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A Double-masked, Placebo-controlled Study With Open Label Period to Evaluate MEDI-551 in Neuromyelitis Optica and Neuromyelitis Optica Spectrum Disorders

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02200770
Recruitment Status : Active, not recruiting
First Posted : July 25, 2014
Results First Posted : December 26, 2019
Last Update Posted : June 11, 2020
Sponsor:
Information provided by (Responsible Party):
MedImmune LLC

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Neuromyelitis Optica and Neuromyelitis Optica Spectrum Disorders Drug: Inebilizumab Other: Placebo Phase 2 Phase 3

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 231 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : January 6, 2015
Actual Primary Completion Date : October 26, 2018
Estimated Study Completion Date : October 21, 2022


Arm Intervention/treatment
Placebo Comparator: Total Placebo
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 entered OLP will receive IV inebilizumab 300 mg on both Day 1 and Day 15 in OLP and will be 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.
Drug: Inebilizumab
Participants will receive IV inebilizumab 300 mg.
Other Name: MEDI-551

Other: Placebo
Participants will receive IV placebo matched to inebilizumab.

Experimental: Total Inebilizumab
AQP4-IgG sero positive and sero negative participants will receive IV dose of inebilizumab 300 mg on Day 1 and Day 15 of RCP. The participants who entered OLP will receive IV inebilizumab 300 mg on Day 1 and matching placebo on Day 15 of OLP and will be 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.
Drug: Inebilizumab
Participants will receive IV inebilizumab 300 mg.
Other Name: MEDI-551

Other: Placebo
Participants will receive IV placebo matched to inebilizumab.




Primary Outcome Measures :
  1. Time to Adjudication Committee (AC)-Determined Neuromyelitis Optica Spectrum Disorder (NMOSD) Attack During Randomized Controlled Period (RCP) [ Time Frame: Day 1 (Baseline) through Day 197 ]
    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.


Secondary Outcome Measures :
  1. Percentage of Participants With Worsening in Expanded Disability Severity Scale (EDSS) Score From Baseline to the Last Visit of RCP [ Time Frame: Day 1 (Baseline) through Day 197 ]
    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.

  2. Change From Baseline in Low-Contrast Visual Acuity Binocular Score to the Last Visit of RCP [ Time Frame: Day 1 (Baseline) through Day 197 ]
    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.

  3. Cumulative Number of Active Magnetic Resonance Imaging (MRI) Lesions During RCP [ Time Frame: From Screening (Day -28) to Day 197 ]
    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.

  4. Number of NMOSD-related In-patient Hospitalizations During RCP [ Time Frame: Day 1 (Baseline) through Day 197 ]
    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.

  5. Annualized AC-determined NMOSD Attack Rate During Any Exposure to Inebilizumab [ Time Frame: 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) ]
    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.

  6. Number of Participants With Treatment Emergent Adverse Events TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) During RCP [ Time Frame: Day 1 (Baseline) through Day 197 ]
    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.

  7. Number of Participants With TEAEs and TESAEs During OLP [ Time Frame: Day 198 through end of OLP period (maximum of 3 years after the last participant enters, until regulatory approval or study discontinuation, whichever occurs first) (approximately 3 years) ]
    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 OLP.

  8. Number of Participants With at Least a 2-Grade Shift From Baseline to Worst Toxicity Grade in Hematology and Chemistry During RCP [ Time Frame: 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 RCP is reported.

  9. Number of Participants With at Least a 2-Grade Shift From Baseline to Worst Toxicity Grade in Hematology and Chemistry During OLP [ Time Frame: 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) ]
    Number of participants with at least a 2-grade shift from baseline to worst toxicity grade in hematology and chemistry during OLP is reported.

  10. Time to Maximum Serum Concentration (Tmax) of Inebilizumab (During RCP) [ Time Frame: 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) ]
    Time to maximum serum concentration of inebilizumab during RCP is reported.

