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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT05603104




Registration number
NCT05603104
Ethics application status
Date submitted
13/10/2022
Date registered
2/11/2022
Date last updated
27/08/2024

Titles & IDs
Public title
Intensified Pharmacological Treatment for Schizophrenia, Major Depressive Disorder and Bipolar Depression After a First-time Treatment Failure
Scientific title
A Randomised, Controlled Trial to Investigate the Effect of an Intensified Pharmacological Treatment for Schizophrenia, Major Depressive Disorder and Bipolar Depression in Subjects Who Had a First-time Treatment Failure on Their First-line Treatment.
Secondary ID [1] 0 0
2022-502185-24-00 (EU CT #)
Universal Trial Number (UTN)
Trial acronym
INTENSIFY
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Condition category
Condition code
Mental Health 0 0 0 0
Depression
Mental Health 0 0 0 0
Schizophrenia
Mental Health 0 0 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Clozapine
Treatment: Drugs - Esketamine Nasal Product
Treatment: Drugs - Escitalopram
Treatment: Drugs - Sertraline
Treatment: Drugs - Duloxetine
Treatment: Drugs - Venlafaxine
Treatment: Drugs - Lithium
Treatment: Drugs - Lamotrigine
Treatment: Drugs - Valproate acid
Treatment: Drugs - Quetiapine
Treatment: Drugs - Second-line Antidepressants
Treatment: Drugs - Second-line Antipsychotics
Treatment: Drugs - Ketamine Hydrochloride
Treatment: Drugs - Esketamine hydrochloride

Experimental: Schizophrenia EIPT: Switch to clozapine - Schizophrenia randomized to EIPT: Switch to clozapine. Brand, dosage, frequency and duration up to the investigator's discretion

Active Comparator: Schizophrenia TAU: second-line antispychotic - Schizophrenia randomized to TAU: switch to second-line antispychotic. Compound, brand, dosage, frequency and duration up to the investigator's discretion (in accordance with SmPC)

Experimental: Major Depressive Disorder EIPT: second-line antidepressant + esketamine nasal spray - Major depressive disorder randomized to EIPT: Switch to second-line antidepressant + esketamine nasal spray or (es)ketamine infusion. Antidepressant: Compound, brand, dosage, frequency and duration up to the investigator's discretion (in accordance with SmPC).
Esketamine nasal spray: 2 times per week for 4 weeks. Initial dose 28 mg, after that increases can be made with 28 mg per increase (up to 84 mg per week). This decision is up to the investigator's discretion (in accordance with SmPC).
(Es)ketamine infusion: performed twice weekly for 4 weeks. Compound, brand up to the investigator's discretion (in accordance with SmPC).

Active Comparator: Major Depressive Disorder TAU: second-line antidepressant - Major depressive disorder randomized to TAU: Switch to second-line antidepressant + esketamine nasal spray or ketamine IV or esketamine IV . Antidepressant: Compound, brand, dosage, frequency and duration up to the investigator's discretion (in accordance with SmPC).

Experimental: Bipolar Depression EIPT: Switch to one of the following combinations: - Bipolar Depression randomized to EIPT: Switch to 1. one of the following: escitalopram, sertraline, duloxetine or venlafaxine plus 2. two of the following: lithium, lamotrigine, valproate acid or quetiapine

Active Comparator: Bipolar Depression TAU: Switch to quetiapine plus lithium or valproate acid or lamotrigine - Bipolar Depression randomized to TAU: Switch to quetiapine plus lithium or valproate acid or lamotrigine Compound, brand, dosage, frequency and duration up to the investigator's discretion (in accordance with SmPC).


