The Effect of a Six Week Intensified Pharmacological Treatment for Schizophrenia Compared to Treatment as Usual in Subjects Who Had a First-time Treatment Failure on Their First-line Treatment.

NCT05958875 | Recruiting Phase 4 DMC

• 1 other identifier: 2023-506602-39-00 (EU CT#)
• Study Type: interventional
• Target: 418
• Locations: 5 countries
• Sites: 13

Brief Summary

Schizophrenia (SZ) affects approximately 4.5 million people across the European Union (EU) and is associated with annual healthcare and societal costs of 29 billion Euros. The impact on the daily life of patients is huge, ranging from frequent relapses and hospitalisations, the inability to maintain a job or continue scholing, to a low quality of life, impaired cognitive functioning, suicidal ideation and an increase morbidity rate, next to the large burden for carers 1. When diagnosed with schizophrenia or related disorder, patients are commonly prescribed antipsychotics. One-third of the schizophrenia patients are regarded treatment-resistant (TR), meaning that at least two antipsychotic trials have failed. Typically, clozapine is prescribed for TR patients, which is effective for approximately 40% of patients. Clozapine is among the most effective treatments, with the lowest all-cause mortality. Although it is among the most effective antipsychotics, it is generally not used earlier in the illness course due to a small risk of severe neutropenia/agranulocytosis, which is why patients treated with clozapine are intensely monitored. However, this small risk outweighs the burden of not receiving an effective treatment. Since clozapine is among the most effective treatments, this leads to the research question whether earlier initiation of third-line treatment ('early intensified' pharmacological treatment; EIPT) would be more beneficial than the current second-line treatments (treatment as usual; TAU). If this is indeed the case, this could lead to the prevention of unnecessary trials of ineffective treatments, hospitalisations, and recommendations for adaptations of worldwide guidelines as well as a reduction of healthcare and societal costs The INTENSIFY-Schizophrenia trial is part of the larger Horizon 2021 project Psych-STRATA, with the central goal of paving the way for a shift towards a treatment decision-making process tailored for the individual at risk for treatment resistance. To that end, the inestigators aim to establish evidence-based criteria to make decisions of early intense treatment in individuals at risk for treatment resistance across the major psychiatric disorders of schizophrenia, bipolar disorder and major depression. The current protocol focuses on the sample of schizophrenia patients.

Conditions

Schizophrenia and Related Disorders; Early Treatment-Resistance

Keywords

Schizophrenia; Schizoaffective disorder; Schizophreniform disorder; Clozapine; Treatment as usual; Early treatment-Resistance

Outcome Measures

Primary Outcomes (1)

• Change in symptom severity on Positive and Negative Syndrome Scale

  Change in symptom severity (EIPT vs. TAU) total score from baseline (visit 2) to end of treatment (visit 4). This is measured using the Positive And Negative Syndrome Scale. Minimum score is 30, maimum score 210. A bigger mean change means a better outcome.

  6 weeks

Secondary Outcomes (18)

• Compare symptomatic remission.

  6 weeks

• To compare changes in PANSS subscale scores (positive, negative and general) between the two treatment arms.

  6 weeks

• Compare changes in the levels of depression and anxiety

  6 weeks

• To compare changes in cognitive performance as measured through the Trail Making Test

  6 weeks

• To compare changes cognitive performance as measured through the Digit Symbol Substitution Test

  6 weeks

Study Arms (2)

Schizophrenia early intensified treatment (EIPT): Switch to clozapine

EXPERIMENTAL

Subject with schizophrenia, randomized to EIPT: Switch to clozapine. Brand, dosage, frequency and duration up to the investigator's discretion

Drug: Clozapine

Schizophrenia treatment as usual (TAU): second-line antispychotic

ACTIVE COMPARATOR

Subject with schizophrenia or related disorder randomized to TAU: switch to second-line antispychotic. Compound, brand, dosage, frequency and duration up to the investigator's discretion (in accordance with SmPC)

Drug: Second-line Antipsychotics (treatment as usual)

Interventions

Clozapine DRUG

Participants are randomized to clozapine or second-line antipsychotics. When randomised to clozapine, they will receive clozapine for six weeks.

Also known as: ATC code: N05AH02

Schizophrenia early intensified treatment (EIPT): Switch to clozapine

Second-line Antipsychotics (treatment as usual) DRUG

Participants are randomized to clozapine or second-line antipsychotics. When randomized to second-line antipsychotics, this means participants will receive treatment as usual. The physician has the choice to administer any second-line antipsychotic. More specification is not possible, as this is a choice the physician makes with the participant based on the characteristic and preference of the participant (in line with standard clinical practice).

