A Phase 2 Study of the Effects of Sapropterin Dihydrochloride on Symptomatic Peripheral Arterial Disease
Condition: Intermittent Claudication
MeSH terms: Peripheral Arterial Disease; Peripheral Vascular Diseases; Intermittent Claudication
Intervention: Placebo; Sapropterin Dihydrochloride
Intervention description: Subjects receive matching oral Placebo twice daily for 24 weeks.; Subjects receive 400 mg oral sapropterin dihydrochloride twice daily for 24 weeks.
Intervention MeSH terms: Verapamil
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 190.0
Sex: All
Minimum age: 40 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Intermittent Claudication; IC; Symptomatic Peripheral Arterial Disease; Peripheral Arterial Disease; PAD; 6R-BH4; BH4; sapropterin dihydrochloride; endothelial dysfunction; Nitric Oxide; NO

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).
    

Eligibility 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