Therapeutic Use of Tadekinig Alfa in NLRC4 Mutation and XIAP Deficiency

Overview

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.

Full Title of Study: “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”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: October 2021

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)

Interventions

  • 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: 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.

Arms, Groups and Cohorts

  • Experimental: Tadekinig alfa
    • Patients that have completed the SAOL phase without a flare will receive Tadekinig alfa for addition 8 weeks.
  • Placebo Comparator: 0.9% sodium chloride
    • Patients that have completed the SAOL phase without a flare will receive placebo comparator for addition 8 weeks.

Clinical Trial Outcome Measures

Primary Measures

  • 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 Measures

  • Flare rate
    • Time Frame: 8 weeks
    • Number of flares experienced per week while each subject is on study treatment during the RW phase
  • 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
  • Intensity of flares
    • Time Frame: 8 weeks
    • Intensity of flares (defined by the level of activity given by the mAIDAI)
  • Serum CRP, Serum Ferritin
    • Time Frame: 8 weeks
    • Laboratory measure ug/mL for CRP, and ng/mL for Ferritin
  • Improvement of fevers, improvement of hepato/splenomegaly
    • Time Frame: 8 weeks
    • Clinical assessments if present at Baseline
  • Improvement in serum albumin and liver transaminases, anemia and/or platelet count
    • Time Frame: 8 weeks
    • Laboratory measures if present at Baseline
  • Hospital length of stay
    • Time Frame: 8 weeks
    • Length of hospitalisation
  • Change in Physician Global Assessment (PGA)
    • Time Frame: 8 weeks
    • Change from RW baseline to Week 26 in the PGA symptom severity score
  • 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
  • Presence of skin rash – evolution if present at Baseline or appearance during the study
    • Time Frame: 8 weeks
    • Measured by the local tolerability index
  • 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
  • Improvement of stool output for hospitalized patients if intestinal dysfunction was present at Baseline
    • Time Frame: 8 weeks
    • mL per 24hours
  • Adverse events will be reported
    • Time Frame: 26 weeks (SAOL + RW phases)
    • Including AESI (Adverse Events of Special Interest)
  • Physical examination findings and vital signs
    • Time Frame: 26 weeks (SAOL + RW phases)
    • Clinically significant changes from Baseline
  • 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)
  • Immunogenicity evaluation
    • Time Frame: 26 weeks (SAOL + RW phases)
    • Generation of anti-recombinant human IL-18BP (anti-rhIL-18BP) antibodies
  • Local tolerability at the injection site
    • Time Frame: 26 weeks (SAOL + RW phases)
    • Evaluated by a standardized assessment

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: N/A

Maximum Age: 17 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • AB2 Bio Ltd.
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Ed M Behrens, MD, Principal Investigator, Children Hospital of Philadelphia
  • Overall Contact(s)
    • Eduardo Schiffrin, MD, +41 21 694 00 43, eduardo.schiffrin@ab2bio.com

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