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Therapeutic Use of Tadekinig Alfa in NLRC4 Mutation and XIAP Deficiency

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ClinicalTrials.gov Identifier: NCT03113760
Recruitment Status : Recruiting
First Posted : April 14, 2017
Last Update Posted : April 9, 2018
Sponsor:
Information provided by (Responsible Party):
AB2 Bio Ltd.

Brief Summary:
This is a Phase 3 study to assess the safety and efficacy of Tadekinig alfa in patients with monogenic, interleukin-18 (IL 18) driven autoinflammation due to Nucleotide-binding oligomerization domain, leucine-rich repeat and caspase recruiting domain (CARD domain) containing 4 (NLRC4) - Macrophage activation syndrome (MAS) mutation (NLRC4-MAS mutation) or X-linked inhibitor of apoptosis (XIAP) deficiency. Because of the likelihood for pathogenic IL-18 in certain monogenic diseases, patients known to harbor deleterious mutations in NLRC4-MAS or XIAP and who have a history of ongoing inflammation will be enrolled if they have ferritin ≥ 500 ng/mL or persistent C reactive protein (CRP) elevation > 2 times the upper limit of normal (ULN) and the patients should have a Modified Autoinflammatory Disease Activity Index (mAIDAI) ≥ 4.

Condition or disease Intervention/treatment Phase
NLRC4-MAS XIAP Deficiency Drug: Tadekinig alfa Drug: Placebo Phase 3

Detailed Description:
The study is designed with a Randomized Double-Blind Placebo-Controlled (RDBPC) 18-week treatment phase, followed by an 8-week Randomized Withdrawal (RW) period for further efficacy and safety evaluation, with no interruption between the two phases of treatment.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Multicenter, Randomized, Double-blind, Placebo-controlled Trial With Tadekinig Alfa (r-hIL-18BP) in Patients With IL-18 Driven Monogenic Auto Inflammatory Conditions: NLRC4 Mutation and XIAP Deficiency
Actual Study Start Date : July 21, 2017
Estimated Primary Completion Date : May 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Tadekinig alfa
Eligible subjects will be randomised to receive either Tadekinig alfa in addition of standard of care during 18 weeks of the Randomised Double Blind Placebo Control (RDBPC) phase, followed by an 8 weeks treatment in the Randomised Withdrawal (RW) phase.
Drug: Tadekinig alfa
Tadekinig alfa is a soluble glycoprotein of 164 amino acids produced from Chinese Hamster Ovary cell line. Tadekinig alfa is supplied as a colorless to slightly yellow, sterile solution for injection in glass vials containing sodium chloride, and 0.02M sodium phosphate buffer as excipients. It is available in a concentration of 20mg/0.5mL.
Other Names:
  • IL-18BP
  • r-hIL-18BP

Placebo Comparator: Placebo
Eligible subjects will be randomised to receive the placebo in addition of standard of care, in this double blind study, during 18 weeks of the Randomised Double Blind Placebo Control (RDBPC) phase, followed by an 8 weeks treatment in the Randomised Withdrawal (RW) phase.
Drug: Placebo
To ensure that the treatment remains blinded for the entire study period, the placebo solutions will be supplied in identical vials and similar labelling as the active drug and will be indistinguishable in terms of their texture, color, and smell.




Primary Outcome Measures :
  1. Incidence rate of flares [ Time Frame: 18 weeks ]

    The primary outcome is the incidence rate of flares (number of flares over the 18-week treatment RDBPC phase) corrected for duration of treatment.

    Method of assessment : Biomarkers (CRP / Ferritin) and clinical manifestations of inflammation.



Secondary Outcome Measures :
  1. Time to flare [ Time Frame: 26 weeks ]
    measured by the time spent from the resolution of the initial flare to the reactivation of the disease

  2. Intensity of flares [ Time Frame: 26 weeks ]
    Defined by the level of activity given by biomarkers and clinical manifestations

  3. Treatment failures [ Time Frame: 26 weeks ]
    Measured by the number of patients that do not respond to the combined treatment of standard of care with the study treatment

  4. Serum CRP, Serum Ferritin [ Time Frame: 26 weeks ]
    Laboratory measure ug/mL for CRP, and ng/mL for Ferritin

  5. Improvement of fevers, improvement of hepato/splenomegaly [ Time Frame: 26 weeks ]
    Clinical assessments if present at Baseline

  6. Improvement in serum albumin and liver transaminases, anemia and/or platelet count [ Time Frame: 26 weeks ]
    Laboratory measures if present at Baseline

  7. Hospital length of stay [ Time Frame: 26 weeks ]
    Length of hospitalisation

  8. Physician Global Assessment [ Time Frame: 26 weeks ]
    Measured through a scale 0 to 10

  9. Presence of skin rash - evolution if present at Baseline or appearance during the study [ Time Frame: 26 weeks ]
    Measured by the local tolerability index

