Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12607000639426
Ethics application status
Approved
Date submitted
13/09/2007
Date registered
14/12/2007
Date last updated
9/07/2021
Date data sharing statement initially provided
9/07/2021
Date results information initially provided
9/07/2021
Type of registration
Retrospectively registered

Titles & IDs
Public title
Neuroprotective Properties of Quetiapine versus Lithium in a First Episode Mania Cohort: 12-month Neuroanatomical, Neurochemical and Neuro-cognitive Effects and Preliminary Data of Prophylactic Properties
Scientific title
Neuroprotective Properties of Quetiapine versus Lithium in a First Episode Mania Cohort: 12-month Neuroanatomical, Neurochemical and Neuro-cognitive Effects and Preliminary Data of Prophylactic Properties
Secondary ID [1] 304748 0
nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
First episode mania (bipolar and schizoaffective illnesses) 2378 0
Condition category
Condition code
Mental Health 2480 2480 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study investigates the outcomes of using the medication quetiapine versus lithium for long term treatment following a manic episode. Patients will be stabilised on a combination of these treatments and then randomly removed from one medication if they consent to the study procedures. The dose of both medications are prescribed as clinically indicated so the patient and their treating physician will be able to tailor their treatment including the use of other medications as necessary to their own needs. Both quetiapine and lithium are taken daily in oral form and regular blood tests may be required to monitor the concentrations of these medications. The trial will last for 12 months and over this period, after which patients may choose to remain on their current medication or switch to another.
Intervention code [1] 2100 0
Treatment: Drugs
Comparator / control treatment
Quetiapine versus lithium (control) treatment. The dose of the medications will be based on clinical algorithm and appropriate medication levels for each patient. Medications will be administered orally and regular blood monitoring will be required in the lithium condition to ensure effective plasma levels of the drug.
Control group
Active

Outcomes
Primary outcome [1] 3377 0
Neuroanatomical changes as measured through Magnetic Resonance Imaging (MRI) comparisons.
Timepoint [1] 3377 0
Baseline (manic episode stabilisation), three months and 12 months.
Secondary outcome [1] 5596 0
Neuropsychological changes across the study period will be assessed and correlated with neuroanatomical changes as will symptomatic and functional recovery.
Timepoint [1] 5596 0
Baseline (manic episode stabilisation), two weeks, four weeks, eight weeks, three

Eligibility
Key inclusion criteria
Meet Diagnostic and Statistical Manual IV Text Revised (DSM-IV TR) diagnosis for mania as part of bipolar I disorder or schizoaffective disorder. Have a Young Mania Rating Scale at baseline of at least 20. Not have had a previous treated manic episode. Have the capacity to provide informed consent to the study and comply with study procedures. Be utilising effective contraception if female, sexually active and of childbearing age. Patients will need to have been on quetiapine and lithium as standard therapy for at least 1 month prior to randomisation.
Minimum age
18 Years
Maximum age
25 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion from the trial includes:
-Patients with a known or suspected clinically relevant systemic medical disorder.
-Individuals who are pregnant or lactating.
-Patients who have had a prior sensitivity or allergy to quetiapine, lithium or their components.
-Inability to comply with either the requirements of informed consent or the treatment protocol.
-Non-fluency in English.
-History of epilepsy.
-Clinically relevant biochemical or haematological abnormalities at baseline.
-Patients at immediate risk of self harm or risk to others.
-Organic mental disease, including mental retardation (Full scale IQ<70).
-Use of any of the following cytochrome P450 3A4 inhibitors in the 14 days preceding enrolment including but not limited to: ketoconazole, itraconazole, fluconazole, erythromycin, clarithromycin, troleandomycin, indinavir, nelfinavir, ritonavir, fluvoxamine and saquinavir
-Use of any of the following cytochrome P450 inducers in the 14 days preceding enrollment including but not limited to: phenytoin, carbamazepine, barbiturates, rifampin, St. John’s Wort, and glucocorticoids
-A patient with Diabetes Mellitus (DM) fulfilling one of the following criteria:
•Unstable DM defined as enrollment glycosylated hemoglobin (HbA1c) >8.5%.
•Admitted to hospital for treatment of DM or DM related illness in past 12 weeks.
•Not under physician care for DM
•Physician responsible for patient’s DM care has not indicated that patient’s DM is controlled.
•Physician responsible for patient’s DM care has not approved patient’s participation in the study
•Has not been on the same dose of oral hypoglycaemic drug(s) and/or diet for the 4 weeks prior to randomization. For thiazolidinediones (glitazones) this period should not be less than 8 Weeks.
•Taking insulin whose daily dose on one occasion in the past 4 weeks has been more than 10% above or below their mean dose in the preceding 4 weeks
Note: If a diabetic patient meets one of these criteria, the patient is to be excluded even if the treating physician believes that the patient is stable and can participate in the study.
-An absolute neutrophil count (ANC) of 1.5 x 109 per liter

