| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| New-onset or recent-onset epilepsy. |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10015037 |
| E.1.2 | Term | Epilepsy |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to evaluate the effects of topiramate monotherapy compared with levetiracetam, another standard antiepileptic drug (AED), as monotherapy for new-onset or recent-onset epilepsy on pediatric growth and maturation, bone mineralization, and kidney stone formation in children 2 to 15 years of age. |
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| E.2.2 | Secondary objectives of the trial |
| Overall safety will be assessed |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1 Subject must be a child or adolescent (male or female) 2 to 15 years of age with a clinical diagnosis of new-onset or recent-onset epilepsy characterized by POS (with or without secondary generalization) or PGTCS in accordance with criteria of the International League Against Epilepsy. The epilepsy diagnosis must be within the previous 2 years before screening.2 Subject must have clinical or electroencephalogram (EEG) evidence of POS (simple or complex), with or without secondary generalization, or PGTCS at least 3 months prior to the first day of screening. Subjects should have at least 1, but no more than 2, unprovoked seizures during the 3 months prior to screening. Acceptable evidence of POS includes 1 of the following:
•Documented recurrent clinical seizures with asymmetric motor features or characteristic behavioral alterations. The interictal EEGs may be negative or inconclusive, provided that the clinical criterion for POS is met.
•A routine EEG or video EEG showing focal or asymmetric EEG findings (epileptiform discharges, focal slowing, focal attenuation, or a combination), with or without secondary generalization. Clinical seizures with symmetric or behavioral features are acceptable in the presence of EEG evidence of an asymmetric origin.
Acceptable evidence of PGTCS includes 1 of the following:
•Documented recurrent clinical seizures with seizures that are initially generalized, associated with tonic contractions and clonic movements
•EEG expression that is a generalized, synchronous, symmetrical discharge
•Interictal EEGs may be normal or show generalized discharges such as spikes, polyspike, spike-wave, and polyspike wave.
3 At screening, subject 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 CDC). 4 Subject must never have been treated for epilepsy (treatment-naïve) or have been treated with no more than 1 standard AED if temporary or urgent AED use was necessary. Previous AED exposure must not exceed either of the following:
•Thirty-one days immediately preceding enrollment, or
•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
5 If subject is currently treated with an AED, inadequacy of current epilepsy treatment must be documented on a worksheet provided to the investigator. Criteria for inadequacy include:
•AED dosage is considered optimized (including, if clinically appropriate, recent demonstration of adequate blood levels) in the opinion of the investigator and unchanged for at least 5 half-lives prior to the first day of screening and found to be:
-Inadequate in controlling seizures in the opinion of the investigator, as shown in part by a retrospective history of at least 1 seizure in the 3 months prior to screening, or
-Not well tolerated
6 Parents (or legally acceptable representatives) of the subject 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. Subjects 7 years of age and older, capable of understanding the nature of the study, must provide assent for their participation. 7 Caregivers (parents or legally acceptable representatives) of the subject must be able to accurately maintain the subject take-home record and seizure diary. 8 Subject must have had a computerized tomography or magnetic resonance imaging scan within 2 years prior to study entry, to confirm the absence of a progressive lesion, such as a tumor, with the exception of lesions of tuberous sclerosis and Sturge-Weber syndrome, which are allowed. The report must be included in the source documents. 9 Subject must have an electrocardiogram (ECG) at screening with no “abnormal, clinically significant” interpretations by a local cardiologist. 10 Subject must be otherwise healthy on the basis of physical examination, medical history, vital signs, clinical laboratory tests, and 12-lead ECG performed at screening. If there are abnormalities, they must be consistent with the underlying illness in the study population. This determination must be recorded in the subject's source documents and initialed by the investigator. 11 Subject must be ambulatory and must have normal activity levels based on the Habitual Activity Estimation Scale (HAES; see Attachment 1) at screening, according to recommended levels. 12 Before randomization, a girl must be either:
•Not of childbearing potential: premenarchal; permanently sterilized (eg, tubal occlusion, hysterectomy, bilateral salpingectomy); or otherwise be incapable of pregnancy
Please refer to protocol for all Inclusion Criteria |
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| E.4 | Principal exclusion criteria |
1 Subject has a surgically implanted and functioning vagus nerve stimulator. 2 Subject 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. 3 Subject has had uncontrolled seizures while previously taking either topiramate or levetiracetam. 4 Subject has a history of nonepileptic seizures within 2 weeks prior to the first day of screening. 5 Subject has myoclonic or absence seizures. 6 Subject has a history of status epilepticus within 2 weeks prior to first day of screening. Status epilepticus is defined as 30 minutes of continuous motor seizures. 7 Subject has had epilepsy surgery within 3 months prior to the first day of screening. 8 Subject has any progressive neurologic disorder, including malignancy, brain tumor, active central nervous system infection, demyelinating disease, or degenerative or progressive central nervous system disease, with the exception of tuberous sclerosis and Sturge Weber syndrome. 9 Subject has any clinically significant uncontrolled medical illness, including hepatic or renal failure, ischemic cardiac disease, bone disorders, growth and maturation disorders of any type, malignancy, physical impairments that prevent normal ambulation, or any disorder that, in the opinion of the investigator, places the subject at risk through participation in a clinical study. 10 Subject has nephrocalcinosis, renal stones of any type, or hydronephrosis, as evidenced by medical history or screening examination. 11 Subject has a history of ≥2 long bone fractures if the subject is ≤10 years old; ≥3 long bone fractures if the subject is >10 years old, where at least 1 of the fractures was a low-impact fracture, defined as slight trauma that may include:
•Falling to the ground from <0.5 m (standing height)
•Falling to a resilient surface (rubber or sand) from 0.5 to 3 m
•Falling from a bed or cot
•Playing injuries, including playground scuffles
12 Subject has indwelling hardware, or has an abnormality of the skeleton or spine, such as scoliosis of 20 degrees or more, kyphosis, or skeletal dysplasia. 13 Subject has clinically relevant abnormalities noted on renal ultrasound or DEXA scans. Subjects with baseline BMD Z-scores ≤-2, for either posterior-anterior lumbar spine (L1 L4) or total body less head, will not be enrolled. 14 Subject has congenital glaucoma or known ocular deficits, or is receiving any ocular medications except lubricating eye drops or topical antibiotics. 15 Subject has a known history of central hyperthermia, dysautonomia, or other disturbances of autonomic function. 16 Subject has a known history of inborn errors of metabolism, mitochondrial dysfunction, or prior evidence of hyperammonemia. 17 Subject has any clinically significant abnormality in laboratory tests at screening, including but not limited to:
•WBC count <3,000/mL or absolute neutrophil count <1,000 /mL in the last 6 months
•Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or gamma-glutamyltransferase (GGT) 3 times the ULN
•Total bilirubin 1.5 mg/dL or conjugated bilirubin 20% of total
•Venous ammonia 2 times the ULN
•25-hydroxy-vitamin D (normal reference range is ≥20.0 ng/mL)
•Parathyroid hormone (normal reference range is 14.0 to 72.0 pg/mL)
•1,25-dihydroxy-vitamin D, as determined by the age-dependent reference ranges (see lab manual)
•Insulin-like growth factor 1 (IGF-1), as determined by the age-dependent reference ranges (see lab manual)
