Rationale and Design of the IN.PACT BTK Randomized Pilot Study: A Paclitaxel Drug-Coated Balloon vs Standard Percutaneous Transluminal Angioplasty for Infrapopliteal Chronic Total Occlusions

Study design. The IN.PACT BTK study is a prospective, multicenter, randomized, pilot study to evaluate the safety and effectiveness of the IN.PACT 014 DCB vs PTA in the treatment of patients with CTOs (100% stenosis with total lesion length ≥40 mm by visual estimation) in the infrapopliteal arteries. Participant flow through the study is shown in Figure 1. A total of 50 participants were enrolled and randomized 1:1 into DCB (n = 23) or PTA (n = 27) treatment groups. The study will continue follow-up through 1, 3, 6, 9, 12, 24, and 36 months post procedure. After the initial protocol approval, Medtronic and regulators worldwide want to better understand the long-term effects of paclitaxel-coated DCBs in patients with vascular disease; therefore, it was decided to extend the length of follow-up from 36 months to 60 months. Angiography will be performed 9 months after the procedure, or sooner for symptomatic patients. 

There is an additional follow-up schedule for participants with ischemic wounds on the target limb at baseline or those who develop new ischemic wounds on the target limb during the study (Figure 2). Participants with wounds are assessed once a week for the first month after the index procedure, for a minimum of 3 assessments between the procedure and 1-month follow-up visit. Thereafter, participants with wounds are assessed once a month until the wound heals. Wound-care follow-up occurs at a dedicated wound-care or foot clinic with a wound-care specialist who is part of the study team.

Participants were those with chronic CLTI who met all eligibility criteria and were candidates for percutaneous endovascular intervention. A list of inclusion and exclusion criteria is presented in Table 1. Participants were recruited from patients referred to an angiography suite or a non-invasive vascular laboratory for assessment of PAD, or patients presenting to an investigator’s clinical practice with chronic symptoms of PAD in the lower extremity. Participants with a signed and dated informed consent form and who met all study eligibility criteria were eligible for enrollment. This included intraprocedural anatomical eligibility criteria, such as successful predilation of the target lesion(s). If the aforementioned criteria were fulfilled, the patient could be randomized to one of the treatment arms and, at that point, the patient was considered enrolled. The point of enrollment was defined to occur after successful predilation of the target lesion(s) because, until then, only standard-of-care procedures were followed. After successful predilation and randomization, subjects in the PTA arm did not receive further treatment unless delayed recoil, flow-limiting dissection not previously detected, persistent >50% residual stenosis, or other untoward event required additional PTA or bail-out stent. Subjects in the treatment arm received additional angioplasty with DCB. In the event of >50% residual stenosis, perforation, occlusive complication (recoil), or a flow-limiting dissection, prolonged balloon inflation was allowed. If this prolonged balloon inflation did not provide the expected result, bail-out stenting was allowed. All other adjunctive therapies (including but not limited to laser, atherectomy, cryoplasty, cutting/scoring balloons, or brachytherapy) were not allowed. The schedule of study procedures and assessments is presented in Table 2.

Randomization was 1:1, stratified by study site, and performed after confirmation that the participant met all eligibility criteria. Randomization was processed centrally by means of a web-based system that provided the assigned treatment arm. Randomization was at the participant level, including those with multiple target lesions.

Multiple design elements were incorporated to minimize bias during the study. The use of multiple study sites ensured that a representative sample of physicians was performing the procedures. This is a pilot study with small sample size and preferably 1 interventional operator per site was identified to perform all procedures to minimize interoperator-induced bias. Since the duplex ultrasound (DUS) examination is operator dependent, all efforts were made to have 1 dedicated operator per site performing all study-required DUS examinations.

The study is being monitored by a data-monitoring committee and a blinded independent clinical-events committee that will adjudicate all major adverse events including revascularization events (Syntactx). An independent DUS core laboratory (VasCore) and angiography core laboratory (Beth Israel Deaconess Medical Center Angiographic Core Lab) will analyze all images. Members of the DUS and angiography core laboratories that analyze follow-up images are blinded to the treatment assignment. Due to the nature of the procedure, it was not possible to blind the patient, clinician performing the intervention, or study site staff.

Index Procedure 

Medication. Participants were administered dual-antiplatelet therapy per institutional standard of care. For the purposes of this study, the recommended duration of dual-antiplatelet therapy has been 3 months. Prolonged antiplatelet therapy can be given at the discretion of the physician and should be considered after stent placement. 