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)
Patients will be enrolled through the youth entry teams and triage services in each of the Southern Health, Barwon Health and ORYGEN Youth Health sites. On presentation with mania all patients will be stabilised on a combination of lithium and quetiapine. Following stabilization, allocation concealment was maintained according to a random computer allocation using the Access program performed by a reserch fellow and then provided to the treating clinician (ie. allocation involved contacting the holder of the allocation schedule who was at a central administration site).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomization according to a randomization table created by computer software. This randomization will be stratified based on testing site (so each site will have similar sample sizes).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/08/2007
Actual
1/08/2007
Date of last participant enrolment
Anticipated
Actual
30/04/2015
Date of last data collection
Anticipated
Actual
30/04/2016
Sample size
Target
66
Accrual to date
Final
61
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment postcode(s) [1] 339 0
3427, 3429, 3875, 3028-3034, 3036-3043, 3058-3061, 3055-3056, 3046-3049, 3051-3053
Recruitment postcode(s) [2] 518 0
3211-3212, 3214-3228, 3230, 3232-3233, 3235-3243, 3249-3251, 3254, 3256, 3269, 3321-3322
Recruitment postcode(s) [3] 519 0
3328-3334, 3352, 3159, 3781-3783, 3807-3815, 3978, 2984, 3802-3807, 3975-3980, 3156
Recruitment postcode(s) [4] 520 0
3177, 3189-3197, 3201-3202, 3169-3172, 3147-3150, 3166-3170, 3125, 3171-3175, 3975, 3000
Recruitment postcode(s) [5] 521 0
3011-3013, 3015-3016, 3025-3026, 3018-3023, 3025-3026, 3335, 3337, 3340, 3338, 3341

Funding & Sponsors
Funding source category [1] 2628 0
Commercial sector/Industry
Name [1] 2628 0
AstraZeneca
Country [1] 2628 0
Australia
Primary sponsor type
University
Name
The University of Melbourne
Address
The University of Melbourne
Parkville VIC 3010
Country
Australia
Secondary sponsor category [1] 2376 0
None
Name [1] 2376 0
Address [1] 2376 0
Country [1] 2376 0
Secondary sponsor category [2] 2599 0
None
Name [2] 2599 0
Address [2] 2599 0
Country [2] 2599 0
Other collaborator category [1] 39 0
Hospital
Name [1] 39 0
ORYGEN Youth Health
Address [1] 39 0
35 Poplar Road
Parkville VIC 3052
Country [1] 39 0
Australia
Other collaborator category [2] 40 0
Hospital
Name [2] 40 0
Southern Health
Address [2] 40 0
Dandenong Hospital
Dandenong VIC 3175
Country [2] 40 0
Australia
Other collaborator category [3] 41 0
Hospital
Name [3] 41 0
Barwon Health
Address [3] 41 0
Kitchener House
Ryrie Street
Geelong VIC 3220
Country [3] 41 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 4547 0
Melbourne Health Research and Ethics Committee
Ethics committee address [1] 4547 0
PO Royal Melbourne Hospital
Parkville VIC 3050
Ethics committee country [1] 4547 0
Australia
Date submitted for ethics approval [1] 4547 0
Approval date [1] 4547 0
20/06/2007
Ethics approval number [1] 4547 0
2006.044
Ethics committee name [2] 4820 0
Melbourne Health Research and Ethics Committee
Ethics committee address [2] 4820 0
PO Royal Melbourne Hospital
Parkville VIC 3050
Ethics committee country [2] 4820 0
Australia
Date submitted for ethics approval [2] 4820 0
Approval date [2] 4820 0
20/06/2007
Ethics approval number [2] 4820 0
2006.044

