Intermittent Claudication, Peripheral Arterial Disease, Peripheral Vascular Disease
Conditions
Keywords
Peripheral Vascular Disease, Peripheral Arterial Disease, Intermittent Claudication, Peak Walking Time, Claudication Onset Time, Cilostazol, Carnitine
Brief summary
The purpose of this study is to see how safe and effective L carnitine taken with cilostazol is compared to placebo taken with cilostazol for people with intermittent claudication. A second purpose of the study is to see if L-carnitine is absorbed into the blood stream.
Detailed description
Peripheral Artery Disease (PAD) is a narrowing of the blood vessels that supply the leg with blood. It is caused by atherosclerosis (hardening of the arteries). Muscles require oxygen carried by the blood. When the leg muscles do not get enough blood and oxygen, this can cause pain, cramping, fatigue, and/or discomfort in the leg muscles during walking or exercise. These symptoms are called intermittent claudication (IC). In more severe cases, tissues do not get enough blood and oxygen at rest, and pain may also be present when the legs are resting. Peripheral Artery Disease (PAD)is one of the most common causes of pain and disability in people between 55 and 75 years of age. Cilostazol is a medication currently available by prescription for intermittent claudication. L-carnitine is an over-the-counter supplement. It is a natural substance in the human body and is also in some red meats, nuts, and energy drinks. Some subjects in the study will take L-carnitine with cilostazol and others will take placebo with cilostazol. The purpose of this study is to see how safe and effective L carnitine taken with cilostazol is compared to placebo taken with cilostazol for people with intermittent claudication. A placebo is a tablet or pill that looks like regular medication, but it doesn't have any actual medicine in it. A second purpose of the study is to see if L-carnitine is absorbed into the blood stream.
Interventions
DIETARY_SUPPLEMENTLevocarnitine tartrate
Capsule form, 1,002 mg (3 capsules) taken by mouth two times per day (morning and evening). L-carnitine will be taken from Day 0 to Day 180.
DRUGcilostazol
Background therapy beginning at 50mg (1 pill) taken by mouth two times per day for two to three weeks. Then 100 mg (1 pill) to be taken by mouth two times per day (morning and evening) for one to two weeks. Randomized therapy will consist of 100 mg (1 pill) to be taken by mouth two times per day (morning and evening) for approximately 180 days.
Sponsors
Otsuka Pharmaceutical Co., Ltd.
Colorado Prevention Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The subject is \>40 years old. * The subject has a diagnosis of Intermittent Claudication (IC) due to Peripheral Artery Disease (PAD). * Ankle brachial index (ABI) \< 0.90 in at least one extremity, or if Ankle brachial index (ABI)is ≥ 0.90 to ≤ 1.0, a reduction of at least 20% in Ankle brachial index (ABI), in at least one extremity, when measured within 1 minute after claudication-limiting treadmill testing. If the subject has non-compressible arteries then a toe brachial index (TBI) \< 0.70 is required in at least one extremity. * Symptoms of Intermittent Claudication (IC)must be stable for at least 3 months prior to Screening 1. * Peak Walking Time (PWT) of ≥ 1 to ≤ 12 minutes on a Gardner protocol at Screening 2. * If the subject is currently on statin therapy, they need to have been on statin therapy for at least 3 months prior to Screening 1. Subjects who have recently discontinued statin therapy must wash-out for at least one month prior to Screening 1. * Tolerance to background therapy of cilostazol (approximately 2 weeks of 50 mg by mouth (PO) twice daily (BID), approximately 1 week of 100 mg PO BID) between Screening 2 and Baseline Visit. * Subjects must be either male or females that are post-menopausal, surgically incapable of bearing children or if they are of childbearing potential must have a negative serum pregnancy test at Screening 1 and a negative urine pregnancy test at Day 0 and must agree to use double-barrier contraceptive methods until the end of investigational therapy (Day 180 Visit). * The subject is able to comply with scheduled visits, treatment plan and laboratory tests. * The subject is willing to participate in this study as documented by written informed consent. * During the tolerance phase of the Screening period, the subject demonstrates at least 70% compliance with cilostazol and is willing to continue treatment.