Angiography. Baseline, postprocedural, and late angiography were conducted following a prespecified protocol that ensured visualization of the target lesion in a consistent and unforeshortened view sequentially during the study. A radiopaque ruler was placed on the leg before the start of the procedure and used to define anatomical measurement references and assess lesion length. Selective angiography of the index limb was performed, including ipsilateral femoral, popliteal, and tibioperoneal vessels (up to and including the pedal level) to identify the anatomical characteristics of the vasculature and to visualize and define the lesion(s).

Non-target lesions. Successful treatment of an inflow lesion was defined by residual diameter stenosis of ≤30%. Inflow lesions were treated per institutional standard of care. If an inflow lesion was treated within or above the P3 segment of the popliteal artery, a minimum of 3 cm of healthy tissue was required between the inflow lesion and the infrapopliteal target lesion. Non-target lesions in the index limb, including outflow lesions, had to be treated per institutional standard of care before enrollment. Intervention for any contralateral disease that required treatment was to be performed at least 30 days after the index procedure. 

Target-vessel/target-lesion predilation. All eligible participants underwent predilation of the target vessel/lesion. Operators followed a rigorous imaging protocol to characterize vascular anatomy before and after predilation. Before predilation, the operator acquired both digital subtraction standard angiography and duplex images of the target lesion to visualize the occlusion in a view that minimized the degree of vessel overlap. The operator also acquired DUS imaging according to core lab guidelines that supported reference vessel diameter (RVD) measurement. 

After imaging, predilation was performed with a non-drug coated semicompliant balloon. The predilation balloon was sized at a 1:1 ratio to the RVD as determined by ultrasound, and a length that covered the entire length of the target lesion. More than one predilation balloon was allowed, and the balloon could be inflated more than once according to protocol. The inflation time of 3 minutes is recommended, but prolonged inflation is allowed at the discretion of the operator. Any CE-marked PTA balloon could be used. 

Multiple lesions in 1 vessel should be treated as a single lesion, with no gaps left untreated. Multiple lesions in separate vessels can also be treated, but all lesions must meet the protocol-specified criteria and must be treated with the assigned randomized treatment including subsequent target lesions. In cases with multiple target lesions, the operator could select the first target lesion for predilation at their discretion. If a lesion had a CTO with a section of stenosis that also required treatment, the entire lesion (occluded and stenotic sections) was to be treated as a single lesion. No other vessel-preparation devices, such as cutting/scoring balloons, were allowed.

After predilation, the operator used angiography and DUS to image the target lesion, distal run-off vessels, and the entire vessel distally through the pedal arch and evaluate the flow. Successful predilation was defined as residual stenosis ≤30% per visual estimation, and intraprocedural Doppler exam showing a biphasic (with rapid take-off) or triphasic wave signal, with absence of a major (grade D) flow-limiting dissection (observed on 2 orthogonal views). Participants who met the above criteria for successful predilation were formally enrolled in the study and randomized into treatment groups.  

Target-vessel/target-lesion treatment. For participants randomized to the PTA arm, no additional treatment was performed after successful predilation according to the study protocol. Those randomized to the treatment arm received an IN.PACT 014 DCB that was sized at a 1:1 ratio to the RVD. The coating of this investigational device includes paclitaxel as the antiproliferative agent at a dose of 3.5 μg/mm² with urea as the excipient. IN.PACT 014 is available in 2 usable catheter lengths — 100 cm and 150 cm — in a range of balloon sizes from 2.0-4.0 mm in cylindrical balloon diameter and 40-120 mm in length. The guidewire lumen (central lumen) will permit the use of guidewires to facilitate advancement of the IN.PACT 014 catheter to and through the stenosis to be dilated. The catheter will be compatible with 0.014˝ diameter guidewires. An inflation for 3 minutes was strongly recommended with a nominal pressure for all DCB sizes of 8 atm while the rated burst pressure (RBP) is 14 atm for all sizes. The length of the DCB was sized to ensure the balloon extended beyond the proximal and distal edges of the target lesion by 1 cm. In cases where the target lesion required treatment with multiple DCBs, a 1 cm overlap was required to maintain continuous coverage of the target lesion. To minimize the risk of embolic events, the operator was encouraged to consider using a single DCB and maximizing balloon length when treating a long lesion. 

