European Long-acting Antipsychotics in Schizophrenia Trial

Study Overview
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Brief Summary
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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
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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.

Official Title
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European Long-acting Antipsychotics in Schizophrenia Trial

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: Aripiprazole
* Drug: Aripiprazole depot
* Drug: Paliperidone
* Drug: Paliperidone palmitate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of schizophrenia as defined by DSM-IV-R (Diagnostic and Statistical Manual) as determined by the M.I.N.I.plus Age 18 or older. 3. The first psychosis occurred at least 6 months and no more than 7 years ago.* If patients are using an antipsychotic drug, a medication switch is currently under consideration. 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: 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. Pregnancy or lactation. Patients who are currently using clozapine. Patients who do not fully comprehend the purpose or are not competent to make a rational decision whether or not to participate. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: aripiprazole oral<br>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<br>* Administration in once-a-day schedule without regard to meals.<br>* Other names: Abilify;|
| Active Comparator: Aripiprazole depot<br>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<br>* 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.<br>* Other names: Abilify maintena;|
| Active Comparator: Paliperidone<br>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<br>* Administration once a day orally standardised in relation to food intake.<br>* Other names: Invega;|
| Active Comparator: Paliperidone palmitate<br>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<br>* 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.<br>* Other names: Xeplion;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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depot, oral, antipsychotics, paliperidone, aripiprazole