Statins to Prevent Immune Checkpoint Inhibitor-induced PRogression of AtherosLerosis

NCT ID: NCT06785974

Last Updated: 2025-01-22

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 140 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-02-28
• Study Completion Date: 2030-02-28

Brief Summary

The goal of this interventional study is to test whether atorvastatin prevents accelerated progression of atherosclerosis in melanoma patients who receive immune checkpoint inhibitor (ICI) therapy. The main questions it aims to answer are:

• difference in percentage growth of total atherosclerotic plaque volume (+ calcified and non-calcified plaque volume) in the descending thoracic segment of the aorta
• difference in percentage growth of total atherosclerotic plaque volume (+ calcified and non-calcified plaque volume) in coronary arteries.

Researchers will compare patients that receive ICI-therapy and atorvastatin with patients that receive ICI-therapy + placebo to see if atorvastatin will prevent accelerated ICI induced plaque growth.

Detailed Description

Rationale: Immune checkpoint inhibitors (ICIs) are often highly effective anti-cancer therapies but predispose patients receiving this treatment to cardiovascular disease and thrombotic events. One of the mechanisms by which ICIs increase cardiovascular risk is by stimulation of inflammation and atherosclerosis. Statins (e.g., atorvastatin) are frequently prescribed and effective anti-atherogenic agents, which could provide protective effects on the cardiovascular system in this patient population whilst and after receiving ICI, minimizing cardiovascular sequelae.

The objective of this study is to study if addition of atorvastatin prevents accelerated progression of atherosclerosis during ICI therapy. In addition, the investigators would like to study the effects of atorvastatin during ICI therapy on endothelial function, epicardial fat volume, and hemostatic and inflammatory parameters.

The main study endpoint is the difference in percentage growth of total atherosclerotic plaque volume in the descending thoracic segment of the aorta between intervention and control group, expressed in indexed percentage growth /year.

Secondary endpoints are differences in non-calcified and calcified plaque volume in the thoracic arteries and coronary arteries, epicardial fat volume, endothelial function, and quality of life. Exploratory endpoints include effect on hemostatic and inflammation markers, lipid levels, progression free survival, event free survival, and overall survival.

Trial design Placebo controlled prospective randomised controlled trial.

Trial population Melanoma patients who are scheduled to receive ICI therapy (nivolumab, pembrolizumab, or a combination of anti-PD1/ipilimumab; (neo)adjuvant, irresectable or metastasized melanoma) according to standard-of-care who are also eligible to initiate statin therapy.

The intervention group receives atorvastatin 20mg daily together with ICI therapy. The control group receives placebo together with ICI therapy.

Both groups will undergo two coronary and thoracic CT-scans. In addition, blood withdrawal will take place fourthly during the study. Furthermore, endothelial function will be assessed by means of the EndoPAT device at baseline and after one year of follow-up.

Ethical considerations relating to the clinical trial including the expected benefit to the individual subject or group of patients represented by the trial subjects as well as the nature and extent of burden and risks: Patients in the intervention group will receive atorvastatin, of which safety and tolerability will be carefully monitored. Coronary atherosclerosis will be assessed via two coronary CT-scans, yielding a total limited extra radiation exposure of 4-10mSv. Blood withdrawal will be combined with regular blood withdrawal time points for standard care or will be withdrawn from the intravenous catheter for ICI administration. Vascular endothelial dysfunction will be assessed via Endothelial Peripheral Arterial Tonometry (EndoPAT) by recording finger arterial pulsatile volume change. This non-invasive method forms a minimal extra burden for participating patients. The investigators hypothesize that atorvastatin prevents accelerated progression of atherosclerosis and ameliorates ICI-induced vascular endothelial dysfunction.

Conditions

Atherosclerosis; Melanoma; Immune-related Adverse Event

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Intervention/ Atorvastatin arm

Patient will receive 20mg of atorvastatin daily together with ICI-therapy

Group Type: EXPERIMENTAL

Atorvastatin

Intervention Type: DRUG

Daily 20mg atorvastatin.

Placebo arm

Patient will receive placebo daily together with ICI-therapy

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Daily Placebo in combination with ICI-therapy

Interventions

Atorvastatin

Daily 20mg atorvastatin.

Intervention Type: DRUG

Placebo

Daily Placebo in combination with ICI-therapy

Intervention Type: DRUG

Other Intervention Names

Lipitor; Atorvastatin Mylan

Eligibility Criteria

Inclusion Criteria

• In order to be eligible to participate in this study, a subject must meet all of the following criteria:
• Age ≥ 18 years
• Able to understand the written information and able to give informed consent
• Melanoma diagnosis with planned ICI treatment according to standard of care (nivolumab, pembrolizumab, monotherapy or combination therapy with ipilimumab)
• Presence of atherosclerosis in the descending thoracic aorta at baseline.

Exclusion Criteria

• Pregnancy or lactation
• Baseline statin use or previously reported statin intolerance
• Current or recent (≤1 year) history of alcohol or drug abuse
• Contra-indication for statin therapy, including:

• Active liver disease, including ALT/AST levels ≥ 3x ULN
• (History of) myopathy Congenital muscular disorder History of (drug-induced) rhabdomyolysis History of drug-induced myopathy with elevated creatine kinase (CK)
• Severe kidney failure (creatinine clearance < 30 ml/min)
• Use of essential medication with (potential) interactions with atorvastatin, including:

• strong CYP3A4 inhibitors such as clarithromycin, ciclosporin, itraconazol, ketoconazole, voriconazol, posconazol, HCV agents, HIV protease inhibitors
• BCRP inhibitors such as elbasvir and grazoprevir
• Fibrates (including gemfibrozil)
• Life expectancy < 12 months
• High MESA-score at baseline

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Amphia Hospital

OTHER

Sponsor Role: collaborator

Erasmus Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Jorie Versmissen

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jorie Versmissen, MD,PhD

Role: PRINCIPAL_INVESTIGATOR

Department Internal Medicine, Hospital Pharmacy, Erasmus MC Rotterdam

Locations

Erasmus Universitair Medisch Cetrum Rotterdam

Rotterdam, South Holland, Netherlands

Countries

Netherlands

Central Contacts

Tom Uyl, MD

Role: CONTACT

t.uyl@erasmusmc.nl

010-7033202

Jorie Versmissen, MD, PhD

Role: CONTACT

j.versmissen@erasmusmc.nl

010-7033202

Facility Contacts

Jorie Versmissen, MD, PhD

Role: primary

j.versmissen@erasmusmc.nl

Tom Uyl, MD

Role: backup

t.uyl@erasmusmc.nl

Related Links

https://www.mvdwfoundation.nl/ondersteunde-projecten/verminderen-van-hart-en-vaatziekte-bij-immunotherapie

Maarten van der Weijden Foundation

Other Identifiers

11670

Identifier Type: -

Identifier Source: org_study_id