|Principal Investigator: Matthew Sweney|
|Keywords: Seizures , USL261||Department: Pediatric Administration|
|IRB Number: 00084971|
|Specialty: Pediatric Neurology|
|Recruitment Status: Recruiting|
This is a study of an experimental intranasal (in the nose) spray containing a drug called midazolam. Midazolam is approved by the United States Food and Drug Administration (FDA) to be given by intravenous injection (needle inserted directly in the vein) and intramuscular injection (needle inserted directly in the muscle) to sedate (relax, make a person sleepy) and/or lower anxiety in patients before an operation or during short-term uncomfortable or painful procedures (e.g., getting stitches ). It is also approved as an anesthetic (sleeping) agent during some operations. Doctors have also used midazolam “off-label” (this means without approval from the FDA) for treatment of seizures.
In this study, a spraying device will be used to spray midazolam into the nose. The liquid formulation (drug preparation) of intranasal midazolam used in this study is called USL261. The use of USL261 in this study is experimental because giving midazolam by spraying it into the nose and the preparation of midazolam to be used in the study have not been approved by the FDA or any other regulatory authority.
The purpose of this study is to learn about the safety of USL261 on seizures when the seizures occur one after the other in clusters (seizure cluster). When completed, this study may become part of the application that Upsher-Smith Laboratories, Inc. will submit to the FDA and other regulatory authorities outside the US to allow them to decide whether to approve the drug for sale for the purpose of treating seizure clusters.
- Caregiver-recorded respiration rate at 10 minutes, 15 minutes, 30 minutes, 1 hour, 2
- hours and 4 hours after study drug administration.
- Clinical laboratory tests.
- Physical, nasal, and neurological examinations.
- Vital sign measurements (systolic and diastolic blood pressure, pulse rate, respiration
- rate, and temperature) as recorded by the study center personnel.
- Requirement for unscheduled emergency room (ER) or emergency medical service
- (EMS) visits within 24 hours after study drug administration.
Each subject must meet the following criteria to be enrolled in this study.
In order to be eligible for study participation, subjects must have seizure clusters composed of 2 or more seizures. The entire seizure cluster, including ictal and interictal periods, must last more than 10 minutes with another seizure occurring between 10 minutes and 6 hours of recognition of the seizure cluster, as defined in the protocol. Seizure clusters have distinguishable characteristics that are easily recognized by patients and caregivers. The type, duration, and number of seizures in the cluster are highly variable between subjects, Patients with seizure clusters have a number of individual seizures over a period of minutes to hours and typically recover between seizures.
1. Subject or subject’s legally acceptable representative (LAR) has provided written informed consent, and subject has provided written assent where required by local law or Institutional Review Board (IRB)/Independent Ethics Committee (IEC) policy.
2. Subject has a competent, adult (age ≥ 18 years) caregiver(s) who is able to recognize and observe the subject’s seizure cluster episodes, who is willing to be trained in the study procedures, and has provided written informed consent; the caregiver(s) must be a relative, partner, friend, or LAR of the subject, or a person who provides daily care to the subject who has a significant personal relationship with the subject. (If it would not be safe for treatment to be delayed for 10 minutes or the caregiver would not be able/willing to wait 10 minutes between doses, then the subject is not eligible for the study)
3. Subject is 12 years of age or older at Visit 1.
4. Subject has an established diagnosis of partial or generalized epilepsy.
5. Subject has a documented history of seizure clusters that includes all of the following:
- The subject’s seizure cluster pattern is observable, stereotyped, and recognizably different from the subject’s other non-cluster seizure activity (if any) in seizure type, duration, severity, or frequency, and of the same type as that approved by the central reviewer in study P261-401.
- A documented history of seizure clusters lasting a minimum of 10 minutes from the time the seizure cluster is recognized.
- As part of the subject’s stereotyped seizure cluster pattern, a second seizure typically occurs within 6 hours from the time of recognition of the seizure cluster.
- The subject’s stereotyped seizure cluster pattern is composed of multiple (≥ 2) partial or generalized seizures.
- The subject’s stereotyped seizure cluster pattern was established > 3 months before Visit 1 of study P261-401.
- A frequency of ≥ 3 stereotyped seizure clusters during the year before Visit 1 of study P261-401.
