A Three-period Multicenter Study, With a Randomized-withdrawal, Double-blind, Placebo-controlled Design to Evaluate the Clinical Efficacy, Safety and Tolerability of MAS825 in Patients With Monogenic IL-18 Driven Autoinflammatory Diseases, Including NLRC4-GOF, XIAP Deficiency, or CDC42 Mutations
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 17
- 试验地点
- 16
- 主要终点
- 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
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
Subject, investigator, and sponsor blinding via manual randomization during Period 2, Randomized Withdrawal Period
入排标准
- 年龄范围
- 0 Years 至 100 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •For all Patients:
- •Male and female patients weighing at least 3 kg
- •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:
- •Patients with a genetic diagnosis of either NLRC4-GOF, XIAP deficiency, or CDC42 mutation
- •Clinical history and investigations consistent with autoinflammation and infantile enterocolitis (AIFEC/NLRC4-GOF), XIAP or CDC
- •XIAP patients must have persistent disease or be resistant to escalating therapy.
- •At first treatment, evidence of active disease as assessed by inflammatory markers and PGA
- •Cohort 2 specific inclusion criteria:
- •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).
排除标准
- •History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes or to any of the excipients.
- •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.
- •Any conditions or significant medical problems, which in the opinion of the investigator places the patient at unacceptable risk for MAS825 therapy
- •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.
- •A positive HIV test result at Screening. Evidence of prior testing within 3 months is sufficient.
- •A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result at Screening. Evidence of prior testing within 3 months is sufficient.
- •Presence of tuberculosis infection as defined by a positive TB test at Screening. Evidence of prior testing within 3 months is sufficient.
- •Live vaccinations within 1 month prior to MAS825 treatment, during the trial, and up to 3 months following the last dose.
- •Pregnant or nursing (lactating) females.
- •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
- •Patients weighing >160 kg at Screening.
- •For CDC42 mutation patients: Takenouchi-Kosaki syndrome - CDC42 mutations associated with a diverse syndrome characterized by variable development delays, cardiac, brain and hematological abnormalities.
研究组 & 干预措施
Placebo
matching placebo
干预措施: Placebo (Biological)
MAS825
Experimental drug
干预措施: MAS825 (Biological)
结局指标
主要结局
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
时间窗: Period 2
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
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
时间窗: 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
次要结局
- All cohorts: Number and severity of safety assessments and adverse events(Screening through EOS (End of Study))
- All cohorts: Physician Severity Assessment of Disease Signs and Symptoms scale(Screening through EOS)
- All cohorts: Patient / Parent global assessment of disease activity (PPGA) scale(Screening through EOS)
- All cohorts: Confirmation of serological markers of MAS825(Day 1 through EOS)
- Cohort 1: PGA and inflammatory markers(Day 29, end of Period 1, end of Period 2)
- Cohort 1: Serological remission via inflammatory markers(Day 29, end of Period 1, and end of Period 2)
- Cohort 1: Glucocorticoid therapy <0.2mg/kg by end of period 1(End of Period 1)
- Cohort 1: Time to first flare(Period 2)
- Cohort 1: Glucocorticoid therapy <0.2mg/kg by end of period 1(End of Period 1 (approximately 6 months))
- All cohorts: Number and severity of safety assessments and adverse events(Screening through EOS (End of Study) (up to approximately 11 years))
- All cohorts: Confirmation of serological markers of MAS825(Day 1 through EOS (up to approximately 11 years))
- 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))
- 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))
- Cohort 1: Time to first flare(Period 2 (during the randomized, placebo-controlled period of up to 6 months))
- All cohorts: Physician Severity Assessment of Disease Signs and Symptoms scale (PSADSS)(Screening through EOS (up to approximately 11 years))
- All cohorts: Patient / Parent global assessment of disease activity (PPGA) scale(Screening through EOS (up to approximately 11 years))