E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10015052 |
E.1.2 | Term | Epileptic seizure |
E.1.2 | System Organ Class | 100000004852 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the long-term safety and tolerability of USL-261 in the treatment of seizure clusters using the following assessments:
• Caregiver-recorded respiration rate at 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours and 4 hours after study drug administration.
• Adverse events (AEs).
• 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.
• Columbia-Suicide Severity Rating Scale (C-SSRS).
• Requirement for unscheduled emergency room (ER) or emergency medical service (EMS) visits within 24 hours after study drug administration. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
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.
3. Subject is between 14 and 66 years of age, inclusive, 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
the following:
a. 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 that was approved by the central reviewer in study P261-
401.
b. A documented history of seizure clusters lasting a minimum of 10
minutes from the time the seizure cluster is recognized.
c. 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.
d. The subject's stereotyped seizure cluster pattern is composed of
multiple (≥2) partial or
generalized seizures.
e. The subject's stereotyped seizure cluster pattern was established > 3
months before Visit
1 of study P261-401.
f. A frequency of ≥3 stereotyped seizure clusters during the year before
Visit 1 of study P261-401.
g. 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.
7. 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 as determined in study P261-
401?
c. Is the subject a female who has written medical documentation of
being permanently 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 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.
8. Subject's weight is 40 kg to 125 kg, inclusive, at Visit 1.
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E.4 | Principal exclusion criteria |
1. Subject experienced status epilepticus during or since the P261-401 study.
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
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 Columbia-Suicide Severity Rating Scale (CSSRS) 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The following safety endpoints will be summarized using the Safety Population:
• Treatment Emergent Adverse Events (TEAEs) will be presented by treatment received, severity, relationship to study drug and age group (< 18 vs. ≥18 years).
• Clinical laboratory results will be presented by visit.
• Vital sign measurements (systolic and diastolic blood pressure, pulse rate, respiration rate, and temperature) performed by study center staff will be summarized at each visit.
• Caregiver-recorded respiration rate will be presented using descriptive statistics at each time point and for each treatment. The number of subjects who have < 8 breaths per minute and > 24 breaths per minute after study drug administration will be presented by time point and for each treatment.
• Number of subjects requiring an unscheduled ER or EMS visit within 24 hours after study drug administration will be presented for each treatment.
• Suicidal behavior and ideation using the C-SSRS will be summarized at each visit.
• Physical, nasal and neurological examination results will be presented by visit.
The following efficacy endpoints will be summarized using the Efficacy Evaluable Population:
• Short and long term efficacy of USL261 as the outpatient treatment of seizure clusters based on Treatment Success based on appropriate longitudinal model
• Kaplan-Meier analysis of time to return to baseline functionality |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
• Treatment Emergent Adverse Events: Throughout the study
• Clinical laboratory results and vital sign measurements: at each visit
• Caregiver-recorded respiration rate: at 10, 15 and 30 minutes and 1, 2, and 4 hours after USL261 administration
• Number of subjects requiring an unscheduled ER or EMS: within 24 hours after study drug administration
• Suicidal behavior and ideation using the C-SSRS and physical, nasal and neurological examination results: At each visit
• The proportion of subjects who achieve Kaplan-Meier analysis of time to return to baseline functionality: after study drug administration |
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Open-Label Safety Study of USL 261 |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
European Union |
Israel |
New Zealand |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |