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Trial registered on ANZCTR


Registration number
ACTRN12616001702404
Ethics application status
Approved
Date submitted
2/12/2016
Date registered
12/12/2016
Date last updated
31/05/2021
Date data sharing statement initially provided
27/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy of Lithium versus Lamotrigine for the treatment of bipolar II disorder
Scientific title
Efficacy of Lithium versus Lamotrigine for the treatment of bipolar II disorder
Secondary ID [1] 290672 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Bipolar II Disorder 301202 0
Condition category
Condition code
Mental Health 300964 300964 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study is a randomised controlled trial which will compare Lithium or Lamotrigine open-label monotherapy for patients newly diagnosed with bipolar II disorder and who have not previously been treated with either medication. Patients will be randomised 1:1 to receive either Lithium or Lamotrigine and assessed over a 28-week period, with the study expected to be conducted over a three-year period. Eligible participants will be recruited principally through the Black Dog Institute clinics, following initial diagnosis of that condition and meeting other study inclusion/exclusion criteria. Potential participants will be informed about the trial by a research assistant and that it seeks to compare two effective bipolar II medications in terms of their comparative cost/benefits in terms of stabilising their mood swings. Following provision of consent, participants will be randomised to one of the two treatment conditions detailed below. All patients will be informed about which treatment group they are allocated, and have the possible risks and side-effects associated with their particular medication(s) detailed. Patients will be managed and assessed by a psychiatrist at the Black Dog Institute three times in the first six weeks and then once every four weeks for 28 weeks as part of the trial – and on a needs basis if any clinical problems arise. During such visits they will be assessed in terms of their mood state over the preceding interval by a research assistant blind to their actual drug treatment.

Details of Treatment Groups

Group 1: Will receive Lamotrigine as a monotherapy (Trade name, Lamictal) and titrated over 8 weeks in the following manner: 25 mg/day for the first week, increasing 25 mg each week to reach 200 mg at week 8 and allowed to be increased at a similar rate to a maximum dose of 300 mg/day as judged by treating clinician (Further increases or decreases will be dictated by consideration of clinical symptoms, maximum dosing, and tolerability). As noted below, the serum Lamotrigine level will be assessed on two occasions.

Group 2: Will receive Lithium (Trade name, Quilonum SR) which will be titrated starting at 450 mg/day for a week then its serum Lithium concentration will be obtained and dose adjusted until the Lithium concentration reaches 0.8 mEq/L. Lithium has linear kinetics so if 450 mg Lithium gives a serum level of 0.4, then the Lithium dose of 450 mg will be doubled to seek a 0.8 level. If level 0.6 then Lithium dose increased from 450 mg to 625 mg. At the next scheduled visit the serum level will be checked to confirm serum level of 0.8 and, if not, any further adjustments will be made. Once a 0.8 serum level has been obtained then serum levels will be checked every 3 months including at the last visit, along with the creatinine level and thyroid function tests,
Lithium dosing will be dictated by clinical response, tolerability, and blood levels (minimum 0.8 to maximum 1.2 mEq/L).

For all participants the managing psychiatrist will assess clinical progress and side-effects at each individual consultation for the first six weeks, and then monthly until week 28.

Both Lamotrigine and Lithium will be administered orally.

Medication adherence will be monitered by checking serum Lithium levels at intervals noted above and for Lamotrigine, levels tested at 12 weeks and at trial end
Intervention code [1] 296554 0
Treatment: Drugs
Comparator / control treatment
Comparing between Lithium and Lamotrigine
Control group
Active

Outcomes
Primary outcome [1] 300390 0
Proportion of participants with a decrease in hypomania. Hypomania is assessed using a daily rating scale of mood. The daily rating scale allows for a measure of the total area above the line (the line being a euthymic state). The area above the line generates an interval hypomanic score which captures the duration and severity of hypomania for each day of the study period.

