Tetrahydrobiopterin in Patients With Chronic Kidney Disease (CKD) and Albuminuria

NCT00625820 | Completed Phase 2 Results

• 1 other identifier: HUM00016705
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Kidney Disease; Albuminuria

Keywords

Kidney Disease; Albuminuria; Glomerular filtration rate

Outcome Measures

Primary Outcomes (1)

• The Primary Outcome Measure is Level of Albuminuria.

  Early morning urine specimens were collected to calculate albumin and creatinine ratio (albuminuria) at 6 and 12 weeks of therapy.

  12 weeks

Secondary Outcomes (2)

• Systolic Blood Pressure Measured at 6 and 12 Weeks of Therapy.

  12 weeks

• Estimated Glomerular Filtration Rate (eGFR) Measured at 6 and 12 Weeks of Therapy.

  12 weeks

Study Arms (1)

6R BH4

EXPERIMENTAL

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 nitric oxide (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, estimated glomerular filtration rate (eGFR), and blood pressure .

Drug: 6R BH4; Dietary Supplement: Vitamin C

Interventions

6R BH4 DRUG

400 mg 6R BH4 oral BID for 6 weeks then 400 mg of 6R BH4 for another 6 weeks in all arms

Also known as: Tetrahydrobiopterin

6R BH4

Vitamin C DIETARY_SUPPLEMENT

500 mg Vitamin C oral BID for another 6 weeks

6R BH4

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Michigan: lead
• BioMarin Pharmaceutical: collaborator

Study Sites (1)

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

MeSH Terms

Conditions

Kidney Diseases; Albuminuria

Interventions

phenoptin; sapropterin; Ascorbic Acid

Condition Hierarchy (Ancestors)

Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Proteinuria; Urination Disorders; Urological Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Sugar Acids; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Hydroxy Acids; Carbohydrates

Limitations and Caveats

It was a small single center non-randomized pilot study \& was not powered to detect significant changes in albuminuria.

Results Point of Contact

• Title: Rajiv Saran, MD
• Organization: University of Michigan

rsaran@umich.edu

734-763-6611

Study Officials

• Rajiv Saran, MD

  University of Michigan

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, MS, MRCP, Associate Professor

Study Record Dates

• First Submitted: February 19, 2008
• First Posted: February 28, 2008
• Study Start: May 1, 2008
• Primary Completion: September 1, 2008
• Study Completion: September 1, 2008
• Last Updated: October 18, 2016
• Results First Posted: October 18, 2016

Record last verified: 2016-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)