  11. Maximum Observed Serum Concentration (Cmax) of Inebilizumab (During RCP) [ Time Frame: 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 of inebilizumab during RCP is reported.

  12. Area Under the Serum Concentration Time Curve of the Dosing Interval (AUC0-14d) of Inebilizumab (During RCP) [ Time Frame: 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 is reported.

  13. Number of Participants With Positive Anti-Drug Antibodies (ADA) Titer to Inebilizumab (During RCP) [ Time Frame: Pre and post dose on Day 1; and on Days 29, 85, and 197 ]
    Number of participants with positive ADA titer to inebilizumab during RCP is reported.

  14. Number of Participants With Positive Anti-Drug Antibodies (ADA) Titer to Inebilizumab (RCP+OLP) [ Time Frame: RCP: Pre and post dose on Day 1; and on Days 29, 85, and 197; OLP: Pre and post dose on Day 1; and on Days 92, 183, 274, and then every 6 months until maximum of 3 years ]
    Number of participants with positive ADA titer to inebilizumab in RCP and OLP (combined) is reported.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Men and women 18 years or older with diagnosis of NMO/NMOSD
  2. Confirmation of NMO/NMOSD status:

    1. 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
    2. 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
  3. Able and willing to give written informed consent and comply with the requirements of the study protocol.
  4. EDSS <= 7.5 (8 in special circumstances)
  5. 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:

  1. Lactating and pregnant females
  2. Treatment with any investigational agent within 4 weeks of screening
  3. Known history of a severe allergy or reaction to any component of the investigational product formulation or history of anaphylaxis following any biologic therapy.
  4. Known active severe bacterial, viral, or other infection or any major episode of infection requiring hospitalization.
  5. History of alcohol, drug, or chemical abuse, or a recent history of such abuse < 1 year prior to randomization
  6. Receipt of the following at any time prior to randomization:

    1. Alemtuzumab
    2. Total lymphoid irradiation
    3. Bone marrow transplant
    4. T-cell vaccination therapy
  7. Receipt of rituximab or any experimental B-cell depleting agent within 6 months prior screening and B-cells below the lower limit of normal.
  8. Receipt of intravenous immunoglobulin (IVIG) within 1 month prior to randomization.
  9. Receipt of any of the following within 3 months prior to randomization:

    1. Natalizumab (Tysabri®).
    2. Cyclosporin
    3. Methotrexate
    4. Mitoxantrone
    5. Cyclophosphamide
    6. Tocilizumab
    7. Eculizumab
  10. History of Hepatitis B and/or Hepatitis C (Hep B/C at screening)
  11. Known history of a primary immunodeficiency (congenital or acquired) or an underlying condition such as human immunodeficiency virus (HIV) infection
  12. 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
  13. 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02200770


Locations
Show Show 106 study locations
Sponsors and Collaborators
MedImmune LLC
  Study Documents (Full-Text)

Documents provided by MedImmune LLC:
Study Protocol  [PDF] October 11, 2018
Statistical Analysis Plan  [PDF] October 18, 2018

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: MedImmune LLC
ClinicalTrials.gov Identifier: NCT02200770    
Other Study ID Numbers: CD-IA-MEDI-551-1155
2014-000253-36 ( EudraCT Number )
First Posted: July 25, 2014    Key Record Dates
Results First Posted: December 26, 2019
Last Update Posted: June 11, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by MedImmune LLC:
NMO, NMOSD, Neuromyelitis Optica, Neuromyelitis Optica Spectrum Disorders, autoimmune, demyelination, MEDI-551, monoclonal antibody, Devic's syndrome, B-cell
Additional relevant MeSH terms:
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Neuromyelitis Optica
Disease
Pathologic Processes
Myelitis, Transverse
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Optic Neuritis
Optic Nerve Diseases
Cranial Nerve Diseases
Demyelinating Diseases
Eye Diseases
Autoimmune Diseases
Immune System Diseases