Peripheral Artery Disease, Vascular Disease, Critical Limb Ischemia
Conditions
Keywords
angioplasty, peripheral artery disease, peripheral vascular disease, atherosclerosis, balloon angioplasty, dexamethasone, drug coated balloon, paclitaxel, walking, claudication
Brief summary
This is a prospective, multicenter, randomized trial to determine the mechanisms of vascular healing. The study will evaluate subjects with peripheral artery disease (PAD) who require an endovascular intervention of the femoro-popliteal (SFA) artery to restore blood flow to the leg.
Detailed description
Peripheral artery disease (PAD) affects at least 12 million Americans annually with more than half a million patients undergoing an endovascular or surgical revascularization procedure in order to treat the disease. Unfortunately, about two-thirds of patients still have blockages in the leg arteries, even after these procedures. Advances in Magnetic resonance imaging (MRI) offer promise for understanding the mechanism of failure through insights into vessel wall composition, remodeling, and inflammation. Restenosis has a known relationship to inflammation. Advances in micro-catheter technologies offer the ability to deliver anti-inflammatory medications such as Dexamethasone (DEX) directly to the adventitia and advances in drug delivery on balloon surfaces to deliver paclitaxel to the intima of the artery. This study aims to investigate if patient-specific parameters affect angioplasty outcomes, if DEX has a biological effect on the vessel wall, and if this effect is through the reduction of inflammation. In response to an FDA issued Letter to Healthcare Providers dated August 9, 2019 that reported the relative risk for increased mortality at 5 years was 1.57 (95% confidence interval 1.16 - 2.13), which corresponds to a 57% relative increase in mortality in patients treated with paclitaxel-coated devices, participant enrollment in the paclitaxel drug coated balloon arm was stopped and a plain balloon angioplasty arm was added to the protocol.
Interventions
DRUGDexamethasone infusion
Participants will receive dexamethasone infusion following plain balloon angioplasty
DEVICEDrug coated balloon
Participants will receive angioplasty with a drug-coated balloon following plain balloon angioplasty
Participants will receive plain balloon angioplasty only
Sponsors
University of Washington
National Heart, Lung, and Blood Institute (NHLBI)
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
35 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Screening: 1. Male or non-pregnant female ≥ 35 years of age 2. Atherosclerotic, infrainguinal PAD 3. Rutherford Clinical Category 2-6 4. Stenosis detected by radiology that in the clinician's opinion is the reason for the PAD symptoms 5. Patient is willing to provide informed consent and comply with the required follow up visits, testing schedule, and medication regimen 6. Estimated Glomerular Filtration Rate (eGFR) ≥ 30 and/or threshold established by the local Institutional Review Board or Committee of Human Research Procedural Criteria: 1. De novo atherosclerotic lesion qualifying for angioplasty 2. A patent artery proximal to the index lesion. Concomitant inflow procedures, including open femoral artery endarterectomy and/or stenting of the iliac arteries, are permissible. 3. \>50% diameter stenosis of the superficial femoral artery and/or popliteal artery (between the profunda and tibioperoneal trunk) 4. Reference vessel diameter ≥3 mm and ≤ 8mm 5. Successful wire crossing of lesion 6. Successful angioplasty of the index lesion or part of the index lesion, defined as ≤30% residual lumen stenosis compared with adjacent non-diseased lumen diameter, without flow-limiting dissection
Exclusion criteria
Screening Criteria: 1. Any contraindication to receiving an MRI 2. Pregnant, nursing, or planning on becoming pregnant in \< 2yrs 3. Life expectancy of \< 1 yr 4. History of solid organ transplantation 5. Patient actively participating in another investigational device or drug study 6. History of hemorrhagic stroke within 3 months of index procedure 7. Previous or planned surgical or interventional procedure within 30 days of index procedure 8. Chronic renal insufficiency with eGFR \< 30 9. Prior bypass surgery, stenting, atherectomy or angioplasty of the index lesion 10. Inability to take required study medications 11. Contra-indication or known hypersensitivity to dexamethasone sodium phosphate, contrast media, gadolinium, aspirin or Plavix 12. Systemic fungal infection 13. Acute limb ischemia 14. Prior participation of the index limb in the current study (contralateral treatment is allowed) 15. Patient is being treated with long-term steroids (not including treatment of a bronchial condition with inhaled steroids) Procedural Criteria: 1. Index lesions extending into the tibial trifurcation or above the profunda. Note: the outflow tibial artery can be treated concomitantly. Similarly, the common femoral artery can be treated concomitantly, either with open endarterectomy and patch angioplasty or with endovascular methods. However, the index lesion cannot be contiguous with either the common femoral artery or the tibial trifurcation. 2. Circumferential calcification at index lesion, which in the judgment of the investigator would prevent penetration of the Micro-Infusion catheter needle through the vessel wall 3. Inadequate distal outflow defined as no patent tibial arteries (\>50% stenosis). The outflow vessel can be established at the time of primary treatment 4. Use of adjunctive therapies other than angioplasty. Chocolate balloons and/or scoring balloons are allowed, if used below reference diameter.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Percent Wall Volume (PWV) | From Post-Operative Day One to 12 Months | The change in percent wall volume (PWV) of the treated segment between the postoperative and 12 month time points as measured by MRI |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Wall Volume (WV) Without a Change in Total Vessel Volume (TVV) | From Post-Operative Day One to 12 Months | The change in wall volume (WV) without change in total vessel volume (TVV) of the treated segment between the postoperative and 12 month time points as measured by MRI |
| Change in Perioperative Inflammatory Profile (MCP-1) | From Post-Operative Day One to 12 Months | The serum concentration of monocyte chemoattractant protein-1 (MCP-1) between postprocedure day 1 and 12 months postprocedure. Reported as the area under the curve (AUC) of the MCP-1 concentration (postprocedure day 1, 1 month and 12 months) |
| Change in Perioperative Inflammatory Profile (CRP) | From Post-Operative Day One to 12 Months | The serum concentration of C-reactive protein (CRP) between postprocedure day 1 and 12 months postprocedure. Reported as the area under the curve (AUC) of the CRP concentration (postprocedure day 1, 1 month and 12 months). |
| Change in Transfer Constant (Ktrans) | From 1 Month to 6 Months | The change in adventitial transfer constant (Ktrans) of the treated segment between the postoperative and 6 month time points as measured by dynamic contrast enhanced MRI |
| Change in Lumen Volume (LV) Relative to Total Vessel Volume (TVV) | From Post-Operative Day One to 12 Months | The change in lumen volume (LV) relative to total vessel volume (TVV) of the treated segment between the postoperative and 12 month time points as measured by MRI |
| Percentage of Subjects With Clinically Significant Restenosis That Undergo Reintervention of Greater Than or Equal to 75% of the Treated Segment | From Post-Operative Day One to 12 Months | Percentage of subjects with clinically significant restenosis that undergo reintervention of greater than or equal to 75% of the treated segment by the 12 month timepoint. |
| Change in Perioperative Inflammatory Profile (IL-1beta) | From Post-Operative Day One to 12 Months | The serum concentration of interleukin-1beta (IL-1beta) between postprocedure day 1 and 12 months postprocedure. Reported as the area under the curve (AUC) of the IL-1beta concentration (postprocedure day 1, 1 month and 12 months). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Extended Clinical Adverse Events Monitoring | From Post-Operative Day One to 36 Months | Participant monitoring for clinical adverse events |
Countries
United States
Participant flow
Pre-assignment details
Of 33 enrolled participants, 20 met inclusion criteria and were randomized to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Dexamethasone Participants received dexamethasone infusion to the adventitia of the treated artery (1.6mg per cm of artery) following plain-old-balloon-angioplasty (POBA).
Dexamethasone infusion: Dexamethasone infusion to the artery adventitia (1.6mg per cm of artery) following plain balloon angioplasty | 10 |
| Drug-Coated Balloon Participants received additional angioplasty with a paclitaxel drug-coated balloon (DCB) of the treated artery following plain-old-balloon-angioplasty (POBA).
Drug-coated balloon: Angioplasty with a paclitaxel drug-coated balloon following plain balloon angioplasty | 9 |
| Plain Balloon Angioplasty Participants received plain-old-ballon-angioplasty (POBA) only.
