Overview
Sponsor-declared trial summary
Phase
Therapeutic confirmatory (Phase III)
Status
Not authorised
Participants planned
1,254
Countries
4
Sites
12
Schizophrenia, schizoaffective disorder, schizophreniform disorder, major depressive disorder or bipolar disorder type I and II (currently in a depressive episode)
The primary objective is to compare the treatment response, expressed as mean change in symptom severity under an early-intensified pharmacological treatment to that under treatment as usual, in subjects who had a first-time treatment failure on their first-line treatment. This will be investigated in the diagnoses sch…
Key facts
- Sponsor
- University Medical Center Utrecht
- Participant type
- Patients
- Age range
- 18-64 years, 65+ years
- Gender
- Male and Female
- Therapeutic area
- Psychiatry and Psychology [F] - Mental Disorders [F03]
- Decision date (initial)
- 2023-06-19
- Transition trial
- No
- Low-intervention
- No
- Rare-disease indication
- No
- Vulnerable population
- Yes
- Funding sources
- European Commission
External identifiers
- EU CT number
- 2022-502185-24-00
- ClinicalTrials.gov
- NCT05603104
Trial design
CTIS Part I — objectives, methods, condition coding
Main objective
Scope: Therapy
The primary objective is to compare the treatment response, expressed as mean change in symptom severity under an early-intensified pharmacological treatment to that under treatment as usual, in subjects who had a first-time treatment failure on their first-line treatment. This will be investigated in the diagnoses schizophrenia, schizoaffective disorder, schizophreniform disorder (SZ study sample), major depressive disorder (MDD study sample) and bipolar depression (bipolar disorder I/II currently in a depressive episode; BD study sample). The treatments differ between the three study sample, but the overarching goal is equal.
Secondary objectives 10
- All study samples: to compare changes in the severity and improvement sub-scores of the Clinical Global Impression Scale between the two treatment arms over the four (MDD)/ six (SZ/BD) week treatment period (visit 2 versus visit 4).
- All study samples: to compare changes in the levels of depression and anxiety as assessed with the Hospital Anxiety and Depression Scale between the two treatment arms over the four (MDD)/six (SZ/BD) week treatment period (visit 2 versus visit 4).
- All study samples: to compare changes in cognitive performance as measured through the Trail Making Test, Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test as well as the Perceived Deficits Questionnaire, between the two treatment arms over the four (MDD)/six (SZ/BD) week treatment period (visit 2 versus visit 4).
- All study samples: to compare changes in quality of life and functioning measures between the two treatment arms over the four (MDD)/six (SZ/BD) week treatment period (visit 2 versus visit 4).
- All study samples: to compare presence of side effects as measured through GASE and reported spontaneously between the two treatment arms over the four (MDD)/six (SZ/BD) week treatment period (visit 2 versus visit 4).
- All study samples: to compare use of concomitant medication between the two treatment arms over the four (MDD)/six (SZ/BD) week treatment period (visit 2 versus visit 4).
- All study samples: to compare premature discontinuation (timing and reason) between the two treatment arms over the four (MDD)/six (SZ/BD) week treatment period (visit 2 versus visit 4).
- All study samples: to compare long-term effects of the treatment between the two study arms (comparison visit 2, 4 and 5).
- Schizophrenia sample(SZ): to compare changes in Positive And Negative Syndrome Scale subscale scores between the two treatment arms over the six-week treatment period (visit 2 versus visit 4).
- All study samples: comparison of the proportion of participants (EIPT vs. TAU) that is remission at visit 4. For SZ, remission is defined as meeting the PANSS modified Andreasen criteria (Low scores (≤3) P1. Delusions; P3. Hallucinatory behavior; 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. For MDD/BD, remission is defined as a MADRS score ≤ 12.
