LDE-Paclitaxel for Cardiac Allograft Vasculopathy: A Pilot Study

Cardiac allograft vasculopathy (CAV) is a leading cause of late graft failure and death after heart transplantation and has no effective pharmacological treatment. LDE is a cholesterol-rich lipid nanoemulsion that binds to LDL receptors and concentrates in tissues with high receptor expression. In a rabbit heterotopic heart transplant model, LDE-paclitaxel reduced coronary stenosis and macrophage infiltration of the graft without observable toxicity. LDE-paclitaxel (175 mg/m²) was previously well tolerated in patients with breast and ovarian cancer and in patients with aortic atherosclerosis.

In this single-center, randomized (1:1), quadruple-blind, placebo-controlled pilot study, adult heart transplant recipients more than 1 year after transplantation with angiographically documented CAV receive six intravenous infusions, every 3 weeks, of LDE-paclitaxel (paclitaxel 175 mg/m² body surface area) or LDE without paclitaxel (placebo), each infused over 2 hours without premedication. Coronary angiography and IVUS of up to three epicardial vessels are performed at baseline and approximately 1 month after the sixth infusion, and IVUS analyses are performed in matched segments by an analyst blinded to treatment allocation. Laboratory safety tests are performed before each infusion, and participants are followed clinically for 12 months after the follow-up angiography.

The protocol planned 24 participants (20 plus 20% anticipated losses); 22 were enrolled.

Paclitaxel 175 mg/m² body surface area carried in LDE, intravenous infusion over 2 hours, every 3 weeks for 6 cycles.

Drug: LDE-Paclitaxel

LDE without paclitaxel, intravenous infusion over 2 hours, every 3 weeks for 6 cycles.

Drug: Placebo (LDE)

Paclitaxel oleate incorporated into a cholesterol-rich lipid nanoemulsion (LDE), 175 mg/m² IV over 2 hours every 3 weeks, 6 infusions.

Lipid nanoemulsion (LDE) without paclitaxel, identical in appearance, IV over 2 hours every 3 weeks, 6 infusions.

Plazo: From the first infusion through follow-up angiography/IVUS (approximately 1 month after the 6th infusion; about 5 months)

Proportion of randomized participants who (i) receive all 6 study infusions, each within ±7 days of the scheduled date, AND (ii) undergo follow-up coronary angiography/IVUS within ±14 days of the scheduled date, with at least one vessel with analyzable IVUS at both baseline and follow-up.

Plazo: From baseline angiography/IVUS through 30 days after the last infusion or 7 days after follow-up angiography/IVUS, whichever is later (about 5 months)

Proportion of participants with at least one adverse event of grade ≥3 according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0, or at least one serious adverse event, considered at least possibly related to the study drug.

Plazo: From the first infusion through follow-up angiography/IVUS (approximately 1 month after the 6th infusion; about 5 months)

Proportion of randomized participants meeting the strict feasibility criteria, except that a single isolated infusion delay beyond ±7 days is allowed.

Plazo: From baseline angiography/IVUS through 12 months after follow-up angiography/IVUS (about 17 months)

Number of adverse events and proportion of participants with at least one adverse event, classified by CTCAE v5.0 grade, seriousness (serious adverse event criteria) and relatedness to the study drug.

Plazo: From baseline angiography/IVUS through 12 months after follow-up angiography/IVUS (about 17 months)

Proportion of participants with acute cellular or antibody-mediated rejection that required treatment, irrespective of relatedness to the study drug.

Plazo: From baseline angiography/IVUS through 12 months after follow-up angiography/IVUS (about 17 months)

Proportion of participants with infection requiring systemic antimicrobial (antibacterial, antifungal or antiviral) therapy and/or hospitalization.

Plazo: Baseline and follow-up IVUS (approximately 1 month after the 6th infusion; about 5 months)

Absolute change in PAV (percentage points) from baseline to follow-up IVUS. PAV = 100 × Σ plaque volume / Σ external elastic membrane (EEM) volume, with volumes summed across matched segments of all vessels with analyzable IVUS at both time points.

Plazo: Baseline and follow-up IVUS (approximately 1 month after the 6th infusion; about 5 months)

Change in TAVnorm (mm³) from baseline to follow-up IVUS. TAVnorm = (Σ plaque area / number of analyzed frames) × median number of analyzed frames in the study population, to adjust for differing analyzed segment lengths.

Plazo: Baseline and follow-up IVUS (approximately 1 month after the 6th infusion; about 5 months)

Change in MIT (mm) from baseline to follow-up IVUS, using for each participant the largest MIT among vessels with analyzable IVUS at both time points.

Plazo: Baseline and follow-up IVUS (approximately 1 month after the 6th infusion; about 5 months)

Change in MLA (mm²) from baseline to follow-up IVUS, per vessel with analyzable IVUS at both time points.

Plazo: Baseline and follow-up angiography (approximately 1 month after the 6th infusion; about 5 months)

CAV grade according to the International Society for Heart and Lung Transplantation (ISHLT) 2010 standardized nomenclature, assessed on coronary angiography at baseline and follow-up.

Plazo: Baseline (closest routine echocardiogram) to follow-up (closest routine echocardiogram to follow-up angiography; about 5 months)

Change in left ventricular ejection fraction (%) between routine clinical transthoracic echocardiograms performed closest to baseline and to follow-up angiography. Echocardiography was not protocol-mandated.

Treatment of Cardiac Allograft Vasculopathy With Paclitaxel Carried in Lipid Nanoparticles (LDE): a Randomized, Double-Blind Pilot Study of Safety and Feasibility