- At least 1 stereotyped seizure cluster occurring at least once in the 4 months before Visit 1 of study P261-401.
6. Subject has successfully completed study P261-401, and the subject and caregiver have demonstrated adequate compliance with P261-401 study procedures as determined by the investigator OR, if Study P261-401 has been terminated, the subject completed the Test Dose Visit (Visit 2) of Study P261-401 and the subject did not meet any Visit 2 exclusion criteria in Study P261-401.
7. Subject is not likely to conceive, as indicated by a “yes” answer to at least 1 of the following questions:
- Is the subject a male?
- Is the subject a postmenopausal female as determined in study P261-401?
- Is the subject a female who has written medical documentation of being permanently sterilized (e.g. hysterectomy, double oophorectomy, bilateral salpingectomy)?
- Has the subject agreed to use two effective methods of contraception during the entire study if she is sexually active or will become sexually active during the study (except where local law or regulation differs; approval by USL or designee is required in such cases)?
Examples of two effective methods of contraception include the following:
- A diaphragm and a condom with spermicide
- An intrauterine device (IUD) used in combination with a barrier method (e.g., condom, diaphragm, or cervical cap with spermicide)
- Hormonal methods (e.g., high-dose birth control pills, Depo-Provera) or tubal ligation used in combination with a barrier method (e.g., condom, diaphragm, or cervical cap with spermicide)
Note that hormonal contraception alone is not considered adequate for this study and must be used in combination with another method. The type of birth control used must be approved by the investigator or designee.
Any subject who meets 1 or more of the following criteria will be excluded from the study:
1. Subject experienced a seizure cluster progressing to status epilepticus during or since his/her participation in Study P261-401. PI defines status epilepticus as: persistent, sustained seizure activity (without return to typical behavioral baseline, lasting at least 20-30 minutes in duration.
2. Subject has a positive pregnancy test at any visit or is pregnant, considering becoming pregnant, or is breastfeeding (female subjects only).
3. Subject who, in the opinion of the investigator, is experiencing an ongoing, uncontrolled, clinically significant adverse event(s) from P261-401 at Visit 1 or did experience a clinically significant adverse event in study P261-401 that might prevent the subject from safely participating in the study.
4. Subject has consumed any clinically significant CYP450 3A inhibitor/inducer, opioid, or other respiratory depressant, not including antiepileptic drugs (AEDs), within the required washout period before Visit 1 (see Appendix 1, Prohibited Concomitant Substances).
5. Subjects using chronic benzodiazepine(s); chronic use is defined as use for 4 or more days in a 7-day period on average.
6. Subject has a neurological disorder that is likely to progress in the next year.
7. Subject has a history of acute narrow-angle glaucoma.
8. Subject has a medical condition including uncontrolled cardiac, pulmonary, renal, hepatic, or gastrointestinal disease that could interfere with the study, subject safety/safety monitoring, or is not stable despite current therapy.
9. Subject has severe chronic cardio-respiratory disease with baseline room air oxygen saturations < 90%, New York Heart Association class III or IV functional status, or the need for ambulatory oxygen.
10. Subject has had psychogenic, non-epileptic seizure(s) during or since the P261-401 study.
11. Subject has suicidality, defined as any of the following: a) active suicidal plan/intent or active suicidal thoughts during or since the P261-401 study as defined by a C-SSRS suicidal ideation score ≥ 3, b) any suicide attempt during or since the P261-401 study as determined by the C-SSRS or medical history, or c) other clinically significant suicidality as determined by the investigator.
12. Subject, in the investigator’s opinion, has met the criteria for a major depressive episode during or since the P261-401 study (criteria defined by the current edition of the Diagnostic and Statistical Manual of Mental Disorders).
13. Subject has or has had psychosis during or since the P261-401 study, excluding postictal psychosis.
14. Subject has a history of drug or alcohol abuse during or since study P261-401.
15. Subject has a history of allergy or any significant adverse reaction (including rash) to midazolam.
16. Subject is currently using an investigational drug or device or has used such (other than the study drug during P261-401) within 30 days prior to Visit 1.
17. Subject has plasma phenobarbital concentrations > 35 μg/mL at Visit 1 (phenobarbital concentration will be measured in subjects taking phenobarbital and in subjects for which the investigator deems it necessary).
18. Subject is not appropriate for the study for any other reason as determined by the investigator.