A Trial of Generic Substitution of Antiepileptic Drugs
Information source: IRCCS National Neurological Institute "C. Mondino" Foundation
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Epilepsy
Intervention: Experimental (Drug)
Phase: Phase 4
Status: Recruiting
Sponsored by: IRCCS National Neurological Institute "C. Mondino" Foundation Official(s) and/or principal investigator(s): Emilio Perucca, MD, Principal Investigator, Affiliation: IRCCS National Neurological Institute "C. Mondino" Foundation
Overall contact: Cinzia Fattore, MD, Phone: +39 0382 380818, Email: cinzia.fattore@mondino.it
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.
Clinical Details
Official title: A Randomized Controlled Trial of Generic Substitution of Antiepileptic Drugs
Study design: Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label
Primary outcome: Serum drug concentration (25% change in serum drug concentration)
Secondary outcome: Serum drug concentration (15% change in mean serum drug concentration)Serum drug concentration (50% change in mean serum drug concentration) Serum drug concentration (5, 25% and 50% change in either post-absorptive or trough serum drug concentration) Serum drug concentration (distribution in individual serum drug concentrations) Serum drug concentration (mean percent change (and %CV) in serum drug concentration) adverse events adverse events first seizure after randomization products (by type of AED, specific product utilized, and type of switch (brand to generic and generic to generic)
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).
On the day of admission or inclusion in the study (day 1), all subjects fulfilling the
eligibility criteria and enrolled in the study will be allocated by 1: 1 randomization to
two groups, using a centralized telephone-based randomization office located at the
coordinating institution and stratification to ensure that the proportion of patients
receiving a brand or a generic at baseline is comparable between groups. For subjects taking
concomitantly more than one AEDs being tested, separate randomizations will be conducted
separately for each AED (for example, a subject receiving valproic acid and carbamazepine
will be randomized to continue on the same formulation of valproic or to switch to a
different formulation of valproic acid, and at the same time separately randomized to
continue on the same formulation of carbamazepine or to switch to a different formulation of
carbamazepine).
On day 1 (day of admission or day of inclusion in the study), all subjects will continue to
receive their current AED treatment, without any change in formulation (brand or specific
generic product), route and dosing schedule. Two blood samples for the determination of the
serum levels of the AED(s) will be collected, one on day 1 two hours after the evening dose
(absorptive phase sample, close to the expected peak time) and one the next morning (day 2)
just prior to the morning dose (trough sample).
When the randomized allocation requires a switch, the AED(s) currently taken (carbamazepine,
valproic acid, topiramate, oxcarbazepine, levetiracetam and/or lamotrigine) 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, as determined by the randomization scheme, while maintaining unaltered the
dosing regimen and times of administration. For AEDs which are commercially available both
as immediate-release as well as sustained-release dose forms, the substituted product (brand
of generic) will have equivalent release characteristics. The newly allocated treatments
will be continued unchanged for 4 days (days 2,3,4 and 5) or 5 days (days 2,3,4, 5 and 6)
for patients receiving lamotrigine or topiramate without enzyme inducers, or lamotrigine
combined with enzyme inducers plus valproate. No changes in concomitant treatments will be
allowed during the 5/6 days of the study, although addition, withdrawal or dose modification
of drugs not interacting pharmacokinetically with the medications taken by the subject will
be permitted.
When the randomized allocation requires continuation on the same product (control), the AED
product(s) currently taken will be continued unaltered, with the same dosing regimen and
times of administration. No changes in concomitant treatments will be allowed during the 5/6
days of the study, although addition, withdrawal or dose modification of drugs not
interacting pharmacokinetically with the medications taken by the subject will be permitted.
In both the test and the control allocations, two further blood samples for the
determination of the serum levels of the AED(s) will be collected again 4 days later (5 days
later for patients remaining on randomized treatment for 5 days), one two hours after the
evening dose (absorptive phase sample) on day 5 (day 6 for patients remaining on randomized
treatment for 6 days) and one in the next morning (day 6 or 7) just prior to the morning
dose (trough sample). Care will be taken to ensure that the samples on days 5 and 6/7 be
collected at the same times, not only in relation to times of dosing but also in relation to
actual time of the day and meal times. A 4-day interval for the post-randomization
pharmacokinetic assessment is sufficient to reach steady state for AEDs with expected
half-lives of about 12 h or less (carbamazepine, levetiracetam, valproic acid, topiramate
combined with enzyme inducers, lamotrigine combined with enzyme inducers, and the
monohydoxyderivative (MHD) of oxcarbazepine, for which oxcarbazepine is a prodrug).
