A multicenter, double-blind, randomized, placebo-controlled, 4 parallel groups, dose-ranging trial evaluating the efficacy and safety of ucb 34714 used as adjunctive treatment at doses of 50, 150 and 400 mg/day in b.i.d. administration (oral capsules of 25 or 50 mg) for a maximum of 13 weeks in subjects from 16 to 65 years with refractory epilepsy suffering from partial onset seizures whether or not secondarily generalized - ucb 34714 dose-ranging

• Register: EUCTR
• Last refreshed on: 8 May 2012
• Main ID: EUCTR2004-001856-35-FI
• Date of registration: 20/12/2004
• Prospective Registration: Yes
• Primary sponsor: UCB S.A. Pharma Sector
• Public title: A multicenter, double-blind, randomized, placebo-controlled, 4 parallel groups, dose-ranging trial evaluating the efficacy and safety of ucb 34714 used as adjunctive treatment at doses of 50, 150 and 400 mg/day in b.i.d. administration (oral capsules of 25 or 50 mg) for a maximum of 13 weeks in subjects from 16 to 65 years with refractory epilepsy suffering from partial onset seizures whether or not secondarily generalized - ucb 34714 dose-ranging
• Scientific title: A multicenter, double-blind, randomized, placebo-controlled, 4 parallel groups, dose-ranging trial evaluating the efficacy and safety of ucb 34714 used as adjunctive treatment at doses of 50, 150 and 400 mg/day in b.i.d. administration (oral capsules of 25 or 50 mg) for a maximum of 13 weeks in subjects from 16 to 65 years with refractory epilepsy suffering from partial onset seizures whether or not secondarily generalized - ucb 34714 dose-ranging
• Date of first enrolment: 04/04/2005
• Target sample size: 245
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2004-001856-35
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Czech Republic, Finland, Germany, Spain, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
•An IEC approved written informed consent signed and dated by the subject or by parent(s) or legal representative. The consent form or a specific assent form, where required, will be signed and dated by minors.
•Well-characterized focal epilepsy or epileptic syndrome according to the ILAE classification, which was supported by adequate diagnostic documentation (EEG and MRI/CT scan).
•Subjects with a history of partial onset seizures whether or not secondarily generalized.
•Subjects having at least 4 partial onset seizures whether or not secondarily generalized during the 4-week Baseline Period and at least 2 partial onset seizures whether or not secondarily generalized per month during the 3 months preceding V1.
•Subjects being uncontrolled while treated by 1 or 2 concomitant AED(s). Vagal Nerve Stimulation (VNS) is allowed and will not be counted as a concomitant AED.
•Concomitant AED(s) being stable from at least 1 month before Visit 1 and during the whole trial period.
•Male/female subjects from 16 to 65 years, both inclusive. Subjects under 18 years may only be included where legally permitted and ethically accepted.
•Female subjects without childbearing potential (2 years post-menopausal, bilateral oophorectomy or tubal ligation, complete hysterectomy) are eligible. Female subjects with childbearing potential are eligible if they use a medically accepted contraceptive method. Oral or depot contraceptive treatment with at least 30 µg ?or 50 µg if associated with carbamazepine (CBZ)? ethinylestradiol per intake or double-barrier contraception are acceptable methods. The subject must understand the consequences and potential risks of inadequately protected sexual activity, be educated about and understand the proper use of contraceptive methods, and undertake to inform the Investigator of any potential change in status.
•Subject/legally acceptable representative considered as reliable and capable of adhering to the protocol (e.g. able to understand and complete diaries and questionnaires), visit schedule or medication intake according to the judgment of the Investigator.

Are the trial subjects under 18? yes
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)
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
•Seizure type IA non-motor as only seizure type.
•History or presence of seizures occurring only in clustered patterns, defined as repeated seizures occurring over a short period of time, i.e. < 20 minutes, with or without function regained between 2 ictal events during the last 5 years before V1.
•History or presence of status epilepticus during the last five years before V1.
•History or presence of known pseudo-seizures.
•Subjects on felbamate or having been on felbamate.
•Subjects currently on vigabatrine. Subjects having been on vigabatrine if no visual fields examination report available including standard static (Humphrey or Octopus) or cinetic perimetry (Goldman).
•Subject taking any drug with possible CNS effects. The use of benzodiazepine (BZD) is allowed if taken less than once a week. If taken more than once a week (for any indication), BZD will be considered as a concomitant AED.
•Subjects taking any drug that may significantly influence the metabolism of ucb 34714 (CYP2C or CYP3A potent inducers/inhibitors) except if the dose has been kept stable at least 1 month before V1, and will be kept stable during the entire trial duration.
•History of cerebrovascular accident (CVA), including transient ischemic attack (TIA), after which the subject’s condition had not stabilized and recurrence could not be excluded.
•Subjects suffering from severe cardiovascular disease.
•Presence of any sign (clinical or imaging techniques) suggesting rapidly progressing (i.e. not expected to stay stable during trial participation) brain disorder or brain tumor. Stable arteriovenous malformations, meningiomas or other benign tumors may be acceptable with prior approval by UCB.
•Any clinical conditions (e.g. bone marrow depression, chronic hepatic disease and/or severe renal impairment) which may contraindicate the use of ucb 34714, impair reliable participation in the trial or necessitate the use of medication not allowed by protocol.
•Presence of terminal illness
•Presence of a serious infection.
•Subjects with history of severe adverse hematologic reaction to any drug.
•Subjects suffering from severe disturbance of haemostasis.
•Subjects suffering from severe hyperuricaemia.
•Presence of unstable hyperthyroidism.
•Impaired hepatic function: ALAT/SGPT, ASAT/SGOT, alkaline phosphatase, ?GT value of more than three times the upper limit of the reference range.
•Subject having clinically significant deviations from reference range values for laboratory parameters: creatinine clearance < 50 ml/min, platelets < 100,000/?l, or neutrophil cells < 1,800/?l).
•Clinically significant ECG abnormalities according to Investigator.
•History of suicide attempt, current suicidal ideation or other serious psychiatric disorders [i.e. bipolar disorder, severe depression (with hallucinations and illusions), psychosis] requiring or having required hospitalization or medication within the previous five years.
•Known allergic reaction or intolerance to pyrrolidine derivatives and/or investigational product excipients.
•Known multiple drug allergies or severe drug allergy.
•Pregnant, lactating or sexually active women with childbearing potential who are not using a medically accepted birth control method.
•Subjects with a body weight less than 45 kg.
•Known alcohol or drug addiction or abuse within the last two years.
•Subject institutionalized under judicial decision.
•Subject taking part in another clinical/pharmacological trial in the three months preceding enrolmen

