Therapeutic Use of Tadekinig Alfa in NLRC4 Mutation and XIAP Deficiency

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

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.

Study Overview

• Status: Completed
• Conditions: NLRC4-MAS; XIAP Deficiency
• Intervention / Treatment: Drug: Tadekinig alfa; Other: 0.9% sodium chloride

Detailed Description

The study is designed with single-arm, open-label phase (SAOL) of Tadekinig alfa treatment duration for 18-week followed by an up to 16-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 Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, ON M5G 1X8
      • The Hospital for Sick Children
  • Providence
    • Montréal, Providence, Canada, QC H3T 1C5
      • CHU Sainte-Justine
• Germany
  • Baden-Württemberg
    • Freiburg, Baden-Württemberg, Germany, 79106
      • Universitätsklinikum Freiburg, Centrum für Chronische Immundefizienz (CCI) - Paediatric Unit
• United States
  • California
    • La Jolla, California, United States, 92056
      • UCSD _ Department of Pediatrics / Rady Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta at Egleston
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children Hospital of Philadelphia
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital _ Baylor College of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

INCLUSION CRITERIA

1. Patients with genetic diagnosis of NLRC4-MAS mutation or XIAP deficiency (caused by BIRC4 gene mutation) as confirmed by analysis performed at the central genetics laboratory. If possible, flow cytometry assay will be performed in parallel to confirm diagnosis of XIAP deficiency. (Note: Previous flow cytometry assay results will be permitted for confirmation of XIAP deficiency diagnosis.)
2. Patients with XIAP deficiency and a previous bone marrow transplantation are allowed, if they show evidence of primary or secondary graft failure, or failure to achieve phenotypic correction with evidence of XIAP-related disease recurrence or clinically significant mixed chimerism.
3. Ferritin ≥ 500 ng/mL or persistent elevation of CRP ≥ 2x ULN and mAIDAI ≥4
4. Patients receiving corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) or disease modifying anti-rheumatic drugs (DMARDs), and/or IL-1 blockade with insufficient response to treatment upon 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 (if UPT is positive, a blood test for human chorionic gonadotropin (hCG) to be performed) and who agree to follow highly effective birth control recommendations during the study and until 1 month after the end of the treatment. Birth control methods considered highly effective are: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner or sexual abstinence. In each case of delayed menstrual period (over one month between menstruations, confirmation of absence of pregnancy is strongly recommended. This recommendation also applies to women of childbearing potential with infrequent or irregular menstrual cycles. A post-study contraception duration of 4 weeks is recommended taking into account the median half-life of Tadekinig alfa of almost 40h and 5 half-lives representing a duration of 200 hours.

EXCLUSION CRITERIA

1. Patients with life-threatening co-morbidities not associated with the underlying NLRC4-mutation or XIAP deficiency
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 (i.e. seizures, altered mental status, signs of increased intracranial pressure, chronic papilledema, loss of vision, other sensorineural deficiencies, etc.)
7. Patients suffering from biallelic mutations in any of the following genes: PRF1/Perforin, UNC13D/Munc 13-4, STX11/Syntaxin11, STXB2/Munc 18-2, RAB27A/Rab27a (Griscelli syndrome type 2), LYST (Chediak-Higashi syndrome), AP3B1, ADTB3A, HPS2 mutations (Hermansky-Pudlak syndrome 2) and X-linked lymphoproliferative syndrome (XLP)-1 with SH2D1A mutation
8. Patients who are pregnant or nursing, women of childbearing potential who are unwilling to use highly effective birth control methods (see definition in Inclusion Criteria above) through 4 weeks after the end of their participation in the study
9. Concomitant use of immunosuppression therapies excluded by the protocol. Note: NSAIDs, glucocorticoids, cyclosporine, tacrolimus, and IL-1 inhibitors (anakinra, canakinumab, or rilonacept, or others) are allowed
10. Patients and/or parents (or legal representative, if applicable) not willing to sign assent/informed consent
11. Hypersensitivity to the active substance or one of the excipients of the investigational product

