A Phase 3 interventional study of SHP615 in Nervous System Diseases, sponsored by Shire. Completed at 23 sites in Japan. Open to participants aged 3 Months to 216 Months. Per ClinicalTrials.gov, last updated 2020-07-31.
Sponsored by Shire · Phase 3, Interventional, and Treatment
The purpose of this study is to assess the efficacy, safety and pharmacokinetics of MHOS/SHP615 administered buccally in children with status epilepticus (convulsive) in a healthcare setting.
Participant with generalized tonic-clonic SE with seizures accompanied by loss of consciousness with any of the following characteristics persistent at the time of study drug administration:
Exclusion Criteria:
Participants will receive a single age-specific dose (approximately 0.25 to 0.5 milligram per kilogram \[mg/kg\] as midazolam) of SHP615 oromucosal solution through buccal route upon onset of seizures.
Drug: SHP615
SHP615 oromucosal solution will be administered as a single age-specific dose (2.5, 5, 7.5 and 10 mg).
Also known as: Midazolam hydrochloride oromucosal solution, MHOS
Percentage of Participants With Response Rate
Response rate was defined as the percentage of participants with therapeutic success. Therapeutic success was defined as the cessation of visible seizure activity within 10 minutes with a sustained absence of visible seizure activity for 30 minutes following a single dose of MHOS/SHP615 without the need for additional rescue medication.
Time frame: From start of study drug administration up to 30 minutes post-dose
Percentage of Participants Who Had Sustained Absence of Seizure Activity for at Least 1, 4 and 6 Hours
Percentage of participants whose seizure event stopped within 10 minutes of single dose administration of SHP615 and who had sustained absence of seizure activity for at least 1, 4, and 6 hours were reported.
Time frame: From start of study drug administration up to 1, 4 and 6 hours post-dose
Number of Participants With Time to Resolution of Seizures (Convulsions)
Time to resolution of seizures (convulsions) was calculated as time from IP administration to the end of the initial seizure or administration of rescue anti-convulsant medication, whichever occurs first. Initial seizure referred to the seizure that triggered the use of the IP. Number of participants with time to resolution of seizures (convulsions) from the administration of SHP615 were reported.
Time frame: From start of study drug administration up to follow-up (Day 8)
Number of Participants With Time to Recovery of Consciousness
Time to recovery of consciousness (in minutes) was calculated only for participants who lost consciousness pre-dose at time from investigational product administration to recovery of consciousness post-dose or administration of rescue anticonvulsant medication, whichever occurs first. Number of participants with time to recovery of consciousness were reported.
Time frame: From start of study drug administration up to follow-up (Day 8)
Percentage of Participants Who Required Additional Anticonvulsant Medication for Ongoing Status Epilepticus (SE)
Percentage of participants who required additional anticonvulsant medication for ongoing SE, 10 minutes after a single dose of SHP615 were reported.
Time frame: 10 minutes post-dose
Percentage of Participants Who Failed to Respond to the Treatment With SHP615
Treatment failure/non-responder was defined as participants with continuing seizure activity and/or the need for any additional rescue medication according to the participating healthcare setting protocol or guideline, for 10 mins or more after a single dose of the IP.
Time frame: 10 minutes post-dose
Concentration of SHP615 in Plasma at 10 Minutes (C10)
Concentration of SHP615 in plasma at 10 minutes were reported.
Time frame: 10 minutes post-dose
Maximum Plasma Concentration (Cmax) of SHP615
Cmax of SHP615 in plasma were reported.
Time frame: 1, 3, 6 hours post-dose
Area Under the Concentration-time Curve From Time Zero to 10 Minutes (AUC0-10) of SHP615 in Plasma
AUC0-10 of SHP615 in plasma were reported. Here "min ng/mL" was minutes nanogram per milliliter.
Time frame: Pre-dose, 10 minutes post-dose
Area Under the Concentration-time Curve From Time Zero to 60 Minutes (AUC0-60) of SHP615 in Plasma
AUC0-60 of SHP615 in plasma were reported.
Time frame: Pre-dose, 60 minutes post-dose
Area Under the Concentration-time Curve From Time Zero to 180 Minutes (AUC0-180) of SHP615 in Plasma
AUC0-180 of SHP615 in plasma were reported.
Time frame: Pre-dose, 180 minutes post-dose
Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of SHP615 in Plasma
AUC(0-infinity) of SHP615 in plasma were reported.
Time frame: Pre-dose, 1, 3, and 6 hours post-dose
Time at Maximum Concentration (Tmax) of SHP615 in Plasma
Tmax of SHP615 in plasma were reported.
Time frame: 1, 3, and 6 hours post-dose
Elimination Half-life (T1/2) of SHP615 in Plasma
T1/2 of SHP615 in plasma were reported.
Time frame: 1, 3, and 6 hours post-dose
Number of Participants With Respiratory Depression
Respiratory depression, included the following measures within 24 hours after administration of the IP: i) Persistent decrease in oxygen saturation to \< 92 percent (%) measured at 10, 30 minutes, and 4, 6, and 24 hours post-dose (i.e, \< 92 % on room air for 2 minutes or more after dosing while monitoring \[per healthcare setting protocol and/or the clinical judgment of the physician\]) ii) Increase in respiratory effort such that assisted ventilation is used (bag-valve-mask ventilation or endotracheal intubation). Number of participants with respiratory depression were reported.
Time frame: From start of study drug administration up to follow-up (Day 8)
Number of Participants With Aspiration Pneumonia Reported as Treatment Emergent Adverse Events (TEAEs)
TEAEs was defined as AEs that start or deteriorate on or after the date of the first dose of investigational product and no later than 3 days following the last dose of IP. Number of participants with aspiration pneumonia identified as TEAEs were reported.
Time frame: From start of study drug administration up to follow-up (Day 8)
Change From Baseline in Riker Sedation-Agitation Scale at 24 Hours Post-dose
Sedation-Agitation was assessed, using the "Riker Sedation-Agitation Scale" (SAS) by the following 7-point scale: 7. dangerous agitation; 6. very agitated; 5. agitated; 4. calm, cooperative; 3. sedated; 2. very sedated; 1. unarousable. Change from baseline in riker sedation-agition scale at 24 hours post-dose were reported.
Time frame: Baseline, 24 hours post-dose
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. TEAEs was defined as AEs that start or deteriorate on or after the date of the first dose of investigational product and no later than 3 days following the last dose of IP. Number of participants with TEAEs were reported.
Time frame: From start of study drug administration up to follow-up (Day 8)
Change From Baseline in Oxygen Saturation Percentage at 24 Hours Post-dose
Oxygen saturation at baseline was measured and recorded on room air. The investigator had recorded the oxygen saturation, oxygen delivery system and amount of oxygen administered during the study. Change from baseline in oxygen saturation percentage at 24 hours post-dose were reported.
Time frame: Baseline, 24 hours post-dose
The study was conducted at 28 study centers in the Japan between 23 October 2017 (first participant first visit) and 19 August 2019 (last participant last visit).
| Milestone | SHP615 |
|---|---|
| Started | 25 |
| Completed | 25 |
| Not completed | 0 |
Response rate was defined as the percentage of participants with therapeutic success. Therapeutic success was defined as the cessation of visible seizure activity within 10 minutes with a sustained absence of visible seizure activity for 30 minutes following a single dose of MHOS/SHP615 without the need for additional rescue medication.
| Percentage of participants | SHP615 |
|---|---|
| Percentage of Participants With Response Rate | 80.0 |
Percentage of participants whose seizure event stopped within 10 minutes of single dose administration of SHP615 and who had sustained absence of seizure activity for at least 1, 4, and 6 hours were reported.
| Percentage of participants | SHP615 |
|---|---|
| Sustained Absence for at least 1 hour | 68.0 |
| Sustained Absence for at least 4 hours | 36.0 |
| Sustained Absence for at least 6 hours | 32.0 |
Time to resolution of seizures (convulsions) was calculated as time from IP administration to the end of the initial seizure or administration of rescue anti-convulsant medication, whichever occurs first. Initial seizure referred to the seizure that triggered the use of the IP. Number of participants with time to resolution of seizures (convulsions) from the administration of SHP615 were reported.
| Participants | SHP615 |
|---|---|
| Number of Participants With Time to Resolution of Seizures (Convulsions) | 21 |
Time to recovery of consciousness (in minutes) was calculated only for participants who lost consciousness pre-dose at time from investigational product administration to recovery of consciousness post-dose or administration of rescue anticonvulsant medication, whichever occurs first. Number of participants with time to recovery of consciousness were reported.
| Participants | SHP615 |
|---|---|
| Number of Participants With Time to Recovery of Consciousness | 19 |
Percentage of participants who required additional anticonvulsant medication for ongoing SE, 10 minutes after a single dose of SHP615 were reported.
| Percentage of Participants | SHP615 |
|---|---|
| Percentage of Participants Who Required Additional Anticonvulsant Medication for Ongoing Status Epilepticus (SE) | 16.0 |
Treatment failure/non-responder was defined as participants with continuing seizure activity and/or the need for any additional rescue medication according to the participating healthcare setting protocol or guideline, for 10 mins or more after a single dose of the IP.
| Percentage of participants | SHP615 |
|---|---|
| Percentage of Participants Who Failed to Respond to the Treatment With SHP615 | 16.0 |
Concentration of SHP615 in plasma at 10 minutes were reported.
| nanogram per milliliter (ng/mL) | SHP615 |
|---|---|
| Concentration of SHP615 in Plasma at 10 Minutes (C10) | 45.2 ± 21.3 |
Cmax of SHP615 in plasma were reported.
| ng/mL | SHP615 |
|---|---|
| Maximum Plasma Concentration (Cmax) of SHP615 | 78.0 ± 16.4 |
AUC0-10 of SHP615 in plasma were reported. Here "min ng/mL" was minutes nanogram per milliliter.
| min ng/mL | SHP615 |
|---|---|
| Area Under the Concentration-time Curve From Time Zero to 10 Minutes (AUC0-10) of SHP615 in Plasma | 304 ± 149 |
AUC0-60 of SHP615 in plasma were reported.
