Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000703909
Ethics application status
Approved
Date submitted
29/04/2020
Date registered
26/06/2020
Date last updated
22/04/2024
Date data sharing statement initially provided
26/06/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
The Candesartan Adjunctive Bipolar Depression Trial - CADET: A double-blind, randomised, placebo-controlled trial
Scientific title
The Candesartan Adjunctive Bipolar Depression Trial - CADET: A double-blind, randomised, placebo-controlled trial to evaluate the effect of Candesartan on mood in patients with bipolar depression
Secondary ID [1] 299021 0
Nil known
Universal Trial Number (UTN)
U1111-1239-7900
Trial acronym
CADET-BD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Bipolar depression 314320 0
Condition category
Condition code
Mental Health 312670 312670 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
16 weeks of adjunctive candesartan 16mg oral tablet, once a day. Treatment adherence will be assessed by tablet count of returned trial medication bottles.
Intervention code [1] 315508 0
Treatment: Drugs
Comparator / control treatment
Matched placebo tablets, 16mg once a day
Control group
Placebo

Outcomes
Primary outcome [1] 321320 0
Change in severity of mood symptoms, measured using Montgomery-Åsberg Depression Rating Scale (MADRS)
Timepoint [1] 321320 0
Conducted at all trial visits - Baseline (week 0) and Weeks 2, 4, 8, 12 and 16 (primary endpoint).
Secondary outcome [1] 374648 0
Change in severity of mood symptoms, measured using Montgomery-Åsberg Depression Rating Scale Self-report Version (MADRS-S)
Timepoint [1] 374648 0
Conducted at all trial visits - Baseline (week 0) and Weeks 2, 4, 8, 12 and 16.
Secondary outcome [2] 374649 0
Change in severity of bipolar symptomatology, measured using Bipolar Disorder Rating Scale (BDRS)
Timepoint [2] 374649 0
Conducted at all trial visits - Baseline (week 0) and Weeks 2, 4, 8, 12 and 16.
Secondary outcome [3] 374650 0
Change in severity of mania symptomatology, measured using Young Mania Rating Scale (YMRS)
Timepoint [3] 374650 0
Conducted at all trial visits - Baseline (week 0) and Weeks 2, 4, 8, 12 and 16.
Secondary outcome [4] 374651 0
Change in severity of anxiety symptoms, measured using Hamilton Anxiety Rating Scale (HAM-A)
Timepoint [4] 374651 0
Conducted at all trial visits - Baseline (week 0) and Weeks 2, 4, 8, 12 and 16.
Secondary outcome [5] 374652 0
Change in Clinical Global Impression Scale for bipolar disorder (CGI-BP) (Severity and improvement)
Timepoint [5] 374652 0
Conducted at all trial visits - Baseline (week 0) and Weeks 2, 4, 8, 12 and 16.
Secondary outcome [6] 374653 0
Change in Patient Global Impression Scale (PGI)
Timepoint [6] 374653 0
Conducted at all trial visits - Baseline (week 0) and Weeks 2, 4, 8, 12 and 16.
Secondary outcome [7] 374655 0
Change in quality of life, measured by Quality of life Enjoyment and Satisfaction Questionnaire – Short Form (Q-LES-Q-SF)
Timepoint [7] 374655 0
Conducted at all trial visits - Baseline (week 0) and Weeks 2, 4, 8, 12 and 16.
Secondary outcome [8] 374658 0
Change in functioning, measured by the Social and Occupational Functioning Scale (SOFAS),
Timepoint [8] 374658 0
Conducted at all trial visits - Baseline (week 0) and Weeks 2, 4, 8, 12 and 16.
Secondary outcome [9] 374659 0
Change in functioning, measured by the Range of Impaired Functioning Tool (LIFE-RIFT)
Timepoint [9] 374659 0
Conducted at all trial visits - Baseline (week 0) and Weeks 2, 4, 8, 12 and 16.
Secondary outcome [10] 374660 0
Change in inflammatory markers (CRP), cytokines (TNFa, IL6, IL10, IL1)
Timepoint [10] 374660 0
Bloods collected from consenting participants at baseline Week 4 and Week 16
Secondary outcome [11] 374661 0
Change in angiotensin II, and ACE activity,
Timepoint [11] 374661 0
Bloods collected from consenting participants at baseline Week 4 and Week 16
Secondary outcome [12] 374662 0
Change in neurotrophic factors (BDNF)
Timepoint [12] 374662 0
Bloods collected from consenting participants at baseline Week 4 and Week 16
Secondary outcome [13] 374663 0
Change in markers of oxidative stress (thiobarbituric acid reactive substances – TBARS, nitric oxide, malondialdehyde, glutathione – GSH, and the activities of the antioxidant enzymes catalase – CAT, and glutathione peroxidase – GPX, superoxide dismutase – SOD)
Timepoint [13] 374663 0
Bloods collected from consenting participants at baseline Week 4 and Week 16
Secondary outcome [14] 374664 0
Change in microglial markers (quinolinic acid, kynurenine, kynurenic acid).
Timepoint [14] 374664 0
Bloods collected from consenting participants at baseline Week 4 and Week 16
Secondary outcome [15] 374665 0
Economic evaluation of adjunctive candesartan treatment compared to placebo, where $50,000 per quality adjusted life year (QALY) is the accepted benchmark for cost-effectiveness. Measured using the Resource Use Questionnaire, Work Productivity and Activity Impairment Questionnaire: General Health (WPAI-GH) and the Assessment of Quality of Life (AQoL-4D).
Timepoint [15] 374665 0
Conducted at baseline and Week 16
Secondary outcome [16] 374666 0
Changes in cognition as measured on pen and paper tasks (forward and backward digit span, trail making and symbol digit task)
Timepoint [16] 374666 0
Comparison between baseline and Week 16
Secondary outcome [17] 374667 0
Change in kidney function measured by blood urea, electolytes and creatinine
Timepoint [17] 374667 0
Blood collected from all participants at Baseline, Week 4 and Week 16
Secondary outcome [18] 374668 0
Change in lithium blood levels
Timepoint [18] 374668 0
Bloods collected from all applicable participants taking lithium at Baseline and weeks 2,4 and 16
Secondary outcome [19] 381678 0
Change in quality of life, measured by the Assessment of Quality of Life (AQoL-4D) scale.
Timepoint [19] 381678 0
Conducted monthly - Baseline (week 0) and Weeks, 4, 8, 12 and 16.

Eligibility
Key inclusion criteria
I. A DSM-5 diagnosis of bipolar disorder I or II, determined using the SCID-5-RV;
II. Currently experiencing a major depressive episode, determined using the SCID-5-RV
III. Moderate to severe depression indexed by a MADRS score of greater than or equal to 20. If there is a delay of >7 days between screening and baseline assessments, or baseline assessment and medication commencement, the inclusion scale (MADRS) should be administered again to ensure the participant still meets eligibility criteria;
IV. Aged 18 years and above;
V. Have the capacity to consent to the study and to follow its instructions and procedures;
VI. Participants will need to have been on stable pre-existing pharmacological or psychotherapy regimens for two weeks prior to study entry;
VII. Be using effective contraception if female, sexually active and of childbearing age,
VIII. Be able to speak, read, write and understand the English language,
IX. Participants will be required to nominate a current treating physician,
X. Willing to consent to blood collection for safety monitoring.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
I. A diagnosis of another psychotic disorder and/or current substance use disorder, assessed using the SCID-5-RV;
II. Undergoing electroconvulsive therapy (ECT) or transcranial magnetic stimulus (TMS) therapy within one month of randomisation in the study;
III. Known or suspected clinically unstable systemic medical disorder, including heart disease especially congestive heart failure, cerebrovascular, liver or kidney disease including renal artery stenosis;
IV. Participants on current use of any AT1R blockers or ACE inhibitors medications (such as captopril, enalapril, losartan, irbesartan) will be ineligible, although previous use of these (i.e., cessation at least two weeks prior to entrance in the study) will not preclude participation;
V. Systolic blood pressure less than 110mmHg at the baseline;
VI. Symptoms or measures of postural hypotension (reduction in systolic blood pressure of 20mmHg or more after standing from sitting/lying for at least one minute),
VII. Safety blood results not cleared by a Principal Investigator or eGFR less than 30 at the baseline;
VIII. Current pregnancy or breastfeeding for females;
IX. Current use of medications contraindicated with concurrent use of candesartan: aliskiren, digoxin, spironolactone, diuretics, or daily use of non-steroidal anti-inflammatory drugs (such as ibuprofen or celecoxib; PRN use will be accepted);
X. Intolerance or allergy to candesartan or any of the trial preparations;
XI. Current enrolment in another psychiatric intervention study.
XII. Participants on lithium will be accepted on the study but will require additional monitoring of lithium levels;
XIII. Participants with current suicidal ideation with a specific plan, defined as a score of 5 or 6 on the MADRS item 10.