Treatment: Drugs: Clozapine
See arm description

Treatment: Drugs: Esketamine Nasal Product
See arm description

Treatment: Drugs: Escitalopram
See arm description

Treatment: Drugs: Sertraline
See arm description

Treatment: Drugs: Duloxetine
See arm description

Treatment: Drugs: Venlafaxine
See arm description

Treatment: Drugs: Lithium
See arm description

Treatment: Drugs: Lamotrigine
See arm description

Treatment: Drugs: Valproate acid
See arm description

Treatment: Drugs: Quetiapine
See arm description

Treatment: Drugs: Second-line Antidepressants
See arm description

Treatment: Drugs: Second-line Antipsychotics
See arm description

Treatment: Drugs: Ketamine Hydrochloride
See arm description

Treatment: Drugs: Esketamine hydrochloride
See arm description
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Change in symptom severity
Timepoint [1] 0 0
4-6 weeks
Secondary outcome [1] 0 0
All study samples: to compare changes in the severity and improvement
Timepoint [1] 0 0
4-6 weeks
Secondary outcome [2] 0 0
All study samples: to compare changes in the levels of depression and anxiety
Timepoint [2] 0 0
4-6 weeks
Secondary outcome [3] 0 0
All study samples: to compare changes in cognitive performance #1
Timepoint [3] 0 0
4-6 weeks
Secondary outcome [4] 0 0
All study samples: to compare changes in cognitive performance #2
Timepoint [4] 0 0
4-6 weeks
Secondary outcome [5] 0 0
All study samples: to compare changes in cognitive performance #3
Timepoint [5] 0 0
4-6 weeks
Secondary outcome [6] 0 0
All study samples: to compare changes in cognitive performance #4
Timepoint [6] 0 0
4-6 weeks
Secondary outcome [7] 0 0
All study samples: to compare changes in functioning measure #1
Timepoint [7] 0 0
4-6 weeks
Secondary outcome [8] 0 0
All study samples: to compare changes in functioning measure #2
Timepoint [8] 0 0
4-6 weeks
Secondary outcome [9] 0 0
All study samples: to compare changes in quality of life #1
Timepoint [9] 0 0
4-6 weeks
Secondary outcome [10] 0 0
All study samples: to compare changes in quality of life #2
Timepoint [10] 0 0
4-6 weeks
Secondary outcome [11] 0 0
All study samples: to compare presence of side effects
Timepoint [11] 0 0
4-6 weeks
Secondary outcome [12] 0 0
All study samples: to compare use of concomitant medication
Timepoint [12] 0 0
4-6 weeks
Secondary outcome [13] 0 0
All study samples: to compare premature discontinuation
Timepoint [13] 0 0
4-6 weeks
Secondary outcome [14] 0 0
All study samples: to compare long-term effects of the treatment
Timepoint [14] 0 0
4-6 weeks
Secondary outcome [15] 0 0
Schizophrenia sample: to compare changes in Positive and Negative syndrome subscale scores
Timepoint [15] 0 0
4-6 weeks
Secondary outcome [16] 0 0
All study samples: comparison of the proportion of participants (EIPT vs. TAU) that is remission at visit 4.
Timepoint [16] 0 0
4-6 weeks

Eligibility
Key inclusion criteria
1. In- or out patients, at least 18 years of age up until 70 (SZ study sample), 65 years (MDD study sample) and no limit for the BD study..

Being willing and able to provide written informed consent. Having a legal guardian to cosign is allowed. Informed consent will be signed at visit 1, before any study procedure.

3. Female subjects of child bearing potential must be willing to ensure that they use effective contraception during the trial and as per the requirements in the protocol (section 8.2.1).Male subjects that will use valproate acid during the trial must use effective contraceptive measures during the trial (see section 8.2.1).

4. Meeting diagnostic criteria for a primary diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder, major depressive disorder (without psychotic features) or bipolar depression (bipolar disorder type I and II currently in a depressive episode), according to DSM-5. The primary diagnosis will be confirmed by the Mini International Neuropsychiatric Interview (MINI v7.0.2).

5. Subject currently experiences his/her first treatment failure due to lack of efficacy; this treatment is a first-line pharmacotherapeutic agent for the primary DSM-5 diagnosis, and was prescribed for at least 4 weeks within the dose range as specified in the Summary of Product Characteristics (SmPCs).

6. Subject has failed on current psychopharmacological treatment of current episode of SZ/MDD/BD, as confirmed by a CGI-I =3.

7. Subject and clinician intend to change pharmacotherapeutic treatment. 8. A minimum symptom severity threshold needs to be present (moderate level; see below) and subject needs to experience functional impairment.

