Continuous Spike and Wave During Sleep, Epileptic Encephalopathy
Conditions
Brief summary
This is a phase 2, double-blind study to assess the efficacy, safety, tolerability, and pharmacokinetics of NBI-827104 when administered once daily for 13 weeks in pediatric subjects with Epileptic Encephalopathy with Continuous Spike-and-Wave During Sleep (EECSWS).
Interventions
DRUGNBI-827104
Triple T-type calcium channel blocker.
DRUGPlacebo
Non-active dosage form.
Sponsors
Neurocrine Biosciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
4 Years to 12 Years
Healthy volunteers
No
Inclusion criteria
1. Signed informed consent by the parent(s) or legal representative(s) and, if applicable, assent from developmentally capable pediatric subjects. 2. Diagnosis of EECSWS. 3. Have diagnosis of EECSWS confirmed by the Diagnosis Confirmation Panel (DCP). 4. Stable dosage and stable time of intake of at least 1 and up to 3 antiseizure medications (ASMs) excluding systemic corticosteroids and intravenous immunoglobulin (IVIG), from 4 weeks prior to screening and anticipated to be stable from screening until end of study (EOS). Vagal nerve stimulator (VNS) and ketogenic diet are not counted as ASMs. 5. Treatment other than ASMs (excluding systemic corticosteroids and IVIG) must be at a stable dosage from 2 weeks prior to screening and anticipated to be stable from screening until EOS.
Exclusion criteria
1. Lennox-Gastaut syndrome, Doose syndrome (epilepsy with myoclonic-atonic seizures), or Dravet syndrome. 2. Presence of a relevant psychiatric disease interfering with cognitive or behavioral functioning (eg, depression, schizophrenia, autism spectrum disorder) unless associated with the EECSWS diagnosis as assessed by the investigator. 3. Presence of relevant neurological disorders other than EECSWS and its underlying conditions as judged by the investigator. Symptomatic conditions underlying EECSWS (eg, neonatal strokes) have to be stable for at least 1 year prior to screening. 4. Body weight \<10 kg at randomization. 5. Clinically relevant findings in systolic blood pressure (SBP), diastolic blood pressure (DBP), or pulse rate at screening or Day 1 as determined by the investigator. 6. Have an average triplicate ECG corrected QT interval using Fridericia's formula (QTcF) \>450 msec or presence of any significant cardiac abnormality at screening. 7. Clinically relevant findings in clinical laboratory tests (hematology, clinical chemistry including thyroid function parameters, and urinalysis) at screening as determined by the investigator. 8. Have aspartate aminotransferase (AST), alanine aminotransferase (ALT), or gamma-glutamyl transferase (GGT) levels \>2 × the upper limit of normal (ULN) at screening. 9. Have mild to severe renal impairment as determined by the investigator. 10. Have taken cannabinoids, excluding Epidiolex®/Epidyolex®, within 30 days of screening. 11. Pulse therapy such as systemic corticosteroids and IVIG are prohibited for at least 8 weeks prior to screening. 12. Planned surgical intervention related to structural abnormalities of the brain from screening through the duration of the study. 13. Have received any other investigational drug within 30 days or 5 half-lives (if known), whichever is longer, of Day 1 or plan to use an investigational drug (other than the study treatment) during the study. 14. Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ratio of Spike-Wave Index (SWI) During First Hour of Nonrapid Eye Movement (NREM) Sleep at Week 6 | Baseline to Week 6 | The ratio of SWI at the end of Week 6 to baseline during the first hour (60 minutes) of NREM sleep based on centralized video-electroencephalograph (EEG) reading using a log base 10 scale. Baseline was defined as the last value measured prior to intake of study treatment on Day 1. SWI was defined as the percentage of seconds with ≥1 spike-wave complex(es) during defined periods of overnight NREM sleep. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ratio of SWI During First Hour of NREM Sleep at Week 12 | Baseline to Week 12 | The ratio of SWI at the end of Week 12 to baseline during the first hour (60 minutes) of NREM sleep based on centralized video-EEG reading using a log base 10 scale. Baseline was defined as the last value measured prior to intake of study treatment on Day 1. SWI was defined as the percentage of seconds with ≥1 spike-wave complex(es) during defined periods of overnight NREM sleep. |
| Number of Participants Considered as Responders as Assessed by the Caregiver Global Impression of Change (CaGI-C) Score | Week 6 and Week 12 | The CaGI-C is a 7-point scale that rates the caregiver's assessment of the overall improvement in the participants symptoms since the initiation of study treatment, ranging from 1 (very much improved) to 7 (very much worse). A responder was defined as a participant with a score of 1 (very much improved) or 2 (much improved). |
| Number of Participants Considered as Responders as Assessed by the Clinician Global Impression of Change (CGI-C) Score | Week 6 and Week 12 | The CGI-C is a 7-point scale that rates the clinician's assessment of overall improvement in the participant's symptoms since the initiation of study treatment, ranging from 1 (very much improved) to 7 (very much worse). A responder was defined as a participant with a score of 1 (very much improved) or 2 (much improved). |
| Number of Participants Considered as Responders as Assessed by the Clinical Global Impression of Severity (CGI-S) Scores | Weeks 6 and 12 | The CGI-S is a 7-point scale that rates the clinician's assessment of overall symptom severity, ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). A responder was defined as a participant with at least 1-point improvement in the CGI-S score from baseline. |
Countries
Canada, Denmark, Spain, Switzerland, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| NBI-827104 NBI-827104 administered orally daily for up to 13 weeks. | 16 |
| Placebo Placebo administered orally daily for up to 13 weeks. | 8 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Deviation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | NBI-827104 | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 16 Participants | 8 Participants | 24 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 8 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 15 Participants | 7 Participants | 22 Participants |
| Sex: Female, Male Female | 7 Participants | 3 Participants | 10 Participants |
| Sex: Female, Male Male | 9 Participants | 5 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 8 |
| other Total, other adverse events | 11 / 16 | 8 / 8 |
| serious Total, serious adverse events | 1 / 16 | 0 / 8 |
Outcome results
Primary
Ratio of Spike-Wave Index (SWI) During First Hour of Nonrapid Eye Movement (NREM) Sleep at Week 6
The ratio of SWI at the end of Week 6 to baseline during the first hour (60 minutes) of NREM sleep based on centralized video-electroencephalograph (EEG) reading using a log base 10 scale. Baseline was defined as the last value measured prior to intake of study treatment on Day 1. SWI was defined as the percentage of seconds with ≥1 spike-wave complex(es) during defined periods of overnight NREM sleep.
Time frame: Baseline to Week 6
Population: Full Analysis Set included all randomized participants who had at least 1 dose of study treatment and at least 1 efficacy video EEG assessment. The number of participants analyzed = the number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NBI-827104 | Ratio of Spike-Wave Index (SWI) During First Hour of Nonrapid Eye Movement (NREM) Sleep at Week 6 | -0.02 Log-transformed ratio | Standard Error 0.02 |
| Placebo | Ratio of Spike-Wave Index (SWI) During First Hour of Nonrapid Eye Movement (NREM) Sleep at Week 6 | 0.01 Log-transformed ratio | Standard Error 0.04 |
p-value: 0.4326ANCOVA
Secondary
Number of Participants Considered as Responders as Assessed by the Caregiver Global Impression of Change (CaGI-C) Score
The CaGI-C is a 7-point scale that rates the caregiver's assessment of the overall improvement in the participants symptoms since the initiation of study treatment, ranging from 1 (very much improved) to 7 (very much worse). A responder was defined as a participant with a score of 1 (very much improved) or 2 (much improved).
Time frame: Week 6 and Week 12
Population: Full Analysis Set included all randomized participants who had at least 1 dose of study treatment and at least 1 efficacy video EEG assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| NBI-827104 | Number of Participants Considered as Responders as Assessed by the Caregiver Global Impression of Change (CaGI-C) Score | Week 6 | 1 Participants |
| NBI-827104 | Number of Participants Considered as Responders as Assessed by the Caregiver Global Impression of Change (CaGI-C) Score | Week 12 | 2 Participants |
| Placebo | Number of Participants Considered as Responders as Assessed by the Caregiver Global Impression of Change (CaGI-C) Score | Week 6 | 1 Participants |
| Placebo | Number of Participants Considered as Responders as Assessed by the Caregiver Global Impression of Change (CaGI-C) Score | Week 12 | 1 Participants |
Secondary
Number of Participants Considered as Responders as Assessed by the Clinical Global Impression of Severity (CGI-S) Scores
The CGI-S is a 7-point scale that rates the clinician's assessment of overall symptom severity, ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). A responder was defined as a participant with at least 1-point improvement in the CGI-S score from baseline.
Time frame: Weeks 6 and 12
Population: Full Analysis Set included all randomized participants who had at least 1 dose of study treatment and at least 1 efficacy video EEG assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| NBI-827104 | Number of Participants Considered as Responders as Assessed by the Clinical Global Impression of Severity (CGI-S) Scores | Week 6 | 3 Participants |
| NBI-827104 | Number of Participants Considered as Responders as Assessed by the Clinical Global Impression of Severity (CGI-S) Scores | Week 12 | 4 Participants |
| Placebo | Number of Participants Considered as Responders as Assessed by the Clinical Global Impression of Severity (CGI-S) Scores | Week 6 | 1 Participants |
| Placebo | Number of Participants Considered as Responders as Assessed by the Clinical Global Impression of Severity (CGI-S) Scores | Week 12 | 4 Participants |
Secondary
Number of Participants Considered as Responders as Assessed by the Clinician Global Impression of Change (CGI-C) Score
The CGI-C is a 7-point scale that rates the clinician's assessment of overall improvement in the participant's symptoms since the initiation of study treatment, ranging from 1 (very much improved) to 7 (very much worse). A responder was defined as a participant with a score of 1 (very much improved) or 2 (much improved).
Time frame: Week 6 and Week 12
Population: Full Analysis Set included all randomized participants who had at least 1 dose of study treatment and at least 1 efficacy video EEG assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| NBI-827104 | Number of Participants Considered as Responders as Assessed by the Clinician Global Impression of Change (CGI-C) Score | Week 6 | 1 Participants |
| NBI-827104 | Number of Participants Considered as Responders as Assessed by the Clinician Global Impression of Change (CGI-C) Score | Week 12 | 1 Participants |
| Placebo | Number of Participants Considered as Responders as Assessed by the Clinician Global Impression of Change (CGI-C) Score | Week 6 | 1 Participants |
| Placebo | Number of Participants Considered as Responders as Assessed by the Clinician Global Impression of Change (CGI-C) Score | Week 12 | 1 Participants |
Secondary
Ratio of SWI During First Hour of NREM Sleep at Week 12
The ratio of SWI at the end of Week 12 to baseline during the first hour (60 minutes) of NREM sleep based on centralized video-EEG reading using a log base 10 scale. Baseline was defined as the last value measured prior to intake of study treatment on Day 1. SWI was defined as the percentage of seconds with ≥1 spike-wave complex(es) during defined periods of overnight NREM sleep.
Time frame: Baseline to Week 12
Population: Full Analysis Set included all randomized participants who had at least 1 dose of study treatment and at least 1 efficacy video EEG assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NBI-827104 | Ratio of SWI During First Hour of NREM Sleep at Week 12 | -0.05 Log-transformed ratio | Standard Error 0.02 |
| Placebo | Ratio of SWI During First Hour of NREM Sleep at Week 12 | 0.03 Log-transformed ratio | Standard Error 0.03 |