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 to treatment arms will be randomly assigned in a 1:1 ratio (active to placebo) using permutated block randomisation. To ensure blinding, block sizes will not be identified to any of the blinded parties. An independent researcher, utilising computerised number generator and randomly permuted blocks methods will generate and retain the random allocation list. Copies of the randomisation list will be sealed in an opaque envelope in a locked filing cabinet with the CPI and in pharmacy.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permutated block randomisation utilising a block design on a computer-generated randomisation.
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
Phase
Phase 2 / Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Analyses will be based on all randomised participants. Reporting of research findings will be in accordance with CONSORT guidelines. The biostatistician will be blinded to group allocation until analysis stage. To examine the primary hypothesis, generalised estimating equation (GEE) four continuous outcomes will be used. The GEE model will include the fixed categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariate of baseline MADRS score. The two-way treatment-by-visit interaction at post intervention follow-ups will estimate baseline adjusted between-group mean differences and hence are the primary comparisons. The GEE includes all available data at each time point and is the preferred method of analysing longitudinal clinical trial data to deal with missingness assuming missing at random (i.e. an intention to treat approach). Within-participant autocorrelation will be accounted for by an unstructured working correlation matrix. Planned comparisons will be done with the GEE models to determine baseline-adjusted between-group mean differences in symptom change from baseline to week 16. Sensitivity analysis to evaluate missing at random assumption for missing follow-up data is planned. Multiple imputation of missing data will be considered where necessary. All secondary continuous outcome measures will be analysed using the same approach as the primary outcome. Dichotomous data will be presented as proportions, with their respective 95% confidence intervals (CIs), and reporting Chi-square or Fisher’s exact p-value where appropriate. GEE approach with logit link will be used to compare dichotomous outcomes. Non-parametric statistics will be used when parametric assumptions are violated. Effect sizes will be calculated using Cohen’s guidelines. Pearson Product Moment Correlations will be used to examine the relationships between symptom and biological markers change. All tests will be conducted using a two-sided alpha level of 0.05 and 95% CIs will be reported. A detailed statistical analysis plan will be developed prior to unblinding of data.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
3/08/2020
Actual
1/09/2021
Date of last participant enrolment
Anticipated
3/03/2025
Actual
Date of last data collection
Anticipated
24/11/2025
Actual
Sample size
Target
240
Accrual to date
38
Final
Recruitment in Australia
Recruitment state(s)
QLD,VIC
Recruitment hospital [1] 14741 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [2] 14742 0
The Melbourne Clinic - Richmond
Recruitment hospital [3] 14746 0
Albert Road Clinic - Melbourne
Recruitment hospital [4] 15932 0
Box Hill Hospital - Box Hill
Recruitment hospital [5] 16687 0
Toowong Specialist Clinic - Toowong
Recruitment postcode(s) [1] 27788 0
3004 - Melbourne
Recruitment postcode(s) [2] 27784 0
3121 - Richmond
Recruitment postcode(s) [3] 29401 0
3128 - Box Hill
Recruitment postcode(s) [4] 27783 0
3220 - Geelong
Recruitment postcode(s) [5] 27790 0
4066 - Toowong

