ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12625000327482

Ethics application status

Approved

Date submitted

12/02/2025

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 Schizophrenia Compared to Treatment as Usual (Second-Line Medication) in Participants Who Did Not Respond to a First-Line Medication Treatment.

Scientific title

Randomised, Controlled Trial to Investigate the Effect of a six-week Intensified Pharmacological Treatment for Schizophrenia Compared to Treatment as Usual in Participants Who Had a First-time Treatment Failure on Their First-line Treatment for -Schizophrenia Cohort.

Secondary ID [1]

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 No 101057454.
The registration (INTENSIFY SZ) is the Australian cohort of the NCT05958875 sz registered on ClinicalTrials.gov. The Australian Protocol is unique to Australia and considered a sister site to NCT05958875.

Health condition

Health condition(s) or problem(s) studied:

Schizophrenia

Condition category

Condition code

Mental Health

Schizophrenia

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

This is a phase IV multicentre controlled, randomised open label trial for Schizophrenia
Participants are randomised to either Treatment as usual (TAU) or Early Intensified Pharmacological Treatment (EIPT)

Treatment as Usual (TAU):
Switch to second line antipsychotic

Early-Intensified Pharmacological Treatment (EIPT):
Switch to clozapine

If participants are randomised to the early-intensified pharmacological treatment (EIPT), there will be a switch to clozapine (investigational product). The clozapine initiation dosing regime, target dose, and safety monitoring regime will be according to SA Health clinical practice guidelines. Prescribing will be done by the study doctor(s) and dispensing of the product will be through the Lyell McEwin Hospital pharmacy.

Participants in the EIPT group will receive Clozapine for a period of 6 weeks.

The SA Health Clozapine Clinical Management Guidelines V2.0 dated 12/07/22 will be followed for prescription and management of clozapine. Initial dose: 12.5 mg orally once a day. Total daily dose increments of 25 mg to 50 mg to a target dose of 200 mg per day (administered in divided doses) by the end of week 2. From day 14 the dose can be increased in 50mg intervals every two to three days, depending on efficacy and side effects. Maximum dose is 900mg/day. For this study we are limited to a maximum of 600 mg/day by titration guidelines mandated by SA Health. The possibility of increased adverse reactions occurring at doses over 450 mg/day must be borne in mind.

Clozapine prescribing and monitoring will be managed by the Principal Investigators/Psychiatrists and Sub Investigator/study doctor as per SA Health Clozapine Management Clinical Guideline Version 2.0 dated 12/07/22 (10) during the trial. This will include pre-commencement specific history taking, physical examination, blood tests, and outpatient echocardiogram outside of study time between screening and baseline visits. Participants will receive their clozapine treatment through the Lyell McEwin Pharmacy acting as treatment centre for the duration of the trial. They will be given a thermometer and instructed on how to take their temperature daily for the first 28 days of treatment, and to contact study staff immediately if they have a fever of greater than 38 degrees. The required weekly blood tests will be collected, processed and reported by their local pathology collection centre. The participants will be required to attend the Clinical Trials Unit weekly for medical review with a study doctor within 48 hours of blood testing each week that they are taking clozapine. This will be combined with study visits where possible to reduce the time burden on the participants. ECGs on weeks 1,2 and 4 of clozapine treatment will be completed and reported by their local collection centre.

If EIPT-SZ participants wish to continue clozapine following completion of the trial and are not eligible for PBS-subsidy under Australian regulations, they can do so using a private (non-PBS) script issued by their treating clinician. If they wish to switch to a standard second-line antipsychotic (which will be fully subsidized by PBS), their prescribing physician will be advised by the study team to follow the switching instructions outlined in the clozapine PI, and to monitor their patient closely. Additionally, all EIPT-SZ patients will be seen at the LMH clinical trials unit by the study team weekly for another 4 weeks following conclusion of the 6-week trial. At all times during this period, they will be treated with a pharmacologically appropriate maintenance dose of an approved antipsychotic medication

To ensure that the SZ TAU groups have an equal number of contact moments with the study team as the EIPT participants who are receiving treatment in the Clinical Trial unit once weekly these participants will be contacted by phone by the study team once a week (same timepoints as the EIPT medication administration). Similar questions on medication adherence and general wellbeing will be asked in the contact moments, either in person (EIPT group) or via a phone call (TAU group). These are expected to take 5 to 10 minutes.