Exclusion criteria
* Evidence of critical limb ischemia (CLI) (e.g., ischemic rest pain or ischemic ulceration). * The subject has had a major amputation of the leg or any other amputation that limits walking ability. * The subject has diabetes mellitus type 1 or poorly controlled diabetes mellitus type 2 (hemoglobin A1c (HbA1c) \> 10). * The subject has had a transient ischemic attack (TIA) or deep vein thrombosis in the last 3 months. * The subject has had a stroke within the last 6 months. * The subject has participated in an angiogenic gene therapy study, unless known to be given placebo. * The subject has any of the following laboratory parameters at Screening 1: * Alanine aminotransferase (ALT), aspartate aminotransferase (AST) or total bilirubin \>3 times the upper limit of normal (ULN) * Serum creatinine \>2.5 mg/dL * Hemoglobin (Hb) \<10 g/dL * White blood cell (WBC) count \<3.0 x 103/µL; or \> 15 x 103/µL * Platelet count \<100 x 103/µL * The subject walks less than 1 minute at 2 miles per hour (mph), 0% grade as determined during the Screening 1 treadmill familiarization. * The subject has clinically significant electrocardiogram (ECG) abnormalities at rest or changes during exercise or post-exercise at Screening 2 or Day 0. * The subject has any history or clinical evidence of congestive heart failure (CHF), with which the clinician-investigator concurs. * The subject has uncontrolled hypertension (resting blood pressure (BP) \> 180/100 mmHg) or uncontrolled arrhythmic disorders at Screening 1. * History of coronary or peripheral revascularization within 6 months prior to Screening 1. * The subject plans to undergo coronary or peripheral revascularization during the course of the study. * The subject is currently taking L-carnitine or medication for claudication (including pentoxifylline or cilostazol). In this situation, the subject would become eligible for Screening 1 after a 6 week washout of the medication. * Subjects currently taking or those who anticipate taking ketoconazole, itraconazole, or erythromycin. The subject would become eligible for Screening 1 immediately after completion of therapy or discontinuation of the drug(s). * The subject has a known, active malignancy that requires active anti-neoplastic therapy. (stable basal cell skin cancer allowed. Cancer being treated soley with hormonal therapy is allowed.) * The subject has a severe co-morbidity with an expected survival of less than 2 years. * The subject's Peak Walking Time (PWT) is limited by symptoms other than claudication (e.g., shortness of breath (SOB), fatigue, angina, arthritis, etc.). If, in the opinion of the investigator, the subject were to improve their Peak Walking Time (PWT) from study therapy to the extent that his or her walking would then be limited by a symptom other than claudication, the subject should not be enrolled. * The subject has a history of alcohol or other substance abuse within 6 months of Screening 1. * The subject has an inability to tolerate oral medication administration. * The subject has a known or suspected allergy to the study medication(s) or class of study medication(s) (cilostazol or L-carnitine) to be administered. * The subject has initiated an exercise training program within 3 months of Screening 1, has the inability to maintain his or her current level of physical activity throughout the study, or the subject plans on enrolling in an exercise training program during the study. * The subject plans to change his/her smoking status during the planned duration of this study (subjects will be advised that stopping smoking is best for his/her health). * The subject is currently pregnant or breastfeeding. * The subject has received an investigational drug or biological agent within 30 days prior to Screening 1. * The subject is currently participating in or plans to enroll in another clinical trial during this study. * The subject has any other clinically significant medical or psychiatric condition that in the opinion of the Investigator could impact the subject's ability to successfully complete this trial. * In the Investigator's opinion, the subject experienced any Adverse Events (AEs) during the tolerance phase of the Screening period that present a potential ongoing safety concern.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Peak Walking Time (PWT) at Day 180 | Baseline, Day 180 | Subjects were asked to complete a standardized exercise treadmill test using a modified Gardner protocol. Subjects walked on the treadmill until they were physically unable to walk further either as a result of their peripheral artery disease (PAD) symptoms or other non-PAD symptoms. This maximum time walked is referred to as the peak walking time (PWT) and reported in minutes/seconds. The exercise treadmill test was conducted at Screening, Baseline, Day 90, and Day 180 visits. The log transformation is used to make highly skewed distributions less skewed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Peak Walking Time at Day 180 | Baseline, Day 180 | Subjects were asked to complete a standardized exercise treadmill test using a modified Gardner protocol. Subjects walked on the treadmill until they were physically unable to walk further either as a result of their peripheral artery disease (PAD) symptoms or other non-PAD symptoms. This maximum time walked is referred to as the peak walking time (PWT) and reported in minutes/seconds. The exercise treadmill test was conducted at Screening, Baseline, Day 90, and Day 180 visits. The log transformation is used to make highly skewed distributions less skewed. |