Conditions and MedDRA coding
Schizophrenia, schizoaffective disorder, schizophreniform disorder, major depressive disorder or bipolar disorder type I and II (currently in a depressive episode)
| Version | Level | Code | Term | System organ class |
|---|---|---|---|---|
| 20.0 | HLT | 10039620 | Schizoaffective and schizophreniform disorders | 10037175 |
| 21.1 | LLT | 10081270 | Major depressive disorder | 10037175 |
| 20.0 | PT | 10039626 | Schizophrenia | 100000004873 |
| 21.1 | LLT | 10004936 | Bipolar depression | 10037175 |
Study design 1 period
| # | Title | Allocation | Blinding | Roles blinded | Arms |
|---|---|---|---|---|---|
| 1 | Randomisation during the entire study After it is confirmed during the screening visit that the subject meets the eligibility criteria, subjects can be randomised. This can be done between visit 1 (screening) and visit 2 (baseline) or at visit 2. Subjects can be randomised to treatment as usual or early intensified pharmacological treatment. The total overview of the potential medication can be found in the protocol and protocol synopsis (table format). There is only one randomisation per subject, for the duration of the study.
|
Randomised Controlled | Single | [{"id":14695,"code":2,"name":"Investigator"}] | Treatment as usual: Treatment as usual for each study sample (major depressive disorder, schizophrenia, bipolar depression) separately. More details can be found in the table of the synopsis and in the protocol (equal table). Early intensified pharmacological treatment: Early intensified pharmacological treatment for each study sample (major depressive disorder, schizophrenia, bipolar depression) separately. More details can be found in the table of the synopsis and in the protocol (equal table). |
Eligibility criteria
Principal inclusion / exclusion criteria as submitted by sponsor
Inclusion criteria 8
- In- or out patients, at least 18 years of age up until 70.
- Being willing and able to provide written informed consent. If unable, having a legal guardian to provide written informed consent is allowed (participant’s opinion will also be considered in these cases).
- 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).
- 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
- 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.
- Subject has failed on current psychopharmacological treatment of current episode of SZ/MDD/BD, as confirmed by a CGI-I ≥3.
- Subject and clinician intend to change pharmacotherapeutic treatment.
- A minimum symptom severity threshold needs to be present (moderate level; more details in the protocol section 6.2) and subject needs to experience functional impairment.
Exclusion criteria 12
- Being pregnant or breastfeeding.
- For the SZ sample only: schizophrenia subjects cannot meet the modified Andreasen criteria for remission.
- For the BD sample only: a score of 8 or higher on the Young Mania Rating Scale in order to exclude subjects with predominant manic symptoms or mixed symptoms.
- 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.
- Subject has a known intolerance to clozapine (SZ only), esketamine intranasal/ (es)ketamine IV (MDD only) or quetiapine (BD only) or to all medication and excipients options for a study sample (related to the TAU treatment arms).
- 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), as specified within the applicable SmPC.
- 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.
- Subject currently uses more than the allowed psychotropic concomitant medication and needs to stay on this medication during the study.
- Subject experiences any other significant disease or disorder which, in the opinion of the investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant’s ability to participate in the trial.
- Current active suicidal ideation within the last 2 weeks, defined as a score of 1 or higher on CDSS question 8, followed by an assessment by the treating clinician who determines it is not safe for the patient to participate in the study.
- Subject meets criteria for current alcohol and/or drugs substance use disorderdependency, as confirmed by the Mini International Neuropsychiatric Interview (MINI v7.0.2). For all study samples: Nnicotine 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.
- Subjects who are admitted in the (psychiatric) clinic due to a court or administrative order are not allowed to participate in the study.
Endpoints
Primary and secondary outcome measures (English text)
Primary endpoints 1
- Change in symptom severity total score from baseline (visit 2) to four-weeks (MDD)/six-weeks (SZ/BD) (visit 4). For SZ, this is measured using the Positive And Negative Syndrome Scale. For MDD and BD, Montgomery Asberg Depression Rating Scale is applied.
