Critical Lower Limb Ischemia
Conditions
Keywords
BTK, CLI, PTA
Brief summary
This is a prospective, multi-center, randomized (2:1) trial of symptomatic patients with critical limb ischemia (CLI) secondary to atherosclerotic lesions (stenotic or occluded) of the infrapopliteal vessels. Patients will undergo a percutaneous transluminal endovascular procedure with either the IN.PACT Amphirion™ drug eluting balloon or with a standard (Percutaneous Transluminal Angioplasty) PTA balloon. Patients will be followed with pre-study, post-study, and follow-up evaluations.
Interventions
DEVICEIN.PACT Amphirion
Balloon Angioplasty
DEVICEStandard PTA
Balloon Angioplasty
Sponsors
Medtronic Endovascular
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
General Inclusion Criteria * Age ≥18 years and ≤85 years * Patient or patient's legal representative have been informed of the nature of the study, agrees to participate and has signed an Ethical Committee approved consent form * Female patients of childbearing potential have a negative pregnancy test ≤7 days before the procedure and are willing to use a reliable method of birth control for the duration of study participation * Patient has documented chronic Critical Limb Ischemia (CLI) in the target limb prior to the study procedure with Rutherford Category 4, 5 or 6 * Life expectancy \>1 year in the Investigator's opinion General Angiographic Inclusion Criteria * Reference vessel(s) diameter between 2 and 4 mm * Single or multiple lesions with ≥70% diameter stenosis (DS) of different lengths in one or more main afferent crural vessels including the tibioperoneal trunk * At least one non occluded crural vessel with angiographically documented run-off to the foot either direct or through collaterals Angiographic Inclusion Criteria for Late Lumen Loss (LLL) assessment * Angio-target lesion (TL) is one identifiable single solitary or series of multiple adjacent lesions with a diameter stenosis (DS) ≥70% and a cumulative length ≤100 mm that can be covered by a single IN.PACT Amphirion™ (10 mm balloon landing zone in both edges is mandatory) * Angio-target lesion (TL) is the only lesion in that vessel (only one Angio-TL per patient is allowed)
Exclusion criteria
General
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Late Lumen Loss (LLL) of the Target Lesion by Quantitative Vascular Angiography (QVA) | 12 months or at Target Lesion Revascularization (TLR) time | The difference between minimum lumen diameter (MLD) immediately after Percutaneous Transluminal Angioplasty (PTA) and MLD at 12 months follow-up |
| Clinically Driven Target Lesion Revascularization (TLR) of the Target Lesion in the Amputation Free Surviving Patients | 12 months | Percentage of participants in the amputation free survival population with Clinically driven Target Lesion Revascularization (CD-TLR) at 12 months, CD-TLR defined as any TLR of the target lesion associated with Deterioration of Rutherford Class and / or increase in size of pre-existing wounds and / or occurrence of a new wound(s). |
| Composite of All Cause Death, Major Amputation and Clinically Driven Target Lesion Revascularization (CD-TLR) | 6 months | Percentage of participants experiencing all cause death, major amputation and clinically driven Target Lesion Revascularization (CD-TLR) at 6 months. CD-TLR defined as any TLR of the target lesion associated with Deterioration of Rutherford Class and / or increase in size of pre-existing wounds and / or occurrence of a new wound(s) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Amputation Free Survival and Resolved Critical Limb Ischemia (CLI) | 12 months | Percentage of participants with an amputation free survival and resolved Critical Limb Ischemia (CLI) at 1 year. |
| Death, Amputation and Clinically Driven Target Lesion Revascularization (TLR) | 12 months | Percentage of participants that experienced death, amputation and clinically driven Target Lesion Revascularization (TLR) at 1 year. |
| Primary Sustained Clinical Improvement | 12 months | Percentage of participants that experienced primary sustained clinical improvement at 1 year, specified as an improvement shift in the Rutherford classification of one class in amputation free, clinically driven target lesion revascularization (TLR) free surviving subjects. |
| Secondary Sustained Clinical Improvement | 12 months | Percentage of participants that experienced a secondary sustained clinical improvement, specified as an improvement shift in the Rutherford classification of one class including the need for clinically driven TLR in amputation free surviving subjects at 1 year. |
| Quality of Life Assessment by EQ5D | 12 months | Quality of life assessment by EQ5D at 1 year compared to baseline. EQ-5D is a standardised measure of health status and economic appraisal. The EQ-5D-3L essentially consists of 2 parts:the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D-3L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: (1) no problems, (2) some problems, (3) extreme problems. The EQ VAS records the respondent's self-rated health on a vertical, visual analogue scale where the endpoints are labelled 'Best imaginable health state' and 'Worst imaginable health state'. EQ-5D health states can be converted into a single summary index where 0.0='worst possible outcome' and 1.0='best possible outcome'. |
