Clinical trial NCT00088452: Childhood Absence Epilepsy Rx PK-PD-Pharmacogenetics Study
Official title: Childhood Absence Epilepsy Rx PK-PD-Pharmacogenetics Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Childhood Absence Epilepsy
Petit Mal Epilepsy
Epilepsy
Seizures
Keywords: childhood absence epilepsy
CAE
petit mal epilepsy
epilepsy
seizures
ethosuximide
lamotrigine
valproic acid
Lead sponsor: Children's Hospital Medical Center, Cincinnati
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2004-07-27
Enrollment: 453
Sex: ALL
Minimum age (years): 30
Maximum age (years): 13
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine the best initial treatment for childhood absence epilepsy.

Detailed description: Childhood absence epilepsy (CAE) is a common pediatric epilepsy syndrome that affects 10 to 15 percent of all children with epilepsy. Individuals with CAE have brief staring spell seizures that occur suddenly, unpredictably, and frequently throughout the day. These seizures impair the children's ability to learn and play, and lead to higher injury rates.

There are many medications used to treat seizures, but only 3 generally are used as the first treatment for children with CAE: ethosuximide, lamotrigine, and valproic acid. The goal of this study is to determine which of these 3 medicines is the best first choice as treatment for children with CAE.

Approximately 439 children, recruited over a 3-year period at 32 medical centers in the US, will take part in this 5-year study. Participants will be randomly given one of the 3 common CAE treatments-ethosuximide, lamotrigine, or valproic acid-and will make regular visits to a clinic every 1 to 3 months for approximately 2 years. During the visits, participants will undergo regular testing to determine if the medicine is working, to watch for side effects, and to help researchers learn more about the responses to these medicines. In addition, researchers hope to develop methods that may be used in the future to help choose the best medicine for each individual diagnosed with CAE.

Also included in the study will be pharmacokinetics and pharmacogenetics research. Pharmacokinetics is the study of how the body absorbs, distributes, metabolizes, and excretes drugs. Pharmacogenetics is the study of genetic determinants of the response to drugs. Knowledge gained from this study may lead to individualized treatment for children with CAE, and may also be beneficial for other pediatric and adult seizure disorders.

Eligibility criteria: Inclusion Criteria:

* Diagnosis: Clinical diagnosis of Childhood Absence Epilepsy consistent with the International League against Epilepsy Proposal for Revised Classification of Epilepsies and Epileptic Syndromes (3).
* EEG: Interictal EEG demonstrating bilateral synchronous symmetrical approximate 3 Hz spike waves on a normal background with at least one burst lasting \>/= (greater than or equal to) 3 seconds.
* Age \> 2.5 years and \< 13 years of age at study entry.
* Body weight \>/= (greater than or equal to) 10 kilograms.
* Body Mass Index: BMI for age =/\< 99th percentile (based on the CDC BMI for age growth curves for boys/girls \[http://www.cdc.gov/growthcharts\], Appendix 1).
* Hepatic:
* AST/ALT \< 2.5 times the upper limit of normal
* Total bilirubin \< 1.5 times the upper limit of normal.
* Hematologic:
* Absolute neutrophil count \>/= (greater than or equal to) 1500/mm3.
* Platelets \>/= (greater than or equal to) 120, 000 /mm3.
* Female subjects must be premenarchal at the time of enrollment and must be willing to practice abstinence for the duration of the study.
* Parent/legal guardian(s) willing to sign an IRB approved informed consent.
* Subject assent (when appropriate and as dictated by local IRB).

Exclusion Criteria:

* Treatment for CAE with anti-seizure medications (AED) for a period of greater than 7 days prior to randomization.
* History of a major psychiatric disease (e.g., psychosis, major depression).
* History of autism or pervasive development disorder.
* History of non-febrile seizures other than typical absence seizures. This includes a history of an afebrile generalized tonic clonic seizure.
* Clinical signs and symptoms consistent with a diagnosis of juvenile absence epilepsy or juvenile myoclonic epilepsy as delineated by the International League against Epilepsy Proposal for Revised Classification of Epilepsies and Epileptic Syndromes (3).
* History of recent or present significant or medical disease, i.e., cardiovascular, hepatic, renal, gynecologic, musculoskeletal, metabolic, or endocrine.
* History of a severe dermatologic reaction (e.g., Stevens Johnson, toxic epidermolysis necrosis) to medication.
* Subject or parent/legal guardian might not be reasonably expected to be compliant with or to complete the study.
* Participation in a trial of an investigational drug or device within 30 days prior to screening.
* Use of systemic contraceptive for any indication, including acne.

