NLRC4-GOF, AIFEC (Autoinflammation With Infantile Enterocolitis), XIAP Deficiency, CDC42 Mutations
Conditions
Keywords
NLRC4-GOF, AIFEC, enterocolitis, autoinflammation, MAS, NLRC4 (SCAN4), XIAP deficiency, CDC42 mutations
Brief summary
This study is a Phase 2 trial designed to evaluate the clinical efficacy, safety, and tolerability of MAS825 in patients with NLRC4-GOF, XIAP deficiency, or CDC42 mutations.
Detailed description
This is a three-period study, with an open-label, single-arm active treatment in Period 1 followed by a randomized-withdrawal, double-blinded, placebo-controlled design in Period 2, and an open label, long-term safety follow-up in Period 3, Period 3s, & Period 3s open label extension. The total study duration is up to approximately 11 years. Patients who enter Period 2 will be randomized to MAS825 or matching placebo in a 1:1 ratio. Cohort 1 patients will complete all periods of the study. Cohort 2: Patients who are receiving MAS825 in a Novartis Managed Access Program with a diagnosis of NLRC4-GOF, XIAP deficiency, or CDC42 mutation who meet criteria will be eligible to directly enter into Period 3 open-label long-term safety follow-up. They can continue into Period 3s, and Period 3s open-label extension.
Interventions
BIOLOGICALMAS825
Experimental drug
BIOLOGICALPlacebo
matching placebo
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Subject, investigator, and sponsor blinding via manual randomization during Period 2, Randomized Withdrawal Period
Intervention model description
This study includes: * Screening * Period 1: Open-Label Treatment Period to identify responders to MAS825 * Period 2: Randomized Withdrawal Period consists of a randomized treatment withdrawal period to primarily assess the efficacy of MAS825 compared to placebo. * Period 3: Open-Label, Long-Term Safety follow-up * Period 3s: Open-Label, transition to new route of administration and safety follow-up * Period 3s: Open-Label Extension * End of Study Patients can participate in all 3 periods of the study (including the open label extension) if they have never been treated with MAS825 before. Patients who are enrolled from the Managed Access program can participate in Period 3, Period 3s, and Period 3s Open-Label Extension only after completing screening and baseline assessments.
Eligibility
Sex/Gender
ALL
Age
0 Years to No maximum
Healthy volunteers
No
Inclusion criteria
For all Patients: 1. Male and female patients weighing at least 3 kg 2. Written informed consent by parent(s)/legal guardian(s) for the pediatric patients and assent by the pediatric patient (depending on local requirements) must be obtained before any study-specific assessment is performed. For adult patients, written informed consent by patients capable of giving consent, or when the patient is not capable of giving consent, by his/her legal/authorized representative (if allowed according to local requirements). Cohort 1 specific inclusion criteria: 3. Patients with a genetic diagnosis of either NLRC4-GOF, XIAP deficiency, or CDC42 mutation 4. Clinical history and investigations consistent with autoinflammation and infantile enterocolitis (AIFEC/NLRC4-GOF), XIAP or CDC42. XIAP patients must have persistent disease or be resistant to escalating therapy. 5. At first treatment, evidence of active disease as assessed by inflammatory markers and PGA Cohort 2 specific inclusion criteria: 6. Patients with a genetic diagnosis of NLRC4-GOF, XIAP deficiency, or CDC42 mutations who are being treated with MAS825 in a Novartis Managed Access Program (MAP).
Exclusion criteria
1. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes or to any of the excipients. 2. Signs and symptoms, in the judgment of the investigator, of clinically significant active bacterial, fungal, parasitic or viral infections, excluding chronic Epstein-Barr Virus (EBV). \- COVID-19 specific: If in line with health and governmental authority guidance, it is highly recommended that testing to exclude COVID-19 using PCR or comparable approved methodology be completed within 1 week prior to first dosing. 3. Any conditions or significant medical problems, which in the opinion of the investigator places the patient at unacceptable risk for MAS825 therapy 4. Previous treatment with anti-rejection and/or immunomodulatory drugs within the past 28 days or 5 half-lives (whichever is the longer) for immunomodulatory therapeutic antibodies (or as listed in the prohibited medications section) prior to MAS825 treatment with the exceptions of glucocorticoids, cyclosporin and targeted binding or blocking therapies. 5. A positive HIV test result at Screening. Evidence of prior testing within 3 months is sufficient. 6. A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result at Screening. Evidence of prior testing within 3 months is sufficient. 7. Presence of tuberculosis infection as defined by a positive TB test at Screening. Evidence of prior testing within 3 months is sufficient. 8. Live vaccinations within 1 month prior to MAS825 treatment, during the trial, and up to 3 months following the last dose. 9. Pregnant or nursing (lactating) females. 10. Female patients of child-bearing potential (or Tanner stage 2 or above) who are or might become sexually active, agree to use highly effective contraceptive methods to prevent pregnancy while on MAS825 therapy 11. Patients weighing \>160 kg at Screening. 12. For CDC42 mutation patients: Takenouchi-Kosaki syndrome - CDC42 mutations associated with a diverse syndrome characterized by variable development delays, cardiac, brain and hematological abnormalities.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cohort 1: Occurrence of disease flare in patients with MAS825 treated patients compared with placebo during Period 2 assessed by Physician's Global Assessment and inflammatory markers | Period 2 (during the randomized, placebo-controlled period of up to 6 months) | To determine the efficacy of MAS825 in prevention of flares in patients with monogenic IL-18 driven autoinflammatory diseases, including NLRC4-GOF, XIAP deficiency or CDC42 mutations |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All cohorts: Number and severity of safety assessments and adverse events | Screening through EOS (End of Study) (up to approximately 11 years) | To evaluate the safety and tolerability of MAS825 |
| All cohorts: Confirmation of serological markers of MAS825 | Day 1 through EOS (up to approximately 11 years) | Evaluate the serological markers of MAS825 |
| Cohort 1: PGA and inflammatory markers | Day 29, end of Period 1 (approximately 6 months), end of Period 2 (year 1), end of Period 3 (year 4), and end of Period 3s (up to year 6) | Evaluate the efficacy of MAS825 to improve the clinical status of patients with NLRC4-GOF, XIAP deficiency or CDC42 mutations |
| Cohort 1: Serological remission via inflammatory markers | Day 29, end of Period 1 (up to 6 months), and end of Period 2 (year 1), end of Period 3 (year 4), and end of Period 3s (up to year 6) | Evaluate efficacy of MAS825 to achieve serological remission |
| Cohort 1: Glucocorticoid therapy <0.2mg/kg by end of period 1 | End of Period 1 (approximately 6 months) | Evaluate the effect of MAS825 on concomitant glucocorticoid administration |
| Cohort 1: Time to first flare | Period 2 (during the randomized, placebo-controlled period of up to 6 months) | Evaluate effect of MAS825 on the time to first flare |
| All cohorts: Physician Severity Assessment of Disease Signs and Symptoms scale (PSADSS) | Screening through EOS (up to approximately 11 years) | Evaluate the efficacy of MAS825 to improve signs and symptoms of the disease |
| All cohorts: Patient / Parent global assessment of disease activity (PPGA) scale | Screening through EOS (up to approximately 11 years) | Evaluate effect of MAS825 on patient reported outcomes over time |
Countries
Czechia, France, Italy, Japan, Spain, United Kingdom, United States
Outcome results
None listed