Secondary endpoints 1
- The secondary endpoints are already described in the secondary objectives
Investigational products
Investigational medicinal products (IMPs), comparators, placebo, auxiliary
Test 13
SCP60073 · ATC
- Active substance
- Quetiapine
- Route of administration
- ORAL
- Max daily dose
- 600 mg milligram(s)
- Max total dose
- 25200 mg milligram(s)
- Max treatment duration
- 6 Week(s)
- Authorisation status
- Authorised
- ATC code
- N05AH04 — QUETIAPINE
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SCP20043393 · ATC
- Active substance
- Esketamine
- Route of administration
- INFUSION
- Max daily dose
- 1.0 mg/kg milligram(s)/kilogram
- Max total dose
- 8 mg/kg milligram(s)/kilogram
- Max treatment duration
- 4 Week(s)
- Authorisation status
- Authorised
- ATC code
- N01AX14 — ESKETAMINE
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SCP182488 · ATC
- Active substance
- Bupropion Hydrochloride
- Substance synonyms
- AMFEBUTAMONE HYDROCHLORIDE
- Route of administration
- ORAL
- Max daily dose
- 450 mg milligram(s)
- Max total dose
- 18900 mg milligram(s)
- Max treatment duration
- 6 Week(s)
- Authorisation status
- Authorised
- ATC code
- N07BA02 — BUPROPION
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SCP713118 · ATC
- Active substance
- Clozapine
- Route of administration
- ORAL
- Max daily dose
- 900 mg milligram(s)
- Max total dose
- 37800 mg milligram(s)
- Max treatment duration
- 6 Week(s)
- Authorisation status
- Authorised
- ATC code
- N05AH02 — CLOZAPINE
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SCP8137199 · ATC
- Active substance
- Ketamine
- Route of administration
- INFUSION
- Max daily dose
- 1 mg/kg milligram(s)/kilogram
- Max total dose
- 8 mg/kg milligram(s)/kilogram
- Max treatment duration
- 4 Week(s)
- Authorisation status
- Authorised
- ATC code
- N01AX03 — KETAMINE
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Spravato 28 mg nasal spray, solution
PRD7778029 · Product
- Active substance
- Esketamine Hydrochloride
- Pharmaceutical form
- NASAL SPRAY, SOLUTION
- Route of administration
- NASAL SPRAY
- Max daily dose
- 84 mg milligram(s)
- Max total dose
- 672 mg milligram(s)
- Max treatment duration
- 4 Week(s)
- Authorisation status
- Authorised
- ATC code
- N06AX27 — -
- Marketing authorisation
- EU/1/19/1410/001
- MA holder
- JANSSEN-CILAG INTERNATIONAL NV
- MA country
- EU
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SCP713547 · ATC
- Active substance
- Lamotrigine
- Route of administration
- ORAL
- Max daily dose
- 200 mg milligram(s)
- Max total dose
- 8400 mg milligram(s)
- Max treatment duration
- 6 Week(s)
- Authorisation status
- Authorised
- ATC code
- N03AX09 — LAMOTRIGINE
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SCP31885 · ATC
- Active substance
- Duloxetine
- Route of administration
- ORAL
- Max daily dose
- 120 mg milligram(s)
- Max total dose
- 5040 mg milligram(s)
- Max treatment duration
- 6 Week(s)
- Authorisation status
- Authorised
- ATC code
- N06AX21 — DULOXETINE
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SCP1153665 · ATC
- Active substance
- Sertraline
- Route of administration
- ORAL
- Max daily dose
- 200 mg milligram(s)
- Max total dose
- 8400 mg milligram(s)
- Max treatment duration
- 6 Week(s)
- Authorisation status
- Authorised
- ATC code
- N06AB06 — SERTRALINE
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SCP16258179 · ATC
- Active substance
- Venlafaxine
- Route of administration
- ORAL
- Max daily dose
- 375 mg milligram(s)
- Max total dose
- 15750 mg milligram(s)
- Max treatment duration
- 6 Week(s)
- Authorisation status
- Authorised
- ATC code
- N06AX16 — VENLAFAXINE
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SCP259737 · ATC
- Active substance
- Lithium
- Route of administration
- ORAL
- Max daily dose
- 800 mg milligram(s)
- Max total dose
- 33600 mg milligram(s)
- Max treatment duration
- 6 Week(s)
- Authorisation status
- Authorised
- ATC code
- N05AN01 — LITHIUM
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SCP61082 · ATC
- Active substance
- Escitalopram
- Substance synonyms
- (S)-CITALOPRAM
- Route of administration
- ORAL
- Max daily dose
- 20 mg milligram(s)
- Max total dose
