Clinical Trial Results:
European Long-acting Antipsychotics in Schizofrenia Trial EULAST
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Summary
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EudraCT number |
2014-002765-30 |
Trial protocol |
NL AT IT NO BE ES DK HU RO CZ GR |
Global end of trial date |
26 Aug 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
13 Jul 2024
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First version publication date |
13 Jul 2024
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
ABR49490
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02146547 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
EGRIS Foundation
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Sponsor organisation address |
Retstraat 13, Beneden-leeuwen, Netherlands, 6658 DB
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Public contact |
Inge Winter, University Medical Center Utrecht , +31 614674276, i.winter@umcutrecht.nl
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Scientific contact |
Inge Winter, University Medical Center Utrecht , +31 614674276, i.winter@umcutrecht.nl
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
01 Sep 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
26 Aug 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
26 Aug 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To 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) over an 18 month follow-up period.
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Protection of trial subjects |
All medication administered in this study is used in clinical practice for the treatment of schizophrenia and schizophreniform disorder in Europe, some longer than others. During the conduct of the EULAST study, potential adverse events were reviewed by the investigator by asking the patient whether they were suffering from adverse events and by the use of the Systematic Monitoring of Adverse events Related to TreatmentS (SMARTS) questionnaire.
The safety of the study was monitored by an independent Data Safety Monitoring Board (DSMB), at a frequency of at least once a year.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Oct 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Norway: 16
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Country: Number of subjects enrolled |
Poland: 10
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Country: Number of subjects enrolled |
Romania: 37
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Country: Number of subjects enrolled |
Spain: 21
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Country: Number of subjects enrolled |
United Kingdom: 42
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Country: Number of subjects enrolled |
Austria: 32
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Country: Number of subjects enrolled |
Belgium: 57
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Country: Number of subjects enrolled |
Bulgaria: 12
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Country: Number of subjects enrolled |
Netherlands: 2
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Country: Number of subjects enrolled |
Czechia: 4
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Country: Number of subjects enrolled |
Denmark: 1
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Country: Number of subjects enrolled |
Germany: 61
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Country: Number of subjects enrolled |
Greece: 24
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Country: Number of subjects enrolled |
Hungary: 17
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Country: Number of subjects enrolled |
Italy: 59
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Country: Number of subjects enrolled |
Israel: 116
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Worldwide total number of subjects |
511
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EEA total number of subjects |
353
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
509
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From 65 to 84 years |
2
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients were recruited at the participating health-care facilities and through public advertisements. Participants were recruited between February 24, 2015, and December 15, 2018. | |||||||||
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Pre-assignment
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Screening details |
533 patients signed the informed consent and were assessed for eligibility. For 22 patients (4%), data could not be included in the analyses for various reasons. Patients with schizophrenia, aged 18 years or older, having experienced their first psychotic episode six months to seven years before screening, were included. | |||||||||
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Period 1
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Period 1 title |
Assignment and baseline (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Oral antipsychotics | |||||||||
Arm description |
Combined arm of patients who were randomized to aripiprazole oral or paliperidone oral. | |||||||||
Arm type |
Active comparator | |||||||||
Investigational medicinal product name |
Aripiprazole oral
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
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. Enhanced efficacy at doses higher than a daily dose of 15 mg has not been demonstrated although individual patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg.
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Investigational medicinal product name |
Paliperidone oral
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Investigational medicinal product code |
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Other name |
Invega
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
The recommended dose of INVEGA for the treatment of schizophrenia in adults 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.
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Arm title
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Long Acting Injections | |||||||||
Arm description |
Combined arm of patients who were randomized to aripiprazole depot or paliperidone depot. | |||||||||
Arm type |
Active comparator | |||||||||
Investigational medicinal product name |
Aripiprazole depot
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Investigational medicinal product code |
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Other name |
Abilify Maintena
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Pharmaceutical forms |
Injection
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Routes of administration |
Injection
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Dosage and administration details |
Patients who have never taken aripiprazole, tolerability with oral aripiprazole must occur prior to initiating treatment with Abilify Maintena. On the day of initiation, administer one injection of 400 mg Abilify Maintena and continue treatment with 10 mg to 20 mg oral aripiprazole per day for 14 consecutive days to maintain therapeutic aripiprazole concentrations during initiation of therapy.
After the injection start, the recommended maintenance dose of Abilify Maintena is 400 mg. Abilify Maintena should be administered once monthly as a single injection (no sooner than 26 days after the previous injection).
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Investigational medicinal product name |
Paliperidone depot
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Investigational medicinal product code |
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Other name |
Xeplion
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Pharmaceutical forms |
Injection
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Routes of administration |
Injection
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Dosage and administration details |
Recommended initiation of Xeplion is with a dose of 150 mg on treatment day 1 and 100 mg one week later (day 8), both administered in the deltoid muscle in order to attain therapeutic concentrations rapidly. The third dose should be administered one month after the second initiation dose. The recommended monthly maintenance dose is 75 mg; some patients may benefit from lower or higher doses within the recommended range of 25 to 150 mg based on individual patient tolerability and/or efficacy.
