Clinical trial NCT00441896: A Randomized, Controlled Trial of Ganaxolone in Patients With Infantile Spasms
Official title: A Double-blind, Placebo-controlled, Dose-ranging Clinical Study to Evaluate the Safety, Tolerability, and Antiepileptic Activity of Ganaxolone in Treatment of Patients With Infantile Spasms
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Infantile Spasms
Keywords: infantile spasms
anticonvulsant
pediatric epilepsy
West Syndrome
epileptic spasms
Lead sponsor: Marinus Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2007-03-01
Enrollment: 57
Sex: ALL
Minimum age (years): 4
Maximum age (years): 24
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: The study consists of cohorts where participants are randomized, in a 2:1 ratio, to 1 of 2 sequences, A and B. In each cohort, Sequence A, comprised of participants, who will receive ascending doses of ganaxolone and ascending doses of placebo. Sequence B, comprised of participants, who will receive ascending doses of placebo and ascending doses of ganaxolone. The dosing level in each subsequent cohort will be based upon experience gained from previous cohorts.

Detailed description: Male or female, 4 to 24 months of age (inclusive) with a diagnosis of IS with a 24 hour video EEG (vEEG) recording confirming the diagnosis and previously treated with 3 or fewer antiepileptic drugs (AEDs) are eligible for the study. The subject is able to continue treatment with concomitant AEDs (no more than 2; adrenocorticotropic hormone \[ACTH\], corticosteroids, felbamate, and vigabatrin are not allowed concomitantly). A ketogenic diet is permitted if it can be maintained for the duration of the study.

There will be a total of three weekly 24-hr video EEGs (baseline, end of weeks 1 and 2 of treatment). Dosing titration begins the day after each video EEG during the inpatient stay. All subjects will be receiving ganaxolone the day after the second video EEG.

A Data Monitoring Board (DMB) will determine whether successive cohorts of subjects can be dosed at an increased dose level; up to a maximum of 6 cohorts.

Eligibility criteria: Inclusion Criteria:

* Be diagnosed with IS (regardless of etiology- except for a progressive neurologic illness). Diagnostic Criteria: Seizures consisting of single or repetitive short muscular contractions leading to flexion or extension. Spasms may be characterized as tonic or myoclonic contractions, may occur singly or in clusters, and typically occur bilaterally and symmetrically. The EEG pattern must be consistent with the diagnosis of IS (hypsarrhythmia, modified hypsarrhythmia, multifocal spike wave discharges, etc).
* Have a vEEG recording confirming the diagnosis of IS.
* Have had a magnetic resonance imaging (MRI) performed to determine any possible causes of IS.
* Have been previously treated with 3 or fewer AEDs.
* If being treated with concomitant AEDs

  * Current AEDs have been at a constant daily dose for at least 2 weeks; Note: Subjects with minor dose adjustments may be allowed to enter the study after shorter periods after detailed discussion with the medical monitor.
  * Have a stable clinical response/plateau for at least 2 weeks
  * Are able to continue treatment with no more than 2 concomitant AEDs (ACTH, corticosteroids, felbamate, and vigabatrin are not allowed concomitantly).
  * A ketogenic diet is permitted if it can be maintained for the duration of the study.
* Be a male or female, 4 to 24 months of age (inclusive)
* Have a Parent/Guardian who is properly informed of the nature and risks of the clinical study, who is willing and capable of complying with all clinical study procedures, and has given informed consent in writing prior to entering the clinical study
* Be able to participate for the full term of the clinical study.

Exclusion Criteria:

* Treatment with corticosteroids, ACTH, vigabatrin, felbamate, or any AED not approved by Regulatory Agencies, 2 weeks prior to randomization.
* Treatment with more than two AEDs at baseline.
* Have an active CNS infection, demyelinating disease, degenerative neurological disease, or CNS disease deemed progressive (with the exception of tuberous sclerosis) as evaluated by brain imaging (MRI).
* Have any disease or condition (medical or surgical) at screening that might compromise the hematologic, cardiovascular, pulmonary, renal, gastrointestinal, or hepatic systems; or other conditions that might interfere with the absorption, distribution, metabolism, or excretion of the investigational product, or would place the subject at increased risk.
* Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin greater than four times the upper limit of normal (ULN) or clinical laboratory value deemed clinically significant by the Investigator.
* History of recurrent status epilepticus.
* Have been exposed to any other investigational drug within 30 days prior to randomization.

Primary outcomes:
measure: Change From Baseline in Frequency of Spasm Clusters at Day 10
timeFrame: Baseline (Day 0) and Day 10
Secondary outcomes:
measure: Change From Baseline in Frequency of Spasm Clusters at Day 20
timeFrame: Baseline (Day 0) and Day 20
measure: Number of Participants With Absence of Hypsarrhythmia
timeFrame: Day 10 and Day 20
measure: Number of Participants With Change in Clinical Status on the Investigator's Global Assessment
timeFrame: Baseline (Day 0), Day 10 and Day 20
measure: Number of Participants With Change in Clinical Status on Caregiver's Global Assessment
timeFrame: Baseline (Day 0), Day10 and Day 20
measure: Number of Participants With Spasm-free Durations
timeFrame: Day 10 and Day 20
measure: Number of Participants With Seizure-free Days
timeFrame: From Day 8 to Day 10 and From Day 18 to Day 20
measure: Number of Responders
timeFrame: Day 10 and Day 20
measure: Developmental Assessment Using Denver-II Developmental Test at Day 20
timeFrame: At Day 20
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital of Los Angeles
state: California
city: Los Angeles
country: United States
facility: Mattel Children's Hospital at UCLA
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Miami
country: United States
facility: Miami Children's Hospital, The Brain Institute
state: Florida
city: Pensacola
country: United States
facility: Child Neurology Care Center of Northwest Florida
state: Florida
city: Pensacola
country: United States
facility: Child Neurology Center of Northwest Florida
state: Florida
city: Chicago
country: United States
facility: University of Chicago Comer Children's Hospital
state: Illinois
city: Saint Paul
country: United States
facility: Minnesota Epilepsy Group, P.A.
state: Minnesota
city: Bronx
country: United States
facility: Montefiore Medical Center- Albert Einstein College of Medicine
state: New York
city: Memphis
country: United States
facility: Le Bonheur Children's Medical Center
state: Tennessee
city: Dallas
country: United States
facility: Dallas Pediatric Neurology Associates
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University Health System
state: Virginia
city: Seattle
country: United States
facility: Children's Hospital and Regional Medical Center
state: Washington
city: Milwaukee
country: United States
facility: Children's Hospital of Wisconsin
state: Wisconsin
Study officials:
References: