Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618000106235
Ethics application status
Approved
Date submitted
19/12/2017
Date registered
24/01/2018
Date last updated
12/08/2019
Date data sharing statement initially provided
12/08/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
The ALiAS Trial: Examining the potential for lithium treatment to help patients with suicidality
Scientific title
The Adjunctive Lithium for Acute Suicidality (ALiAS) Trial: A randomised controlled trial examining the effect of adjunctive lithium on acute suicidality in patients with a mood disorder
Secondary ID [1] 292429 0
None
Universal Trial Number (UTN)
Trial acronym
The ALiAS Trial
Linked study record
NA

Health condition
Health condition(s) or problem(s) studied:
Suicidality 304223 0
Condition category
Condition code
Mental Health 303575 303575 0 0
Suicide

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The ALiAS Trial is a 5-week randomised, double-blind, placebo-controlled treatment trial. During the trial participants will receive treatment as usual with either lithium carbonate or placebo prescribed as an adjunctive treatment. Treatment as usual is defined as treatment as directed by the treating doctor of the participant.

Lithium will be prescribed in addition to treatment as usual for 5 weeks, allowing one week to titrate doses to achieve a suitable lithium plasma concentration level (typically 0.6-0.8 mmol/L). Therefore there will be 1 week of titration and up to 4 weeks of lithium therapy at a stable dose.

Dose: The dose will be variable for each participant and dependent on their lithium plasma concentration measured by weekly blood tests. In the titration week daily doses will increase from 250mg (Day 1) to 1250mg (Day 7). At the end of the titration week, all participants will undergo a blood test and their prescribed dosage for the following week will be dependent on whether the participant has reached a suitable level. Typically patients will be prescribed between 1000mg and 1500mg per day, but no more than 2000mg per day.

Duration: Participants will participate in the trial and will receive adjunctive lithium therapy or placebo for a total of 5 weeks.

Mode: The lithium tablets are administered orally with water after a meal at 20:00 (8:00pm) each night.

Adherence: Trial medication adherence for participants that are outpatients will be measured by participant self-report and will be reflected in the blood tests. For participants that are involved in the study while they are inpatients at The Northside Clinic, the nursing staff will record trial medication adherence, and adherence will also be validated by blood test results.
Intervention code [1] 298764 0
Treatment: Drugs
Comparator / control treatment
Placebo tablets have been made to replicate the Lithicarb tablets but do not contain any acitive ingredients. Participants and selected researchers will be blind to the treatment group that each participant has been allocated to (e.g. whether they are being prescribed lithium or placebo). The dose, duration and mode of administration are all the same as the active treatment, including regular blood tests. The blood test will be returned with sham results to ensure the trial psychiatrist and researchers remain blind whist adjusting dosage and assessing participants.
Control group
Placebo

Outcomes
Primary outcome [1] 302932 0
The primary outcome measure for the current study is the level of suicidality. This is will be measured by the Sheehan Suicidality Tracking Scale (S-STS; Coric et al., 2009). The S-STS will be administered by a researcher.

To further elucidate the results for the S-STS, the Paykel Scale and the Beck Scale for Suicide Ideation will be administered.
Timepoint [1] 302932 0
All three questionnaires will be administered at baseline, weekly at each appointment throughout the trial and at the endpoint (the final weekly appointment at the end of the five week period; the primary endpoint).
Secondary outcome [1] 337475 0
A secondary composite outcome is measuring the correlates of suicidality. These correlates are the cognitive psychological constructs of impulsiveness, hopelessness, and defeat and entrapment. The measures assessing these correlates are the Barratt Impulsiveness Scale (BIS; Patton & Stanford, 1995), the Beck Hopelessness Scale (BHS; Beck et al., 1974) and the Short Defeat and Entrapment Scale (SDES; Griffiths et al., 2015)
Timepoint [1] 337475 0
These measures will be assessed by self-report questionnaires at baseline and at each weekly appointment throughout the 5 week intervention including the endpoint (the final weekly appointment) to determine whether these constructs are modulated with acute lithium therapy.
Secondary outcome [2] 337476 0
Overall clinical presentation is another secondary outcome. To measure this the Principal Investigator will administer the Clinical Global Impression Scale for Bipolar Disorder-Severity Scale (Busner & Targum, 2007).
Timepoint [2] 337476 0
This scale will be administered at baseline and at the endpoint (the final weekly appointment at the end of the five week period).
Secondary outcome [3] 337477 0
Researcher ratings of patients’ mood are also a secondary composite outcome and these will be measured by the Hamilton Depression Scale (Hamilton, 1960), the Montgomery-Asberg Depression Scale (MADRS; Montgomery & Asberg, 1979) and the Young Mania Rating Scale (Young et al., 1978).
Timepoint [3] 337477 0
The Hamilton Depression Scale will be administered at baseline and endpoint (the final weekly appointment at the end of the five week period), while the Montgomery-Asberg Depression Scale and the Young Mania Rating Scale will be administered at baseline, at each weekly trial visit, and at the endpoint.
Secondary outcome [4] 337478 0
Medication adherence is another secondary outcome. To measure medication adherence participants will complete the self-report 8-item Morisky Medication Adherence Scale (Morisky, Green & Levine, 1986).
Timepoint [4] 337478 0
This scale will be completed by participants at baseline and at the endpoint (the final weekly appointment at the end of the five week period).
Secondary outcome [5] 342150 0
Treatment response is another secondary outcome. To measure this the Principal Investigator will administer the Episodes Questionnaire.
Timepoint [5] 342150 0
This scale will be administered at baseline and at the endpoint (the final weekly appointment at the end of the five week period).
Secondary outcome [6] 342151 0
Self-reported side-effects is another secondary outcome. To measure side-effects experienced by participants, the participants will complete the Side Effects Questionnaire.
Timepoint [6] 342151 0
This scale will be completed by participants at baseline and at the endpoint (the final weekly appointment at the end of the five week period).
Secondary outcome [7] 342152 0
Quality of life is another secondary outcome. To measure quality of life over trial period participants will complete the Quality of Life Enjoyment and Satisfaction Questionnaire-Short From (Q-LES-Q-SF; Stevanovic, 2011).
Timepoint [7] 342152 0
This scale will be completed by participants at baseline and at the endpoint (the final weekly appointment at the end of the five week period).

