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A Phase 2 Study of the Effects of 6R-BH4 on Symptomatic Peripheral Arterial Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00403494
Recruitment Status : Completed
First Posted : November 23, 2006
Last Update Posted : February 13, 2020
Sponsor:
Information provided by (Responsible Party):
BioMarin Pharmaceutical

Tracking Information
First Submitted Date  ICMJE November 21, 2006
First Posted Date  ICMJE November 23, 2006
Last Update Posted Date February 13, 2020
Study Start Date  ICMJE December 2006
Actual Primary Completion Date November 2008   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 24, 2008)
To compare oral 6R-BH4 to placebo with respect to change from Baseline to Week 24 in peak walking time (PWT) [ Time Frame: Baseline, Week 24 ]
Original Primary Outcome Measures  ICMJE
 (submitted: November 21, 2006)
To compare oral 6R-BH4 to placebo with respect to change from Baseline to Week 24 in peak walking time (PWT)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 24, 2008)
  • To compare oral 6R-BH4 to placebo with respect to change from Baseline to Week 24 in claudication onset time (COT) [ Time Frame: Baseline, Week 24 ]
  • Tertiary Outcome: To compare oral 6R-BH4 to placebo with respect to change from Baseline to Weeks 12 and 24 in functional status as measured by the Walking Impairment Questionnaire (WIQ) and Medical Outcomes Scale Short Form (MOS SF-36) [ Time Frame: Baseline, Week 12, Week 24 ]
  • Tertiary Outcome: To compare oral 6R-BH4 to placebo with respect to change from Baseline to Weeks 12 and 24 in mean systolic blood pressure (BP) (seated, rested) and mean diastolic BP (seated, rested) [ Time Frame: Baseline, Week 12, Week 24 ]
  • Tertiary Outcome: To compare oral 6R-BH4 to placebo with respect to change from Baseline to Weeks 12 and 24 in ankle-brachial index (ABI) or toe-brachial index (TBI) [ Time Frame: Baseline, Week 12, Week 24 ]
  • Tertiary Outcome: To compare oral 6R-BH4 to placebo with respect to change from Baseline to Weeks 12 & 24 in International Index of Erectile Function (IIEF; short form) or the Female Sexual Function Index (FSFI),if available in subject's primary language [ Time Frame: Baseline, Week 12, Week 24 ]
  • Tertiary Outcome: To compare oral 6R-BH4 to placebo with respect to change from Baseline to Weeks 12 and 24 in insulin sensitivity [ Time Frame: Baseline, Week 12, Week 24 ]
  • Tertiary Outcome: To compare oral 6R-BH4 to placebo with respect to change from Baseline to Weeks 12 and 24 in biomarkers of eNOS activity and oxidative stress as measured by cGMP and 8-isoprostane, respectively [ Time Frame: Baseline, Week 12, Week 24 ]
  • Tertiary Outcome: To compare oral 6R-BH4 to placebo with respect to change from Baseline to Weeks 12 and 24 in endothelial function as measured by peripheral arterial tonometry (PAT) [ Time Frame: Baseline, Week 12, Week 24 ]
  • Safety Objective: To assess the safety of oral dosing of 6R-BH4 [ Time Frame: Baseline, Week 0, 1, 2, 4, 8, 12, 16, 20, 24, 25 ]
  • Tertiary Outcome: To compare oral 6R-BH4 to placebo with respect to change from Baseline to Week 12 in PWT and COT [ Time Frame: Baseline, Week 12 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: November 21, 2006)
  • To compare oral 6R-BH4 to placebo with respect to change from Baseline to Week 24 in claudication onset time (COT)
  • Tertiary Outcome: To compare oral 6R-BH4 to placebo with respect to change from Baseline to Week 12 in PWT and COT
  • To compare oral 6R-BH4 to placebo with respect to change from Baseline to Weeks 12 and 24 in functional status as measured by the Walking Impairment Questionnaire (WIQ) and Medical Outcomes Scale Short Form (MOS SF-36)
  • To compare oral 6R-BH4 to placebo with respect to change from Baseline to Weeks 12 and 24 in mean systolic and diastolic blood pressure (BP) (seated, rested)
  • To compare oral 6R-BH4 to placebo with respect to change from Baseline to Weeks 12 and 24 in ankle-brachial index (ABI) or toe-brachial index (TBI)
  • To compare oral 6R-BH4 to placebo with respect to change from Baseline to Week 12 and 24 in International Index of Erectile Function (IIEF; short form) or the Female Sexual Function Index (FSFI)
  • To compare oral 6R-BH4 to placebo with respect to change from Baseline to Weeks 12 and 24 in insulin sensitivity
  • Safety Outcome: To assess the safety of oral dosing of 6R-BH4 in subjects with IC caused by PAD
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase 2 Study of the Effects of 6R-BH4 on Symptomatic Peripheral Arterial Disease
Official Title  ICMJE A Phase 2, Multicenter, Multinational, Randomized, Double-blind, Placebo-controlled, Parallel Study of the Effects of 6R-BH4 on Symptomatic Peripheral Arterial Disease
Brief Summary The purpose of this study is to evaluate whether 6R-BH4 (sapropterin dihydrochloride) is safe and effective in the treatment of intermittent claudication (IC) caused by peripheral arterial disease (PAD).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Intermittent Claudication
Intervention  ICMJE
  • Drug: Placebo for 6R-BH4 (sapropterin dihydrochloride)
    Placebo to be administered in the same manner as that of the investigational product for 24 weeks
  • Drug: 6R-BH4 (sapropterin dihydrochloride)
    800 mg/day 6R-BH4 tablets, divided into two doses, administered orally for 24 weeks
  • Drug: 6R-BH4 (sapropterin dihydrochloride)
    800 mg/day of 6R-BH4 tablets, divided into two doses, administered orally, plus 1000mg/day Vitamin C caplets, divided into two doses, administered orally for 24 weeks
  • Drug: Placebo for 6R-BH4 (sapropterin dihydrochloride)
    Placebo to be administered in the same manner as that of the investigational product, plus 1000mg/day Vitamin C, divided into two doses, for 24 weeks
Study Arms  ICMJE
  • Experimental: 6R-BH4
    800 mg/day of 6R-BH4, divided into two doses each day, for 24 weeks
    Intervention: Drug: 6R-BH4 (sapropterin dihydrochloride)
  • Placebo Comparator: Placebo
    Placebo to be administered in the same manner as that of the investigational product, 6R-BH4
    Intervention: Drug: Placebo for 6R-BH4 (sapropterin dihydrochloride)
  • Experimental: 6R-BH4 + Vitamin C
    800 mg/day of 6R-BH4, divided into two doses, plus 1000mg/day Vitamin C, divided into two doses, for 24 weeks
    Intervention: Drug: 6R-BH4 (sapropterin dihydrochloride)
  • Placebo Comparator: Placebo + Vitamin C
    Placebo to be administered in the same manner as that of the investigational product, plus 1000mg/day Vitamin C, divided into two doses
    Intervention: Drug: Placebo for 6R-BH4 (sapropterin dihydrochloride)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 22, 2009)
190
Original Enrollment  ICMJE
 (submitted: November 21, 2006)
210
Actual Study Completion Date  ICMJE January 2009
Actual Primary Completion Date November 2008   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • At least 40 years and no more than 80 years old
  • A 6-month (or longer) history of walking limitation because of IC, severity of which has not changed in the past 3 months
  • Diagnosis of PAD secondary to atherosclerosis, with PAD documented at Screening by one of the following criteria:

