EpilepsyNCT01607333
WEUKBRE5557: IMI PROTECT(Work Package 2): Antiepileptics & Suicide
An observational study of Epilepsy, run by GlaxoSmithKline.
Trial summary
The studies described in this protocol are all performed within the framework of PROTECT (Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium) Workpackage 2 and Workgroup 1. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Epilepsy
- What is being tested?
- Lamotrigine use
- How many people
- 1 participants
- Where
- No sites listed yet
- Study dates
- Dec 2011to Jul 2014
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: For the descriptive studies that compare six European databases: All patients with at least one prescription of an AED between January 1, 2000 and December 31, 2009 from the following databases: National Databases (Denmark), General Practice Research Database [GPRD] (UK), Health Improvement Network [THIN] (UK), the Mondriaan database (Netherlands), BIFAP [Base de Datos para la Investigación Farmacoepidemiologica en Atencion Primaria] (Spain), and the Bavarian health-insurance database (Germany). Additional descriptive and analytic studies comparing the study populations from GPRD and Danish data sources: study cohorts consisting of patients who have received a first prescription to at least one AED on July 1, 1996 or later to December 31, 2009.
Inclusion Criteria for the descriptive studies to compare the six European databases:
- patients with at least one prescription to an AED between January 1, 2000 and December 31, 2009
- patients who fulfill the quality criteria of the respective database
Inclusion Criteria for the additional descriptive studies comparing the study populations from GPRD and Danish data sources and cohort study:
- patients who have received a first prescription to at least one AED at July 1, 1996 or later in the UK or Denmark
- patients who are an age of 15 years and older at the index date
- patients who have a registration history of at least 6 months prior to the index date (first date of AED prescription)
- patients who have fulfilled research data criteria in GPRD
Exclusion Criteria for the descriptive studies to compare the six European databases and the nested case-control study:
- patients without a prescription to an AED between January 1, 2000 and December 31, 2009
- patients who do not fulfill the quality criteria of the respective database
Exclusion Criteria for the additional descriptive studies comparing the study populations from GPRD and Danish data sources and cohort study:
- patients without a first prescription to at least one AED at July 1, 1996 or later in the UK or Denmark
- patients younger than age of 15 years at the index date
- patients who do not have a registration history of at least 6 months prior to the index date (first date of AED prescription)
- patients who have not fulfilled research data criteria in GPRD
- patients with records of coded suicidality (wide definition, including suicidal ideation) in the six months prior to the index date
About this study
Official title: WEUKBRE5557: IMI PROTECT (Work Package 2): Use of Antiepileptics and Risk of Suicidality
The studies described in this protocol are all performed within the framework of PROTECT (Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium) Workpackage 2 and Workgroup 1. Primary aim of these studies is to develop, test and disseminate methodological standards for the design, conduct and analysis of Pharmacoepidemiological (PE) studies applicable to different safety issues and using different data sources. To achieve this, results from PE studies on five key adverse events (AEs) performed in different databases will be evaluated. Therefore, emphasis will be on the methodological aspects of the studies in this protocol and not on the clinical consequences of the association under investigation.
In the present project, investigators use Columbia Classification Algorithm of suicide assessment (C-CASA) definitions as a basis to specify the operational definitions of the different aspects of suicidality. The focus of the main analyses is on attempted suicide including completed suicide. This is due to statistical power issues. However, investigators will apply two additional outcome definitions in sensitivity analyses: 1) completed suicide only and 2) completed suicide, suicide attempt, preparatory acts toward imminent suicidal behavior, suicidal ideation plus indeterminate or potentially suicidal events. Investigators will not include terms which clearly indicate an accidental event, or self-injurious behavior without a suicidal intent. These definitions are listed in the statistical analysis plan together with lists of terms from the dictionaries used in the different databases.
The objectives of this study are to 1) Compare the study results which are based on two data sources (he UK General Practice Research Database (GPRD) and Danish registries) and different designs and evaluate the impact of design and population differences on the outcome of the study results (the UK database 'The Health Improvement Network' (THIN) may be included in these analyses as well); 2) Evaluate the strengths and weaknesses of the two data sources to study a possible association of antiepileptic drug (AED) use and suicidality, in particular the specific outcomes of death from suicide, hospitalization due to suicide attempt, and reports of the aspects of suicidality by the patients; 3) Estimate risks of completed suicide, completed suicide and attempted suicide, and completed suicide, suicide attempt, preparatory acts toward imminent suicidal behavior, suicidal ideation plus indeterminate or potentially suicidal events overall for all AEDs and by individual AEDs prescribed in UK and Denmark; and 4) Describe the patterns of AED prescribing in six European databases (GPRD and THIN, UK; Danish registries; Mondriaan, Netherlands; Bavaria, Germany; Base de Datos para la Investigación Farmacoepidemiologica en Atencion Primaria (BIFAP), Spain).
