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SIZOMUS Safety of Ixazomib Targeting Plasma Cells in Multiple Sclerosis (SIZOMUS)

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ClinicalTrials.gov Identifier: NCT03783416
Recruitment Status : Not yet recruiting
First Posted : December 21, 2018
Last Update Posted : January 11, 2019
Sponsor:
Collaborator:
Takeda Pharmaceuticals International, Inc.
Information provided by (Responsible Party):
Queen Mary University of London

Brief Summary:
The study seeks to investigate safety and efficacy of ixazomib (NINLARO), a proteasome inhibitor, in multiple sclerosis (MS). Participants will receive either ixazomib capsules or placebo capsules for up to 24 months.

Condition or disease Intervention/treatment Phase
Relapsing Remitting Multiple Sclerosis Primary Progressive Multiple Sclerosis Secondary Progressive Multiple Sclerosis Drug: Ixazomib (NINLARO®) capsules / Matching placebo capsules Phase 1

Detailed Description:
The production of antibodies in the form of oligoclonal bands (OCBs) from plasma cells (cells involved in the body's immune response), is the hallmark of MS. Recent evidence suggests that plasma cells are resident in the meninges (protective membranes of the brain and spinal cord) of people with Multiple Sclerosis (pwMS). Ixazomib is a drug which has been effective in treating multiple myeloma, a disease caused by aberrant plasma cells. The purpose of this study is to investigate whether ixazomib can reduce or clear OCBs from the cerebrospinal fluid (CSF) of pwMS. Participants will be randomly assigned to receive either ixazomib capsules (active drug arm) or placebo capsules (placebo arm) for up to 24 months. Participants with relapsing remitting MS (who are stable on disease modifying therapy) and those with progressive MS (who are not on disease modifying therapy) will be invited to take part in the study.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This is a double-blind, randomised, placebo-controlled trial. Randomisation will be stratified by disease stage, i.e. RRMS (and established on DMT) versus progressive MS (and not on DMT). The expected study duration is 36 months (a 12-month recruitment period and a 24-month treatment period). There will be 72 participants: 48 on ixazomib; 24 on placebo.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Other
Official Title: Safety of Ixazomib Targeting Plasma Cells in Multiple Sclerosis: A Phase 1b Randomised, Double-blind, Placebo-controlled Trial.
Estimated Study Start Date : June 1, 2019
Estimated Primary Completion Date : June 1, 2022
Estimated Study Completion Date : June 1, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Ixazomib (NINLARO®)
Treatment will follow a 28-day cycle. Participants will take one Ixazomib (NINLARO) capsule orally on days 1, 8, and 15 of each 28-day cycle, followed by one treatment-free week, in sequence, for the duration of the trial.
Drug: Ixazomib (NINLARO®) capsules / Matching placebo capsules
Participants will be treated for a maximum of 24 months

Placebo Comparator: Placebo
Treatment will follow a 28-day cycle. Participants will take one placebo capsule orally on days 1, 8, and 15 of each 28-day cycle, followed by one treatment-free, in sequence, for the duration of the trial.
Drug: Ixazomib (NINLARO®) capsules / Matching placebo capsules
Participants will be treated for a maximum of 24 months




Primary Outcome Measures :
  1. Safety - Adverse events (AE) will be compared between active and placebo arm [ Time Frame: Baseline to 24 months ]
    1. Proportion of AEs in the Ixazomib versus placebo arm in subjects with Relapsing Remitting Multiple Sclerosis (RRMS)
    2. Proportion of serious AEs (SAEs) in the Ixazomib versus placebo arm in subjects with RRMS
    3. Proportion of AEs in the Ixazomib versus placebo arm in subjects with progressive MS
    4. Proportion of serious AEs (SAEs) in the Ixazomib versus placebo arm in subjects with progressive MS
    5. Proportion of AEs in the Ixazomib versus placebo arm in all subjects (subjects with RRMS and subjects with progressive MS)
    6. Proportion of serious AEs (SAEs) in the Ixazomib versus placebo arm in all subjects (subjects with RRMS and subjects with progressive MS)

  2. Efficacy - the proportion of OCB IgG negative subjects will be compared between active and placebo arm [ Time Frame: Baseline to 24 months ]
    1. Proportion of all subjects (Relapsing Remitting Multiple Sclerosis and progressive Multiple Sclerosis subjects) negative for Oligoclonal Bands Immunoglobulin G (OCB IgG) antibodies measured in Cerebrospinal Fluid (CSF) in the Ixazomib versus placebo arm at 24 months
    2. Proportion of subjects negative for Oligoclonal Bands Immunoglobulin G (OCB IgG) antibodies measured in Cerebrospinal Fluid (CSF) in the Ixazomib versus placebo arm at 24 months in subjects with Relapsing Remitting Multiple Sclerosis (RRMS)
    3. Proportion of subjects negative for Oligoclonal Bands Immunoglobulin G (OCB IgG) antibodies measured in Cerebrospinal Fluid (CSF) in the Ixazomib versus placebo arm at 24 months in subjects with progressive Multiple Sclerosis