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Baseline characteristics reporting groups
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Reporting group title |
Oral antipsychotics
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Reporting group description |
Combined arm of patients who were randomized to aripiprazole oral or paliperidone oral. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Long Acting Injections
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Reporting group description |
Combined arm of patients who were randomized to aripiprazole depot or paliperidone depot. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Intent to treat sample
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Of the patients who signed IC and passed the screening assessments, only those patients are included in the main analyses who have received the study medication.
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End points reporting groups
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Reporting group title |
Oral antipsychotics
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Reporting group description |
Combined arm of patients who were randomized to aripiprazole oral or paliperidone oral. | ||
Reporting group title |
Long Acting Injections
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Reporting group description |
Combined arm of patients who were randomized to aripiprazole depot or paliperidone depot. | ||
Subject analysis set title |
Intent to treat sample
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Of the patients who signed IC and passed the screening assessments, only those patients are included in the main analyses who have received the study medication.
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End point title |
Oral Antipsychotics: 19 months follow-up | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Patients could meet ACD criteria all throughout the study.
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Statistical analysis title |
Primary and secondary analyses | ||||||||||||
Statistical analysis description |
Statistical analyses of primary and secondary outcomes were conducted with SPSS and R. Kaplan-Meier curves were generated
using the Survminer (version 0.4.9) R package. Analysis of the primary outcome was performed by ITT using survival analysis, including all randomly allocated participants. For patients who met all-cause discontinuation criteria, the time from randomisation to
all-cause discontinuation was used as survival time.
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Comparison groups |
Long Acting Injections v Oral antipsychotics v Intent to treat sample
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Number of subjects included in analysis |
1022
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.05 | ||||||||||||
Method |
Kaplan-Meier survival analyses | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
1.16
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Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
0.94 | ||||||||||||
upper limit |
1.43 | ||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Starting at informed consent, ending 30 days after last study visit.
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Assessment type |
Non-systematic | ||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||
Dictionary version |
15.0
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Reporting groups
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Reporting group title |
Serious adverse events
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Reporting group description |
- | ||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 3% | |||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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12 Sep 2014 |
• changes in Principal Investigators and addition of sites
• changes in allowed visit windows
• alignment of depot administration with Summary of Product Characteristics
• change in cognitive battery (no assessments were conducted at this time)
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19 Dec 2014 |
• changes in Principal Investigators and addition of sites
• a link is created with the EULAST genetics protocol, indicating the purpose of the genetics analyses and the need for a separate informed consent
• further specification of timing of assessments
• further specification of the timing of discontinuing pre-study antipsychotics
• ‘Time of first psychosis’ (inclusion criteria) is further specified
• ‘Lost to follow-up’ is replaced by ‘drop out’ in the statistical analyses section as well as the section on the replacement of withdrawn subjects
• further specification of the following ACD criterium: medication is switched or augmented with another antipsychotic after visit 4 for more than 1 month (defined as 30 days) continuously OR for more than 3 months (defined as 90 days) cumulative.
• a link is created with the EULAST naturalistic follow-up (NFU) protocol, indicating the purpose of the NFU protocol, and the SAE reporting procedure for the NFU is described
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13 May 2015 |
• changes in Principal Investigators and addition of sites
• Introduction and Rationale is partly re-written to include recent publications
• further specification of the visit windows
• guidelines regarding reminding subjects of study visits were added
• addition of exclusion criteria concerning parallel participating in another trial
• Adjusted of the following exclusion criteria: Patients with a documented history of non-response and/or intolerance to any of the study medications and/or a documented history of non-response to a treatment with one of the study drugs of at least 6 weeks within the registered dose range. Successful past treatment with one of the study drugs is not an exclusion criterion. Based on the SPCs, it is advised not to include patients with severe hepatic illness.
• total amount of ml blood to be drawn is reduced
• further specification of SAE reporting requirements for the NFU protocol
• addition of an SAE reporting requirement for up to 30 days after study medication discontinuation
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11 Jul 2016 |
• changes in Principal Investigators and addition of sites
• lower threshold for the duration of illness is reduced from 1 year to 6 months
• inclusion criterium is changed from excluding patients with an intolerance to one of the study drugs to excluding only patients with intolerance to both of the study drugs; if a patient has shown intolerance to one of the study drugs, the patient can still be randomized between the oral and depot arm of the other study drug
• augmentation with an antipsychotic qualifies as ACD after a certain amount of days: this now includes the oral version of the study medication
• specific Serious Adverse Events are excluded from immediate reporting and instead will be included in the annual line listing
• extension of recruitment period
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27 Nov 2018 |
• changes in Trial Coordinator Central Team and Study Management group, and in Country Coordinators
• change in statistical power from 0.9 to 0.8 and a subsequent reduction in the sample size from 150 randomized patients per treatment arms to 130.
• extension of recruitment period
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/36716759 |
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