The Daily Rating Scale was developed at the Black Dog Institute and utilised in a previous study by Parker, Tully, Olley, & Hadzi-Pavlovic, 2006 - SSRIs as mood stabilizers for Bipolar II Disorder? A proof of concept study. Journal of Affective Disorders, 92(2-3), 205-214
Timepoint [1] 300390 0
Daily for the 28 weeks of treatment
Primary outcome [2] 300428 0
Proportion of participants with a decrease in depression. Depression is assessed using the same daily rating scale of mood. The daily rating scale also allows for a measure of the total area below the line (the line being a euthymic state). The area below the line generates an interval depression score which captures the duration and severity of depression for each day of the study period.

The Daily Rating Scale was developed at the Black Dog Institute and utilised in a previous study by Parker, Tully, Olley, & Hadzi-Pavlovic, 2006 - SSRIs as mood stabilizers for Bipolar II Disorder? A proof of concept study. Journal of Affective Disorders, 92(2-3), 205-214
Timepoint [2] 300428 0
Daily for the 28 weeks of treatment
Primary outcome [3] 300429 0
Composite measure of hypomania and depression over the study period. The composite measure will be created using the daily rating scale of mood. The composite will comprise the total area above and below the line (the line being a euthymic state). This will generate the total duration and severity of hypomania and/or depression for each day of the study period.

The Daily Rating Scale was developed at the Black Dog Institute and utilised in a previous study by Parker, Tully, Olley, & Hadzi-Pavlovic, 2006 - SSRIs as mood stabilizers for Bipolar II Disorder? A proof of concept study. Journal of Affective Disorders, 92(2-3), 205-214
Timepoint [3] 300429 0
Daily for the 28 weeks of treatment
Secondary outcome [1] 329863 0
Severity of depression - assessed by a research assistant at each time-point (not daily),

Depression will be assessed using the following measure:

Hamilton Depression Rating Scale (HAM-D; Hamilton, 1960),

Timepoint [1] 329863 0
The assessment measure will be completed nine times (baseline (week 0), week 2, 4, 8, 12, 16, 20, 24, 28) corresponding with the nine assessment visits
Secondary outcome [2] 329864 0
Severity of hypomania - assessed by a research assistant and a patient self-report measure at each time-point (not daily).

Hypomania will be assessed using the following measures:

Young Mania Rating Scale (YMRS; Young, Biggs, Ziegler, & Meyer, 1978). Rated by the research assistant
Mood Swings Questionnaire (MSQ; Parker, Hadzi-Pavlovic, & Tully, 2006), Rated by patient self-report
Timepoint [2] 329864 0
Each of the assessment measures will be completed nine times (baseline (week 0), week 2, 4, 8, 12, 16, 20, 24, 28) corresponding with the nine assessment visits
Secondary outcome [3] 329957 0
Overall functioning - rated using research assistant and clinician rated questionnaires at each time-point (not daily).

Overall functioning will be assessed using the following measures:

Global Assessment of Functioning (GAF; DSM-IV-TR, 2000). Rated by the research assistant
Clinical Global Impression Scale for Bipolar Disorder (CGI-BP; Spearing et al, 1997). Rated by the managing clinician
Timepoint [3] 329957 0
Each of the assessment measures will be completed nine times (baseline (week 0), week 2, 4, 8, 12, 16, 20, 24, 28) corresponding with the nine assessment visits

