Short-Term Exposure to Lipophilic Anti-proliferative Drugs Delivered by Angiographic Contrast Media

• Late lumen loss [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  Difference between angiographic in-stent minimum lumen diameter at 6 months follow-up and post-intervention
• Restenosis rate [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  Defined as a diameter stenosis of ≥50% (assessed by quantitative coronary angiography) at any control angiography
• Combined clinical endpoints (Major adverse cardiac events, MACE) [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  1. Abrupt and sub-abrupt closure
  2. Target lesion revascularization
  3. Myocardial infarction
  4. Death

This was a randomized, placebo-controlled, multi-centre study, double-blind within each dose level, with four ascending dose levels to test the tolerability and safety of iopromide-paclitaxel in patients with de novo lesions in coronary arteries. Thirty-two patients were included into the trial, which were divided into four treatment groups. A total of four concentration levels of paclitaxel-iopromide concentrations were investigated. In each treatment group, six patients received iopromide-paclitaxel and two patients placebo (iopromide without paclitaxel). In each patient, the doses were adjusted individually as needed.

Background: Non-stent-based immediate release formulations of paclitaxel have been shown to reduce in-stent restenosis in animal experiments and initial clinical trials. Paclitaxel dissolved in the angiographic contrast agent iopromide was well tolerated and inhibited neointimal proliferation in a dose-dependent manner after injection into porcine coronary arteries.

Methods: As a first step in entering clinical development, a phase I trial was performed using 4 ascending paclitaxel dose/concentration levels: samples of up to 100 ml of the contrast agent containing 10, 50, 100 or 200 μM paclitaxel were randomly administered to 6 adult patients each assigned to bare metal stent implantation for single de novo coronary artery lesions, while 8 patients treated with plain contrast medium served as controls. Safety variables and tolerability as well as angiographic parameters were assessed.

• Placebo Comparator: Placebo control
  Contrast medium without Paclitaxel
  Intervention: Device: Implantation of a bare metal stent
• Active Comparator: Iopromide Paclitaxel 0.85 mg
  Iopromide Paclitaxel 0.85 mg
  Intervention: Device: Implantation of a bare metal stent
• Active Comparator: Iopromide Paclitaxel 4.27 mg
  Iopromide Paclitaxel 4.27 mg
  Intervention: Device: Implantation of a bare metal stent
• Active Comparator: Iopromide Paclitaxel 8.54 mg
  Iopromide Paclitaxel 8.54 mg
  Intervention: Device: Implantation of a bare metal stent
• Active Comparator: Iopromide Paclitaxel 17.08 mg
  Iopromide Paclitaxel 17.08 mg
  Intervention: Device: Implantation of a bare metal stent

Inclusion Criteria:

• male and postmenopausal female patients
• aged 18 years and older
• clinical evidence of stable or unstable angina, a positive functional test and a stentable de novo lesion in a native coronary artery
• diameter stenosis > 70% (visual estimate), lesion length < 25 mm, and a vessel diameter ≥ 2.5 mm.

Exclusion Criteria:

• acute myocardial infarction
• left ventricular ejection fraction of < 30%
• aorto-ostial lesion
• unprotected left main lesion or a bypass graft
• clear angiographic calcification in the target lesion
• visible thrombus proximal to the lesion
• chronic total occlusion
• platelet count <100,000 cells/mm3 or >700,000 cells/mm3
• WBC <3,000 cells/mm3
• known hypersensitivity or contraindication to aspirin, heparin, clopidogrel, abciximab, paclitaxel, stainless steel
• sensitivity to contrast media not amenable to adequate premedication
• medical illness (i.e. cancer, liver disease or congestive heart failure) associated with a life expectancy of less than two years