A Trial of Generic Substitution of Antiepileptic Drugs

NCT02429596 | Unknown Phase 4

• 1 other identifier: FARM9A8J83
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 16

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.

Conditions

Epilepsy

Keywords

antiepileptic drugs; generic substitution

Outcome Measures

Primary Outcomes (1)

• Serum drug concentration (25% change in serum drug concentration)

  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.

  After six months

Secondary Outcomes (9)

• 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 (5, 25% and 50% change in either post-absorptive or trough serum drug concentration)

  After six months

• Serum drug concentration (distribution in individual serum drug concentrations)

  After six months

• Serum drug concentration (mean percent change (and %CV) in serum drug concentration)

  After six months

Study Arms (2)

Experimental Treatment

EXPERIMENTAL

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.

Drug: Experimental

No Experimental Treatment

NO INTERVENTION

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.

Interventions

Experimental DRUG

Switch from brand to generic

Also known as: Lamictal, Acido Valproico, Keppra, Topamax, Tegretol, Tolep

Experimental Treatment

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• IRCCS National Neurological Institute "C. Mondino" Foundation: lead

Study Sites (16)

Clinica Neurologica Amaducci, Policlinico di Bari

Bari, Bari, Italy

NOT YET RECRUITING

Dipartimento di Scienze Neurologiche, Università degli Studi di Bologna

Bologna, Bologna, Italy

RECRUITING

Azienda Ospedaliera, Policlinico Universitario Mater Domini

Catanzaro, Catanzaro, 88100, Italy

COMPLETED

Azienda Ospedaliera ospedali Riuniti

Foggia, Foggia, Italy

ACTIVE NOT RECRUITING

Azienda Ospedaliera Universitaria Policlinico Gaetano Martino

Messina, Messina, Italy

NOT YET RECRUITING

UO di Neurologia, Azienda Ospedaliero Universitaria Pisana

Pisa, Pisa, Italy

ACTIVE NOT RECRUITING

Clinica Neurologica, Ospedali Riuniti

Ancona, Italy

NOT YET RECRUITING

U.S.C. Neurologia, Ospedali Riuniti

Bergamo, Italy

ACTIVE NOT RECRUITING

Unità Operativa Complessa di Neurologia, Ospedale di Bellaria

Bologna, Italy

RECRUITING

Centro Regionale dell'Epilessia, Azienda Ospedaliera Spedali Civili

Brescia, Italy

NOT YET RECRUITING

Clinica Neurologica, Ospedale San Gerardo

Monza, Italy

NOT YET RECRUITING

Clinica Neurologica, Azienda Ospedaliero-Universitaria Maggiore della Carità

Novara, Italy

RECRUITING

S.C. di Neurofisiopatologia, Centro di Riferimento Regionale Umbro per l'Epilessia

Perugia, Italy

NOT YET RECRUITING

Centro Regionale Epilessie, Reggio Calabria e Università della Magna Graecia

Reggio Calabria, Italy

RECRUITING

Dipartimento di Scienze Neurologiche, III Clinica Neurologica, Università "La Sapienza"

Roma, Italy

NOT YET RECRUITING

Unità Complessa di Neurologia, Ospedale SS. Giovanni e Paolo

Venezia, Italy

NOT YET RECRUITING

Related Publications (13)

• 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. doi: 10.1111/j.1528-1167.2007.01007.x.

  PMID: 17346246 BACKGROUND

• 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. doi: 10.1111/j.1528-1157.1997.tb01128.x.

  PMID: 9070599 BACKGROUND

• 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. doi: 10.1097/00007691-199702000-00020.

  PMID: 9029758 BACKGROUND

• 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.

  PMID: 18695164 BACKGROUND

• 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.

  PMID: 18589000 BACKGROUND

• 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.

  PMID: 20384761 BACKGROUND

• Kramer 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. doi: 10.1016/j.yebeh.2007.03.014. Epub 2007 May 29.

  PMID: 17537678 BACKGROUND

• Labiner DM, Paradis PE, Manjunath R, Duh MS, Lafeuille MH, Latremouille-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.

  PMID: 20393142 BACKGROUND

• 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.

  PMID: 20329806 BACKGROUND

• 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. doi: 10.1111/j.1528-1167.2006.00871.x.

  PMID: 17239100 BACKGROUND

• 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.

  PMID: 18852829 BACKGROUND

• 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.

  PMID: 18616554 BACKGROUND

• Wilner AN. Therapeutic equivalency of generic antiepileptic drugs: results of a survey. Epilepsy Behav. 2004 Dec;5(6):995-8. doi: 10.1016/j.yebeh.2004.05.011.

  PMID: 15582850 BACKGROUND

MeSH Terms

Conditions

Epilepsy

Interventions

Lamotrigine; Levetiracetam; Topiramate; Carbamazepine

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Triazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Acetamides; Amides; Organic Chemicals; Acetates; Acids, Acyclic; Carboxylic Acids; Pyrrolidinones; Pyrrolidines; Fructose; Hexoses; Monosaccharides; Sugars; Carbohydrates; Ketoses; Dibenzazepines; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Emilio Perucca, MD

  IRCCS National Neurological Institute "C. Mondino" Foundation

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Cinzia Fattore, MD

CONTACT

+39 0382 380818; cinzia.fattore@mondino.it

Emanuela Gerosa, MD

CONTACT

+39 0382 380282; emanuela.gerosa@mondino.it

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 14, 2014
• First Posted: April 29, 2015
• Study Start: May 1, 2012
• Primary Completion: May 1, 2015
• Study Completion: May 1, 2015
• Last Updated: April 29, 2015

Record last verified: 2015-04

Locations

IT (16)