A Phase 2b, Double-Blind, Three Arm, Randomized, Placebo Controlled Trial With Restricted Response Adaptive Randomization Testing the Efficacy and Safety of High Dose Methylprednisolone or Equine Anti-Thymocyte Globulin as Treatment for Acute Liver Failure in Pediatric Patients
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 44
- 试验地点
- 44
- 主要终点
- Survival with native liver (SNL)
研究概览
简要总结
TReatment for ImmUne Mediated PathopHysiology (TRIUMPH) is a multi-center, three arm, randomized, controlled trial of immunosuppressive therapy for children with acute liver failure. The study will determine if suppressing inflammatory responses with either corticosteroids or equine anti-thymocyte globulin therapy improves survival for children with this rare, life-threatening condition.
详细描述
Pediatric Acute Liver Failure (PALF) is a rare, devastating condition that affects an estimated 250 children per year in North America, causing death in approximately 15% and the need for liver transplantation in an additional 20-30%. In the majority of cases, a specific cause of the liver injury is never determined. Recent research supports the theory that many of these patients have liver injury related to a hyperinflammatory immune response to everyday infections or environmental exposures. There is strong evidence to show that equine anti-thymocyte globulin and methylprednisolone slow the body's response to inflammation and improve the recovery of patients with other immune disorders and thus, may help patients with acute liver failure.
This is a phase 2b, double-blind, three arm, randomized, placebo controlled trial with restricted response adaptive randomization. The primary objective is to determine the efficacy and safety of high-dose methylprednisolone or equine anti-thymocyte globulin (eATG or ATGAM®) as compared to supportive care alone (placebo) for the treatment of acute liver failure in pediatric patients.
Approximately 160 patients who are equal to or greater than ≥ 1 and less than ≤ 18 years of age with pediatric acute liver failure (PALF) of undetermined etiology will be randomized to receive either high-dose methylprednisolone (Treatment 1) or eATG (ATGAM®) (Treatment 2) or supportive care alone (Treatment 3) on days 1 to 4 after study enrollment, followed by a gradual prednisolone taper (for the two active treatment arms 1 and 2) or a placebo taper (for treatment arm 3) on days 5 to 42.
The follow-up period includes visits at 1 week (Day 7), 2 weeks (Day 14), and 3 weeks (Day 21) after the day the participant started in the study. Early follow-up assessments will be performed either in the inpatient or ambulatory setting since some participants may be discharged before Day 7. In addition, families will be contacted by phone or email to schedule each follow-up at the study site for the 6 week, 3 month, 6 month and 12 month study visits.
This study includes a prospective observational cohort study of up to 50 patients with PALF who meet the randomized controlled trial (RCT) eligibility criteria and are willing to provide longitudinal observational data.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 1 Year 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patient with liver injury of ≤ 6 weeks duration resulting in an international normalization ratio (INR) of ≥ 1.5 or < 2.0 (not corrected by vitamin K) with evidence of hepatic encephalopathy (HE), INR of ≥ 1.5 or < 2.0 for at least 7 days duration without evidence of HE or INR ≥ 2.0 without evidence of HE.
- •Age is greater than or equal to 1 year and less than 18 years of age.
- •Patient or their legally authorized representative(s) (LAR) must consent (and assent, if applicable) to be in the study and must have signed and dated an approved informed consent form which conforms to federal and institutional guidelines.
- •Females of reproductive potential should not plan on conceiving children during the study and must agree to use a medically accepted form of contraception.
排除标准
- •Evidence of active infection with Hepatitis A, B, C, E or evidence of acute herpes simplex virus (HSV) or adenovirus infection
- •Travel within the past 3 months to an area highly endemic for Hepatitis E
- •Diagnosis of hemophagocytic lymphohistiocytosis (HLH) Note: Patients with a history of consanguinity and/or central nervous system (CNS) dysfunction that is exaggerated compared to the degree of liver dysfunction (as judged by the site investigator) will not be enrolled until results of rapid genetic testing are available. Turn-around time for genetic testing results is estimated to be 72-96 hours.