  10. Tolerance to oral/enteral nutrition for hospitalized patients if intestinal dysfunction was present at Baseline [ Time Frame: 26 weeks ]
    Measured by the kcal per day

  11. Improvement of stool output for hospitalized patients if intestinal dysfunction was present at Baseline [ Time Frame: 26 weeks ]
    mL per 24hours

  12. Adverse events will be reported [ Time Frame: 26 weeks ]
    Including AESI (Adverse Events of Special Interest)

  13. Physical examination findings and vital signs [ Time Frame: 26 weeks ]
    Clinically significant changes from Baseline

  14. Laboratory assessments [ Time Frame: 26 weeks ]
    including clinically significant changes from Baseline in hematology with platelet counts, CRP, ESR, ferritin, fibrinogen, D-dimer, liver enzymes. (Followed until resolution)

  15. Immunogenicity evaluation [ Time Frame: 26 weeks ]
    Generation of anti-recombinant human IL-18BP (anti-rhIL-18BP) antibodies

  16. Local tolerability at the injection site [ Time Frame: 26 weeks ]
    Evaluated by a standardized assessment



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

INCLUSION CRITERIA

  1. Patients ≤ 17 years of age
  2. Patients with genetic diagnosis of NLRC4-MAS mutation or XIAP deficiency (caused by BIRC4 gene mutation)
  3. Ferritin ≥ 500 ng/mL or persistent elevation of CRP ≥ 2x ULN and mAIDAI ≥4
  4. Patients receiving stable doses of corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) or disease modifying anti rheumatic drugs (DMARDs), and/or IL-1 blockade for at least 2 weeks prior to enrollment are allowed into the study. Patients not receiving any of these treatments before start of therapy are also allowed
  5. Women of childbearing potential with negative urine pregnancy test (UPT) at all visits

EXCLUSION CRITERIA

  1. Patients > 17 years of age
  2. Positive test for or prior history of HIV, Hepatitis B or Hepatitis C (serology)
  3. Presence of active infections or a history of pulmonary TB infection with or without documented adequate therapy
  4. Presence of life threatening infections
  5. Oncologic causes of symptoms; current or previous history of malignancy
  6. Presence of CNS manifestations
  7. Patients suffering from familial hemophagocytic lymphohistiocytosis (f HLH)
  8. Patients who are pregnant or nursing, women of childbearing potential who are unwilling to use highly effective birth control methods
  9. Concomitant use of immunosuppression therapies excluded by the protocol.
  10. Patients and/or parents (or legal representative, if applicable) not willing to sign assent/informed consent

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): NCT03113760


Contacts
Contact: Eduardo Schiffrin, MD +41 21 694 00 43 eduardo.schiffrin@ab2bio.com
Contact: Lalla Myriam Mercier-Lamrani, MBA +41 21 694 00 47 myriam.mercier@ab2bio.com

Locations
United States, Alabama
Children's of Alabama (CoA) Not yet recruiting
Birmingham, Alabama, United States, 35233
Contact: Randy Cron, Dr.    205-996-7584      
United States, California
UCSD _ Department of Pediatrics / Rady Children's Hospital Recruiting
La Jolla, California, United States, 92056
Contact: Harold Hoffman, Dr.         
United States, Massachusetts
Boston Children's Hospital Not yet recruiting
Boston, Massachusetts, United States, 02115
Contact: Fatma Dedeoglu, Dr.    617-355-6117      
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Rebecca Marsh, Dr.    513-803-9063      
United States, Pennsylvania
Children Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Ed Behrens, Dr.         
Children's Hospital of Pittsburgh of UPMC Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Contact: Scott Canna, Dr.    412-692-9934      
United States, Texas
Texas Children's Hospital _ Baylor College of Medicine Recruiting
Houston, Texas, United States, 77030
Contact: Lisa Forbes, Dr.    832-824-1319      
Canada
CHU Sainte-Justine Recruiting
Montréal, Canada
Contact: Julie Barsalou, MD    514-345-4931      
Sponsors and Collaborators
AB2 Bio Ltd.
Investigators
Principal Investigator: Eduard Behrens, MD Children Hospital of Philadelphia

Additional Information:
Responsible Party: AB2 Bio Ltd.
ClinicalTrials.gov Identifier: NCT03113760     History of Changes
Other Study ID Numbers: NLRC4/XIAP.2016.001
First Posted: April 14, 2017    Key Record Dates
Last Update Posted: April 9, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: This information will be provided soon

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

Additional relevant MeSH terms:
Lymphoproliferative Disorders
Genetic Diseases, X-Linked
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Genetic Diseases, Inborn