Status: Ongoing
First registered on:
31/03/2017
Last updated on:
05/05/2021
1. Study identification
EU PAS Register NumberEUPAS18358
Official titleNon-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 title acronym
Study typeObservational study
Brief description of the studySacubitril/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).
Was this study requested by a regulator?Yes: EMA
Is the study required by a Risk Management Plan (RMP)?
EU RMP category 3 (required)
Regulatory procedure number (RMP Category 1 and 2 studies only)
Other study registration identification numbers and URLs as applicableCLCZ696B2015
2. Research centres and Investigator details
Coordinating study entity
Centre nameNovartis Pharma AG
Centre locationBasel, Switzerland
Details of (Primary) lead investigator
Title Ms
Last name Clinical Disclosure Office
First name Novartis
Is this study being carried out with the collaboration of a research network?
No
Other centres where this study is being conducted
Multiple centres
In total how many centres are involved in this Study?6
Basel Pharmacoepidemiology Unit, Switzerland
Countries in which this study is being conducted
International study
Denmark
Italy
Netherlands
Spain
United Kingdom
3. Study timelines: initial administrative steps, progress reports and final report
PlannedActual
Date when funding contract was signed01/04/201702/06/2017
Start date of data collection30/06/201701/09/2017
Start date of data analysis
Date of interim report, if expected31/12/201715/03/2018
Date of final study report30/12/2022
4. Sources of funding
Please provide estimates of the percentage of funding by source for this study
Names(s)Approximate % funding
Pharmaceutical companiesNovartis Pharma AG100
Charities
Government body
Research councils
EU funding scheme
5. Contact details for enquiries
Scientific Enquiries
Title Ms
Last name Clinical Disclosure Office
First name Novartis
Address line 1Novartis Pharma AG
Address line 2CH-4002
Address line 3
CityBasel
Postcode
CountrySwitzerland
Phone number (incl. country code)41613241111
Alternative phone number
Fax number (incl. country code)41613248001
Public Enquiries
Title Ms
Last name Clinical Disclosure Office
First name Novartis
Address line 1Novartis Pharma AG
Address line 2CH-4002
Address line 3
CityBasel
Postcode
CountrySwitzerland
Phone number (incl. country code)41613241111
Alternative phone number
Fax number (incl. country code)41613248001
6. Study drug(s) information
Substance class (ATC Code)C09DX04 (valsartan and sacubitril)
Multi-Constituent (Substance INN(s))LCZ696
SACUBITRIL VALSARTAN
7. Medical conditions to be studied
Medical condition(s)Yes
Chronic left ventricular failure
8. Population under study
Age
Adults (18 - 44 years)
Adults (45 - 64 years)
Adults (65 - 74 years)
Adults (75 years and over)
Sex
Male
Female
9. Number of subjects
Estimated total number of subjects40
Additional information
The sample size is calculated following a non-inferiority approach, with the intent to demonstrate that the increased risk due to LCZ696 exposure is less than 3-fold for hepatotoxicity and less than 5-fold for myotoxicity or acute pancreatitis.
10. Source of data
Is this study being carried out with an established data source?Yes
Data sources registered with ENCePP
Sources of data
Administrative database, e.g. claims database
Routine primary care electronic patient registry
Pharmacy dispensing records
11. Scope of the study
What is the scope of the study?
Risk assessment
Primary scope : Risk assessment
12. Main objective(s)
What is the main objective of the study?
To assess individually the relative risk of myotoxic events, hepatotoxic events, and acute pancreatitis associated with concomitant exposure of LCZ696 together with statins compared with statin exposure alone in adult patients with HF using rea-world data.
Are there primary outcomes?Yes
Myotoxic events
Hepatotoxic events
Acute pancreatitis
Are there secondary outcomes?No
13. Study design
What is the design of the study?
Case-control study
14. Follow-up of patients
Will patients be followed up?Not applicable/no follow-up
15. Data analysis plan
Please provide a brief summary of the analysis method
Demographic and clinical characteristics of case and control patients at the index date will be described separately for each outcome of interest using contingency tables for categorical variables and mean, standard deviation (sd), range, median and interquartile range (IQR) for continuous variables in each individual database.
Conditional logistic regression analyses will be used to estimate crude and adjusted odds ratios ([ORs]) of each specific outcome with corresponding 95% confidence intervals (CIs).
The primary analysis is current LCZ696 and statin versus current use of statin (any dose) without current use of LCZ696. Secondary analyses comprise investigation of dose of statin and duration of LZC696, recent use of LZC696 or statins, and individual statins. In dose specific analysis for statins the reference category will be current low dose of statins and non-use of LCZ696.
Control for confounding will be based on matching (1:4 case: control ratio) and confounder adjustment.
16. ENCePP seal
Are you requesting the ENCePP seal for this study?
No
17. Full protocol
Available when the study ends
18. Study Results
Not submitted
Please list the 5 most relevant publications using data from your study
ReferenceLink to web-publication
None
19. Other relevant documents
Conflict(s) of interest of
investigator(s)Not submitted
Composition of Steering Group and
ObserversNot submitted
Other documentsNot
submitted
Signed Code of
Conduct Checklist
Not submitted
Signed Code of Conduct Declaration
Not submitted
Signed Checklist for Study
Protocols
Not submitted