Secondary Outcome Measures :
  1. Magnetic Resonance Imaging (MRI) [ Time Frame: Baseline to 24 months ]
    Change in T2 lesion load and gadolinium enhancing lesions on brain MRI with Ixazomib versus placebo arm at 24 months

  2. Change In Expanded Disability Status Scale (EDSS) with Ixazomib versus placebo arm at 24 months. The EDSS scale ranges from 0 to 10 in 0.5 unit increments that represent higher levels of disability. Scoring is based on an examination by a neurologist [ Time Frame: Baseline to 24 months ]
    Change in EDSS with ixazomib versus placebo at 24 months.


Other Outcome Measures:
  1. Exploratory endpoint - IgG FLC [ Time Frame: Baseline to 24 months ]
    a. Proportion of all subjects who show reduction in total levels of Immunoglobulin G Free Light Chain (IgG FLC) in Cerebrospinal Fluid (CSF) at 24 months in the Ixazomib versus placebo arm.

  2. Exploratory endpoint - CD19 [ Time Frame: Baseline to 24 months ]
    b. Proportion of all subjects who show change in levels of Cluster of Differentiation antigen 19 (CD 19) at 24 months in the Ixazomib versus placebo arm.

  3. Exploratory endpoint - soluble CD 138 [ Time Frame: Baseline to 24 months ]
    c. Proportion of all subjects who show change in levels of soluble CD 138 at 24 months in the Ixazomib versus placebo arm

  4. Exploratory endpoint - CD 27 [ Time Frame: Baseline to 24 months ]
    d. Proportion of all subjects who show change in levels of soluble CD 27 at 24 months in the Ixazomib versus placebo arm

  5. Exploratory endpoint - neurofilament light chain [ Time Frame: Baseline to 24 months ]
    e. Proportion of all subjects who show change in levels of neurofilament light chain at 24 months in the Ixazomib versus placebo arm

  6. Exploratory endpoint - neurofilament heavy chain [ Time Frame: Baseline to 24 months ]
    f. Proportion of all subjects who show change in levels of neurofilament heavy chain at 24 months in the Ixazomib versus placebo arm

  7. Exploratory endpoint - neopterin [ Time Frame: Baseline to 24 months ]
    g. Proportion of all subjects who show change in levels of neopterin at 24 months in the Ixazomib versus placebo arm

  8. Exploratory endpoint - cytokines profile [ Time Frame: Baseline to 24 months ]
    h. Proportion of all subjects who show change in levels of cytokines profile at 24 months in the Ixazomib versus placebo arm

  9. Exploratory endpoint - GFAP [ Time Frame: Baseline to 24 months ]
    i. Proportion of all subjects who show change in levels of Glial fibrillary acidic protein (GFAP) at 24 months in the Ixazomib versus placebo arm

  10. Exploratory endpoint - NCAM [ Time Frame: Baseline to 24 months ]
    j. Proportion of all subjects who show change in levels of Neural cell adhesion molecule (NCAM) at 24 months in the Ixazomib versus placebo arm

  11. Exploratory endpoint - GAP43 [ Time Frame: Baseline to 24 months ]
    k. Proportion of all subjects who show change in levels of Growth Associated Protein 43 (GAP43) at 24 months in the Ixazomib versus placebo arm

  12. Exploratory endpoint - S100B [ Time Frame: Baseline to 24 months ]
    l. Proportion of all subjects who show change in levels of S100 calcium-binding protein B (S100B) at 24 months in the Ixazomib versus placebo arm



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 to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

- Each participant must meet all of the following inclusion criteria to be enrolled in the study:

  1. Male and female patients 18 to 65 years old at screening
  2. Must have a diagnosis of MS, and:

    • Patients with RRMS must be on DMT
    • Patients with progressive MS must not be on DMT
  3. Participants with RRMS must be on stable DMT (i.e. must not have had a relapse within 1 month prior to the screening visit). Patients on tecfidera, cladribine, ocrelizumab, alemtuzumab, fingolimod or natalizumab must be enrolled with caution, at Chief Investigator's (CI) discretion because of the lymphopenia caused by these drugs and the risk of thrombocytopenia in 1-2 % of people after alemtuzumab
  4. OCB positive CSF either from a previous CSF analysis or from the screening CSF analysis
  5. Able and willing to give written informed consent and comply with protocol requirements with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
  6. Agree to the use of effective contraception as follows:

