Efficacy and Safety Of Alirocumab to Prevent Early Cardiac Allograft Vasculopathy in Recent Heart Transplant Recipients

NCT04193306 | Unknown Phase 4 DMC FDA Drug

• 1 other identifier: ACAV2018
• Study Type: interventional
• Target: 126
• Locations: 1 country
• Sites: 1

Brief Summary

Cardiac allograft vasculopathy (CAV) represents the leading cause of late morbidity and mortality in heart transplant recipients as the second most frequent cause of all deaths at 3 years. In distinction from general coronary atherosclerosis, CAV affects diffusely the entire coronary vasculature with marked intimal proliferation and concentric vascular thickening and fibrosis. It was demonstrated that most of the intimal thickening due to CAV occurs during the first year after transplantation. Furthermore, the severity of the CAV appears to correlate with lipid abnormalities and elevated low-density lipoprotein cholesterol (LDL-C) is very common after transplantation with nadir of LDL levels occurring at 6 months. Because of drug-drug interactions, heart transplant recipients cannot be treated with adequate doses of statins to achieve desirable reduction of LDL-C levels (reduction ˂ 60% of LDL-C). The use of alternative lipid-lowering drugs including bile acid sequestrates, fibrates, nicotinic acid or ezetimibe is not recommended in post-transplant scenario. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) increase availability has emerged as a novel drug tool for LDL-C lowering, capable to lower LDL-C by more than 60% even in statin-treated patients with very good safety profile. Although heart transplant recipients fulfill approved indication and standard clinical guidelines of a PCSK9 inhibitor, alirocumab, there are no available data on use of PCSK9 inhibitor in post-transplant situation. The purpose of the ACAV study is to clarify efficacy and safety of alirocumab compared to placebo administered during the first year after transplantation in heart transplant recipients in addition to background atorvastatin therapy. Except lipid profile, optical coherence tomography (OCT) will be performed as the objective efficacy endpoint to examine thickness and lumen of coronary vessels. It is expected that inhibition of PCSK9 in heart transplant recipient will dramatically improve post-transplant lipoprotein levels and perhaps slow down development of CAV in the most critical period of the first year after transplantation.

Conditions

Cardiac Allograft Vasculopathy

Outcome Measures

Primary Outcomes (7)

• calculated LDL cholesterol concentration

  the difference in mean of values from visits 2,3,4,5 and 6 between alirocumab/placebo arms

  the time period between 2 and 12 months after heart transplantation

• HDL cholesterol concentration

  the difference in mean of values from visits 2,3,4,5 and 6 between alirocumab/placebo arms

  the time period between 2 and 12 months after heart transplantation

• total cholesterol

  the difference in mean of values from visits 2,3,4,5 and 6 between alirocumab/placebo arms

  the time period between 2 and 12 months after heart transplantation

• triglycerides

  the difference in mean of values from visits 2,3,4,5 and 6 between alirocumab/placebo arms

  the time period between 2 and 12 months after heart transplantation

• ApoB

  the difference in mean of values from visits 2,3,4,5 and 6 between alirocumab/placebo arms

  the time period between 2 and 12 months after heart transplantation

• Lp (a)

  the difference in mean of values from visits 2,3,4,5 and 6 between alirocumab/placebo arms

  the time period between 2 and 12 months after heart transplantation

• Apo A1

  the difference in mean of values from visits 2, 3, 4 ,5 and 6 between alirocumab/placebo arms

  the time period between 2 and 12 months after heart transplantation

Secondary Outcomes (8)

• calculated LDL cholesterol concentration

  between 1 and 12 months after heart transplantation

• calculated LDL cholesterol concentration

  between 1 and 12 months after heart transplantation

• lipid parameters values

  between 1 and 12 months after heart transplantation

• calculated LDL cholesterol concentration

  between 12 and 15 months after heart transplantation

• lipid parameters values

  between 12 and 15 months after heart transplantation

Study Arms (2)

Alirocumab

EXPERIMENTAL

alirocumab 150 mg s.c. every 2 weeks, for 48 weeks

Drug: Alirocumab

Placebo

PLACEBO COMPARATOR

placebo s.c. every 2 weeks, for 48 weeks

Other: Placebo

Interventions

Alirocumab DRUG

Alirocumab 150 mg s.c. every 2 weeks

Alirocumab

Placebo OTHER

Placebo s.c. every 2 weeks

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• New cardiac transplant recipient ≥ 18 years of age willing to participate in the study.
• Ability to understand study procedures and to comply with them for the entire length of the study.
• Written informed consent obtained from subject or subject's legal representative.
• Heart transplantation surgery performed 3 - 8 weeks before the baseline visit.

You may not qualify if:

• Known hypersensitivity/allergy reaction to study medication.
• Complicated post-transplant outcome with poor neurological status, multiorgan failure or graft dysfunction.
• Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.
• Lipoprotein apheresis is planned of performed.
• Level of LDL-C ≥ 8 mmol/L at screening.
• Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study.
• Participation in any other interventional study.
• Known hypersensitivity/allergy to contrast agent or severe renal insufficiency (eGFR ˂ 30 mL/min/1.75 m2) exclude patient from OCT imaging only, not from the whole study.

Sponsors & Collaborators

• Institute for Clinical and Experimental Medicine: lead

Study Sites (1)

Institute for Clinical and Experimental Medicine

Prague, Czechia

RECRUITING

Related Publications (2)

• Chen Z, Pazdernik M, Zhang H, Wahle A, Guo Z, Bedanova H, Kautzner J, Melenovsky V, Kovarnik T, Sonka M. Quantitative 3D Analysis of Coronary Wall Morphology in Heart Transplant Patients: OCT-Assessed Cardiac Allograft Vasculopathy Progression. Med Image Anal. 2018 Dec;50:95-105. doi: 10.1016/j.media.2018.09.003. Epub 2018 Sep 14.

  PMID: 30253306 BACKGROUND

• Pazdernik M, Chen Z, Bedanova H, Kautzner J, Melenovsky V, Karmazin V, Malek I, Tomasek A, Ozabalova E, Krejci J, Franekova J, Wahle A, Zhang H, Kovarnik T, Sonka M. Early detection of cardiac allograft vasculopathy using highly automated 3-dimensional optical coherence tomography analysis. J Heart Lung Transplant. 2018 Aug;37(8):992-1000. doi: 10.1016/j.healun.2018.04.002. Epub 2018 Apr 6.

  PMID: 29706574 BACKGROUND

MeSH Terms

Interventions

alirocumab

Central Study Contacts

Vojtech Melenovsky, MD, PhD

CONTACT

420 739 528 029; vojtech.melenovsky@ikem.cz

Lenka Hoskova, MD, PhD

CONTACT

lenka.hoskova@ikem.cz

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: double-blinded study with placebo
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Deputy director of the Research Department, senior consultant of the Heart Failure Division

Study Record Dates

• First Submitted: November 26, 2019
• First Posted: December 10, 2019
• Study Start: November 18, 2019
• Primary Completion: May 1, 2025
• Study Completion: July 1, 2025
• Last Updated: October 3, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

CZ (1)