Eligibility
Key inclusion criteria
Participants will be eligible to take part in the ALiAS Trial if they are:
- Aged 18-65 years
- Meet DSM-5 criteria for a mood disorder
- Currently receiving treatment for a mood disorder
- Presenting with suicidality as defined by a score of greater than 8 on the S-STS scale
- Not currently receiving lithium treatment and their treating doctor does not intend to prescribe lithium during the course of the study
- Willing and able to comply to the trial protocol in English
- Willing and able to give written informed consent in English
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants will be not be eligible to take part in the ALiAS Trial if they:
- Are not receiving treatment for a mood disorder
- Have used lithium in the past 6 months
- Meet criteria for personality disorder or substance dependency disorder in accordance with DSM-5 criteria
- Have contraindication for lithium therapy including heart conditions, thyroid, hepatic, renal dysfunction (as checked by blood tests)
- Are pregnant (as checked by blood test) or breastfeeding or are of child-bearing potential and not willing to use effective contraception
- Have participated in another research trial involving an investigational medical product in the past 12 weeks

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)
Only the Clinical Trial Coordinator and the Clinical Trials Pharmacy will have access to participant allocation information. The Principal Investigator (Trial Psychiatrist) will establish eligibility of participants. He will then prescribe the trial medication. This prescription will be taken to the Clinical Trials Pharmacy. Based on the participant's trial identification number the Clinical Trials Pharmacy will dispense the medication (containing either lithium or placebo). The medication will be labelled identically so the Principal Investigator, research personnel, and trial participants will not be aware of what treatment the participant is allocated.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomly allocated 1:1 to have adjunctive lithium therapy or a placebo. The Clinical Trials Coordinator (Dr Tim Othred) will draw on the assistance and support from the study randomisation and statistical advisor (Prof Andrea Cipriani). The Clinical Trials Coordinator will perform the randomisation using a computer-based random number table based on minimisation (a method of stratified sampling; Pocock & Simon, 1975; Treasure & MacRae, 1998), in accordance with CONSORT guidelines. The factors used for stratification are Age (2 levels: less than or equal to 25 years, greater than or equal to 26 years), Gender (2 levels: M, F) and Suicidality Severity S-STS total score at screening (2 levels: 9-20, 21-32).
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
Parallel
Other design features
NA.
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
We expect to recruit 180 participants for this study and have 120 participant complete the study.
In the only previous comparable trial (Khan et al., 2011), full remission of suicidality (score of 0 on the S-STS), was achieved in patients at therapeutic lithium levels at a rate of 45% versus 15% of the placebo group. With an alpha significance level of 0.05 and a remission rate in the placebo group of 15%, a total sample size of 120 is required at 85% power to see an absolute difference of 25% in favour of the intervention group (add-on lithium). Considering that it has been previously estimated that the remission rate in the lithium group is 45% (Khan et al., 2011), this is a conservative calculation of the sample size for this study to reach a significant statistical power. The power calculation is based on the following formulae: n = f(a/2, ß) × [p1 × (100 - p1) + p2 × (100 - p2)] / (p2 - p1) (Arsenault-Lapierre, Kim & Turecki, 2004), where p1 and p2 are the event rate in the control and experimental group respectively, and f(a, ß) = [F-1(a) + F-1(ß)]2, where F-1 is the cumulative distribution function of a standardised normal deviate (Pocock, 1983). Given that the trial is within a clinically nested inpatient setting with the majority of patients remaining in care for the required duration, we assuming a small attrition rate of approximately 5% (e.g., participant dropout) in each group. Thus the adjusted total sample size required is 148 participants overall. Adjustment for non-compliance/withdrawals is based on the formula: nadj = n × 10,000 / (100 - c1 - c2)2, where c1 and c2 are the percent cross-over in the control and experimental group respectively (Pocock, 1983). Hence, we will be required to invite approximately 180 patients for participation, with at least 120 patients completing the trial.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/03/2018
Actual
Date of last participant enrolment
Anticipated
1/03/2022
Actual
Date of last data collection
Anticipated
1/08/2022
Actual
Sample size
Target
120
Accrual to date
0
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 8679 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [2] 8680 0
Northside Clinic Private Hospital - Greenwich
Recruitment postcode(s) [1] 16790 0
2065 - St Leonards
Recruitment postcode(s) [2] 16791 0
2065 - Greenwich

