Endothelial DysfunctionPhase 2NCT00532844
A Phase 2, Pharmacokinetic (PK) Study of 6R-BH4 Alone or 6R-BH4 With Vitamin C in Subjects With Endothelial Dysfunction
A Phase 2 study testing Sapropterin Dihydrochloride and Sapropterin Dihydrochloride and Vitamin C in people with Endothelial Dysfunction, run by BioMarin Pharmaceutical at 1 site in United States.
Trial summary
This Phase 2, randomized, open-label, 2-treatment, 2-sequence, 2-period crossover, pharmacokinetic (PK) study will compare plasma concentrations of BH4 in subjects with endothelial dysfunction following 14 days of treatment by each of 2 regimens: sapropterin dihydrochloride with vitamin C and sapropterin… Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Endothelial Dysfunction
- What is being tested?
- Sapropterin Dihydrochloride and Sapropterin Dihydrochloride and Vitamin C
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 52 participants
- Where
- 1 siteUnited States
- Study dates
- Sep 2007to Mar 2009
- 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
- Willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to any research-related procedures.
- Age is ≥ 18 years and ≤ 75 years.
- Willing and able to comply with all study procedures.
- If currently receiving treatment with or taking any of the following supplements, be willing and able to discontinue taking them throughout the treatment period:
- Vit C supplements
- Multivitamins containing vit C
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- Any other dietary supplements, nutraceuticals, or other over- the-counter products containing vit C
- Vitamin E-containing supplements
- History of cardiovascular disease or cardiovascular risk factors, eg, stable and well-controlled Type 2 diabetes, peripheral arterial disease, obesity, smoking, hypercholesterolemia
- Endothelial dysfunction, documented at screening by an abnormal peripheral arterial tonometry (PAT) of ≤ 1.70.
- Sexually active subjects must be willing to use an acceptable method of contraception while participating in the study.
- Females of childbearing potential must have a negative pregnancy test at Screening and be willing to have additional pregnancy tests during the study. 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
- Hypertension secondary to other medical conditions (e.g., renal failure or steroid usage).
- 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); heart failure; symptomatic coronary disease; arrhythmia; serious neurologic disorders, including seizures; organ transplant; or organ failure.
- Type 2 diabetics that are uncontrolled, unstable, newly diagnosed, or have changed therapy in the last three months and all Type 1 diabetics.
- Any severe comorbid condition that would limit life expectancy to < 6 months.
- Serum creatinine > 2.0 mg/dL, or hepatic enzyme concentrations > 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.
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- Concomitant treatment with:
- Drugs known to inhibit folate metabolism (e.g., methotrexate)
- Levodopa
- A phosphodiesterase (PDE) 5 inhibitor (e.g., Viagra®, Cialis®, Levitra®, or Revatio®)
- A PDE 3 inhibitor (e.g., cilostazol, milrinone, or vesnarinone)
- Use of any investigational product or investigational medical device within 30 days prior to screening, or requirement for any investigational agent prior to completion of all scheduled study assessments.
- Myocardial infarction, stroke, or surgery within the last 60 days prior to screening.
- History of alcohol and/or drug abuse or a positive alcohol or drug test at screening.
- Previous treatment with any formulation of BH4.
- Has known hypersensitivity to 6R-BH4 or its excipients.
- Pregnant or breastfeeding at screening, or planning to become pregnant (self or partner) at any time during the study.
- Any condition that, in the view of the 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: A Phase 2 Randomized Open-label 2-Treatment 2-Sequence 2-Period Crossover PK Study to Compare Plasma Concentrations of BH4 in Subjects With Endothelial Dysfunction Following 14 Days of Treatment by 2 Regimens: 6R-BH4 With Vitamin C and 6R-BH4 Alone
This Phase 2, randomized, open-label, 2-treatment, 2-sequence, 2-period crossover, pharmacokinetic (PK) study will compare plasma concentrations of BH4 in subjects with endothelial dysfunction following 14 days of treatment by each of 2 regimens: sapropterin dihydrochloride with vitamin C and sapropterin dihydrochloride alone.
Read the detailed description
This was a Phase 2, randomized, open-label, 2-treatment, 2-sequence, 2-period crossover, pharmacokinetic (PK) study designed to compare the plasma concentrations of BH4 in subjects with endothelial dysfunction following 14 days of treatment by each of 2 regimens: sapropterin dihydrochloride with vitamin C and sapropterin dihydrochloride alone. Each subject received each regimen; the 2 treatment groups varied only in the sequence of the 2 regimens. The washout period between treatment regimens comprised the 1 day period between the last dose of study drug under the first regimen and the first dose of study drug under the second regimen (Day 14 morning to Day 15 morning).
- Conditions
- Endothelial Dysfunction
- Being tested
- Sapropterin Dihydrochloride, Sapropterin Dihydrochloride and Vitamin C
- Keywords
- 6R-BH4, BH4, BH4 deficiency, sapropterin dihydrochloride, endothelial dysfunction, NO, Hypertension, Nitric Oxide, Vitamin C
- Medical subject headings
- Phenylketonurias, Hypertension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Sapropterin DihydrochlorideDrug
Also called 6R-BH4
Sapropterin Dihydrochloride 5 mg/kg twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 and Day 28.
Sapropterin Dihydrochloride and Vitamin CDrug
Also called 6R-BH4 and Vitamin C
Sapropterin Dihydrochloride 5 mg/kg and 500 mg Vitamin C twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 and Day 28.
| Study group | Role | What they receive |
|---|---|---|
| Sapropterin dihydrochloride | Experimental | Sapropterin dihydrochloride 5 mg/kg twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 and Day 28. Receives: Drug: Sapropterin Dihydrochloride |
| Sapropterin dihydrochloride+Vitamin C | Experimental | Sapropterin dihydrochloride 5 mg/kg and 500 mg Vitamin C twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 and Day 28. Receives: Drug: Sapropterin Dihydrochloride and Vitamin C |
What is being measured
The primary outcome is the main question the study is designed to answer.
Area Under the Curve (AUC0-12hrs) of Plasma BH4 Concentration
Plasma BH4 concentration area under the curve (AUC0-12 hrs) at the end of each regimen in subjects with endothelial dysfunction.
Measured: At 30 minutes prior to dosing, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, and 12.0 hours after dosing.
Secondary outcomes (11)
Area Under the Curve (AUC0-12hrs) of Plasma BH2 and B Concentration
Plasma BH2 and B concentration area under the curve (AUC0-12hrs) at the end of each regimen in subjects with endothelial dysfunction.
Measured: At 30 minutes prior to dosing, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, and 12.0 hours after dosing.
Area Under the Curve (AUC0-12hours) for Calculated BH4 (From Total Biopterin)
Total biopterin concentration area under the curve (AUC0-12hours) at the end of each regimen in subjects with endothelial dysfunction is theoretically the sum of BH4, BH2 and B. Biopterin is the metabolite of BH4 after oxidative conversion of BH4 and BH2 to biopterin. Total biopterin concentrations represent the summation of drug and metabolites: BH4, BH2 and B. The total biopterin concentrations can be converted to BH4 concentration using the conversion factor 2.150.
Measured: At 30 minutes prior to dosing, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, and 12.0 hours after dosing.
Ratio of BH2, B and BH4 Calculated From Total Biopterin Area Under the Curve (0-12hours) for Subjects Administered Sapropterin Dihydrochloride With Vitamin C to Subjects Administered Sapropterin Alone.
Ratio of Mean AUC (0-12 hours) for subjects receiving (Sapropterin dihydrochloride + Vitamin C)/ Mean AUC (0-12 hours) for subjects receiving Sapropterin dihydrochloride alone) for BH4, BH2, B, BH4/BH2 Ratio, and BH4 Calculated from Total Biopterin.
Measured: At 30 minutes prior to dosing, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, and 12.0 hours after dosing.
Change From Baseline in Peripheral Arterial Tonometry (PAT)
PAT measures pulse wave amplitude of the small arteries of the finger as a surrogate to assess endothelial function and arterial stiffness using a finger plethysmographic probe and 5-minute occlusion of the brachial artery. Endothelial dysfunction, a protocol inclusion criteria, is defined by an abnormal PAT of < or = 1.70. Change is calculated as follows: end time measurement - starting time measurement.
Measured: At Baseline, Day 13 and Day 27
Change From Baseline in Systolic Blood Pressure (SBP)
Change is calculated as follows: end time measurement - starting time measurement.
Mean daytime systolic blood pressure measured by ambulatory blood pressure monitoring (ABPM)
Measured: At Baseline, Day 13 and Day 27
Change From Baseline in Diastolic Blood Pressure (DBP)
Change is calculated as follows: end time measurement - starting time measurement.
