Non-interventional post-authorization multi-database safety study to assess the risk of myotoxicity, hepatotoxicity and acute pancreatitis in statin-exposed heart failure patients with or without concomitant use of sacubitril/valsartan (Entresto®)

Study identification

• PURI:
  https://redirect.ema.europa.eu/resource/49003
• EU PAS number:
  EUPAS18358
• Study ID:
  49003
• Official title and acronym:
  Non-interventional post-authorization multi-database safety study to assess the risk of myotoxicity, hepatotoxicity and acute pancreatitis in statin-exposed heart failure patients with or without concomitant use of sacubitril/valsartan (Entresto®)
• DARWIN EU® study:
  No
• Study countries:
  Denmark

  Germany

  Italy

  Netherlands

  Spain

  United Kingdom
• Study description:
  Sacubitril/valsartan is a novel treatment initially approved in the United States, and the EU in 2015. It is indicated in adult patients for treatment of symptomatic chronic heart failure with reduced ejection fraction. Based on the observation that sacubitril inhibits OATP1B1 and OATP1B3 transporters in vitro, a drug-drug interaction (DDI) study with atorvastatin (a HMG-CoA reductase inhibitor statin and OATP1B1 and OATP1B3 substrate) showed that sacubitril/valsartan increased the maximal plasma concentrations of atorvastatin and its metabolites by up to 2-fold. However, the areas under the curve of atorvastatin and its metabolites were not increased to a clinically significant extent. Based on the above, and given the high proportion of patients expected to be on a concomitant statin post-marketing, the Committee for Medicinal Products for Human Use (CHMP) requested Novartis to further evaluate this potential DDI in the post-marketing setting. Novartis therefore committed to perform a case-control study to assess specific statin-associated safety events (namely myotoxicity, hepatotoxicity, and acute pancreatitis) in statin-exposed heart failure (HF) patients with or without concomitant use of sacubitril/valsartan using information from five European healthcare databases (i.e. CPRD Clinical Practice Research Datalink from the UK, PHARMO The PHARMO Database Network from the Netherlands, SIDIAP Sistema d'Informació per al Desenvolupament de la Investigació en Atenció Primària) from Catalonia, Spain, HSD Health Search IMS Health Longitudinal Patient Database from Italy, and the Aarhus University Prescription Database and Danish National Patient Registry from Denmark).
• Study status:
  Ongoing

Research institution and networks

Institutions

Novartis Pharmaceuticals

Basel Pharmacoepidemiology Unit Switzerland

Study timelines

Date when funding contract was signed

Planned: 01/04/2017

Actual: 02/06/2017

Study start date

Planned: 30/06/2017

Actual: 01/09/2017

Date of interim report, if expected

Planned: 31/12/2017

Actual: 15/03/2018

Date of final study report

Planned: 31/12/2022

Sources of funding

Pharmaceutical company and other private sector 

More details on funding

Novartis Pharma AG

Study protocol

Initial protocol

LCZ696B2015-Redacted-Protocol

Updated protocol

LCZ696B2015-v02-Redacted-Protocol

Regulatory

• Was the study required by a regulatory body?:
  Yes
• Is the study required by a Risk Management Plan (RMP)?:
  EU RMP category 3 (required)

Other study registration identification numbers and links

CLCZ696B2015