Funding & Sponsors
Funding source category [1] 303553 0
Government body
Name [1] 303553 0
Medical Research Future Fund (MRFF) National Health and Medical Research Council (NHMRC)
Country [1] 303553 0
Australia
Primary sponsor type
University
Name
Deakin University
Address
Deakin Research
Locked Bag 20000
GEELONG VIC 3220
Country
Australia
Secondary sponsor category [1] 305743 0
None
Name [1] 305743 0
Address [1] 305743 0
Country [1] 305743 0
Other collaborator category [1] 280943 0
University
Name [1] 280943 0
University of Melbourne
Address [1] 280943 0
The University of Melbourne
Victoria 3010
Country [1] 280943 0
Australia
Other collaborator category [2] 280944 0
University
Name [2] 280944 0
University of Sydney
Address [2] 280944 0
The University of Sydney
NSW 2006
Country [2] 280944 0
Australia
Other collaborator category [3] 281255 0
Hospital
Name [3] 281255 0
Barwon Health
Address [3] 281255 0
PO Box 281
Geelong VIC 3220
Country [3] 281255 0
Australia
Other collaborator category [4] 281256 0
Hospital
Name [4] 281256 0
Eastern Health
Address [4] 281256 0
5 Arnold St, Box Hill VIC 3128
Country [4] 281256 0
Australia
Other collaborator category [5] 281257 0
Hospital
Name [5] 281257 0
The Melbourne Clinic
Address [5] 281257 0
130 Church st,
Richmond VIC 3121
Country [5] 281257 0
Australia
Other collaborator category [6] 281258 0
Hospital
Name [6] 281258 0
Albert Road Clinic
Address [6] 281258 0
31 Albert Road,
Melbourne, VIC 3004
Country [6] 281258 0
Australia
Other collaborator category [7] 281259 0
Hospital
Name [7] 281259 0
Royal North Shore Hospital
Address [7] 281259 0
Reserve Rd,
St Leonards NSW 2065
Country [7] 281259 0
Australia
Other collaborator category [8] 281260 0
Other
Name [8] 281260 0
Toowong Specialist Clinic
Address [8] 281260 0
54 Jephson St
Toowong, QLD 4066
Country [8] 281260 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304085 0
Barwon Health Human Research Ethics Committee
Ethics committee address [1] 304085 0
Research Ethics, Governance and Integrity (REGI) Unit
PO BOX 281
Geelong Victoria 3220
Ethics committee country [1] 304085 0
Australia
Date submitted for ethics approval [1] 304085 0
01/11/2019
Approval date [1] 304085 0
16/03/2020
Ethics approval number [1] 304085 0
19/166
Ethics committee name [2] 304273 0
The Melbourne Clinic Research Ethics Committee
Ethics committee address [2] 304273 0
130 Church St,
Richmond VIC 3121
Ethics committee country [2] 304273 0
Australia
Date submitted for ethics approval [2] 304273 0
29/05/2020
Approval date [2] 304273 0
11/09/2020
Ethics approval number [2] 304273 0
334
Ethics committee name [3] 304274 0
Deakin Univeristy Human Research Ethics Committee
Ethics committee address [3] 304274 0
221 Burwood Highway
Burwood Victoria 3125
Ethics committee country [3] 304274 0
Australia
Date submitted for ethics approval [3] 304274 0
29/05/2020
Approval date [3] 304274 0
Ethics approval number [3] 304274 0
Ethics committee name [4] 304275 0
The Northern Sydney Local Health District Human Research Ethics Committee (NSLHD HREC)
Ethics committee address [4] 304275 0
NSLHD Research Office,
Level 13 Kolling Building,
Royal North Shore Hospital,
St Leonards, NSW, 2065
Ethics committee country [4] 304275 0
Australia
Date submitted for ethics approval [4] 304275 0
20/04/2020
Approval date [4] 304275 0
13/11/2020
Ethics approval number [4] 304275 0
2020/ETH00737
Ethics committee name [5] 305422 0
Eastern Health
Ethics committee address [5] 305422 0
5 Arnold St, Box Hill, VIC 3128
Ethics committee country [5] 305422 0
Australia
Date submitted for ethics approval [5] 305422 0
29/05/2020
Approval date [5] 305422 0
18/12/2020
Ethics approval number [5] 305422 0
E20/012/61681
Ethics committee name [6] 309824 0
Deakin University Human Research Ethics Committee
Ethics committee address [6] 309824 0
221 Burwood Highway, Burwood, VIC 3125
Ethics committee country [6] 309824 0
Australia
Date submitted for ethics approval [6] 309824 0
30/11/2020
Approval date [6] 309824 0
16/12/2020
Ethics approval number [6] 309824 0
2020-425

Summary
Brief summary
Depression is the single major unmet need in bipolar disorder and current therapies are more efficacious in mania than depression. Key biological factors in the pathophysiology of bipolar disorder may be targeted by the AT1R antagonist, candesartan. Candesartan reduces stress reactivity, impacts the HPA axis, oxidative and inflammatory stress and enhances neurogenesis; all documented pathological markers. The CADET-BD study will test the efficacy of candesartan 16 mg/day as an adjunctive treatment for bipolar depression. CADET-BD is a multi-site, double-blind, randomised, placebo-controlled 16-week trial of candesartan as an add-on to treatment as usual. We plan to recruit 240 participants aged 18 years and above with moderate to severe bipolar depressive disorder.
Trial website
http://deakinresear.ch/cadet-trial
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 95762 0
Prof Michael Berk
Address 95762 0
IMPACT, Deakin University, HERB-B
P.O. Box 281
Geelong, Victoria
3220
Country 95762 0
Australia
Phone 95762 0
+61 3 4215 3330
Fax 95762 0
Email 95762 0
michael.berk@deakin.edu.au
Contact person for public queries
Name 95763 0
Prof Michael Berk
Address 95763 0
IMPACT, Deakin University, HERB-B
P.O. Box 281
Geelong, Victoria
3220
Country 95763 0
Australia
Phone 95763 0
+61 3 4215 3330
Fax 95763 0
Email 95763 0
michael.berk@deakin.edu.au
Contact person for scientific queries
Name 95764 0
Prof Michael Berk
Address 95764 0
IMPACT, Deakin University, HERB-B
P.O. Box 281
Geelong, Victoria
3220
Country 95764 0
Australia
Phone 95764 0
+61 3 4215 3330
Fax 95764 0
Email 95764 0
michael.berk@deakin.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All de-identified clinical trial data will be available following publication of the primary data and a-priori secondary data.
When will data be available (start and end dates)?
Data will be available following publication of primary and a-priori secondary outcomes. No end date.
Available to whom?
Available to research staff with appropriate Human Research and Ethics Approval.
Available for what types of analyses?
All types, both individual-level analyses as well as meta-analyses.
How or where can data be obtained?
Data can be directly requested (via email: impact@deakin.edu.au) from the Investigators and will be approved on a case-by-case arrangement.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
4938Study protocol    Intention to publish the study protocol


Results publications and other study-related documents

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