Trial Outcomes & Findings for A Study to Test the Pharmacokinetics, Efficacy, and Safety of Brivaracetam in Newborns With Repeated Electroencephalographic Seizures (NCT NCT03325439)
NCT ID: NCT03325439
Last Updated: 2024-04-08
Results Overview
Pharmacokinetic blood samples were taken 0.5 to 1 hour, 2 to 4 hours, and 8 to 12 hours after the BRV infusion on Day 1 to determine the BRV plasma concentration.
TERMINATED
PHASE3
9 participants
Pharmacokinetic blood samples were taken 0.5 to 1 hour, 2 to 4 hours, and 8 to 12 hours after the BRV infusion on Day 1
2024-04-08
Participant Flow
The study started to enroll participants in May 2019 and concluded in May 2021.
No eligible study participants were enrolled in the Confirmatory Cohorts. The study stopped prematurely due to enrolment challenges, the termination was not linked to any safety issues. The Participant Flow refers to the All Subjects Screened.
Participant milestones
| Measure |
Exploratory Cohort
Participants in this arm received brivaracetam (BRV) 0.5 milligram per kilogram (mg/kg) administered as an intravenous (iv) solution for injection twice daily (bid) during the 48-hour Evaluation Period. An additional 3 doses of BRV (0.5 mg/kg) could have been administered every 12 hours for 48 hours (at the discretion of the Investigator). Treatment with antiepileptic drugs (AEDs) per standard of care (SToC) (first-line, second-line, or subsequent treatment) were continued in parallel with BRV treatment.
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|---|---|
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Overall Study
STARTED
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9
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Overall Study
Treated
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6
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Overall Study
COMPLETED
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6
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Overall Study
NOT COMPLETED
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3
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Reasons for withdrawal
| Measure |
Exploratory Cohort
Participants in this arm received brivaracetam (BRV) 0.5 milligram per kilogram (mg/kg) administered as an intravenous (iv) solution for injection twice daily (bid) during the 48-hour Evaluation Period. An additional 3 doses of BRV (0.5 mg/kg) could have been administered every 12 hours for 48 hours (at the discretion of the Investigator). Treatment with antiepileptic drugs (AEDs) per standard of care (SToC) (first-line, second-line, or subsequent treatment) were continued in parallel with BRV treatment.
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Overall Study
Ineligibility
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3
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Baseline Characteristics
A Study to Test the Pharmacokinetics, Efficacy, and Safety of Brivaracetam in Newborns With Repeated Electroencephalographic Seizures
Baseline characteristics by cohort
| Measure |
Exploratory Cohort
n=9 Participants
Participants in this arm received brivaracetam (BRV) 0.5 milligram per kilogram (mg/kg) administered as an intravenous (iv) solution for injection twice daily (bid) during the 48-hour Evaluation Period. An additional 3 doses of BRV (0.5 mg/kg) could have been administered every 12 hours for 48 hours (at the discretion of the Investigator). Treatment with antiepileptic drugs (AEDs) per standard of care (SToC) (first-line, second-line, or subsequent treatment) were continued in parallel with BRV treatment.
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Age, Continuous
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39.2 weeks
STANDARD_DEVIATION 1.9 • n=5 Participants
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Age, Customized
Gestational Age <37 weeks
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2 Participants
n=5 Participants
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Age, Customized
Gestational Age >=37 weeks
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7 Participants
n=5 Participants
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Sex: Female, Male
Female
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6 Participants
n=5 Participants
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Sex: Female, Male
Male
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3 Participants
n=5 Participants
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Race/Ethnicity, Customized
White
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8 Participants
n=5 Participants
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Race/Ethnicity, Customized
Other/mixed
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1 Participants
n=5 Participants
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PRIMARY outcome
Timeframe: Pharmacokinetic blood samples were taken 0.5 to 1 hour, 2 to 4 hours, and 8 to 12 hours after the BRV infusion on Day 1Population: The Pharmacokinetic Per-Protocol Set (PK-PPS) consisted of all study participants who provided at least 1 measurable post-Baseline plasma sample (with recorded sampling time) on at least 1 post-Baseline Visit with documented study drug intake times. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. Here, 'n' (Number analyzed) signifies participants who were evaluable at specified time points.
Pharmacokinetic blood samples were taken 0.5 to 1 hour, 2 to 4 hours, and 8 to 12 hours after the BRV infusion on Day 1 to determine the BRV plasma concentration.
Outcome measures
| Measure |
Exploratory Cohort
n=6 Participants
Participants in this arm received brivaracetam (BRV) 0.5 milligram per kilogram (mg/kg) administered as an intravenous (iv) solution for injection twice daily (bid) during the 48-hour Evaluation Period. An additional 3 doses of BRV (0.5 mg/kg) could have been administered every 12 hours for 48 hours (at the discretion of the Investigator). Treatment with antiepileptic drugs (AEDs) per standard of care (SToC) (first-line, second-line, or subsequent treatment) were continued in parallel with BRV treatment.
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Confirmatory Cohort
For the Confirmatory Cohorts, 3 consecutive cohorts were planned to evaluate the efficacy of BRV. However, no study participants were enrolled in the Confirmatory Cohorts due to the lack of enrollment of eligible study participants.
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Plasma Concentration of Brivaracetam (BRV) Following First Dose on Day 1
0.5-1 hour
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534.2 nanograms per milliliter (ng/mL)
Geometric Coefficient of Variation 15.4
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—
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Plasma Concentration of Brivaracetam (BRV) Following First Dose on Day 1
2-4 hours
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500.1 nanograms per milliliter (ng/mL)
Geometric Coefficient of Variation 28.2
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—
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Plasma Concentration of Brivaracetam (BRV) Following First Dose on Day 1
8-12 hours
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342.7 nanograms per milliliter (ng/mL)
Geometric Coefficient of Variation 13.2
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—
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SECONDARY outcome
Timeframe: From Baseline to 3 hours after the initial BRV treatmentPopulation: Efficacy was not evaluated since the study was stopped after the completion of required enrollment of the Exploratory Cohort due to the lack of enrollment of eligible study participants in the Confirmatory Cohorts. Efficacy analyses was planned to be performed on Confirmatory Cohorts only.
A BRV responder was defined as a participant who achieved the following reduction in seizure burden (electroencephalographic neonatal seizures (ENS) in minutes per hour) without need for rescue medication, compared to the seizure burden measured during the Baseline Period immediately prior to BRV administration, evaluated for a 2-hour period starting 1 hour after the start of initial BRV treatment: At least 80% reduction in nonsevere seizure burden (Nonsevere seizure burden is defined as \<=50% seizure activity on video-electroencephalography (VEEG) in all 30-minute timespans), OR At least 50 % reduction in severe seizure burden (Severe seizure burden is defined as \>50 % seizure activity on VEEG in any 30-minute timespan). Timespans of 30 minutes refer to the following intervals within the 2-hour period: 0 to \<= 30 minutes, \> 30 to \<= 60 minutes, \>60 to \<= 90 minutes, and \>90 to \<= 120 minutes.
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: From Baseline to 3 hours after the initial BRV treatmentPopulation: Efficacy was not evaluated since the study was stopped after the completion of required enrollment of the Exploratory Cohort due to the lack of enrollment of eligible study participants in the Confirmatory Cohorts. Efficacy analyses was planned to be performed on Confirmatory Cohorts only.
Nonsevere seizure burden was defined as \<=50% seizure activity on VEEG in all 30-minute timespans. Seizure burden was measured during the Baseline Period immediately prior to BRV administration and evaluated for a 2-hour period starting 1 hour after the start of initial BRV. Timespans of 30 minutes refer to the following intervals within the 2-hour period: 0 to \<= 30 minutes, \> 30 to \<= 60 minutes, \>60 to \<= 90 minutes, and \>90 to \<= 120 minutes.
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: From Baseline to 3 hours after the initial BRV treatmentPopulation: Efficacy was not evaluated since the study was stopped after the completion of required enrollment of the Exploratory Cohort due to the lack of enrollment of eligible study participants in the Confirmatory Cohorts. Efficacy analyses was planned to be performed on Confirmatory Cohorts only.
Severe seizure burden was defined as \>50% seizure activity on VEEG in any 30-minute timespan. Seizure burden was measured during the Baseline Period immediately prior to BRV administration and evaluated for a 2-hour period starting 1 hour after the start of initial BRV. Timespans of 30 minutes refer to the following intervals within the 2-hour period: 0 to \<= 30 minutes, \> 30 to \<= 60 minutes, \>60 to \<= 90 minutes, and \>90 to \<= 120 minutes.
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: From Baseline to the end of the 96-hour Evaluation PeriodPopulation: Efficacy was not evaluated since the study was stopped after the completion of required enrollment of the Exploratory Cohort due to the lack of enrollment of eligible study participants in the Confirmatory Cohorts. Efficacy analyses was planned to be performed on Confirmatory Cohorts only.
Seizure burden was measured by continuous video-electroencephalography (VEEG). Baseline seizure burden is defined as seizure burden measured on the continuous VEEG (total electroencephalographic neonatal seizures (ENS) in minutes per hour) during a period of up to 1 hour immediately prior to the first administration of study drug.
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: From Baseline to the end of the 96-hour Evaluation PeriodPopulation: Efficacy was not evaluated since the study was stopped after the completion of required enrollment of the Exploratory Cohort due to the lack of enrollment of eligible study participants in the Confirmatory Cohorts. Efficacy analyses was planned to be performed on Confirmatory Cohorts only.
Seizure burden was measured by continuous video-electroencephalography (VEEG). Baseline seizure burden was defined as seizure burden measured on the continuous VEEG (total electroencephalographic neonatal seizures (ENS) in minutes per hour) during a period of up to 1 hour immediately prior to the first administration of study drug.
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: From Baseline to the end of the 96-hour Evaluation PeriodPopulation: Efficacy was not evaluated since the study was stopped after the completion of required enrollment of the Exploratory Cohort due to the lack of enrollment of eligible study participants in the Confirmatory Cohorts. Efficacy analyses was planned to be performed on Confirmatory Cohorts only.
A BRV responder was defined as a participant who achieves the following reduction in seizure burden (electroencephalographic neonatal seizures (ENS) in minutes per hour) without need for rescue medication, compared to the seizure burden measured during the Baseline Period immediately prior to BRV administration, evaluated for a 2-hour period starting 1 hour after the start of initial BRV treatment: At least 80% reduction in nonsevere seizure burden (Nonsevere seizure burden is defined as \<=50% seizure activity on VEEG in all 30-minute timespans), OR At least 50% reduction in severe seizure burden (Severe seizure burden is defined as \>50% seizure activity on VEEG in any 30-minute timespan).
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: From Baseline to 24 hours after the initial BRV treatmentPopulation: Efficacy was not evaluated since the study was stopped after the completion of required enrollment of the Exploratory Cohort due to the lack of enrollment of eligible study participants in the Confirmatory Cohorts. Efficacy analyses was planned to be performed on Confirmatory Cohorts only.
Seizure freedom is defined as 100 % reduction in seizure burden from Baseline.
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: From Baseline to the first timepoint when BRV responder criteria are met (up to 96-hour Evaluation Period)Population: Efficacy was not evaluated since the study was stopped after the completion of required enrollment of the Exploratory Cohort due to the lack of enrollment of eligible study participants in the Confirmatory Cohorts. Efficacy analyses was planned to be performed on Confirmatory Cohorts only.
A BRV responder was defined as a participant who achieves the following reduction in seizure burden (electroencephalographic neonatal seizures (ENS) in minutes per hour) without need for rescue medication, compared to the seizure burden measured during the Baseline Period immediately prior to BRV administration, evaluated for a 2-hour period starting 1 hour after the start of initial BRV treatment: At least 80% reduction in nonsevere seizure burden (Nonsevere seizure burden is defined as \<=50% seizure activity on VEEG in all 30-minute timespans), OR At least 50% reduction in severe seizure burden (Severe seizure burden is defined as \>50% seizure activity on VEEG in any 30-minute timespan).
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: From Baseline to the end of the Down-Titration Period (up to 97 days)Population: Efficacy was not evaluated since the study was stopped after the completion of required enrollment of the Exploratory Cohort due to the lack of enrollment of eligible study participants in the Confirmatory Cohorts. Efficacy analyses was planned to be performed on Confirmatory Cohorts only.
Seizure freedom was defined as 100% reduction in seizure burden from Baseline.
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: From Baseline to the end of the 96-hour Evaluation PeriodPopulation: Efficacy was not evaluated since the study was stopped after the completion of required enrollment of the Exploratory Cohort due to the lack of enrollment of eligible study participants in the Confirmatory Cohorts. Efficacy analyses was planned to be performed on Confirmatory Cohorts only.
