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

Primary Purpose

Relapsing Remitting Multiple Sclerosis, Primary Progressive Multiple Sclerosis, Secondary Progressive Multiple Sclerosis

Status
Recruiting
Phase
Phase 1
Locations
United Kingdom
Study Type
Interventional
Intervention
Ixazomib (NINLARO®) capsules / Matching placebo capsules
Sponsored by
Queen Mary University of London
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Relapsing Remitting Multiple Sclerosis

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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to give written informed consent and comply with protocol requirements with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.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.

Sites / Locations

  • Royal London Hospital, Barts Health NHS Foundation TrustRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Ixazomib (NINLARO®)

Placebo

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Safety - Adverse events (AE) will be compared between active and placebo arm
Proportion of AEs in the Ixazomib versus placebo arm in subjects with Relapsing Remitting Multiple Sclerosis (RRMS) Proportion of serious AEs (SAEs) in the Ixazomib versus placebo arm in subjects with RRMS Proportion of AEs in the Ixazomib versus placebo arm in subjects with progressive MS Proportion of serious AEs (SAEs) in the Ixazomib versus placebo arm in subjects with progressive MS Proportion of AEs in the Ixazomib versus placebo arm in all subjects (subjects with RRMS and subjects with progressive MS) Proportion of serious AEs (SAEs) in the Ixazomib versus placebo arm in all subjects (subjects with RRMS and subjects with progressive MS)
Efficacy - the proportion of OCB IgG negative subjects will be compared between active and placebo arm
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 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) 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

Magnetic Resonance Imaging (MRI)
Change in T2 lesion load and gadolinium enhancing lesions on brain MRI with Ixazomib versus placebo arm at 24 months
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
Change in EDSS with ixazomib versus placebo at 24 months.

Full Information

First Posted
December 10, 2018
Last Updated
February 17, 2022
Sponsor
Queen Mary University of London
Collaborators
Takeda Pharmaceuticals International, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT03783416
Brief Title
SIZOMUS Safety of Ixazomib Targeting Plasma Cells in Multiple Sclerosis
Acronym
SIZOMUS
Official Title
Safety of Ixazomib Targeting Plasma Cells in Multiple Sclerosis: A Phase 1b Randomised, Double-blind, Placebo-controlled Trial.
Study Type
Interventional

2. Study Status

Record Verification Date
February 2022
Overall Recruitment Status
Recruiting
Study Start Date
August 20, 2020 (Actual)
Primary Completion Date
August 20, 2023 (Anticipated)
Study Completion Date
August 20, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Queen Mary University of London
Collaborators
Takeda Pharmaceuticals International, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Relapsing Remitting Multiple Sclerosis, Primary Progressive Multiple Sclerosis, Secondary Progressive Multiple Sclerosis