After treatment of the target lesion was complete, the operator performed angiography to image the target lesion run-off of all vessels distal to the treatment area including the dorsal pedis, pedal arch, and plantar arteries.

Adjunctive therapies. Additional prolonged balloon inflation was allowed in cases of a suboptimal result, such as >50% residual stenosis, perforation, occlusive complication, or flow-limiting dissection. Bail-out stenting was allowed if prolonged balloon inflation did not provide the expected result. All other adjunctive therapies were not allowed, including but not limited to laser, atherectomy, cryoplasty, cutting/scoring balloons, and brachytherapy.

Endpoints and assessments. The primary effectiveness endpoint is late lumen loss (LLL) at 9 months after the procedure for DCB vs standard PTA. LLL is assessed by comparing the minimal lumen diameter (MLD) within the treated segment immediately after the procedure with the MLD of the treated segment 9 months later, or sooner in the event of recurrent symptoms due to restenosis. Based on the recognized limitations of using a single MLD value to represent angiographic restenosis along the entire length of a treated segment, due to axial relocation of the MLD, additional analyses will be performed to assess the totality of vessel narrowing within the treated segment (Figure 3). For the purposes of these analyses, each treated lesion is divided into a tandem array of 10 equally spaced subsegments. For example, a 25 cm-long lesion would be subdivided into a series of ten 2.5 cm subsegments. Subsegmental measures are then taken to determine the mean and minimal diameters within each subsegment, which are matched with the baseline, postprocedural, and follow-up angiograms. These measures are used to calculate subsegmental mean and minimal acute lumen gain immediately after the procedure, mean and minimal LLL at follow-up, mean and minimal net lumen gain from baseline to follow-up, mean and minimal loss index (defined as the ratio of LLL divided by acute gain), percent stenosis at follow-up, and presence of stenosis ≥50% at follow-up. Taken together, the subsegmental analysis of treated lesions will provide more detailed insight into the totality of lumen renarrowing between active and control treatments (Figure 4). 

Secondary endpoints include a composite safety endpoint and the rate of major adverse events at each follow-up visit. The composite safety endpoint is a composite of freedom from device- and procedure-related mortality within 30 days, and freedom from major target-limb amputation and freedom from clinically driven target-lesion revascularization (CD-TLR) within 9 months post index procedure. Major adverse events are defined as a composite of all-cause mortality, major target-limb amputation, and CD-TLR. A full list of all study endpoints is presented in Table 3. 

Statistical analysis

Sample size considerations. Pilot feasibility studies do not have the statistical power of large trials, but may provide scientific signals to be validated in larger studies. The number of participants considered valuable for this type of investigation was described previously.¹⁷ Since no formal hypothesis is specified for the IN.PACT BTK study, the sample size is justified by a precision approach, which provides acceptable precision on the primary endpoint estimate. The sample size was calculated based on previous BTK studies with reported LLL data.^10,13-15 All of the studies reported LLL data at 6 months or 12 months post index procedure. Based on these studies, the standard deviation of LLL at 9 months was estimated to be approximately 0.60 mm for the DCB and PTA groups. Assuming 15% attrition due to death and loss to follow-up, and multiple lesions per participant (approximately 1.1 on average) allowed in the study, it is estimated that there will be 21 participants with 23 evaluable LLL measurements at 9 months in each treatment group. The precision of the estimated LLL was assessed by calculating the distance from the upper limit of the 95% confidence interval to the mean. With 23 lesions in each group, the precision (half of the width of the confidence interval) of the LLL estimate was calculated to be 0.25 mm. The precision of the LLL difference between the 2 groups was calculated to be 0.35 mm. 

Statistical methods. The intention-to-treat analysis cohort will include all randomized participants in the groups to which they are randomized regardless of the treatment received and will serve as the primary analysis cohort for each objective unless otherwise specified. Baseline demographics and characteristics will be summarized on a participant basis, and lesion characteristics will be summarized on a lesion basis. For baseline characteristics, continuous variables will be described as mean ± standard deviation, and comparisons between treatment groups will be performed with the Student’s t-test. Dichotomous and categorical variables will be described as counts and proportions, and comparisons between treatment groups will be performed with the Fisher’s exact test or Cochran-Mantel-Haenszel test. Overall missing data will not be imputed, and the level of statistical significance will be set at .05 for 2-sided test and .025 for 1-sided test. Statistical analyses will be performed using SAS, version 9.4 (SAS Institute).