For this study, an ENS was defined as an EEG seizure lasting for at least 10 seconds on VEEG. Baseline seizure burden was defined as seizure burden measured on the continuous VEEG (total ENS in minutes per hour) during a period of up to 1 hour immediately prior to the first administration of study drug.
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: From 3 hours following the start of the initial BRV treatment to the end of the 96-hour Evaluation PeriodPopulation: Efficacy was not evaluated since the study was stopped after the completion of required enrollment of the Exploratory Cohort due to the lack of enrollment of eligible study participants in the Confirmatory Cohorts. Efficacy analyses was planned to be performed on Confirmatory Cohorts only.
Seizure freedom was defined as 100% reduction in seizure burden from Baseline.
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: From Baseline to the end of the 24-hour Evaluation PeriodPopulation: Efficacy was not evaluated since the study was stopped after the completion of required enrollment of the Exploratory Cohort due to the lack of enrollment of eligible study participants in the Confirmatory Cohorts. Efficacy analyses was planned to be performed on Confirmatory Cohorts only.
Seizures was measured by continuous video-electroencephalography (VEEG).
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: From Baseline to the end of the 24-hour Evaluation PeriodPopulation: Efficacy was not evaluated since the study was stopped after the completion of required enrollment of the Exploratory Cohort due to the lack of enrollment of eligible study participants in the Confirmatory Cohorts. Efficacy analyses was planned to be performed on Confirmatory Cohorts only.
Seizures was measured by continuous video-electroencephalography (VEEG).
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: Adverse Events were collected from Screening Period until the Safety Follow-Up Visit (up to Day 75)Population: The All Study Participants Screened Set consisted of all study participants who had signed the ICF and underwent the study inclusion and exclusion criteria of the current protocol.
An adverse event (AE) was any untoward medical occurrence in a patient or clinical investigation study participant administered a pharmaceutical product that did not necessarily have a causal relationship with this treatment.
Outcome measures
| Measure |
Exploratory Cohort
n=9 Participants
Participants in this arm received brivaracetam (BRV) 0.5 milligram per kilogram (mg/kg) administered as an intravenous (iv) solution for injection twice daily (bid) during the 48-hour Evaluation Period. An additional 3 doses of BRV (0.5 mg/kg) could have been administered every 12 hours for 48 hours (at the discretion of the Investigator). Treatment with antiepileptic drugs (AEDs) per standard of care (SToC) (first-line, second-line, or subsequent treatment) were continued in parallel with BRV treatment.
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Confirmatory Cohort
For the Confirmatory Cohorts, 3 consecutive cohorts were planned to evaluate the efficacy of BRV. However, no study participants were enrolled in the Confirmatory Cohorts due to the lack of enrollment of eligible study participants.
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Percentage of Participants With Adverse Events (AEs) as Reported by the Investigator
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55.6 percentage of participants
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—
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Adverse Events
Exploratory Cohort
Serious adverse events
| Measure |
Exploratory Cohort
n=9 participants at risk
Participants in this arm received brivaracetam (BRV) 0.5 milligram per kilogram (mg/kg) administered as an intravenous (iv) solution for injection twice daily (bid) during the 48-hour Evaluation Period. An additional 3 doses of BRV (0.5 mg/kg) could have been administered every 12 hours for 48 hours (at the discretion of the Investigator). Treatment with antiepileptic drugs (AEDs) per standard of care (SToC) (first-line, second-line, or subsequent treatment) were continued in parallel with BRV treatment.
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Respiratory, thoracic and mediastinal disorders
Apnoea
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11.1%
1/9 • Number of events 1 • Adverse Events were collected from Screening Period until the Safety Follow-Up Visit (up to Day 75)
An AE was any untoward medical occurrence in a patient or clinical investigation study participant administered pharmaceutical product that did not necessarily have a causal relationship with this treatment. Safety analysis was done on All Study Participants Screened Set. Only 6 of 9 participants were treated with BRV. No eligible study participants were enrolled in Confirmatory Cohorts. The study stopped prematurely due to enrolment challenges, termination was not linked to any safety issues.
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Other adverse events
| Measure |
Exploratory Cohort
n=9 participants at risk
Participants in this arm received brivaracetam (BRV) 0.5 milligram per kilogram (mg/kg) administered as an intravenous (iv) solution for injection twice daily (bid) during the 48-hour Evaluation Period. An additional 3 doses of BRV (0.5 mg/kg) could have been administered every 12 hours for 48 hours (at the discretion of the Investigator). Treatment with antiepileptic drugs (AEDs) per standard of care (SToC) (first-line, second-line, or subsequent treatment) were continued in parallel with BRV treatment.
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Blood and lymphatic system disorders
Anaemia
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11.1%
1/9 • Number of events 1 • Adverse Events were collected from Screening Period until the Safety Follow-Up Visit (up to Day 75)
An AE was any untoward medical occurrence in a patient or clinical investigation study participant administered pharmaceutical product that did not necessarily have a causal relationship with this treatment. Safety analysis was done on All Study Participants Screened Set. Only 6 of 9 participants were treated with BRV. No eligible study participants were enrolled in Confirmatory Cohorts. The study stopped prematurely due to enrolment challenges, termination was not linked to any safety issues.
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Eye disorders
Dry eye
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11.1%
1/9 • Number of events 1 • Adverse Events were collected from Screening Period until the Safety Follow-Up Visit (up to Day 75)
An AE was any untoward medical occurrence in a patient or clinical investigation study participant administered pharmaceutical product that did not necessarily have a causal relationship with this treatment. Safety analysis was done on All Study Participants Screened Set. Only 6 of 9 participants were treated with BRV. No eligible study participants were enrolled in Confirmatory Cohorts. The study stopped prematurely due to enrolment challenges, termination was not linked to any safety issues.
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Investigations
Ammonia increased
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11.1%
1/9 • Number of events 1 • Adverse Events were collected from Screening Period until the Safety Follow-Up Visit (up to Day 75)
An AE was any untoward medical occurrence in a patient or clinical investigation study participant administered pharmaceutical product that did not necessarily have a causal relationship with this treatment. Safety analysis was done on All Study Participants Screened Set. Only 6 of 9 participants were treated with BRV. No eligible study participants were enrolled in Confirmatory Cohorts. The study stopped prematurely due to enrolment challenges, termination was not linked to any safety issues.
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Investigations
Liver function test abnormal
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11.1%
1/9 • Number of events 1 • Adverse Events were collected from Screening Period until the Safety Follow-Up Visit (up to Day 75)
An AE was any untoward medical occurrence in a patient or clinical investigation study participant administered pharmaceutical product that did not necessarily have a causal relationship with this treatment. Safety analysis was done on All Study Participants Screened Set. Only 6 of 9 participants were treated with BRV. No eligible study participants were enrolled in Confirmatory Cohorts. The study stopped prematurely due to enrolment challenges, termination was not linked to any safety issues.
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Investigations
Oxygen saturation decreased
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11.1%
1/9 • Number of events 1 • Adverse Events were collected from Screening Period until the Safety Follow-Up Visit (up to Day 75)
An AE was any untoward medical occurrence in a patient or clinical investigation study participant administered pharmaceutical product that did not necessarily have a causal relationship with this treatment. Safety analysis was done on All Study Participants Screened Set. Only 6 of 9 participants were treated with BRV. No eligible study participants were enrolled in Confirmatory Cohorts. The study stopped prematurely due to enrolment challenges, termination was not linked to any safety issues.
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Metabolism and nutrition disorders
Hyperglycaemia
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11.1%
1/9 • Number of events 1 • Adverse Events were collected from Screening Period until the Safety Follow-Up Visit (up to Day 75)
An AE was any untoward medical occurrence in a patient or clinical investigation study participant administered pharmaceutical product that did not necessarily have a causal relationship with this treatment. Safety analysis was done on All Study Participants Screened Set. Only 6 of 9 participants were treated with BRV. No eligible study participants were enrolled in Confirmatory Cohorts. The study stopped prematurely due to enrolment challenges, termination was not linked to any safety issues.
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Metabolism and nutrition disorders
Hypokalaemia
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11.1%
1/9 • Number of events 1 • Adverse Events were collected from Screening Period until the Safety Follow-Up Visit (up to Day 75)
An AE was any untoward medical occurrence in a patient or clinical investigation study participant administered pharmaceutical product that did not necessarily have a causal relationship with this treatment. Safety analysis was done on All Study Participants Screened Set. Only 6 of 9 participants were treated with BRV. No eligible study participants were enrolled in Confirmatory Cohorts. The study stopped prematurely due to enrolment challenges, termination was not linked to any safety issues.
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Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place
Restriction type: GT60