A Phase 2 Study of the Effects of Sapropterin Dihydrochloride on Symptomatic Peripheral Arterial Disease

A Phase 2, Multicenter, Multinational, Randomized, Double-blind, Placebo-controlled, Parallel Study of the Effects of Sapropterin Dihydrochloride on Symptomatic Peripheral Arterial Disease

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).

Study Overview

• Status: Completed
• Conditions: Intermittent Claudication
• Intervention / Treatment: Drug: Sapropterin Dihydrochloride; Other: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 190
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
  • Corrientes, Argentina
  • Santa Fe, Argentina
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85054
  • California
    • Sacramento, California, United States
    • San Diego, California, United States
    • Santa Ana, California, United States
    • Santa Rosa, California, United States
  • Florida
    • Clearwater, Florida, United States
    • Jacksonville, Florida, United States
  • Georgia
    • Conyers, Georgia, United States
  • Indiana
    • Indianapolis, Indiana, United States
  • Maine
    • Auburn, Maine, United States
  • North Carolina
    • Charlotte, North Carolina, United States
  • Oregon
    • Portland, Oregon, United States
  • Tennessee
    • Knoxville, Tennessee, United States
  • Texas
    • Dallas, Texas, United States
    • San Antonio, Texas, United States
  • Virginia
    • Norfolk, Virginia, United States
    • Richmond, Virginia, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Peak Walking Time (PWT) From Baseline	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).	Baseline and up to Week 24
Number of Subjects With Adverse Events (AEs)	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.	Up to 24-weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Claudication Onset Time (COT) From Baseline	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.	Baseline and up to Week 24

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Peak Walking Time From Baseline With and Without Vitamin C	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.	Baseline up to 24 weeks

Collaborators and Investigators

• Sponsor: BioMarin Pharmaceutical

Publications and helpful links

Helpful Links

• BioMarin Pharmaceutical Inc. website

Study record dates

Study Major Dates

• Study Start: December 1, 2006
• Primary Completion (Actual): November 1, 2008
• Study Completion (Actual): January 1, 2009

Study Registration Dates

• First Submitted: November 21, 2006
• First Submitted That Met QC Criteria: November 21, 2006
• First Posted (Estimate): November 23, 2006

Study Record Updates

• Last Update Posted (Actual): January 7, 2021
• Last Update Submitted That Met QC Criteria: December 14, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: PAD; endothelial dysfunction; Peripheral Arterial Disease; Nitric Oxide; NO; Intermittent Claudication; IC; BH4; 6R-BH4; sapropterin dihydrochloride; Symptomatic Peripheral Arterial Disease
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Peripheral Arterial Disease; Peripheral Vascular Diseases; Intermittent Claudication; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Vasodilator Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Verapamil
• Other Study ID Numbers: PAD-001