Evaluation of Reporting of Immune Checkpoint Inhibitor Associated Cardio-vascular Adverse Reactions (RAFALE)

Evaluation of Reporting of Immune Checkpoint Inhibitor Associated Cardio-vascular Adverse Reactions Using International Pharmacovigilance Database

Immune checkpoint inhibitors (ICIs) might have high grade immune-related adverse events (irAEs) on the cardio-vascular system. This study investigates reports of cardio-vascular toxicity with treatment including anti-PD1, Anti-PDL-1, and Anti CTLA4 classes using the World Health Organization (WHO) database VigiBase.

Study Overview

• Status: Completed
• Conditions: Myocarditis; Cardiac Complication
• Intervention / Treatment: Drug: ICI

Detailed Description

ICIs have dramatically improved clinical outcomes in multiple cancer types and are increasingly being tested in earlier disease settings and used in combination. However, irAEs can occur. Here the investigators use VigiBase (http://www.vigiaccess.org/), the World Health Organization (WHO) database of individual safety case reports, to identify cases of cardiovascular adverse drug reaction following treatment with ICIs.

• Study Type: Observational
• Enrollment (Actual): 104

Contacts and Locations

Study Locations

• France
  • Paris, France, 75013
    • AP-HP, Pitié-Salpêtrière Hospital, Department of Pharmacology, CIC-1421, Pharmacovigilance Unit, INSERM.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients treated with an ICI for a cancer

Description

Inclusion Criteria:

• Case reported in the World Health Organization (WHO) database of individual safety case reports to 12/31/2017
• Adverse event reported were including the MedDRA terms: Cardiac and vascular investigations (excl enzyme tests) (HLGT), Vascular disorders (SOC), Skeletal and cardiac muscle analyses (HLT), Sudden death (PT), Sudden cardiac death (PT), Cardiac disorders (SOC), Cardiac arrhythmias (HLGT), Cardiac disorder signs and symptoms (HLGT), Cardiac neoplasms (HLGT), Cardiac valve disorders (HLGT), Congenital cardiac disorders (HLGT), Coronary artery disorders (HLGT), Endocardial disorders (HLGT), Heart failures (HLGT), Myocardial disorders (HLGT), Pericardial disorders (HLGT)
• Patients treated with ICIs included in the ATC: Ipilimumab (L01XC11), Nivolumab (L01XC17), Pembrolizumab (L01XC18), Durvalumab (L01XC28), Avelumab (L01XC31), Atezolizumab (L01XC32).

Exclusion Criteria:

• Chronology not compatible between the drug and the toxicity

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Myocarditis induced by Immune check point inhibitor; Case reported in the World Health Organization (WHO) of myocarditis of patient treated by ICI, with a chronology compatible with the drug toxicity	Drug: ICI; Immune checkpoint inhibitor targeting either PD-1, PD-L1 or CTLA-4, and included in the following list (ATC classification): Ipilimumab (L01XC11), Nivolumab (L01XC17), Pembrolizumab (L01XC18), Durvalumab (L01XC28), Avelumab (L01XC31), Atezolizumab (L01XC32).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardio-vascular toxicity of ICIs.	Identification and report of the cardio-vascular toxicity of ICIs. The research includes the report with MedDRA terms: SOC Cardiac Disorders, SOC Vascular Disorders, Sudden death (PT), Cardiac and vascular investigations (excl enzyme tests) (HLGT), Skeletal and cardiac muscle analyses (HLT). Drugs investigated are ICIs: Ipilimumab (L01XC11), Nivolumab (L01XC17), Pembrolizumab (L01XC18), Durvalumab (L01XC28), Avelumab (L01XC31), Atezolizumab (L01XC32).	Case reported in the World Health Organization (WHO) database of individual safety case reports to 12/31/2017

Secondary Outcome Measures

Outcome Measure	Time Frame
Causality assessment of reported cardiovascular events according to the WHO system	Case reported in the World Health Organization (WHO) database of individual safety case reports to 12/31/2017
Description of the type of cardiotoxicity depending on the category of ICIs	Case reported in the World Health Organization (WHO) database of individual safety case reports to 12/31/2017
Description of the duration of treatment when the toxicity happens (role of cumulative dose)	Case reported in the World Health Organization (WHO) database of individual safety case reports to 12/31/2017
Description of the drug-drug interactions associated with adverse events	Case reported in the World Health Organization (WHO) database of individual safety case reports to 12/31/2017
Description of the pathologies (cancer) for which the incriminated drugs have been prescribed	Case reported in the World Health Organization (WHO) database of individual safety case reports to 12/31/2017
Description of the population of patients having a cardio-vascular adverse event	Case reported in the World Health Organization (WHO) database of individual safety case reports to 12/31/2017

Collaborators and Investigators

• Sponsor: Groupe Hospitalier Pitie-Salpetriere
• Collaborators: Vanderbilt University Medical Center; Vanderbilt University; Institute of Cardiometabolism and Nutrition, France

Publications and helpful links

General Publications

• Dressler D, Potter H. Molecular mechanisms in genetic recombination. Annu Rev Biochem. 1982;51:727-61. doi: 10.1146/annurev.bi.51.070182.003455. No abstract available.
• Moslehi JJ, Salem JE, Sosman JA, Lebrun-Vignes B, Johnson DB. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet. 2018 Mar 10;391(10124):933. doi: 10.1016/S0140-6736(18)30533-6. No abstract available.
• Moslehi JJ, Salem JE, Sosman JA, Lebrun-Vignes B, Johnson DB. Reporting of immune checkpoint inhibitor-associated myocarditis - Authors' reply. Lancet. 2018 Aug 4;392(10145):384-385. doi: 10.1016/S0140-6736(18)31556-3. No abstract available.
• Salem JE, Manouchehri A, Moey M, Lebrun-Vignes B, Bastarache L, Pariente A, Gobert A, Spano JP, Balko JM, Bonaca MP, Roden DM, Johnson DB, Moslehi JJ. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol. 2018 Dec;19(12):1579-1589. doi: 10.1016/S1470-2045(18)30608-9. Epub 2018 Nov 12.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 2, 2017
• Primary Completion (ACTUAL): December 4, 2017
• Study Completion (ACTUAL): December 31, 2017

Study Registration Dates

• First Submitted: December 22, 2017
• First Submitted That Met QC Criteria: December 22, 2017
• First Posted (ACTUAL): January 2, 2018

Study Record Updates

• Last Update Posted (ACTUAL): September 26, 2019
• Last Update Submitted That Met QC Criteria: September 24, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: Anti-PD-1; Anti-PD-L1; Anti CTLA-4; Immune checkpoint inhibitors
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Cardiomyopathies; Myocarditis
• Other Study ID Numbers: CIC1421-17-12

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes