Persistence and adherence to controlled release formulations of sodium valproate for the treatment of epilepsy and their clinical and resource use implications.

Date of ISAC Approval: 
30/05/2018
Lay Summary: 
Epilepsy is a common condition that affects the brain and causes frequent seizures. Seizures are bursts of electrical activity in the brain that temporarily affect how it works. They can cause a wide range of symptoms. Different types of epilepsy are often treated with anti-seizure medications, such as sodium valproate. There are many forms of medications available, including tablets, capsules, and even "modified release" forms which can delay the release of a drug into the bloodstream. The form of the medication may influence whether or not patients, especially young children will take them according to how they should be taken, which is a concept known as adherence. Adherence is important because taking too few medications may allow seizures to recur, while taking too much medication may lead to toxic effects. The primary aim of this study is to look at how different epilepsy medications, and their forms, would influence adherence. We plan to perform this study in primary care general practitioner practices (i.e. GP practices) where prescription data is available. We will compare Episenta and Epilim Chrono, which both contain sodium valproate but in different forms. We will be comparing the proportion of days patients were actually on the drug (i.e. Proportion of Days Covered, or PDC) for each form, which is a common way to measure adherence. The PDC will be measured by the number of days covered by the drug divided by the number of days in between repeat prescriptions. Other measures of adherence will also be performed. We will also be comparing how many admissions to hospital these patients have, as well as outpatient appointments, accident & emergency attendances, and other interactions with healthcare services. This will help us to determine whether the form of epilepsy medication will influence these outcomes.
Technical Summary: 
The primary objective of this study is to describe the persistence and adherence to modified release formulations of sodium valproate for the treatment of epilepsy and their clinical and resource use implications, for two alternative forms of oral CR valproate (Episenta and Epilim Chrono). Treatment adherence will be measured by Proportion of Days Covered (PDC) and Medication Possession Ratio (MPR). CR valproate-naive adult and paediatric (under 18 years) sub-groups of patients with diagnosed epilepsy will be assigned cohort membership based on their first-ever exposure to either Episenta formulations (minitablets in either capsules or sachets) or Epilim Chrono monolithic tablets. The cohorts will be randomly matched according to age group; and propensity score using parsimonious matching (no recycling) and a caliper of 0.1 in a ratio of 1 to 4 respectively. The primary endpoint will be proportion of patients achieving high adherence as determined by PDC>0.8. The margin of non-inferiority is empirically set as -0.1 (a 10% difference in proportion). If non-inferiority is met, a superiority hypothesis will be alternatively tested. The combined cohorts will also be used to explore the association between measures of anti-epileptic drug (AED) treatment adherence and the outcomes of seizure frequency and healthcare resource use using UK linked primary care and Hospital Episode Statistics records to maximise case ascertainment. The choice of valproate as a reference for the study is primarily because it is the first line treatment for most seizure types and syndromes according to NICE guidelines, particularly for children and young adults. These guidelines have made sodium valproate one of the most commonly used agents in the country for epilepsy in that population, serving as a good reference for AED treatment modifications.
Health Outcomes to be Measured: 
A. Proportion of Days Covered (PDC) - (total days all drug(s) available/days in follow-up period) B. Medication Possession Ratio (MPR) - (total Rx days of supply/last Rx date - first Rx date + last Rx days of supply) C. Time to switch/discontinuation (days) - discontinuation will be said to have occurred when any gap between CR valproate prescriptions exceeds a maximum allowable gap duration (MAGD) of (1.5 x the number of days supply of the last prescription). D. Incidence rate of overall emergency admission or A&E visit - assessed only in HES eligible patients E. Incidence rate of epilepsy-related emergency admission or A&E visit - assessed only in HES eligible patients F. Incidence rate of overall Outpatient contacts - assessed only in HES eligible patients G. Incidence rate of overall primary healthcare care professional contacts H. Incidence rate of epilepsy related primary healthcare care professional contacts - where the consultation includes a Read code related to epilepsy (see Appendix) I. Annualised tariff cost of D) ppy observed - assessed only in HES eligible patients applying current payment-by-results tariff (18) to the Health Resource Group allocation for the admission J. Annualised estimated cost of G) ppy observed - derived by applying published costs for units of Healthcare (19) K. Annualised total primary care medication costs ppy observed - derived by applying electronic Drug Tariff costs to prescriptions issued during observation period (20)
Collaborators: 

Mr Hassan Chaudhury - Chief Investigator - Imperial College London
Dr Austen El-Osta - Collaborator - Imperial College London
Dr Chris Poole - Collaborator - Boehringer-Ingelheim - UK

Linkages: 
HES Admitted;HES Outpatient