Status: Finalised
First registered on:
29/09/2014
Last updated on:
21/03/2019
1. Study identification
EU PAS Register NumberEUPAS7545
Official titleThe risk of ischemic cardiovascular events associated with oxycodone/naloxone use
Study title acronym
Study typeObservational study
Brief description of the studyOpioid-induced constipation (OIC) is one of the most common adverse effects of opioid therapy and several approaches have been made to reverse OIC without compromising pain relief. Targin® is an oral fixed combination of the extended-release (ER) high potency opioid (HPO) oxycodone and the opioid antagonist naloxone. It is approved in Germany for the treatment of severe pain and has been proven to provide comparable analgesic efficacy to that of oxycodone, while improving OIC. However, the long-term safety of opioid antagonists is not clear. The FDA for example expressed concerns over potential cardiac safety risks associated with use of opioid antagonists discussing withdrawal as possible cause for these risks. This study will estimate the risk of cardiovascular events such as myocardial infarction or ischemic stroke in patients receiving oxycodone/naloxone compared to those being treated with ER oxycodone or another ER HPO.
Was this study requested by a regulator?No
Is the study required by a Risk Management Plan (RMP)?
Not applicable
Regulatory procedure number (RMP Category 1 and 2 studies only)
Other study registration identification numbers and URLs as applicable
2. Research centres and Investigator details
Coordinating study entity
Centre to which the investigator belongsBIPS GmbH
Department/Research groupClinical Epidemiology
Organisation/affiliationLeibniz Inst. for Prevention Research and Epidem.
Details of (Primary) lead investigator
Title Dr
Last name Schink
First name Tania
Is this study being carried out with the collaboration of a research network?
No
Other centres where this study is being conducted
Not applicable (single centre)
Countries in which this study is being conducted
National study
Germany
3. Study timelines: initial administrative steps, progress reports and final report
PlannedActual
Date when funding contract was signed08/09/201308/09/2013
Start date of data collection01/01/200401/01/2004
Start date of data analysis15/04/201415/04/2014
Date of interim report, if expected15/10/201405/12/2014
Date of final study report31/12/201431/12/2014
4. Sources of funding
Please provide estimates of the percentage of funding by source for this study
Names(s)Approximate % funding
Pharmaceutical companiesPurdue Pharma L.P.100
Charities
Government body
Research councils
EU funding scheme
5. Contact details for enquiries
Scientific Enquiries
Title Dr
Last name Schink
First name Tania
Address line 1Achterstraße 30
Address line 2
Address line 3
CityBremen
Postcode28359
CountryGermany
Phone number (incl. country code)004942121856860
Alternative phone number
Fax number (incl. country code)
Public Enquiries
Title Dr
Last name Gerds
First name Heike
Address line 1Achterstraße 30
Address line 2
Address line 3
CityBremen
Postcode28359
CountryGermany
Phone number (incl. country code)004942121856860
Alternative phone number
Fax number (incl. country code)
6. Study drug(s) information
Substance class (ATC Code)N02AA01 (morphine)
Substance class (ATC Code)N02AA03 (hydromorphone)
Substance class (ATC Code)N02AG04 (hydromorphone and antispasmodics)
Substance class (ATC Code)N02AA05 (oxycodone)
Substance class (ATC Code)N02AA55 (oxycodone, combinations)
Substance class (ATC Code)N02AB03 (fentanyl)
Substance class (ATC Code)N02AE01 (buprenorphine)
Substance class (ATC Code)N02AX06 (tapentadol)
7. Medical conditions to be studied
Medical condition(s)Yes
Acute myocardial infarction
Ischaemic stroke
8. Population under study
Age
Infants and toddlers (28 days - 23 months)
Children (2 - 11 years)
Adolescents (12 - 17 years)
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 subjects300000
Additional information
All users of extended-release high potency opioids (ER HPO).
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
11. Scope of the study
What is the scope of the study?
Risk assessment
Drug utilisation study
Primary scope : Risk assessment
12. Main objective(s)
What is the main objective of the study?
The main study objective is to estimate the risk of ischemic Cardiovascular (CV) events in patients receiving Targin® compared to those being prescribed extended-release (ER) oxycodone or another ER high potency opioid (HPO).
Are there primary outcomes?Yes
The primary outcome is the combined endpoint of acute myocardial Infarction (MI) or acute ischemic stroke (IS).
Are there secondary outcomes?Yes
The secondary outcome will be based on a broader outcome definition examining additional ischemic CV events such as angina or transient ischemic attacks.
13. Study design
What is the design of the study?
Cohort study
Case-control study
Drug utilisation 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
Cohort entry is defined as the first dispensation of an extended-release high potency opioid (ER HPO). Baseline covariates will be assessed in the year preceding cohort entry. In the cohort analyses, first a drug utilization part including characteristics of HPO users as well as patterns of opioid use will be conducted. Furthermore two models will be established examining predictive factors for (i) the choice of ER HPO and (ii) for the occurrence of ischemic cardiovascular events. Following this, incidence rates overall and stratified for baseline covariates will be calculated for the outcomes in users of Targin®, ER oxycodone, ER morphine and other extended-release HPO, including patches. Additionally, a nested case-control analysis within this user cohort will be conducted to obtain confounder-adjusted estimates for the risk of myocardial infarction and ischemic stroke associated with (i) current HPO treatment or (ii) recent discontinuation or (iii) recent switch of HPO therapy.
16. ENCePP seal
Are you requesting the ENCePP seal for this study?
No
17. Full protocol
Not submitted
18. Study Results
Please list the 5 most relevant publications using data from your study
ReferenceLink to web-publication
Jobski, K., et al. (2015). "The Risk of Opioid Intoxications or Related Events and the Effect of Alcohol-Related Disorders: A Retrospective Cohort Study in German Patients Treated with High-Potency Opioid Analgesics." Drug Safety 38(9): 811-822.https://link.springer.com/article/10.1007%2Fs40264-015-0312-x
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