| Change From Baseline in Peak Walking Time at Day 90 | Baseline, Day 90 | Subjects were asked to complete a standardized exercise treadmill test using a modified Gardner protocol. Subjects walked on the treadmill until they were physically unable to walk further either as a result of their peripheral artery disease (PAD) symptoms or other non-PAD symptoms. This maximum time walked is referred to as the peak walking time (PWT) and reported in minutes/seconds. The exercise treadmill test was conducted at Screening, Baseline, Day 90, and Day 180 visits. The log transformation is used to make highly skewed distributions less skewed. |
| Change From Baseline in Claudication Onset Time at Day 180 | Baseline, Day 180 | Subjects were asked to complete a standardized exercise treadmill test using a modified Gardner protocol. Subjects walked on the treadmill until they were physically unable to walk further either as a result of their peripheral artery disease (PAD) symptoms or other non-PAD symptoms. The time during the conduct of the exercise treadmill test at which the subject first reported claudication symptoms is referred to as the claudication onset time (COT) and reported in minutes/seconds. The exercise treadmill test was conducted at Screening, Baseline, Day 90, and Day 180 visits. The log transformation is used to make highly skewed distributions less skewed. |
| Change From Baseline in Claudication Onset Time at Day 90 | Baseline, Day 90 | Subjects were asked to complete a standardized exercise treadmill test using a modified Gardner protocol. Subjects walked on the treadmill until they were physically unable to walk further either as a result of their peripheral artery disease (PAD) symptoms or other non-PAD symptoms. The time during the conduct of the exercise treadmill test at which the subject first reported claudication symptoms is referred to as the claudication onset time (COT) and reported in minutes/seconds. The exercise treadmill test was conducted at Screening, Baseline, Day 90, and Day 180 visits. The log transformation is used to make highly skewed distributions less skewed. |
| Change From Baseline in Walking Impairment Questionnaire for Walking Distance at Day 180 | Baseline, Day 180 | Subjects completed the Walking Impairment Questionnaire (WIQ) whereby they were asked about their maximal walking distance before having to rest as a result of claudication symptoms associated with their peripheral artery disease (PAD). The WIQ was administered at the Baseline, Day 90, and Day 180 visits. On the WIQ subjects were asked a series of questions related to their degree of physical difficulty that best described how hard it was for the subject to walk on level ground without stopping to rest. The questions began by asking the degree of difficulty walking around indoors, then 50 feet, 150 feet, 300 feet, 600 feet, 900 feet, and lastly 1500 feet. The responses range from None (best outcome) to Slight, then Some, then Much, then lastly Unable (worst outcome). The walking distance score was calculated from the 7 questions in the section by way of a weighted sum. A score of 100 indicated no walking impairment. A score of 0 corresponded to the highest degree of walking impairment |
| Change From Baseline in Walking Impairment Questionnaire for Walking Distance at Day 90 | Baseline, Day 90 | Subjects completed the Walking Impairment Questionnaire (WIQ) whereby they were asked about their maximal walking distance before having to rest as a result of claudication symptoms associated with their peripheral artery disease (PAD). The WIQ was administered at the Baseline, Day 90, and Day 180 visits. On the WIQ subjects were asked a series of questions related to their degree of physical difficulty that best described how hard it was for the subject to walk on level ground without stopping to rest. The questions began by asking the degree of difficulty walking around indoors, then 50 feet, 150 feet, 300 feet, 600 feet, 900 feet, and lastly 1500 feet. The responses range from None (best outcome) to Slight, then Some, then Much, then lastly Unable (worst outcome). The walking distance score was calculated from the 7 questions in the section by way of a weighted sum. A score of 100 indicated no walking impairment. A score of 0 corresponded to the highest degree of walking impairment |
Countries
United States
Participant flow
Recruitment details
The first participant was randomized on September 19th, 2008 and the last subject was randomized on May 7, 2010. Clinical study sites were a mixture of university/hospital settings, Veteran Affairs hospitals, professional research centers and medical clinics.
Pre-assignment details
The study included a cilostazol run in period. From the 164 participants who remained eligible at the end of the run in period, only 1 participant did not subsequently receive treatment. This was due to voluntary withdrawal by the participant.
Participants by arm
| Arm | Count |
|---|---|
| Cilostazol + L-Carnitine Levocarnitine tartrate : Capsule form, 1,002 mg (3 capsules) taken by mouth two times per day (morning and evening). L-carnitine will be taken from Day 0 to Day 180.
cilostazol : Background therapy beginning at 50mg (1 pill) taken by mouth two times per day for two to three weeks. Then 100 mg (1 pill) to be taken by mouth two times per day (morning and evening) for one to two weeks.
