Novel Therapies for Resistant FSGS
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 21
- 试验地点
- 2
- 主要终点
- Safety and tolerance of medications
研究概览
简要总结
The current management of primary FSGS is predicated on the assumption that the disease is caused by an immune-mediated disturbance in glomerular barrier function. Therefore, most treatment protocols have involved immunosuppressive drugs given singly or in combination. However, the efficacy of this type of therapy has been disappointing and the long-term prognosis for renal survival in patients with resistant FSGS is poor. An alternative approach that targets the fibrosis pathway may represent a novel approach to the treatment of resistant FSGS. In this R21, the investigators will test the hypothesis that two novel agents - a tumor necrosis factor-alpha (TNF-α) antagonist and a peroxisome proliferator activator receptor-gamma (PPARγ) agonist - can be administered safely to patients with resistant FSGS. In the R21 feasibility/pilot phase, pharmacokinetic studies will be conducted to assess the impact of proteinuria on the kinetics of the novel drugs in children and adults.
Specific Aim #1: To assess the safety and tolerability of two novel drugs - a TNF-α antagonist and a PPARγ agonist - in patients with resistant FSGS.
Specific Aim #2: To conduct a pharmacokinetic (PK) assessment of the selected agents to enable selection of medication regimens for investigation in a randomized Phase II study.
详细描述
Description of study visits
Screening Visit: Eligibility Studies
- History and physical examination
- Urine protein and creatinine excretion. Proteinuria (Up/c) will be expressed as the protein:creatinine ratio (mg:mg) in a single early morning specimen.
- Serum creatinine and calculated GFR. The GFR will be calculated using the Schwartz formula for patients below 18 years of age and Cockroft-Gault for those 18 years or older.
- Serum Na+, K+, HCO3-, Cl-, glucose, BUN, albumin, cholesterol, AST, ALT, alkaline phosphatase, CBC, ANA, CH50, pregnancy test
- HIV, Hepatitis B and C serology, if not done in the previous 12 months
- TB skin test, if not done in the previous 12 months
- Existing renal biopsy tissue will be assessed for all subjects who have not had the diagnosis of FSGS confirmed by an FSGS-CT core pathologist (only in screen failures).
Baseline Visit: Week 0 Visit
- Serum glucose, albumin, and creatinine concentrations
- TNF-alpha level
- Baseline anti-adalimumab antibody (AAA) level in patients assigned to Humira® treatment
- A urine, plasma, serum and DNA sample will be collected for storage in the NIDDK FONT Biorepositories at Fisher Bioservice and the Rutgers Cell & DNA Repository for patients who consent to this procedure. A request will be made to store any residual renal tissue collected for clinical indications during the FONT trial in the NIDDK Biorepository.
- PK assessment (see below)
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
- None
入排标准
- 年龄范围
- 2 Years 至 40 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Aged 2-42 years at onset of proteinuria
- •Aged ≤ 42 years at time of randomization (randomization date before 43rd birthday)
- •Estimated glomerular filtration rate (GFR) ≥ 40 ml/min/1.73 m2 at most recent measurement prior to randomization
- •For patients < age 18 years: Schwartz formula
- •For patients ≥ age 18 years: Cockroft-Gault formula
- •Up/c > 1.0 g/g creatinine on first morning void at time of randomization
- •Biopsy confirmed as primary FSGS (including all subtypes) by study pathologist.
- •Steroid resistance: During the last treatment course with high dose steroids prior to randomization, the patient must have demonstrated steroid resistance defined below and not have had a complete remission of proteinuria (Up/c < 0.2 or dipstick urine protein negative/trace) subsequently. The course of steroid treatment that defines resistance must be the same or equivalent to at least 4 weeks of every day dosing with a minimum cumulative dose of 56 mg/kg or 1680 mg of prednisone or its equivalent.
- •May be taking angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocking agent (ARB), vitamin E, or lipid lowering therapy
- •Willingness to comply with clinical trial protocol, medications, and follow-up visits, etc.
- •Screen failure in FSGS-CT based on prior treatment with excluded medication
- •Treatment failure in FSGS-CT based on failure to achieve remission after 26 weeks or 52 weeks of test therapy, i.e., cyclosporine or mycophenolate mofetil (MMF) + oral dexamethasone pulses
- •Exclusion Criteria
- •Secondary FSGS
- •Treated with cyclophosphamide, chlorambucil, levamisole, methotrexate, nitrogen mustard, or other immunosuppressive medications in the 30 days prior to randomization
- •Lactation, pregnancy, or refusal of birth control in women of child bearing potential
- •Participation in another therapeutic trial concurrently or for 30 days prior to randomization
- •Active/serious infection (including, but not limited to hepatitis B or C, HIV)
- •Systemic lupus erythematosus (SLE) or multiple sclerosis
- •Hepatic disease defined as serum AST/ALT > 2.5X the upper limit of normal
- •Patients with blood pressure > 140/95 or > 95th percentile for age/height while receiving maximal doses of 3 or more antihypertensive agents.
- •Diabetes mellitus (DM) type I or II.
- •Hematocrit < 30%
- •Organ transplantation
- •Obesity (based on estimated dry weight at disease onset prior to steroid therapy) defined as:
- •Body mass index (BMI) > 97th percentile for age if aged 2-20 years
- •BMI > 40 kg/m2 if aged ≥ 21 years
- •Allergy to study medications
- •Inability to consent/assent
排除标准
- 未提供
研究组 & 干预措施
1
Avandia (rosiglitazone)
干预措施: Rosiglitazone (Avandia) (Drug)
2
Humira (adalimumab)
干预措施: Adalimumab (Humira) (Drug)
结局指标
主要结局
Safety and tolerance of medications
时间窗: 16 week treatment period
次要结局
- Reduction in proteinuria(16 week treatment period)