Throughout the study adherence and safety of treatment is measured by the comparison of side effects scale GASE - General Assessment of side Effects Questionnaires related to Medication Adherence, premature discontinuation timing and reason between treatment arms and the comparison use of concomitant medication between the two treatment arms over the six weeks treatment period (visit 2 versus visit 4).

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 studied in the current trial are widely used (alone or in combination) in clinical practice and the risks for side effects are well established. In the current study, clinical practice is mimicked as much as possible to maximize generalizability and for feasibility purposes. Site visits and assessments are kept to a minimum to keep subject burden at an acceptable level, while meeting the objectives of the study. Blood samples are only collected when subjects provide consent; safety measures are performed as part of clinical routine.

Overall, the risks are similar to daily clinical practice; the only difference relative to clinical practice is the application of early-intensified pharmacological treatment earlier in the illness. However, these intense treatment options are also commonly prescribed by clinicians. There are no indications in existing literature that the earlier introduction of these medications poses a safety risk.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Treatment as Usual -Switch to second line antipsychotic

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)
Compound, brand, dosage, frequency and duration up to the investigator's discretion (in accordance with Product Information
The aim of this study is to stay as close to daily clinical practice as possible, and it is important to adhere to the definition of TAU

List of the most common antipsychotics including name to choose from for the SZ-TAU study arm.

Asenapine
Lurasidone
Aripiprazole
Brexpiprazole
Cariprazine
Olanzapine
Paliperidone
Zuclopenthixol
Quetiapine
Risperidone
Ziprasidone
Amisulpride
Haloperidol
Chlorpromazine

To ensure that the SZ TAU groups have an equal number of contact moments with the study team as the EIPT participants who are receiving treatment in the Clinical Trial unit once weekly these participants will be contacted by phone by the study team once a week (same timepoints as the EIPT medication administration). Similar questions on medication adherence and general wellbeing will be asked in the contact moments, either in person (EIPT group) or via a phone call (TAU group). These are expected to take 5 to 10 minutes.

Control group

Active

Outcomes

Primary outcome [1]

To compare changes in the severity

Timepoint [1]

Change in symptom severity total score from baseline (visit 2) to end of treatment (visit 4)

Secondary outcome [1]

To compare changes in suicidal ideation between treatment arms

Timepoint [1]

Assessed at screening, at commencement of treatment visit two (baseline) visit 3 week 2 and visit 4-week six completion of treatment

Secondary outcome [2]

To compare changes in wellbeing #2

Timepoint [2]

Assessed across the treatment period week 1 – 6

Secondary outcome [3]

to compare changes in quality of life #2 [Time Frame: 6 weeks]

Timepoint [3]

Assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention

Secondary outcome [4]

To compare changes in cognitive performance #1

Timepoint [4]

assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention

Secondary outcome [5]

to compare changes in quality of life #1 [Time Frame: 6 weeks]

Timepoint [5]

Assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention

Secondary outcome [6]

To compare presence of side effects over the six weeks treatment period (visit 2 versus visit 4)

Timepoint [6]

Assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention

Secondary outcome [7]

To compare changes in functioning measure #1

Timepoint [7]

assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention

Secondary outcome [8]

To compare changes in Positive and Negative Symptoms of Schizophrenia Scale (PANSS) subscale scores (positive, negative and general) between the two treatment arms

Timepoint [8]

Assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention

Secondary outcome [9]

To compare the naturalistic clinical care and wellbeing of participants following the end of the treatment period

Timepoint [9]

Assessed at visit 4 (6 weeks post commencement of intervention) and visit 5 (12 weeks post commencement of intervention)".

