Therapeutic Use of Tadekinig Alfa in NLRC4 Mutation and XIAP Deficiency

• ClinicalTrials.gov Identifier: NCT03113760
• Recruitment Status: Active, not recruiting
• First Posted: April 14, 2017
• Last Update Posted: March 10, 2023
• Sponsor: AB2 Bio Ltd.
• Information provided by (Responsible Party): AB2 Bio Ltd.

Study Description

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 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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 15 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 up to 16-week randomized withdrawal phase (RW). All patients who showed response to treatment at the end of the SAOL phase will be enrolled 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: May 30, 2023
• Estimated Study Completion Date: July 30, 2023

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Prevention of flares [ Time Frame: 16 weeks ]

   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.

Secondary Outcome Measures :

1. Best response [ Time Frame: 18 weeks ]
   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.
2. Duration of response [ Time Frame: 18 weeks ]
   Duration of response to therapy during the SAOL phase
3. Intensity of flares [ Time Frame: 16 weeks ]
   Intensity of flares (defined by the level of activity given by the mAIDAI)
4. Serum CRP, Serum Ferritin [ Time Frame: 34 weeks ]
   Laboratory measure ug/mL for CRP, and ng/mL for Ferritin
5. Improvement of fevers, improvement of hepato/splenomegaly [ Time Frame: 34 weeks ]
   Clinical assessments if present at Baseline
6. Improvement in serum albumin and liver transaminases, anemia and/or platelet count [ Time Frame: 34 weeks ]
   Laboratory measures if present at Baseline
7. Hospital length of stay [ Time Frame: 34 weeks ]
   Length of hospitalisation
8. Change in Physician Global Assessment (PGA) [ Time Frame: 34 weeks ]
   Change from RW baseline to EOS in the PGA symptom severity score
9. Quality of life [ Time Frame: 34 weeks ]
   Change of patient's/Caregiver's qualitative evaluation of health status during the study duration
10. Presence of skin rash - evolution if present at Baseline or appearance during the study [ Time Frame: 34 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: 34 weeks ]
    Measured by the kcal per day
12. Improvement of stool output for hospitalized patients if intestinal dysfunction was present at Baseline [ Time Frame: 34 weeks ]
    mL per 24hours
13. Adverse events will be reported [ Time Frame: 34 weeks (SAOL + RW phases) ]
    Including AESI (Adverse Events of Special Interest)
14. Physical examination findings and vital signs [ Time Frame: 34 weeks (SAOL + RW phases) ]
    Clinically significant changes from Baseline
15. Laboratory assessments [ Time Frame: 34 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: 34 weeks (SAOL + RW phases) ]
    Generation of anti-recombinant human IL-18BP (anti-rhIL-18BP) antibodies
17. Local tolerability at the injection site [ Time Frame: 34 weeks (SAOL + RW phases) ]
    Evaluated by a standardized assessment
18. Disease reactivation rate [ Time Frame: 18 weeks ]
    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)
19. Treatment failures [ Time Frame: 34 weeks ]
    Treatment failures (i.e. patients who experience at least one disease reactivation)

Other Outcome Measures:

1. Response to therapy [ Time Frame: 18 weeks ]
   Response to therapy in the SAOL phase from Week 10 onwards

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, California

UCSD _ Department of Pediatrics / Rady Children's Hospital

La Jolla, California, United States, 92056

United States, Georgia

Children's Healthcare of Atlanta at Egleston

Atlanta, Georgia, United States, 30322

United States, Massachusetts

Boston Children's Hospital

Boston, Massachusetts, United States, 02115

United States, Ohio

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States, 45229

United States, Pennsylvania

Children Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

United States, Texas

Texas Children's Hospital _ Baylor College of Medicine

Houston, Texas, United States, 77030

Canada, Ontario

The Hospital for Sick Children

Toronto, Ontario, Canada, ON M5G 1X8

Canada, Providence

CHU Sainte-Justine

Montréal, Providence, Canada, QC H3T 1C5

Germany

Universitätsklinikum Freiburg, Centrum für Chronische Immundefizienz (CCI) - Paediatric Unit

Freiburg, Baden-Württemberg, Germany, 79106

Sponsors and Collaborators

AB2 Bio Ltd.

Investigators

• Principal Investigator: Ed M Behrens, MD; Children Hospital of Philadelphia

More Information

Additional Information:

Sponsor details 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: AB2 Bio Ltd.
• ClinicalTrials.gov Identifier: NCT03113760
• Other Study ID Numbers: NLRC4/XIAP.2016.001
• First Posted: April 14, 2017
• Last Update Posted: March 10, 2023
• Last Verified: July 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided
• 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