Tetrahydrobiopterin in Patients With Chronic Kidney Disease (CKD) and Albuminuria
Condition: Kidney Disease; Albuminuria
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Albuminuria
Intervention: 6R BH4; Vitamin C
Intervention description: 400 mg 6R BH4 oral BID for 6 weeks then 400 mg of 6R BH4 for another 6 weeks in all arms; 500 mg Vitamin C oral BID for another 6 weeks
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 17.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Kidney Disease; Albuminuria; Glomerular filtration rate

Summary:

      Patients with chronic kidney disease (CKD) and albuminuria are at increased risk of
      developing cardiovascular disease (CVD) 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 (NO) 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 NO and that is a key mediator of endothelial dysfunction. Changes
      in NO availability are believed to contribute to endothelial dysfunction seen in CKD and
      common CVD 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 CKD. 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 CVD.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients with controlled hypertension (blood pressure (BP) less than 150/90 mmHg)
             using standard antihypertensive medications.

          -  Stable chronic kidney disease (CKD) with estimated glomerular filtration rate (eGFR)
             40-90 ml/min/173m2 by the abbreviated Modification of Diet in Renal Disease (MDRD)
             equation and with a rate of decline of eGFR no greater than 1ml/min/1.73m2 per month
             over the prior 3 months with albuminuria (urine albumin excretion in the 24-hr urine
             sample of between 300-3000mg).

          -  No concomitant use with:

               -  Vitamin C supplements

               -  Multivitamins containing vitamin C

               -  Any other dietary supplements, nutraceuticals, or other over-the- counter
                  products containing vitamin C

               -  Vitamin E containing supplements

          -  Concurrently taking study approved antihypertensive medications at a stable dose for
             at least 3 months prior to screening.

          -  Sexually active subjects must be willing and able to use an acceptable method of
             contraception

          -  Females of childbearing potential must have a negative pregnancy test at screening.
             Females considered not of childbearing potential include those who have been in
             menopause at least 2 years, or had tubal ligation at least 1 year prior to screening,
             or who have had total hysterectomy.

        Exclusion Criteria:

          -  Uncontrolled hypertension with BP greater than 150/90 or with frequent changes to
             antihypertensive regimen during the last 3 months.

          -  Concurrent disease or condition that would interfere with study participation or
             safety, such as bleeding disorders, history of syncope or vertigo; severe
             gastroesophageal reflux disease (GERD) or gastric ulcers; heart failure; symptomatic
             coronary or peripheral vascular disease; arrhythmia; serious neurologic disorders,
             including seizures; or organ transplant.

          -  Diabetics that are uncontrolled, unstable, newly diagnosed, or have undergone major
             changes in therapy in the last three months or HbA1C consistently greater than 9.0.

          -  Any severe comorbid condition that would limit life expectancy to less than 6 months.

          -  Advanced stage III CKD or worse , i.e. eGFR less than 40 ml/min/1.73m2 (by abbreviated
             MDRD formula).

          -  History of nephrolithiasis.

          -  Patients with albuminuria due to causes other than hypertension and /or diabetes;
             e.g., systemic lupus erythematosus (SLE).

          -  Hepatic enzyme concentrations greater than 2 times the upper limit of normal.

          -  HIV infection, hepatic cirrhosis, other preexisting liver disease, or positive HIV,
             Hepatitis B or C test at screening.

          -  Concomitant treatment with drugs known to inhibit folate metabolism, Levodopa,
             phosphodiesterase (PDE) 5 inhibitors or PDE 3 inhibitors.

          -  Myocardial infarction, stroke, or surgery within the last 60 days prior to screening.

          -  History of alcohol and/or drug abuse.

          -  Pregnant or breastfeeding at screening, or planning to become pregnant (subject or
             partner) at any time during the study.

          -  Previous treatment with tetrahydrobiopterin (6R-BH4).

          -  Has known hypersensitivity to 6R-BH4 or its excipients.

          -  Any condition that, in the view of the principal investigator (PI), places the subject
             at high risk of poor treatment compliance or of not completing the study.