Primary outcomes:
measure: Number of Participants With Freedom From Treatment Failure at 16-20 Weeks of Double Blind Therapy
timeFrame: First 16-20 weeks of double blind therapy
Secondary outcomes:
measure: Number of Participants With Attention Deficit as Measured by the Confidence Index of the CPT-II and the K-CPT
timeFrame: First 16-20 weeks of double blind therapy
measure: Number of Participants With Freedom From Treatment Failure at 12 Months of Double Blind Therapy
timeFrame: First 12 months of double blind therapy
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: The Children's Hospital of Alabama
state: Alabama
city: Phoenix
country: United States
facility: St. Joseph's Hospital and Medical Center
state: Arizona
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: La Jolla
country: United States
facility: University of California at San Diego
state: California
city: Los Angeles
country: United States
facility: Mattel Children's Hospital at UCLA
state: California
city: Denver
country: United States
facility: Children's Hospital of Denver
state: Colorado
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Jacksonville
country: United States
facility: Nemours Children's Clinic
state: Florida
city: Miami
country: United States
facility: Miami Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Chicago
country: United States
facility: Children's Memorial Hospital
state: Illinois
city: Detroit
country: United States
facility: Children's Hospital of Michigan
state: Michigan
city: Saint Louis
country: United States
facility: Washington University in St. Louis
state: Missouri
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Buffalo
country: United States
facility: Women and Children's Hospital of Buffalo
state: New York
city: New York
country: United States
facility: NYU Comprehensive Epilepsy Center, Manhattan
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital
state: Ohio
city: Cleveland
country: United States
facility: Rainbow Babies & Children's Hospital
state: Ohio
city: Columbus
country: United States
facility: Children's Hospital, Inc., PCTI
state: Ohio
city: Portland
country: United States
facility: Doernbecher Children's Hospital
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Memphis
country: United States
facility: LeBonheur Children's Medical Center
state: Tennessee
city: Dallas
country: United States
facility: Dallas Pediatric Neurology Associates
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah/Primary Children's Medical Center
state: Utah
city: Norfolk
country: United States
facility: Children's Hospital of The King's Daughter (Monarch Medical Research)
state: Virginia
city: Seattle
country: United States
facility: Children's Hospital & Regional Medical Center
state: Washington
city: Milwaukee
country: United States
facility: Children's Hospital of Wisconsin
state: Wisconsin
Study officials:
affiliation: Children's Hospital Medical Center, Cincinnati
name: Tracy A. Glauser, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital of Philadelphia
name: Peter Adamson, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's National Research Institute
name: Avital Cnaan, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Glauser TA, Cnaan A, Shinnar S, Hirtz DG, Dlugos D, Masur D, Clark PO, Adamson PC; Childhood Absence Epilepsy Study Team. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy: initial monotherapy outcomes at 12 months. Epilepsia. 2013 Jan;54(1):141-55. doi: 10.1111/epi.12028. Epub 2012 Nov 21.
citation: Cnaan A, Shinnar S, Arya R, Adamson PC, Clark PO, Dlugos D, Hirtz DG, Masur D, Glauser TA; Childhood Absence Epilepsy Study Group. Second monotherapy in childhood absence epilepsy. Neurology. 2017 Jan 10;88(2):182-190. doi: 10.1212/WNL.0000000000003480. Epub 2016 Dec 16.
citation: Shinnar S, Cnaan A, Hu F, Clark P, Dlugos D, Hirtz DG, Masur D, Mizrahi EM, Moshe SL, Glauser TA; Childhood Absence Epilepsy Study Group. Long-term outcomes of generalized tonic-clonic seizures in a childhood absence epilepsy trial. Neurology. 2015 Sep 29;85(13):1108-14. doi: 10.1212/WNL.0000000000001971. Epub 2015 Aug 26.
citation: Glauser TA, Cnaan A, Shinnar S, Hirtz DG, Dlugos D, Masur D, Clark PO, Capparelli EV, Adamson PC; Childhood Absence Epilepsy Study Group. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N Engl J Med. 2010 Mar 4;362(9):790-9. doi: 10.1056/NEJMoa0902014.
citation: Shinnar RC, Shinnar S, Cnaan A, Clark P, Dlugos D, Hirtz DG, Hu F, Liu C, Masur D, Weiss EF, Glauser TA; Childhood Absence Epilepsy Study Group. Pretreatment behavior and subsequent medication effects in childhood absence epilepsy. Neurology. 2017 Oct 17;89(16):1698-1706. doi: 10.1212/WNL.0000000000004514. Epub 2017 Sep 15.