7. Study Design

Primary Purpose
Other
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
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
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
72 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Ixazomib (NINLARO®)
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Ixazomib (NINLARO®) capsules / Matching placebo capsules
Intervention Description
Participants will be treated for a maximum of 24 months
Primary Outcome Measure Information:
Title
Safety - Adverse events (AE) will be compared between active and placebo arm
Description
Proportion of AEs in the Ixazomib versus placebo arm in subjects with Relapsing Remitting Multiple Sclerosis (RRMS) Proportion of serious AEs (SAEs) in the Ixazomib versus placebo arm in subjects with RRMS Proportion of AEs in the Ixazomib versus placebo arm in subjects with progressive MS Proportion of serious AEs (SAEs) in the Ixazomib versus placebo arm in subjects with progressive MS Proportion of AEs in the Ixazomib versus placebo arm in all subjects (subjects with RRMS and subjects with progressive MS) Proportion of serious AEs (SAEs) in the Ixazomib versus placebo arm in all subjects (subjects with RRMS and subjects with progressive MS)
Time Frame
Baseline to 24 months
Title
Efficacy - the proportion of OCB IgG negative subjects will be compared between active and placebo arm
Description
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 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) 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
Time Frame
Baseline to 24 months
Secondary Outcome Measure Information:
Title
Magnetic Resonance Imaging (MRI)
Description
Change in T2 lesion load and gadolinium enhancing lesions on brain MRI with Ixazomib versus placebo arm at 24 months
Time Frame
Baseline to 24 months
Title
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
Description
Change in EDSS with ixazomib versus placebo at 24 months.
Time Frame
Baseline to 24 months
Other Pre-specified Outcome Measures:
Title
Exploratory endpoint - IgG FLC
Description
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.
Time Frame
Baseline to 24 months
Title
Exploratory endpoint - CD19
Description
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.
Time Frame
Baseline to 24 months
Title
Exploratory endpoint - soluble CD 138
Description
c. Proportion of all subjects who show change in levels of soluble CD 138 at 24 months in the Ixazomib versus placebo arm
Time Frame
Baseline to 24 months
Title
Exploratory endpoint - CD 27
Description
d. Proportion of all subjects who show change in levels of soluble CD 27 at 24 months in the Ixazomib versus placebo arm
Time Frame
Baseline to 24 months
Title
Exploratory endpoint - neurofilament light chain
Description
e. Proportion of all subjects who show change in levels of neurofilament light chain at 24 months in the Ixazomib versus placebo arm
Time Frame
Baseline to 24 months
Title
Exploratory endpoint - neurofilament heavy chain
Description
f. Proportion of all subjects who show change in levels of neurofilament heavy chain at 24 months in the Ixazomib versus placebo arm
Time Frame
Baseline to 24 months
Title
Exploratory endpoint - neopterin
Description
g. Proportion of all subjects who show change in levels of neopterin at 24 months in the Ixazomib versus placebo arm
Time Frame
Baseline to 24 months
Title
Exploratory endpoint - cytokines profile
Description
h. Proportion of all subjects who show change in levels of cytokines profile at 24 months in the Ixazomib versus placebo arm
Time Frame
Baseline to 24 months
Title
Exploratory endpoint - GFAP
Description
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
Time Frame
Baseline to 24 months
Title
Exploratory endpoint - NCAM
Description
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
Time Frame
Baseline to 24 months
Title
Exploratory endpoint - GAP43
Description
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
Time Frame
Baseline to 24 months
Title
Exploratory endpoint - S100B
Description
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
Time Frame
Baseline to 24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: - Each participant must meet all of the following inclusion criteria to be enrolled in the study: Male and female patients 18 to 65 years old at screening Must have a diagnosis of MS, and: Patients with RRMS must be on DMT Patients with progressive MS must not be on DMT 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 OCB positive CSF either from a previous CSF analysis or from the screening CSF analysis 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. 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 Clinical laboratory values: Absolute neutrophil count (ANC) ≥ 1 x 109/L Platelet count ≥ 100 x 109/L Total bilirubin ≤ 1.5 × the upper limit of the normal range (ULN) Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 3 × ULN. Calculated creatinine clearance ≥ 30 mL/min Exclusion Criteria: Participants meeting any of the following exclusion criteria are not to be enrolled in the study: EDSS > 8.5 at screening MS relapse within 1 month prior to screening Female patients who are lactating or have a positive serum pregnancy test at screening Major surgery within 14 days before baseline 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 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 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 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 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 Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib including difficulty swallowing 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 Patient has ≥ Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical examination during the screening period 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. Patients that have previously been treated with ixazomib or participated in a study with ixazomib whether treated with ixazomib or placebo Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent Any pre-existing central nervous system disease or involvement other than MS History of uncontrolled drug or alcohol abuse within 6 months prior to screening.
Facility Information:
Facility Name
Royal London Hospital, Barts Health NHS Foundation Trust
City
London
State/Province
Greater London
ZIP/Postal Code
E1 1BB
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sharmilee Gnanapavan, MD
Phone
+44 2073777000
Ext
42157
Email
Sharmilee.gnanapavan@bartshealth.nhs.uk
First Name & Middle Initial & Last Name & Degree
Lucia Bianchi, PhD
Phone
+44 20 7882 2598
Email
Lucia.bianchi@bartshealth.nhs.uk
First Name & Middle Initial & Last Name & Degree
Sharmilee Gnanapavan, MD

12. IPD Sharing Statement

Plan to Share IPD
No

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SIZOMUS Safety of Ixazomib Targeting Plasma Cells in Multiple Sclerosis

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