Plain balloon angioplasty: Participants will receive plain balloon angioplasty only | 1 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 1 | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 |
| Overall Study | Physician Decision | 2 | 0 | 1 |
Baseline characteristics
| Characteristic | Dexamethasone | Drug-Coated Balloon | Plain Balloon Angioplasty | Total |
|---|---|---|---|---|
| Age, Continuous | 67 years STANDARD_DEVIATION 7.5 | 67.6 years STANDARD_DEVIATION 9.9 | 76 years STANDARD_DEVIATION 0 | 67.7 years STANDARD_DEVIATION 8.5 |
| Coronary artery disease | 6 Participants | 2 Participants | 1 Participants | 9 Participants |
| C-Reactive Protein (CRP) | 3.5 mg/L | 2.0 mg/L | .33 mg/L | 2.1 mg/L |
| Diabetes mellitus | 5 Participants | 3 Participants | 0 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 9 Participants | 1 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Hematocrit | 37.5 percentage of hematocrit STANDARD_DEVIATION 4.8 | 38.8 percentage of hematocrit STANDARD_DEVIATION 3.2 | 43.2 percentage of hematocrit STANDARD_DEVIATION 0 | 38.4 percentage of hematocrit STANDARD_DEVIATION 4.1 |
| Hemoglobin | 12.3 g/dL STANDARD_DEVIATION 1.6 | 12.9 g/dL STANDARD_DEVIATION 1.1 | 14.6 g/dL STANDARD_DEVIATION 0 | 12.7 g/dL STANDARD_DEVIATION 1.4 |
| Hyperlipidemia | 9 Participants | 6 Participants | 0 Participants | 15 Participants |
| Hypertension | 10 Participants | 8 Participants | 1 Participants | 19 Participants |
| Interleukin 1 Beta (IL-1beta) | 0.19 pg/mL | 0.17 pg/mL | 0 pg/mL | 0.19 pg/mL |
| Monocyte Chemotactic Protein 1 (MCP-1) | 72.6 pg/mL STANDARD_DEVIATION 21.5 | 77.1 pg/mL STANDARD_DEVIATION 19.6 | 62.0 pg/mL STANDARD_DEVIATION 0 | 73.9 pg/mL STANDARD_DEVIATION 19.8 |
| Platelet count | 225.1 10^9 platelets/L STANDARD_DEVIATION 62.3 | 244.5 10^9 platelets/L STANDARD_DEVIATION 62.9 | 157 10^9 platelets/L STANDARD_DEVIATION 0 | 229.9 10^9 platelets/L STANDARD_DEVIATION 62.3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 6 Participants | 1 Participants | 16 Participants |
| Rutherford category Rutherford category 1 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Rutherford category Rutherford category 2 | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Rutherford category Rutherford category 3 | 7 Participants | 8 Participants | 1 Participants | 16 Participants |
| Rutherford category Rutherford category 4 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Rutherford category Rutherford category 5 | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 10 Participants | 8 Participants | 1 Participants | 19 Participants |
| White blood cell count | 8.6 10^9 cells/L STANDARD_DEVIATION 1.8 | 7.9 10^9 cells/L STANDARD_DEVIATION 2.2 | 8 10^9 cells/L STANDARD_DEVIATION 0 | 8.2 10^9 cells/L STANDARD_DEVIATION 1.9 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 10 | 1 / 9 | 0 / 1 |
| other Total, other adverse events | 1 / 10 | 1 / 9 | 0 / 1 |
| serious Total, serious adverse events | 7 / 10 | 7 / 9 | 1 / 1 |
Outcome results
Primary
Change in Percent Wall Volume (PWV)
The change in percent wall volume (PWV) of the treated segment between the postoperative and 12 month time points as measured by MRI
Time frame: From Post-Operative Day One to 12 Months
Population: No data was collected for the Plain Balloon Angioplasty group
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexamethasone | Change in Percent Wall Volume (PWV) | 12.3 Percent Wall Volume | Standard Deviation 11.6 |
| Drug-Coated Balloon | Change in Percent Wall Volume (PWV) | 3.9 Percent Wall Volume | Standard Deviation 4.3 |
Comparison: Power calculations were performed based on an expected reproducibility variance of 8% and an effect size of 7% was assumed based on data from pilot studies. It was estimated that 22 subjects/treatment assignment were needed to detect a 7% difference in PWV at a power level of 80%. Assigning a 20% attrition rate due to loss to follow up or index lesion revascularization, the goal enrollment was 27 subjects per arm.~No subjects in the plain balloon angioplasty group had MRI data for analysis.p-value: 0.22t-test, 2 sided
Secondary
Change in Lumen Volume (LV) Relative to Total Vessel Volume (TVV)
The change in lumen volume (LV) relative to total vessel volume (TVV) of the treated segment between the postoperative and 12 month time points as measured by MRI
Time frame: From Post-Operative Day One to 12 Months
Population: No data was collected for the Plain Balloon Angioplasty group
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexamethasone | Change in Lumen Volume (LV) Relative to Total Vessel Volume (TVV) | -12.3 mm*3 | Standard Deviation 11.6 |
| Drug-Coated Balloon | Change in Lumen Volume (LV) Relative to Total Vessel Volume (TVV) | -3.88 mm*3 | Standard Deviation 4.28 |
Comparison: No subjects in the plain balloon angioplasty group had MRI data for analysis.p-value: 0.22t-test, 2 sided
Secondary
Change in Perioperative Inflammatory Profile (CRP)
The serum concentration of C-reactive protein (CRP) between postprocedure day 1 and 12 months postprocedure. Reported as the area under the curve (AUC) of the CRP concentration (postprocedure day 1, 1 month and 12 months).
