Therapeutic Use of Tadekinig Alfa in NLRC4 Mutation and XIAP Deficiency
- Conditions
- NLRC4-MASXIAP Deficiency
- Interventions
- Other: 0.9% sodium chloride
- Registration Number
- NCT03113760
- Lead Sponsor
- AB2 Bio Ltd.
- 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.
- 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)
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 15
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description 0.9% sodium chloride 0.9% sodium chloride Patients that showed response to treatment in the SAOL phase will receive placebo comparator for up to 16 weeks. Tadekinig alfa Tadekinig alfa Patients that showed response to treatment in the SAOL phase will receive Tadekinig alfa for up to 16 weeks.
- Primary Outcome Measures
Name Time Method Prevention of flares 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
Name Time Method Intensity of flares 16 weeks Intensity of flares (defined by the level of activity given by the mAIDAI)
Serum CRP, Serum Ferritin 34 weeks Laboratory measure ug/mL for CRP, and ng/mL for Ferritin
Best response 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.
Adverse events will be reported 34 weeks (SAOL + RW phases) Including AESI (Adverse Events of Special Interest)
Local tolerability at the injection site 34 weeks (SAOL + RW phases) Evaluated by a standardized assessment
Disease reactivation rate 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)
Duration of response 18 weeks Duration of response to therapy during the SAOL phase
Improvement of fevers, improvement of hepato/splenomegaly 34 weeks Clinical assessments if present at Baseline
Improvement in serum albumin and liver transaminases, anemia and/or platelet count 34 weeks Laboratory measures if present at Baseline
Change in Physician Global Assessment (PGA) 34 weeks Change from RW baseline to EOS in the PGA symptom severity score
Tolerance to oral/enteral nutrition for hospitalized patients if intestinal dysfunction was present at Baseline 34 weeks Measured by the kcal per day
Improvement of stool output for hospitalized patients if intestinal dysfunction was present at Baseline 34 weeks mL per 24hours
Physical examination findings and vital signs 34 weeks (SAOL + RW phases) Clinically significant changes from Baseline
Immunogenicity evaluation 34 weeks (SAOL + RW phases) Generation of anti-recombinant human IL-18BP (anti-rhIL-18BP) antibodies
Hospital length of stay 34 weeks Length of hospitalisation
Quality of life 34 weeks Change of patient's/Caregiver's qualitative evaluation of health status during the study duration
Presence of skin rash - evolution if present at Baseline or appearance during the study 34 weeks Measured by the local tolerability index
Laboratory assessments 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)
Treatment failures 34 weeks Treatment failures (i.e. patients who experience at least one disease reactivation)
Trial Locations
- Locations (9)
Children's Healthcare of Atlanta at Egleston
🇺🇸Atlanta, Georgia, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
Children Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Texas Children's Hospital _ Baylor College of Medicine
🇺🇸Houston, Texas, United States
Boston Children's Hospital
🇺🇸Boston, Massachusetts, United States
UCSD _ Department of Pediatrics / Rady Children's Hospital
🇺🇸La Jolla, California, United States
CHU Sainte-Justine
🇨🇦Montréal, Providence, Canada
Universitätsklinikum Freiburg, Centrum für Chronische Immundefizienz (CCI) - Paediatric Unit
🇩🇪Freiburg, Baden-Württemberg, Germany
The Hospital for Sick Children
🇨🇦Toronto, Ontario, Canada