European Long-acting Antipsychotics in Schizophrenia Trial

Phase 4

Completed

• Conditions: Schizophrenia
• Interventions: Drug: Aripiprazole depot; Drug: Aripiprazole; Drug: Paliperidone palmitate; Drug: Paliperidone

• Registration Number: NCT02146547
• Lead Sponsor: UMC Utrecht

Brief Summary

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.

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 Timeline

• Study First Submitted: 2014-05-21
• Study First Submitted QC: 2014-05-21
• Study First Posted: 2014-05-26
• Study Start: 2015-02
• Status Verified: 2020-08
• Primary Completion: 2020-08-26
• Study Completion: 2020-08-26
• Last Update Submitted: 2020-08-31
• Last Update Posted: 2020-09-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 536

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.

6. 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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Aripiprazole depot	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.
aripiprazole oral	Aripiprazole	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.
Paliperidone palmitate	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.
Paliperidone	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.

Primary Outcome Measures

Name	Time	Method
All cause discontinuation rates	18 months	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.

Secondary Outcome Measures

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

Trial Locations

Locations (49)

ZNA, department of Psychiatry, locatie Stuivenberg; 🇧🇪 Antwerp, Lange Beeldekensstraat 267, Belgium

Sitalul Clinic Judetean Mures; 🇷🇴 Targu Mureş, Romania

University Hospital of Neurology and Psychiatry 'St. Naum' 1; 🇧🇬 Sofia, Louben Roussev Str., Bulgaria

University Medical Center; 🇳🇱 Utrecht, Netherlands

Spitalul Clinic de Neuropsihiatrie Craiova; 🇷🇴 Craiova, Romania

Department of Biological Psychiatry, Innsbruck University Clinics; 🇦🇹 Innsbruck, Anichstrasse 35, Austria

Psychiatrisch Ziekenhuis Duffel; 🇧🇪 Antwerp, Stationsstraat 22C, Belgium

Psychiatrická klinika LF UK; 🇨🇿 Hradec Králové, Fakultní Nemocnice, Czechia

Psychosoziale Dienste; 🇦🇹 Vienna, Modecenterstraße, Austria

Dr. Mohr; 🇨🇿 Praha, Czechia

Dr. Ustohal; 🇨🇿 Brno, Czechia

Center for Neuropsychiatric Research; 🇩🇰 Glostrup, Ndr. Ringvej, Denmark

Klinik und Poliklinik für Psychiatrie und Psychotherapie der Heinrich-Heine-Universität; 🇩🇪 Düsseldorf, Bergische Landstraße 2, Germany

Technische Universität München (TUM; 🇩🇪 München,, Ismaningerstrasse 22, Germany

Department of Psychiatry and Psychotherapy; 🇩🇪 München, Nussbaumstrasse 7, Germany

Klinik für Psychiatrie, Psychotherapie und Psychosomatik der Martin-Luther-Universität; 🇩🇪 Halle, Julius-Kühn-Straße 7, Germany

National and Kapodistrian University of Athens Medical School, Eginition Hospital; 🇬🇷 Athens, Greece

Abravanel Mental Health Center; 🇮🇱 Bat-Yam, Israel

Department of Psychiatry and Psychotherapy, Semmelweis University; 🇭🇺 Budapest, Hungary

Dr. Csekey; 🇭🇺 Balassagyarmat, Hungary

Be'er-Ness Mental Health Center; 🇮🇱 Be'er Ya'aqov, Israel

The Jerusalem Mental Health Center; 🇮🇱 Jerusalem, Israel

Lev-Hasharon Medical Center for Mental Health; 🇮🇱 Pardesiyya, Israel

The Chaim Sheba Medical Center; 🇮🇱 Tel-Hashomer, Israel

Geha Medical Health Center; 🇮🇱 Petach-Tikva, Israel

Department of Psychiatry, University of Naples SUN; 🇮🇹 Naples, Largo Madonna Delle Grazie 1, Italy

Università degli Studi di Torino. Dipartimento di Neuroscienze; 🇮🇹 Turin, Sezione Di Psichiatriavia Cherasco, 11, Italy

Servizio Psichiatrico Universitario di Diagnosi e Cura. Presidio Ospedaliero "San Salvatore" Università degli Studi dell'Aquila.; 🇮🇹 L'Aquila, Italy

Helse Bergen HF Haukeland University Hospital, Division of Psychiatry; 🇳🇴 Bergen, Norway

Stavanger University Hospital; 🇳🇴 Stavanger, Norway

II Klinika Psychiatrii Uniwersytet Medyczny w Lublinie; 🇵🇱 Lublin, Ul. Głuska 1, Poland

St Olavs Hospital avd Østmarka / INM NTNU; 🇳🇴 Trondheim, Norway

Instytut psychiatrii i neurologii; 🇵🇱 Warsaw, Sobieskiego 9, Poland

Spitalul Clinic de Psihiatrie "Prof. Dr. Alexandru Obregia"; 🇷🇴 Bucharest, Romania

Spitalul Clinic Judetean de Urgenta Arad - Clinica de Psihiatrie; 🇷🇴 Arad, Romania

Spitalul Clinic de Psihiatrie "Prof. Dr. Alexandru Obregia; 🇷🇴 Bucharest, Romania

Spitalul de Psihiatrie si pentru Masuri de Siguranta, Sapoca, Buzau; 🇷🇴 Buzău, Romania

Hospital Universitario Marqués de Valdecilla, Servicio de Psiquiatría; 🇪🇸 Santander, Cantabria, Spain

Hospital Clínic de Barcelona. Unidad de Esquizofrenia; 🇪🇸 Barcelona, C/Villarroel, 170. Escalera12, Planta 0, Spain

West London Mental Health Trust. East Recovery Team; 🇬🇧 London, Avenue House 43-47 Avenue Road, United Kingdom

Facultad de Medicina Center; 🇪🇸 Oviedo, Julián Clavería S/n, Spain

Greater Manchester West Mental Health NHS Foundation Trust; 🇬🇧 Manchester, Crowell House, Cromwell Road, United Kingdom

Child and Adolescent Psychiatry Department. Hospital General Universitario Gregorio Marañón. Servicio Madrileño de Salud; 🇪🇸 Madrid, Spain

Northumberland; 🇬🇧 Newcastle, United Kingdom

Tees, Ask and Wearvalleys; 🇬🇧 Middlesbrough, United Kingdom

Imperial College, Centre for Mental Health, Faculty of Medicine,; 🇬🇧 London, United Kingdom

Edmund Ward, St Martins Hospital Littlebourne Road Canterbury; 🇬🇧 Kent, United Kingdom

Oxford Health NHS Foundation Trust; 🇬🇧 Oxford, United Kingdom

Surrey and Borders Partnership NHS Foundation Trust; 🇬🇧 Surrey, United Kingdom