HypertensionEarly Phase 1NCT00208780
Effects of Tetrahydrobiopterin on Blood Pressure
A Early Phase 1 study testing Tetrahydrobiopterin in people with Hypertension, run by Emory University at 1 site in United States.
Trial summary
Tetrahydrobiopterin (BH4) is a cofactor for the nitric oxide (NO) synthase enzymes, such that its insufficiency results in uncoupling of the enzyme, leading to release of superoxide rather than NO in disease states, including hypertension. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Hypertension
- What is being tested?
- Tetrahydrobiopterin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 1 siteUnited States
- Study dates
- Dec 2004to Dec 2005
- Phase
- Early Phase 1
- Are there results?
- None posted in the registry
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
- Male or female patients without childbearing potential between the ages of 18 and 75 years
- History of documented essential hypertension or newly diagnosed hypertension (BP >140 mmHg systolic and/or 90 mmHg diastolic measured on 2 separate occasions)
- Patients on conventional anti-hypertensive therapy with poorly controlled hypertension (BP >135/85 mmHg). Their anti-hypertensive regimen will remain unchanged throughout the study period. Patients will not need to stop taking their prescribed anti-hypertensives.
- Controls will be recruited for part 2 of the study. These will be patients who meet the age and childbearing criteria above, who have no history of hypertension, arterial BP of <130 systolic and <85 diastolic, no evidence of diabetes mellitus, total cholesterol <240 and be non-smoking for at least six months.
- Patients can be at any stage of hypertension. They can be at any performance status. The only requirement will be that they be able to come to scheduled follow up visits either by themselves or with assistance. Patients will need to be able to give informed consent.
Who cannot join
- Female subjects with childbearing potential.
- History of symptomatic coronary or peripheral vascular disease.
- Known secondary causes for hypertension
- Severe uncontrolled hypertension (BP >180 mmHg systolic and /or 110 mmHg diastolic).
- Severe co-morbid conditions which would limit life expectancy to less than 6 months.
- Patients unable to give informed consent or adhere to the protocol.
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- Patients participating in another study protocol.
- Patients with organ failure, creatinine >2.5 mg/dL or hepatic enzymes >2X normal
- Recent (within 6 weeks) alteration of any concomitant therapy.
- Presence of intercurrent illness
- Bleeding disorders
Trial locations and contacts
1 site in 1 country.
About this study
Tetrahydrobiopterin (BH4) is a cofactor for the nitric oxide (NO) synthase enzymes, such that its insufficiency results in uncoupling of the enzyme, leading to release of superoxide rather than NO in disease states, including hypertension. We hypothesized that oral BH4 will reduce arterial blood pressure (BP) and improve endothelial function in hypertensive subjects. Oral BH4 was given to subjects with poorly controlled hypertension (BP >135/85 mm Hg) and weekly measurements of BP and endothelial function made. In Study 1, 5 or 10 mg kg-1 day-1 of BH4 (n=8) was administered orally for 8 weeks, and in Study 2, 200 and 400 mg of BH4 (n=16) was given in divided doses for 4 weeks
Read the detailed description
Problem of Interest:
Blood vessels are lined by a single layer of cells called the endothelium. These cells actively release substances that influence a variety of functions including blood flow in the arteries. Nitric oxide (NO) is among the most important of these substances. Decrease in NO reduces blood vessel size and increases blood pressure (BP). Subjects with hypertension (high blood pressure) and those with a strong family history of hypertension but without high blood pressure also exhibit endothelial dysfunction and decreased NO activity. This abnormality predisposes individuals with high blood pressure to an increased long term risk of adverse cardiovascular events such as heart attack and stroke.
NO is produced in cells by a reaction mediated by the enzyme endothelial nitric oxide synthase (eNOS). Experimental studies performed at Emory University have shown that tetrahydrobiopterin (BH4), a naturally produced substance, is an essential factor for eNOS to be normally active, because in the event of BH4 deficiency, eNOS switches from producing NO to generating oxygen free radicals that increase oxidant stress in blood vessels leading to vascular damage. Moreover, studies have shown that administration of BH4 to animals with hypertension decreases blood pressure.
A recently completed study performed by the researchers at Emory University showed that BH4 pills given twice a day to 8 patients with poorly controlled high blood pressure for eight weeks improved endothelial function and decreased blood pressure without any significant side effects. After stopping BH4, the blood pressure and endothelial function returned to baseline.
Hypertension has also been linked with diastolic heart failure, a condition where the squeeze of the heart is normal but it relaxes abnormally causing shortness of breath, edema and fatigue. Up to one half of cases of heart failure are caused by diastolic heart failure. Recent evidence shows that the lining cells of the heart also produce NO and that this promotes relaxation of the heart. In addition, studies here at Emory have shown that in animals with high blood pressure, NO production in the heart is reduced compared to normals.
How problem will be studied:
The study will consist of three parts:
We, the researchers at Emory University, will recruit patients with hypertension and randomize them to various doses of BH4 to find out what the lowest dose is that produces a significant response This dose will then be used in patients with hypertension who will be randomized to BH4 or a placebo. Patients will be followed for blood pressure response and for markers of endothelial function using ultrasound and for markers of inflammation using blood samples.
Patients from part 2 with evidence of abnormal heart relaxation on echocardiogram will have repeat echocardiograms after drug administration to study the effects of BH4 on heart relaxation.
Advancement in Scientific Knowledge
This study will advance scientific knowledge by looking at the effects of BH4, a naturally occurring substance without known major side effects, on blood pressure. We will also examine the effect of BH4 on NO and relaxation of the heart muscle. Improvement in blood pressure with BH4 will allow this to be an option for treatment of high blood pressure and potentially reducing the complications associated with this condition.
Standard of care:
Currently the standard of care for patients with high blood pressure includes treatment with Food and Drug Administration (FDA) approved medications such as beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, diuretics and calcium-channel blockers to a goal BP of less than 135/85.
- Conditions
- Hypertension
- Being tested
- Tetrahydrobiopterin
- Keywords
- Oxidative Stress, Endothelium
- Medical subject headings
- Hypertension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TetrahydrobiopterinDrug
TetrahydrobiopterinDrug
| Study group | Role | What they receive |
|---|---|---|
| Dose-response of oral BH4 | Experimental | Eight subjects received 100 mg of oral BH4 twice a day and 8 received 200 mg twice daily. Receives: Drug: Tetrahydrobiopterin |
| Onset & duration of action of oral BH4 | Experimental | Eight hypertensive subjects were assigned to either 5 mg kg-1 day-1 (n=4) or 10 mg kg-1 day-1 (n=4) of BH4, given in two divided doses orally for 8 weeks. Receives: Drug: Tetrahydrobiopterin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Evaluate the effects of BH4 on BP
Secondary outcomes (1)
Evaluate the effects of BH4 on vascular function
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Sep 2005 (estimated)
- Study startDec 2004
- Primary completionDec 2005
- Study completionDec 2005
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for HypertensionStudies of the same condition, open and under way.
- More trials run by Emory UniversityThe 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
- Early Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 24 participants (actual)
Sponsor and investigators
- Lead sponsor
- Emory University
- Sponsor type
- University, hospital or other
- Collaborators
- American Heart Association
- Responsible party
- Principal investigator, Arshed A. Quyyumi, Emory University
- Investigators
- Arshed A Quyyumi, MD, Principal investigator, Emory University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00208780
- Sponsor's protocol ID
- 0476-2004
- Status last verified
- Nov 2013
- First submitted
- 13 Sep 2005
- Last updated
- 18 Nov 2013
- Results posted
- No
- Data monitoring committee
- No
Publications
Porkert M, Sher S, Reddy U, Cheema F, Niessner C, Kolm P, Jones DP, Hooper C, Taylor WR, Harrison D, Quyyumi AA. Tetrahydrobiopterin: a novel antihypertensive therapy. J Hum Hypertens. 2008 Jun;22(6):401-7. doi: 10.1038/sj.jhh.1002329. Epub 2008 Mar 6.
PubMed 18322548
Study at a glance
From the registry record, last updated by the sponsor on 18 Nov 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effects of Tetrahydrobiopterin on Blood Pressure
- ClinicalTrials.gov ID
- NCT00208780
- Acronym / sponsor ID
- 0476-2004
- Conditions
- Hypertension
- Keywords
- Oxidative Stress, Endothelium
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 24 participants (actual)
- Lead sponsor
- Emory UniversityUniversity, hospital or other
- Collaborators
- American Heart Association
- Study start
- Dec 2004
- Primary completion
- Dec 2005 (actual)
- Study completion
- Dec 2005 (actual)
- First posted
- 21 Sep 2005 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Tetrahydrobiopterin (BH4) is a cofactor for the nitric oxide (NO) synthase enzymes, such that its insufficiency results in uncoupling of the enzyme, leading to release of superoxide rather than NO in disease states, including hypertension. We hypothesized that oral BH4 will reduce arterial blood pressure (BP) and improve endothelial function in hypertensive subjects. Oral BH4 was given to subjects with poorly controlled hypertension (BP >135/85 mm Hg) and weekly measurements of BP and endothelial function made. In Study 1, 5 or 10 mg kg-1 day-1 of BH4 (n=8) was administered orally for 8 weeks, and in Study 2, 200 and 400 mg of BH4 (n=16) was given in divided doses for 4 weeks
Detailed description
Problem of Interest:
Blood vessels are lined by a single layer of cells called the endothelium. These cells actively release substances that influence a variety of functions including blood flow in the arteries. Nitric oxide (NO) is among the most important of these substances. Decrease in NO reduces blood vessel size and increases blood pressure (BP). Subjects with hypertension (high blood pressure) and those with a strong family history of hypertension but without high blood pressure also exhibit endothelial dysfunction and decreased NO activity. This abnormality predisposes individuals with high blood pressure to an increased long term risk of adverse cardiovascular events such as heart attack and stroke.
