Recently published data from the ILLUMENATE first-in-human (FIH) study1 are promising, and more and equally robust clinical trials are well underway to assess the safety and effectiveness of the Stellarex™ drug-coated balloon (DCB; Spectranetics Corporation).

ILLUMENATE FIRST-IN-HUMAN STUDY

The purpose of the ILLUMENATE FIH study was to assess the safety and effectiveness of the Stellarex™ DCB to inhibit restenosis in the superficial femoral (SFA) and/or popliteal artery. ILLUMENATE FIH was a prospective, single-arm, multicenter study with independent adjudication by angiographic and duplex ultrasound core laboratories (VasCore). The study was composed of two sequentially enrolled patient cohorts. In the first 50-patient cohort, lesions were treated with traditional predilatation with an uncoated angioplasty balloon prior to inflation of the DCB. In the second 30-patient cohort, lesions were treated by direct DCB application without predilatation.

The primary efficacy endpoint was 6-month late lumen loss, as determined by the angiographic core laboratory. The major secondary endpoint was major adverse event rate at 6 months, which was defined as cardiovascular death, amputation, and/or clinically driven target lesion revascularization (TLR).

In the first cohort (the predilatation group, n = 58 lesions), the mean lesion length was 7.2 cm, and baseline stenosis was 75.1%. Calcification was present in 62.1% of lesions, and 12.1% were occluded. Both endpoints met their prespecified performance goals: At 6 months, the major adverse event rate was 4%, and the mean late lumen loss was 0.54 mm. The Kaplan-Meier estimate of primary patency, as determined by the duplex ultrasound core laboratory was 89.5%i at 12 months and 80.3% at 24 months, whereas freedom from clinically driven TLR was 90.0%ii at 12 months and 85.8% at 24 months. Additionally, there were no amputations or cardiovascular deaths reported through 24 months (Figure 1).

These promising results instill high confidence in this second-generation DCB technology, which is set to further advance the treatment options for patients with peripheral artery disease. When these results are reviewed in context with other multicenter DCB trials reporting primary patency rates by duplex core lab adjudication, ILLUMENATE FIH compares favorably.2,3 These promising long-term findings suggest that the Stellarex™ coating is the right formulation that balances deliverability with durability and transfers an effective amount of the antirestenotic drug to the treatment site.

ECONOMIC IMPACT

The economic implications of durable results are at the forefront of everyone’s minds as the prevalence of peripheral artery disease increases and medical costs rise. Data from the ILLUMENATE FIH and historical plain-old balloon angioplasty (POBA) data were used to construct a budget impact model through 2 years.1,2,4,5 The model was based on the total cost of the baseline procedure plus revascularizations (determined by clinically driven TLR rates). Costs for the baseline procedure and clinically driven TLR were assigned to both groups using the 2013 German G-DRG reimbursement tariffs. The budget impact model demonstrated cost advantages for Stellarex™ through 24 months. At 12 months, a patient treated with Stellarex™ cost ~€450 less than with PTA (3,575 vs 4,027); at 24 months, the difference increased to 741 (3,668 vs 4,409). Extrapolated to 25,000 patients with peripheral artery disease, the use of Stellarex™ has the potential to save the health care system more than 11,000,000 at 12 months and more than 18,500,000 at 24 months. The number of patients treated with Stellarex™ (compared to PTA) to prevent one TLR was four at 12 months and three at 24 months.

An interesting element of the ILLUMENATE FIH study was the previously mentioned “direct cohort,” in which lesions were treated without predilatation. Twenty-eight patients with 37 lesions were included in the direct DCB cohort analysis; two patients were excluded because they were predilatated. The mean lesion length was 6.4 cm, and calcification was present in 48.6% of lesions. At 6 months, the mean late lumen loss was 0.08 mm, indicating a good drug effect. However, the primary patency rate was 77.5% at 12 months,iii which was lower than the 89.5% observed in the predilatation cohort. The freedom from the clinically driven TLR rate, per Kaplan-Meier estimate, was 85.4% at 12 months.iv The lower patency and freedom from TLR rates in the direct cohort can partially be explained by two TLRs that were thrombotic occlusions that occurred in two patients who were not compliant with their prescribed antiplatelet medications. It is noteworthy that the rates of postdilatation (35.1% vs 12.1%) and stent placement (8.1% vs 5.2%) were higher in the direct cohort versus the predilatation cohort. These findings suggest a role for predilatation in potentially improving outcomes and lowering the need for permanent implants, thus supporting the value proposition of DCBs.

