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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
BioMarin Pharmaceutical
ClinicalTrials.gov Identifier:
NCT00403494
First received: November 21, 2006
Last updated: September 4, 2014
Last verified: September 2014
  Purpose

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).


Condition Intervention Phase
Intermittent Claudication
Drug: Placebo for 6R-BH4 (sapropterin dihydrochloride)
Drug: 6R-BH4 (sapropterin dihydrochloride)
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 2, Multicenter, Multinational, Randomized, Double-blind, Placebo-controlled, Parallel Study of the Effects of 6R-BH4 on Symptomatic Peripheral Arterial Disease

Resource links provided by NLM:


Further study details as provided by BioMarin Pharmaceutical:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: No ]

Enrollment: 190
Study Start Date: December 2006
Study Completion Date: January 2009
Primary Completion Date: November 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 6R-BH4
800 mg/day of 6R-BH4, divided into two doses each day, for 24 weeks
Drug: 6R-BH4 (sapropterin dihydrochloride)
800 mg/day 6R-BH4 tablets, divided into two doses, administered orally for 24 weeks
Placebo Comparator: Placebo
Placebo to be administered in the same manner as that of the investigational product, 6R-BH4
Drug: Placebo for 6R-BH4 (sapropterin dihydrochloride)
Placebo to be administered in the same manner as that of the investigational product for 24 weeks
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
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
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
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

  Eligibility

Ages Eligible for Study:   40 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00403494

Locations
United States, Arizona
Scottsdale, Arizona, United States
United States, California
Sacramento, California, United States
San Diego, California, United States
Santa Ana, California, United States
Santa Rosa, California, United States
United States, Florida
Clearwater, Florida, United States
Jacksonville, Florida, United States
United States, Georgia
Conyers, Georgia, United States
United States, Indiana
Indianapolis, Indiana, United States
United States, Maine
Auburn, Maine, United States
United States, North Carolina
Charlotte, North Carolina, United States
United States, Oregon
Portland, Oregon, United States
United States, Tennessee
Knoxville, Tennessee, United States
United States, Texas
Dallas, Texas, United States
San Antonio, Texas, United States
United States, Virginia
Norfolk, Virginia, United States
Richmond, Virginia, United States
Argentina
Buenos Aires, Argentina
Corrientes, Argentina
Santa Fe, Argentina
Sponsors and Collaborators
BioMarin Pharmaceutical
Investigators
Study Director: Don Nwose, MD BioMarin Pharmaceutical
  More Information

Additional Information:
No publications provided

Responsible Party: BioMarin Pharmaceutical
ClinicalTrials.gov Identifier: NCT00403494     History of Changes
Other Study ID Numbers: PAD-001
Study First Received: November 21, 2006
Last Updated: September 4, 2014
Health Authority: United States: Food and Drug Administration
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica

Keywords provided by BioMarin Pharmaceutical:
Intermittent Claudication
IC
Symptomatic Peripheral Arterial Disease
Peripheral Arterial Disease
PAD
6R-BH4
BH4
sapropterin dihydrochloride
endothelial dysfunction
Nitric Oxide
NO

Additional relevant MeSH terms:
Intermittent Claudication
Peripheral Arterial Disease
Peripheral Vascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Cardiovascular Diseases
Signs and Symptoms
Atherosclerosis
Ascorbic Acid
Vitamins
Verapamil
Antioxidants
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protective Agents
Physiological Effects of Drugs
Micronutrients
Growth Substances
Anti-Arrhythmia Agents
Cardiovascular Agents
Therapeutic Uses
Calcium Channel Blockers
Membrane Transport Modulators
Vasodilator Agents

ClinicalTrials.gov processed this record on September 14, 2014