Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12625000328471
Ethics application status
Approved
Date submitted
13/02/2025
Date registered
17/04/2025
Date last updated
17/04/2025
Date data sharing statement initially provided
17/04/2025
Type of registration
Prospectively registered

Titles & IDs
Public title
The INTENSIFY Trial: The Effect of a Six-Week Intensified Pharmacological Treatment (Third-Line Medication) for Bipolar Disorder Compared to Treatment as Usual (Second-Line Medication) in Participants Who Did Not Respond to a First-Line Medication Treatment.
Scientific title
A randomised, controlled trial to investigate the effect of a six-week intensified pharmacological treatment for Bipolar Depression compared to treatment as usual in participants who had a first-time treatment failure on their first-line treatment- Bipolar Disorder Cohort (BD)
Secondary ID [1] 313903 0
Nil Known
Universal Trial Number (UTN)
U1111-1307-5545
Trial acronym
INTENSIFY
Linked study record
The Australian Intensify trial contributes to work package 3 of the broader Psych-STRATA project funded by the European Union’s Horizon Europe research and innovation programme under grant agreement NCT05603104
This registration (INTENSIFY BD ) is the Australian cohort of the NCT05973786 INTENSIFY BD study registered on ClinicalTrials.gov.
The Australian INTENSIFY has its own unique Protocol and is considered a sister site to the NCT05973786 INTENSIFY BD study registered on ClinicalTrials.gov


Health condition
Health condition(s) or problem(s) studied:
Bipolar Disorder 336591 0
Condition category
Condition code
Mental Health 333099 333099 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a phase III multicentre controlled, randomised open label trial for bipolar disorder, subjects are randomised to a 6 week pharmacological treatment as usual (second-line treatment) or to the early-intensified pharmacological treatment (third-line treatment).

Overview of treatment randomisation per study sample.

Treatment as Usual (TAU) Switch to quetiapine plus lithium or valproate acid
Early-Intensified Pharmacological Treatment (EIPT) Switch to
1.one of the following: escitalopram, sertraline, duloxetine, bupropion or venlafaxine plus
2.two of the following: lithium, valproate acid or quetiapine

Frequency and Duration of Medication

Escitalopram: The recommended dose is 10 mg orally (one 10 mg tablet) once daily. Depending on individual participant response, the dose may be increased to a maximum of 20 mg (one 20 mg tablet) daily. Usually, 2-4 weeks are necessary for antidepressant response, although the onset of therapeutic effect may be seen earlier.
Sertraline: Sertraline treatment should be initiated with a dose of 50 mg orally once daily. The usual therapeutic dose for depression is 50 mg/day. Participants not responding to a dose of 50 mg/day may benefit from dose increases. Due to the elimination half-life of sertraline, dose changes should be made in steps of 50 mg at intervals of at least 1 week up to a maximum of 200 mg/day. The onset of therapeutic effect may be seen within 7 days; however, for full activity, 2 to 4 weeks are usually necessary for depression.

Bupropion: Bupropion is produced as immediate-release, sustained-release, and extended-release tablets.
Immediate-release tablets: initial dose: 100 mg orally twice a day, increase if necessary after 3 days to 100 mg orally three times a day. Maintenance dose: 100 mg orally three times a day. Maximum dose: 450 mg/day in up to 4 divided doses; single doses should not exceed 150 mg.
Sustained-release tablets: initial dose: 150 mg orally once a day in the morning, increase if necessary, after 3 days to 150 mg orally twice a day. Maintenance dose: 150 mg orally twice a day. Maximum dose: 400 mg/day; maximum single dose should not exceed 200 mg.
Extended-release tablets: initial dose: 150 mg orally once a day in the morning, increase if necessary, after 4 days to 300 mg orally once a day. Maintenance dose: 300 mg orally once a day. Maximum dose: 450 mg/day

Venlafaxine: The recommended initial dose is 75 mg taken once daily orally. Participants not responding to the initial 75 mg/day dose may benefit from dose increases up to a maximum dose of 375 mg/day. Dosage increases can be made at intervals of 2 weeks or more. If clinically warranted due to symptom severity, dose increases can be made at more frequent intervals, but not less than 4 days.

Lithium: Dosage should be adjusted to maintain a serum lithium concentration 0.6 to 0.8 mmol/L. Dosage will vary from one individual to another, but usually 900mg to 1200mg per day in divided doses will maintain this concentration. Serum lithium concentration should be assessed frequently during the acute phase, and in uncomplicated cases/during maintenance, every 2 months. Recommended start-dose is 450-500 mg/day orally, depending on the formulation used (450mg tablet or 2x250mg tablet). As specified in the PI, (excluding rapid dosing) the lithium blood levels should be determined to inform further dosing 4-5 days after each dose change and this task will remain with the regular treating doctor. For treatment of depressive symptoms, plasma levels between 0.4-0.8 mmol/l are recommended.
Valproate acid: Initially dosage should start with 500 mg daily increasing by 500 mg/day at three-day intervals until symptom control is achieved. This is generally within the range 1,000 to 2,000 mg/day, (i.e. 20 to 30 mg/kg/day). Where adequate control is not achieved within this range the dose may be further increased to 2,500 mg/day

Valproate acid: Initially dosage should start with 500 mg daily increasing by 500 mg/day at three-day intervals until symptom control is achieved. This is generally within the range 1,000 to 2,000 mg/day, (i.e. 20 to 30 mg/kg/day). Where adequate control is not achieved within this range the dose may be further increased to 2,500 mg/day

Quetiapine: When treating depressive episodes in bipolar disorder, treatment should be initiated either by the treating psychiatrist or by the general practitioner after consultation with the psychiatrist. Tablets should be administered once daily at bedtime with titration as follows: 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3) and 300 mg (Day 4). The dose may be adjusted up to 600 mg/day in increments of 100 mg/day depending on the clinical response and tolerability of the individual patient.

Ethical considerations relating to the clinical trial including the expected benefit to the individual subject or group of subjects represented by the trial subjects as well as the nature and extent of burden and risks All medications as part of this study are widely used (alone or in combination) in clinical practice and carry well-known safety profiles. The study has a naturalistic design, meaning that the medication is used commercially, as in daily clinical practice. Therefore, the minimum effective dose, target dose, the dose ranges and dose titrations as described in the latest applicable Product Information sheets available on the Australian Government Therapeutic Goods Administration websites are to be followed. Medication doses may be modified at any time during the treatment phase as per the treating doctor’s discretion.

Current clinical practice treatment guidelines are quite heterogeneous on the order and combination of treatments, as the disease is heterogeneous and needs to be tailored to the patient. In clinical practice, all psychopharmacological treatments that are selected for this study sample are used in different orders in patients in different phases of their disease; therefore, there is no expected difference from TAU regarding adverse effects.

Overall, the risks are similar to daily clinical practice; the only difference relative to clinical practice is the application of three pharmacological treatments (EIPT) versus two (TAU) earlier in the illness. Still, these additional treatment options are also commonly prescribed by clinicians. There are no indications in existing literature or clinical practice that the earlier introduction of these medications poses a safety risk when used in an earlier illness phase than indicated in the


The first two weeks of the chosen medication will be supplied by the study team for participant convenience, but all ongoing prescriptions must be from their regular treating doctor.

It is not expected nor required that participants return their used and unused medication. Compliance will be monitored using standardised self-report, two questions are asked to rate medication adherence: “In the past week, how difficult was it to take your medication as how they were prescribed to you?” and “In the past week, how many days have you taken your medication the way they are prescribed to you?” Both questions are answered on a 7-point Likert scale.
Intervention code [1] 330493 0
Treatment: Drugs
Comparator / control treatment
Active Comparator: Treatment as usual (second line treatment.)
Treatment options are recommended as per study protocol, but ultimate choice and prescribing will be done by the participant’s usual treating doctor, most likely a general practitioner or a psychiatrist.

Treatment as usual.

Switch to quetiapine, plus one of the following
Lithium or
Valproate acid

Quetiapine Minimum dose daily 50mg maximum dose daily 800mg oral. (tablet)
Lithium: Minimum dose daily 600mg maximum dose 2500 mg oral (Tablet, Syrup)
Valproate: Minimum dose daily 600mg maximum dose daily 2500mg oral (Tablet)

These options are given to the treating physician who will make a choice of medication and dosage. The study doctor will prescribe the new medication for the first 14 days after discussion with the regular treating doctor, and then transfer ongoing prescribing and usual patient care, including monitoring medication levels in the blood, back to the regular treating doctor.

For psychiatric treatment there are no universally accepted treatment algorithms available. The choice of second-line treatment (TAU in the current trial) is not prescribed by the trial. In an effort to emulate normal clinical practice, where the choice of the next treatment is a clinician’s choice based on relevant Australian clinical guidelines, selecting medication is flexible. TAU in this protocol for each participant will be chosen by the participants usual treating doctor in collaboration with the study doctor from a supplied list of usual treatment options. The selection of medication is also “flexible”, because it is based on many participant factors including previous treatment(s), symptoms profile, comorbid diseases and, participant and treating doctor’s preference.
TAU in this trial is as follows:

For BD, the best proven and most widely used second-line treatment options are
quetiapine with lithium or valproate acid

The medication studied in the current trial is registered for the disorders and/or used in daily clinical practice
Control group
Active

Outcomes
Primary outcome [1] 340635 0
Comparing the change in symptom severity on Montgomery Asberg Depression Rating Scale Time Frame: 6 weeks
Timepoint [1] 340635 0
Baseline (visit 2) and six-week treatment (visit 4)
Secondary outcome [1] 444800 0
To compare changes in the severity and improvement [Time Frame: 6 weeks]
Timepoint [1] 444800 0
assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention)
Secondary outcome [2] 444801 0
To compare changes in the levels of depression and anxiety.
Timepoint [2] 444801 0
assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention)
Secondary outcome [3] 444802 0
To compare changes in quality of life #1 Time frame 6 weeks
Timepoint [3] 444802 0
Assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention)
Secondary outcome [4] 444803 0
To compare changes in cognitive performance #1
Timepoint [4] 444803 0
assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention)
Secondary outcome [5] 444804 0
To compare presence of side effects -Time Frame: 6 weeks
Timepoint [5] 444804 0
assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention)
Secondary outcome [6] 444805 0
To compare use of concomitant medication
Timepoint [6] 444805 0
assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention)
Secondary outcome [7] 444806 0
To compare premature treatment discontinuation (timing and reason) between treatment arms.
Timepoint [7] 444806 0
assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention)
Secondary outcome [8] 444807 0
To compare changes in suicidal ideation between treatment arms.
Timepoint [8] 444807 0
Assessed at Screening, baseline visit 2 and follow up visits 3 and visit 4, 6 weeks commencement of treatment.
Secondary outcome [9] 444808 0
To compare the naturalistic clinical care and wellbeing of participants following the end of the treatment period this will be measured as a composite outcome,
Timepoint [9] 444808 0
Assessed from treatment period endpoint at visit 4 (week 6) and follow-up at visit 5 (week 12);
Secondary outcome [10] 444809 0
To compare occurrence of (hypo)manic episode during the study between the treatment arms
Timepoint [10] 444809 0
Occurrence of (hypo)manic episodes throughout the study including V5 follow up visit week 12.
Secondary outcome [11] 444810 0
To compare the proportion of participants (EIPT vs. TAU) that is in symptomatic remission at visit 4.
Timepoint [11] 444810 0
At Visit 4-time frame 6 weeks.
Secondary outcome [12] 445554 0
to compare changes in functioning measure #2 [Time Frame: 4-6 weeks]
Timepoint [12] 445554 0
assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention.
Secondary outcome [13] 445555 0
to compare changes in quality of life #2 [Time Frame: 6 weeks]
Timepoint [13] 445555 0
Assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention
Secondary outcome [14] 445556 0
to compare changes in cognitive performance #2 [Time Frame: 6 weeks]
Timepoint [14] 445556 0
Assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention.
Secondary outcome [15] 445557 0
To compare changes in cognitive performance #3
Timepoint [15] 445557 0
Assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention
Secondary outcome [16] 445558 0
to compare changes in cognitive performance #4 [Time Frame: 6 weeks]
Timepoint [16] 445558 0
Assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention
Secondary outcome [17] 446447 0
Exploratory analysis of transdiagnostic predictors for treatment response (OPT IN ONLY).#1
Timepoint [17] 446447 0
Visit 2 baseline
Secondary outcome [18] 446448 0
Exploratory analysis of transdiagnostic predictors for treatment response (OPT IN ONLY).#2
Timepoint [18] 446448 0
Assessed at visit 2 (baseline), v3 and visit 4, end of treatment.
Secondary outcome [19] 446449 0
Exploratory analysis, to investigate whether gut microbiome can predict response to treatment
Timepoint [19] 446449 0
Assessed at Visit 2 baseline, and Visit 4 end of treatment
Secondary outcome [20] 446450 0
(Exploratory analysis to compare changes in wellbeing #1
Timepoint [20] 446450 0
Assessed across treatment days 0-3, treatment days 21-24, and treatment days 38-41
Secondary outcome [21] 446451 0
(exploratory) to compare changes in wellbeing #2
Timepoint [21] 446451 0
Assessed across the treatment period week 1 – 6
Secondary outcome [22] 446452 0
Exploratory to compare of changes in well- being #3
Timepoint [22] 446452 0
assessed from visit 2 until visit 4, end of treatment (continuously)

Eligibility
Key inclusion criteria
1. In- or outpatient, 18-65 years old. (18-50 if the person identifies as an Aboriginal or Torres Strait Islander person).
2. Being willing and able to provide written informed consent. Having a legal guardian to co-sign is allowed. Informed consent will be signed at visit 1, before any study procedure.
3. Female participants of childbearing potential must use effective contraception during the trial and as per the requirements of the applicable PIs. WOCBP must also have a negative pregnancy test at visit 1 and visit 2.
4. According to the DSM-5-TR, meeting diagnostic criteria for a primary diagnosis of: bipolar depression (bipolar disorder type I and II currently in a depressive episode). The primary diagnosis will be confirmed by the Mini International Neuropsychiatric Interview (MINI v7.0.2).
5. Participant currently experiences their first treatment failure due to lack of efficacy in this current episode, as confirmed by a CGI-I equal to 3 this treatment is a first-line pharmacotherapeutic agent for the primary DSM-5-TR diagnosis and was prescribed for at least 4 weeks within an effective dose range as specified in the Product Information (PI).
6. Participant and treating clinician intend to change pharmacotherapeutic treatment
A minimum symptom severity threshold needs to be present (moderate level; see below) and participant needs to experience functional impairment.
The minimum symptom severity threshold for:
BD participants is a score of 20 on the Montgomery Åsberg Depression Rating Scale (MADRS)
Functional impairment is defined as a score of 5 or higher on any of the three scales of the Sheehan Disability Scale (SDS).

Further information:

If participants have already stopped the previous pharmacological treatment, the stopped treatment should still be the first treatment failure on a first line pharmacotherapeutic agent prescribed for at least 4 weeks within the dose range as specified in the PI. If the participant used more than one pharmacological treatment in the past, the reason for discontinuing these previous treatments should not be recorded as non-efficacy; in total there should be one treatment failure (now or in the past).

Preferably, the CGI-I is obtained from the (previous) treating doctor or clinical team, who decided that there is a treatment failure. If this is not possible, it is acceptable for the study team to obtain this information from the participant.

Change is considered a full change (tapering off previous treatment (if not already stopped) and initiating the new treatment as indicated by the randomisation arm, or keeping the old antidepressant/antipsychotic and augment with the addition of medications as indicated by the randomisation arm (BD TAU treatment group). Only increasing the dosage of the old first-line medication (antidepressant – MDD, or antipsychotic is not considered as a change.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
a potential participant who meets ANY of the following criteria will be excluded from participation in this study.
1. Being pregnant or breastfeeding.
2. Participant has participated in another clinical trial in which the participant received an experimental or investigational drug or agent within 30 days prior to visit 1.
3. Participant experiences any other significant disease or disorder which, in the opinion of the study doctor, may either put the participant at risk because of participation in the trial, or may influence the results of the trial, or the participants ability to participate in the trial.
4. Participants with active suicidal ideation with some intent to act, without specific plan (“Yes” to question 4 of the Columbia-Suicide Severity Rating Scale (C-SSRS)) or active suicidal ideation with specific plan and intent (“Yes” to question 5 of the C-SSRS), followed by an assessment by the treating clinician who determines it is not safe for the participant to continue in the study ) *
5. Participant meets criteria for current substance abuse disorder, as confirmed by Module I (Alcohol use disorder) and J (substance use disorder (non-alcohol) of the (MINI v7.0.2). Nicotine dependence is allowed as is mild and moderate alcohol and/or cannabis use disorder as defined by MINI v7.0.2. Severe alcohol and/or cannabis use disorder is not allowed.
6. Participant has been committed to an institution by virtue of an order from a legal authority such as a tribunal, magistrate, or office of the Chief Psychiatrist
7. Participants personally affiliated with the sponsor, investigators or trial site must be excluded from participation in advance.
* The decision to include the participant is at the clinician’s discretion. If the score on the C-SSRS does not exceed the threshold, but the clinician still considers the risk of a suicide attempt too high, it still can be decided to exclude the participant. If the score on suicidal ideation is 4 or 5, there will follow a clinical judgement that should be documented in the source.
excluded from participation in this study.
8. Participant has failed previously on quetiapine due to inefficacy (after treatment duration of 4 weeks within an efficacious dose range according to the PI.
9. Participant has a known intolerance to quetiapine or to all TAU medication options.
10. Participant meets any contraindications for quetiapine or to all TAU medication options, as specified within the applicable PI, supported by clinically significant abnormal values on local laboratory tests, electrocardiogram (ECG) or physical examination.
11. A score of 12 or higher on the Young Mania Rating Scale (YMRS) (64) in order to exclude participants with predominant manic symptoms or mixed symptoms

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)
Central randomisation by computer
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
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
30/04/2025
Actual
Date of last participant enrolment
Anticipated
6/03/2026
Actual
Date of last data collection
Anticipated
30/06/2026
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA

Funding & Sponsors
Funding source category [1] 318375 0
Government body
Name [1] 318375 0
National Health and Medical Research Council
Country [1] 318375 0
Australia
Primary sponsor type
University
Name
The University of Adelaide
Address
Country
Australia
Secondary sponsor category [1] 320773 0
Hospital
Name [1] 320773 0
Lyell McEwin Hospital
Address [1] 320773 0
Country [1] 320773 0
Australia
Other collaborator category [1] 283422 0
University
Name [1] 283422 0
Universitat Munster
Address [1] 283422 0
Country [1] 283422 0
Germany
Other collaborator category [2] 283423 0
University
Name [2] 283423 0
University Medical Centre Utrecht
Address [2] 283423 0
Country [2] 283423 0
Netherlands
Other collaborator category [3] 283424 0
University
Name [3] 283424 0
Ludwig Maximillian University of Munich
Address [3] 283424 0
Country [3] 283424 0
Germany

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 317007 0
Central Adelaide Local Health Network HREC
Ethics committee address [1] 317007 0
Ethics committee country [1] 317007 0
Australia
Date submitted for ethics approval [1] 317007 0
28/06/2024
Approval date [1] 317007 0
29/08/2024
Ethics approval number [1] 317007 0

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

Contacts
Principal investigator
Name 139714 0
A/Prof K Oliver Schubert
Address 139714 0
Northern Community Mental Health Service 7 Park Terrace Salisbury SA 5108
Country 139714 0
Australia
Phone 139714 0
+61 874854300
Fax 139714 0
Email 139714 0
[email protected]
Contact person for public queries
Name 139715 0
Deb Hobbs
Address 139715 0
Clinical Trials Unit,Lyell McEwin Hospital, Haydown Road, Elizabeth Vale SA 5112
Country 139715 0
Australia
Phone 139715 0
+61 8 82829554
Fax 139715 0
Email 139715 0
[email protected]
Contact person for scientific queries
Name 139716 0
K.Oliver Schubert
Address 139716 0
Northern Community Mental Health Service, 7 Park Terrace,Salisbury, SA 5108
Country 139716 0
Australia
Phone 139716 0
+61 8 8222 5141
Fax 139716 0
Email 139716 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
No


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
No additional documents have been identified.