18 Subject has a bicarbonate level <20 mEq/L, has a diagnosis of metabolic acidosis, or is on alkali therapy. 19 Subject has refractory epilepsy and requires adjunctive AED therapy or is receiving >1 concurrent AED (including benzodiazepines, regardless of the reason for prescription). 20 Subject is being treated with furosemide, hydrochlorothiazide, vigabatrin, vitamin B6 therapy for epilepsy, monoamine oxidase (A or B) inhibitors, felbamate, zonisamide, or any other medication that is a potent carbonic anhydrase inhibitor (eg, acetazolamide). Past treatment with furosemide for more than 2 weeks must be discussed with the sponsor and the discussion documented. 21 Subject is being treated with other drugs that may affect bone metabolism, eg, steroids (intravenous or oral steroids), growth hormone, antacids, or nonsteroidal anti-inflammatory drugs (NSAIDs) for chronic or underlying disorders for more than 7 consecutive days at least 1 month prior to the first day of screening. 22 Subject has been treated with an investigational drug within 5 half-lives prior to the first day of screening. please refer to Protocol for all the exclusion criteria |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
•Percentage of subjects with kidney stones
•Change from baseline in weight Z-score over time
•The following height analyses will be conducted for prepubertal subjects (2 to 9 years of age), subjects 10 to 15 years of age, and subjects 2 to 15 years of age:
-Height at 1 year postbaseline
-Height change from baseline over time
-Height Z-score at 1 year postbaseline
-Change from baseline in height Z-score over time
-Height velocity at 1 year postbaseline
-Height velocity Z-score at 1 year postbaseline
-Percentage of outlier subjects with height Z-score decrease of >0.5, >1.0, and >2.0 over time
•The following BMD and bone mineral content (BMC) endpoints:
-BMD and BMC over time
-BMD and BMC change from baseline over time
-Z-score for BMD and BMC over time
-Change from baseline in Z-score for BMD and BMC over time
-Percent change from baseline in BMD and BMC over time
-Percentage of outlier subjects with BMD Z-score decrease of >0.5, >1.0, and >2.0 over time
•Change from baseline in biochemical markers of bone mineralization including: serum levels of alkaline phosphatase, calcium, phosphorus, parathyroid hormone (intact), 25-hydroxy-vitamin D, 1,25-dihyroxy vitamin D, and IGF-1
•Change from baseline in serum and urine laboratory tests, eg, bicarbonate, ammonia, renal function tests, and LFTs
•Change from baseline in bone age |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The timepoints for the primary is baseline 6 months and 12 months or last visit in case of early termination.
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| E.5.2 | Secondary end point(s) |
Longitudinal endpoints will be analyzed using a mixed-model repeated measures (MMRM) analysis. The MMRM model will include treatment group, age group, visit, treatment-by-visit interaction, baseline measure, and baseline-by-visit interaction. An unstructured covariance will be used. Other appropriate covariance structures will be explored as needed. Confidence intervals with 95% confidence for the estimated treatment differences will be provided at each time point as appropriate. For proportion endpoints, 95% confidence intervals will be provided for the treatment difference. Each of the endpoints will also be summarized by age group.
Seizure counts and cognitive, developmental, and behavioral assessments will be summarized by treatment group and age group. The incidence of suicide-related thoughts and behaviors as determined by the C-SSRS will be summarized by treatment group and age group.
In addition to the above endpoints, other safety-related endpoints may be included in the analyses if deemed necessary.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Labs are done: screen, month 1, Month 3, 6, 9 and 12 or last visit.
Suicidality assessment is done at baseline, months 1-12, each visit.
Behavior assessments are done at baseline, month 3, month 6 and month 12
Seizure counts are done at months 1-12, each visit
Bone age x ray will be done at baseline and month 12
Bone marker assessments will be done at screen, month 6 and 12
The cognitive battery will be done at screen, baseline and months 6 and 12. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Austria |
| Brazil |
| Canada |
| Chile |
| China |
| Colombia |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Germany |
| Hungary |
| Italy |
| Korea, Republic of |
| Latvia |
| Lithuania |
| Malaysia |
| Mexico |
| Netherlands |
| New Zealand |
| Norway |
| Peru |
| Philippines |
| Poland |
| Portugal |
| Puerto Rico |
| Russian Federation |
| Singapore |
| South Africa |
| Spain |
| Sweden |
| Taiwan |
| Thailand |
| Ukraine |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The study is considered completed with the last study assessment for the last subject participating in the study. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 5 |
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