Mean daytime diastolic blood pressure measured by ambulatory blood pressure monitoring (ABPM)
Measured: At Baseline, Day 13 and Day 27
Number of Subjects With Treatment Emergent Adverse Events (TEAEs)
A treatment-emergent Adverse Events (TEAE) is any Adverse Events that newly appeared, increased in frequency or worsened in severity following initiation of study drug administration.
Measured: Up to 56 ± 3 Days.
Change From Baseline in Urinary 8-isoprostane/Creatinine
Biomarkers of endothelial function, oxidative stress, and inflammation as measured by 8-isoprostane.
Measured: At Baseline, Day 14 and Day 28
Change From Baseline in Cyclic Guanosine Monophosphate (cGMP)
Biomarkers of endothelial function, oxidative stress, and inflammation as measured by cyclic guanosine monophosphate (cGMP).
Measured: At Baseline, Day 14 and Day 28.
Change in Urinary Albumin to Creatinine Ratio (mg/g)
Change in Urinary Albumin to Creatinine Ratio (mg/g) from Baseline to Day 14, Baseline to Day 28, and from Day 14 to Day 28
Measured: Baseline, Day 14 and Day 28
Number of Participants With Urinary Albumin to Creatinine Ratio <30 mg/g
Summary of Urinary Albumin to Creatinine Ratio (mg/g) by subjects with ratio <30 mg/g and subjects with ratios >=30 mg/g at Baseline, Day 14 and Day 28
Measured: Baseline, Day 14 and Day 28
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Sep 2007 (estimated)
- Study startSep 2007
- Primary completionNov 2008
- Study completionMar 2009
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 Endothelial DysfunctionStudies of the same condition, open and under way.
- More trials run by BioMarin PharmaceuticalThe 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
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 52 participants (actual)
Sponsor and investigators
- Lead sponsor
- BioMarin Pharmaceutical
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Don Nwose, MD, Study director, BioMarin Pharmaceutical
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00532844
- Sponsor's protocol ID
- HTN-002
- Status last verified
- Apr 2021
- First submitted
- 18 Sep 2007
- Last updated
- 17 May 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 17 May 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 2 Randomized Open-label 2-Treatment 2-Sequence 2-Period Crossover PK Study to Compare Plasma Concentrations of BH4 in Subjects With Endothelial Dysfunction Following 14 Days of Treatment by 2 Regimens: 6R-BH4 With Vitamin C and 6R-BH4 Alone
- ClinicalTrials.gov ID
- NCT00532844
- Acronym / sponsor ID
- HTN-002
- Conditions
- Endothelial Dysfunction
- Keywords
- 6R-BH4, BH4, BH4 deficiency, sapropterin dihydrochloride, endothelial dysfunction, NO, Hypertension, Nitric Oxide
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 52 participants (actual)
- Lead sponsor
- BioMarin PharmaceuticalIndustry (pharma, biotech, devices)
- Study start
- Sep 2007
- Primary completion
- Nov 2008 (actual)
- Study completion
- Mar 2009 (actual)
- First posted
- 20 Sep 2007 (estimated)
- Results
- Posted 17 May 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This Phase 2, randomized, open-label, 2-treatment, 2-sequence, 2-period crossover, pharmacokinetic (PK) study will compare plasma concentrations of BH4 in subjects with endothelial dysfunction following 14 days of treatment by each of 2 regimens: sapropterin dihydrochloride with vitamin C and sapropterin dihydrochloride alone.
Detailed description
This was a Phase 2, randomized, open-label, 2-treatment, 2-sequence, 2-period crossover, pharmacokinetic (PK) study designed to compare the plasma concentrations of BH4 in subjects with endothelial dysfunction following 14 days of treatment by each of 2 regimens: sapropterin dihydrochloride with vitamin C and sapropterin dihydrochloride alone. Each subject received each regimen; the 2 treatment groups varied only in the sequence of the 2 regimens. The washout period between treatment regimens comprised the 1 day period between the last dose of study drug under the first regimen and the first dose of study drug under the second regimen (Day 14 morning to Day 15 morning).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Sapropterin dihydrochloride | Experimental | Drug: Sapropterin DihydrochlorideSapropterin dihydrochloride 5 mg/kg twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 and Day 28. |
| Sapropterin dihydrochloride+Vitamin C | Experimental | Drug: Sapropterin Dihydrochloride and Vitamin CSapropterin dihydrochloride 5 mg/kg and 500 mg Vitamin C twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 and Day 28. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- Willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to any research-related procedures.