Funding & Sponsors
Funding source category [1] 296989 0
Charities/Societies/Foundations
Name [1] 296989 0
Australian Rotary Health
Country [1] 296989 0
Australia
Funding source category [2] 297429 0
Other Collaborative groups
Name [2] 297429 0
Kolling Institute of Medical Research
Country [2] 297429 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
NSW 2006
Country
Australia
Secondary sponsor category [1] 296425 0
None
Name [1] 296425 0
Address [1] 296425 0
Country [1] 296425 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298187 0
Northern Sydney Local Health District Human Research Ethics Committee
Ethics committee address [1] 298187 0
Ethics committee country [1] 298187 0
Australia
Date submitted for ethics approval [1] 298187 0
27/03/2017
Approval date [1] 298187 0
23/06/2017
Ethics approval number [1] 298187 0
HREC/17/HAWKE/95
Ethics committee name [2] 298326 0
The Northside Group Human Research Ethics Committee
Ethics committee address [2] 298326 0
Ethics committee country [2] 298326 0
Australia
Date submitted for ethics approval [2] 298326 0
12/04/2017
Approval date [2] 298326 0
21/08/2017
Ethics approval number [2] 298326 0

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

Contacts
Principal investigator
Name 76262 0
Prof Gin Malhi
Address 76262 0
CADE Clinic,
Level 3, Main Building
Royal North Shore Hospital
St Leonards
NSW 2065
Country 76262 0
Australia
Phone 76262 0
+61 2 94629909
Fax 76262 0
+61 2 99264063
Email 76262 0
gin.malhi@sydney.edu.au
Contact person for public queries
Name 76263 0
Tim Outhred
Address 76263 0
CADE Clinic,
Level 3, Main Building
Royal North Shore Hospital
St Leonards
NSW 2065
Country 76263 0
Australia
Phone 76263 0
+61 2 94629913
Fax 76263 0
+61 2 99264063
Email 76263 0
tim.outhred@sydney.edu.au
Contact person for scientific queries
Name 76264 0
Tim Outhred
Address 76264 0
CADE Clinic,
Level 3, Main Building
Royal North Shore Hospital
St Leonards
NSW 2065
Country 76264 0
Australia
Phone 76264 0
+61 2 94629913
Fax 76264 0
+61 2 99264063
Email 76264 0
tim.outhred@sydney.edu.au

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?

Current supporting documents:
Doc. No.TypeCitationLinkEmailOther DetailsAttachment
3920Study protocol  tim.outhred@sydney.edu.au
3921Statistical analysis plan  tim.outhred@sydney.edu.au
3922Informed consent form  tim.outhred@sydney.edu.au
3923Clinical study report  tim.outhred@sydney.edu.au
3924Ethical approval  tim.outhred@sydney.edu.au
3925Analytic code  tim.outhred@sydney.edu.au


Updated to:
Doc. No.TypeCitationLinkEmailOther DetailsAttachment
3920Study protocol  gin.malhi@sydney.edu.au
3921Statistical analysis plan  gin.malhi@sydney.edu.au
3922Informed consent form  gin.malhi@sydney.edu.au
3923Clinical study report  gin.malhi@sydney.edu.au
3924Ethical approval  gin.malhi@sydney.edu.au
3925Analytic code  gin.malhi@sydney.edu.au

Results publications and other study-related documents

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

Documents added automatically
No additional documents have been identified.