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A Phase 2 Study of the Effects of Sapropterin Dihydrochloride 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
Results First Posted : January 7, 2021
Last Update Posted : January 7, 2021
Sponsor:
Information provided by (Responsible Party):
BioMarin Pharmaceutical

Brief Summary:
The purpose of this study is to evaluate whether sapropterin dihydrochloride is safe and effective in the treatment of intermittent claudication (IC) caused by peripheral arterial disease (PAD).

Condition or disease Intervention/treatment Phase
Intermittent Claudication Other: Placebo Drug: Sapropterin Dihydrochloride Phase 2

Detailed Description:
This was a Phase 2, multicenter, multinational, prospective, randomized, double-blind, placebo-controlled, parallel study designed to assess the efficacy and safety of sapropterin dihydrochloride in subjects with intermittent claudication (IC) caused by peripheral arterial disease (PAD). Subjects who met initial screening criteria were monitored criteria and that dosages of permitted concomitant medications were stable.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 190 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 2, Multicenter, Multinational, Randomized, Double-blind, Placebo-controlled, Parallel Study of the Effects of Sapropterin Dihydrochloride on Symptomatic Peripheral Arterial Disease
Study Start Date : December 2006
Actual Primary Completion Date : November 2008
Actual Study Completion Date : January 2009

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Sapropterin dihydrochloride
Subjects receive 400 mg oral sapropterin dihydrochloride twice daily for 24 weeks.
Drug: Sapropterin Dihydrochloride
Subjects receive 400 mg oral sapropterin dihydrochloride twice daily for 24 weeks.

Placebo Comparator: Placebo
Subjects receive matching oral Placebo twice daily for 24 weeks.
Other: Placebo
Subjects receive matching oral Placebo twice daily for 24 weeks.




Primary Outcome Measures :
  1. Change in Peak Walking Time (PWT) From Baseline [ Time Frame: Baseline and up to Week 24 ]
    This is to assess the effect of oral sapropterin dihydrochloride versus placebo on peak walking time (PWT) in subjects with intermittent claudication (IC) caused by peripheral arterial disease (PAD).

  2. Number of Subjects With Adverse Events (AEs) [ Time Frame: Up to 24-weeks ]
    Adverse events were described and summarized with focus on treatment- emergent events (TEAEs). A TEAE was defined as any AE that presented , increased in frequency or worsened in severity following initiation of study drug administration. If the onset of an AE was missing then the AE was considered treatment emergent. Drug-related AEs are AEs classified by the investigator as possibly or probably related to study drug.


Secondary Outcome Measures :
  1. Change in Claudication Onset Time (COT) From Baseline [ Time Frame: Baseline and up to Week 24 ]
    Time, in minutes, when the subject first begins to experience claudication symptoms, regardless of whether this is manifested as muscle pain, ache, cramp, numbness or fatigue.


Other Outcome Measures:
  1. Change in Peak Walking Time From Baseline With and Without Vitamin C [ Time Frame: Baseline up to 24 weeks ]
    The first 50% of subjects enrolled in the study were randomized to receive sapropterin dihydrochloride at 400 mg BID or oral placebo BID alone (without vitamin C). When approximately 50% enrollment was met, 1000 mg/day vitamin C was added to the dose regimen of newly enrolled subjects in both sapropterin dihydrochloride and placebo treatment groups given orally in two divided doses of 500 mg with study drug.



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Ages Eligible for Study:   40 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
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 ankle-brachial index (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, peak walking time (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 Heart Bar
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00403494


Locations
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United States, Arizona
Scottsdale, Arizona, United States, 85054
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
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Study Director: Don Nwose, MD BioMarin Pharmaceutical
Additional Information:
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Responsible Party: BioMarin Pharmaceutical
ClinicalTrials.gov Identifier: NCT00403494    
Other Study ID Numbers: PAD-001
First Posted: November 23, 2006    Key Record Dates
Results First Posted: January 7, 2021
Last Update Posted: January 7, 2021
Last Verified: December 2020
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:
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Peripheral Arterial Disease
Peripheral Vascular Diseases
Intermittent Claudication
Atherosclerosis
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Cardiovascular Diseases
Verapamil
Anti-Arrhythmia Agents
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Calcium-Regulating Hormones and Agents
Physiological Effects of Drugs
Vasodilator Agents