A Randomized, Double-blind, Parallel-group, Multicenter Study to Evaluate the Retention Rate, Efficacy, Safety, and Tolerability of Carisbamate, Topiramate and Levetiracetam as Adjunctive Therapy in Subjects with Partial Onset Seizures - CaReS (Carisbamate Retention Study)

• Register: EUCTR
• Last refreshed on: 19 March 2012
• Main ID: EUCTR2007-002929-78-PT
• Date of registration: 13/03/2009
• Prospective Registration: Yes
• Primary sponsor: Ortho-McNeil Janssen Scientific Affairs, LLC
• Public title: A Randomized, Double-blind, Parallel-group, Multicenter Study to Evaluate the Retention Rate, Efficacy, Safety, and Tolerability of Carisbamate, Topiramate and Levetiracetam as Adjunctive Therapy in Subjects with Partial Onset Seizures - CaReS (Carisbamate Retention Study)
• Scientific title: A Randomized, Double-blind, Parallel-group, Multicenter Study to Evaluate the Retention Rate, Efficacy, Safety, and Tolerability of Carisbamate, Topiramate and Levetiracetam as Adjunctive Therapy in Subjects with Partial Onset Seizures - CaReS (Carisbamate Retention Study)
• Date of first enrolment: 05/06/2009
• Target sample size: 600
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2007-002929-78
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no

Countries of recruitment

Czech Republic, Finland, France, Italy, Portugal, Spain, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
1. Male or female aged 18 years or older
2. Subjects must weigh at least 45 kg (~100lbs)
3. Established diagnosis, for at least 3 months prior to screening, of epilepsy characterized by partial onset seizures, including simple partial motor, complex partial, or secondarily generalized seizures
4. Must have had since the diagnosis of epilepsy and within the past 5 years a neuroimaging procedure, including a computed tomography (CT) scan or magnetic resonance imaging (MRI), that excluded a progressive neurologic disorder; these procedures may be performed within the 21-day screening phase (prior to
randomization)
5. At least 1 partial onset seizure, but no more than 120 partial onset seizures, during the 3-month retrospective baseline period prior to screening despite adequate AED treatment
6. AED treatment with at least 1, and no more than 2, AEDs given at stable dosage(s) 30 days prior to screening, and throughout the double-blind phase.
7. History of AED treatment failure (due to lack of efficacy or tolerability) to at least 2 but not more than 4 AEDs in the past. Note: The current (baseline) AED treatment should be counted among the previous AED treatment failures.
- Treatment failure due to lack of efficacy is defined as persistence of seizures at the highest tolerated dose of at least one AED, excluding those cases in which the efficacy of a dose within usually effective range could not be assessed due to occurrence of an idiosyncratic adverse reaction.
- The occasional use of rescue medication is not considered prior AED use
8. Females must be postmenopausal for at least 2 years, surgically sterile, abstinent, or, if sexually active, practicing an acceptable method of birth control (eg, intrauterine device, double-barrier method, male partner sterilization) before entry and throughout the study. Females must have a negative serum beta chorionic gonadotropin pregnancy test result at screening/randomization
9. Negative urine drug screen (except for prescription benzodiazepines, prescription barbiturates, or prescription narcotics) at screening
10. Willing to adhere to the prohibitions and restrictions as specified in Section 4.4, Prohibitions and Restrictions
11. Willing to allow the investigator (if not the treating physician) to contact the treating physician to discuss the subject’s participation in the trial. Subjects will only be eligible if the treating physician agrees that their participation is appropriate
12. Must have signed an informed consent form document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study. Adults not competent to consent will not be allowed into the study.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Have a generalized epileptic syndrome
2. Have primary generalized seizures
3. Have atonic seizures
4. Have typical or atypical absence seizures
5. Have only simple partial type seizures with manifestations other than motor symptoms (ie, simple partial sensory)
6. History of unprovoked status epilepticus in the last 6 months prior to screening
7. History of Lennox-Gastaut Syndrome
8. Any previous and/or current treatment with TPM or LEV (or other medications with equivalent international non-proprietary names)
9. More than 3 days of sedative or benzodiazepine use to treat breakthrough seizures in the 3 months prior to screening. Note: The use of benzodiazepines as daily, stably dosed AED treatment is permitted and should be counted among baseline AEDs.
10. Diagnosis of psychotic disorder, bipolar disease, or major depression or other neurologic conditions, serious or medically unstable systemic disease, suicidal ideation or attempts, or homicide attempts at any time in the past 2 years
11. History of nephrolithiasis with symptomatic renal stones within the last 2 years prior to screening
12. Diagnosis of autism and/or pervasive developmental disability not otherwise specified (NOS) and/or mental retardation or evidence of an intelligence quotient (IQ) =70
13. ALT greater than 1.5 times the ULN or total bilirubin above the ULN at screening
14. History of drug-induced liver injury (ie, history of ALT elevation 3 times ULN from prior drug exposure) or severe drug-induced, hypersensitivity reactions
15. History of Steven Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), a drug-related exfoliative rash, or any drug-related rash requiring hospitalization, or rash associated with an AED that involved conjunctiva or mucosa, or a maculopapular rash
that requires discontinuation of an AED.
16. History of any medical conditions that could potentially disqualify the subject for medical or safety reasons (e.g., renal insufficiency; vascular, pulmonary, gastrointestinal, endocrine, hematologic, or metabolic disturbances)
17. Diagnosis of any form of chronic liver disease, cirrhosis, or liver cancer. Examples of chronic liver disease include autoimmune hepatitis, hemochromatosis, Wilson’s disease, primary biliary cirrhosis, sclerosing cholangitis
18. Positive hepatitis serology as determined by multiantigen enzyme immunoassay (EIA): includes Anti-HCV, HBsAg, Anti-HBc, HepBCoreM, and Anti-HBs. Subjects with positive Anti-HCV test results will be excluded from the study. Criteria for excluding subjects based on hepatitis B results are provided in Attachment 1
19. Known to be positive for human immunodeficiency virus/ acquired immunodeficiency syndrome (HIV/AIDS). Note: HIV testing is not required for this study
20. Clinically relevant abnormalities for laboratory test values at screening
21. History of experimental drug or medical device use within the 30 days prior to screening
22. History of prior participation in a clinical trial of CRS or any prior exposure to CRS
23. Current treatment with a vagal nerve stimulator (VNS) or ketogenic diet
24. Planned epilepsy surgery within the next 12 months
25. Subjects with clinical evidence of significant cardiac disease, including unstable angina, myocardial infarction within the past 2 years, uncontrolled heart failure, congenital short QT syndrome, Brugada syndrome, major arrhythmias, or significant shortening or lengthening of QTcF int

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Partial onset seizures
MedDRA version: 9.1 Level: LLT Classification code 10034091 Term: Partial seizures, simple

Intervention(s)

Product Name: Carisbamate
Product Code: RWJ-333369
Pharmaceutical Form: Capsule*
INN or Proposed INN: carisbamate
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Capsule*
Route of administration of the placebo: Oral use

Trade Name: Topamax
Product Name: Topiramate
Pharmaceutical Form: Capsule*
INN or Proposed INN: TOPIRAMATE
CAS Number: 97240794
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-
Pharmaceutical form of the placebo: Capsule*
Route of administration of the placebo: Oral use

Trade Name: Keppra
Product Name: levetiracetam
Pharmaceutical Form: Capsule*
INN or Proposed INN: LEVETIRACETAM
CAS Number: 102767282
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 500-
Pharmaceutical form of the placebo: Capsule*
Route of administration of the placebo: Oral use

Trade Name: Topamax
Product Name: Topiramate
Pharmaceutical Form: Capsule*
INN or Proposed INN: TOPIRAMATE
CAS Number: 97240794
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Capsule*
Route of administration of the placebo: Oral use

Trade Name: Topamax
Product Name: Topiramate
Pharmaceutical Form: Capsule*
INN or Proposed INN: TOPIRAMATE
CAS Number: 97240794
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Capsule*
Route of administration of the placebo: Oral use

Product Name: Carisbamate
Product Code: RWJ-333369
Pharmaceutical Form: Capsule*
INN or Proposed INN: carisbamate
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-
Pharmaceutical form of the placebo: Capsule*
Route of administration of the placebo: Oral use

Product Name: Carisbamate
Product Code: RWJ-333369
Pharmaceutical Form: Tablet
INN or Proposed INN: carisbamate
Concentration unit: mg milligram(s)
Con

Primary Outcome(s)

Secondary Objective: The secondary objective of this study is to determine characteristics of the
study medications that might influence retention rate over a 6-month period, specifically to compare:

- The cognitive side effect profiles of CRS and TPM
- The neuropsychiatric side effect profiles of CRS and LEV
- Reasons for discontinuation among the 3 treatment arms
- Seizure rates among the 3 treatment arms
- Cognitive changes relative to baseline (assessed with computerized cognitive test battery) among the 3 treatment arms
- Subject-reported mood states and behavioral and cognitive side effect changes (patient- and observer-reported) relative to baseline using the POMS questionnaire, the CES-D and the patient- and observer-reported Overall Mental Effects Questionnaire among the 3 treatment arms

Each of the above objectives will also be evaluated at the end of the 6-month double-blind extension phase (12 months after randomization)

Main Objective: The primary objective of this study is to demonstrate the long-term retention rate of CRS versus TPM and LEV when given adjunctively to subjects with partial onset seizures based on discontinuations due to all cause over a 6-month period.

Primary end point(s): The primary efficacy endpoint is time from the first intake of study medication to discontinuation of study medication (all cause) over the 6-month core double-blind phase. This primary endpoint is a clinically meaningful composite measure of efficacy, safety and tolerability over time, reflecting the therapeutic effectiveness of antiepileptic drugs (AEDs).

Secondary ID(s)

2007-002929-78-GB

CARISEPY3007-Amendment INT-2/POR-1