European Long-acting Antipsychotics in Schizophrenia Trial (EULAST)

Schizophrenia is a chronic psychiatric illness with periods of remission and relapse. Patients vary in the frequency and severity of relapse, time until relapse and time in remission. Discontinuation of antipsychotic medication is by far the most important reason for relapse. A possible method to optimize medication adherence is to treat patients with long-term, depot medication rather than oral medication. However, despite its apparent "common sense" this approach has neither been universally accepted by practicing psychiatrists nor unequivocally demonstrated in clinical trials. Therefore, in this study we aim to investigate possible advantages of depot medication over oral antipsychotics in an independently designed and conducted, randomized, pragmatic trial.

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: Aripiprazole; Drug: Aripiprazole depot; Drug: Paliperidone; Drug: Paliperidone palmitate

Detailed Description

It remains unclear if depot medication can reduce relapse rates and improve clinical outcome when offered to all patients in need of continuation treatment with antipsychotics. Before we can conclude whether or not all schizophrenia patients could benefit from a switch to depot formulations, several questions remain to be answered. Is depot medication associated with better continuation rates and outcome? How are depot medications tolerated as compared to oral medication? In order to clarify these important issues we aim to perform a large multi-center trial in which schizophrenia patients in need of continuous treatment who are randomized 1:1:1:1 to two different depot preparations or to two different oral medications.

In this pragmatic, randomized, open label, multicenter, multinational comparative trial, schizophrenic patients aged 18 years or older, having experienced the first psychosis between 6 months and 7 years ago,with an indication (patient or physician initiated) to receive medication or to switch to another antipsychotic drug, will enter the study.

The study duration will be one month for the medication switch and then a follow-up of 18 months. Patients having refused to take part in the study will be asked to give consent and participate in a naturalistic follow-up, during which they will be followed with the Clinical Global Impression list (CGI) as closely related to the study schedule as possible, unless they also refuse this.

