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Trial registered on ANZCTR


Registration number
ACTRN12617001241325
Ethics application status
Approved
Date submitted
10/08/2017
Date registered
25/08/2017
Date last updated
7/02/2019
Date data sharing statement initially provided
7/02/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
A randomised controlled trial of Cognitive Bias Modification training during early recovery from alcohol dependence.
Scientific title
A randomised controlled trial to determine the effectiveness of Cognitive Bias Modification training during inpatient alcohol withdrawal on alcohol consumption rates 2 weeks, 3 months, 6-months, and 1 year post-discharge.
Secondary ID [1] 291702 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Alcohol use disorder 302875 0
Condition category
Condition code
Mental Health 302351 302351 0 0
Addiction

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
CBM Intervention: Many substance abusers have impaired ability to regulate and monitor their behaviour. According to the "dual process" model, addiction arises from an imbalance between overactive “bottom-up” automatic (impulsive) processes that drive behaviours and impaired "top-down" controlling processes that stop behaviours associated with negative consequences. As a result, the individual’s addictive behaviour becomes more easily triggered by alcohol related cues in their environment, but less able to be inhibited once triggered. The exaggerated tendency to attend and react to alcohol related cues is called “cognitive bias”. Cognitive bias modification (CBM) is a computer based training paradigm that trains the brain to inhibit the tendency to approach negative/harmful cues. This approach both minimizes the overactive "bottom-up" processes and improves the "top-down" control processes.

In the intervention CBM task, participants will be exposed to 240 computerised images of 40 different alcoholic and 40 different non-alcoholic drinks and instructed to respond with an approach or avoidance movement according to their orientation (landscape or portrait). While instructions are based on picture orientation, one orientation will contain images of alcoholic beverages 95% of the time (and non-alcoholic beverages 5% of the time) and will require an avoidance movement (pushing of a joystick, which decreases image size). The other orientation will contain non-alcoholic beverages 95% of the time and alcoholic beverages 5% of the time and will require an approach movement (pulling the joystick, which increases image size). The requirement to push away nearly all (95%) of alcohol images is intended to train participants to over-ride their pre-existing tendency to approach alcohol, and we hope that this will generalise to a reduced tendency to approach alcohol and its related cues following discharge from detoxification. This requirement will be reversed on 5% of trials to reduce the likelihood of participants being un-blinded to the nature of the training.

The training task usually takes approximately 15 minutes. It will be repeated on each of the three following days, such that the participant receives four consecutive days of training while in detoxification. The intervention will be administered by trained and qualified researchers employed by Turning Point (Eastern Health) or Monash University.

Training will commence no earlier than the 3rd day of inpatient withdrawal, though may be commenced later as long as there are 4 consecutive days available on which to conduct the training prior to the participant’s planned discharge day. In cases where participants receive the “standard” 7-day inpatient withdrawal, we aim to time sessions such that the final session will occur the day before discharge. However, due to variations in length of admission that sometimes occur, with some admissions lasting up to 2 weeks, the timing of training relative to the date of discharge will vary.

Data collectors will report any deviations from intervention adherence to the project manager, who will maintain a record of these deviations. Deviations may include interruptions to training sessions (e.g. due to computer errors or other unexpected events), non-standard scheduling of sessions (e.g. skipping a day, due to a participant being unwell or unavailable on a day a session is planned), or failure to complete 4 sessions due to unexpected early discharge from the withdrawal unit. All participants who commence training will be included in analyses, according to intention-to-treat principles, but participants who do not complete 4 sessions will be excluded from secondary per-protocol analyses.
Intervention code [1] 297787 0
Behaviour
Intervention code [2] 298864 0
Treatment: Other
Comparator / control treatment
In the control sham-training task, 150 participants will be exposed to 240 computerised images 40 different alcoholic and 40 different non-alcoholic drinks and instructed to respond by using the joystick to move the images to the left or right according to their orientation (landscape or portrait). Each orientation will contain images of alcohol beverages 50% of the time and non-alcoholic beverages 50% of the time. Thus, there will be an equal frequency of requirement to move alcoholic images to the left and to the right, and neither motion expands or shrinks the images, meaning participants in this condition are not systematically trained to either approach or avoid alcoholic images, though this training is matched to the CBM task in terms of exposure to images and requirement to respond to each one. The training will be repeated on each of the three following days, such that the participant receives four consecutive days of training. The sham-training will be administered by trained and qualified researchers employed by Turning Point (Eastern Health) or Monash University.
Control group
Placebo