Read the detailed description
Suicide is a major public heath concern. The estimated global burden of suicide is a million deaths per year. Self-inflicted death accounts for 1.5% of all deaths and is the tenth leading cause of death worldwide.
Compiling evidence on suicidality is fraught with problems. E.g. suicide deaths are generally perceived as underreported or prone to misclassification during cause-of-death ascertainment procedures. The suicide rates may be underestimated by 10% to 22%.
The reliability of suicidality recording in electronic databases has recently been studied. Arana et al investigated data from the United Kingdom database THIN and found that the codes and the algorithm used to identify suicidality had a very high predictive value (97%). The positive predictive values for completed suicide was lower (88%) and 14% of 'true', completed suicides were not identified as having died. Hall who did a validation study of death and suicide recording in the same databases identified seven cases of suicide out of 1394 'true deaths' (0.5%). One had a record of 'suicide' as a Read code, a second case was identified by 'hanging' in the comments section, a third probable suicide case by the Read term 'overdose of drug' plus an additional comment 'paracetamol/propaxyphene', and the four remaining cases were identified by external documents such as death certificates. Hall excluded patients with 'major emotional events' and a history of cancer. This may be one of the reasons why the percentage of suicide deaths was lower than expected (0.5% versus 1.5%) as mentioned above.
Antiepileptic medications are a heterogeneous pharmacologic class characterized by various chemical structures and postulated mechanisms of actions. The main therapeutic applications of antiepileptics include epilepsy, bipolar disorder, depression, neuralgia, and migraine. AEDs are among the most commonly prescribed centrally active agents. In a survey, carried out in a Danish County, 1.1% of the studied people received AEDs. The use of these drugs increased with increasing age.
Patients with the above mentioned indication such as epilepsy, major depression, and bipolar disorders have a higher risk for suicide compared with the general population.
A possible association between antiepileptic drugs and suicidality has been studied using different data sources such as the UK GPRD, the UK THIN, the US HealthCore Integrated Research Database (HIRD), Danish patient registries, Swedish patient registries, and data from clinical trials. The investigators applied different study designs such as cohort, matched case-control, case-crossover studies as well as a meta-analysis.
The published effects of antiepileptic drugs on suicidality covered a range between odds ratio (OR) 0.24 (95% CI: 0.03-2.17) for pregabalin and OR 6.42 (95% CI: 1.24-33.36) for levetiracetam. The effects of individual AEDs differed considerably within studies and between studies. The same holds for different indications. Arana et al found the lowest OR in patients with epilepsy only (OR 0.59; 95% CI: 0.35 - 0.98) and the highest OR in patients with depression only (OR 1.65; 95% CI: 1.24 - 2.19). The authors compared current use of AEDs with no use of AEDs in different indications.
Due to the complexity of the present issue, adequate adjustment for the numerous potential confounders such as socioeconomic aspects, various comorbidities, and concomitantly prescribed medication, is an analytic challenge. Further to this, the availability of a sufficiently large number of patients for investigation is another issue.
- Conditions
- Epilepsy
- Being tested
- Lamotrigine use
- Keywords
- Antiepileptics, suicidality
- Medical subject headings
- Epilepsy, Suicidal Ideation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Lamotrigine useDrug
Lamotrigine prescription during the study period
| Study group | Role | What they receive |
|---|---|---|
| Completed suicide | Patients who completed suicide Receives: Drug: Lamotrigine use | |
| Suicide attempt | Patients who have attempted suicide, or performed preparatory acts toward imminent suicidal behavior, suicidal ideation plus indeterminate or potentially suicidal events Receives: Drug: Lamotrigine use | |
| Not completed suicide | Patients who have not completed suicide Receives: Drug: Lamotrigine use |
What is being measured
The primary outcome is the main question the study is designed to answer.
Suicide attempt including completed suicide identified in GPRD from Read codes and cause of death; and ICD-9 codes and cause of death from Death Registry in Danish database
Measured: Up to 13 and a half years following drug exposure
Secondary outcomes (2)
Completed suicide only identified in GPRD from Read codes and cause of death; and ICD-9 codes and cause of death from Death Registry in Danish database only
Measured: Up to 13 and a half years following drug exposure
Completed suicide, suicide attempt, and including preparatory acts toward imminent suicidal behavior, suicidal ideation plus indeterminate or potentially suicidal events (wide definition) in GPRD only
Measured: Up to 13 and a half years following drug exposure
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 May 2012 (estimated)
- Study startDec 2011
- Primary completionJul 2014
- Study completionJul 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for EpilepsyStudies of the same condition, open and under way.