| Walking Capacity Assessment | 12 months | Walking Impairment assessment by WIQ at 1 year compared to baseline. The Walking Impairment Questionnaire (WIQ) is a questionnaire for evaluating walking impairment in patients with peripheral arterial disease (PAD). This can be used to identify patients with significant impairment and to monitor effectiveness of therapeutic interventions. The questionnaire was self-administered by the patients and contains three domains measuring three important factors of walking impairment in patients with intermittent claudication: (1) difficulty walking a distance during the past month, (2) difficulty walking at a certain speed during the past month, (3) symptoms associated with walking impairment. For each separate domain, a subscore was calculated. The total WIQ score was defined as the mean of the three subscores. A WIQ score of 42.5 or less identified low performers; while a score of 75.5 or more identified high performers. The WIQ score range is 0 (minimum) - 100 (maximum). |
| Amputation Free Survival | 12 months | Percentage of participants with a 1 year amputation free survival. |
| Device Success | Day 1 | Percentage of device success defined as exact deployment of the device according to the instructions for use as documented with suitable imaging modalities |
| Technical Success | Day 1 | Percentage of technical success defined as successful vascular access and completion of the endovascular procedure and immediate morphological success with less or equal to 50% residual diameter reduction of the treated lesion on completion angiography |
| Procedural Success | Day 1 | Percentage of patients with a procedural success defined as combination of technical success, device success and absence of procedural complications |
| Days of Hospitalization | 12 months | Days of hospitalization at 1 year |
| Improvement % Diameter Stenosis (%DS) of the Target Leasion (TL) Assessed by Quantitative Vascular Angiography (QVA) | 12 months | Percentage of participants with an improvement in percent diameter stenosis (%DS) of the target leasion (TL) assessed by Quantitative Vascular Angiography (QVA) |
| MAE (Major Adverse Events) | 12 months | Percentage of participants with a MAE (Major Adverse Events) at 1 year. Major Adverse Events, defined as Death of any Cause, Major Amputation of target limb, Minor Amputation of target limb |
| Rate of Wound Healing | 12 months | Percentage of participants with completed wound healing, wound healing as defined as core lab adjudication of \> 50% area/volume reduction of baseline ulcer(s) in the treated leg at 1 year. |
| Amputation Free Survival and Wound Healing | 12 months | Percentage of participants with a 1 year amputation free survival and wound healing. Wound healing is defined as core lab adjudication of \> 50% area/volume reduction of baseline ulcer(s) in the treated leg at a specified time point. |
Countries
Austria, Belgium, Germany, Italy, Netherlands, Switzerland
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Drug Eluting Balloon IN.PACT Amphirion: Balloon Angioplasty | 239 |
| Standard PTA Standard PTA balloon: Balloon Angioplasty | 119 |
| Total | 358 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 20 | 4 |
| Overall Study | Death | 24 | 10 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Protocol Violation | 15 | 6 |
| Overall Study | Withdrawal by Subject | 14 | 6 |
Baseline characteristics
| Characteristic | Standard PTA | Total | Drug Eluting Balloon |
|---|---|---|---|
| Age, Continuous | 71.7 years STANDARD_DEVIATION 9.9 | 72.5 years STANDARD_DEVIATION 9.05 | 73.3 years STANDARD_DEVIATION 8.2 |
| Region of Enrollment Austria | 25 participants | 72 participants | 47 participants |
| Region of Enrollment Belgium | 31 participants | 91 participants | 60 participants |
| Region of Enrollment Germany | 35 participants | 108 participants | 73 participants |
| Region of Enrollment Italy | 13 participants | 39 participants | 26 participants |
| Region of Enrollment Netherlands | 0 participants | 2 participants | 2 participants |
| Region of Enrollment Switzerland | 15 participants | 46 participants | 31 participants |
| Sex: Female, Male Female | 35 Participants | 92 Participants | 57 Participants |
| Sex: Female, Male Male | 84 Participants | 266 Participants | 182 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 220 / 239 | 108 / 119 |
| serious Total, serious adverse events | 197 / 239 | 92 / 119 |
Outcome results
Primary
Clinically Driven Target Lesion Revascularization (TLR) of the Target Lesion in the Amputation Free Surviving Patients
Percentage of participants in the amputation free survival population with Clinically driven Target Lesion Revascularization (CD-TLR) at 12 months, CD-TLR defined as any TLR of the target lesion associated with Deterioration of Rutherford Class and / or increase in size of pre-existing wounds and / or occurrence of a new wound(s).