Outcomes
Primary outcome [1] 301775 0
The primary outcome is whether, compared to those receiving sham training, participants receiving CBM training will show significantly higher rates of abstinence from alcohol. At the 2-week follow-up, a researcher will conduct a time-line follow-back interview assessing alcohol (and other substance use) during covering the time since discharge.
Timepoint [1] 301775 0
2 weeks post-discharge.
Secondary outcome [1] 333822 0
Difference between groups in rate of abstinence from alcohol at later time points (after the primary time point, i.e. 2-week follow-up). This will be measured by time-line follow-back interviews assessing alcohol (and other substance) use during the 30 days prior to each of the 3-, 6-, and 12-month follow-ups.
Timepoint [1] 333822 0
3-months, 6-months and 12-months post-discharge.
Secondary outcome [2] 333824 0
We aim to test whether stronger baseline approach bias scores will be associated with a larger effect of CBM (i.e., baseline approach biases will moderate CBM’s effect on abstinence). Approach bias will be measured prior to the commencement of the training intervention by using the Alcohol Approach-Avoidance Task (AAT), and we will test whether AAT scores moderate the effect of CBM (i.e. whether there is an interaction between the effects of AAT scores and group) on abstinence from alcohol at follow-up.
Timepoint [2] 333824 0
2-weeks, 3-months, 6-months and 12-months post-discharge.
Secondary outcome [3] 337941 0
Cost saving in the CBM group compared to controls in terms of change in cost of repeated inpatient detoxification treatment and acute health care use during the year following discharge (after accounting for the costs of implementing CBM training in the CBM group). Acute health service and substance withdrawal treatment episodes will be indexed using excerpts from a modified version of the Lifetime Drug Use History. We will record self-reported numbers of ambulance call-outs, emergency department attendances, episodes of substance withdrawal treatment, and hospital inpatient admissions (as well as duration of any substance withdrawal or hospital inpatient admissions) at each follow-up, and use this to estimate each participant's cost of acute health service use and substance withdrawal readmission during the year following discharge. We will compare net spending (cost of CBM intervention + cost of further detoxification/acute health service use ) in the CBM group to net spending (cost of further detoxification/acute health service use) in the control group to test whether the CBM intervention leads to cost-savings for the health care system.
Timepoint [3] 337941 0
One year following discharge from detoxification.
Secondary outcome [4] 338155 0
Cue-induced desire ratings of alcohol images following CBM training, using a measure designed specifically for this study. Participants will view 20 computerised images, 10 of alcoholic beverages and 10 of non-alcoholic beverages. Participants rate ‘wanting’ of images by marking a point along an accompanying 100 mm line with end caps either side indicating “I do not want this at all” to “I really want this”. Scores range from 0-100, based on the ‘mm’ distance between the participant’s mark and the lower end point (i.e. a score of 0 indicates no wanting at all; a score of 100 indicates maximal wanting). Within each of the two beverage categories (alcoholic; non-alcoholic), 5 of the 10 images are identical to images to be used in the CBM training task and the other 5 are novel images not used in other study tasks. Thus, we will test whether the training task reduces cue-induced alcohol desire, and also whether this generalises to other alcohol images not used in the CBM training task.
Timepoint [4] 338155 0
Immediately after session 4

Eligibility
Key inclusion criteria
Participants will be 300 alcohol-dependent patients (aged 18-65) admitted for inpatient detoxification at De Paul House (St. Vincent’s Hospital Melbourne), Wellington House (Eastern Health) or Windana Drug and Alcohol Reovery.
Inclusion criteria are:
1. Current moderate or severe DSM-5 alcohol use disorder (i.e. at least 4 alcohol use disorder criteria met within the past year, according to the Structured Clinical Interview for DSM-5 Disorders – Research Version (SCID-5-RV; First, Williams, Karg, & Spitzer, 2015).
2. Report at least weekly use of alcohol in the past month.
3. Be able to understand English.

Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria are:
1. History of neurological illness or injury or brain trauma involving loss of consciousness for longer than 30 minutes.
2. Intellectual disability.
3. Acutely unwell, as judged by clinical staff.

