Kidney DiseasePhase 2NCT00625820
Tetrahydrobiopterin in Patients With Chronic Kidney Disease (CKD) and Albuminuria
A Phase 2 study testing 6R BH4 and Vitamin C in people with Kidney Disease and Albuminuria, run by University of Michigan at 1 site in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Kidney Disease, Albuminuria
- What is being tested?
- 6R BH4 and Vitamin C
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 17 participants
- Where
- 1 siteUnited States
- Study dates
- May 2008to Sep 2008
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Safety and Efficacy of Tetrahydrobiopterin in Patients With Chronic Kidney Disease (CKD) and Albuminuria: An Open-Label Pilot Study
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.
Read the detailed description
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 (estimated glomerular filtration rate (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.
- Conditions
- Kidney Disease, Albuminuria
- Being tested
- 6R BH4, Vitamin C
- Keywords
- Kidney Disease, Albuminuria, Glomerular filtration rate
- Medical subject headings
- Kidney Diseases, Albuminuria
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
6R BH4Drug
Also called Tetrahydrobiopterin
400 mg 6R BH4 oral BID for 6 weeks then 400 mg of 6R BH4 for another 6 weeks in all arms
Vitamin CDietary supplement
500 mg Vitamin C oral BID for another 6 weeks
| Study group | Role | What they receive |
|---|---|---|
| 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 . Receives: Drug: 6R BH4; Dietary Supplement: Vitamin C |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 12 weeks
Secondary outcomes (2)
Systolic Blood Pressure Measured at 6 and 12 Weeks of Therapy.
Measured: 12 weeks
Estimated Glomerular Filtration Rate (eGFR) Measured at 6 and 12 Weeks of Therapy.
Measured: 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Feb 2008 (estimated)
- Study startMay 2008
- Primary completionSep 2008
- Study completionSep 2008
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Kidney DiseaseStudies of the same condition, open and under way.
- More trials run by University of MichiganThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 17 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Michigan
- Sponsor type
- University, hospital or other
- Collaborators
- BioMarin Pharmaceutical
- Responsible party
- Principal investigator, Rajiv Saran, University of Michigan
- Investigators
- Rajiv Saran, MD, Principal investigator, University of Michigan
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00625820
- Sponsor's protocol ID
- HUM00016705
- Status last verified
- Aug 2016
- First submitted
- 19 Feb 2008
- Last updated
- 18 Oct 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 18 Oct 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Safety and Efficacy of Tetrahydrobiopterin in Patients With Chronic Kidney Disease (CKD) and Albuminuria: An Open-Label Pilot Study
- ClinicalTrials.gov ID
- NCT00625820
- Acronym / sponsor ID
- HUM00016705
- Conditions
- Kidney Disease, Albuminuria
- Keywords
- Kidney Disease, Albuminuria, Glomerular filtration rate
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 17 participants (actual)
- Lead sponsor
- University of MichiganUniversity, hospital or other
- Collaborators
- BioMarin Pharmaceutical
- Study start
- May 2008
- Primary completion
- Sep 2008 (actual)
- Study completion
- Sep 2008 (actual)
- First posted
- 28 Feb 2008 (estimated)
- Results
- Posted 18 Oct 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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 (estimated glomerular filtration rate (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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| 6R BH4 | Experimental | Drug: 6R BH4, Dietary Supplement: Vitamin CSubjects 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 . |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- 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:
- 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
Key exclusion criteria (16 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 6R BH4Also: Tetrahydrobiopterin400 mg 6R BH4 oral BID for 6 weeks then 400 mg of 6R BH4 for another 6 weeks in all arms | Drug | 6R BH4 |
| Vitamin C500 mg Vitamin C oral BID for another 6 weeks | Dietary supplement | 6R BH4 |
Primary outcome
The Primary Outcome Measure is Level of Albuminuria.
Time frame: 12 weeks
Early morning urine specimens were collected to calculate albumin and creatinine ratio (albuminuria) at 6 and 12 weeks of therapy.
2 secondary outcomes
Systolic Blood Pressure Measured at 6 and 12 Weeks of Therapy.
Time frame: 12 weeks
Estimated Glomerular Filtration Rate (eGFR) Measured at 6 and 12 Weeks of Therapy.
Time frame: 12 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Oct 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Rajiv Saran, MD principal investigator
University of Michigan
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing 6R BH4 and Vitamin C in people with Kidney Disease and Albuminuria, run by University of Michigan at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Oct 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 18 Oct 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The Primary Outcome Measure is Level of Albuminuria. (time frame: 12 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Oct 2016.