Time frame: 12 months
Population: Amputation free surviving meaning participants without an amputation at 12 months. This analysis population consists of 196 participants in the Drug Eluting Balloon arm and 107 participants in the Standard PTA arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Drug Eluting Balloon | Clinically Driven Target Lesion Revascularization (TLR) of the Target Lesion in the Amputation Free Surviving Patients | 9.2 percentage of participants analyzed |
| Standard PTA | Clinically Driven Target Lesion Revascularization (TLR) of the Target Lesion in the Amputation Free Surviving Patients | 13.1 percentage of participants analyzed |
Primary
Composite of All Cause Death, Major Amputation and Clinically Driven Target Lesion Revascularization (CD-TLR)
Percentage of participants experiencing all cause death, major amputation and clinically driven Target Lesion Revascularization (CD-TLR) at 6 months. CD-TLR defined as any TLR of the target lesion associated with Deterioration of Rutherford Class and / or increase in size of pre-existing wounds and / or occurrence of a new wound(s)
Time frame: 6 months
Population: Percentage based on number of evaluable subjects for safety events (232 participants in the drug eluting balloon arm and 114 patients in the Standard PTA arm). All randomized subjects experiencing at least one component for the safety endpoint or with follow-up of at least 330 days post-procedure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Drug Eluting Balloon | Composite of All Cause Death, Major Amputation and Clinically Driven Target Lesion Revascularization (CD-TLR) | 17.67 percentage of participants analyzed |
| Standard PTA | Composite of All Cause Death, Major Amputation and Clinically Driven Target Lesion Revascularization (CD-TLR) | 15.79 percentage of participants analyzed |
Primary
Late Lumen Loss (LLL) of the Target Lesion by Quantitative Vascular Angiography (QVA)
The difference between minimum lumen diameter (MLD) immediately after Percutaneous Transluminal Angioplasty (PTA) and MLD at 12 months follow-up
Time frame: 12 months or at Target Lesion Revascularization (TLR) time
Population: ITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Drug Eluting Balloon | Late Lumen Loss (LLL) of the Target Lesion by Quantitative Vascular Angiography (QVA) | 0.605 mm | — |
| Standard PTA | Late Lumen Loss (LLL) of the Target Lesion by Quantitative Vascular Angiography (QVA) | 0.616 mm | Standard Deviation 0.781 |
Secondary
Amputation Free Survival
Percentage of participants with a 1 year amputation free survival.
Time frame: 12 months
Population: Percentage based on number of evaluable subjects for safety events (227 participants in the drug eluting balloon arm and 111 patients in the Standard PTA arm). All randomized subjects experiencing at least one component for the safety endpoint or with follow-up of at least 330 days post-procedure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Drug Eluting Balloon | Amputation Free Survival | 81.1 percentage of participants analyzed |
| Standard PTA | Amputation Free Survival | 89.2 percentage of participants analyzed |
Secondary
Amputation Free Survival and Resolved Critical Limb Ischemia (CLI)
Percentage of participants with an amputation free survival and resolved Critical Limb Ischemia (CLI) at 1 year.
Time frame: 12 months
Population: Percentage based on number of evaluable subjects for safety events (205 participants in the drug eluting balloon arm and 103 patients in the Standard PTA arm). All randomized subjects experiencing at least one component for the safety endpoint or with follow-up of at least 330 days post-procedure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Drug Eluting Balloon | Amputation Free Survival and Resolved Critical Limb Ischemia (CLI) | 57.1 percentage of participants analyzed |
| Standard PTA | Amputation Free Survival and Resolved Critical Limb Ischemia (CLI) | 66.0 percentage of participants analyzed |
Secondary
Amputation Free Survival and Wound Healing
Percentage of participants with a 1 year amputation free survival and wound healing. Wound healing is defined as core lab adjudication of \> 50% area/volume reduction of baseline ulcer(s) in the treated leg at a specified time point.
