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

Study Overview
=================
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).

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.

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

Conditions
-----------------
Intermittent Claudication

Intervention / Treatment
-----------------
* Other: Placebo
* Drug: Sapropterin Dihydrochloride


Participation Criteria
=================
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: 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

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sapropterin dihydrochloride<br>Subjects receive 400 mg oral sapropterin dihydrochloride twice daily for 24 weeks. | Drug: Sapropterin Dihydrochloride<br>* Subjects receive 400 mg oral sapropterin dihydrochloride twice daily for 24 weeks.<br>|
| Placebo Comparator: Placebo<br>Subjects receive matching oral Placebo twice daily for 24 weeks. | Other: Placebo<br>* Subjects receive matching oral Placebo twice daily for 24 weeks.<br>|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Intermittent Claudication, IC, Symptomatic Peripheral Arterial Disease, Peripheral Arterial Disease, PAD, 6R-BH4, BH4, sapropterin dihydrochloride, endothelial dysfunction, Nitric Oxide, NO