Secondary outcome [10]

To compare premature discontinuation (timing and reason) between treatment arms

Timepoint [10]

Assessed up to end of treatment (visit 4 at 6 weeks post commencement of intervention

Secondary outcome [11]

To compare changes in the levels of depression and anxiety this will be measured by a composite score

Timepoint [11]

assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention

Secondary outcome [12]

Exploratory analysis of transdiagnostic predictors for treatment response (OPT IN ONLY).#1

Timepoint [12]

Assessed at visit 2 (baseline)

Secondary outcome [13]

comparison of the proportion of participants (EIPT vs. TAU) that is remission

Timepoint [13]

Assessed at end of treatment (visit 4 at 6 weeks post commencement of intervention

Secondary outcome [14]

To compare premature treatment discontinuation

Timepoint [14]

assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention)".

Secondary outcome [15]

to compare changes in the severity and improvement [Time Frame: 6 weeks]

Timepoint [15]

assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention

Secondary outcome [16]

Exploratory analysis of transdiagnostic predictors for treatment response (OPT IN ONLY).

Timepoint [16]

Assessed at visit 2 (baseline)V3 and V4 end of treatment

Secondary outcome [17]

to compare changes in cognitive performance #4 [Time Frame: 6 weeks]

Timepoint [17]

Assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention

Secondary outcome [18]

To compare changes in well- being #3

Timepoint [18]

Assessed from visit 2 (baseline) to visit 4, end of treatment (continuously)

Secondary outcome [19]

To compare changes in cognitive performance #3 [Time Frame: 6 weeks]

Timepoint [19]

Assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention

Secondary outcome [20]

To compare use of concomitant medication between treatment arms

Timepoint [20]

Assessed at end of treatment (visit 4 at 6 weeks post commencement of intervention

Secondary outcome [21]

Exploratory analysis gut to investigate whether gut microbiome can predict response to treatment

Timepoint [21]

Assessed at visit 2 baseline, and visit 4, end of treatment

Secondary outcome [22]

All study samples: to compare changes in functioning measure #2 [Time Frame: 4-6 weeks]

Timepoint [22]

Assessed at baseline (visit 2) and end of treatment (visit 4 at 6 weeks post commencement of intervention

Secondary outcome [23]

to compare changes in cognitive performance #2

Timepoint [23]

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 schizophrenia, schizoaffective disorder, schizophreniform disorder, 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 and participant needs to experience functional impairment.
The minimum symptom severity threshold for, SZ participants is at least 2 PANSS positive or negative items with a score of 4, or at least one PANSS positive or negative item with a score of 5

Minimum age

18 Years

Maximum age

65 Years

Sex

Both males and females

Can healthy volunteers participate?

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
8. Participant has used clozapine in the past.
9. Participant has a known intolerance to clozapine or to all TAU medication options.
10. Participant meets any of the contraindications for clozapine or to all TAU medication options, as specified within the applicable PI.
11. Participant meets the modified Andreasen criteria for remission.
12. Participant has any clinically significant abnormal values on the local laboratory test (especially ANC/WBC and liver values), electrocardiogram (ECG,) echocardiogram, or study doctor examination.

For clozapine the contraindications are a history of agranulocytosis, bone marrow suppression, severe liver dysfunction, uncontrolled epilepsy or seizures, myocarditis, cardiomyopathy, hypersensitivity, or allergy to clozapine or pharmaceutical excipients, unable to undergo regular blood tests, circulatory collapse and/or central nervous system depression of any cause, severe renal disorders, paralytic ileus, alcoholic and other toxic psychoses, drug intoxication, comatose condition. Clozapine treatment must not be started concurrently with substances known to have a substantial potential for causing agranulocytosis. Concomitant use of depot antipsychotics is to be discouraged.

The Andreasen criteria are defined as: Low scores (equal 3) on eight diagnostically relevant symptoms in the Positive and Negative Syndrome Scale (PANSS): P1. Delusions; P3. Hallucinatory behaviour; P2. Conceptual disorganization; N1. Blunted affect; N4. Passive/apathetic social withdrawal; N6. Lack of spontaneity and flow of conversation; G5. Mannerisms/posturing; G9. Unusual thought content. Originally, this is coupled with a time criterion (duration of 6 months). The time criterion is not applicable in the study, because it is not feasible as this should have been reported in clinical practice where PANSS is not performed

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)

Treatment allocation (TAU or EIPT) is performed using the computerized randomisation module of the EDC system Castor. The randomisation method will be blocked randomisation. Treatment allocation is 1:1, stratified by study site and inpatient or outpatient status at visit 1.
This is an open-label study and therefore emergency unblinding is not applicable. To minimize reporter bias, an investigator who is independent from the local study team will be rating the primary symptomatic study parameter PANSS and will remain blinded to the treatment allocation.

Masking / blinding

Open (masking not 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

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

3/07/2026

Actual

Sample size

Target

150

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council

Address [1]

Country [1]

Australia

Primary sponsor type

Hospital

Name

Lyell McEwin Hospital

Address

Country

Australia

Secondary sponsor category [1]

University

Name [1]

The University of Adelaide

Address [1]

Country [1]

Australia

Other collaborator category [1]

University

Name [1]

Universität Münster

Address [1]

Country [1]

Germany

Other collaborator category [2]

University

Name [2]

University Medical Center Utrecht

Address [2]

Country [2]

Netherlands

Other collaborator category [3]

University

Name [3]

Ludwig Maximilian University of Munich

Address [3]

Country [3]

Germany

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Central Adelaide Local Health Network HREC

Ethics committee address [1]

https://www.rah.sa.gov.au/research/for-researchers/central-adelaide-local-health-network-human-research-ethics-committee

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

28/06/2024

Approval date [1]

29/08/2024

Ethics approval number [1]

2023/HRE00041

Summary

Brief summary

The aim of this study is to test if third-line treatments for Schizophrenia (SZ) should be prescribed earlier in the illness course, after a first-line treatment fails. This study is testing the idea (hypothesis) that medications that are usually only used third-line ( called Early Intensified Pharmacological Treatment - EIPT in this study) are more effective than the medications that currently get used second-line  (Treatment As Usual - TAU). 
This study has a six-week duration and participants are randomised into either the EIPT or TAU group.  Participants must have a regular treating doctor (GP or psychiatrist) who is willing to be contacted by the study team, and who will prescribe and manage the medication for all TAU participants,
There are optional "opt-in' biodata, blood and stool samples that participants may choose to give; these are to help researchers identify predictors for treatment-resistance and treatment response.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

A/Prof K.Oliver Schubert

Address

Northern Community Mental Health Services 7 Park Terrace Salisbury SA 5108

Country

Australia

Phone

+61 8 82225141

Fax

[email protected]

Contact person for public queries

Name

Clinical Trial Coordinator Deb Hobbs

Address

Lyell McEwin Hospital Haydown Road Elizabeth Vale, SA, Australia 5112

Country

Australia

Phone

+61 881829554

Fax

[email protected]

Contact person for scientific queries

Name

A/Prof K.Oliver Schubert

Address

Northern Community Mental Health Service 7 Park Terrace Salisbury SA 5108

Country

Australia

Phone

+61 8 82225141

Fax

[email protected]

Data sharing statement

Will the study consider sharing individual participant data?

What supporting documents are/will be available?

Type	Email	Other Details
Study protocol	[email protected]	v3.1 dated 19 December 2024
Ethical approval	[email protected]	request vi aemail
Informed consent form	[email protected]	request via email

Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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No additional documents have been identified.

Trial Review

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