Intermittent Claudication
Conditions
Keywords
Intermittent Claudication, IC, Symptomatic Peripheral Arterial Disease, Peripheral Arterial Disease, PAD, 6R-BH4, BH4, sapropterin dihydrochloride, endothelial dysfunction, Nitric Oxide, NO
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.
Interventions
OTHERPlacebo
Subjects receive matching oral Placebo twice daily for 24 weeks.
Subjects receive 400 mg oral sapropterin dihydrochloride twice daily for 24 weeks.
Sponsors
BioMarin Pharmaceutical
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Peak Walking Time (PWT) From Baseline | 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). |
| Number of Subjects With Adverse Events (AEs) | 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
| Measure | Time frame | Description |
|---|---|---|
| Change in Claudication Onset Time (COT) From Baseline | 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
| Measure | Time frame | Description |
|---|---|---|
| Change in Peak Walking Time From Baseline With and Without Vitamin C | 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. |
Countries
Argentina, United States
Participant flow
Recruitment details
This is a multicenter, multinational study. 31 principal investigators (PIs) enrolled subjects at 10 sites in Argentina sites and 21 sites in the United States (US). A total of 190 patients were recruited with 96 subjects randomized to Sapropterin dihydrichloride and 94 to Placebo. 65 subjects were in Argentina - (32 Sapropterin dihydrochloride, 33 Placebo), and 125 subjects in the US - (64 Sapropterin dihydrochloride, 61 Placebo)
Participants by arm
| Arm | Count |
|---|---|
| Sapropterin Dihydrochloride Subjects receive 400 mg oral sapropterin dihydrochloride twice daily for 24 weeks. | 87 |
| Placebo Subjects receive matching oral Placebo twice daily for 24 weeks. | 83 |
| Total | 170 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 8 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Inappropriately enrolled | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Protocol noncompliance | 0 | 1 |
| Overall Study | Sponsor Request | 1 | 0 |
| Overall Study | Withdrew Consent | 3 | 2 |
Baseline characteristics
| Characteristic | Sapropterin Dihydrochloride | Total | Placebo |
|---|---|---|---|
| Age < 65 years | 28 Participants | 63 Participants | 35 Participants |
| Age >= 65 years | 59 Participants | 107 Participants | 48 Participants |
| Age >= 75 years | 25 Participants | 35 Participants | 10 Participants |
| Age, Continuous | 68.0 years STANDARD_DEVIATION 8.9 | 67.3 years STANDARD_DEVIATION 8.1 | 66.6 years STANDARD_DEVIATION 7 |
| Country of Study Site Argentina | 27 Participants | 57 Participants | 30 Participants |
| Country of Study Site United States | 60 Participants | 113 Participants | 53 Participants |
| Ethnicity Hispanic or Latino | 29 Participants | 60 Participants | 31 Participants |
| Ethnicity Not Hispanic or Latino | 58 Participants | 110 Participants | 52 Participants |
| Race Asian | 0 Participants | 1 Participants | 1 Participants |
| Race Black/African American | 5 Participants | 12 Participants | 7 Participants |
| Race Other | 2 Participants | 2 Participants | 0 Participants |
| Race White | 80 Participants | 155 Participants | 75 Participants |
| Sex: Female, Male Female | 22 Participants | 45 Participants | 23 Participants |
| Sex: Female, Male Male | 65 Participants | 125 Participants | 60 Participants |
| With/Without Vitamin C Without Vitamin C | 41 Participants | 80 Participants | 39 Participants |
| With/Without Vitamin C With Vitamin C | 46 Participants | 90 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 97 | 0 / 91 |
| other Total, other adverse events | 84 / 97 | 66 / 91 |
| serious Total, serious adverse events | 14 / 97 | 11 / 91 |
Outcome results
Primary
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).
Time frame: Baseline and up to Week 24
Population: Intent-To-Treat Population consisting of all subjects who were randomized, received 1 dose of study drug and had at least 1 post-baselline treadmill test.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sapropterin Dihydrochloride | Change in Peak Walking Time (PWT) From Baseline | Baseline | 5.394 minutes | Standard Deviation 2.803 |
| Sapropterin Dihydrochloride | Change in Peak Walking Time (PWT) From Baseline | Change from Baseline to Week 24 | 1.121 minutes | Standard Deviation 2.775 |
| Placebo | Change in Peak Walking Time (PWT) From Baseline | Baseline | 5.712 minutes | Standard Deviation 2.876 |
| Placebo | Change in Peak Walking Time (PWT) From Baseline | Change from Baseline to Week 24 | 1.493 minutes | Standard Deviation 2.597 |
p-value: 0.72795% CI: [-0.138, 0.097]t-test, 2 sided
Primary
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.
