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Trial registered on ANZCTR


Registration number
ACTRN12616001560482
Ethics application status
Approved
Date submitted
13/10/2016
Date registered
11/11/2016
Date last updated
4/03/2022
Date data sharing statement initially provided
4/03/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
The role of flumazenil infusion in the treatment of benzodiazepine withdrawal
Scientific title
The role of flumazenil infusion in the treatment of benzodiazepine withdrawal
Secondary ID [1] 290282 0
Nil known
Universal Trial Number (UTN)
U1111-­1188-­3738
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Benzodiazepine withdrawal 300519 0
Condition category
Condition code
Mental Health 300380 300380 0 0
Addiction

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A double-blind, placebo-controlled, cross-over, randomised clinical trial of 2 consecutive 96-hour continuous subcutaneous infusions of flumazenil 16 mg (approx. 167 ug/hr) during a symptom-triggered benzodiazepine taper. The treatment phase of the trial will run for 16 consecutive days, during which participants will be administered oral tablet diazepam 10 mg, as required, based on administration of a withdrawal symptom scale by their carer each time medication is requested. This approach allows for a gradual, symptom-triggered taper from benzodiazepines. A symptom score of 2 or higher on the 6-item CIWA-B scale (McGregor et al., 2003) will indicate the need for a dose of diazepam 10 mg, to a maximum of 1 dose per hour. Participants will receive subcutaneous flumazenil infusion during either the first or second 8-days of treatment, based on a randomized, double-blind, placebo-controlled design. An identical saline placebo infusion will be administered on the alternate 8 days of treatment, with no washout period between. Participants are required to attend a day clinic for assessment by a Dr in order to commence the clinical trial treatment, after which they may return home with a carer or opt to stay as an inpatient, with visits to the clinic on treatment days 1, 4, 8, 9, 12 and 16.
Intervention code [1] 296086 0
Treatment: Drugs
Comparator / control treatment
2 consecutive 96-hour continuous subcutaneous placebo infusions. The placebo contains 0.9% Sodium Chloride saline.
Control group
Placebo

Outcomes
Primary outcome [1] 299832 0
Rate of symptom-triggered taper from benzodiazepines, as assessed by daily diazepam dose required.
Timepoint [1] 299832 0
Reduction in daily diazepam dose from day 1 to day 8 of active treatment compared to reduction from day 1 to day 8 of placebo treatment.
Secondary outcome [1] 328235 0
Benzodiazepine withdrawal symptom severity, assessed by CIWA-B scale (Busto et al., 1989).
Timepoint [1] 328235 0
CIWA-B withdrawal scores on days 1, 4 and 8 of active infusion compared to days 1, 4 and 8 of placebo infusion.
Secondary outcome [2] 328236 0
Benzodiazepine craving, assessed by the Breif Substance Craving Scale (Somoza et al., 1995).
Timepoint [2] 328236 0
Craving scale scores on days 1, 4 and 8 of active infusion compared to days 1, 4 and 8 of placebo infusion.
Secondary outcome [3] 328237 0
Anxiety, as assessed by STAI scores (Spielberger, 1985).
Timepoint [3] 328237 0
STAI scores on days 1, 4 and 8 of active infusion compared to days 1, 4 and 8 of placebo infusion.
Secondary outcome [4] 328241 0
Infusion site tissue reactivity (redness, swelling, tenderness, exudation and itchiness), as assessed using a 4-point NRS completed by an investigator.
Timepoint [4] 328241 0
Infusion sites will be inspected on days 1, 4 and 8 of both active and placebo infusions.
Secondary outcome [5] 329151 0
Post-withdrawal abstinence from benzodiazepines, as assessed by participant self-report.
Timepoint [5] 329151 0
Participants will be questioned by the investigators about their benzodiazepine abstinence/use at weeks 2, 4, 8 and 12 post-treatment.

Eligibility
Key inclusion criteria
Patients with daily benzodiazepine use for at least 3 months at a diazepam equivalent dose of 10 mg per day or higher, who want to cease benzodiazepine use.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients will be excluded if they suffer epilepsy or have a history of seizures or fitting, are pregnant or are breastfeeding, are co-dependent on alcohol, are under 18 years of age or are unable or unwilling to provide informed consent.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation will be concealed by using identical packaging for placebo and active treatments which are pre-labelled with participant ID's by an appointed person who does not have any other involvement in the trial or any contact with clinic patients.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple blocked randomisation with randomly selected block sizes was used. The randomisation sequence was created using an online randomisation service,
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Data will be analysed using SPSS. Independent samples 2-tailed t-tests with bonferonni corrections will be used to compare anxiety, CIWA-B scores and benzodiazepine craving between the two treatment groups at each time point. 1-way between-subjects ANOVA with Tukey post-hoc analysis will be used to compare differences across the duration of treatment.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Lack of funding/staff/facilities
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
31/01/2017
Actual
5/08/2017
Date of last participant enrolment
Anticipated
1/05/2018
Actual
18/04/2019
Date of last data collection
Anticipated
1/08/2018
Actual
18/04/2019
Sample size
Target
30
Accrual to date
Final
28
Recruitment in Australia
Recruitment state(s)
QLD,WA
Recruitment hospital [1] 6782 0
Currumbin Clinic - Currumbin
Recruitment postcode(s) [1] 14437 0
4223 - Currumbin
Recruitment postcode(s) [2] 14438 0
6008 - Subiaco

Funding & Sponsors
Funding source category [1] 294656 0
Commercial sector/Industry
Name [1] 294656 0
Go Medical Industries Pty Ltd
Country [1] 294656 0
Australia
Funding source category [2] 294657 0
University
Name [2] 294657 0
The University of Western Australia
Country [2] 294657 0
Australia
Funding source category [3] 294658 0
Other
Name [3] 294658 0
Fresh Start Recovery Programme
Country [3] 294658 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Go Medical Industries Pty Ltd
Address
200 Churchill Ave, Subiaco WA 6008
Country
Australia
Secondary sponsor category [1] 293514 0
None
Name [1] 293514 0
Address [1] 293514 0
Country [1] 293514 0
Other collaborator category [1] 279260 0
Hospital
Name [1] 279260 0
Currumbin Clinic
Address [1] 279260 0
37 Bilinga Street, Currumbin QLD 4223
Country [1] 279260 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296094 0
Southcity Medical Centre Human Research Ethics Committee
Ethics committee address [1] 296094 0
Ethics committee country [1] 296094 0
Australia
Date submitted for ethics approval [1] 296094 0
24/03/2015
Approval date [1] 296094 0
08/09/2015
Ethics approval number [1] 296094 0
002/2015

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 69510 0
A/Prof George O'Neil
Address 69510 0
Fresh Start Recovery Programme
65 Townshend Rd, Subiaco WA 6008
Country 69510 0
Australia
Phone 69510 0
+61 8 9381 1333
Fax 69510 0
Email 69510 0
email@drgeorgeoneil.com
Contact person for public queries
Name 69511 0
George O'Neil
Address 69511 0
Fresh Start Recovery Programme
65 Townshend Rd, Subiaco WA 6008
Country 69511 0
Australia
Phone 69511 0
+61 8 9381 1333
Fax 69511 0
Email 69511 0
email@drgeorgeoneil.com
Contact person for scientific queries
Name 69512 0
George O'Neil
Address 69512 0
Fresh Start Recovery Programme
65 Townshend Rd, Subiaco WA 6008
Country 69512 0
Australia
Phone 69512 0
+61 8 9381 1333
Fax 69512 0
Email 69512 0
email@drgeorgeoneil.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseA double-blind randomised crossover trial of low-dose flumazenil for benzodiazepine withdrawal: A proof of concept.2022https://dx.doi.org/10.1016/j.drugalcdep.2022.109501
EmbaseIs the Precipitation of Anxiety Symptoms Associated with Bolus Doses of Flumazenil a Barrier to Its Use at Low Continuous Doses in Benzodiazepine Withdrawal?.2022https://dx.doi.org/10.3390/jcm11195948
N.B. These documents automatically identified may not have been verified by the study sponsor.