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)
A researcher not involved in recruitment or data collection generated randomisation sequences prior to the commencement of recruitment. Since separate laptop computers will be used for cognitive bias assessment and training at each site, the randomisation sequence for each site was programmed into the corresponding computer, such that the participant is automatically randomised when they commence training (based on the participant’s number in the sequence). The outcome assessor will also be blinded.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The sequence was generated using a computerised random number generator. A 1:1 allocation ratio was used for the randomisation, stratified by site, and based on permuted blocks of variable size within each stratum.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Statistical analysis of main outcome:
The primary outcome is abstinence during the first 14 days post-discharge, assessed at the first follow-up. In the ITT analysis of the primary endpoint, the divisor for the proportion of abstinent participants in an arm will be the number randomised to that arm and individuals for whom alcohol use during the first 14 days post-discharge was not assessed, for any reason, will be deemed to not be abstinent. These proportions will be compared using a two-sample binomial test (two-sided a=0.05) and a 95% confidence interval for the difference in the proportions will also be reported. The Cochran-Mantel-Haenszel Test, stratified by site, will be conducted as a supportive analysis. In a further supportive analysis of the primary endpoint, participants who complete fewer than 4 training sessions or who miss the 2-week assessment, will be excluded from the denominator (and the numerator) when the proportion of abstinent patients is calculated in each arm. This “per-protocol” analysis will use the same statistical methods as the ITT analysis. The moderating effect of baseline approach bias score on abstinence/relapse in the two weeks post discharge (i.e. the primary outcome) will be investigated by logistic regression models that include baseline scores as covariates in the model and tests of the significance of the two-way interaction of treatment arm with the covariate will be conducted. A similar approach will be used to test for a moderating effect of impulsivity, as measured by the BART.

Statistical analysis of secondary outcomes:
Assessments of abstinence in the 30 days prior to each of the 3, 6 and 12 month follow-ups will also be analysed in the same way as the ITT analysis of the primary (2-week) endpoint – participants not assessed for any reason will be deemed to not be abstinent. In a supplementary analysis of all available follow-up assessments (from 3 to 12-months), that assumes any missing follow-ups are missing completely at random, a logistic regression analysis, using the method of generalized estimating equations (GEE), will be used to compare the arms, and changes over time in the arms, adjusting, if need be, for sites. An additional supplementary, missing not at random (MNAR), analysis will use a Bayesian approach, and Markov chain Monte Carlo (MCMC) to jointly model abstinence and missingness. The model will include a random effect for each participant and minimally-informative, normal prior distributions for parameters in the logistic models for abstinence and missingness. Parameter estimates and their associated 95% credible intervals, based on posterior distributions, will be reported. The MNAR approach will also be used to investigate the moderating effect of the baseline approach bias score. Additional exploratory analyses, also using the MNAR approach, will investigate adjusting the estimated difference between the arms for such covariates as age, gender, and severity of alcohol dependence score.

Continuous-scale outcome measures, and ordinal scale outcomes that have 5 or more ordered categories, will be analysed using mixed models, and the restricted maximum likelihood (REML) method, with random effects for participants and assessments within participant, and fixed effects for treatment arm, time and baseline covariates. Diagnostic plots of residuals will be examined and, if required, analyses will be conducted using a variance-stabilising transformation such as the log transformation or the empirical logit transformation.

To determine the economic feasibility of CBM, in terms of savings to the treatment system (evidenced by fewer repeat inpatient detoxifications and episodes of acute health service use at the 12-month follow-up), summary statistics for the whole 12-month follow-up period will be calculated from service use data collected at each follow-up (e.g. number of emergency department admissions at each follow-up will be summed to produce a total for the entire follow-up period, etc.), and costs of this treatment will be estimated. We will compare net spending (cost of CBM intervention + cost of further detoxification/acute health service use for each participant) in the CBM group to net spending (cost of further detoxification/acute health service use) in the control group. Since not all participants will complete their 12-month follow-up exactly 365 days following discharge, cost estimates will be converted according to the formula “365 x (cost/d)”, where “d” is the number of days between discharge and the final follow-up, to standardise cost estimates to a 365 day period. Using this formula will also allow inclusion of data from participants who complete the 3- and/or 6-month follow-up, but who fail to complete a 12-month follow-up, with “d” meaning the number of days between discharge and the final follow-up in these cases. However, these cases will be weighted in analyses (weighting = 0.25 or 0.5 if the final follow-up was the 3-month or 6-month, respectively) to reflect the fact that cost data were generated from a substantially shorter period of time and therefore may be less reliable. Data from participants who only completed the 2-week follow-up will not be included in these analyses. The statistical significance of the difference between the groups in estimated costs will be assessed with a t-test and a variance-stabilising transformation, such as the logarithm, will likely be required.

