A Randomized Controlled Trial of Generic Substitution of Antiepileptic Drugs
Trial Snapshot
- Phase
- Phase 4
- Enrollment
- 200
- Locations
- 16
- Primary Endpoint
- Serum drug concentration (25% change in serum drug concentration)
Study Overview
Brief 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.
Detailed Description
The primary objective is to provide high-quality evidence on potential risks associated with substitution of the currently taken AED product (carbamazepine,valproic acid, topiramate, oxcarbazepine, levetiracetam or lamotrigine) 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.
The study uses an experimental randomized non-inferiority design, and the hypothesis tested is that substitution of the currently taken AED product with another product (either generic or brand) will be associated with changes in serum drug levels which are no greater than those observed in a control group not undergoing any substitution.
The primary endpoint is the proportion of patients who post-randomization, will show a greater than 25% change in serum drug concentration compared with baseline.
The study will be conducted according to an experimental, prospective, randomized, open-label controlled, parallel-group design.
The study will be conducted in adults of either gender, enrolled at the time of hospital admission (or already hospitalized).
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 90 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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.
Arms & Interventions
Experimental Treatment
AED(s) currently taken (CBZ, VPA, TPM, OXC, LEV, LTG) will be substituted, starting with the morning dose on day 2, with an equivalent formulation available in the market. Namely, a brand product will be switched to a generic, randomly chosen among those available in the market, while maintaining unaltered the dosing regimen and times of administration.Likewise, a generic product will be switched to the brand or another generic.
Intervention: Experimental (Drug)
Outcomes
Primary Outcomes
Serum drug concentration (25% change in serum drug concentration)
Time Frame: After six months
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. When comparing differences in serum concentration between post-randomization and baseline, the mean of the two values (post-absorptive and trough) measured on each occasion will be used because this provides a more accurate estimate of relative bioavailability.
Secondary Outcomes
- adverse events(After three years)
- Serum drug concentration (distribution in individual serum drug concentrations)(After six months)
- first seizure after randomization(After three years)
- Serum drug concentration (5, 25% and 50% change in either post-absorptive or trough serum drug concentration)(After six months)
- Serum drug concentration (15% change in mean serum drug concentration)(After six months)
- Serum drug concentration (50% change in mean serum drug concentration)(After six months)
- Serum drug concentration (mean percent change (and %CV) in serum drug concentration)(After six months)
- products (by type of AED, specific product utilized, and type of switch (brand to generic and generic to generic)(After three years)