    Female patients must:

    • Be postmenopausal for at least 1 year before the screening visit (postmenopausal status confirmed by serum Follicle Stimulating Hormone (FSH) and oestrogen levels at screening or from a historical sample), OR
    • Surgically sterile, OR
    • If they are of childbearing potential, must agree to practice two effective methods of contraception concurrently from the time of signing the informed consent form until 90 days after the last dose of study drug, OR
    • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence e.g. calendar, ovulation, symptothermal, post-ovulation methods and withdrawal are not acceptable methods of contraception

    Male patients must:

    • Even if surgically sterilized (post-vasectomy with documentation of azoospermia), agree to practice effective barrier contraception during the entire study treatment period and through to 90 days after the last dose of study drug, OR
    • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence e.g. calendar, ovulation, symptothermal, post-ovulation methods and withdrawal are not acceptable methods of contraception
  7. Clinical laboratory values:

    1. Absolute neutrophil count (ANC) ≥ 1 x 109/L
    2. Platelet count ≥ 100 x 109/L
    3. Total bilirubin ≤ 1.5 × the upper limit of the normal range (ULN)
    4. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 3 × ULN.
    5. Calculated creatinine clearance ≥ 30 mL/min

Exclusion Criteria:

  • Participants meeting any of the following exclusion criteria are not to be enrolled in the study:

    1. EDSS > 8.5 at screening
    2. MS relapse within 1 month prior to screening
    3. Female patients who are lactating or have a positive serum pregnancy test at screening
    4. Major surgery within 14 days before baseline
    5. Any clinically relevant malignancy or infection, as per CI/PI (or delegate) decision, including a possible diagnosis of multiple myeloma: raised erythrocyte sedimentation rate (ESR) and positive urine Bence Jones protein at screening
    6. Infection requiring systemic (intravenous) antibiotic therapy or other serious infection within 14 days before study enrolment. Urinary tract infections (UTIs) will be treated prior to baseline and may delay baseline
    7. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within 6 months of screening
    8. Systemic treatment, within 14 days before the first dose of ixazomib, with strong Cytochrome P450 Isoform 3A (CYP3A) inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John's Wort
    9. History of active hepatitis B or C virus infection, or human immunodeficiency virus (HIV) positive or positive Tuberculin (TB) ELISPOT. If there is positive TB ELISPOT and the TB team decides to treat as latent TB, participants can be reassessed for inclusion after treatment
    10. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol
    11. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib including difficulty swallowing
    12. Diagnosed or treated for malignancy within 2 years before study enrolment or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection
    13. Patient has ≥ Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical examination during the screening period
    14. Participation in other clinical trials involving investigational (unlicensed) medicinal products, licensed medicinal products or alternative medicinal therapies, within 30 days of screening and throughout the duration of this trial. Participation in non-interventional, questionnaire or observational studies whilst enrolled in this study is permitted.
    15. Patients that have previously been treated with ixazomib or participated in a study with ixazomib whether treated with ixazomib or placebo
    16. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent
    17. Any pre-existing central nervous system disease or involvement other than MS
    18. History of uncontrolled drug or alcohol abuse within 6 months prior to screening.

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): NCT03783416


Locations
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United Kingdom
Royal London Hospital, Barts Health NHS Foundation Trust Not yet recruiting
London, Greater London, United Kingdom, E1 1BB
Contact: Sharmilee Gnanapavan, MD    +44 2073777000 ext 42157    Sharmilee.gnanapavan@bartshealth.nhs.uk   
Contact: Lucia Bianchi, PhD    +44 20 7882 2598    Lucia.bianchi@bartshealth.nhs.uk   
Principal Investigator: Sharmilee Gnanapavan, MD         
Sponsors and Collaborators
Queen Mary University of London
Takeda Pharmaceuticals International, Inc.

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Responsible Party: Queen Mary University of London
ClinicalTrials.gov Identifier: NCT03783416     History of Changes
Other Study ID Numbers: 012436
2018-003686-34 ( EudraCT Number )
First Posted: December 21, 2018    Key Record Dates
Last Update Posted: January 11, 2019
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Sclerosis
Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Multiple Sclerosis, Chronic Progressive
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Ixazomib
Glycine
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Glycine Agents
Neurotransmitter Agents
Physiological Effects of Drugs