ANZCTR - Registration

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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 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

Secondary ID [1]

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)

Condition category

Condition code

Mental Health

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]

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]

Neuroanatomical changes as measured through Magnetic Resonance Imaging (MRI) comparisons.

Timepoint [1]

Baseline (manic episode stabilisation), three months and 12 months.

Secondary outcome [1]

Neuropsychological changes across the study period will be assessed and correlated with neuroanatomical changes as will symptomatic and functional recovery.

Timepoint [1]

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?

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

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment postcode(s) [1]

3427, 3429, 3875, 3028-3034, 3036-3043, 3058-3061, 3055-3056, 3046-3049, 3051-3053

Recruitment postcode(s) [2]

3211-3212, 3214-3228, 3230, 3232-3233, 3235-3243, 3249-3251, 3254, 3256, 3269, 3321-3322

Recruitment postcode(s) [3]

3328-3334, 3352, 3159, 3781-3783, 3807-3815, 3978, 2984, 3802-3807, 3975-3980, 3156

Recruitment postcode(s) [4]

3177, 3189-3197, 3201-3202, 3169-3172, 3147-3150, 3166-3170, 3125, 3171-3175, 3975, 3000

Recruitment postcode(s) [5]

3011-3013, 3015-3016, 3025-3026, 3018-3023, 3025-3026, 3335, 3337, 3340, 3338, 3341

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

AstraZeneca

Address [1]

Astra Zeneca Pty Ltd
Alma Road
North Ryde NSW 2113

Country [1]

Australia

Primary sponsor type

University

Name

The University of Melbourne

Address

The University of Melbourne
Parkville VIC 3010

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Secondary sponsor category [2]

None

Name [2]

Address [2]

Country [2]

Other collaborator category [1]

Hospital

Name [1]

ORYGEN Youth Health

Address [1]

35 Poplar Road
Parkville VIC 3052

Country [1]

Australia

Other collaborator category [2]

Hospital

Name [2]

Southern Health

Address [2]

Dandenong Hospital
Dandenong VIC 3175

Country [2]

Australia

Other collaborator category [3]

Hospital

Name [3]

Barwon Health

Address [3]

Kitchener House
Ryrie Street
Geelong VIC 3220

Country [3]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Melbourne Health Research and Ethics Committee

Ethics committee address [1]

PO Royal Melbourne Hospital
Parkville VIC 3050

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

20/06/2007

Ethics approval number [1]

2006.044

Ethics committee name [2]

Melbourne Health Research and Ethics Committee

Ethics committee address [2]

PO Royal Melbourne Hospital
Parkville VIC 3050

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

Approval date [2]

20/06/2007

Ethics approval number [2]

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

Prof Michael Berk

Address

IMPACT Strategic Research Centre (Innovation in Mental and Physical Health and Clinical Treatment). University Hospital Geelong. PO Box 281 Geelong Victoria 3220 Australia

Country

Australia

Phone

+61 3 4215 3330

Fax

mikebe@barwonhealth.org.au

Contact person for public queries

Name

Michael Berk

Address

IMPACT Strategic Research Centre (Innovation in Mental and Physical Health and Clinical Treatment). University Hospital Geelong. PO Box 281 Geelong Victoria 3220 Australia

Country

Australia

Phone

+61 3 4215 3330

Fax

mikebe@barwonhealth.org.au

Contact person for scientific queries

Name

Michael Berk

Address

IMPACT Strategic Research Centre (Innovation in Mental and Physical Health and Clinical Treatment). University Hospital Geelong. PO Box 281 Geelong Victoria 3220 Australia

Country

Australia

Phone

+61 3 4215 3330

Fax

mikebe@barwonhealth.org.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	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.	2016	https://dx.doi.org/10.1016/j.eurpsy.2015.09.460
Embase	Cognitive functioning following stabilisation from first episode mania.	2017	https://dx.doi.org/10.1186/s40345-017-0108-2
Embase	Quetiapine v. lithium in the maintenance phase following a first episode of mania: Randomised controlled trial.	2017	https://dx.doi.org/10.1192/bjp.bp.116.186833
Embase	Differential effect of quetiapine and lithium on functional connectivity of the striatum in first episode mania.	2018	https://dx.doi.org/10.1038/s41398-018-0108-8

N.B. These documents automatically identified may not have been verified by the study sponsor.

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