- Age is ≥ 18 years and ≤ 75 years.
- Willing and able to comply with all study procedures.
- If currently receiving treatment with or taking any of the following supplements, be willing and able to discontinue taking them throughout the treatment period:
- History of cardiovascular disease or cardiovascular risk factors, eg, stable and well-controlled Type 2 diabetes, peripheral arterial disease, obesity, smoking, hypercholesterolemia
Key exclusion criteria (18 listed)
- Hypertension secondary to other medical conditions (e.g., renal failure or steroid usage).
- 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); heart failure; symptomatic coronary disease; arrhythmia; serious neurologic disorders, including seizures; organ transplant; or organ failure.
- Type 2 diabetics that are uncontrolled, unstable, newly diagnosed, or have changed therapy in the last three months and all Type 1 diabetics.
- Any severe comorbid condition that would limit life expectancy to < 6 months.
- Serum creatinine > 2.0 mg/dL, or hepatic enzyme concentrations > 2 times the upper limit of normal
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 |
|---|---|---|
| Sapropterin DihydrochlorideAlso: 6R-BH4Sapropterin Dihydrochloride 5 mg/kg twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 and Day 28. | Drug | Sapropterin dihydrochloride |
| Sapropterin Dihydrochloride and Vitamin CAlso: 6R-BH4 and Vitamin CSapropterin Dihydrochloride 5 mg/kg and 500 mg Vitamin C twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 and Day 28. | Drug | Sapropterin dihydrochloride+Vitamin C |
Primary outcome
Area Under the Curve (AUC0-12hrs) of Plasma BH4 Concentration
Time frame: At 30 minutes prior to dosing, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, and 12.0 hours after dosing.
Plasma BH4 concentration area under the curve (AUC0-12 hrs) at the end of each regimen in subjects with endothelial dysfunction.
11 secondary outcomes
Area Under the Curve (AUC0-12hrs) of Plasma BH2 and B Concentration
Time frame: At 30 minutes prior to dosing, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, and 12.0 hours after dosing.
Area Under the Curve (AUC0-12hours) for Calculated BH4 (From Total Biopterin)
Time frame: At 30 minutes prior to dosing, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, and 12.0 hours after dosing.
Ratio of BH2, B and BH4 Calculated From Total Biopterin Area Under the Curve (0-12hours) for Subjects Administered Sapropterin Dihydrochloride With Vitamin C to Subjects Administered Sapropterin Alone.
Time frame: At 30 minutes prior to dosing, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, and 12.0 hours after dosing.
Change From Baseline in Peripheral Arterial Tonometry (PAT)
Time frame: At Baseline, Day 13 and Day 27
Change From Baseline in Systolic Blood Pressure (SBP)
Time frame: At Baseline, Day 13 and Day 27
Change From Baseline in Diastolic Blood Pressure (DBP)
Time frame: At Baseline, Day 13 and Day 27
Number of Subjects With Treatment Emergent Adverse Events (TEAEs)
Time frame: Up to 56 ± 3 Days.
Change From Baseline in Urinary 8-isoprostane/Creatinine
Time frame: At Baseline, Day 14 and Day 28
Change From Baseline in Cyclic Guanosine Monophosphate (cGMP)
Time frame: At Baseline, Day 14 and Day 28.
Change in Urinary Albumin to Creatinine Ratio (mg/g)
Time frame: Baseline, Day 14 and Day 28
Number of Participants With Urinary Albumin to Creatinine Ratio <30 mg/g
Time frame: Baseline, Day 14 and Day 28
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 May 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- BioMarin Pharmaceutical Inc. websiteLink provided by the sponsor.
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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.
Don Nwose, MD study director
BioMarin Pharmaceutical
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 Sapropterin Dihydrochloride and Sapropterin Dihydrochloride and Vitamin C in people with Endothelial Dysfunction, run by BioMarin Pharmaceutical 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 12 inclusion and 18 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 17 May 2021. 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 17 May 2021). 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?
Area Under the Curve (AUC0-12hrs) of Plasma BH4 Concentration (time frame: At 30 minutes prior to dosing, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, and 12.0 hours after dosing.). 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 17 May 2021.