Use of Nanoparticle Paclitaxel (ABI-007) for the Prevention of In-Stent Restenosis

Phase 1

Completed

Conditions: Coronary Restenosis

Interventions: Drug: Nanoparticle Paclitaxel

Registration Number: NCT00124943

Lead Sponsor: Celgene Corporation

Brief Summary: The purpose of this study was to investigate the use of systemic intracoronary administration of albumin-bound paclitaxel, ABI-007, for the prevention and reduction of restenosis following de novo stenting or following angioplasty for in-stent restenosis.

Detailed Description: This study consisted of a Phase I non-randomized dose escalation phase to determine the maximum tolerated dose and a randomized Phase II component to assess preliminary efficacy. Nanoparticle paclitaxel was administered by intracoronary catheter following either successful and uncomplicated stenting of de novo lesions in native coronary arteries or following successful and uncomplicated balloon angioplasty of instent restenosis (ISR) lesions.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 112

Inclusion Criteria

Male or non-pregnant and non-lactating female, and ≥ 18 years of age.
Diagnosis of angina pectoris or unstable angina pectoris or patients with documented silent ischemia.
Left ventricular ejection fraction ≥30%
Patient has undergone successful and uncomplicated stenting of up to 2 de novo lesions in native coronary arteries OR patient has undergone successful and uncomplicated balloon angioplasty of up to 2 in-stent restenosis (ISR) lesions in native coronary arteries, but not both.
Thrombolysis In Myocardial Infarction (TIMI) 3 coronary flow post-stenting for de novo lesions or post balloon angioplasty for ISR lesions.
No angiographic evidence of thrombus post-procedure.
Target vessel ≥2.5 mm diameter (by angiography).
Each de novo lesion is such that it is stented with ≤ 25 mm of single continuous stent.
Each in-stent restenosis (ISR) lesion is ≤ 25 mm in length.
There is at least 5 mm of non-diseased vessel on either side of target lesion(s).
By intravascular ultrasound (IVUS), stent is fully opposed and has a minimum diameter of 2.5 mm or an in-stent luminal area ≥ 5.0 mm^2
Patient or guardian has provided a signed written informed consent to participate in the study and in all follow-up assessments using a form that is approved by the local Institutional Review Board (IRB)/Ethics Committee of the investigative site.

Exclusion Criteria

Target de novo lesion was treated with a drug-eluting stent
Target ISR lesion requires any treatment other than balloon angioplasty
Patient has both a de novo lesion and an ISR lesion.
If more than 2 lesions are treated with percutaneous coronary intervention (PCI), or it is anticipated that additional lesions will require treatment within 2 months.
Previous PCI within preceding two months.
Intended surgical intervention within 6 months of enrollment in the study.
Unprotected left main disease with >50% stenosis
Malapposition, dissection, or unmasking of a significant narrowing in the inflow or outflow area of the implanted stent.
Women who are pregnant and women of child bearing potential who do not use adequate contraception
Previous participation in another study with any investigational drug or device within the past 30 days or current enrollment in any other clinical protocol or investigational drug or device trial.
Patient has a life expectancy of less than 12 months or there are factors making clinical and/or angiographic follow-up difficult
Any significant medical condition which, in the investigator's opinion, may interfere with the patient's optimal participation in the study
Heart transplant candidate or recipient
Patient is immunosuppressed or is HIV positive.
Patient has experienced a Q wave or a non Q wave myocardial infarction (MI) with documented total creatine kinase (CK) ≥2 times normal within the preceding 24 hours and the CK and creatine kinase-MB fraction (CK-MB) enzymes remain above normal at the time of the procedure.
Cardiogenic shock: sustained systolic blood pressure (SBP) less than 80 mmHg, with no response to fluids or SBP less than 100 mmHg with vasopressors (in absence of bradycardia)
Any individual who may refuse a blood transfusion
Documented major gastro-intestinal bleeding within 3 months
The following lab values at baseline are exclusionary:
- Serum creatinine > 2.5 mg/dl;
- Platelet count < 150,000 cells/mm^3;
- Absolute neutrophil count (ANC) < 2000 cells/mm^3;
- Hemoglobin (HGB) <9 g/dl;
- Total bilirubin >1.5 mg/dl;
- Alanine Aminotransferase (SGPT) > 2.5 x upper limit of normal range (ULN);
- Aspartate Aminotransferase (SGOT) > 2.5 x ULN;
- Alkaline phosphatase > 2.5 x ULN.
Known allergy/hypersensitivity/contraindication to the study drug; to any taxanes; or to any required study treatment: aspirin, clopidogrel bisulfate, stent materials
Pre-existing peripheral neuropathy of National Cancer Institute (NCI) Toxicity Grade > 1.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
35 mg/m^2 nanoparticle paclitaxel	Nanoparticle Paclitaxel	Participants received a single dose of 35 mg/m\^2 nanoparticle paclitaxel administered via intracoronary catheter immediately following percutaneous transluminal coronary angioplasty/stenting (de novo lesions) or balloon angioplasty (in-stent restenosis lesions).
45 mg/m^2 nanoparticle paclitaxel	Nanoparticle Paclitaxel	Participants received a single dose of 45 mg/m\^2 nanoparticle paclitaxel administered via intracoronary catheter immediately following percutaneous transluminal coronary angioplasty/stenting (de novo lesions) or balloon angioplasty (in-stent restenosis lesions).
22 mg/m^2 nanoparticle paclitaxel	Nanoparticle Paclitaxel	Participants received a single dose of 22 mg/m\^2 nanoparticle paclitaxel administered via intracoronary catheter immediately following percutaneous transluminal coronary angioplasty/stenting (de novo lesions) or balloon angioplasty (in-stent restenosis lesions).
10 mg/m^2 nanoparticle paclitaxel	Nanoparticle Paclitaxel	Participants received a single dose of 10 mg/m\^2 nanoparticle paclitaxel administered via intracoronary catheter immediately following percutaneous transluminal coronary angioplasty/stenting (de novo lesion) or balloon angioplasty (in-stent restenosis lesions).

