better vision. | Day 1 (Baseline) through Day 197 | 
| Cumulative Number of Active Magnetic Resonance Imaging (MRI) Lesions During RCP | The number of new gadolinium-enhancing lesions and new or enlarging T2 lesions were measured by MRI of the brain, optic nerve, and spinal cord. | From Screening (Day -28) to Day 197 | 
| Number of NMOSD-related In-patient Hospitalizations During RCP | Participants with relapsing NMOSD have recurrent attacks that can be severe and result in blindness, paralysis, and even death and consequently, such attacks frequently result in in-patient hospitalizations. In-patient hospitalization is defined as a stay in hospital that goes beyond midnight of the first day of admission. | Day 1 (Baseline) through Day 197 | 
| Annualized AC-determined NMOSD Attack Rate During Any Exposure to Inebilizumab | Annualized attack rate is defined as total number of AC-determined attacks divided by total person years. Total person-years is calculated as the sum of the person-years for individual participant. Person-year for individual participant = (Date of last day before safety follow-up period - first inebilizumab dose date +1)/365.25. Annualized AC-determined NMOSD attack rate during any exposure to inebilizumab (in RCP and OLP) is reported. | For participants randomized to inebilizumab: Day 1 of RCP through end of OLP (approximately 3.5 years); and for participants randomized to placebo: Day 1 of OLP through the end of OLP (approximately 3 years) | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) During RCP | An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event is any AE that resulted in death, life threatening, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, is a congenital anomaly/birth defect in offspring of a study participant, is an important medical event that may jeopardize the participant or may require medical intervention. TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug during the RCP. | Day 1 (Baseline) through Day 197 | 
| Number of Participants With TEAEs and TESAEs During OLP | An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event is any AE that resulted in death, life threatening, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, is a congenital anomaly/birth defect in offspring of a study participant, is an important medical event that may jeopardize the participant or may require medical intervention. TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug during the OLP. | Day 198 through end of OLP period (maximum of 3 years after the last participant entered, until regulatory approval or study discontinuation, whichever occurs first) (approximately 3 years) | 
| Number of Participants With TEAEs and TESAEs During SFP (Open-label Population) | An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event is any AE that resulted in death, life threatening, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, is a congenital anomaly/birth defect in offspring of a study participant, is an important medical event that may jeopardize the participant or may require medical intervention. TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug during the OLP. Participant who prematurely discontinued from the RCP or OLP entered in the SFP. | Every 3 months for a total of 1 year after the last dose of study drug (approximately 3 years) | 
| Number of Participants With TEAEs and TESAEs During SFP (Non-OLP Population) | An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event is any AE that resulted in death, life threatening, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, is a congenital anomaly/birth defect in offspring of a study participant, is an important medical event that may jeopardize the participant or may require medical intervention. TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug during the OLP. The SFP started when a participant prematurely discontinues from the RCP or OLP. | Every 3 months for a total of 1 year after the last dose of study drug (approximately 3 years) | 
| Number of Participants With at Least a 2-Grade Shift From Baseline to Worst Toxicity Grade in Hematology and Chemistry During RCP | Number of participants with at least a 2-grade shift from baseline to worst toxicity grade in hematology and chemistry during RCP is reported. | Day 1 (Baseline) through Day 197 | 
| Number of Participants With at Least a 2-Grade Shift From Baseline to Worst Toxicity Grade in Hematology and Chemistry During OLP | Number of participants with at least a 2-grade shift from baseline to worst toxicity grade in hematology and chemistry during OLP is reported. | Day 198 through end of OLP (maximum of 3 years after the last participant enters, until regulatory approval or study discontinuation, whichever occurs first) (approximately 3 years) | 
| Time to Maximum Serum Concentration (Tmax) of Inebilizumab (During RCP) | Time to maximum serum concentration of inebilizumab during RCP is reported. | Dose 1 (Pre and post dose on Day 1 and Day 8); and Dose 2 (pre and post dose on Day 15; and Days 29, 57, 85, 113, 155, and 197) | 
| Maximum Observed Serum Concentration (Cmax) of Inebilizumab (During RCP) | Maximum observed serum concentration of inebilizumab during RCP is reported. | Dose 1 (Pre and post dose on Day 1 and Day 8); and Dose 2 (pre and post dose on Day 15; and Days 29, 57, 85, 113, 155, and 197) | 
| Area Under the Serum Concentration Time Curve of the Dosing Interval (AUC0-14d) of Inebilizumab (During RCP) | Area under the serum concentration time curve of the dosing interval (AUC0-14d) of inebilizumab during RCP is reported. | Dose 1 (Pre and post dose on Day 1 and Day 8); and Dose 2 (pre and post dose on Day 15; and Days 29, 57, 85, 113, 155, and 197) | 
| Number of Participants With Positive Anti-Drug Antibodies (ADA) Titer to Inebilizumab (During RCP) | Number of participants with positive ADA titer to inebilizumab during RCP is reported. | Pre and post dose on Day 1; and on Days 29, 85, and 197 | 
| Number of Participants With Positive Anti-Drug Antibodies (ADA) Titer to Inebilizumab (During OLP) | Number of participants with positive ADA titer to inebilizumab in OLP is reported. | Pre and post dose on Day 1; and on Days 92, 183, 274, and then every 6 months (maximum of 3 years after the last participant enters, until regulatory approval or study discontinuation, whichever occurs first) (approximately 3 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NMO, NMOSD, Neuromyelitis Optica, Neuromyelitis Optica Spectrum Disorders, autoimmune, demyelination, MEDI-551, monoclonal antibody, Devic's syndrome, B-cell