Tetrahydrobiopterin in Patients With Chronic Kidney Disease (CKD) and Albuminuria
Patients with chronic kidney disease and albuminuria are at increased risk of developing cardiovascular disease which is often associated with hypertension, left ventricular hypertrophy, endothelial dysfunction and increased generation of reactive oxygen species (ROS). These patients also manifest a decrease in nitric oxide availability which is thought to play an important role in their progressive vascular disease.
Tetrahydrobiopterin (BH4), an essential cofactor for endothelial nitric oxide synthase(eNOS), an important regulator of nitric oxide (NO) and that is a key mediator of endothelial dysfunction. Changes in nitric oxide availability are believed to contribute to endothelial dysfunction seen in chronic kidney disease and common cardiovascular disease states. 6R-tetrahydrobiopterin (6R-BH4 or sapropterin dihydrochloride) is an investigational oral drug that is being evaluated to determine whether it will restore NO availability, leading to beneficial effects on vascular function and ultimately positive clinical outcomes in patients with chronic kidney disease. The primary endpoint in this study is the level of albuminuria, an easily measured marker that has served as a predictor of kidney disease progression. If 6R-BH4 reduces albuminuria in patients with kidney disease, it may have implications to slow the disease progression as well as decreased risk of cardiovascular disease.
Drug: Tetrahydrobiopterin (6R BH4)
Dietary Supplement: Vitamin C
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Safety and Efficacy of Tetrahydrobiopterin in Patients With Chronic Kidney Disease (CKD) and Albuminuria: An Open-Label Pilot Study|
- The primary outcome measure is level of albuminuria at 6 and 12 weeks of therapy (based on measurement of 24-hour urine albumin and urine albumin:creatinine ratio). [ Time Frame: 16 weeks ] [ Designated as safety issue: Yes ]
- The primary analyses will be repeated using eGFR and blood pressure as secondary outcome measures. [ Time Frame: 16 weeks ] [ Designated as safety issue: Yes ]
|Study Start Date:||May 2008|
|Estimated Study Completion Date:||April 2013|
|Primary Completion Date:||September 2008 (Final data collection date for primary outcome measure)|
Drug: Tetrahydrobiopterin (6R BH4)
400 mg 6R BH4 oral BID for 6 weeks then 400 mg of 6R BH4 for another 6 weeksDietary Supplement: Vitamin C
500 mg Vitamin C oral BID for another 6 weeks
ABSTRACT Background: Chronic kidney disease (CKD) is characterized by a high propensity to cardiovascular disease (CVD); therefore treatments that impact both CKD and CVD are needed. CKD is accompanied by endothelial dysfunction and nitric oxide (NO) deficiency. Tetrahydrobiopterin (BH4), an important co-factor for endothelial NO synthase (eNOS) increases the availability of NO. Administration of BH4 has the potential to improve endothelial function and thereby reduce albuminuria in CKD.
Patients and Methods: This Phase 2 open-label study is designed to assess the efficacy and safety of twice daily oral dosing of 6R-BH4 in 30 subjects with CKD (eGFR ≥40ml/min/1.73m2). .
Trial Design: Subjects will receive 6R-BH4 400mg bid for 6 weeks, sequentially followed by 6R-BH4 plus Vitamin C 500mg bid for another 6 weeks. Patients will have scheduled visits at Weeks 0,3,6,9 and 12, with an exit-visit at week 16. Albuminuria will be assessed in 24-hour urine collections as well as early morning spot urine samples for albumin:creatinine ratio. Blood and urine will be tested for routine clinical laboratory tests, blood NO, and also archived for later assays for special biomarkers. The primary outcome will be level of albuminuria as measured in a 24-hour urine collection at 6 and 12 weeks of therapy. Secondary outcomes will include urine albumin/creatinine ratio, eGFR, and blood pressure. Adverse events will be monitored closely.
Data analysis: For all patients combined and for each of the above outcomes, we will sequentially compare each time point to the baseline level using paired t-tests. For the comparison of 6R-BH4 versus 6R-BH4+vitamin C, we will compare albuminuria at 6 and 12-weeks, adjusted for baseline values, using regression analysis. We will also use regression to test for an interaction between baseline value and treatment group.
Anticipated results: We postulate that 6R-BH4 alone or in conjunction with high dose vitamin C will reduce albuminuria in patients with CKD by improvement in endothelial function that is integral to glomerular filtration.
Future Implications: Reduction in albuminuria if demonstrable, will have implications for simultaneous renal and cardiovascular protection. This will need to be confirmed in a larger randomized controlled clinical trial in subjects with CKD.
|United States, Michigan|
|University of Michigan, GCRC Clinic, C302 Med Inn Bldg, 1500 East Medical Center Dr.|
|Ann Arbor, Michigan, United States, 48109|
|Principal Investigator:||Rajiv Saran, MD||University of Michigan|