A Study to Investigate the Safety of the Drugs Topiramate and Levetiracetam in Treating Children Recently Diagnosed With Epilepsy

• ClinicalTrials.gov Identifier: NCT02201251
• Recruitment Status: Completed
• First Posted: July 28, 2014
• Results First Posted: May 17, 2021
• Last Update Posted: May 27, 2022
• Sponsor: Janssen Research & Development, LLC
• Information provided by (Responsible Party): Janssen Research & Development, LLC

Study Description

Brief Summary:

The purpose of this study is to evaluate the safety of topiramate monotherapy compared with levetiracetam another standard antiepileptic drug (AED), as monotherapy for new-onset or recent-onset epilepsy (seizure disorder) on pediatric growth and maturation, bone mineralization, and kidney stone formation in children aged 2 to 15 years.

Condition or disease	Intervention/treatment	Phase
Epilepsy	Drug: Topiramate; Drug: Levetiracetam	Phase 3

Detailed Description:

This is a randomized (study medication assigned to participants by chance), open-label, multi-centric (conducted in more than one center) and 2-arm flexible-dose monotherapy study of topiramate compared with 1 another AED (levetiracetam) in pediatric participants with epilepsy. The total study duration will be up to of 1 year and 2 months per participant. The study consists of 3 parts: Screening (that is, up to 35 days before study commences on Day 1); Treatment (1 year) and post-treatment (30 days). Safety will primarily be evaluated by percentage of participants with kidney stones and change from baseline in bone mineral density at Month 12.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 63 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Health Services Research
• Official Title: A Randomized, Active-Controlled, Open-Label, Flexible-Dose Study to Assess the Safety and Tolerability of Topiramate as Monotherapy Compared With Levetiracetam as Monotherapy in Pediatric Subjects With New or Recent-Onset Epilepsy
• Actual Study Start Date: October 6, 2014
• Actual Primary Completion Date: April 30, 2020
• Actual Study Completion Date: April 30, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Topiramate; Topiramate weight based dosing for participants 2 to less than (<) 10 years of age not to exceed 350 mg/day (milligram per day), as tolerated; not to exceed 400 mg/day in participants 10-15 years of age, as tolerated.	Drug: Topiramate; Topiramate weight based dosing for participants 2 to <10 years of age not to exceed 350 mg/day, as tolerated; not to exceed 400 mg/day in participants 10-15 years of age, as tolerated.
Active Comparator: Levetiracetam; Levetiracetam weight based dosing for all participants 2-15 years of age, not to exceed 60 milligram per kilogram per day (mg/kg/day), as tolerated. The maximum recommended daily dosage is 3,000 milligram (mg).	Drug: Levetiracetam; Levetiracetam weight based dosing for all participants 2-15 years of age, not to exceed 60 mg/kg/day, as tolerated. The maximum recommended daily dosage is 3,000 mg.

