USL261-401 Seizure Clusters

Principal Investigator: Matthew  Sweney
Keywords: Midazolam , USL261 , Seizure , Neurology Department: Pediatric Administration
IRB Number: 00084862 Co Investigator:  
Specialty: Pediatric Neurology, Neurology
Sub Specialties: Seizures
Recruitment Status: Recruiting

Contact Information

Maxwell Kilcoyne
maxwell.kilcoyne@hsc.utah.edu
8012133367

Brief Summary

 
This is a phase III multicenter study, with 2 distinct phases and 4 study center visits. The first phase is the Test-Dose Phase where subjects will receive 2 doses of open-label 5.0 mg USL261 administered 10 minutes apart at the study center. 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, double-blind, 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). If the treated seizure cluster has not terminated within 10 minutes after the initial drug administration, OR another seizure occurs between 10 minutes and 6 hours after administration of the study drug, AND the subject does not have < 8 breaths per minute, does not require emergency rescue treatment with assisted breathing or intubation and does not have excessive, uncharacteristic sedation (as defined by the investigator in the Patient Management Plan), the double-blind dose of study medication may be followed by a single dose of 5.0 mg USL261. Any time between 24 to 120 hours after study drug administration, subjects and caregivers will return to the study center for a post-dose study visit.
 
A maximum of approximately 350 subjects, aged 12 years or older, with a documented history of seizure clusters and on a stable antiepileptic drug (AED) regimen will be enrolled in the Test-Dose Phase. Before any subject continues to the Comparative Phase, safety data from at least 25 subjects in the Test- Dose Phase will be reviewed by an independent Data and Safety Monitoring Board (DSMB).
 
Enrollment will temporarily halt once approximately 25 subjects complete the Test-Dose Phase, to allow the DSMB to review the safety data. If the safety data from this initial cohort supports continuation of the trial according to the DSMB, enrollment into the Test-Dose Phase will resume and the initial 25 subjects will proceed to the Comparative Phase. All subsequent subjects will progress directly from Test-Dose Phase to the Comparative Phase.
 
 
Efficacy Objectives:
Primary Efficacy Objective:
To evaluate the efficacy of USL261 compared with that of intranasal (IN) placebo for the outpatient
treatment of seizure clusters based on Treatment Success, which is defined as achieving both of the
following:
 Termination of seizure(s) within 10 minutes after study drug administration, and
 No recurrence of seizure(s) beginning 10 minutes after study drug administration to 6 hours
after study drug administration
Secondary Efficacy Objective(s):
To evaluate the efficacy of USL261 compared with that of IN placebo for the outpatient treatment of
seizure clusters using the following:
 Proportion of subjects with recurrence of seizure(s) beginning 10 minutes after study drug
administration to 4 hours after study drug administration
 Time to next seizure with a start time > 10 minutes after study drug administration
 

 Safety Objective:

To evaluate the safety and tolerability of USL261 for the treatment of seizure clusters using the
following assessments:
 Adverse events (AEs)
 Caregiver-recorded respiration rate at 15 minutes, 30 minutes, 1 hour, 2 hours and 4 hours after
study drug administration in the Comparative Phase
 Clinical laboratory tests
 Vital signs measurements (systolic and diastolic blood pressure, pulse rate, respiration rate and temperature) as recorded by the study center personnel
 Physical, nasal and neurological examinations
 Brief Smell Identification Test (B-SIT)
 Columbia-Suicide Severity Rating Scale (C-SSRS)
 Requirement for unscheduled emergency room (ER) or emergency medical service (EMS) visit within 24 hours after study drug administration

Inclusion Criteria

A subject will be eligible for enrollment in the study if all of the following criteria apply:

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 IRB/Independent ethics committee (IEC) policy

2. Subject has a competent, adult (age ≥ 18) caregiver(s) who is able to recognize and observe the subject’s seizure cluster episodes, 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

3. Subject is 12 years of age or older at Visit 1

4. Subject is not likely to conceive, as indicated by a “yes” answer to at least 1 of the following questions:

  • Is the subject is a male?
  • 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?
  •  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 becomes 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.

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’s other non-cluster seizure activity (if any) in seizure type, duration, severity or frequency
  • 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
  • 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 (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)
  • 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
  • A frequency of ≥ 3 stereotyped seizure clusters during the year before Visit 1
  • At least 1 stereotyped seizure cluster occurring ≤ 4 months before Visit 1
  • The seizure cluster pattern described above is confirmed by a central reviewer (see Section 9.3.1)

6. Subject is receiving a regimen of AED(s) that has been stable (i.e., no changes in the type of AED) since Visit 1 and for ≥ 7 days before Visit 2. Changes in dose of an AED are allowed during the study; however, the new dose level must be kept stable for at 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 they are typically used ≤ 3 days in a 7-day period on average 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 other 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 bpm, inclusive
  •  No clinically significant vital sign values as determined by the investigator

Note: At the discretion of the investigator, out-of-range BP or HR measurements may be repeated once, and the repeat measurement used in relation to this inclusion criterion.