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tadekinig alfa; Patients that showed response to treatment in the SAOL phase will receive Tadekinig alfa for up to 16 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 showed response to treatment in the SAOL phase will receive placebo comparator for up to 16 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevention of flares	The primary outcome measure is the time to first occurrence of disease reactivation during the 16-week RW phase. Method of assessment : Biomarkers (CRP / Ferritin) and clinical manifestations of systemic inflammation and end-organ damage.	16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best response	Best response to therapy during the SAOL phase including either complete response, partial response or disease improvement Method of assessment : Biomarkers (CRP / Ferritin) and clinical manifestations of systemic inflammation and end-organ damage.	18 weeks
Duration of response	Duration of response to therapy during the SAOL phase	18 weeks
Intensity of flares	Intensity of flares (defined by the level of activity given by the mAIDAI)	16 weeks
Serum CRP, Serum Ferritin	Laboratory measure ug/mL for CRP, and ng/mL for Ferritin	34 weeks
Improvement of fevers, improvement of hepato/splenomegaly	Clinical assessments if present at Baseline	34 weeks
Improvement in serum albumin and liver transaminases, anemia and/or platelet count	Laboratory measures if present at Baseline	34 weeks
Hospital length of stay	Length of hospitalisation	34 weeks
Change in Physician Global Assessment (PGA)	Change from RW baseline to EOS in the PGA symptom severity score	34 weeks
Quality of life	Change of patient's/Caregiver's qualitative evaluation of health status during the study duration	34 weeks
Presence of skin rash - evolution if present at Baseline or appearance during the study	Measured by the local tolerability index	34 weeks
Tolerance to oral/enteral nutrition for hospitalized patients if intestinal dysfunction was present at Baseline	Measured by the kcal per day	34 weeks
Improvement of stool output for hospitalized patients if intestinal dysfunction was present at Baseline	mL per 24hours	34 weeks
Adverse events will be reported	Including AESI (Adverse Events of Special Interest)	34 weeks (SAOL + RW phases)
Physical examination findings and vital signs	Clinically significant changes from Baseline	34 weeks (SAOL + RW phases)
Laboratory assessments	Including clinically significant changes from Baseline in hematology with platelet counts, CRP, ESR, ferritin, fibrinogen, D-dimer, liver enzymes. (Followed until resolution)	34 weeks (SAOL + RW phases)
Immunogenicity evaluation	Generation of anti-recombinant human IL-18BP (anti-rhIL-18BP) antibodies	34 weeks (SAOL + RW phases)
Local tolerability at the injection site	Evaluated by a standardized assessment	34 weeks (SAOL + RW phases)
Disease reactivation rate	Disease reactivation rate for individual subjects (number of disease reactivations experienced per week while each subject is on the study treatment during the SAOL phase)	18 weeks
Treatment failures	Treatment failures (i.e. patients who experience at least one disease reactivation)	34 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response to therapy	Response to therapy in the SAOL phase from Week 10 onwards	18 weeks

Collaborators and Investigators

• Sponsor: AB2 Bio Ltd.
• Investigators: Principal Investigator: Ed M Behrens, MD, Children Hospital of Philadelphia

Publications and helpful links

General Publications

• Krei JM, Moller HJ, Larsen JB. The role of interleukin-18 in the diagnosis and monitoring of hemophagocytic lymphohistiocytosis/macrophage activation syndrome - a systematic review. Clin Exp Immunol. 2021 Feb;203(2):174-182. doi: 10.1111/cei.13543. Epub 2020 Nov 23.

Helpful Links

• Sponsor details

Study record dates

Study Major Dates

• Study Start (Actual): July 21, 2017
• Primary Completion (Actual): October 31, 2023
• Study Completion (Actual): November 2, 2023

Study Registration Dates

• First Submitted: February 28, 2017
• First Submitted That Met QC Criteria: April 10, 2017
• First Posted (Actual): April 14, 2017

Study Record Updates

• Last Update Posted (Actual): February 2, 2024
• Last Update Submitted That Met QC Criteria: February 1, 2024
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Lymphatic Diseases; Immunoproliferative Disorders; Genetic Diseases, Inborn; Lymphoproliferative Disorders; Genetic Diseases, X-Linked
• Other Study ID Numbers: NLRC4/XIAP.2016.001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: This information will be provided soon

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No