Clinical trial NCT06785974: Statins to Prevent Immune Checkpoint Inhibitor-induced PRogression of AtherosLerosis
Official title: Statins to Prevent Immune Checkpoint Inhibitor-induced PRogression of AtherosLerosis
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE4
Conditions: Atherosclerosis
Melanoma
Immune-related Adverse Event
Keywords: Statin
Immune Checkpoint Inhibitor
Lead sponsor: Erasmus Medical Center
Sponsor class: OTHER
Collaborators: name: Amphia Hospital
First posted: 2025-01-22
Enrollment: 140
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Percentual annual growth of atherosclerotic plaques in the descending thoracic aorta
timeFrame: 1 year
Secondary outcomes:
measure: Difference in percentage increase in non-calcified and calcified atherosclerotic plaque volume in the descending thoracic aorta
timeFrame: 1 year
measure: Difference in percentage increase in total, non-calcified and calcified coronary artery atherosclerotic plaque volume
timeFrame: 1 year
measure: Difference in increase in coronary calcification score (Agatston score) and Multi-Ethnic Study of Atherosclerosis (MESA) score
timeFrame: 1 year
measure: Difference in change in epicardial fat volume
timeFrame: 1 year
measure: Difference in reactive hyperaemia in-dex
timeFrame: 1 year
measure: Difference in Quality of Life between intervention and control group using the FACT-M and EQ5D5L questionnaire.
timeFrame: Baseline, 3 months, 6 months and 1 year after the start of ICI therapy
measure: Differences in the number of adverse events
timeFrame: 1 year
Other outcomes:
measure: The effect of atorvastatin on median Progression Free Survival in months
timeFrame: 1 and 3 years
measure: The effect of statins on the median Overall Survival in months
timeFrame: 1 and 3 years
measure: The effect of statins on the median Event Free Survival in months
timeFrame: 1 and 3 years
measure: Difference in various concentration levels of hemostatic biomarkers
timeFrame: Baseline, 3 months, 6 months and 1 year after the start of ICI therapy
measure: Difference in serum concentration of cardiovascular risk profile biomarkers
timeFrame: Baseline, 3 months, 6 months and 1 year after the start of ICI therapy
Locations:
city: Rotterdam
country: Netherlands
facility: Erasmus Universitair Medisch Cetrum Rotterdam
state: Zuid Holland
Study officials:
affiliation: Department Internal Medicine, Hospital Pharmacy, Erasmus MC Rotterdam
name: Jorie Versmissen, MD,PhD
role: PRINCIPAL_INVESTIGATOR
References: