Therapeutic Use of Tadekinig Alfa in NLRC4 Mutation and XIAP Deficiency

Study Overview
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Brief Summary
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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.

Detailed Description
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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)

Official Title
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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

Conditions
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NLRC4-MAS, XIAP Deficiency

Intervention / Treatment
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* Drug: Tadekinig alfa
* Other: 0.9% sodium chloride


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA 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.) 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. Ferritin ≥ 500 ng/mL or persistent elevation of CRP ≥ 2x ULN and mAIDAI ≥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. 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 Patients with life-threatening co-morbidities not associated with the underlying NLRC4-mutation or XIAP deficiency Positive test for or prior history of HIV, Hepatitis B or Hepatitis C (serology) Presence of active infections or a history of pulmonary TB infection with or without documented adequate therapy Presence of life threatening infections Oncologic causes of symptoms; current or previous history of malignancy Presence of CNS manifestations (i.e. seizures, altered mental status, signs of increased intracranial pressure, chronic papilledema, loss of vision, other sensorineural deficiencies, etc.) 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 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 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 Patients and/or parents (or legal representative, if applicable) not willing to sign assent/informed consent Hypersensitivity to the active substance or one of the excipients of the investigational product
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tadekinig alfa<br>Patients that showed response to treatment in the SAOL phase will receive Tadekinig alfa for up to 16 weeks. | Drug: Tadekinig alfa<br>* 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.<br>* Other names: r-hIL-18BP;|
| Placebo Comparator: 0.9% sodium chloride<br>Patients that showed response to treatment in the SAOL phase will receive placebo comparator for up to 16 weeks. | Other: 0.9% sodium chloride<br>* 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.<br>|

What is the study measuring?
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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 |