A Trial of Generic Substitution of Antiepileptic Drugs

• Status: Unknown status
• Trial end date: 2015-05-01
• Target enrollment: 0
• Participant gender: All

Summary

Background. Anecdotal reports and uncontrolled studies have described an association between generic substitution of antiepileptic drugs (AEDs) and adverse events, including loss of seizure control. Although these results are likely to be influenced by methodological bias, they have led to a strong opposition, among physicians and patients, to the use of generic products in epilepsy.

Objectives. The primary objective is to assess potential risks associated with substitution of the currently taken AED product with an equivalent product, using as endpoint changes in serum drug levels at steady-state after substitution compared with baseline. Secondary objectives will be the assessment of inter-subject variability in serum drug concentration on an unchanged treatment schedule, and evaluation of potential short-term changes in seizure control and adverse events rate.

Methods. The study will use an experimental randomized open-label non-inferiority design. The population will consist of 200 adults stabilized on chronic treatment with carbamazepine, valproic acid, topiramate, oxcarbazepine, levetiracetam or lamotrigine and admitted to hospital for diagnostic evaluation or other indications, with no expected treatment changes during the subsequent 5 to 6 days. Patients will be randomized to two groups. One group will continue to receive the AED products used before enrollment (brand or generic), whereas the other group will be switched to an alternative equivalent product. Dosing schedules of the AEDs being tested as well as comedications will be unaltered throughout the 6- to 7day period of the study. Serum AED levels (mean of two values obtained at peak and trough, respectively in the evening and the next morning) will be measured on day 1 (baseline) and 5 days post-randomization (6 days for patients receiving AEDs with half-lives above 12 h). The primary outcome endpoint will be the proportion of patients who, post-randomization, show a greater than 25% change in serum drug concentration compared with baseline. Secondary endpoints will include comparison of distributions of rough serum concentration changes between groups, other pharmacokinetic parameters, time to first seizure, total number of seizures, and adverse events.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: IRCCS National Neurological Institute "C. Mondino" Foundation
• Treatments: Anticonvulsants; Carbamazepine; Lamotrigine

Criteria

Inclusion Criteria:

• 18 years of age or older;

• currently being treated and at steady-state with any product (brand or generic) of carbamazepine, valproic acid, topiramate, oxcarbazepine, levetiracetam and/or lamotrigine administered in two or three divided daily doses, either alone or in combination with other drugs;

• a diagnosis of epilepsy or any other condition justifying prescription of AED therapy;

• being admitted to hospital (or being already in hospital) for observation/diagnostic evaluation or any other indication;

• expected to remain on the currently prescribed drug treatment for at least 5 days (or 6 days for patients receiving lamotrigine or topiramate without enzyme inducers, or receiving lamotrigine combined with enzyme inducers plus valproate);

• willingness to provide free, informed consent.

Exclusion Criteria:

• a history of known or suspected poor compliance;

• recent changes in drug treatment, including potentially interacting comedication, which may have prevented attainment of steady-state conditions of the AED(s) being tested;

• known disorders of gastric motility;

• pregnancy or lactation;

• any condition which is expected to alter the pharmacokinetics of the study drug(s) over the subsequent 5/6 days;

• inability to fully understand the nature and implications of the study.