Benzodiazepine overdose Injury, Occupational Diseases, Poisoning
Conditions
Interventions
This is a multicentre, Phase II/III, randomised, double-blind, dose-escalation then parallel-group study to evaluate the safety and efficacy of intramuscular (IM) flumazenil. The study will first iden
Sponsors
University of Edinburgh
Eligibility
Sex/Gender
All
Age
16 Years to 100 Years
Inclusion criteria
Inclusion criteria: 1. Acute suspected unintentional BZD overdose presenting to hospital with reduced consciousness after administration of clinically adequate doses of naloxone. Mixed overdoses suspected to include BZDs will be included 2. Other common causes of reduced consciousness (such as hypoglycaemia) will have been excluded 3. RASS score of -5 (unrousable) to -3 (moderate sedation) 4. Aged, or believed to be aged, 16 years and over
Exclusion criteria
Exclusion criteria: 1. RASS score above -3 2. Past medical history of epilepsy or chronic brain injury 3. Seizure pre-hospital following the overdose or after hospital admission, before recruitment 4. Clinically apparent pregnancy or medical record of current pregnancy (urine-HCG test not practicable in patients with reduced consciousness) 5. Prolonged QRS duration (>120 msec, unless due to pre-existing bundle branch block) on electrocardiogram 6. Prisoner or under arrest 7. Currently detained under the Mental Health Act 8. HIV positive with detectable virus load, or no virus load data from previous 12 months, or not currently on therapy 9. Patients who have previously participated in the study (according to the recruitment log). In Stage 1, as we explore the safety of flumazenil, we will have additional exclusion criteria to further reduce the risk of seizures. 10. No access to medical records at recruitment 11. Unknown patient (precluding use of medical records). To ensure external validity for future clinical practice, when medical records will usually not be immediately available, these will not be used once stage 1 has identified potentially safe doses. The risk of seizures in these patients with a dose found to be safe in Stage 1 is likely to be outweighed by the chance of benefit if used pre-hospital in future.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Stage 1 Primary Endpoint (safety) The occurrence of a tonic-clonic seizure as measured by visual observation of the participant by an experienced clinician up to 1 h after drug administration Primary Endpoint (efficacy) The level of sedation as measured using the Richmond Agitation-Sedation Score (RASS) score is in the -2 [light sedation] to 0 [alert, calm] range at 15 min after drug administration Stage 2 Primary Endpoint (efficacy) The level of sedation as measured using the Richmond Agitation-Sedation Score (RASS) score is in the -2 [light sedation] to 0 [alert, calm] range at 15 min after drug administration Stage 3 Primary Endpoint (safety) The occurrence of a tonic-clonic seizure as measured by visual observation of the participant by an experienced clinician up to 1 h after drug administration | — |
Secondary
| Measure | Time frame |
|---|---|
| Current key secondary outcome(s) as of 22/06/2026: Stage 1 1. Reversal of respiratory depression measured using falling PaCO2 on venous (alternatively arterial) blood-gas analysis at 15 and 30 min 2. Level of sedation measured using RASS, Glasgow Coma Scale/Score (GCS), and Alert, Voice, Pain, Unresponsive (AVPU) scores over 60 min post drug administration 3. Need for/duration of intubation, or death, recorded until hospital discharge 4. Adverse events (AEs) and serious adverse events (SAEs) recorded from the time of administration of flumazenil or placebo until hospital discharge Stage 2 1. Reversal of respiratory depression measured using falling PaCO2 on venous (alternatively arterial) blood-gas analysis at 15 and 30 min 2. Level of sedation measured using RASS, GCS, and AVPU scores over 60 min post drug administration 3. Need for/duration of intubation, or death, recorded until hospital discharge 4. AEs and SAEs recorded from the time of administration of flumazenil or placebo until hospital discharge Stage 3 1. Reversal of respiratory depression measured using falling PaCO2 on venous (alternatively arterial) blood-gas analysis at 15 and 30 min 2. Level of sedation measured using RASS, GCS, and AVPU scores over 60 min post drug administration 3. Need for/duration of intubation, or death, recorded until hospital discharge 4. AEs and SAEs recorded from the time of administration of flumazenil or placebo until hospital discharge Physiological secondary endpoints measured using blood and breath samples until 150 min. Other secondary endpoints measured until hospital discharge. _____ Previous key secondary outcome(s): Stage 1 1. Reversal of respiratory depression measured using falling PaCO2 on venous (alternatively arterial) blood-gas analysis at 15 and 30 min 2. Level of sedation measured using RASS, Glasgow Coma Scale/Score (GCS), and Alert, Voice, Pain, Unresponsive (AVPU) scores over 60 min post drug administration 3. Need for/duration of intubation, or | — |
Countries
England, Scotland, United Kingdom
Outcome results
None listed