Epilepsy
Conditions
Keywords
Epilepsy, seizure clusters, acute repetitive seizures, rescue treatment, ARTEMIS
Brief summary
The purpose of this study is to examine the safety and effectiveness of USL261 for the outpatient treatment of seizure clusters.
Detailed description
Qualifying participants underwent an in-clinic administration (Test Dose Phase \[TDP\]) of two doses of USL261 (intranasal midazolam 5 mg), separated by 10 minutes, in the absence of seizures. Eligible participants were then randomized to USL261 versus Placebo in an outpatient Comparative Phase (CP). When the participant had a qualifying seizure cluster episode, as described in an individualized patient management plan, the participant's caregiver administered the double-blind dose. An open-label USL261 dose could be administered after 10 minutes and up to 6 hours after the double-blind dose, if the participant had persistent or recurrent seizures. Initial participants could not proceed to CP until an independent data safety monitoring board (DSMB) reviewed safety data from at least the first 25 participants in TDP; the DSMB performed additional safety reviews at pre-set intervals based on enrollment.
Interventions
DRUGUSL261
DRUGPlacebo
Sponsors
UCB Biopharma S.P.R.L.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has a competent, adult caregiver who can recognize and observe the subject's seizure cluster episodes * Has an established diagnosis of partial or generalized epilepsy that includes the following: * A documented history of seizure clusters lasting a minimum of 10 minutes * Seizure cluster pattern is observable, stereotyped, and recognizably different from the subject's other non-cluster seizure activity (if any) * A second seizure in the seizure cluster typically occurring within 6 hours from the time of cluster recognition * A seizure cluster pattern composed of multiple (≥ 2) partial or generalized seizures * A seizure cluster pattern established \> 3 months before Visit 1 * 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 is confirmed by a central reviewer * Currently on a stable regimen of anti-epileptic drugs (AEDs) with no changes in type of AEDs since Visit 1 and for ≥ 7 days before Visit 2, with or without intermittent use of benzodiazepines at a constant dose * Weight is 40 kg to 125 kg, inclusive
Exclusion criteria
* Has a neurological disorder that is likely to progress in the next year * Has severe chronic cardio-respiratory disease * Has had psychogenic, non-epileptic seizure(s) within the 5 years before Visit 1 * Has a history of their stereotypical seizure cluster progressing to status epilepticus within the 2 years before Visit 1 * Has a history of acute narrow-angle glaucoma. * Has had active suicidal plan/intent or active suicidal thoughts in the 6 months before Visit 1 or a suicide attempt in the past 5 years * Currently using a vagal nerve stimulator (VNS) unless the device has been implanted for at least 6 months and the setting stable for 4 weeks before Visit 1
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants Who Met the Criteria for Treatment Success After Administration of the Double-blind Dose in the Comparative Phase (CP) | 6 hours | Treatment Success is defined as achieving both of the following: 1) termination of seizure(s) within 10 minutes after double-blind study drug administration, and 2) no recurrence of seizure(s) beginning 10 minutes after study drug administration to 6 hours after study drug administration. Participants who received the open-label second dose within 6 hours of administration of the double-blind dose were analyzed as having had a seizure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Participants With Seizure(s) >10 Minutes to 4 Hours After Administration of the Double-blind Dose | 4 hours | Participants with recurrence of seizure(s) \>10 minutes and up to 4 hours after administration of the double-blind dose in the CP. Participants who received the open-label second dose within 4 hours of administration of the double-blind dose were analyzed as having had a seizure. |
| Occurrence of Seizure With a Start Time >10 Minutes After Administration of the Double-blind Dose | 24 hours | Occurrence of next seizure with a start time \>10 minutes and up to 24 hours after administration of the double-blind dose in the CP. Participants who did not have another seizure before the end of the 24-hour observation period were censored at the end of the observation period. Participants administered the open-label second dose who did not have a seizure were censored at the time of the administration. |
| Time to Next Seizure With a Start Time >10 Minutes After Administration of the Double-blind Dose | 24 hours | Time to next seizure with a start time \>10 minutes and up to 24 hours after administration of the double-blind dose in the CP. Participants who did not have another seizure before the end of the 24-hour observation period were censored at the end of the observation period. Participants administered the open-label second dose who did not have a seizure were censored at the time of the administration. |
Countries
Australia, Canada, Germany, Hungary, Israel, Italy, New Zealand, Poland, Spain, Ukraine, United States
Participant flow
Pre-assignment details
Participants underwent in-clinic administration of open-label USL261 5 mg followed by USL261 5 mg 10 minutes in absence of a seizure (Test Dose Phase \[TDP\]). Participants were then randomized to double-blind USL261 5 mg or Placebo to be administered by caregiver to treat a seizure cluster in Comparative Phase (CP) in the outpatient setting.
Participants by arm
| Arm | Count |
|---|---|
| USL261 Test Dose Participants who received at least 1 open-label USL261 5 mg dose in Test Dose Phase (TDP) | 292 |
| Total | 292 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Comparative Phase | Withdrawal by Subject | 0 | 1 | 0 |
| Test Dose Phase | Adverse Event | 17 | 0 | 0 |
| Test Dose Phase | Caregiver no longer available | 5 | 0 | 0 |
| Test Dose Phase | Logistical | 6 | 0 | 0 |
| Test Dose Phase | Lost to Follow-up | 2 | 0 | 0 |
| Test Dose Phase | Noncompliance | 2 | 0 | 0 |
| Test Dose Phase | No treated seizure cluster episode | 37 | 0 | 0 |
| Test Dose Phase | Protocol Violation | 8 | 0 | 0 |
| Test Dose Phase | Study/Site closure | 6 | 0 | 0 |
| Test Dose Phase | Withdrawal by Subject | 8 | 0 | 0 |
Baseline characteristics
| Characteristic | USL261 Test Dose |
|---|---|
| Age, Categorical <=18 years | 18 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 272 Participants |
| Age, Continuous | 31.5 years |
| Body mass index | 24.69 kg/m^2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 22 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 270 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants |
| Race (NIH/OMB) White | 275 Participants |
| Region of Enrollment Australia | 19 participants |
| Region of Enrollment Canada | 4 participants |
| Region of Enrollment Germany | 13 participants |
| Region of Enrollment Hungary | 18 participants |
| Region of Enrollment Israel | 18 participants |
| Region of Enrollment Italy | 5 participants |
| Region of Enrollment New Zealand | 1 participants |
| Region of Enrollment Poland | 14 participants |
| Region of Enrollment Spain | 12 participants |
| Region of Enrollment Ukraine | 70 participants |
| Region of Enrollment United States | 118 participants |
| Seizure cluster episodes in year before Visit 1 of study | 15 seizure cluster episodes |
| Sex: Female, Male Female | 146 Participants |
| Sex: Female, Male Male | 146 Participants |
| Typical duration of seizure cluster episode | 67.5 minutes |
| Typical number of seizures in seizure cluster episode | 6.0 seizures |
| Years had seizure cluster episodes prior to study | 6.0 years |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 292 | 0 / 91 | 0 / 43 | 0 / 26 | 0 / 41 |
| other Total, other adverse events | 78 / 292 | 17 / 91 | 10 / 43 | 3 / 26 | 7 / 41 |
| serious Total, serious adverse events | 2 / 292 | 0 / 91 | 0 / 43 | 0 / 26 | 1 / 41 |
Outcome results
Primary
Participants Who Met the Criteria for Treatment Success After Administration of the Double-blind Dose in the Comparative Phase (CP)
Treatment Success is defined as achieving both of the following: 1) termination of seizure(s) within 10 minutes after double-blind study drug administration, and 2) no recurrence of seizure(s) beginning 10 minutes after study drug administration to 6 hours after study drug administration. Participants who received the open-label second dose within 6 hours of administration of the double-blind dose were analyzed as having had a seizure.
Time frame: 6 hours
Population: Randomized participants who received the double-blind dose in the CP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| USL261 CP | Participants Who Met the Criteria for Treatment Success After Administration of the Double-blind Dose in the Comparative Phase (CP) | 72 Participants |
| Placebo CP | Participants Who Met the Criteria for Treatment Success After Administration of the Double-blind Dose in the Comparative Phase (CP) | 23 Participants |
p-value: 0.0109Fisher Exact
Secondary
Occurrence of Seizure With a Start Time >10 Minutes After Administration of the Double-blind Dose
Occurrence of next seizure with a start time \>10 minutes and up to 24 hours after administration of the double-blind dose in the CP. Participants who did not have another seizure before the end of the 24-hour observation period were censored at the end of the observation period. Participants administered the open-label second dose who did not have a seizure were censored at the time of the administration.
Time frame: 24 hours
Population: Randomized participants who received the double-blind dose in the CP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| USL261 CP | Occurrence of Seizure With a Start Time >10 Minutes After Administration of the Double-blind Dose | 50 Participants |
| Placebo CP | Occurrence of Seizure With a Start Time >10 Minutes After Administration of the Double-blind Dose | 31 Participants |
p-value: 0.0124Log Rank
Secondary
Participants With Seizure(s) >10 Minutes to 4 Hours After Administration of the Double-blind Dose
Participants with recurrence of seizure(s) \>10 minutes and up to 4 hours after administration of the double-blind dose in the CP. Participants who received the open-label second dose within 4 hours of administration of the double-blind dose were analyzed as having had a seizure.
Time frame: 4 hours
Population: Randomized participants who received the double-blind dose in the CP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| USL261 CP | Participants With Seizure(s) >10 Minutes to 4 Hours After Administration of the Double-blind Dose | 51 Participants |
| Placebo CP | Participants With Seizure(s) >10 Minutes to 4 Hours After Administration of the Double-blind Dose | 40 Participants |
p-value: 0.0043Fisher Exact
Secondary
Time to Next Seizure With a Start Time >10 Minutes After Administration of the Double-blind Dose
Time to next seizure with a start time \>10 minutes and up to 24 hours after administration of the double-blind dose in the CP. Participants who did not have another seizure before the end of the 24-hour observation period were censored at the end of the observation period. Participants administered the open-label second dose who did not have a seizure were censored at the time of the administration.
Time frame: 24 hours
Population: Randomized participants who received the double-blind dose in the CP
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| USL261 CP | Time to Next Seizure With a Start Time >10 Minutes After Administration of the Double-blind Dose | NA Hours |
| Placebo CP | Time to Next Seizure With a Start Time >10 Minutes After Administration of the Double-blind Dose | 12.1 Hours |
Comparison: Kaplan-Meier estimates.p-value: 0.0124Log Rank