A Pilot, Open-label, Single Arm, Multicenter Study to Evaluate Safety, Tolerability, Pharmacokinetics and Efficacy of Intravenous Administrations of Emapalumab, an Anti-interferon Gamma (Anti-IFNγ) Monoclonal Antibody, in Patients With Systemic Juvenile Idiopathic Arthritis (sJIA) or Adult-onset Still's Disease (AOSD) Developing Macrophage Activation Syndrome/Secondary HLH (MAS/sHLH)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 14
- 试验地点
- 5
- 主要终点
- Number of Participants Withdrawn Due to Safety Reasons
研究概览
简要总结
Macrophage Activation Syndrome (MAS) is a rare, life-threatening condition characterized by uncontrolled hyperinflammation which may develop on the background of systemic Juvenile Idiopathic Arthritis (sJIA) or Adult-onset Still's Disease (AOSD). Emapalumab is a monoclonal antibody neutralizing interferon-gamma (IFN-gamma), a key cytokine which contributes to the inflammation and tissue damage seen in MAS. The purpose of this study is to assess the safety, tolerability and efficacy of emapalumab in sJIA or AOSD participants developing MAS, presenting an inadequate response to high dose glucocorticoid treatment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 0 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients of both genders
- •For sJIA patients: Confirmed sJIA diagnosis. For patients presenting with MAS in the context of the onset of sJIA, high presumption of sJIA will suffice for eligibility. For AOSD patients: confirmed AOSD diagnosis as per Yamaguchi criteria.
- •Diagnosis of active MAS.
- •An inadequate response to high dose i.v. glucocorticoid treatment administered for at least 3 days as per local standard of care (including but not limited to pulses of 30 mg/kg PDN on 3 consecutive days). High dose i.v. glucocorticoid should not be lower than 2 mg/kg/day of PDN equivalent in 2 divided doses (or at least 60 mg/day in patients of 30 kg or more). In case of rapid worsening of the patient's condition and/or lab parameters, inclusion may occur within less than 3 days from starting high dose i.v. glucocorticoids.
- •Tocilizumab, TNF inhibitors and canakinumab, if administered, have to be discontinued before emapalumab initiation.
- •Having received guidance on contraception for both male and female patients sexually active and having reached puberty. Females of child-bearing potential require use of highly effective contraceptive measures. Males with partners(s) of child-bearing potential must agree to take appropriate precautions.
- •Informed consent provided by the patient (as required by local law), or by the patient's legally authorized representative(s) with the assent of patients who are legally capable of providing it, as applicable.
排除标准
- •Diagnosis of suspected or confirmed primary HLH or HLH consequent to a neoplastic disease.
- •Active mycobacteria (typical and atypical), Histoplasma Capsulatum, Shigella, Salmonella, Campylobacter and Leishmania infections.
- •Clinical suspicion of latent tuberculosis.
- •Positive serology for HIV antibodies.
- •Presence of malignancy.
- •Patients who have another concomitant disease or malformation severely affecting the cardiovascular, pulmonary, CNS, liver or renal function that in the opinion of the Investigator may significantly affect likelihood to respond to treatment and/or assessment of emapalumab safety.
- •History of hypersensitivity or allergy to any component of the study drug
- •Receipt of a BCG vaccine within 12 weeks prior to screening.
- •Receipt of live or attenuated live vaccines (other than BCG) within 6 weeks prior to screening.
- •Pregnant or lactating female patients.
研究组 & 干预措施
Emapalumab
干预措施: Emapalumab (Drug)
结局指标
主要结局
Number of Participants Withdrawn Due to Safety Reasons
时间窗: Up to Week 8
Number of Participants Achieving MAS Remission at Week 8 After Initiation of Emapalumab Treatment
时间窗: Week 8
Remission from MAS was evaluated according to the following criteria: Resolution of clinical signs and symptoms according to the investigator (MAS clinical signs and symptoms activity score ≤ 1) and Normalization of laboratory parameters relevant to MAS, as follows: * WBC count and platelet count above the LLN. * LDH below 1.5 × the ULN. * ALT and AST both below 1.5 × the ULN. * Fibrinogen higher than 100 mg/dL. * Ferritin levels decreased by at least 80 % from values at screening or baseline (whichever was higher) or below 2000 ng/mL, whichever was lower.
Incidence, Severity, Causality, and Outcomes of AEs (Serious and Nonserious)
时间窗: Up to Week 8
Evolution of Laboratory Parameters
时间窗: Up to Week 8
Shifts from baseline in the following MAS-relevant laboratory parameters are reported: * Leukocytes * Platelets * Lactate dehydrogenase (LDH) * Alanine aminotransferase (ALT) * Aspartate aminotransferase (AST) * Ferritin * C-reactive protein * Activated partial thromboplastin time (aPTT) * Prothrombin time * D-dimer * Fibrinogen
Time to Achievement of Permanent Glucocorticoids Tapering
时间窗: Up to Week 8
Time to achievement of permanent glucocorticoid tapering by at least 50% of the equivalent dose of prednisone administered at emapalumab treatment start.
Time to First MAS Remission
时间窗: Up to Week 8
Number of Participants for Whom Glucocorticoids Could be Permanently Tapered at Any Time During the Study
时间窗: Up to Week 8
Permanently tapering by at least 50% of the equivalent dose of prednisone. This was defined as achieving reduction of 50% of the baseline dose \[SD0\] and maintaining the reduction until the end of study).
Survival Time
时间窗: Up to Week 8
Number of participants alive at the end of the study
Number of Participants Withdrawn From the Study Due to Lack of Efficacy
时间窗: Up to Week 8
Number of participants withdrawn from the study due to lack of efficacy
Levels of Emapalumab Concentration
时间窗: Data from the following time points are presented: SD0 (pre- and post-dose), Week 4 Visit 2 (pre- and post-dose), and 4-week follow-up visit/EoS.
On all infusion days, PK samples were collected before the infusion start and between 15 and 30 minutes after infusion completion. In addition, following the first emapalumab infusion, PK samples were collected approximately 24 and 48 hours post-infusion, and following the second emapalumab infusion, PK samples were collected approximately 48 hours post-infusion. Upon treatment completion, PK samples were collected on all non-infusion visits until the 4-week follow-up visit/EOS.
Pharmacodynamic Parameters
时间窗: Up to Week 8
Levels of total INF-gamma, CXCL9 and CXCL10
Number of Participants Who Demonstrated a Presence of Circulating Antibodies Against Emapalumab to Determine Immunogenicity
时间窗: Up to Week 8
The presence of circulating antibodies against emapalumab was inferred by positive results for anti-drug antibodies (ADAs).
次要结局
未报告次要终点