Eligibility
Key inclusion criteria
The general inclusion criteria are that the patient is/has:
1. Aged 18-65
2. Having a first-onset or new onset of bipolar II disorder as per DSM-5 criteria
3. Willing to accept randomised assignment to one of the two treatment options
4. Willing to remain on all current medication at the same doses until the trial is ceased or if the managing clinician judges that such medications are unwarranted or have become contra-indicated
5. If any rescue drugs or new medications are introduced during the study, these, and reasons for their introduction will be recorded.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria are the following:
1. Previously trialled LTG or Li
2. History of psychotic symptoms
3. Pregnancy or breast feeding (The assessing clinician will take responsibility for asking all women where appropriate if they are pregnant or possibly pregnant and if there is any doubt, a pregnancy test will be undertaken [with the patient’s consent]. All patients will be told to inform the clinician if they become pregnant during the study).
4. A medical condition which contraindicates one of the treatment groups (for instance, significant renal or cardiovascular disease)
5. Acutely suicidality
6. A substantive contributory or associated medical/alcohol/illicit drug condition or severe other co-morbid psychiatric condition

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 not be concealed to the psychiatrist who assesses eligibility criteria and who prescribes the medication. Allocation will be concealed to the research assistant who makes monthly assessments of mood. Allocation will be concealed using central computer randomisation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Clinical response rates for the two treatment groups – the Lamotrigine group and the Lithium group have been estimated on clinical grounds (as there are no data due to the lack of previous studies) to be 50-60%, and 40-50% respectively. A power analysis using those data – at a level of 80% power (Cohen, 1988) estimated that approximately 100 participants/group would be required. If the response rates differ more distinctly (by some 20%) the power analysis indicated that 50 participants/group would be sufficient.

Data analyses will include mixed effects random regression, logistic regression, comparison of means and chi square analyses.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Safety concerns
Date of first participant enrolment
Anticipated
1/02/2017
Actual
6/03/2017
Date of last participant enrolment
Anticipated
3/06/2019
Actual
21/05/2019
Date of last data collection
Anticipated
Actual
26/05/2020
Sample size
Target
200
Accrual to date
Final
44
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 7063 0
Black Dog Institute - Randwick
Recruitment postcode(s) [1] 14791 0
2031 - Randwick

Funding & Sponsors
Funding source category [1] 295102 0
Government body
Name [1] 295102 0
National Health and Medical Research Council Program Grant (1037196)
Country [1] 295102 0
Australia
Primary sponsor type
Individual
Name
Professor Gordon Parker
Address
Black Dog Institute, Prince of Wales Hospital, Hospital Road, Randwick NSW 2031
Country
Australia
Secondary sponsor category [1] 293920 0
None
Name [1] 293920 0
Address [1] 293920 0
Country [1] 293920 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296458 0
University of New South Wales Human Research Ethics Committee
Ethics committee address [1] 296458 0
Ethics committee country [1] 296458 0
Australia
Date submitted for ethics approval [1] 296458 0
26/10/2016
Approval date [1] 296458 0
13/12/2016
Ethics approval number [1] 296458 0
HC16876

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

Contacts
Principal investigator
Name 70914 0
Prof Gordon Parker
Address 70914 0
Black Dog Institute, Prince of Wales Hospital, Hospital Road, Randwick NSW 2031
Country 70914 0
Australia
Phone 70914 0
+61 (02) 9382 4372
Fax 70914 0
Email 70914 0
[email protected]
Contact person for public queries
Name 70915 0
Gordon Parker
Address 70915 0
Black Dog Institute, Prince of Wales Hospital, Hospital Road, Randwick NSW 2031
Country 70915 0
Australia
Phone 70915 0
+61 (02) 9382 4372
Fax 70915 0
Email 70915 0
[email protected]
Contact person for scientific queries
Name 70916 0
Gordon Parker
Address 70916 0
Black Dog Institute, Prince of Wales Hospital, Hospital Road, Randwick NSW 2031
Country 70916 0
Australia
Phone 70916 0
+61 (02) 9382 4372
Fax 70916 0
Email 70916 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Data contains diagnosis information and notes for each patient (albeit anonymously and not identifiable) so will not be made publicly available.


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
EmbaseThe utility of daily mood ratings in clinical trials of patients with bipolar II disorder.2021https://dx.doi.org/10.1177/10398562211014226
N.B. These documents automatically identified may not have been verified by the study sponsor.