For cue-induced wanting, outcomes will be assessed with a repeated measures ANOVA assessing within-subjects variables of ‘time’ (pre-training/post-training), ‘picture-type’ (alcohol/non-alcohol), and ‘novelty’ (used in training/not used in training), with the between-subjects conditions of ‘group’ (CBM/Control). This will be followed up by separately testing effects of time, picture, type, and group at each level of novelty, i.e. conducting separate analyses for those images that were used in training and for those images that weren’t, to examine generalisability.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment postcode(s) [1] 15786 0
3183 - St Kilda East
Recruitment postcode(s) [2] 16688 0
3128 - Box Hill
Recruitment postcode(s) [3] 16689 0
3065 - Fitzroy

Funding & Sponsors
Funding source category [1] 296202 0
Government body
Name [1] 296202 0
National Health and Medical Research Council (NHMRC)
Address [1] 296202 0
Research Committee Secretariat NHMRC GPO Box 1421 Canberra ACT 2601
Country [1] 296202 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Wellington Rd, Clayton VIC, 3800
Country
Australia
Secondary sponsor category [1] 295110 0
None
Name [1] 295110 0
Address [1] 295110 0
Country [1] 295110 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297441 0
St Vincent's Hospital Melbourne Human Research Ethics Committee (HREC)
Ethics committee address [1] 297441 0
41 Victoria Parade Fitzroy VIC 3065
PO Box 2900 Fitzroy VIC 3065
Ethics committee country [1] 297441 0
Australia
Date submitted for ethics approval [1] 297441 0
08/02/2017
Approval date [1] 297441 0
09/03/2017
Ethics approval number [1] 297441 0
HREC/17/SVHM/21

Summary
Brief summary
This multi-site parallel groups randomised controlled trial will aim to recruit 300 alcohol-dependent patients (aged 18-65) admitted for inpatient detoxification at De Paul House (St. Vincent’s Hospital Melbourne), Wellington House (Eastern Health) or Windana Drug and Alcohol Recovery. The primary aim is to determine the effectiveness of CBM training during inpatient alcohol detoxification in terms of increased abstinence rates 2 weeks following discharge,relative to controls who receive sham training. We also aim to explore rates of abstinence, 3, 6, and 12 months post-discharge as a secondary outcome. Another secondary aim is to determine if pre-training levels of approach or attentional bias moderate the effectiveness of CBM, based on the hypothesis that those who drink due to strong cognitive biases are likely to benefit from treatments targeting these biases, while those with low cognitive biases, whose drinking is driven by other factors (e.g. relief from distress) may benefit less from CBM. We also aim to measure the difference between groups in rates of use of further inpatient withdrawal and acute health services during the year following discharge to assess whether CBM training leads to cost savings to the health system, and to measure differences between groups in cue-induced desire for alcohol following CBM training.

We hypothesise that, compared to those receiving sham training, participants receiving CBM training will show significantly higher rates of abstinence from alcohol at all followups. We also anticipate that stronger baseline attention and approach bias will be associated with a larger effect of CBM (i.e., baseline attention/approach biases will moderate CBM’s effect on abstinence). We expect significant net cost saving in the CBM group compared to controls in terms of reduced cost of repeated inpatient detoxification treatment and acute health care use during the year following discharge (after accounting for the costs of implementing CBM training in the CBM group). Compared to those receiving sham training, participants receiving CBM training will show significantly reduced cue-induced desire to alcohol images (but not to images of non-alcoholic beverages). We expect that this interaction will remain, with similar effect size, when analyses are restricted to images not included in the training task, demonstrating generalisation of reduced cue-induced desire beyond the specific stimuli that participants were trained to avoid.
Trial website
Trial related presentations / publications
Public notes
Attachments [2] 1767 1767 0 0
Attachments [3] 1768 1768 0 0
Attachments [5] 2091 2091 0 0

Contacts
Principal investigator
Name 74046 0
Dr Victoria Manning
Address 74046 0
Turning Point
54 Gertrude Street
Fiztroy, VIC 3121
Country 74046 0
Australia
Phone 74046 0
+61 3 9412 9951
Fax 74046 0
+61 3 9416 3420
Email 74046 0
victoriam@turningpoint.org.au
Contact person for public queries
Name 74047 0
Dr Victoria Manning
Address 74047 0
Turning Point
54 Gertrude Street
Fiztroy, VIC 3121
Country 74047 0
Australia
Phone 74047 0
+61 3 9412 9951
Fax 74047 0
+61 3 9416 3420
Email 74047 0
victoriam@turningpoint.org.au
Contact person for scientific queries
Name 74048 0
Dr Victoria Manning
Address 74048 0
Turning Point
54 Gertrude Street
Fiztroy, VIC 3121
Country 74048 0
Australia
Phone 74048 0
+61 3 9412 9951
Fax 74048 0
+61 3 9416 3420
Email 74048 0
victoriam@turningpoint.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
It is a condition of the ethics approval that participant data will remain confidential and will not be released for people outside the research team to conduct additional analyses on without further ethical approval. Researchers seeking access to data for further analyses will need to contact the chief investigator to discuss this.
What supporting documents are/will be available?
Statistical analysis plan
Attachments/websites
Type [1] 1314 0
Statistical analysis plan
URL/details/comments [1] 1314 0
Summary results
Not applicable