- 840 mg milligram(s)
- Max treatment duration
- 6 Week(s)
- Authorisation status
- Authorised
- ATC code
- N06AB10 — ESCITALOPRAM
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SCP4322815 · ATC
- Active substance
- Sodium Valproate
- Substance synonyms
- VALPROATE SODIUM, Sodium Dipropylacetate
- Route of administration
- ORAL
- Max daily dose
- 2000 mg milligram(s)
- Max total dose
- 84000 mg milligram(s)
- Max treatment duration
- 6 Week(s)
- Authorisation status
- Authorised
- ATC code
- N03AG01 — VALPROIC ACID
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Comparator 2
-
N05A · Product
- Pharmaceutical form
- -
- Route of administration
- ORAL
- Max daily dose
- 1000000 mg milligram(s)
- Max total dose
- 1000000 mg milligram(s)
- Max treatment duration
- 6 Week(s)
- Authorisation status
- Authorised
- ATC code
- N05A — ANTIPSYCHOTICS
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
-
N06A · Product
- Pharmaceutical form
- -
- Route of administration
- ORAL USE
- Max daily dose
- 1000000 mg milligram(s)
- Max total dose
- 1000000 mg milligram(s)
- Max treatment duration
- 4 Week(s)
- Authorisation status
- Authorised
- ATC code
- N06A — ANTIDEPRESSANTS
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Sponsors and contacts
Sponsor organisations, regulatory contacts, third parties
University Medical Center Utrecht
- Sponsor organisation
- University Medical Center Utrecht
- Address
- Heidelberglaan 100
- City
- Utrecht
- Postcode
- 3584 CX
- Country
- Netherlands
Scientific contact point
- Organisation
- University Medical Center Utrecht
- Contact name
- Dr. Inge Winter
Public contact point
- Organisation
- University Medical Center Utrecht
- Contact name
- Dr. Inge Winter
Third parties 3
| Organisation | City, country | Duties |
|---|---|---|
| Ludwig Maximilian University Of Munich ORG-100028102
|
Munich, Germany | Other |
| Fraunhofer-Institut für Algorithmen und Wissenschaftliches ORL-000000325
|
Sankt Augustin, Germany | Data management |
| Kairos ORL-000000063
|
Bochum, Germany | E-data capture |
Locations
4 EU/EEA countries · 12 investigational sites
By country
| Country | MS status | Planned subjects | Sites |
|---|---|---|---|
| Austria | Not authorised | 70 | 1 |
| Germany | Not authorised | 500 | 6 |
| Italy | Not authorised | 340 | 4 |
| Spain | Not authorised | 35 | 1 |
| Rest of world
Israel, United Kingdom, Australia
|
— | 309 | — |
Investigational sites
Medizinische Universitaet Innsbruck
Universitätsklinik für Psychiatrie I, Anichstrasse 35, 6020, Innsbruck
Bezirkskliniken Schwaben
Department of Psychiatry, Psychotherapy and Psychosomatics, Geschwister-Schoenert-Strasse 4, 86156, Augsburg
Westfaelische Wilhelms Universitaet Muenster
Klinik für Psychische Gesundheit, Gebäude A3, Albert-Schweitzer-Campus 1, Münster
University Hospital Frankfurt am Main
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Heinrich-Hoffmann-Strasse 10, 60528, Frankfurt am Main
Technische Universitat Dresden
Department of Psychiatry and Psychotherapy, Fetscherstrasse 74, Johannstadt-Nord, Dresden
Klinik für Psychiatrie und Psychotherapie der Universitätsmedizin Mainz
Klinik für Psychiatrie und Psychotherapie der Universitätsmedizin Mainz, Untere Zahlbacher Strasse 8, 55131, Mainz
Universitätsklinik für Psychiatrie und Psychotherapie Bielefeld
Psychiatrie und Psychotherapy, Remterweg 69/71, 33617, Bielefeld
Clinica Psichiatrica, 1st floor
Clinica Psichiatrica, 1st floor, Via Romagna 16, 09127, Cagliari
Universita Degli Studi Di Brescia
Department of Mental Health and Addiction Services, Piazza Del Mercato 15, 25121, Brescia
Università degli studi della Campania Luigi Vanvitelli
Dipartemento di salute mentale e fisica e medicina preventiva, Largo Madonna delle Grazie 1, 80138, Naples
Azienda Ospedaliera Universitaria Citta Della Salute E Della Scienza Di Torino
Dipartimento di Neuroscienze, Sezione di Psichiatria, Via Cherasco 15, 10126, Turin
Application history
1 submissions — initial application plus substantial / non-substantial modifications
| # | Type | Code | Submitted | Reference MS | Conclusion | Decision date |
|---|---|---|---|---|---|---|
| 1 | INITIAL | IN | 2023-02-16 | Italy | Not acceptable 2023-06-12
|
2023-06-16 |