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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 : June 9, 2020
Sponsor:
Information provided by (Responsible Party):
AB2 Bio Ltd.

Study Description
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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 Other: 0.9% sodium chloride Phase 3

Detailed Description:
The study is designed with single-arm, open-label phase (SAOL) of Tadekinig alfa treatment duration for 18-week followed by an 8-week Randomized Withdrawal (RW) period for efficacy and safety evaluation, with no interruption between the two phases of treatment. The screening period will occur before the SAOL phase and before the first dose of Investigational Medicinal Product (IMP)
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Initial phase of 18 weeks is a single arm, open-label (SAOL) period where Tadekinig alfa is administered in addition to the standard of care treatment used for the control of flares. The SAOL period will be followed by an 8-week randomized withdrawal phase (RW). All patients who completed the study without an ongoing flare at the end of the SAOL phase will be enrollled in the RW phase. In the RW phase patients will be randomized to either Tadekinig alfa or placebo.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Multicenter, Double-blind, Placebo-controlled, Randomized Withdrawal Trial With Tadekinig Alfa (r-hIL-18BP) in Patients With IL-18 Driven Monogenic Autoinflammatory Conditions: NLRC4 Mutation and XIAP Deficiency
Actual Study Start Date : July 21, 2017
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : May 2021

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Tadekinig alfa
Patients that have completed the SAOL phase without a flare will receive Tadekinig alfa for addition 8 weeks.
 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: 0.9% sodium chloride
Patients that have completed the SAOL phase without a flare will receive placebo comparator for addition 8 weeks.
 Other: 0.9% sodium chloride
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.


Outcome Measures
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Primary Outcome Measures :
  1. Prevention of flares [ Time Frame: 8 weeks ]

    The primary endpoint is time to first occurrence of flare (time to flare) during the 8-week RW phase.

    Method of assessment : Biomarkers (CRP / Ferritin) and clinical manifestations of systemic inflammation and end-organ damage.



Secondary Outcome Measures :
  1. Flare rate [ Time Frame: 8 weeks ]
    Number of flares experienced per week while each subject is on study treatment during the RW phase

  2. Response to therapy/treatment failures [ Time Frame: 8 weeks ]
    Measured by the number of patients that do not respond to the combined treatment of standard of care with the study treatment during the RW phase

  3. Intensity of flares [ Time Frame: 8 weeks ]
    Intensity of flares (defined by the level of activity given by the mAIDAI)

  4. Serum CRP, Serum Ferritin [ Time Frame: 8 weeks ]
    Laboratory measure ug/mL for CRP, and ng/mL for Ferritin

  5. Improvement of fevers, improvement of hepato/splenomegaly [ Time Frame: 8 weeks ]
    Clinical assessments if present at Baseline

  6. Improvement in serum albumin and liver transaminases, anemia and/or platelet count [ Time Frame: 8 weeks ]
    Laboratory measures if present at Baseline

  7. Hospital length of stay [ Time Frame: 8 weeks ]
    Length of hospitalisation

  8. Change in Physician Global Assessment (PGA) [ Time Frame: 8 weeks ]
    Change from RW baseline to Week 26 in the PGA symptom severity score

  9. Change in mAIDAI score [ Time Frame: 8 weeks ]
    Change from RW baseline to week 26 (i.e. week 8 of the RW phase) in the mAIDAI total score

  10. Presence of skin rash - evolution if present at Baseline or appearance during the study [ Time Frame: 8 weeks ]
    Measured by the local tolerability index

  11. Tolerance to oral/enteral nutrition for hospitalized patients if intestinal dysfunction was present at Baseline [ Time Frame: 8 weeks ]
    Measured by the kcal per day

  12. Improvement of stool output for hospitalized patients if intestinal dysfunction was present at Baseline [ Time Frame: 8 weeks ]
    mL per 24hours

  13. Adverse events will be reported [ Time Frame: 26 weeks (SAOL + RW phases) ]
    Including AESI (Adverse Events of Special Interest)

  14. Physical examination findings and vital signs [ Time Frame: 26 weeks (SAOL + RW phases) ]
    Clinically significant changes from Baseline

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

  16. Immunogenicity evaluation [ Time Frame: 26 weeks (SAOL + RW phases) ]
    Generation of anti-recombinant human IL-18BP (anti-rhIL-18BP) antibodies

  17. Local tolerability at the injection site [ Time Frame: 26 weeks (SAOL + RW phases) ]
    Evaluated by a standardized assessment


Eligibility Criteria
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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
Contacts and Locations
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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
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Contact: Eduardo Schiffrin, MD +41 21 694 00 43 eduardo.schiffrin@ab2bio.com
Contact: Friederike Stein, PhD +41 21 694 00 40 friederike.stein@ab2bio.com

Locations
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United States, California
UCSD _ Department of Pediatrics / Rady Children's Hospital Recruiting
La Jolla, California, United States, 92056
Contact: Harold Hoffman, M.D.    858-966-1700 ext 3422      
United States, Florida
Shands Children's Hospital, University of Florida Recruiting
Gainesville, Florida, United States, 32610
Contact: Akaluck Thatayatikom, MD         
United States, Georgia
Children's Healthcare of Atlanta at Egleston Recruiting
Atlanta, Georgia, United States, 30322
Contact: Shanmuganathan Chandrakasan, M.D.    404-727-8877      
United States, Massachusetts
Boston Children's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Fatma Dedeoglu, M.D.    617-355-6117      
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Rebecca Marsh, M.D.    513-803-9063      
United States, Pennsylvania
Children Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Ed Behrens, M.D.    267-426-0142    behrens@email.chop.edu   
Children's Hospital of Pittsburgh of UPMC Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Contact: Scott Canna, M.D.    412-692-9934      
United States, Texas
Texas Children's Hospital _ Baylor College of Medicine Recruiting
Houston, Texas, United States, 77030
Contact: Lisa Forbes-Satter, M.D.    832-824-1319      
Canada, Ontario
The Hospital for Sick Children Recruiting
Toronto, Ontario, Canada, ON M5G 1X8
Contact: Ronald Laxer, M.D.    416-813-5068      
Canada, Providence
CHU Sainte-Justine Recruiting
Montréal, Providence, Canada, QC H3T 1C5
Contact: Julie Barsalou, MD    514-345-4931      
Germany
Universitätsklinikum Freiburg, Centrum für Chronische Immundefizienz (CCI) - Paediatric Unit Recruiting
Freiburg, Baden-Württemberg, Germany, 79106
Contact: Stephan Ehl, MD    0049 761 270-7755    Stephan.ehl@uniklinik-freiburg.de   
Sponsors and Collaborators
AB2 Bio Ltd.
Investigators
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Principal Investigator: Ed M Behrens, MD Children Hospital of Philadelphia
More Information
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Additional Information:

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Responsible Party: AB2 Bio Ltd.
ClinicalTrials.gov Identifier: NCT03113760    
Other Study ID Numbers: NLRC4/XIAP.2016.001
First Posted: April 14, 2017    Key Record Dates
Last Update Posted: June 9, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: This information will be provided soon

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lymphoproliferative Disorders
Genetic Diseases, X-Linked
Lymphatic Diseases
 Immunoproliferative Disorders
Immune System Diseases
Genetic Diseases, Inborn