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in Weight Z-score up to Month 1 [ Time Frame: Baseline up to Month 1 ]
   The Z-Score indicates how many standard deviations (SD) a participant has from the population normal values. The body weight z-scores were designed to take into account the amount of weight gain that was expected due to normal growth in children and adolescents. Body weight data were converted to Z-scores using the Statistical Analysis System (SAS) programs provided by the Centers for Disease Control (CDC) for the calculation of the 2000 CDC growth charts. The mean (SD) change in Z scores from baseline up to Month 1 for the total safety population for all age cohorts combined were presented. A negative Z-score indicates values lower than the mean while a positive Z-score indicates values higher than the mean.
2. Change From Baseline in Weight Z-score up to Month 3 [ Time Frame: Baseline up to Month 3 ]
   The Z-Score indicates how many SD a participant has from the population normal values. The body weight z-scores were designed to take into account the amount of weight gain that was expected due to normal growth in children and adolescents. Body weight data were converted to Z-scores using the SAS programs provided by the CDC for the calculation of the 2000 CDC growth charts. The mean (SD) change in Z scores from baseline up to Month 3 for the total safety population for all age cohorts combined were presented. A negative Z-score indicates values lower than the mean while a positive Z-score indicates values higher than the mean.
3. Change From Baseline in Weight Z-score up to Month 6 [ Time Frame: Baseline up to Month 6 ]
   The Z-Score indicates how many SD a participant has from the population normal values. The body weight z-scores were designed to take into account the amount of weight gain that was expected due to normal growth in children and adolescents. Body weight data were converted to Z-scores using the SAS programs provided by the CDC for the calculation of the 2000 CDC growth charts. The mean (SD) change in Z scores from baseline up to Month 6 for the total safety population for all age cohorts combined were presented. A negative Z-score indicates values lower than the mean while a positive Z-score indicates values higher than the mean.
4. Change From Baseline in Weight Z-score up to Month 9 [ Time Frame: Baseline up to Month 9 ]
   The Z-Score indicates how many SD a participant has from the population normal values. The body weight z-scores were designed to take into account the amount of weight gain that was expected due to normal growth in children and adolescents. Body weight data were converted to Z-scores using the SAS programs provided by the CDC for the calculation of the 2000 CDC growth charts. The mean (SD) change in Z scores from baseline up yo Month 9 for the total safety population for all age cohorts combined were presented. A negative Z-score indicates values lower than the mean while a positive Z-score indicates values higher than the mean.
5. Change From Baseline in Weight Z-score up to Month 12 [ Time Frame: Baseline up to Month 12 ]
   The Z-Score indicates how many SD a participant has from the population normal values. The body weight z-scores were designed to take into account the amount of weight gain that was expected due to normal growth in children and adolescents. Body weight data were converted to Z-scores using the SAS programs provided by the CDC for the calculation of the 2000 CDC growth charts. The mean (SD) change in Z scores from baseline to Month 12 for the total safety population for all age cohorts combined were presented. A negative Z-score indicates values lower than the mean while a positive Z-score indicates values higher than the mean.
6. Change From Baseline in Height Z-score up to Month 1 [ Time Frame: Baseline up to Month 1 ]
   Z-Score was a statistical measure to evaluate how a single data point compares to a standard. It described whether a mean was above or below the standard and how unusual the measurement is with range from minus (-) 3 to plus (+) 3; 0 equal to (=) same mean, greater than (>) 0 a greater mean, and less than (<) 0 a lesser mean than the standard. Growth parameters were compared to a standard defined by CDC growth charts. The mean (SD) change in Z scores from baseline up to Month 1 for the total safety population for all age cohorts combined were presented. A negative Z-score indicates values lower than the mean while a positive Z-score indicates values higher than the mean.