Randomized therapy will consist of 100 mg (1 pill) to be taken by mouth two times per day (morning and evening) for approximately 180 days. | 80 |
| Cilostazol + Placebo cilostazol : Background therapy beginning at 50mg (1 pill) taken by mouth two times per day for two to three weeks. Then 100 mg (1 pill) to be taken by mouth two times per day (morning and evening) for one to two weeks.
Randomized therapy will consist of 100 mg (1 pill) to be taken by mouth two times per day (morning and evening) for approximately 180 days. | 83 |
| Total | 163 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 12 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Lost to Follow-up | 3 | 1 |
| Overall Study | Other | 0 | 1 |
| Overall Study | site closed | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 4 |
Baseline characteristics
| Characteristic | Cilostazol + Placebo | Cilostazol + L-Carnitine | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 56 Participants | 37 Participants | 93 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants | 43 Participants | 70 Participants |
| Age, Continuous | 67.3 years STANDARD_DEVIATION 8 | 65.8 years STANDARD_DEVIATION 9.39 | 66.5 years STANDARD_DEVIATION 8.74 |
| Region of Enrollment United States | 83 participants | 80 participants | 163 participants |
| Sex: Female, Male Female | 16 Participants | 14 Participants | 30 Participants |
| Sex: Female, Male Male | 67 Participants | 66 Participants | 133 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 19 / 80 | 22 / 83 |
| serious Total, serious adverse events | 11 / 80 | 10 / 83 |
Outcome results
Primary
Change From Baseline in Peak Walking Time (PWT) at Day 180
Subjects were asked to complete a standardized exercise treadmill test using a modified Gardner protocol. Subjects walked on the treadmill until they were physically unable to walk further either as a result of their peripheral artery disease (PAD) symptoms or other non-PAD symptoms. This maximum time walked is referred to as the peak walking time (PWT) and reported in minutes/seconds. The exercise treadmill test was conducted at Screening, Baseline, Day 90, and Day 180 visits. The log transformation is used to make highly skewed distributions less skewed.
Time frame: Baseline, Day 180
Population: modified Intent to Treat Population (mITT)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cilostazol + L-Carnitine | Change From Baseline in Peak Walking Time (PWT) at Day 180 | 0.241 Log Minutes | Standard Deviation 0.3836 |
| Cilostazol + Placebo | Change From Baseline in Peak Walking Time (PWT) at Day 180 | 0.134 Log Minutes | Standard Deviation 0.3343 |
p-value: 0.076two-sample equal-variances t-test
Secondary
Change From Baseline in Claudication Onset Time at Day 180
Subjects were asked to complete a standardized exercise treadmill test using a modified Gardner protocol. Subjects walked on the treadmill until they were physically unable to walk further either as a result of their peripheral artery disease (PAD) symptoms or other non-PAD symptoms. The time during the conduct of the exercise treadmill test at which the subject first reported claudication symptoms is referred to as the claudication onset time (COT) and reported in minutes/seconds. The exercise treadmill test was conducted at Screening, Baseline, Day 90, and Day 180 visits. The log transformation is used to make highly skewed distributions less skewed.
Time frame: Baseline, Day 180
Population: modified Intent to Treat Population (mITT)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cilostazol + L-Carnitine | Change From Baseline in Claudication Onset Time at Day 180 | 1.065 Log Minutes | Standard Deviation 0.668 |
| Cilostazol + Placebo | Change From Baseline in Claudication Onset Time at Day 180 | 0.896 Log Minutes | Standard Deviation 0.7364 |
Secondary
Change From Baseline in Claudication Onset Time at Day 90
Subjects were asked to complete a standardized exercise treadmill test using a modified Gardner protocol. Subjects walked on the treadmill until they were physically unable to walk further either as a result of their peripheral artery disease (PAD) symptoms or other non-PAD symptoms. The time during the conduct of the exercise treadmill test at which the subject first reported claudication symptoms is referred to as the claudication onset time (COT) and reported in minutes/seconds. The exercise treadmill test was conducted at Screening, Baseline, Day 90, and Day 180 visits. The log transformation is used to make highly skewed distributions less skewed.
Time frame: Baseline, Day 90
Population: modified Intent to Treat Population (mITT)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cilostazol + L-Carnitine | Change From Baseline in Claudication Onset Time at Day 90 | 1.001 Log Minutes | Standard Deviation 0.6476 |
| Cilostazol + Placebo | Change From Baseline in Claudication Onset Time at Day 90 | 0.815 Log Minutes | Standard Deviation 0.7 |
Secondary
Change From Baseline in Peak Walking Time at Day 180
Subjects were asked to complete a standardized exercise treadmill test using a modified Gardner protocol. Subjects walked on the treadmill until they were physically unable to walk further either as a result of their peripheral artery disease (PAD) symptoms or other non-PAD symptoms. This maximum time walked is referred to as the peak walking time (PWT) and reported in minutes/seconds. The exercise treadmill test was conducted at Screening, Baseline, Day 90, and Day 180 visits. The log transformation is used to make highly skewed distributions less skewed.
