Status: Ongoing
First registered on:
24/03/2017
Last updated on:
05/05/2021
1. Study identification
EU PAS Register NumberEUPAS18214
Official titleNon-interventional post-authorization multi-database safety study to characterize the risk of angioedema and other specific safety events of interest in association with use of Entresto® (sacubitril/valsartan) in adult patients with heart failure
Study title acronym
Study typeObservational study
Brief description of the studySacubitril/valsartan exhibits a novel mechanism of action to treat heart failure (HF) by simultaneously inhibiting neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metabolite of the prodrug sacubitril, and by blocking the angiotensin II type-1 (AT1) receptor via valsartan. It was approved in the European Union (EU) in November 2015 for treatment of symptomatic chronic heart failure with reduced ejection fraction.
As agreed with the Committee for Medicinal Products for Human Use (CHMP), the Marketing Authorisation Holder of Sacubitril/valsartan will conduct a non-imposed non-interventional Post-Authorization Safety Study (PASS; category 3) to estimate the incidence and relative risks of angioedema, as well as the incidence of hypotension, hyperkalaemia, hepatotoxicity, and renal impairment in adult patients diagnosed with HF (prevalent and incident) newly starting sacubitril/valsartan or using angiotensin-converting enzyme inhibitors (ACEIs).
Therefore, a multi-database cohort study with secondary use of five European healthcare databases will be performed. The following databases will be used: CPRD (The 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 applicableCLCZ696B2014
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 Officer
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
3. Study timelines: initial administrative steps, progress reports and final report
PlannedActual
Date when funding contract was signed01/04/201708/06/2017
Start date of data collection30/06/201701/09/2017
Start date of data analysis
Date of interim report, if expected31/03/201815/03/2018
Date of final study report31/12/2022
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 Officer
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 Officer
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))SACUBITRIL VALSARTAN
LCZ696
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 subjects24000
Additional information
24,000 patient-years of exposure with ACE inhibitors
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 estimate the incidence of angioedema (primary event of interest), hypotension, hyperkalemia, hepatotoxicity, and renal impairment (secondary events of interest) in HF patients newly starting treatment with sacubitril/valsartan (regardless of prior use of ACEIs or ARBs; and separately in those without prior exposure to ACEIs or ARBs
Are there primary outcomes?Yes
Angioedema is the primary safety event of interest
Are there secondary outcomes?Yes
hypotension, hyperkalemia, hepatotoxicity, and renal impairment are secondary safety events of interest
13. Study design
What is the design of the study?
Cohort study
14. Follow-up of patients
Will patients be followed up?Yes
Please describe duration of follow up
Patients will be followed up from cohort entry until occurrence of outcome of interest, death, last date of follow-up available in data set, or study end date.
Patients will be censored: If they discontinue sacubitril/valsartan or ACEI; add treatment with a RAAS blocking agent; switch initial treatment to a RAAS blocking agent; patient stops contributing data to database; whichever occurs first
15. Data analysis plan
Please provide a brief summary of the analysis method
Demographic and baseline characteristics of patients initiating sacubitril/valsartan or ACEIs will be described using contingency tables for categorical variables and mean, SD, range, median and IQR for continuous variables in each database. The risk of the outcomes of interest will be assessed as incidence rates (IRs) along with 95% confidence intervals (CIs) in users of sacubitril/valsartan and ACEIs.
Exploratory: Adjusted relative risks for the outcomes of interest will be estimated as hazard ratios (HRs) with 95% CIs among new users of sacubitril/valsartan, (a) who are treatment-naïve to ACEIs and ARBs, and (b) separately, in LCZ696 initiators regardless of prior ACEI or ARB use, relative to new users of ACEIs (treatment-naïve to ACEIs) by using Cox regression models. Comparative analyses will be conducted separately in each database; pooled estimates will be provided by using a meta-analytical approach.
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