NO is produced in cells by a reaction mediated by the enzyme endothelial nitric oxide synthase (eNOS). Experimental studies performed at Emory University have shown that tetrahydrobiopterin (BH4), a naturally produced substance, is an essential factor for eNOS to be normally active, because in the event of BH4 deficiency, eNOS switches from producing NO to generating oxygen free radicals that increase oxidant stress in blood vessels leading to vascular damage. Moreover, studies have shown that administration of BH4 to animals with hypertension decreases blood pressure.
A recently completed study performed by the researchers at Emory University showed that BH4 pills given twice a day to 8 patients with poorly controlled high blood pressure for eight weeks improved endothelial function and decreased blood pressure without any significant side effects. After stopping BH4, the blood pressure and endothelial function returned to baseline.
Hypertension has also been linked with diastolic heart failure, a condition where the squeeze of the heart is normal but it relaxes abnormally causing shortness of breath, edema and fatigue. Up to one half of cases of heart failure are caused by diastolic heart failure. Recent evidence shows that the lining cells of the heart also produce NO and that this promotes relaxation of the heart. In addition, studies here at Emory have shown that in animals with high blood pressure, NO production in the heart is reduced compared to normals.
How problem will be studied:
The study will consist of three parts:
We, the researchers at Emory University, will recruit patients with hypertension and randomize them to various doses of BH4 to find out what the lowest dose is that produces a significant response This dose will then be used in patients with hypertension who will be randomized to BH4 or a placebo. Patients will be followed for blood pressure response and for markers of endothelial function using ultrasound and for markers of inflammation using blood samples.
Patients from part 2 with evidence of abnormal heart relaxation on echocardiogram will have repeat echocardiograms after drug administration to study the effects of BH4 on heart relaxation.
Advancement in Scientific Knowledge
This study will advance scientific knowledge by looking at the effects of BH4, a naturally occurring substance without known major side effects, on blood pressure. We will also examine the effect of BH4 on NO and relaxation of the heart muscle. Improvement in blood pressure with BH4 will allow this to be an option for treatment of high blood pressure and potentially reducing the complications associated with this condition.
Standard of care:
Currently the standard of care for patients with high blood pressure includes treatment with Food and Drug Administration (FDA) approved medications such as beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, diuretics and calcium-channel blockers to a goal BP of less than 135/85.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Dose-response of oral BH4 | Experimental | Drug: TetrahydrobiopterinEight subjects received 100 mg of oral BH4 twice a day and 8 received 200 mg twice daily. |
| Onset & duration of action of oral BH4 | Experimental | Drug: TetrahydrobiopterinEight hypertensive subjects were assigned to either 5 mg kg-1 day-1 (n=4) or 10 mg kg-1 day-1 (n=4) of BH4, given in two divided doses orally for 8 weeks. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Male or female patients without childbearing potential between the ages of 18 and 75 years
- History of documented essential hypertension or newly diagnosed hypertension (BP >140 mmHg systolic and/or 90 mmHg diastolic measured on 2 separate occasions)
- Patients on conventional anti-hypertensive therapy with poorly controlled hypertension (BP >135/85 mmHg). Their anti-hypertensive regimen will remain unchanged throughout the study period. Patients will not need to stop taking their prescribed anti-hypertensives.
- Controls will be recruited for part 2 of the study. These will be patients who meet the age and childbearing criteria above, who have no history of hypertension, arterial BP of <130 systolic and <85 diastolic, no evidence of diabetes mellitus, total cholesterol <240 and be non-smoking for at least six months.
- Patients can be at any stage of hypertension. They can be at any performance status. The only requirement will be that they be able to come to scheduled follow up visits either by themselves or with assistance. Patients will need to be able to give informed consent.
Key exclusion criteria (11 listed)
- Female subjects with childbearing potential.
- History of symptomatic coronary or peripheral vascular disease.
- Known secondary causes for hypertension
- Severe uncontrolled hypertension (BP >180 mmHg systolic and /or 110 mmHg diastolic).
- Severe co-morbid conditions which would limit life expectancy to less than 6 months.
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 |
|---|---|---|
| Tetrahydrobiopterin | Drug | Onset & duration of action of oral BH4 |
| Tetrahydrobiopterin | Drug | Dose-response of oral BH4 |
Primary outcome
Evaluate the effects of BH4 on BP
1 secondary outcome
Evaluate the effects of BH4 on vascular function
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Nov 2013.
- Results publication: PubMed 18322548Porkert M, Sher S, Reddy U, Cheema F, Niessner C, Kolm P, Jones DP, Hooper C, Taylor WR, Harrison D, Quyyumi AA. Tetrahydrobiopterin: a novel antihypertensive therapy. J Hum Hypertens. 2008 Jun;22(6):401-7. doi: 10.1038/sj.jhh.1002329. Epub 2008 Mar 6.
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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.
Arshed A Quyyumi, MD principal investigator
Emory University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing Tetrahydrobiopterin in people with Hypertension, run by Emory University 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 5 inclusion and 11 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 Nov 2013. 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?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Evaluate the effects of BH4 on BP. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00208780, which also lists 1 linked publication.
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 Nov 2013.