Repurposing flumazenil for intramuscular treatment of coma due to unintentional drug overdose - a dose-finding safety and efficacy phase II/III study
Benzodiazepine overdose
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 identify two likely safe and efficacious doses of IM flumazenil in a dose-escalation design, then gain more precise estimates of efficacy for these two doses, before measuring safety (incidence of seizures) in the lowest efficacious IM dose in a non-inferiority comparison to placebo. The study will be conducted in three stages. Stage 1 In Stage 1, there will be up to six dose escalation cohorts, each including 12 participants. Participants will be randomised to flumazenil or saline placebo in a 5:1 ratio for each cohort of 12 participants (10 flumazenil: 2 placebo). The first four dose cohorts will receive 0.2 mg, 0.4 mg, 0.8 mg and 1.2 mg of flumazenil by IM injection over <10 sec, as long as dose escalation is recommended by the Data Monitoring Committee (DMC). The last two dose cohorts are currently proposed as 2.0 mg and 3.0 mg but these doses may be modified if there has been a clear response at the 1.2 mg dose. Stage 2 The two doses identified by the DMC as being effective in stage 1 will be given to participants in stage 2. The first dose in stage 1 which elicits an improvement in consciousness, as shown by an increase in RASS score in >50% of participants, and does not induce tonic-clonic seizures will be the first dose for stage 2. A decision on whether to escalate to the next proposed dose level or a different dose will be made by the DMC. Up to 189 participants will be randomised to one of the two flumazenil doses or placebo in a 1:1:1 ratio in stage 2. Stage 3 The most efficacious flumazenil dose (improved consciousness as shown by increased RASS scores in the -2 to 0 range) from stage 2 will be selected for stage 3. Up to 374 participants in stage 3 will be randomised in a 1:1 ratio to the most efficacious flumazenil dose or placebo. A total of up to 635 p
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
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.