• Study Type: Interventional
• Enrollment (Actual): 536
• Phase: Phase 4

Contacts and Locations

Study Locations

• Austria
  • Anichstrasse 35
    • Innsbruck, Anichstrasse 35, Austria, A-6020
      • Department of Biological Psychiatry, Innsbruck University Clinics
  • Modecenterstraße
    • Vienna, Modecenterstraße, Austria, 1030
      • Psychosoziale Dienste
• Belgium
  • Lange Beeldekensstraat 267
    • Antwerp, Lange Beeldekensstraat 267, Belgium, 2060
      • ZNA, department of Psychiatry, locatie Stuivenberg
  • Stationsstraat 22C
    • Antwerp, Stationsstraat 22C, Belgium, 2570
      • Psychiatrisch Ziekenhuis Duffel
• Bulgaria
  • Louben Roussev Str.
    • Sofia, Louben Roussev Str., Bulgaria, 1113
      • University Hospital of Neurology and Psychiatry 'St. Naum' 1
• Czechia
  • Brno, Czechia
    • Dr. Ustohal
  • Praha, Czechia
    • Dr. Mohr
  • Fakultní Nemocnice
    • Hradec Králové, Fakultní Nemocnice, Czechia, 500 05
      • Psychiatrická klinika LF UK
• Denmark
  • Ndr. Ringvej
    • Glostrup, Ndr. Ringvej, Denmark, 2600
      • Center for Neuropsychiatric Research
• Germany
  • Bergische Landstraße 2
    • Düsseldorf, Bergische Landstraße 2, Germany, 40629
      • Klinik und Poliklinik für Psychiatrie und Psychotherapie der Heinrich-Heine-Universität
  • Ismaningerstrasse 22
    • München,, Ismaningerstrasse 22, Germany, 81675
      • Technische Universität München (TUM
  • Julius-Kühn-Straße 7
    • Halle, Julius-Kühn-Straße 7, Germany, 06112
      • Klinik für Psychiatrie, Psychotherapie und Psychosomatik der Martin-Luther-Universität
  • Nussbaumstrasse 7
    • München, Nussbaumstrasse 7, Germany, 80336
      • Department of Psychiatry and Psychotherapy
• Greece
  • Athens, Greece
    • National and Kapodistrian University of Athens Medical School, Eginition Hospital
• Hungary
  • Balassagyarmat, Hungary
    • Dr. Csekey
  • Budapest, Hungary
    • Department of Psychiatry and Psychotherapy, Semmelweis University
• Israel
  • Bat-Yam, Israel
    • Abravanel Mental Health Center
  • Be'er Ya'aqov, Israel
    • Be'er-Ness Mental Health Center
  • Jerusalem, Israel
    • The Jerusalem Mental Health Center
  • Pardesiyya, Israel
    • Lev-Hasharon Medical Center for Mental Health
  • Petach-Tikva, Israel
    • Geha Medical Health Center
  • Tel-Hashomer, Israel, 52621
    • The Chaim Sheba Medical Center
• Italy
  • L'Aquila, Italy
    • Servizio Psichiatrico Universitario di Diagnosi e Cura. Presidio Ospedaliero "San Salvatore" Università degli Studi dell'Aquila.
  • Largo Madonna Delle Grazie 1
    • Naples, Largo Madonna Delle Grazie 1, Italy, 80138
      • Department of Psychiatry, University of Naples SUN
  • Sezione Di Psichiatriavia Cherasco, 11
    • Turin, Sezione Di Psichiatriavia Cherasco, 11, Italy, 10126
      • Università degli Studi di Torino. Dipartimento di Neuroscienze
• Netherlands
  • Utrecht, Netherlands
    • University Medical Center
• Norway
  • Bergen, Norway, 5021
    • Helse Bergen HF Haukeland University Hospital, Division of Psychiatry
  • Stavanger, Norway
    • Stavanger University Hospital
  • Trondheim, Norway, 7441
    • St Olavs Hospital avd Østmarka / INM NTNU
• Poland
  • Sobieskiego 9
    • Warsaw, Sobieskiego 9, Poland, 02-957
      • Instytut Psychiatrii i Neurologii
  • Ul. Głuska 1
    • Lublin, Ul. Głuska 1, Poland, 20-439
      • II Klinika Psychiatrii Uniwersytet Medyczny w Lublinie
• Romania
  • Arad, Romania
    • Spitalul Clinic Judetean de Urgenta Arad - Clinica de Psihiatrie
  • Bucharest, Romania
    • Spitalul Clinic de Psihiatrie "Prof. Dr. Alexandru Obregia"
  • Bucharest, Romania
    • Spitalul Clinic de Psihiatrie "Prof. Dr. Alexandru Obregia
  • Buzău, Romania
    • Spitalul de Psihiatrie si pentru Masuri de Siguranta, Sapoca, Buzau
  • Craiova, Romania
    • Spitalul Clinic de Neuropsihiatrie Craiova
  • Targu Mureş, Romania
    • Sitalul Clinic Judetean Mures
• Spain
  • Madrid, Spain
    • Child and Adolescent Psychiatry Department. Hospital General Universitario Gregorio Marañón. Servicio Madrileño de Salud
  • C/Villarroel, 170. Escalera12, Planta 0
    • Barcelona, C/Villarroel, 170. Escalera12, Planta 0, Spain, 08036
      • Hospital Clínic de Barcelona. Unidad de Esquizofrenia
  • Cantabria
    • Santander, Cantabria, Spain, 39011
      • Hospital Universitario Marqués de Valdecilla, Servicio de Psiquiatría
  • Julián Clavería S/n
    • Oviedo, Julián Clavería S/n, Spain, 33006
      • Facultad de Medicina Center
• United Kingdom
  • Kent, United Kingdom
    • Edmund Ward, St Martins Hospital Littlebourne Road Canterbury
  • London, United Kingdom
    • Imperial College, Centre for Mental Health, Faculty of Medicine,
  • Middlesbrough, United Kingdom
    • Tees, Ask and Wearvalleys
  • Newcastle, United Kingdom
    • Northumberland
  • Oxford, United Kingdom
    • Oxford Health NHS Foundation Trust
  • Surrey, United Kingdom
    • Surrey and Borders Partnership NHS Foundation Trust
  • Avenue House 43-47 Avenue Road
    • London, Avenue House 43-47 Avenue Road, United Kingdom, W38NJ
      • West London Mental Health Trust. East Recovery Team
  • Crowell House, Cromwell Road
    • Manchester, Crowell House, Cromwell Road, United Kingdom
      • Greater Manchester West Mental Health NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Diagnosis of schizophrenia as defined by DSM-IV-R (Diagnostic and Statistical Manual) as determined by the M.I.N.I.plus
2. Age 18 or older.
3. 3. The first psychosis occurred at least 6 months and no more than 7 years ago.*
4. If patients are using an antipsychotic drug, a medication switch is currently under consideration.

5. Capable of providing written informed consent

   • Time of first psychosis is defined as the first contact with a health care professional in relation to psychotic symptoms.

Exclusion Criteria:

1. Intolerance / hypersensitivity to both* of the drugs (including active substances, metabolites and excipients) in this study including oral paliperidone and aripiprazole and/or hypersensitivity to risperidone.
2. Pregnancy or lactation.
3. Patients who are currently using clozapine.
4. Patients who do not fully comprehend the purpose or are not competent to make a rational decision whether or not to participate.
5. Patients with a documented history of intolerance to both* of the study medications and/or a documented history of non-response to a treatment with both* study drugs of at least 6 weeks within the registered dose range.7. Patients who have been treated with an investigational drug within 30 days prior to screening.

8. Simultaneous participation in another intervention study (neither medication or psychosocial intervention).

* If intolerance/hypersensitivity or non-response in the past to one of the compounds is documented, the patient can still participate; however, randomization will take place by blocking that specific compound. That is, the patient will be randomized on either the oral or the depot arm of the other compound. This procedure of blocking one compound is also accepted for patients who have experienced too many side effects to one of the compounds in the past, as documented in the patient's medical record. The decision to block that specific compound for randomization in these cases is up to the discretion of the treating physician who will carefully balance this decision and clearly document it in the medical record.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: aripiprazole oral; the recommended starting dose for aripiprazole is 10 or 15 mg/day with a maintenance dose of 15 mg/day administered on a once-a-day schedule without regard to meals.Aripiprazole is effective in a dose range of 10 to 30 mg/day.	Drug: Aripiprazole; Administration in once-a-day schedule without regard to meals.; Other Names: Abilify
Active Comparator: Aripiprazole depot; The recommended starting and maintenance dose of aripiprazole depot is 400 mg. Titration of the dose of this medicinal product is not required. It should be administered once monthly as a single injection (no sooner than 26 days after the previous injection). After the first injection, treatment with 10 mg to 20 mg oral aripiprazole should be continued for 14 consecutive days to maintain therapeutic aripiprazole concentrations during initiation of therapy. If there are adverse reactions with the 400 mg dosage, reduction of the dose to 300 mg once monthly should be considered.	Drug: Aripiprazole depot; Abilify Maintena is an intramuscular (IM) depot formulation of oral aripiprazole. It provides the efficacy and safety profile of oral aripiprazole in a once-monthly injection.; Other Names: Abilify maintena
Active Comparator: Paliperidone; The recommended dose of paliperidone for the treatment of schizophrenia is 6 mg once daily, administered in the morning. Initial dose titration is not required. Some patients may benefit from lower or higher doses within the recommended range of 3 mg to 12 mg once daily. Dosage adjustment, if indicated, should occur only after clinical reassessment. When dose increases are indicated, increments of 3 mg/day are recommended and generally should occur at intervals of more than 5 days.	Drug: Paliperidone; Administration once a day orally standardised in relation to food intake.; Other Names: Invega
Active Comparator: Paliperidone palmitate; The first two administrations of paliperidone palmitate (150 mg at visit 3 and 100 mg one week later) need to be administered deep into the deltoid muscle in order to attain therapeutic concentrations rapidly. No oral supplementation with paliperidone is needed. Following the second dose, monthly maintenance doses can be administered in either the deltoid or gluteal muscle. The recommended monthly maintenance dose is 75 mg, although some patients may benefit from lower doses within the recommended range of 25 to 150 mg based on individual patient tolerability and/or efficacy.	