* The minimum symptom severity threshold for SZ subjects 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.
* The minimum symptom severity threshold for MDD is a score of = 20 on the Montgomery Åsberg Depression Rating Scale (MADRS)
* The minimum symptom severity threshold for BD is a score of =20 on the Montgomery Åsberg Depression Rating Scale (MADRS)
* For all study samples: Functional impairment is defined as a score of 5 or higher on any of the three scales of the Sheehan Disability Scale (SDS).
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria:

1. Being pregnant or breastfeeding.
2. Subject has failed previously on the EIPT study medication (i.e. SZ: clozapine; MDD: esketamine intranasal/(es)ketamine IV) or the TAU treatment for BD (quetiapine) due to inefficacy. Treatment duration as = 4 weeks within an efficacious dose range according to the SmPC.
3. Subject has a known intolerance to clozapine (SZ only), esketamine intranasal/ (es)ketamine IV (MDD only) or quetiapine (BD only) or to all medication options for a study sample (related to the TAU treatment arms) or all EIPT medications (BD study sample).
4. Meeting any of the contraindications of clozapine (SZ only), esketamine intranasal/ (es)ketamine IV (MDD only) or quetiapine (BD only), or to all medication options for a study sample (related to the TAU treatment arms), or all EIPT medications (BD study sample), as specified within the applicable SmPC.
5. Subject has participated in another clinical trial in which the subject received an experimental or investigational drug or agent within 30 days before visit 1.
6. Subject currently uses more than the allowed psychotropic concomitant medication and needs to stay on this medication during the study.
7. Subject experiences any other significant disease or disorder which, in the opinion of the investigator, may either put the subjects at risk because of participation in the trial, or may influence the result of the trial, or the subject's ability to participate in the trial.
8. Subject experiences any other significant disease or disorder which, in the opinion of the investigator, may either put the subjects at risk because of participation in the trial, or may influence the result of the trial, or the subject's ability to participate in the trial.
9. Moderate or high suicidal ideation within the last 2 weeks, defined as a score of 9 or higher on Module B (Suicidality) of the Mini International Neuropsychiatric Interview (MINI v7.0.2)
10. Subject meets criteria for current substance use disorder, as confirmed by the Mini International Neuropsychiatric Interview (MINI v7.0.2). Nicotine dependency is allowed, as well as mild alcohol and/or cannabis use disorder (as defined by MINI v7.0.2). Moderate and severe alcohol and/or cannabis use disorder are not allowed.
11. Subjects have not been committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
12. Subjects dependent on the sponsor, investigator or trial site must be excluded from participation in advance.
13. For the SZ sample only: schizophrenia subjects cannot meet the modified Andreasen criteria for remission.
14. For the SZ sample only: Subjects that have any clinically significant abnormal values on the local laboratory test (especially ANC/WBC and liver values), electrocardiogram (ECG) or physician examinations.
15. For the BD sample only: a score of 12 or higher on the Young Mania Rating Scale (YMRS) in order to exclude subjects with predominant manic symptoms or mixed symptoms.
16. For the BD study sample only: Subjects with a history of antidepressant-induced mania or hypomania or recent rapid cycling (based on the medical file of the potential participant or the clinical judgment of the clinician).
17. For the BD study sample only: Subjects with pre-existing severe liver damage (as tested within the local laboratory test at visit 1).

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
30/09/2024
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
30/06/2026
Actual
Sample size
Target
1254
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
Israel
State/province [1] 0 0
Ramat Gan

Funding & Sponsors
Primary sponsor type
Other
Name
Dr. Inge Winter
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Schizophrenia, bipolar and major depressive disorders collectively affect over 10 million people across the EU and are associated with annual healthcare and societal costs in excess of 100 billion Euros. When diagnosed with one of these disorders, patients are prescribed psychotropic medication such as antidepressants, mood stabilisers or antipsychotics. It is unknown whether this first-line treatment will be successful. After this first-line treatment fails, usually a second-line treatment is initiated, and when this is not successful either a third-line treatment is initiated. Third-line treatments are quite successful, especially when compared to second-line treatments. The research question is whether the third-line treatments (early-intensified treatments) would be more efficacious than the current second-line treatments (treatment as usual) for schizophrenia, bipolar and major depressive disorders. If this is indeed the case, this could lead to the prevention of unnecessary trials of ineffective treatments and adaptations of worldwide guidelines as well as a reduction of healthcare and societal costs.
Trial website
https://clinicaltrials.gov/study/NCT05603104
Trial related presentations / publications
Public notes
This record is viewable in the ANZCTR as it had previously listed Australia and/or New Zealand as a recruitment site, however these sites have since been removed

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Inge Winter, Dr.
Address 0 0
Country 0 0
Phone 0 0
+31875553227
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT05603104