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IC14 for Treatment of Amyotrophic Lateral Sclerosis

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ClinicalTrials.gov Identifier: NCT03508453
Recruitment Status : Not yet recruiting
First Posted : April 25, 2018
Last Update Posted : July 2, 2018
Sponsor:
Information provided by (Responsible Party):
Implicit Bioscience

Brief Summary:
Fifty patients with amyotrophic lateral sclerosis that is progressing rapidly will be randomized to receive either the monoclonal antibody IC14 or placebo to be given intravenously over two hours twice weekly for 12 weeks. Blood and urine tests will be done to measure biomarkers in order to evaluate clinical response and to monitor for safety. Other evaluations include patient questionnaires about function, quality of life and mental function; pulmonary function test; and sniff nasal pressure.

Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis Motor Neuron Disease Biological: IC14 Other: Placebo Phase 2

Detailed Description:

This will be a placebo-controlled, double-blind, parallel-group comparison.

Fifty patients with rapidly progressive ALS will be randomised to receive one of the following regimens:

  • IC14 4 mg/kg given intravenously twice weekly for 12 weeks; or
  • Identical-appearing placebo given intravenously twice weekly for 12 weeks. There will be an interim safety review by an independent Data Safety Monitoring Board after the initial 20 subjects have completed 4 weeks and 8 weeks of treatment. Study observation will continue until 12 weeks after the last dose of study drug.

The primary endpoint is:

• Treatment-related change in disease biomarker profiles [e.g., neurofilaments (Nf), urinary p75 neurotrophin receptor (p75NTR), cytokines, and soluble CD14].

The secondary endpoints are:

  • Safety, tolerability and lack of immunogenicity of IC14.
  • Treatment-related change in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R).
  • Treatment-related change in respiratory function by seated forced vital capacity (FVC) parameters.
  • Treatment-related change in inspiratory muscle strength by sniff nasal pressure (SNP) test.
  • Treatment-related change in quality of life by the ALS Specific Quality of Life-Revised (ALSSQOL-R) score.
  • Treatment-related change in cognitive function by Edinburgh Cognitive and Behavioural Assessment (ECAS) score.
  • Treatment-related changes stratified by disease severity and prognostic indicators.
  • Peak serum IC14 concentration following administration of the initial dose and peak serum concentration following a course of treatment.
  • Area under the serum IC14 concentration versus time curve (AUC) following administration of the initial dose and following a course of treatment.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized, Double-Blind, Placebo-Controlled
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Pharmacy preparation of identical-appearing placebo
Primary Purpose: Treatment
Official Title: A Phase 2, Randomised, Double-Blind, Placebo-Controlled Study of IC14 for Treatment of Patients With Rapidly Progressive Motor Neuron Disease
Estimated Study Start Date : August 15, 2018
Estimated Primary Completion Date : May 15, 2020
Estimated Study Completion Date : December 15, 2020


Arm Intervention/treatment
Active Comparator: IC14 (monoclonal anti-CD14 antibody)
IC14 4 mg/kg intravenously twice weekly for 12 weeks
Biological: IC14
Monoclonal antibody against CD14

Placebo Comparator: Placebo
Placebo intravenously twice weekly for 12 weeks
Other: Placebo
sterile normal saline for injection prepared to be identical to study drug




Primary Outcome Measures :
  1. Neurofilament (biomarker) [ Time Frame: 12 weeks ]
    Treatment-related change in concentration of neurofilament (picograms per milliliter)

  2. Urinary p75 neurotrophin receptor (biomarker) [ Time Frame: 12 weeks ]
    Treatment-related change in concentration of urinary p75 neurotrophin receptor (nanograms per milligram creatinine)

  3. Monocyte CD14 receptor occupancy [ Time Frame: 12 weeks ]
    Treatment-related change in percent monocyte receptor occupancy


Secondary Outcome Measures :
  1. Functional status [ Time Frame: 12 weeks ]
    Treatment-related change in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [0 (worst) to 48 (best)]

  2. Respiratory function [ Time Frame: 12 weeks ]
    Treatment-related change in percent normal Forced Vital Capacity [0% (worst) to 100%(best)]

  3. Muscle function [ Time Frame: 12 weeks ]
    Treatment-related change in percent normal Sniff Nasal Pressure [0% (worst) to 100% (best)]

  4. Quality of life [ Time Frame: 12 weeks ]
    Treatment-related change in Amyotrophic Lateral Sclerosis Specific Quality of Life - Revised questionnaire [0 (worst) to 460 (best)]

  5. Cognitive and behavioural assessment [ Time Frame: 12 weeks ]
    Treatment-related change in Edinburgh Cognitive and Behavioural Assessment Score [0(worst) to 136 (best)]

  6. Maximum plasma concentration (Cmax) [ Time Frame: 12 weeks ]
    Maximum serum IC14 concentration (micrograms per milliliter)

  7. Area under the curve [ Time Frame: 12 weeks ]
    Area under the curve for serum IC14 (microgram x hr/mL)

  8. Immunogenicity [ Time Frame: 16 weeks ]
    Development of human anti-monoclonal antibodies following treatment

  9. Adverse events (safety, tolerability) [ Time Frame: 16 weeks ]
    Incidence of treatment-emergent adverse events (safety, tolerability) classified by MedDRA



