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

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.

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:

• Resting ankle-brachial index (ABI) < 0.9 in at least one leg
• If resting ABI is 0.9-1.0, minimum post-exercise drop in ABI of at least 25% in at least one leg
• 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