- More trials run by GlaxoSmithKlineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Time perspective
- Retrospective
- Enrolment
- 1 participants (actual)
Sponsor and investigators
- Lead sponsor
- GlaxoSmithKline
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- GSK Clinical Trials, Study director, GlaxoSmithKline
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01607333
- Sponsor's protocol ID
- 115737
- Other IDs
- WEUKBRE5557
- Status last verified
- Mar 2015
- First submitted
- 10 May 2012
- Last updated
- 27 Mar 2015
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 27 Mar 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- WEUKBRE5557: IMI PROTECT (Work Package 2): Use of Antiepileptics and Risk of Suicidality
- ClinicalTrials.gov ID
- NCT01607333
- Acronym / sponsor ID
- 115737
- Conditions
- Epilepsy
- Keywords
- Antiepileptics, suicidality
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 1 participants (actual)
- Lead sponsor
- GlaxoSmithKlineIndustry (pharma, biotech, devices)
- Study start
- Dec 2011
- Primary completion
- Jul 2014 (actual)
- Study completion
- Jul 2014 (actual)
- First posted
- 30 May 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The studies described in this protocol are all performed within the framework of PROTECT (Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium) Workpackage 2 and Workgroup 1. Primary aim of these studies is to develop, test and disseminate methodological standards for the design, conduct and analysis of Pharmacoepidemiological (PE) studies applicable to different safety issues and using different data sources. To achieve this, results from PE studies on five key adverse events (AEs) performed in different databases will be evaluated. Therefore, emphasis will be on the methodological aspects of the studies in this protocol and not on the clinical consequences of the association under investigation.
In the present project, investigators use Columbia Classification Algorithm of suicide assessment (C-CASA) definitions as a basis to specify the operational definitions of the different aspects of suicidality. The focus of the main analyses is on attempted suicide including completed suicide. This is due to statistical power issues. However, investigators will apply two additional outcome definitions in sensitivity analyses: 1) completed suicide only and 2) completed suicide, suicide attempt, preparatory acts toward imminent suicidal behavior, suicidal ideation plus indeterminate or potentially suicidal events. Investigators will not include terms which clearly indicate an accidental event, or self-injurious behavior without a suicidal intent. These definitions are listed in the statistical analysis plan together with lists of terms from the dictionaries used in the different databases.
The objectives of this study are to 1) Compare the study results which are based on two data sources (he UK General Practice Research Database (GPRD) and Danish registries) and different designs and evaluate the impact of design and population differences on the outcome of the study results (the UK database 'The Health Improvement Network' (THIN) may be included in these analyses as well); 2) Evaluate the strengths and weaknesses of the two data sources to study a possible association of antiepileptic drug (AED) use and suicidality, in particular the specific outcomes of death from suicide, hospitalization due to suicide attempt, and reports of the aspects of suicidality by the patients; 3) Estimate risks of completed suicide, completed suicide and attempted suicide, and completed suicide, suicide attempt, preparatory acts toward imminent suicidal behavior, suicidal ideation plus indeterminate or potentially suicidal events overall for all AEDs and by individual AEDs prescribed in UK and Denmark; and 4) Describe the patterns of AED prescribing in six European databases (GPRD and THIN, UK; Danish registries; Mondriaan, Netherlands; Bavaria, Germany; Base de Datos para la Investigación Farmacoepidemiologica en Atencion Primaria (BIFAP), Spain).
Detailed description
Suicide is a major public heath concern. The estimated global burden of suicide is a million deaths per year. Self-inflicted death accounts for 1.5% of all deaths and is the tenth leading cause of death worldwide.
Compiling evidence on suicidality is fraught with problems. E.g. suicide deaths are generally perceived as underreported or prone to misclassification during cause-of-death ascertainment procedures. The suicide rates may be underestimated by 10% to 22%.