Time frame: 12 months
Population: Percentage based on number of evaluable subjects for safety events (206 participants in the drug eluting balloon arm and 103 patients in the Standard PTA arm). All randomized subjects experiencing at least one component for the safety endpoint or with follow-up of at least 330 days post-procedure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Drug Eluting Balloon | Amputation Free Survival and Wound Healing | 58.7 percentage of participants analyzed |
| Standard PTA | Amputation Free Survival and Wound Healing | 68.0 percentage of participants analyzed |
Secondary
Days of Hospitalization
Days of hospitalization at 1 year
Time frame: 12 months
Population: All randomized subjects with available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Drug Eluting Balloon | Days of Hospitalization | 4.5 days | Standard Deviation 8.5 |
| Standard PTA | Days of Hospitalization | 4.0 days | Standard Deviation 7.2 |
Secondary
Death, Amputation and Clinically Driven Target Lesion Revascularization (TLR)
Percentage of participants that experienced death, amputation and clinically driven Target Lesion Revascularization (TLR) at 1 year.
Time frame: 12 months
Population: Percentage based on number of evaluable subjects for safety events (227 participants in the drug eluting balloon arm and 111 patients in the Standard PTA arm). All randomized subjects experiencing at least one component for the safety endpoint or with follow-up of at least 330 days post-procedure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Drug Eluting Balloon | Death, Amputation and Clinically Driven Target Lesion Revascularization (TLR) | 39.6 percentage of participants analyzed |
| Standard PTA | Death, Amputation and Clinically Driven Target Lesion Revascularization (TLR) | 34.2 percentage of participants analyzed |
Secondary
Device Success
Percentage of device success defined as exact deployment of the device according to the instructions for use as documented with suitable imaging modalities
Time frame: Day 1
Population: Number of device deployments
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Drug Eluting Balloon | Device Success | 98.0 percentage of device deployments |
| Standard PTA | Device Success | 96.3 percentage of device deployments |
Secondary
Improvement % Diameter Stenosis (%DS) of the Target Leasion (TL) Assessed by Quantitative Vascular Angiography (QVA)
Percentage of participants with an improvement in percent diameter stenosis (%DS) of the target leasion (TL) assessed by Quantitative Vascular Angiography (QVA)
Time frame: 12 months
Population: Angiographic subgroup only. Angio-target lesion is one identifiable single solitary or series of multiple adjacent lesions with a diameter stenosis higher than 70% and a cumulative length less than 100 mm that can be covered by a single IN.PACT Amphirion™; and Angio-target lesion is the only lesion in that vessel.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Drug Eluting Balloon | Improvement % Diameter Stenosis (%DS) of the Target Leasion (TL) Assessed by Quantitative Vascular Angiography (QVA) | 82.0 percentage of participants analyzed |
| Standard PTA | Improvement % Diameter Stenosis (%DS) of the Target Leasion (TL) Assessed by Quantitative Vascular Angiography (QVA) | 71.0 percentage of participants analyzed |
Secondary
MAE (Major Adverse Events)
Percentage of participants with a MAE (Major Adverse Events) at 1 year. Major Adverse Events, defined as Death of any Cause, Major Amputation of target limb, Minor Amputation of target limb
Time frame: 12 months
Population: Percentage based on number of evaluable subjects for safety events (227 participants in the drug eluting balloon arm and 111 patients in the Standard PTA arm). All randomized subjects experiencing at least one component for the safety endpoint or with follow-up of at least 330 days post-procedure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Drug Eluting Balloon | MAE (Major Adverse Events) | 35.2 percentage of participants analyzed |
| Standard PTA | MAE (Major Adverse Events) | 25.2 percentage of participants analyzed |
Secondary
Primary Sustained Clinical Improvement
Percentage of participants that experienced primary sustained clinical improvement at 1 year, specified as an improvement shift in the Rutherford classification of one class in amputation free, clinically driven target lesion revascularization (TLR) free surviving subjects.