Primary Outcome Measures

Name	Time	Method
Phase I: Number of Participants With Dose-limiting Toxicities	Up to 1 week following percutaneous coronary intervention.	Toxicities were evaluated based on the U.S. National Cancer Institute (NCI) Common Terminology Criteria (CTC) for Adverse Events version 3.0. Any drug-related toxicities considered CTC Grade 3 or 4 were considered dose limiting. The maximum tolerated dose was defined as the lesser of 45 mg/m\^2 or the dose at which any drug related toxicities were observed.
Number of Participants With Treatment Emergent Adverse Events (AEs)	Up to 6 months.	An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. An SAE is any event that: * is fatal or life threatening * results in persistent or significant disability or or incapacity; * requires or prolongs existing hospitalization; * is a congenital anomaly/birth defect in the offspring of a patient who received medication; * conditions not included above that may jeopardize the patient or require intervention to prevent one of the outcomes listed above.
Number of Participants With Major Adverse Cardiac Events (MACE) at 1 Month	From the day of Percutaneous Coronary Intervention to 1 Month.	Major Adverse Cardiac Events (MACE) includes cardiac death, Coronary Artery Bypass Surgery, Myocardial Infarction, Target Vessel Revascularization (TVR) or Target Lesion Revascularization (TLR) and stent/vessel thrombotic occlusion.
Number of Participants With Major Adverse Cardiac Events (MACE) at 6 Months	From the day of Percutaneous Coronary Intervention to Month 6.	Major Adverse Cardiac Events (MACE) includes cardiac death, Coronary Artery Bypass Surgery, Myocardial Infarction, Target Vessel Revascularization (TVR) or Target Lesion Revascularization (TLR) and stent/vessel thrombotic occlusion.
Number of Participants With Procedural Complications	From Day 0 - Day 1 (from study drug administration until 24 hours post-procedure).	Procedural complications include the following: 1. Haemodynamic monitoring: changes in heart rate, arterial blood pressure or electrocardiogram changes; 2. Arrhythmia: premature ventricular complexes, brady or tachyarrhythmia; 3. Allergic reactions: rash, flushing, pyrexia, urticaria, angio-oedema; 4. Angiographic complications: coronary artery spasm, dissection, thrombosis, TIMI (Thrombolysis In Myocardial Infarction) flow, no reflow; 5. Clinical changes: chest pain.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Binary Restenosis	6 months	Binary restenosis was assessed by quantitative coronary angiography and defined as \>50% diameter stenosis within the stented region (In-stent) or the stented region plus 5 mm on either side of the stent (In-segment) at follow-up. Angiograms were centrally assessed by the Angiographic Core Laboratory.
Late Lumen Loss	Day 0 (post-procedure baseline) and 6 months.	Late lumen loss represents the extent of neointimal hyperplasia within the stented region (In-stent) or the stented region plus 5 mm on either side of the stent (In-segment) and was measured by quantitative coronary angiography. Late Loss = Minimum Lumen Diameter (MLD) Post Procedure minus the MLD at Follow-up.
Percentage of In-Stent Volume Obstruction at 6 Months	6 months	In-stent volume obstruction at 6 months was measured by intra-vascular ultrasound (IVUS) and centrally assessed by the IVUS Core Laboratory. Percent in-stent volume obstruction was calculated as neointimal volume / stent volume \* 100.