Therapeutic Use of Tadekinig Alfa in NLRC4 Mutation and XIAP Deficiency

• ClinicalTrials.gov Identifier: NCT03113760
• Recruitment Status: Recruiting
• First Posted: April 14, 2017
• Last Update Posted: June 7, 2021
• 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 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

• 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: May 30, 2022
• Estimated Study Completion Date: July 30, 2022

Arms and Interventions

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

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

• 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 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 (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

Contacts

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

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

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: Fabien Touzot, 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

• 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, Møller 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: June 7, 2021
• Last Verified: January 2021

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