Study design

This page outlines the background information and study design for each stage of the trial.

Background

Detail Description
Trial title Repurposing flumazenil for intramuscular treatment of coma due to unintentional drug overdose - a dose-finding safety and efficacy phase II/III RCT
Study acronym RUFUS
Clinical Phase Phase II/III
Trial Design Multicentre, phase II/III, randomised, double blind, dose-escalation then parallel group, study to evaluate safety and efficacy of intramuscular flumazenil
Trial Participants Patients with reduced consciousness (Richmond Agitation-Sedation Score [RASS]: -5 to -3) due to suspected benzodiazepine (BZD) overdose after adequate naloxone administration
Planned Number of Participants Up to 635 (stage 1: up to n=72 [max 6 cohorts of 12]; stage 2: n=189; stage 3: n=374)
Planned Number of Sites 4
Treatment Duration Single bolus intramuscular injection (<1 min)
Follow up Duration Until hospital discharge
Total Planned Trial Duration 54 months

Primary Objective

  • Identify two likely safe (regarding tonic-clonic seizures) and efficacious IM doses of flumazenil

Secondary Objectives (SO)

  • SO 1. Gain more information on reversal of sedation through assessment of blood gases and sedation scores over 1 h post-administration of IM flumazenil
  • SO 2. Establish the safety profile of IM flumazenil

Exploratory Objective

  • (Edinburgh only): Explore the pharmacokinetics/pharmacodynamics of flumazenil’s interaction with BZDs

Primary Endpoint

  • Primary Endpoint (safety): Occurrence of a tonic-clonic seizure by 1 h
  • Primary Endpoint (efficacy): Richmond Agitation-Sedation Score (RASS) score in the -2 [light sedation] to 0 [alert, calm] range at 15 min

Secondary Endpoints

  • Reversal of respiratory depression (falling PaCO2 on venous [alternatively arterial] blood-gas analysis at 15 and 30 min) (SO1)
  • Level of sedation (RASS, GCS, and AVPU scores) over 60 min post drug administration (SO1)
  • Need for/duration of intubation, or death, until hospital discharge (SO1 and SO2).
  • AEs and SAEs occurring from the time of administration of flumazenil or placebo until hospital discharge (SO2)

Exploratory Endpoint

  • Flumazenil pharmacokinetics/pharmacodynamics with BZDs, using blood and breath concentrations for pharmacokinetics, and sedation and pupil movement for pharmacodynamics

Primary Objective

  • Gain more precise estimates for efficacy for these two IM doses (identified in stage 1)

Secondary Objectives (SO)

  • SO 1. Gain more information on reversal of sedation through assessment of blood gases and sedation scores over 1 h post-administration of IM flumazenil
  • SO 2. Establish the safety profile of IM flumazenil

Exploratory Objective

  • (Edinburgh only): Explore the pharmacokinetics/pharmacodynamics of flumazenil’s interaction with BZDs

Primary Endpoint

  • Primary Endpoint (efficacy): Richmond Agitation-Sedation Score (RASS) score in the -2 [light sedation] to 0 [alert, calm] range at 15 min

Secondary Endpoints

  • Reversal of respiratory depression (falling PaCO2 on venous [alternatively arterial] blood-gas analysis at 15 and 30 min) (SO1)
  • Level of sedation (RASS, GCS, and AVPU scores) over 60 min post drug administration (SO1)
  • Need for/duration of intubation, or death, until hospital discharge (SO1 and SO2).
  • AEs and SAEs occurring from the time of administration of flumazenil or
    placebo until hospital discharge (SO2)

Exploratory Endpoint

  • Flumazenil pharmacokinetics/pharmacodynamics with BZDs, using blood and breath concentrations for pharmacokinetics, and sedation and pupil movement for pharmacodynamics

Primary Objective

  • Establish the incidence of tonic-clonic seizures for an effective IM dose of flumazenil (identified in stage 2), compared to placebo

Secondary Objectives (SO)

  • SO 1. Gain more information on reversal of sedation through assessment of blood gases and sedation scores over 1 h post-administration of IM flumazenil
  • SO 2. Establish the safety profile of IM flumazenil

Exploratory Objective

  • (Edinburgh only): Explore the pharmacokinetics/pharmacodynamics of flumazenil’s interaction with BZDs

Primary Endpoint

  • Primary Endpoint (safety): Occurrence of a tonic-clonic seizure by 1 h

Secondary Endpoints

  • Reversal of respiratory depression (falling PaCO2 on venous [alternatively arterial] blood-gas analysis at 15 and 30 min) (SO1)
  • Level of sedation (RASS, GCS, and AVPU scores) over 60 min post drug administration (SO1)
  • Need for/duration of intubation, or death, until hospital discharge (SO1 and SO2).
  • AEs and SAEs occurring from the time of administration of flumazenil or placebo until hospital discharge (SO2)

Exploratory Endpoint

  • Flumazenil pharmacokinetics/pharmacodynamics with BZDs, using blood and breath concentrations for pharmacokinetics, and sedation and pupil movement for pharmacodynamics

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