Protocol P261-401: A Randomized, Double Blind, Placebo Controlled Study of the Safety and Efficacy of Intranasal Midazolam in the Outpatient Treatment of Subjects with Seizure Clusters

Study ID
STU 062011-040

Cancer Related
No

Healthy Volunteers
No

Study Sites

Contact
Erica Howard
214-648-5606
erica.howard@utsouthwestern.edu

Principal Investigator
Paul Van Ness

Summary

This is a phase iii, double-blind, multicenter study, of intranasal Midazolam, with 2 distinct phases and 4 study center visits. The Test-Dose Phase is designed to assess the safety, tolerability, and pharmacokinetics (PK) of uSL261 in a monitored setting and provide the caregivers with training on the study procedures. The Test-Dose Phase will be followed by the Comparative Phase, an outpatient, doubleblind, placebo-controlled, parallel-group phase. in the Comparative Phase, all subjects will be randomized 2:1 to receive 5.0 mg uSL261 or placebo. During the Comparative Phase, the subject's caregiver will administer the double-blind study drug when the subject experiences a seizure cluster that meets the study criteria, as described in the subject's individualized Patient Management Plan (PMP).

each subject is required to have at least one caregiver in order to take part in the study. The caregiver will administer up to three doses of the nasal spray study drug to the subject, then observe the subject and make certain measurements after they give the study drug. The caregiver must also be able to accurately record the measurements of respirations and level of consciousness/sleepiness and come to the research center with the subject for 4 visits. Caregivers are also being asked to learn what to do and how to take action if the subject's seizures do not stop or if the subject becomes too sleepy or breathes too slowly after receiving the study drug. The caregiver will be trained by a member of the research staff for this study.

Participant Eligibility

[?]Inclusion/Exclusion Criteria:
Inclusion
1. Subject or subject[Single Quote]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/Independent Ethics Committee policy
2. Subject has a competent, adult (age >= 18) caregiver(s) who is able to recognize and observe the
subject[Single Quote]s seizure cluster episodes, 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 who has a
significant personal relationship with the subject
3. Subject is between 14 and 65 years of age, inclusive at Visit 1.
4. Subject is not likely to conceive, as indicated by a
* yes
* answer to at least 1 of the following
questions:
a. Is the subject a male?
b. Is the subject a postmenopausal female with greater than 1 year since last menses and a
follicular stimulating hormone value greater than 40 mIU/mL?
c. Is the subject a female who has written medical documentation of being permenantly sterilized (e.g. hysterectomy, double oophorectomy, bilateral salpingectomy)?
d. 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 acceptable methods of contraception include:

* 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 (eg, 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.
5. Subject has an established diagnosis of partial or generalized epilepsy that includes all of the
following:

* A documented history of seizure clusters lasting a minimum of 10 minutes from the time the seizure cluster is recognized

* The seizure cluster pattern is observable, stereotyped, and recognizably different from the subject[Single Quote]s other non-cluster seizure activity, (if any) in seizure type, duration, severity, or frequency

* As part of the subject's stereotyped seizure cluster patter, a second seizure typically occurs within 6 hours from the time of recognition of seizure cluster

* In the investigator's opinion, it would be safe for the subject to receive placebo as a first dose of study drug followed by active treatment (USL261) as the second dose of study drug no earlier than 10 minutes after the first dose

* A seizure cluster pattern composed of multiple (>= 2) partial or generalized seizures

* A seizure cluster pattern established > 3 months before Visit 1 with a pattern that is
observable, stereotyped, and recognizable different from the subject[Single Quote]s other non-cluster
seizure activity, if any

* A frequency of >= 3 seizure clusters during the year before Visit 1

* At least 1 seizure cluster occurring <= 4 months before Visit 1

* Seizure cluster pattern described above is confirmed by a central reviewer
6. Subject is receiving a regimen of AEDs that has been stable (ie, no changes in the type and dosing of AED) since Visit 1 and for >= 7 days before Visit 2, with or without intermittent use of
benzodiazepines at a constant dose. Changes in dose of an AED are allowed during the study; however, the new dose level must be kep stable for ate least 7 days before the subject receives study drug. Benzodiazepines that are used for rescue therapy of seizures or for non-epilepsy indications are allowed provided that they are typically used <= 3 times within a 7-day period on averag and always at the same dose. Daily use of a benzodiazepine as a chronic AED is not permitted.
7. Subject has had a documented brain computerized tomography or magnetic resonance imaging [?]review, performed after diagnosis of epilepsy and before Visit 1, that confirms the absence of a progressive neurological disorder
8. Subject weight is 40 kg to 125 kg (inclusive)
9. Subject must have a screening (Visit 1) 12-lead electrocardiogram (ECG) that meets the following criteria:

* QTcF interval <= 450 msec for males and <= 470 msec for females

* Consistent sinus rhythm as determined by the investigator

* No left bundle branch block (LBBB)

* No clinically significant conduction disorders as determined by the investigator
10) Subject must have screening (Visit 1) vital sign values that meet the following criteria:

* Systolic blood pressure of <= 160 mm Hg

* Diastolic blood pressure of <= 90 mm Hg

* Pulse rate of 50 to 115 bm, inclusive

* No clinically significant vital sign values as determined by the investigator
Note: At the discretion of the investigator, out-of-range blood pressure or heart rate measurements may be repeated once, and the repeate measurement used in relation to this inclusion.