A Pilot, Open-Label Single Center Trial of TP10 in Pediatric and Adult Patients With C3 Glomerulopathy (C3G)
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 试验地点
- 1
- 主要终点
- C3 serum measurements, serum C3 breakdown products, and/or alternative pathway (AP) complement activity.
研究概览
简要总结
The purpose of this study is to evaluate the safety of repeated TP10 dosing in pediatric and adult patients with C3G and to evaluate the activity of TP10 in pediatric and adult patients with C3G, as measured by the proportion of patients with normalization of serum C3, serum C3 breakdown products, or alternative pathway (AP) complement activity.
详细描述
Overview of Study Design: This study is a pilot Phase I, open-label, non-randomized, single-arm, clinical trial of TP10 in 5 patients with C3G, aged 4 years or older. The study consists of a 4-week screening period followed by a 26-week treatment period. (See Schedule of Events, Table 1.) The 26-week treatment period is further divided into an Induction Period of up to 4 weeks, followed by a Maintenance Period, which allows for continued treatment to a total of 26 weeks.
Screening Period: Patients will be identified for possible enrollment in this study through a number of mechanisms, including physician or patient-self referral and participation in an on-going study of C3G in which renal pathology is reviewed to confirm the diagnosis of C3G and genetic and complement studies are performed. Patients who appear to meet eligibility criteria for this study upon initial review will be asked to contact Drs. Nester and Smith if they are interested in this study. Those patients who express interest in this study will be scheduled for a screening clinic visit at which time they will meet the study team and review the study design and requirements. A consent for study participation will be obtained. During this visit those events/tests noted on Table 1, Screening Visit, will be completed. If not already vaccinated within the time period of active coverage specified by the vaccine manufacturer, patients will be administered meningococcal, pneumococcal and haemophilus influenzae vaccines prior to study drug administration.
Treatment Period: All patients will be enrolled through the University of Iowa. This study will follow a patient-specific dose-escalation scheme during the Induction Period and subsequent dose adjustments based on complement levels during the Maintenance Period (as described under Investigational Product Dosing and Administration).
Safety Monitoring: Safety data for this trial will be reviewed by a Data Monitoring and Safety Person (DMSP) consisting of one reviewer who is otherwise independent of trial conduct, as well as study investigators. The DMSP will review safety data on a periodic basis based on the accrual rate and emergence of safety data. The DMSP will evaluate patient data with the purpose of identifying safety concerns that may require a modification of the current study protocol and will also be responsible for determining if criteria for halting of the trial are met (see below).
Study Stopping Rules: If any of the following criteria are met, further enrollment into the trial will be halted and the data reviewed with the DMSP. The trial will only be reopened after a mutually agreed plan is defined with the DMSP.
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
- 4 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patient must have C3G as confirmed by renal biopsy within six months of enrollment (confirmation by University of Iowa investigators is required). If the patient is post transplant, the repeat renal transplant biopsy must show C3 dominant glomerulonephritis, and the patient must have a history of known C3G in the native kidney.
- •C3 serum must be less than 75% of the lower limit of normal.
- •Signs of alternative pathway dysregulation must be present. C3 breakdown products or C3Nef activity must be detectable in plasma using assays described and validated at the University of Iowa
- •Serum creatinine level must be abnormal (>97 percentile for age or <80 ml/min using the Cockroft Gault equation for adults).
- •Must have either 24 hour urine protein >1000 mg/day, or urine protein:creatinine ratio >1.
- •Screening laboratory values must meet the following criteria:
- •hemoglobin ≥ 9.0 g/dL
- •platelet count ≥ 100,000/mm3
- •alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 3.0 x ULN
- •Must use adequate birth control measures.
- •Patient must be willing and able to comply with study procedures including vaccination against meningitis, haemophilus and pneumococci at least 2 weeks prior to starting the Induction Period and agree to a renal biopsy at the conclusion of the study.
- •Any anti-proteinuric medications (eg, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers) must be at a stable dose for at least four weeks prior to first dose of TP10.
排除标准
- •Dialysis or patients with an estimated glomerular filtration rate (eGFR; using Cockroft Gault equation) of less than 30 ml/min/1.73 m2 for over a four-week period prior to the Screening Period
- •Presence or suspicion of active or untreated systemic bacterial infection that in the opinion of the investigator precludes treatment with TP10
- •Pregnancy or lactation
- •Rituximab therapy, unless discontinued with B cell levels and immunoglobulin levels normalized by study entry
- •Patients receiving immunosuppressive therapies (except for low dose steroids [≤10 mg of prednisone or equivalent per day] given for non-C3G related conditions such as asthma). Patients receiving steroids for C3G must complete a taper prior to study entry. Exceptions will be made for renal transplant patients, who may receive any appropriate therapies as needed to maintain the transplant (i.e., to prevent rejection).
- •Receipt of any complement inhibitor within 2 months of study entry
- •Receipt of any other investigational drug or device or experimental procedures beginning four weeks prior to study enrollment
- •For renal transplant patients only: histology findings of treatable rejection (i.e. that the usual transplant physician would seek to treat). Chronic allograft nephropathy is not exclusionary provided the patient's GFR meets other entry criteria.
- •A preexisting condition with a reported association as a potential cause of C3G (i.e., Monoclonal Gammopathy of Undetermined Significance [MGUS]) or an alternate glomerular disease that may interfere with the interpretation of study results
- •Malignancy except for adequately treated and cured basal or squamous cell skin cancer, curatively treated in situ disease, or other cancer from which the patient has been disease-free for ≥ 5 years
- •Patients with myocardial infarction (MI) within 1 year of screening, congestive heart failure, arrhythmia persistent on medication at screening or clinically evident chronic lung disease
- •Known Human Immunodeficiency Virus (HIV), Hepatitis B or Hepatitis C infection
- •Any medical or psychological condition that, in the opinion of the investigator, would increase the patient's risk by participation in this study or would interfere with interpretation of the study
研究组 & 干预措施
Screening/ Active Treatment Arm
Screening Period: This includes diagnosis confirmation, consent, required tests and vaccinations.
Treatment Period: All patients will be enrolled through the University of Iowa. This study will follow a patient-specific TP10 dose-escalation scheme during the Induction Period and subsequent dose adjustments based on complement levels during the Maintenance Period
干预措施: TP10 (Drug)
结局指标
主要结局
C3 serum measurements, serum C3 breakdown products, and/or alternative pathway (AP) complement activity.
时间窗: 2 years
次要结局
- Appropriate dose range and regimen for TP10.(2 years)
研究者
Richard JH Smith
MD (Principal Investigator)
University of Iowa