Time frame: 12 months
Population: Analysis population consists of amputation free, clinically driven (target lesion revascularization)TLR free surviving subjects
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Drug Eluting Balloon | Primary Sustained Clinical Improvement | 69.3 percentage of participants analyzed |
| Standard PTA | Primary Sustained Clinical Improvement | 68.1 percentage of participants analyzed |
Secondary
Procedural Success
Percentage of patients with a procedural success defined as combination of technical success, device success and absence of procedural complications
Time frame: Day 1
Population: All randomized subjects with available data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Drug Eluting Balloon | Procedural Success | 98.3 percentage of participants analyzed |
| Standard PTA | Procedural Success | 100 percentage of participants analyzed |
Secondary
Quality of Life Assessment by EQ5D
Quality of life assessment by EQ5D at 1 year compared to baseline. EQ-5D is a standardised measure of health status and economic appraisal. The EQ-5D-3L essentially consists of 2 parts:the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D-3L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: (1) no problems, (2) some problems, (3) extreme problems. The EQ VAS records the respondent's self-rated health on a vertical, visual analogue scale where the endpoints are labelled 'Best imaginable health state' and 'Worst imaginable health state'. EQ-5D health states can be converted into a single summary index where 0.0='worst possible outcome' and 1.0='best possible outcome'.
Time frame: 12 months
Population: Effectiveness Analysis sets - all randomized subjects with available data for EQ5D at baseline and 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Drug Eluting Balloon | Quality of Life Assessment by EQ5D | 0.6975 units on a scale | Standard Deviation 0.308 |
| Standard PTA | Quality of Life Assessment by EQ5D | 0.7445 units on a scale | Standard Deviation 0.3035 |
Secondary
Rate of Wound Healing
Percentage of participants with completed wound healing, wound healing as defined as core lab adjudication of \> 50% area/volume reduction of baseline ulcer(s) in the treated leg at 1 year.
Time frame: 12 months
Population: Patients with pre-existing wounds and/or occurence of new wounds
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Drug Eluting Balloon | Rate of Wound Healing | 73.8 percentage of patients analyzed |
| Standard PTA | Rate of Wound Healing | 76.9 percentage of patients analyzed |
Secondary
Secondary Sustained Clinical Improvement
Percentage of participants that experienced a secondary sustained clinical improvement, specified as an improvement shift in the Rutherford classification of one class including the need for clinically driven TLR in amputation free surviving subjects at 1 year.
Time frame: 12 months
Population: Analysis population consists of amputation free, clinically driven (target lesion revascularization)TLR free surviving subjects
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Drug Eluting Balloon | Secondary Sustained Clinical Improvement | 73.6 percentage of participants analyzed |
| Standard PTA | Secondary Sustained Clinical Improvement | 78.0 percentage of participants analyzed |
Secondary
Technical Success
Percentage of technical success defined as successful vascular access and completion of the endovascular procedure and immediate morphological success with less or equal to 50% residual diameter reduction of the treated lesion on completion angiography
Time frame: Day 1
Population: Number of device deployments
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Drug Eluting Balloon | Technical Success | 93.2 percentage of device deployments |
| Standard PTA | Technical Success | 88.4 percentage of device deployments |
Secondary
Walking Capacity Assessment
Walking Impairment assessment by WIQ at 1 year compared to baseline. The Walking Impairment Questionnaire (WIQ) is a questionnaire for evaluating walking impairment in patients with peripheral arterial disease (PAD). This can be used to identify patients with significant impairment and to monitor effectiveness of therapeutic interventions. The questionnaire was self-administered by the patients and contains three domains measuring three important factors of walking impairment in patients with intermittent claudication: (1) difficulty walking a distance during the past month, (2) difficulty walking at a certain speed during the past month, (3) symptoms associated with walking impairment. For each separate domain, a subscore was calculated. The total WIQ score was defined as the mean of the three subscores. A WIQ score of 42.5 or less identified low performers; while a score of 75.5 or more identified high performers. The WIQ score range is 0 (minimum) - 100 (maximum).
Time frame: 12 months
Population: Effectiveness Analysis sets - all randomized subjects with available data for Walking Impairment assessment at baseline and 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Drug Eluting Balloon | Walking Capacity Assessment | 74.6 units on a scale | Standard Deviation 35.2 |
| Standard PTA | Walking Capacity Assessment | 75.4 units on a scale | Standard Deviation 31.7 |