Schizophrenia treatment as usual (TAU): second-line antispychotic

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• In- or out patients, at least 18 years of age up until 70.
• 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.
• Female subjects of child bearing potential must use effective contraception during the trial as per the requirements of the applicable SmPCs and should have a negative pregnancy test at visit 1 or 2 (before randomisation; section 8.2).
• Meeting diagnostic criteria for a primary diagnosis of schizophrenia, schizoaffective disorder, or schizophreniform disorder, according to DSM-5. The primary diagnosis will be confirmed by the Mini International Neuropsychiatric Interview (MINI v7.0.2).
• Subject experiences a treatment failure due to lack of efficacy in the current episode, as confirmed by a CGI-I ≥3; preferably this treatment is a first-line pharmacotherapeutic agent for the primary DSM-5 diagnosis, and was prescribed for at least 4 weeks within an effective dose range as specified in the Summary of Product Characteristics (SmPCs). However, other lines of treatment are accepted as well.
• Subject and clinician intend to change pharmacotherapeutic treatment.
• 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 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.
• Functional impairment is defined as a score of 5 or higher on any of the three scales of the Sheehan Disability Scale (SDS).

You may not qualify if:

• Being pregnant or breastfeeding.
• Subject has used clozapine in the past.
• Subject has a known intolerance to clozapine or to all TAU medication options.
• Meeting any of the contraindications of clozapine or to all TAU medication options, 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 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.
• Subjects 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 subject to participate in the study
• 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 and moderate alcohol and/or cannabis use disorder (as defined by MINI v7.0.2). Severe alcohol and/or cannabis use disorder are not allowed.
• Subjects have not been committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
• Subjects who meet the modified Andreasen criteria for remission.
• Subjects that have any clinically significant abnormal values on the local laboratory test (especially ANC/WBC and liver values), electrocardiogram (ECG) or physician examinations.
• Subjects dependent on the sponsor, investigator or trial site must be excluded from participation in advance

Sponsors & Collaborators

• Dr. Inge Winter: lead
• Universität Münster: collaborator

Study Sites (13)

Medical University Innsbruck

Innsbruck, Austria

RECRUITING

Bezirkskliniken Schwaben, Bezirkskrankenhaus Augsburg

Augsburg, 86156, Germany

NOT YET RECRUITING

Universitätsklinik für Psychiatrie und Psychotherapie Bielefeld

Bielefeld, Germany

RECRUITING

LWL-Klinik Dortmund, Bereich Forschung & Wissenschaft

Dortmund, 44287, Germany

RECRUITING

University Hospital Frankfurt am Main - Goethe University

Frankfurt am Main, Germany

RECRUITING

Klinik für Psychiatrie und Psychotherapie der Universitätsmedizin Mainz

Mainz, Germany

RECRUITING

Westfälische Wilhelms-Universität Münster

Münster, Germany

RECRUITING

Universita degli Studi di Brescia

Brescia, Italy

RECRUITING

University of Cagliari

Cagliari, Italy

RECRUITING

Università degli studi della Campania Luigi Vanvitelli

Naples, 80138, Italy

RECRUITING

Azienda Ospedaliero-Universitaria "Città della Salute e della Scienza di Torino"

Turin, Italy

RECRUITING

Fundació Clínic per a la Recerca Biomèdica

Barcelona, Spain

RECRUITING

King's College London, Psychiatry & Cognitive Neuroscience

London, SE5 8AF, United Kingdom

RECRUITING

MeSH Terms

Conditions

Schizophrenia; Psychotic Disorders

Interventions

Clozapine; Therapeutics

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Dibenzazepines; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Central Study Contacts

Inge Winter, Dr.

CONTACT

+31875553227; i.winter@umcutrecht.nl

Cynthia Okhuijsen-Pfeifer, Dr.

CONTACT

+31875553227; c.pfeifer@umcutrecht.nl

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Open label, except for the assessors of the primary outcome
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Parallel randomization to the 2 arms, treatment as usual (TAU) or early-intensified pharmacological treatment (EIPT).

Study Record Dates

• First Submitted: June 30, 2023
• First Posted: July 25, 2023
• Study Start: August 1, 2024
• Primary Completion (Estimated): June 30, 2028
• Study Completion (Estimated): June 30, 2028
• Last Updated: September 26, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, CSR

Locations

ES (1); GB (1); AU (1); IT (4); DE (6)