Time frame: From Post-Operative Day One to 12 Months
Population: No data was collected for the Plain Balloon Angioplasty group
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexamethasone | Change in Perioperative Inflammatory Profile (CRP) | 1721 mg*d/L | Standard Deviation 1171 |
| Drug-Coated Balloon | Change in Perioperative Inflammatory Profile (CRP) | 1863 mg*d/L | Standard Deviation 1475 |
Comparison: No subjects in the plain balloon angioplasty group had complete CRP data for analysis.p-value: 0.88t-test, 2 sided
Secondary
Change in Perioperative Inflammatory Profile (IL-1beta)
The serum concentration of interleukin-1beta (IL-1beta) between postprocedure day 1 and 12 months postprocedure. Reported as the area under the curve (AUC) of the IL-1beta concentration (postprocedure day 1, 1 month and 12 months).
Time frame: From Post-Operative Day One to 12 Months
Population: No subject had measurable serum IL-1beta at the 12month timepoint
Secondary
Change in Perioperative Inflammatory Profile (MCP-1)
The serum concentration of monocyte chemoattractant protein-1 (MCP-1) between postprocedure day 1 and 12 months postprocedure. Reported as the area under the curve (AUC) of the MCP-1 concentration (postprocedure day 1, 1 month and 12 months)
Time frame: From Post-Operative Day One to 12 Months
Population: No data was collected for the Plain Balloon Angioplasty group
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexamethasone | Change in Perioperative Inflammatory Profile (MCP-1) | 27933 pg*d/mL | Standard Deviation 3267 |
| Drug-Coated Balloon | Change in Perioperative Inflammatory Profile (MCP-1) | 277745 pg*d/mL | Standard Deviation 4000 |
Comparison: No subjects in the plain balloon angioplasty group had complete MCP-1 data for analysis.p-value: 0.95t-test, 2 sided
Secondary
Change in Transfer Constant (Ktrans)
The change in adventitial transfer constant (Ktrans) of the treated segment between the postoperative and 6 month time points as measured by dynamic contrast enhanced MRI
Time frame: From 1 Month to 6 Months
Population: No data was collected for the Plain Balloon Angioplasty group
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexamethasone | Change in Transfer Constant (Ktrans) | -0.0002 min^-1 | Standard Deviation 0.003 |
| Drug-Coated Balloon | Change in Transfer Constant (Ktrans) | -0.0067 min^-1 | Standard Deviation 0.006 |
Comparison: No subjects in the plain balloon angioplasty group had MRI data for analysis.p-value: 0.055t-test, 2 sided
Secondary
Change in Wall Volume (WV) Without a Change in Total Vessel Volume (TVV)
The change in wall volume (WV) without change in total vessel volume (TVV) of the treated segment between the postoperative and 12 month time points as measured by MRI
Time frame: From Post-Operative Day One to 12 Months
Population: No data was collected for the Plain Balloon Angioplasty group
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexamethasone | Change in Wall Volume (WV) Without a Change in Total Vessel Volume (TVV) | 28.7 mm*3 | Standard Deviation 78.5 |
| Drug-Coated Balloon | Change in Wall Volume (WV) Without a Change in Total Vessel Volume (TVV) | 4.5 mm*3 | Standard Deviation 66.6 |
Comparison: No subjects in the plain balloon angioplasty group had MRI data for analysis.p-value: 0.64t-test, 2 sided
Secondary
Percentage of Subjects With Clinically Significant Restenosis That Undergo Reintervention of Greater Than or Equal to 75% of the Treated Segment
Percentage of subjects with clinically significant restenosis that undergo reintervention of greater than or equal to 75% of the treated segment by the 12 month timepoint.
Time frame: From Post-Operative Day One to 12 Months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dexamethasone | Percentage of Subjects With Clinically Significant Restenosis That Undergo Reintervention of Greater Than or Equal to 75% of the Treated Segment | 4 Participants |
| Drug-Coated Balloon | Percentage of Subjects With Clinically Significant Restenosis That Undergo Reintervention of Greater Than or Equal to 75% of the Treated Segment | 4 Participants |
| Plain Balloon Angioplasty | Percentage of Subjects With Clinically Significant Restenosis That Undergo Reintervention of Greater Than or Equal to 75% of the Treated Segment | 1 Participants |
p-value: 0.81Fisher Exact
Other Pre-specified
Extended Clinical Adverse Events Monitoring
Participant monitoring for clinical adverse events
Time frame: From Post-Operative Day One to 36 Months