7. Change From Baseline in Height Z-score up to Month 3 [ Time Frame: Baseline up to Month 3 ]
   Z-Score was a statistical measure to evaluate how a single data point compares to a standard. It described whether a mean was above or below the standard and how unusual the measurement is with range from -3 to +3; 0 =same mean, >0 a greater mean, and <0 a lesser mean than the standard. Growth parameters were compared to a standard defined by CDC growth charts. The mean (SD) change in Z scores from baseline up to Month 3 for the total safety population for all age cohorts combined were presented. A negative Z-score indicates values lower than the mean while a positive Z-score indicates values higher than the mean.
8. Change From Baseline in Height Z-score up to Month 6 [ Time Frame: Baseline up to Month 6 ]
   Z-Score was a statistical measure to evaluate how a single data point compares to a standard. It described whether a mean was above or below the standard and how unusual the measurement is with range from -3 to +3; 0 =same mean, >0 a greater mean, and <0 a lesser mean than the standard. Growth parameters were compared to a standard defined by CDC growth charts. The mean (SD) change in Z scores from baseline up to Month 6 for the total safety population for all age cohorts combined were presented.
9. Change From Baseline in Height Z-score up to Month 9 [ Time Frame: Baseline up to Month 9 ]
   Z-Score was a statistical measure to evaluate how a single data point compares to a standard. It described whether a mean was above or below the standard and how unusual the measurement is with range from -3 to +3; 0 =same mean, >0 a greater mean, and <0 a lesser mean than the standard. Growth parameters were compared to a standard defined by CDC growth charts. The mean (SD) change in Z scores from baseline up to Month 9 for the total safety population for all age cohorts combined were presented. A negative Z-score indicates values lower than the mean while a positive Z-score indicates values higher than the mean.
10. Change From Baseline in Height Z-score up to Month 12 [ Time Frame: Baseline up to Month 12 ]
    Z-Score was a statistical measure to evaluate how a single data point compares to a standard. It described whether a mean was above or below the standard and how unusual the measurement is with range from -3 to +3; 0 =same mean, >0 a greater mean, and <0 a lesser mean than the standard. Growth parameters were compared to a standard defined by CDC growth charts. The mean (SD) change in Z scores from baseline up to Month 12 for the total safety population for all age cohorts combined were presented. A negative Z-score indicates values lower than the mean while a positive Z-score indicates values higher than the mean.
11. Change From Baseline in Bone Mineral Density (BMD) Z-score up to Month 6 [ Time Frame: Baseline up to Month 6 ]
    The BMD was measured by dual energy X-ray absorptiometry (DEXA) for the posterior-anterior lumbar spine (L1_L4) and total body less head area. The Z-Score is the number of standard deviations a participant's BMD differs from the average BMD of their age, sex and ethnicity. Positive scores indicate BMD above the mean; positive values are "best values" and negative values are "worst values". Positive changes from baseline indicated an improvement in condition.
12. Change From Baseline in BMD Z-score up to Month 12 [ Time Frame: Baseline up to Month 12 ]
    The BMD was measured by DEXA for the posterior-anterior lumbar spine (L1_L4) and total body less head area. The Z-Score is the number of standard deviations a participant's BMD differs from the average BMD of their age, sex and ethnicity. Positive scores indicate BMD above the mean; positive values are "best values" and negative values are "worst values". Positive changes from baseline indicated an improvement in condition.
13. Change From Baseline in Bone Mineral Content (BMC)-Z Score up to Month 6 [ Time Frame: Baseline up to Month 6 ]
    The BMC is an estimate of the amount of mineral (such as calcium) in the bone, which was assessed by DEXA scan for the posterior-anterior lumbar spine (L1_L4) and total body less head area. Positive changes from baseline indicated an improvement in condition.
14. Change From Baseline in BMC-Z Score up to Month 12 [ Time Frame: Baseline up to Month 12 ]
    The BMC is an estimate of the amount of mineral (such as calcium) in the bone, which was assessed by DEXA scan for the posterior-anterior lumbar spine (L1_L4) and total body less head area. Positive changes from baseline indicated an improvement in condition.