| min ng/mL | SHP615 |
|---|---|
| Area Under the Concentration-time Curve From Time Zero to 60 Minutes (AUC0-60) of SHP615 in Plasma | 2965 ± 592 |
AUC0-180 of SHP615 in plasma were reported.
| min ng/mL | SHP615 |
|---|---|
| Area Under the Concentration-time Curve From Time Zero to 180 Minutes (AUC0-180) of SHP615 in Plasma | 4411 ± 1140 |
AUC(0-infinity) of SHP615 in plasma were reported.
| min ng/mL | SHP615 |
|---|---|
| Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of SHP615 in Plasma | 5847 ± 2599 |
Tmax of SHP615 in plasma were reported.
| minutes | SHP615 |
|---|---|
| Time at Maximum Concentration (Tmax) of SHP615 in Plasma | 20.5 (15.5 to 28.0) |
T1/2 of SHP615 in plasma were reported.
| minutes | SHP615 |
|---|---|
| Elimination Half-life (T1/2) of SHP615 in Plasma | 115 (90.6 to 303) |
Respiratory depression, included the following measures within 24 hours after administration of the IP: i) Persistent decrease in oxygen saturation to \< 92 percent (%) measured at 10, 30 minutes, and 4, 6, and 24 hours post-dose (i.e, \< 92 % on room air for 2 minutes or more after dosing while monitoring \[per healthcare setting protocol and/or the clinical judgment of the physician\]) ii) Increase in respiratory effort such that assisted ventilation is used (bag-valve-mask ventilation or endotracheal intubation). Number of participants with respiratory depression were reported.
| Participants | SHP615 |
|---|---|
| Persistent Decrease in Oxygen Saturation | 0 |
| Increase in Respiratory Effort | 1 |
TEAEs was defined as AEs that start or deteriorate on or after the date of the first dose of investigational product and no later than 3 days following the last dose of IP. Number of participants with aspiration pneumonia identified as TEAEs were reported.
| Participants | SHP615 |
|---|---|
| Number of Participants With Aspiration Pneumonia Reported as Treatment Emergent Adverse Events (TEAEs) | 0 |
Sedation-Agitation was assessed, using the "Riker Sedation-Agitation Scale" (SAS) by the following 7-point scale: 7. dangerous agitation; 6. very agitated; 5. agitated; 4. calm, cooperative; 3. sedated; 2. very sedated; 1. unarousable. Change from baseline in riker sedation-agition scale at 24 hours post-dose were reported.
| Score on the scale | SHP615 |
|---|---|
| Change From Baseline in Riker Sedation-Agitation Scale at 24 Hours Post-dose | 2.2 ± 1.23 |
An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. TEAEs was defined as AEs that start or deteriorate on or after the date of the first dose of investigational product and no later than 3 days following the last dose of IP. Number of participants with TEAEs were reported.
| Participants | SHP615 |
|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 9 |
Oxygen saturation at baseline was measured and recorded on room air. The investigator had recorded the oxygen saturation, oxygen delivery system and amount of oxygen administered during the study. Change from baseline in oxygen saturation percentage at 24 hours post-dose were reported.
| Percentage of oxygen saturation | SHP615 |
|---|---|
| Change From Baseline in Oxygen Saturation Percentage at 24 Hours Post-dose | 3.7 ± 10.21 |
Collected over From start of study drug administration to follow-up (8 days).. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| SHP615 | 0/25 (0%) | 3/25 (12%) | 2/25 (8%) |
| Event | SHP615 |
|---|---|
| Seizure clusterNervous system disorders | 1/25 |
| Status epilepticusNervous system disorders | 1/25 |
| Respiratory depressionRespiratory, thoracic and mediastinal disorders | 1/25 |
| Event | SHP615 |
|---|---|
| Respiratory depressionRespiratory, thoracic and mediastinal disorders | 2/25 |
Safety set consisted of all participants who had received a single dose of the investigational product (IP), regardless of whether IP administration was documented to be complete or not on the IP administration page of the electronic case report form (eCRF).
| Age, Continuous(Years) | SHP615 |
|---|---|
| Mean | 4.63 ± 4.033 |
| Sex: Female, Male(Participants) | SHP615 |
|---|---|
| Female | 16 |
| Male | 9 |
| Ethnicity (NIH/OMB)(Participants) | SHP615 |
|---|---|
| Hispanic or Latino | 0 |
| Not Hispanic or Latino | 25 |
| Unknown or Not Reported | 0 |
| Race (NIH/OMB)(Participants) | SHP615 |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 25 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 0 |
| White | 0 |
| More than one race | 0 |
| Unknown or Not Reported | 0 |
Documents are hosted by the registry — open the source record to download them.
Plan to share: Yes — Shire provides access to the de-identified individual participant data for eligible studies to aid qualified researchers in addressing legitimate scientific objectives. These IPDs will be provided following approval of a data sharing request, and under the terms of a data sharing agreement.
Supporting information: Study protocol, Sap, Icf, Csr
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