A Phase 2a, Open-label, Proof-of-Concept Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Intranasal Clonazepam in Adult Subjects with Epileptic Seizures

• Conditions: Recurrent Acute Repetitive Seizures (ARS); MedDRA version: 9.1Level: LLTClassification code 10039910Term: Seizures

• Registration Number: EUCTR2007-003307-13-FI
• Lead Sponsor: Jazz Pharmaceuticals, Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2007-11-20
• Last Update Posted: 19 March 2012

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 45

Inclusion Criteria

1. Diagnosis of refractory epilepsy (a failure of at least 2 antiepileptic drugs to control seizures) for at least 2 months prior to study start. Identifiable partial or generalized seizure types are allowed provided they have a clear or reproducible EEG component.
2. Epilepsy subjects with a history of predictable daily seizure patterns. Subjects must average at least 7 seizures per week, with no more than 2 seizure-free days per week.
3. No nasal conditions that would preclude the use of an intranasal product.
4. Adult male and female subjects ages 18 to 65 years, inclusive.
5. Body Mass Index (BMI) less than 35 kg/m2.
6. Body weight no less than 100 lbs/45.5 kgs.
7. Has maintained stable doses of concomitant AEDs for at least 1 month prior to study entry (Day -1).
8. Willingness and ability to maintain a stable dose of current medications used to treat epilepsy (or other conditions) for the duration of the study
9. Good general health as determined by physical and neurological examination, medical history, clinical laboratory findings, and ECG at screening, as determined by the investigator.
10. Consent to use a medically acceptable method of contraception throughout the entire study period and for one week after the study is completed. Medically acceptable methods of contraception that may be used by the subject and/or the partner include abstinence, hormonal contraceptives, diaphragm and spermicide, intrauterine device (IUD), condom and vaginal spermicide, surgical sterilization, post-menopausal, and vasectomy (>6 months prior to Baseline).
11. Negative drug and alcohol screens at screening and baseline (Day -1). Subjects who test positive for barbiturates and benzodiazepines will not be excluded from the study, provided these drugs have been prescribed as AEDs for treatment of their epilepsy or anxiety.
12. No clinically significant hematological abnormalities in laboratory screening.
13. Ability for subject to read, understand, and provide written informed consent before enrolling in the study, and willingness to comply with all study procedures.
14. Agreement to remain in the study facility for the duration of the study (up to 9 calendar days).
15. Negative pregnancy test for all females at screening and baseline (Day -1).

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) no
F.1.3.1 Number of subjects for this age range

Exclusion Criteria

1. Subjects with a clinically significant unstable medical abnormality, chronic disease, or history or presence of significant hepatic, renal, endocrine, cardiovascular, gastrointestinal, pulmonary, psychiatric, or metabolic disease or any other abnormality (other than epilepsy) that could interfere with evaluation of the study drug.
2. Subjects in the EMU for pre-surgical evaluation.
3. Biochemical evidence of significant liver disease at screening.
4. Subjects who have experienced psychogenic non-epileptic seizures within the last 2 years.
5. Vagus nerve stimulator (VNS) implant within 3 months prior to enrollment (Day -1) or VNS setting adjusted within 30 days prior to enrollment.
6. Subjects who have experienced status epilepticus within the last 12 months.
7. Acute narrow angle glaucoma.
8. Subjects with any severe drug allergy, history of allergic or severe adverse drug reactions, or intolerance to clonazepam, other benzodiazepines, or the excipients used in the intranasal spray.
9. Subjects taking more than three concurrent AEDs (may be included after consultation with the medical monitor).
10. Subjects currently or regularly taking clonazepam
11. Use of an epilepsy rescue medication within five drug half-lives of clinic entry (Day -1).
12. Use of an OTC or prescription intranasal product within five drug half-lives of clinic entry (Day -1).
13. Subjects who require the use of a rescue medication more than twice per week.
14. Subjects with clinically significant illness (other than refractory epilepsy) within 30 days of screening, as determined by the investigator.
15. Subjects with a clinically significant abnormal finding (other than epilepsy) on physical or neurological examination, ECG, or clinical laboratory tests, as determined by the investigator at screening.
16. Subjects with a history of alcohol or drug abuse that in the investigator’s judgment will affect the subject’s safety and/or ability to complete the study.
17. Females who are pregnant, breastfeeding, or lactating.
18. Subjects who self-report ingestion of alcohol within 48 hours prior to dosing through completion of the study.
19. Subjects who used any other investigational drug or device within 30 days or five half-lives (whichever is longer) before clinic entry (Day -1), or plans to use an investigational drug (other than the study drug) during the study.
20. Subjects who have made any blood donation within 56 days of clinic entry (Day -1).
21. Subjects who have made any plasma donation within 7 days of clinic entry (Day -1).
22. Subjects who cannot understand or comply with the study procedures or whom the investigator suspects cannot understand or comply with the procedures.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To determine the minimum effective dose (MED) of intranasal clonazepam, defined as the lowest dose that can effectively reduce epileptiform activity in adult epilepsy subjects over the 24 hours following the onset of an epileptic seizure.;Secondary Objective: - To establish the safety and tolerability of intranasal clonazepam at the MED and at one higher dose, up to 4 mg<br>- To evaluate the PK characteristics of intranasal clonazepam at multiple dose levels, up to 4 mg<br>;Primary end point(s): The primary efficacy endpoint is change in epileptiform activity. In particular, the following endpoints will be analyzed:<br>• Number of spikes and sharp waves<br>• Number of spike-wave bursts lasting more than one second<br>• Electroclinical seizures<br>These endpoints will be measured from 24-hour video EEG recordings that will be compared between Baseline and Treatment Days.