- •Aplastic anemia as defined by standardized criteria [1] diagnosed prior to enrollment
- •Diagnosis of autoimmune Hepatitis (AIH)
- •Diagnosis of acute Wilson disease
- •Diagnosis of inborn error of metabolism Note: Suspicion of metabolic disease is not an exclusion for entry into the Trial.
- •Diagnosis of acute drug or toxin-induced liver injury
- •History of recreational drug use within the past 4 weeks
- •Therapy with an immunosuppressive agent, including chemotherapy, biological therapies or an experimental drug or device within the past 6 weeks
- •Liver injury due to ischemia
- •Liver dysfunction diagnosed more than 6 weeks prior to screening
- •History of allergy to horse dander
- •Imminent risk of death as judged by the clinical site investigator, including but not limited to; signs of cerebral herniation at the time of enrollment and presence of intractable arterial hypotension
- •Solid organ or stem cell transplant recipient
- •Pregnant or breast-feeding at the time of proposed study entry
- •Clinical AIDS or HIV positive
- •History of any form of malignant neoplasm and/or tumors treated within five years prior to study entry (other than non-melanoma skin cancer or in situ cervical cancer) or where there is current evidence of recurrent or metastatic disease
- •Received a live-virus vaccine within 4 weeks of study entry
- •Patients with positive respiratory secretion testing for respiratory viral infection including SARS-CoV-2, influenza and respiratory syncytial virus only if they also have declining respiratory function
- •Psychiatric or addictive disorders that would preclude obtaining informed consent/assent
- •Patient is unwilling or unable to adhere with study requirements and procedures
- •Currently receiving other experimental therapies
研究组 & 干预措施
Observational Cohort
This study includes a prospective observational cohort study of patients with Pediatric Acute Liver Failure who meet the randomized controlled trial eligibility criteria and are willing to provide longitudinal observational data. Patients who provide consent will receive the enrolling institution's standard of care and will be followed for up to 90-days for clinical (observational) assessments and biospecimen collection for the biorepository.
Equine anti-thymocyte globulin
Intravenous equine anti-thymocyte globulin at a dose of 40 mg/kg/day for 4 days.
干预措施: Equine anti-thymocyte globulin (Drug)
Equine anti-thymocyte globulin
Intravenous equine anti-thymocyte globulin at a dose of 40 mg/kg/day for 4 days.
干预措施: Diphenhydramine (Drug)
High-dose methylprednisolone
Intravenous methylprednisolone at an initial dose of 10 mg/kg/day for 3 days, 5 mg/kg/day on day 4.
干预措施: High-dose methylprednisolone (Drug)
Supportive care
Supportive care will be administered as determined by the clinical team at participating clinical sites in accordance with their local practices and standards.
干预措施: Placebo for prednisolone (Drug)
Supportive care
Supportive care will be administered as determined by the clinical team at participating clinical sites in accordance with their local practices and standards.
干预措施: Placebo for infusions (Drug)
Equine anti-thymocyte globulin
Intravenous equine anti-thymocyte globulin at a dose of 40 mg/kg/day for 4 days.
干预措施: Prednisolone (Drug)
High-dose methylprednisolone
Intravenous methylprednisolone at an initial dose of 10 mg/kg/day for 3 days, 5 mg/kg/day on day 4.
干预措施: Prednisolone (Drug)
Equine anti-thymocyte globulin
Intravenous equine anti-thymocyte globulin at a dose of 40 mg/kg/day for 4 days.
干预措施: Methylprednisolone (Drug)
结局指标
主要结局
Survival with native liver (SNL)
时间窗: 21 days
Alive and without a liver transplant 21 days following randomization
次要结局
- Survival with native liver (SNL)(180 days)