Time frame: Up to 24-weeks
Population: Of the 188 patients (96 randomized to study drug and 94 to placebo.) 2 subjects randomized to receive placebo, received at least 1 dose of study drug and were included in the study drug group. 1 participant from each group was excluded from the safety analysis because they did not have at least 1 post-Baseline safety assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sapropterin Dihydrochloride | Number of Subjects With Adverse Events (AEs) | Study Drug-related AEs | 29 Participants |
| Sapropterin Dihydrochloride | Number of Subjects With Adverse Events (AEs) | Study Drug-related AEs leading to Study WIthdrawal | 4 Participants |
| Sapropterin Dihydrochloride | Number of Subjects With Adverse Events (AEs) | Study-Drug-related SAEs | 0 Participants |
| Sapropterin Dihydrochloride | Number of Subjects With Adverse Events (AEs) | Any SAEs Leading to Study Withdrawal | 4 Participants |
| Sapropterin Dihydrochloride | Number of Subjects With Adverse Events (AEs) | Any SAEs | 14 Participants |
| Sapropterin Dihydrochloride | Number of Subjects With Adverse Events (AEs) | Study Drug-related SAEs Leading to Study Withdrawal | 0 Participants |
| Sapropterin Dihydrochloride | Number of Subjects With Adverse Events (AEs) | Any AEs leading to Study Withdrawal | 11 Participants |
| Sapropterin Dihydrochloride | Number of Subjects With Adverse Events (AEs) | Deaths | 1 Participants |
| Sapropterin Dihydrochloride | Number of Subjects With Adverse Events (AEs) | Any AEs | 84 Participants |
| Placebo | Number of Subjects With Adverse Events (AEs) | Deaths | 0 Participants |
| Placebo | Number of Subjects With Adverse Events (AEs) | Any AEs | 66 Participants |
| Placebo | Number of Subjects With Adverse Events (AEs) | Study Drug-related AEs | 30 Participants |
| Placebo | Number of Subjects With Adverse Events (AEs) | Any SAEs | 11 Participants |
| Placebo | Number of Subjects With Adverse Events (AEs) | Study-Drug-related SAEs | 1 Participants |
| Placebo | Number of Subjects With Adverse Events (AEs) | Any AEs leading to Study Withdrawal | 7 Participants |
| Placebo | Number of Subjects With Adverse Events (AEs) | Study Drug-related AEs leading to Study WIthdrawal | 5 Participants |
| Placebo | Number of Subjects With Adverse Events (AEs) | Any SAEs Leading to Study Withdrawal | 1 Participants |
| Placebo | Number of Subjects With Adverse Events (AEs) | Study Drug-related SAEs Leading to Study Withdrawal | 1 Participants |
Secondary
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.
Time frame: Baseline and up to Week 24
Population: Intent-To-Treat Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sapropterin Dihydrochloride | Change in Claudication Onset Time (COT) From Baseline | Baseline | 2.159 minutes | Standard Deviation 1.611 |
| Sapropterin Dihydrochloride | Change in Claudication Onset Time (COT) From Baseline | Change from Baseline to Week 24 | 0.903 minutes | Standard Deviation 1.9 |
| Placebo | Change in Claudication Onset Time (COT) From Baseline | Baseline | 2.313 minutes | Standard Deviation 1.689 |
| Placebo | Change in Claudication Onset Time (COT) From Baseline | Change from Baseline to Week 24 | 1.015 minutes | Standard Deviation 1.902 |
Other Pre-specified
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.
Time frame: Baseline up to 24 weeks
Population: Intent-to-Treat Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sapropterin Dihydrochloride | Change in Peak Walking Time From Baseline With and Without Vitamin C | Baseline without vitamin C | 4.776 minutes | Standard Deviation 2.65 |
| Sapropterin Dihydrochloride | Change in Peak Walking Time From Baseline With and Without Vitamin C | Change from Baseline week 24; without vitamin C | 0.264 minutes | Standard Deviation 2.064 |
| Sapropterin Dihydrochloride | Change in Peak Walking Time From Baseline With and Without Vitamin C | Baseline with vitamin C | 5.944 minutes | Standard Deviation 2.849 |
| Sapropterin Dihydrochloride | Change in Peak Walking Time From Baseline With and Without Vitamin C | Change from Baseline week 24; with vitamin C | 1.826 minutes | Standard Deviation 3.093 |
| Placebo | Change in Peak Walking Time From Baseline With and Without Vitamin C | Change from Baseline week 24; with vitamin C | 2.255 minutes | Standard Deviation 2.716 |
| Placebo | Change in Peak Walking Time From Baseline With and Without Vitamin C | Baseline without vitamin C | 5.201 minutes | Standard Deviation 2.781 |
| Placebo | Change in Peak Walking Time From Baseline With and Without Vitamin C | Baseline with vitamin C | 6.164 minutes | Standard Deviation 2.914 |
| Placebo | Change in Peak Walking Time From Baseline With and Without Vitamin C | Change from Baseline week 24; without vitamin C | 0.607 minutes | Standard Deviation 2.166 |