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

Health Condition(s) or Problem(s) studied

Epilepsy - Refractory Partial Onset Seizure wheter or not secondarily generalized.
MedDRA version: 7.1 Level: LLT Classification code 10061334

Intervention(s)

Product Code: ucb 34714
Pharmaceutical Form: Capsule*
INN or Proposed INN: not yet available
CAS Number: 357336-20-0
Current Sponsor code: ucb 34714
Other descriptive name: (a1S, 4R)-a-ethyl-2-oxo-4-propyl- 1-pyrrolidineacetamide
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

Product Code: ucb 34714
Pharmaceutical Form: Capsule*
INN or Proposed INN: not yet available
CAS Number: 357336-20-0
Current Sponsor code: ucb 34714
Other descriptive name: (a1S, 4R)-a-ethyl-2-oxo-4-propyl- 1-pyrrolidineacetamide
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

Primary Outcome(s)

Secondary Objective: - To evaluate the dose/clinical response relationship and narrow down the dose range of clinical interest.
- To explore tolerability of ucb 34714 in the same population.
- To collect data on seizure-free days and seizure-free subjects.

Primary end point(s): The intention-to-treat population (ITT) will consist of all randomized subjects who took at least one dose of trial medication.

The per-protocol population (PP) is a subset of the intention-to-treat population, consisting of those subjects who had no major protocol deviations affecting the primary efficacy variable, as confirmed during a pre-analysis meeting prior to unblinding of the data.

The analyses will be based on the ITT population unless stated otherwise.

The periods considered in the definition of efficacy and safety variables are the following:
•Baseline Period (V1 until V2).
•Up-titration period (V2 to V5).
•Treatment Period (V2 until the earlier of V8 and Early Discontinuation Visit).
•Maintenance Period (V5 until the earlier of V8 and Early Discontinuation Visit).
•Conversion Period (V8 until V11).
•Down-titration Period (V8 or Early Discontinuation Visit until V11).
•Post-treatment Period (V11 until V12).

Efficacy variables
Seizure frequency per week will be derived from the seizure count information recorded on the DRC and is defined as the number of seizures standardized to a seven day period. It is computed as the number of seizures recorded over the period, divided by the total number of days in that period, multiplied by 7.

The primary efficacy variable is the partial onset seizure frequency per week (type I) over the Maintenance Period.

The secondary efficacy variables are as follows:
•Seizure frequency per week for all seizures (types I+II+III) over the Maintenance Period.
•Reductions and percentage reductions from Baseline in seizure frequency per week for partial onset seizures (type I) and for all seizures (types I+II+III) over the Maintenance Period.
•Responder rate in partial onset seizures (type I) over the Maintenance Period. A responder is defined as a subject with a = 50% reduction in seizure frequency per week from the Baseline Period to the Maintenance Period.
•Response to treatment in partial onset seizures (type I) over the Maintenance Period. The percentage reduction from Baseline in partial seizure frequency per week over the Maintenance Period will be grouped in 4 categories: < -25%, -25% to < 25%, 25% to < 75%, 75% to 100%.
•Percentage of seizure-free subjects over the Maintenance Period.
•Percentage of seizure-free days over Baseline and Maintenance Periods.

Exploratory variables
•Patient’s Global Evaluation Scale at V8 or Early Discontinuation Visit.
•Investigator’s global Evaluation Scale at V8 or Early Discontinuation Visit.
•Health-Related Quality of Life (QOLIE-31-P) at V2 and at V8 or Early Discontinuation Visit.
•Hospital Anxiety and Depression Scale (HADS) at V2 and at V8 or Early Discontinuation Visit.
•Medical resources used over the Baseline Period and over the Evaluation Period, including health care provider consultations not foreseen by the protocol, concurrent medical procedures, concomitant medications, hospitalizations and length of stay.

Safety variables
Safety assessments will be made using adverse events, laboratory tests (including blood and urine), electrocardiogram (ECG), physical and neurological examinations, vital signs and body weight.

The number of subjects who follow the fallback option, the time to fallback and the reason of fallback will also be investigated in order to give the most accurate information on the data used for the primary efficacy analysis.

Pharmacokinetic variables
•ucb 34714 (parent compound only): plasma levels in all subjects, at each specified visit under trial drug
•Concomitant AED(s) (and/or relevant metabolites): plasma levels in all subjects at baseline and at each specified visit under trial drug.

Main Objective: To evaluate efficacy of ucb 34714 at the doses of 50, 150 and 400 mg/day in b.i.d. administration in reducing seizure frequency in subjects with focal epilepsy not fully controlled despite treatment with 1 or 2 concomitant AED(s).

Secondary ID(s)

N01114