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 Improvement in Laboratory Markers - Hemoglobin 18 weeks Change from Baseline mean value to Week 18 mean value
Change in Patient/Caregiver Qualitative Evaluation of Health Status in Randomized Withdrawal Phase 16 weeks The individual disease-related symptoms score is the sum of (x) individual symptom scores within domain each ranging from 0 (None) to 5 (Very severe) for: general wellbeing (5), gastrointestinal (7), musculoskeletal (5), skin (2), eye (2), central nervous system (3), and lymphatic (2). Highest values indicate more severe disease-related symptoms within total score range from 0-130.
Improvement in Laboratory Markers - Erythrocyte Sedimentation Rate 18 weeks Change from Baseline mean value to Week 18 mean value
Hospital Length of Stay 34 weeks Length of hospitalisation; emergency room attendance and unscheduled visits for treatment of disease reactivations not included
Change in Physician Global Assessment (PGA) 34 weeks The PGA is a direct surrogate of how a patient functions and assesses the severity of disease-related (auto-inflammatory) symptoms by selecting an integer score from 0 (no impact on subject; no symptoms) to 10 (no normal activities possible; highest severity of symptoms possible).
The outcome lists the change from baseline of treatment phase to end of treatment phase/study in the PGA symptom severity score.Local Tolerability at the Injection Site (as Defined by Number of Participants With Adverse Events of Special Interest) 34 weeks (SAOL + RW phases) Adverse events of special interest (AESIs) are defined for this protocol as injection site reactions (including pruritus, erythema, swelling).
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.Improvement in Laboratory Markers - Fibrinogen 18 weeks Change from Baseline mean value to Week 18 mean value
Improvement in Laboratory Markers - D-Dimer 18 weeks Change from Baseline mean value to Week 18 mean value
Immunogenicity Evaluation 34 weeks (SAOL + RW phases) Generation of anti-recombinant human IL-18BP (anti-rhIL-18BP) antibodies
Duration of Response During the SAOL Phase (Until End of Phase or Disease Reactivation) The actual mean treatment duration in the SAOL phase was 17.6 weeks (minimum / maximum 5.9 / 22.1 weeks). Duration of response to therapy during the SAOL phase is assessed for patients having achieved a complete or partial response to therapy during the SAOL phase. It is defined as the time from first evaluation of partial or complete response until the time of subsequent disease reactivation or end of SAOL phase, whichever occurs first.
Of the 11 patients achieving partial or complete response during the SAOL phase, 8 maintained treatment response until the end of the SAOL phase.
2 of the 11 patients had a temporary disease reactivation during the protocol mandated steroid weaning in the SAOL phase; 1 of the 11 patients was withdrawn from blinded treatment following a disease reactivation.Change From Baseline in mAIDAI Total Score in the SAOL Phase 18 weeks The mAIDAI (modified autoinflammatory disease activitiy index) is an assessment of global disease activity that measures 14 different components for disease as either absent (0 points) or present (2 points for Uveitis 3+/4+ and 1 point for all other symptoms) at each visit. The mAIDAI total score is the sum of the points assigned across all components and ranges from 0 to 15, with a higher score indicating more severe disease activity.
Change From Baseline in Serum Ferritin 34 weeks Laboratory measure
Change From Baseline in Serum CRP 34 weeks Laboratory measure
Improvement in Laboratory Markers - Albumin 18 weeks Change from Baseline mean value to Week 18 mean value
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)
Treatment Failures 18 weeks Treatment failures (i.e. patients who experience at least one disease reactivation) during the SAOL phase
Resolution of Fevers, Hepato/Splenomegaly and Skin Rash 18 weeks Clinical assessments if present at Baseline; number displays percentage of patients with resolution of individual disease component at Week 18 or early termination visit based on the number of patients with a baseline assessment for the component of interest.
Improvement in Laboratory Markers - AST (SGOT) 18 weeks Change from Baseline mean value to Week 18 mean value
Improvement in Laboratory Markers - ALT (SGPT) 18 weeks Change from Baseline mean value to Week 18 mean value
Improvement in Laboratory Markers - Platelets 18 weeks Change from Baseline mean value to Week 18 mean value
Trial Locations
- Locations (9)
UCSD _ Department of Pediatrics / Rady Children's Hospital
🇺🇸La Jolla, California, United States
Children's Healthcare of Atlanta at Egleston
🇺🇸Atlanta, Georgia, United States
Boston Children's Hospital
🇺🇸Boston, Massachusetts, 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
The Hospital for Sick Children
🇨🇦Toronto, Ontario, Canada
CHU Sainte-Justine
🇨🇦Montréal, Providence, Canada
Universitätsklinikum Freiburg, Centrum für Chronische Immundefizienz (CCI) - Paediatric Unit
🇩🇪Freiburg, Baden-Württemberg, Germany
UCSD _ Department of Pediatrics / Rady Children's Hospital🇺🇸La Jolla, California, United States