Drug: Paliperidone palmitate; In selected patients with schizophrenia and previous responsiveness to oral paliperidone or risperidone, Xeplion may be used without prior stabilization with oral treatment if psychotic symptoms are mild to moderate and a long-acting injectable is needed.; Other Names: Xeplion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All cause discontinuation rates	Compare all cause discontinuation rates in patients with schizophrenia randomized to oral antipsychotic medications (i.e., aripiprazole or paliperidone) versus depot antipsychotic medications (i.e., paliperidone palmitate or aripiprazole depot). Discontinuation consist of (multiple options are possible): the allocated treatment is stopped or used at doses outside the allowed range.; medication is switched or augmented with another antipsychotic after visit 4 for more than 1 month continuously or for more than 3 months cumulative over the 18 months of the trial.; a patient misses a monthly visit and does not show up after reminding him; patient withdraws consent for the study.; clinician decision to withdraw the patient.	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subjective Wellbeing under Neuroleptics	Change from baseline in Subjective Wellbeing under Neuroleptics	18 months
EuroQoL quality of life scale	Change from baseline in EuroQoL quality of life scale	18 months
Side effects assessment	Change from baseline in SMARTS (Systematic Monitoring of Adverse events Related to TreatmentS) and the Abnormal and Involuntary Movement Scale.	18 months
Assessment of cognitive functioning	Compare the combined oral medication group with the combined depot treatment arms regarding cognitive functioning	18 months
Assessment of Positive and Negative Symptom Scale	Compare the combined oral medication group with the combined depot treatment arms regarding changes in different dimensions of psychopathology of schizophrenia	18 months
Assessment of Personal and Social Performance Scale	Compare the combined oral medication group with the combined depot	18 months
Change from baseline of Personal and Social Performance Scale	Compare the combined oral medication group with the combined depot	Baseline until 18 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison between depot arms and the oral treatment arms on the one side	The comparisons will also be made between the depot arms and the oral treatment arms on the one side and the patients who are followed up naturalistically.Depot arms are compared regarding augmentation with oral antipsychotics after visit 4.	18 months
Treatment success regarding outcomes in patients who have not given consent for the main trial	compare treatment success regarding the outcomes mentioned above to those achieved in a group of patients who did not agree to participate in the trial but could be followed up with the CGI.	up to 18 months
Compare side effects between combined oral medication groups & combined depot treatment	Compare side effects and general wellbeing under antipsychotic medication between the combined oral medication groups with the combined depot treatment arms.	18 months
Immune parameters	Associations between immune parameters on the one hand, and primary as well as secondary outcome measures on the other.	18 months

Collaborators and Investigators

• Sponsor: UMC Utrecht
• Investigators: Principal Investigator: Rene S Kahn, professor, UMC Utrecht; Principal Investigator: Wolfgang Fleischhacker, professor, Department of Biological Psychiatry, Innsbruck University Clinics; Principal Investigator: Michael Davidson, professor, Department of Psychiatry, Sackler Faculty of Medicine, Tel Aviv University, Israel

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2015
• Primary Completion (Actual): August 26, 2020
• Study Completion (Actual): August 26, 2020

Study Registration Dates

• First Submitted: May 21, 2014
• First Submitted That Met QC Criteria: May 21, 2014
• First Posted (Estimate): May 26, 2014

Study Record Updates

• Last Update Posted (Actual): September 1, 2020
• Last Update Submitted That Met QC Criteria: August 31, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: depot, oral, antipsychotics, paliperidone, aripiprazole
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Antidepressive Agents; Dopamine Agonists; Dopamine Agents; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Dopamine D2 Receptor Antagonists; Dopamine Antagonists; Aripiprazole; Paliperidone Palmitate
• Other Study ID Numbers: ABR49490

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No