Exclusion Criteria

A subject will not be eligible for this study if any of the following criteria apply:

At Visit 1 (Screening)

1. Subject has a neurological disorder that is likely to progress in the next year

2. Subject has acute narrow-angle glaucoma

3. 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

4. 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

5. Subject has had psychogenic, non-epileptic seizure(s) within the 5 years before Visit 1

6. Subject has suicidality, defined as any of the following: a) active suicidal plan/intent or active suicidal thoughts in the 6 months before Visit 1 as defined by a Columbia-Suicide Severity Rating Scale (C-SSRS) suicidal ideation score ≥ 3, b) any suicide attempt in the past 5 years as determined by the C-SSRS or medical history, or c) other clinically significant suicidality as determined by the investigator

7. Subject, in the investigator’s opinion, has met the criteria for a major depressive episode at any time within 6 months before Visit 1 (criteria defined by the current edition of the Diagnostic and Statistical Manual of Mental Disorders)

8. Subject has or has had psychosis in the 12 months before Visit 1, excluding postictal psychosis

9. Subject has a history of their stereotypical seizure cluster (for which they are being enrolled in the study) progressing to status epilepticus (as determined by the investigator - PI defines status epilepticus as: persistent, sustained seizure activity (without return to typical behavioral baseline, lasting at least 20-30 minutes in duration) within the 2 years before  Visit 1

10. Subject has a history of drug or alcohol abuse within 1 year before Visit 1

11. Subject has a positive pregnancy test at Visit 1 or is currently pregnant or breastfeeding (females only) 12. Subject has a history of allergy or any significant adverse reaction (including rash) to midazolam

13. Subject is currently using an investigational drug or device or has used such within 30 days before Visit 1

14. Subject is currently using a vagal nerve stimulator (VNS) unless the device has been implanted for at least 6 months and the settings have not changed within 4 weeks before Visit 1

15. Subject has plasma phenobarbital concentrations > 35 μg/mL at Visit 1 (phenobarbital concentrations will be measured in subjects taking phenobarbital and in subjects for which the investigator deems it necessary)

16. Subject has any clinically significant laboratory abnormality as determined by the investigator and as confirmed by repeat testing (see Section 6.2.2.7.2), or has any of the following laboratory abnormalities at Visit 1 as confirmed by repeat testing:

  • Alanine transaminase (ALT) and/or aspartate transaminase (AST) results > 2
  • times the upper limit of normal
  • White blood cell count (WBC) < 2.5x109/L
  • Sodium < 128 mEq/L
  • Creatinine > 2.0 mg/dL

17. Subject is not appropriate for the study for any other reason as determined by the investigator

At Visit 2

18. Subject has developed a new medical condition, suffered a change in status of an established medical condition, developed a laboratory abnormality, or required a new treatment or medication which meets any previously described study exclusion criteria

19. Subject has a positive pregnancy test (females only)

20. Subject has active suicidal plan/intent or suicidal thoughts as defined by a C-SSRS suicidal ideation score ≥ 3 or has had a suicide attempt since the last visit 21. Subject has consumed any clinically significant CYP450 3A inhibitor/inducer, opioid, or other respiratory depressant (excluding antiepileptic drugs) within the required washout period before Visit 2 (see Appendix 1)

22. Subject has any of the following during the observation period after administration of the USL261 test dose at Visit 2:

  • Blood pressure (BP)
  • Systolic blood pressure (SBP) < 85 mm Hg and the change from baseline (pre-dose evaluation) in SBP is deemed clinically significant by the investigator
  • A ≥ 40 mm Hg decrease from baseline (pre-dose evaluation) in SBP
  • Diastolic blood pressure (DBP) < 50 mm Hg and the change from baseline (pre-dose evaluation) in DBP is deemed clinically significant by the investigator
  • A ≥ 30 mm Hg decrease from baseline (pre-dose evaluation) in DBP
  • Heart Rate (HR)
  • HR > 120 or < 50 bpm and change from baseline (pre-dose evaluation) in HR is deemed clinically significant by the investigator
  • A ≥ 40 bpm change from baseline (pre-dose evaluation) in HR
  • Respiratory rate (RR)
  • RR > 24 breaths per minute and change from baseline (pre-dose evaluation) in RR is deemed clinically significant by the investigator
  • RR < 8 breaths per minute while awake or after arousing
  • Sedation to the degree that the subject does not respond to mild prodding or shaking
  • Oxygen saturation < 90% for > 30 seconds or requires oxygen at any time
  • Clinically-significant ECG findings as determined by the investigator

Note: At the discretion of the investigator, out-of-range BP or HR measurements may be repeated once, and the repeat measurement used in relation to exclusion criteria, as long as the rules outlined in Section 6.2.2.3 are followed.

At Visit 3

23. Subject has developed a new medical condition, suffered a change in status of an established medical condition, developed a laboratory abnormality, or required a new treatment or medication which meets any previously described study exclusion criteria

24. Subject has a positive pregnancy test

25. Subject has active suicidal plan/intent or suicidal thoughts as defined by a C-SSRS suicidal ideation score ≥ 3 or has had a suicide attempt since the last visit