Time frame: Baseline, Day 180
Population: Per Protocol (PP) Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cilostazol + L-Carnitine | Change From Baseline in Peak Walking Time at Day 180 | 0.267 Log Minutes | Standard Deviation 0.3516 |
| Cilostazol + Placebo | Change From Baseline in Peak Walking Time at Day 180 | 0.145 Log Minutes | Standard Deviation 0.3124 |
p-value: 0.048two-sample equal-variances t-test
Secondary
Change From Baseline in Peak Walking Time at Day 90
Subjects were asked to complete a standardized exercise treadmill test using a modified Gardner protocol. Subjects walked on the treadmill until they were physically unable to walk further either as a result of their peripheral artery disease (PAD) symptoms or other non-PAD symptoms. This maximum time walked is referred to as the peak walking time (PWT) and reported in minutes/seconds. The exercise treadmill test was conducted at Screening, Baseline, Day 90, and Day 180 visits. The log transformation is used to make highly skewed distributions less skewed.
Time frame: Baseline, Day 90
Population: modified Intent to Treat Population (mITT)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cilostazol + L-Carnitine | Change From Baseline in Peak Walking Time at Day 90 | 0.166 Log Minutes | Standard Deviation 0.3571 |
| Cilostazol + Placebo | Change From Baseline in Peak Walking Time at Day 90 | 0.139 Log Minutes | Standard Deviation 0.3293 |
p-value: 0.65two-sample equal-variances t-test
Secondary
Change From Baseline in Walking Impairment Questionnaire for Walking Distance at Day 180
Subjects completed the Walking Impairment Questionnaire (WIQ) whereby they were asked about their maximal walking distance before having to rest as a result of claudication symptoms associated with their peripheral artery disease (PAD). The WIQ was administered at the Baseline, Day 90, and Day 180 visits. On the WIQ subjects were asked a series of questions related to their degree of physical difficulty that best described how hard it was for the subject to walk on level ground without stopping to rest. The questions began by asking the degree of difficulty walking around indoors, then 50 feet, 150 feet, 300 feet, 600 feet, 900 feet, and lastly 1500 feet. The responses range from None (best outcome) to Slight, then Some, then Much, then lastly Unable (worst outcome). The walking distance score was calculated from the 7 questions in the section by way of a weighted sum. A score of 100 indicated no walking impairment. A score of 0 corresponded to the highest degree of walking impairment
Time frame: Baseline, Day 180
Population: modified Intent to Treat Population (mITT)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cilostazol + L-Carnitine | Change From Baseline in Walking Impairment Questionnaire for Walking Distance at Day 180 | 13.20 score on a scale | Standard Deviation 22.001 |
| Cilostazol + Placebo | Change From Baseline in Walking Impairment Questionnaire for Walking Distance at Day 180 | 6.57 score on a scale | Standard Deviation 24.288 |
Secondary
Change From Baseline in Walking Impairment Questionnaire for Walking Distance at Day 90
Subjects completed the Walking Impairment Questionnaire (WIQ) whereby they were asked about their maximal walking distance before having to rest as a result of claudication symptoms associated with their peripheral artery disease (PAD). The WIQ was administered at the Baseline, Day 90, and Day 180 visits. On the WIQ subjects were asked a series of questions related to their degree of physical difficulty that best described how hard it was for the subject to walk on level ground without stopping to rest. The questions began by asking the degree of difficulty walking around indoors, then 50 feet, 150 feet, 300 feet, 600 feet, 900 feet, and lastly 1500 feet. The responses range from None (best outcome) to Slight, then Some, then Much, then lastly Unable (worst outcome). The walking distance score was calculated from the 7 questions in the section by way of a weighted sum. A score of 100 indicated no walking impairment. A score of 0 corresponded to the highest degree of walking impairment
Time frame: Baseline, Day 90
Population: modified Intent to Treat Population (mITT)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cilostazol + L-Carnitine | Change From Baseline in Walking Impairment Questionnaire for Walking Distance at Day 90 | 12.98 score on a scale | Standard Deviation 25.251 |
| Cilostazol + Placebo | Change From Baseline in Walking Impairment Questionnaire for Walking Distance at Day 90 | 10.01 score on a scale | Standard Deviation 21.354 |