Secondary Outcome Measures :

1. Number of Participants With Treatment-emergent Adverse Events (TEAE) [ Time Frame: Up to Day 390 ]
   An adverse event (AE) is any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. TEAE are defined as AEs with onset during the treatment period or that are a consequence of a pre-existing condition that has worsened since baseline.
2. Percentage of Participants With Kidney Stones [ Time Frame: Up to Day 390 ]
   Percentage of participants with kidney stones were reported.

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 15 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Participant with a clinical diagnosis of new-onset or recent-onset epilepsy characterized by partial-onset seizures (POS) (with or without secondary generalization) or primary generalized tonic-clonic seizures (PGTCS) in accordance with criteria of the International League Against Epilepsy. The epilepsy diagnosis must be within the previous 2 years before screening
• Caregivers (parents or legally acceptable representatives) of the participant must be able to accurately maintain the participant take-home record and seizure diary
• At screening, participant must have weight and height values within the 5th to 95th percentile for chronological age (based on standard Child Height and Weight Charts from the Centers for Disease Control [CDC])
• Participant must never have been treated for epilepsy (treatment-naïve) or have been treated with no more than 1 standard antiepileptic drug (AED) if temporary or urgent AED use was necessary. Previous AED exposure must not exceed either of the following: 1.)Thirty-one days immediately preceding enrollment, or 2.)A total of 6 months of previous AED exposure in the past if the AED has been discontinued for at least 1 year prior to enrollment
• Parents (or legally acceptable representatives) of the participant must sign an informed consent/permission document, indicating that they understand the purpose of and procedures required for the study and are willing to give permission for their child to participate in the study. Participant 7 years of age and older, capable of understanding the nature of the study, must provide assent for their participation

Exclusion Criteria:

• Participant has a surgically implanted and functioning vagus nerve stimulator
• Participant has a history of seizures as a result of a correctable medical condition, such as metabolic disturbance, toxic exposure, neoplasm, or active infection within 2 weeks prior to the first day of Screening
• Participant has had uncontrolled seizures while previously taking either topiramate or levetiracetam
• Participant has a history of non-epileptic seizures within 2 weeks prior to the first day of Screening
• Participant has myoclonic or absence seizures

Contacts and Locations

Locations

United States, Alabama

Birmingham, Alabama, United States

United States, California

Los Angeles, California, United States

United States, Florida

Gulf Breeze, Florida, United States

Orlando, Florida, United States

Tampa, Florida, United States

Wellington, Florida, United States

United States, Kentucky

Louisville, Kentucky, United States

United States, Ohio

Columbus, Ohio, United States

Toledo, Ohio, United States

United States, Oregon

Portland, Oregon, United States

United States, Texas

San Antonio, Texas, United States

Temple, Texas, United States

Argentina

Buenos Aires, Argentina

Cordoba, Argentina

Australia

Queensland, Australia

Austria

Graz, Austria

Belgium

Leuven, Belgium

Namur, Belgium

Canada, Saskatchewan

Saskatoon, Saskatchewan, Canada

France

Brest, France

Bron, France

Paris, France

Toulouse, France

Germany

Munchen, Germany

Tübingen, Germany

Hungary

Balassagyarmat, Hungary

Budapest N/a, Hungary

Debrecen, Hungary

Veszprém, Hungary

Philippines

Cebu, Philippines

Manila, Philippines

Poland

Krakow, Poland

Poznan, Poland

Warsaw, Poland

Warszawa, Poland

Russian Federation

Saint Petersburg, Russian Federation

Ulyanovsk, Russian Federation

South Africa

Durban, South Africa

Taiwan

Kaohsiung, Taiwan

New Taipei City, Taiwan

Taichung, Taiwan

Taipei, Taiwan

Sponsors and Collaborators

Janssen Research & Development, LLC

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial; Janssen Research & Development, LLC

  Study Documents (Full-Text)

Documents provided by Janssen Research & Development, LLC:

Study Protocol  [PDF] November 3, 2017

Statistical Analysis Plan  [PDF] June 8, 2020

More Information

• Responsible Party: Janssen Research & Development, LLC
• ClinicalTrials.gov Identifier: NCT02201251
• Other Study ID Numbers: CR104425; TOPMATEPY4067 ( Other Identifier: Janssen Research & Development, LLC ); 2012-001552-19 ( EudraCT Number )
• First Posted: July 28, 2014
• Results First Posted: May 17, 2021
• Last Update Posted: May 27, 2022
• Last Verified: May 2022

• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Janssen Research & Development, LLC:

Epilepsy; Topiramate; Levetiracetam; Pediatric

Additional relevant MeSH terms:

Epilepsy; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Topiramate; Levetiracetam; Anticonvulsants; Hypoglycemic Agents; Physiological Effects of Drugs; Nootropic Agents