The reliability of suicidality recording in electronic databases has recently been studied. Arana et al investigated data from the United Kingdom database THIN and found that the codes and the algorithm used to identify suicidality had a very high predictive value (97%). The positive predictive values for completed suicide was lower (88%) and 14% of 'true', completed suicides were not identified as having died. Hall who did a validation study of death and suicide recording in the same databases identified seven cases of suicide out of 1394 'true deaths' (0.5%). One had a record of 'suicide' as a Read code, a second case was identified by 'hanging' in the comments section, a third probable suicide case by the Read term 'overdose of drug' plus an additional comment 'paracetamol/propaxyphene', and the four remaining cases were identified by external documents such as death certificates. Hall excluded patients with 'major emotional events' and a history of cancer. This may be one of the reasons why the percentage of suicide deaths was lower than expected (0.5% versus 1.5%) as mentioned above.
Antiepileptic medications are a heterogeneous pharmacologic class characterized by various chemical structures and postulated mechanisms of actions. The main therapeutic applications of antiepileptics include epilepsy, bipolar disorder, depression, neuralgia, and migraine. AEDs are among the most commonly prescribed centrally active agents. In a survey, carried out in a Danish County, 1.1% of the studied people received AEDs. The use of these drugs increased with increasing age.
Patients with the above mentioned indication such as epilepsy, major depression, and bipolar disorders have a higher risk for suicide compared with the general population.
A possible association between antiepileptic drugs and suicidality has been studied using different data sources such as the UK GPRD, the UK THIN, the US HealthCore Integrated Research Database (HIRD), Danish patient registries, Swedish patient registries, and data from clinical trials. The investigators applied different study designs such as cohort, matched case-control, case-crossover studies as well as a meta-analysis.
The published effects of antiepileptic drugs on suicidality covered a range between odds ratio (OR) 0.24 (95% CI: 0.03-2.17) for pregabalin and OR 6.42 (95% CI: 1.24-33.36) for levetiracetam. The effects of individual AEDs differed considerably within studies and between studies. The same holds for different indications. Arana et al found the lowest OR in patients with epilepsy only (OR 0.59; 95% CI: 0.35 - 0.98) and the highest OR in patients with depression only (OR 1.65; 95% CI: 1.24 - 2.19). The authors compared current use of AEDs with no use of AEDs in different indications.
Due to the complexity of the present issue, adequate adjustment for the numerous potential confounders such as socioeconomic aspects, various comorbidities, and concomitantly prescribed medication, is an analytic challenge. Further to this, the availability of a sufficiently large number of patients for investigation is another issue.
Study design
- Time perspective
- Retrospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Completed suicide | – | Drug: Lamotrigine usePatients who completed suicide |
| Suicide attempt | – | Drug: Lamotrigine usePatients who have attempted suicide, or performed preparatory acts toward imminent suicidal behavior, suicidal ideation plus indeterminate or potentially suicidal events |
| Not completed suicide | – | Drug: Lamotrigine usePatients who have not completed suicide |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- For the descriptive studies that compare six European databases: All patients with at least one prescription of an AED between January 1, 2000 and December 31, 2009 from the following databases: National Databases (Denmark), General Practice Research Database [GPRD] (UK), Health Improvement Network [THIN] (UK), the Mondriaan database (Netherlands), BIFAP [Base de Datos para la Investigación Farmacoepidemiologica en Atencion Primaria] (Spain), and the Bavarian health-insurance database (Germany). Additional descriptive and analytic studies comparing the study populations from GPRD and Danish data sources: study cohorts consisting of patients who have received a first prescription to at least one AED on July 1, 1996 or later to December 31, 2009.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Lamotrigine useLamotrigine prescription during the study period | Drug | Completed suicide, Not completed suicide, Suicide attempt |
Primary outcome
Suicide attempt including completed suicide identified in GPRD from Read codes and cause of death; and ICD-9 codes and cause of death from Death Registry in Danish database
Time frame: Up to 13 and a half years following drug exposure
2 secondary outcomes
Completed suicide only identified in GPRD from Read codes and cause of death; and ICD-9 codes and cause of death from Death Registry in Danish database only
Time frame: Up to 13 and a half years following drug exposure
Completed suicide, suicide attempt, and including preparatory acts toward imminent suicidal behavior, suicidal ideation plus indeterminate or potentially suicidal events (wide definition) in GPRD only
Time frame: Up to 13 and a half years following drug exposure
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Mar 2015.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
GSK Clinical Trials study director
GlaxoSmithKline
Questions about this trial
What is this clinical trial studying?
An observational study of Epilepsy, run by GlaxoSmithKline.
The full registered description is in the About this study section and the official record.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 Mar 2015. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Suicide attempt including completed suicide identified in GPRD from Read codes and cause of death; and ICD-9 codes and cause of death from Death Registry in Danish database (time frame: Up to 13 and a half years following drug exposure). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Mar 2015.