ONGOING STUDIES

The ILLUMENATE FIH study is the first in a series of five robust studies that will evaluate the safety and effectiveness of the Stellarex™ DCB in a broader population.

ILLUMENATE EU-RCT

The ILLUMENATE European randomized, controlled study will enroll up to 360 patients at approximately 24 sites in the European Union. Subjects with symptoms of claudication or rest pain are being randomized to treatment with the Stellarex™ DCB or a bare PTA balloon catheter for de novo or restenotic lesions in the SFA and/or popliteal arteries. Patients will be followed for 5 years.

ILLUMENATE Pivotal

The ILLUMENATE Pivotal randomized clinical trial is being conducted at approximately 45 centers in the United States. It is a prospective, randomized, multicenter, single-blind study that will enroll up to 360 subjects with symptoms of claudication or rest pain, with follow-up through 5 years. The study is being led by Dr. Sean Lyden of the Cleveland Clinic in Cleveland, Ohio, and Dr. Prakash Krishnan of Mount Sinai Heart in New York City, New York.

ILLUMENATE Global

ILLUMENATE Global is a prospective, single-arm, multicenter study that is enrolling patients in Europe, Australia, New Zealand, Canada, and Colombia. All subjects enrolled will undergo treatment with the Stellarex™ DCB and will be followed for 3 years. Prof. Thomas Zeller from Herz-Zentrum Bad Krozingen in Germany is the Global Principal Investigator. The International Principal Investigators are Dr. Yann Goueffic from the Hopital Nord Laennec in France, Dr. Andrew Holden from the Auckland City Hospital in New Zealand, and Dr. Carlos Mena of Yale University in the United States.

ILLUMENATE PK

ILLUMENATE PK is a prospective, nonrandomized, single-arm, multicenter, pharmacokinetic study that is currently ongoing in New Zealand and is led by Dr. Andrew Holden. All subjects enrolled will undergo treatment with the Stellarex™ DCB and have periodic blood draws to measure the amount of paclitaxel in their blood. The study will enroll 25 subjects.

CASE REPORT

The angiograms in Figure 2 show an interesting case of a 50-year-old man with symptomatic (Rutherford class 3) bilateral SFA disease. Two lesions in the right SFA were treated with a direct DCB technique. The 7.9-cm lesion in the mid-SFA and the proximal 5.9-cm lesion were both treated with 5- X 80-mm Stellarex™ DCBs. The left SFA was treated with an uncoated angioplasty balloon. Approximately 1 year later, the artery treated with the Stellarex™ DCB is patent, whereas the artery treated with POBA is restenotic.

We are excited about the data published to date and clinical work that is currently underway. We have a dedicated group of physicians around the world participating in these trials, and we look forward the next wave of data.

1. Schroeder H, Meyer D-R, Lux B, et al. Two-year results of a low-dose drug-coated balloon for revascularization of the femoropopliteal artery: outcomes from the ILLUMENATE first-in-human study [published online ahead of print February 23, 2015]. Catheter Cardiovasc Interv.

2. Scheinert D, Duda S, Zeller T, et al, The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-in-human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty. JACC Cardiovasc Interv. 2014;7:10-19.

3. Tepe G. IN.PACT SFA 1-year primary outcomes. Presented at the Charing Cross meeting; London, United Kingdom; April 5–8, 2014.

4. Micari A, Cioppa A, Vadala G, et al. Clinical evaluation of a paclitaxel-eluting balloon for treatment of femoropopliteal arterial disease: 12-month results from a multicenter Italian registry. JACC Cardiovasc Interv. 2012;5:331-338.

5. Tepe G, Zeller T, Albrecht T, et al. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med. 2008;358:689-699.

i.  The primary patency rate was 89.5% at day 365 and 87.7% at day 395, the upper end of the follow-up window. The primary patency rate was 80.3% throughout the 24-month follow-up window (at day 730 and day 760).
ii.  The freedom from clinically driven TLR was 90.0% at day 365 and 87.9% at day 395, the upper end of the follow-up window. The rate was 85.8% throughout the 24-month follow-up window (at day 730 and day 760).
iii.  The primary patency rate was 77.5% throughout the 12-month follow-up window (at day 365 and day 395).
iv.  The freedom from clinically driven TLR rate was 85.4% throughout the 12-month follow-up window (at day 365 and day 395).