Summary
Brief summary
Evidence shows that many people with bipolar disorder may have problems with concentration and memory after an acute episode of the illness. It was believed that this was caused by the medication used to treat bipolar disorder, however there is increasing evidence that it may be the disorder itself that leads to memory and cognitive impairments. In particular, new technology in psychiatry has allowed researchers to look at images of the brain of patients with bipolar disorder and compare these to people with no psychiatric illness. The results of these studies show that there are a range of changes in the brain that may account for memory and cognitive problems following episodes. These findings raise a number of questions about the response of the brain in bipolar disorder. The first of these is if there are significant changes in the brain over the year following the first acute episode of bipolar disorder. This has implications for how assertively clinicians treat the disorder and the cognitive problems associated with this phase of the illness. Secondly, some findings from new research on lithium’s effects on the brain suggest that lithium can prevent this neuronal damage and hence these cognitive and memory problems. While some evidence for lithium’s role in this neuro-protection has been established, no groups have yet demonstrated similar protective properties of other medications commonly used for the treatment of bipolar disorder. Neuroprotective effects of antipsychotic medicines are shown in schizophrenia, and are suggested in bipolar disorder by laboratory studies. One such drug is quetiapine, an atypical antipsychotic which has become increasingly used for the treatment of bipolar disorder, particularly when psychotic features dominate the clinical picture.
The aim of this study is to;
1.) Investigate if cognitive and memory performance changes over the year following a first episode of bipolar disorder.
2.) Investigate whether quetiapine is more or less effective at preventing this deterioration than lithium.
3.) Investigate whether time to and quality of symptomatic recovery differs between lithium and quetiapine.
4.) Use neuroimaging technology to discover if there are structural changes in the brain and whether these are associated with cognitive and memory performance.
To complete this study 66 patients will be recruited across three sites with the intention of 52 completing the protocol. Patients will be recruited following stabilisation of their first manic episode. At entry to the study, baseline assessments will be conducted on all participants including neuroimaging. Regular symptomatic scales will be used at regular intervals and neuroimaging and neuropsychological measures will be taken again at 3 and 12 months. Symptomatic and neuropsychological measures will be obtained from clinical interview and structured computer tasks. Neuroimaging will involve participants undergoing an MRI that take around 45 minutes on 3 occasions over a 12-month period.
Prior to the start of the study all participants will have been stabilised on lithium and quetiapine combination therapy. At the commencement of the study these participants will be placed on either lithium monotherapy or quetiapine monotherapy. If participants suffer relapse or a new episode during the study period they will be considered drop-outs and other routine therapies will be adopted.
Trial website
None
Trial related presentations / publications
Quetiapine v. lithium in the maintenance phase following a first episode of mania: randomised controlled trial. Michael Berk, Rothanthi Daglas, Orwa Dandash, Murat Yu¨ cel, Lisa Henry, Karen Hallam, Craig Macneil, Melissa Hasty, Christos Pantelis, Brendan P. Murphy, Linda Kader, Saji Damodaran, Michael T. H. Wong, Philippe Conus, Aswin Ratheesh, Patrick D. McGorry and Sue M. Cotton. Br J Psychiatry. 2017 Jun;210(6):413-421. doi: 10.1192/bjp.bp.116.186833

Neuroprotection after a first episode of mania: a randomized controlled maintenance trial comparing the effects of lithium and quetiapine on grey and white matter volume. Berk M, Dandash O, Daglas R, Cotton SM, Allott K, Fornito A, Suo C, Klauser P, Liberg B, Henry L, Macneil C, Hasty M, McGorry P, Pantelis C, Yücel M. Transl Psychiatry. 2017 Feb 21;7(2):e1041. doi: 10.1038/tp.2017.13

A single-blind, randomised controlled trial on the effects of lithium and quetiapine monotherapy on the trajectory of cognitive functioning in first episode mania: A 12-month follow-up study. R. Daglas et al. European Psychiatry 31 (2016) 20–28. http://dx.doi.org/10.1016/j.eurpsy.2015.09.460
Public notes

Contacts
Principal investigator
Name 28056 0
Prof Michael Berk
Address 28056 0
IMPACT Strategic Research Centre (Innovation in Mental and Physical Health and Clinical Treatment). University Hospital Geelong. PO Box 281 Geelong Victoria 3220 Australia
Country 28056 0
Australia
Phone 28056 0
+61 3 4215 3330
Fax 28056 0
Email 28056 0
[email protected]
Contact person for public queries
Name 11213 0
Michael Berk
Address 11213 0
IMPACT Strategic Research Centre (Innovation in Mental and Physical Health and Clinical Treatment). University Hospital Geelong. PO Box 281 Geelong Victoria 3220 Australia
Country 11213 0
Australia
Phone 11213 0
+61 3 4215 3330
Fax 11213 0
Email 11213 0
[email protected]
Contact person for scientific queries
Name 2141 0
Michael Berk
Address 2141 0
IMPACT Strategic Research Centre (Innovation in Mental and Physical Health and Clinical Treatment). University Hospital Geelong. PO Box 281 Geelong Victoria 3220 Australia
Country 2141 0
Australia
Phone 2141 0
+61 3 4215 3330
Fax 2141 0
Email 2141 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


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseA single-blind, randomised controlled trial on the effects of lithium and quetiapine monotherapy on the trajectory of cognitive functioning in first episode mania: A 12-month follow-up study.2016https://dx.doi.org/10.1016/j.eurpsy.2015.09.460
EmbaseCognitive functioning following stabilisation from first episode mania.2017https://dx.doi.org/10.1186/s40345-017-0108-2
EmbaseQuetiapine v. lithium in the maintenance phase following a first episode of mania: Randomised controlled trial.2017https://dx.doi.org/10.1192/bjp.bp.116.186833
EmbaseDifferential effect of quetiapine and lithium on functional connectivity of the striatum in first episode mania.2018https://dx.doi.org/10.1038/s41398-018-0108-8
N.B. These documents automatically identified may not have been verified by the study sponsor.