Likewise, a 5-day interval is sufficient to reach steady state for AEDs with expected
half-lives of about 24 h (lamotrigine and topiramate not combined with enzyme inducers, and
lamotrigine combined with both enzyme inducers and valproic acid).
All subjects will be kept under medical observation during the study with a daily
unstructured interview and any additional investigation if needed, and any relevant change
in clinical status, including any treatment-emergent adverse event, will be recorded in the
CRF. During the 6/7-day observation period, subjects may undergo any clinical and laboratory
investigations (eg., hematology and blood chemistry tests, neuroimaging tests, EEGs) as
clinically indicated for their condition.
Patients will exit the study on day 6 or 7 as applicable and thereafter will be managed as
considered indicated by the attending physician. This could involve substituting the AED
product taken at that time in compliance with the policy on generic substitution implemented
at that hospital.
If a change in dose of the AEDs being tested or any potentially interacting comedication is
necessary prior to day 5/6, the two post-randomization samples may be collected 24 h earlier
for AEDs with half lives of about 12 h or less (carbamazepine, levetiracetam, valproic acid,
topiramate combined with enzyme inducers, MHD, and lamotrigine combined with enzyme
inducers). Because in these patients the half-life of the AED being tested allows attainment
of steady-steady conditions within 72 h. After collection of the post-randomization samples,
the subject will exit the study. In all other situations requiring premature termination of
the allocated treatment, subjects will exit the study and will be considered as drop-outs
with no evaluable pharmacokinetic outcome data.
At enrollment (baseline), the subject's medical and pharmacological history and results of
physical examination will be recorded. Historical data on seizure types and seizure
frequency will be collected, and assessment of adverse effects of AED therapy by
unstructured interview and application of the Adverse Event Profile (AEP) 21-item
questionnaire developed by Baker et al. (1997) . The AEP questionnaire and the physical
examination will be repeated on day 6/7. Occurrence of seizures will be recorded daily.
The AED products tested will include exclusively products commercially available in the
Italian market. In accordance with the current regulation (DM 17. 12. 2012), the hospital
pharmacy of each study site will stock the full range of available brand and generic
products of study drugs sufficient to cover at least 6-day treatment at average dosages. All
drug products will be stored, dispensed and tracked according to GCP guidelines.
Eligibility
Minimum age: 18 Years.
Maximum age: 90 Years.
Gender(s): Both.
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.
Locations and Contacts
Cinzia Fattore, MD, Phone: +39 0382 380818, Email: cinzia.fattore@mondino.it
Clinica Neurologica, Ospedali Riuniti, Ancona, Italy; Not yet recruiting Leandro Provinciali, MD, Email: leandroprovinciali@gmail.com
Clinica Neurologica Amaducci, Policlinico di Bari, Bari, Italy; Not yet recruiting Angela La Neve, MD, Email: centroepilessia@neurol.uniba.it Angela La Neve, MD, Principal Investigator
U.S.C. Neurologia, Ospedali Riuniti, Bergamo, Italy; Active, not recruiting
Dipartimento di Scienze Neurologiche, Università degli Studi di Bologna, Bologna, Italy; Recruiting Agostino Baruzzi, MD, Email: agostino.baruzzi@unibo.it Barbara Mostacci, MD, Email: barbara.mostacci@unibo.it Agostino Baruzzi, MD, Principal Investigator
Unità Operativa Complessa di Neurologia, Ospedale di Bellaria, Bologna, Italy; Recruiting Roberto Michelucci, MD, Email: roberto.michelucci@ausl.bologna.it Lilia Volpi, MD, Email: lilia.volpi@ausl.bologna.it
Centro Regionale dell'Epilessia, Azienda Ospedaliera Spedali Civili, Brescia, Italy; Not yet recruiting Luisa Antonini, MD, Email: luisa.antonini@spedalicivili.brescia.it
Azienda Ospedaliera, Policlinico Universitario Mater Domini, Catanzaro 88100, Italy; Completed
Azienda Ospedaliera ospedali Riuniti, Foggia, Italy; Active, not recruiting
Azienda Ospedaliera Universitaria Policlinico Gaetano Martino, Messina, Italy; Not yet recruiting Edoardo Spina, MD, Email: espina@unime.it Edoardo Spina, MD, Principal Investigator
Clinica Neurologica, Ospedale San Gerardo, Monza, Italy; Not yet recruiting Carlo Ferrarese, MD, Email: carlo.ferrarese@unimib.it Simone Beretta, MD, Email: simone.beretta@unimib.it
Clinica Neurologica, Azienda Ospedaliero-Universitaria Maggiore della Carità, Novara, Italy; Recruiting Roberto Cantello, MD Claudia Varrasi, MD, Email: claudia.varrasi@libero.it
S.C. di Neurofisiopatologia, Centro di Riferimento Regionale Umbro per l'Epilessia, Perugia, Italy; Not yet recruiting Teresa Anna Cantisani, MD, Email: cantisani@yahoo.com
UO di Neurologia, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy; Active, not recruiting
Centro Regionale Epilessie, Reggio Calabria e Università della Magna Graecia, Reggio Calabria, Italy; Recruiting Umberto Aguglia, MD, Email: u.aguglia@tin.it Sara Gasparini, MD
Dipartimento di Scienze Neurologiche, III Clinica Neurologica, Università "La Sapienza", Roma, Italy; Not yet recruiting Anna Teresa Giallonardo, MD, Email: annateresa.giallonardo@uniroma1.it
Unità Complessa di Neurologia, Ospedale SS. Giovanni e Paolo, Venezia, Italy; Not yet recruiting Francesco Paladin, MD
Additional Information
Related publications: Andermann F, Duh MS, Gosselin A, Paradis PE. Compulsory generic switching of antiepileptic drugs: high switchback rates to branded compounds compared with other drug classes. Epilepsia. 2007 Mar;48(3):464-9. Baker GA, Jacoby A, Buck D, Stalgis C, Monnet D. Quality of life of people with epilepsy: a European study. Epilepsia. 1997 Mar;38(3):353-62. Bartoli A, Marchiselli R, Gatti G. A rapid and specific assay for the determination of lamotrigine in human plasma by normal-phase HPLC. Ther Drug Monit. 1997 Feb;19(1):100-7. Berg MJ, Gross RA, Tomaszewski KJ, Zingaro WM, Haskins LS. Generic substitution in the treatment of epilepsy: case evidence of breakthrough seizures. Neurology. 2008 Aug 12;71(7):525-30. doi: 10.1212/01.wnl.0000319958.37502.8e. Berg MJ, Gross RA, Haskins LS, Zingaro WM, Tomaszewski KJ. Generic substitution in the treatment of epilepsy: patient and physician perceptions. Epilepsy Behav. 2008 Nov;13(4):693-9. doi: 10.1016/j.yebeh.2008.06.001. Epub 2008 Sep 10. Bialer M, Midha KK. Generic products of antiepileptic drugs: a perspective on bioequivalence and interchangeability. Epilepsia. 2010 Jun;51(6):941-50. doi: 10.1111/j.1528-1167.2010.02573.x. Epub 2010 Apr 8. Review. Krämer G, Biraben A, Carreno M, Guekht A, de Haan GJ, Jedrzejczak J, Josephs D, van Rijckevorsel K, Zaccara G. Current approaches to the use of generic antiepileptic drugs. Epilepsy Behav. 2007 Aug;11(1):46-52. Epub 2007 May 29. Review. Labiner DM, Paradis PE, Manjunath R, Duh MS, Lafeuille MH, Latrémouille-Viau D, Lefebvre P, Helmers SL. Generic antiepileptic drugs and associated medical resource utilization in the United States. Neurology. 2010 May 18;74(20):1566-74. doi: 10.1212/WNL.0b013e3181df091b. Epub 2010 Apr 14. Kesselheim AS, Stedman MR, Bubrick EJ, Gagne JJ, Misono AS, Lee JL, Brookhart MA, Avorn J, Shrank WH. Seizure outcomes following the use of generic versus brand-name antiepileptic drugs: a systematic review and meta-analysis. Drugs. 2010 Mar 26;70(5):605-21. doi: 10.2165/10898530-000000000-00000. Review. Perucca E, Albani F, Capovilla G, Bernardina BD, Michelucci R, Zaccara G. Recommendations of the Italian League against Epilepsy working group on generic products of antiepileptic drugs. Epilepsia. 2006;47 Suppl 5:16-20. Privitera MD. Generic antiepileptic drugs: current controversies and future directions. Epilepsy Curr. 2008 Sep-Oct;8(5):113-7. doi: 10.1111/j.1535-7511.2008.00261.x. Zachry WM 3rd, Doan QD, Clewell JD, Smith BJ. Case-control analysis of ambulance, emergency room, or inpatient hospital events for epilepsy and antiepileptic drug formulation changes. Epilepsia. 2009 Mar;50(3):493-500. doi: 10.1111/j.1528-1167.2008.01703.x. Epub 2008 Jun 26. Wilner AN. Therapeutic equivalency of generic antiepileptic drugs: results of a survey. Epilepsy Behav. 2004 Dec;5(6):995-8.
Starting date: May 2012
Last updated: April 28, 2015
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