    1. Resting ABI < 0.9 in at least one leg
    2. If resting ABI is 0.9-1.0, minimum post-exercise drop in ABI of at least 25% in at least one leg
    3. If resting ABI is > 1.3 (indicating non-compressible vessels), vascular etiology documented by toe-brachial index (TBI) < 0.7 in at least one leg
  • On Gardner graded treadmill protocol, PWT of at least 1 minute, but no more than 12 minutes
  • Variation in PWT between two consecutive screening treadmill tests less than or equal to 25%
  • If currently receiving treatment with or taking any of the following, willing and able to discontinue for 30 days before Screening and throughout the entire study (including the follow-up period): phosphodiesterase (PDE) 5 inhibitor (eg, Viagra®, Cialis®, Levitra®, or Revatio™), any PDE 3 inhibitor (eg, cilostazol, milrinone, or vesnarinone), pentoxifylline (Trental®), nitrates, L-arginine, ginkgo biloba, or HeartBar
  • For the approximately 50% of subjects enrolled to receive vitamin C with study drug or placebo, subjects must be willing to discontinue taking vitamin C supplements or a multivitamin containing vitamin C during study.
  • Antihypertensive therapy, cholesterol-lowering therapy (eg, statins), and diabetic therapy (if applicable) has been stable for 30 days prior to Screening.
  • Has not changed smoking or exercise habits in 30 days prior to randomization and is unlikely to do so during the study period
  • 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
  • Willing and able to comply with all study-related procedures
  • 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

Exclusion Criteria:

  • Critical leg ischemia, manifested by pain at rest, ulceration, gangrene, or leg amputation
  • Surgical intervention to alleviate symptoms of claudication (eg, vascular reconstruction, sympathectomy) within 6 months or any endovascular interventions or cardiovascular surgery within 3 months
  • Walking limited by reasons other than claudication (eg, arthritis, lung disease, exercise-limiting cardiac disease, or skin or foot lesions that limit walking)
  • Clinically significant ECG change during or after exercise treadmill test at Screening or Baseline visit(s)
  • Myocardial infarction, deep vein thrombosis, or cerebrovascular infarct within 3 months of Screening
  • Body mass index > 40 (gross obesity)
  • Hypertension at Screening, defined as seated mean resting BP value of > 160 mmHg systolic, > 110 mmHg diastolic, or both
  • Hypotension at Screening, defined as seated mean resting BP values of < 100 mmHg systolic or < 55 mmHg diastolic, or as clinically significant symptomatic (orthostatic) hypotension
  • Non-atherosclerotic vascular disease (eg, Buerger's disease or popliteal entrapment syndrome)
  • Previous treatment with any formulation of BH4
  • Known allergy or hypersensitivity to any excipient of 6R-BH4
  • Concurrent disease or condition that would interfere with study participation or safety such as bleeding disorders, history of severe gastrointestinal reflux disease, arrhythmia, organ transplant, organ failure, current neoplasm, type 1 diabetes mellitus, or serious neurological disorders (including seizures)
  • Previous treatment with gene therapy or other vascular endothelial growth factor (VEGF)-related treatment
  • Any severe co-morbid condition that would limit life expectancy to less than 6 months
  • Serum creatinine > 2.0 mg/dL or hepatic enzyme levels more than 2 times the upper limit of normal
  • Concomitant treatment with levodopa
  • Requirement for concomitant treatment with any drug known to inhibit folate metabolism (eg, methotrexate)
  • Use of any investigational product or device within 30 days prior to Screening, or requirement for any investigational agent prior to completion of all scheduled study assessments
  • Pregnant or breastfeeding at Screening or planning to become pregnant (subject or partner) at any time during the study
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00403494
Other Study ID Numbers  ICMJE PAD-001
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party BioMarin Pharmaceutical
Study Sponsor  ICMJE BioMarin Pharmaceutical
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Don Nwose, MD BioMarin Pharmaceutical
PRS Account BioMarin Pharmaceutical
Verification Date September 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP