Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12625000329460
Ethics application status
Approved
Date submitted
17/10/2024
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 Major Depressive 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 Major Depressive Disorder, compared to Treatment as Usual in Participants Who Had a First-time Treatment Failure on Their First-line Treatment for -Major Depressive Disorder Cohort.
Secondary ID [1] 313877 0
Nil Known
Universal Trial Number (UTN)
U1111-1307-5545
Trial acronym
INTENSIFY
Linked study record
THE PSYCH-STRATA CONSORTIUM

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 No 101057454.
This registration (INTENSIFY MDD) is the Australian cohort of the NCT05973851 INTENSIFY MDD study registered on ClinicalTrials.gov
Australia has its own protocol and is considered a sister site.

Health condition
Health condition(s) or problem(s) studied:
Depression 333496 0
Condition category
Condition code
Mental Health 330172 330172 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a phase III multicentre controlled, randomised open label trial for Major Depressive Disorder (MDD)
Treatment allocation is 1:1 randomisation using a computer application. Participants are randomised to either Treatment as usual (TAU) or Early Intensified Pharmacological Treatment (EIPT)

Participants randomised to the interventional group for MDD will receive a total of ten Ketamine Intravenous Infusions at a low dose (0.5mg/kg with max dose 55mg per infusion) over 40 minutes once or twice a week for six weeks. These will be administered in the Clinical Trials Unit at The Lyell McEwin Hospital by a study doctor and nurse team. These participants will also be prescribed a second-line oral antidepressant to be taken for the duration of the six study weeks.
Any second line oral antidepressant medication available on the PBS may be chosen by the participant’s regular treating doctor. The first two weeks of this medication will be supplied by the study team for participant convenience, but all ongoing prescriptions must be from their regular treating doctor. 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.

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] 328378 0
Treatment: Drugs
Comparator / control treatment
Participants randomised to the control group will receive usual care - second-line treatment/treatment as usual. with medication choice and dose as per their regular treating doctor (likely a General Practitioner or a Psychiatrist)

For the Major Depression Arm: commence treatment with a second line oral antidepressant as per their regular treating doctor


Control group
Active

Outcomes
Primary outcome [1] 338106 0
Change in symptom severity, Time Frame: 6 weeks
Timepoint [1] 338106 0
Baseline (visit 2) and six-week treatment (visit 4)
Secondary outcome [1] 446464 0
Exploratory analysis to investigate whether gut microbiome can predict response to treatment
Timepoint [1] 446464 0
Assessed at visit 2 baseline, and visit 4, end of treatment
Secondary outcome [2] 434546 0
To compare presence of side effects between treatment arms
Timepoint [2] 434546 0
Assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention
Secondary outcome [3] 434550 0
To compare changes in suicidal ideation between treatment arms.
Timepoint [3] 434550 0
Assessed at Screening, baseline visit 2 and follow up visits 3 and visit 4, (6 weeks post commencement of study drug)
Secondary outcome [4] 446446 0
To compare changes in wellbeing #3
Timepoint [4] 446446 0
Assessed from visit 2 baseline to visit 4 end, of treatment (continuously)
Secondary outcome [5] 434548 0
To compare use of concomitant medication
Timepoint [5] 434548 0
Assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention
Secondary outcome [6] 446439 0
Exploratory analysis of transdiagnostic predictors for treatment response (OPT IN ONLY).#1
Timepoint [6] 446439 0
Assessed at visit 2 (baseline)
Secondary outcome [7] 445544 0
To compare changes in cognitive performance #2 [Time Frame: 6 weeks]
Timepoint [7] 445544 0
assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention)
Secondary outcome [8] 445552 0
To compare changes in quality of life #1 [Time Frame: 6 weeks]
Timepoint [8] 445552 0
Assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention
Secondary outcome [9] 446440 0
Exploratory analysis of transdiagnostic predictors for treatment response (OPT IN ONLY).#2
Timepoint [9] 446440 0
Assessed at visit 2 baseline, visit 3 and visit 4 end of treatment.
Secondary outcome [10] 434549 0
To compare premature discontinuation (timing and reason) between treatment arms.
Timepoint [10] 434549 0
Assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention.
Secondary outcome [11] 445543 0
To compare changes in functioning measure #2 Time Frame: 4-6 weeks
Timepoint [11] 445543 0
Assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention)".
Secondary outcome [12] 434540 0
To compare changes in the levels of depression between treatment arms.
Timepoint [12] 434540 0
Changes from baseline (visit 2) and six-week treatment (visit 4); EIPT vs TAU.
Secondary outcome [13] 445550 0
to compare changes in cognitive performance #3 [Time Frame: 6 weeks]
Timepoint [13] 445550 0
Assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention
Secondary outcome [14] 434552 0
To compare the naturalistic clinical care and wellbeing of participants following the end of the treatment period - composite outcome
Timepoint [14] 434552 0
From treatment period endpoint at visit 4 (week 6) and follow-up at visit 5 (week 12); EIPT vs TAU.
Secondary outcome [15] 445553 0
To compare changes in quality of life #2 [Time Frame: 6 weeks]
Timepoint [15] 445553 0
Assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention
Secondary outcome [16] 434539 0
To compare changes in severity and improvement
Timepoint [16] 434539 0
Over the six weeks treatment period (visit 2 versus visit 4).
Secondary outcome [17] 446443 0
To compare changes in wellbeing #1
Timepoint [17] 446443 0
Time points are treatment days 0-3, treatment days 21-24, and treatment days 38-41
Secondary outcome [18] 434553 0
To compare the proportion of participants (EIPT vs. TAU) that is in symptomatic remission at visit 4.
Timepoint [18] 434553 0
Presence of symptomatic remission at visit 4; EIPT vs TAU.
Secondary outcome [19] 434541 0
To compare changes in functioning measure #1
Timepoint [19] 434541 0
Changes from baseline (visit 2) and six-week treatment (visit 4); EIPT vs TAU. Time Frame 4- 6 weeks
Secondary outcome [20] 446466 0
To compare changes in wellbeing #2
Timepoint [20] 446466 0
Assessed across the treatment period week 1 – 6
Secondary outcome [21] 434543 0
To compare changes in cognitive performance between # 1
Timepoint [21] 434543 0
Assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention)".
Secondary outcome [22] 445551 0
To compare changes in cognitive performance #4 [Time Frame: 6 weeks]
Timepoint [22] 445551 0
Assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention

Eligibility
Key inclusion criteria
To be eligible to participate in this study, a participant must meet ALL of the following 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: major depressive disorder (without psychotic features) r 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; this treatment is a first-line pharmacotherapeutic agent for the primary DSM-5-TR diagnosis,and was prescribed for at least 4 weeks within the dose range as specified in the Product Information (PI).

6. Participant has failed on current psychopharmacological treatment of current episode of MDD as confirmed by a CGI-I equal to 3.

7. Participant and treating clinician intend to change pharmacotherapeutic treatment

8. 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: MDD is a score of greater than 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) for MDD participants.

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 the addition of medications as indicated by the randomisation arm.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria
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. Participants personally affiliated with the sponsor, investigators or trial site must be excluded from participation in advance.
8.Participant has used (es) ketamine in the past.
9. Participant has a known intolerance to ketamine or to all TAU medication options.
10. Participant meets any of the contraindications for ketamine 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.

Participant has a known intolerance to all TAU medication options.
For clarity, if the participant is currently on a first-line treatment that is not efficacious and will be switched within the study, this medication does not count for this criterion. This criterion focuses on other psychotropic concomitant medication (not on the primary diagnosis). Last, “more” means that the participant requires a higher dose than the maximum for the allowed benzodiazepines/antipsychotics throughout the study.

The decision to include the participant is at the study doctor’s discretion. If the score on Module B (Suicidality) of the MINI v7.0.2 is lower than 9, but the study doctor still considers the risk of a suicide attempt too high, it can still be decided to exclude the participant.

Significant diseases, disorders or conditions preventing use of ketamine are: hypersensitivity to benzethonium chloride or other excipients, conditions where increasing blood pressure or intercranial pressure would lead to a serious hazard, severe coronary or myocardial disease. We refer to the PIs for significant conditions that prevent use of oral antidepressant medication.

Some Product Information Sheets specify precautions. These are not considered as contraindications in this trial or in clinical practice. If investigators take precautionary measures, participants can still be initiated on the medication, as this is in line with clinical practice and the Product Information

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 is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
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] 316430 0
Government body
Name [1] 316430 0
National Health and Medical Research Council (NHMRC)
Country [1] 316430 0
Australia
Primary sponsor type
Government body
Name
Northern Adelaide Local Health Network
Address
Country
Australia
Secondary sponsor category [1] 318446 0
University
Name [1] 318446 0
The University of Adelaide
Address [1] 318446 0
Country [1] 318446 0
Australia
Other collaborator category [1] 283255 0
University
Name [1] 283255 0
Ludwig Maximilian University of Munich
Address [1] 283255 0
Country [1] 283255 0
Germany
Other collaborator category [2] 283041 0
University
Name [2] 283041 0
Universität Münster
Address [2] 283041 0
Country [2] 283041 0
Germany
Other collaborator category [3] 283107 0
University
Name [3] 283107 0
University Medical Center Utrecht
Address [3] 283107 0
Country [3] 283107 0
Netherlands

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315078 0
Central Adelaide Local Health Network HREC
Ethics committee address [1] 315078 0
Ethics committee country [1] 315078 0
Australia
Date submitted for ethics approval [1] 315078 0
28/06/2024
Approval date [1] 315078 0
29/08/2024
Ethics approval number [1] 315078 0
2023/HRE00041

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

Contacts
Principal investigator
Name 133602 0
A/Prof K Oliver Schubert
Address 133602 0
Northern Community Mental Health Service 7 Park Terrace Salisbury SA 5108
Country 133602 0
Australia
Phone 133602 0
+61 8 82225141
Fax 133602 0
Email 133602 0
[email protected]
Contact person for public queries
Name 133603 0
Deb Hobbs
Address 133603 0
Clinical Trials Unit, Lyell McEwin Hospital, Haydown Road, Elizabeth Vale SA 5112
Country 133603 0
Australia
Phone 133603 0
+61 08 81829554
Fax 133603 0
Email 133603 0
[email protected]
Contact person for scientific queries
Name 133604 0
K Oliver Schubert
Address 133604 0
Northern Community Mental Health Service 7 Park Terrace Salisbury SA 5108
Country 133604 0
Australia
Phone 133604 0
+61 8 82225141
Fax 133604 0
Email 133604 0
[email protected]

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


What supporting documents are/will be available?

TypeCitationLinkEmailOther DetailsAttachment
Study protocol  [email protected] 3.1 available via email request
Ethical approval  [email protected] Will be available via email request
Informed consent form  [email protected] Will be available on request via email


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.