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed informed consent prior to initiation of any study-specific procedures.
  2. Familial or sporadic MND defined as clinically possible, probable, or definite by Awaji-Shima Consensus Recommendations.
  3. Rapidly progressive MND as defined by a decline of 3 or more points in the ALSFRS-R score during the prior 3 months.
  4. First symptoms of MND within 3 years of informed consent.
  5. Age between 18 and 75 years at time of informed consent.
  6. Seated Forced Vital Capacity (FVC) ≥ 65% of predicted value.
  7. Not taking riluzole or edaravone or on a stable dose of riluzole or edaravone for at least 3 months prior to screening visit.
  8. Adequate bone marrow reserve, renal and liver function:

    • absolute neutrophil count ≥ 1.5 x 109/L
    • lymphocyte count < 6.0 x 109/L
    • platelet count ≥ 150 x 109/L
    • hemoglobin ≥ 110 g/L
    • eGFR ≥ 40 mL/min/1.73 m2
    • ALT and/or AST ≤ 2x ULN
    • total bilirubin ≤ 1.5x ULN
    • serum albumin ≥ 28 g/L
  9. Females of childbearing potential should be using and committed to continue using one of the following acceptable birth control methods:

    • Sexual abstinence (inactivity) for 1 month prior to screening through study completion; or
    • Intrauterine device (IUD) in place for at least 3 months prior to study through study completion; or
    • Stable hormonal contraception for at least 3 months prior to study through study completion; or
    • Surgical sterilization (vasectomy) of male partner at least 6 months prior to study.
  10. To be considered of non-childbearing potential, females should be surgically sterilized (bilateral tubal ligation, hysterectomy, or bilateral oophorectomy at least 2 months prior to study) or be post-menopausal and at least 3 years since last menses.
  11. Males with female partners of childbearing potential must use contraception through study completion.
  12. Able to give informed consent and able to comply with all study visits and all study procedures.

Exclusion Criteria:

  1. Dependence on mechanical ventilation, defined as being unable to lay supine without it, unable to sleep without it, or continuous daytime use; presence of tracheostomy at screening; or presence of diaphragm pacing system at screening.
  2. Treatment with a drug or device within the last 30 days that has not received regulatory approval.
  3. Treatment within 12 months with immunomodulator or immunosuppressant agent (including but not limited to cyclophosphamide, cyclosporine, interferon-α, interferon-β-1a, rituximab, alemtuzumab, azathioprine, etanercept, infliximab, adalimumab, certolizumab, golimumab, anakinra, rilonacept, secukinumab, tocilizumab, mycophenolate mofetil, methotrexate, haematopoietic stem cell transplantation, anti-sense drugs, gene therapy, cell-depleting agents, total lymphoid irradiation). Treatment with intravenous immunoglobulin within 2 months or dimethyl fumarate within 3 months. Non-steroidal anti-inflammatory drugs are acceptable.
  4. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other opportunistic infections; or major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks.
  5. Live-attenuated vaccines within 30 days before dosing. Subjects must agree to forego live-attenuated vaccines throughout the study, including 12 weeks after the last dose of study drug.
  6. History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies.
  7. Presence of any of the following clinical conditions:

    • History of one or more of the following: cardiac insufficiency (New York Heart Association [NYHA] III/IV), uncontrolled cardiac arrhythmias, unstable ischemic heart disease, or uncontrolled hypertension (systolic blood pressure > 170 mmHg or diastolic blood pressure > 110 mmHg).
    • History of venous thromboembolic disease within 12 months, myocardial infarction, or cerebrovascular accident.
    • Unstable pulmonary, renal, hepatic, endocrine or hematologic disease.
    • Autoimmune disease, mixed connective tissue disease, scleroderma, polymyositis, or significant systemic involvement secondary to rheumatoid arthritis.
    • Evidence of active malignant disease, malignancies diagnosed within the previous 5 years, or breast cancer diagnosed within the previous 5 years (except skin cancers other than melanoma).
    • History of human immunodeficiency virus infection or other immunodeficiency illness.
    • Unstable psychiatric illness defined as psychosis or untreated major depression within 90 days.
    • History of drug abuse (not including marijuana use) or alcoholism within the past 12 months.
    • Significant neuromuscular disease other than MND.
    • Other ongoing disease that may cause neuropathy, such as toxin exposure, dietary deficiency, uncontrolled diabetes, hyperthyroidism, cancer, systemic lupus erythematosus or other connective diseases, infection with HIV, hepatitis B virus (HBV), or hepatitis C (HCV), Lyme disease, multiple myeloma, Waldenström's macroglobulinemia, amyloid, and hereditary neuropathy.
  8. Pregnancy or breastfeeding.
  9. Deprivation of freedom by administrative or court order.

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): NCT03508453


Contacts
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Contact: Susan Heggie +61 7 3646 1478 susan.heggie@health.qld.gov.au
Contact: Kathryn Thorpe +61 7 3646 0016 kathryn.thorpe@health.qld.gov.au

Locations
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Australia, Queensland
Royal Brigham and Women's Hospital
Herston, Queensland, Australia, 4006
Sponsors and Collaborators
Implicit Bioscience
Investigators
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Study Chair: Robert D Henderson, MBBS Royal Brisbane & Women's Hospital

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Responsible Party: Implicit Bioscience
ClinicalTrials.gov Identifier: NCT03508453     History of Changes
Other Study ID Numbers: ALS03
First Posted: April 25, 2018    Key Record Dates
Last Update Posted: July 2, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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 Implicit Bioscience:
monoclonal antibody

Additional relevant MeSH terms:
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Sclerosis
Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Antibodies
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs