Clinical Trial Results:
A Phase IV double blind multi-site, individually randomised parallel group controlled trial investigating the use of citalopram, sertraline, fluoxetine and mirtazapine in preventing relapse in patients in primary care who are taking long term maintenance antidepressants but now feel well enough to consider stopping medication.
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Summary
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EudraCT number |
2015-004210-26 |
Trial protocol |
GB |
Global end of trial date |
08 Mar 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
14 May 2022
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First version publication date |
14 May 2022
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Other versions |
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Summary report(s) |
ANTLER full report ANTLER supplementary |
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 |
14/0647
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Additional study identifiers
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ISRCTN number |
ISRCTN15969819 | ||
US NCT number |
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WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
University College London
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Sponsor organisation address |
Tottenham Court Road, London, United Kingdom,
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Public contact |
Anne Marie Downey, PRIMENT Clinical Trials Unit, UCL , sponsor.priment@ucl.ac.uk
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Scientific contact |
Anne Marie Downey, PRIMENT Clinical Trials Unit, UCL , sponsor.priment@ucl.ac.uk
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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? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
08 Mar 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 estimate the effectiveness and cost-effectiveness of antidepressant medication in preventing relapse in UK primary care in people who have had two or more episodes of depression (including the current episode) have taken antidepressants for at least 9 months and are now well enough to consider stopping the antidepressant.
We will carry out an individually randomised controlled trial that will compare (1) continuing with antidepressant medication (citalopram 20mg, sertraline 100mg, fluoxetine 20mg or mirtazapine 30mg) with (2) replacement of the medication with a placebo after a tapering period. We will follow up participants for 12 months.
Primary outcome will be time to depressive relapse.
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Protection of trial subjects |
1. Risk of relapse
This risk was explained to participants and their GP. If the participant was concerned about the possibility of relapse they were told to immediately seek medical opinion from their GP or the PI. The PI could withdraw the participant from study medication and refer back to their GP for further treatment.
2. Risk of withdrawal symptoms
To reduce the risk, there was a 4 week period after randomisation when IMP dose (citalopram, sertraline and mirtazapine) was halved, then another 4 weeks when the dose was quartered before the placebo was introduced. Patients who were taking fluoxetine received 20 mg of IMP and placebo on alternate days in the first month. Since fluoxetine has a long half-life patients received placebo only from the second month. We also monitored withdrawal symptoms.
3. Risk of self-harm
People with depression have an increased risk of self-harm and suicide. We had a Suicidal Ideation SOP and staff were trained to follow this procedure.
4. Potential risk associated with other medical conditions
It was possible that some potential participants with other medical conditions would have been taking antidepressants even though they were subject to a caution. As the person had been taking antidepressants for at least 9 months the decision to prescribe antidepressants had already been taken by their GP. We did not exclude those people. However, the PI made the final decision about their enrolment person into the trial.
5. Risk of QT prolongation with citalopram
Citalopram can prolong the QT interval in higher doses. In ANTLER only people were taking 20mg citalopram so the risk was low. PI considered if there were any other medications that might also prolong the QT interval and took a decision whether participant should be randomised.
6. Risk associated with IMP distribution
IMP was dispensed from a central pharmacy via Royal Mail by recorded delivery to participant home addresses or GP practices.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Jan 2017
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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 |
United Kingdom: 478
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Worldwide total number of subjects |
478
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EEA total number of subjects |
0
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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) |
349
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From 65 to 84 years |
129
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85 years and over |
0
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Recruitment
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Recruitment details |
We recruited patients from 150 general practices across four research sites in England (Bristol, London, Southampton, and York). Recruitment was done through database searches of electronic health records, after which potentially eligible patients were sent an invitation letter, or via direct referral at primary care visits. | ||||||||||||||||||
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Pre-assignment
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Screening details |
Eligible participants had at least two episodes of depression; were aged 18–74 years; were taking antidepressants for 9 months or more and were on citalopram 20mg, sertraline 100mg, fluoxetine 20mg or mirtazapine 30 mg; and were well enough to consider stopping their medication. Participants were excluded if they met ICD-10 criteria for depression | ||||||||||||||||||
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Period 1
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Period 1 title |
Overall Trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||
Roles blinded |
Subject, Investigator | ||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Discontinuation arm | ||||||||||||||||||
Arm description |
Placebo arm: 1 month of the current medication at half the dose, taken as 1 oral capsule per day of citalopram 10mg, sertraline 50mgor mirtazapine 15mg. This will be followed by one month of the medication at a quarter of the dose taken as 1 oral capsule per day alternating between a half dose capsule (citalopram 10mg, sertraline 50mg or mirtazapine 15mg) and a placebo capsule on odd and even days of the month. From the third month on participants will be taking placebo 1 capsule per day for the remainder of the study. Placebo arm for fluoxetine: 1 month of the current medication at half the dose, taken as 1 oral capsule a day alternating between fluoxetine 20mg and a placebo capsule on odd and even days of the month. From the second month on participants will be taking placebo 1 capsule per day for the remainder of the study. | ||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||
Investigational medicinal product name |
Citalopram
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Citalopram 20mg,
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Arm title
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Maintenance arm | ||||||||||||||||||
Arm description |
The active medication arm will take 1 capsule per day orally (citalopram 20mg, sertraline 100mg, fluoxetine 20mg or mirtazapine 30mg) for 12 months. | ||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||
Investigational medicinal product name |
Citalopram
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Citalopram 20mg,
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Investigational medicinal product name |
Sertraline
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Sertraline 100mg
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Investigational medicinal product name |
Fluoxetine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Fluoxetine 20mg
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Investigational medicinal product name |
Mirtazapine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Mirtazapine 30mg
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Baseline characteristics reporting groups
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Reporting group title |
Overall Trial
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Reporting group description |
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End points reporting groups
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Reporting group title |
Discontinuation arm
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Reporting group description |
Placebo arm: 1 month of the current medication at half the dose, taken as 1 oral capsule per day of citalopram 10mg, sertraline 50mgor mirtazapine 15mg. This will be followed by one month of the medication at a quarter of the dose taken as 1 oral capsule per day alternating between a half dose capsule (citalopram 10mg, sertraline 50mg or mirtazapine 15mg) and a placebo capsule on odd and even days of the month. From the third month on participants will be taking placebo 1 capsule per day for the remainder of the study. Placebo arm for fluoxetine: 1 month of the current medication at half the dose, taken as 1 oral capsule a day alternating between fluoxetine 20mg and a placebo capsule on odd and even days of the month. From the second month on participants will be taking placebo 1 capsule per day for the remainder of the study. | ||
Reporting group title |
Maintenance arm
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Reporting group description |
The active medication arm will take 1 capsule per day orally (citalopram 20mg, sertraline 100mg, fluoxetine 20mg or mirtazapine 30mg) for 12 months. | ||
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End point title |
Primary outcome [1] | |||||||||
End point description |
The primary outcome was the first relapse of depression during the 52-week trial period, as evaluated in a time-to event analysis.
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End point type |
Primary
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End point timeframe |
Primary outcome was assessed at 12 weeks follow-up
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Further details on statistical analyses included in the attached report. |
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| No statistical analyses for this end point | ||||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
Since this was a phase 4 trial of licensed medications within their licensed indications, we recorded adverse events of special interest only, using the Toronto and DESS scales at each follow-up.
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Adverse event reporting additional description |
Serious adverse events were recorded by investigators using a recording-and-reporting form created by the trial sponsor. The principal investigator at each site rated each event according to seriousness, causal relationship to a trial medication, severity, and outcome.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
3
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Reporting groups
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Reporting group title |
Overall
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Reporting group description |
As the data is blinded, the figures provided is a sum of the events reported in both the maintenance and discontinuation arm. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: As this trial is a phase IV trial of licensed medications used within its licensed indication with a well-established safety profile, AEs were not recorded (apart from those AEs of special interest included in the follow up assessments). |
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| Frequency threshold for reporting non-serious adverse events: 0.05% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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19 Dec 2016 |
1. Amendment includes an additional follow-up questionnaire 6 weeks after randomisation in order to capture information regarding withdrawal symptoms. The original follow-up was at 12 weeks but after discussion with PPI and others we decided it was important to include a further assessment towards the end of the tapering period to assess symptoms of depression, anxiety, physical symptoms and withdrawal symptoms. This questionnaire will be completed by participants either by post or over the telephone and will be accompanied by the cover letter.
2. The schedule of dispensing medication for participants was changed in order to reduce the cost and to make it more convenient for the participants. The scheduling has changed from dispensing one month’s supply at months 0 and 2 and then bimonthly thereafter; to dispensing medication bimonthly for the duration of the 12 month follow-up period. The new schedule will be familiar to the trial participants because it is in lines with their GP repeat prescription system. The exclusion criteria for the PHQ9 score is a score of above 12. In some places in the protocol this was stated as ‘above 10’ or ‘12 and above’ (pages 19 and 20), therefore the protocol has been updated to ensure the exclusion criteria for the PHQ9 score is consistent throughout.
3. The BDI-II is mentioned in the list of self-administered questionnaires on page 52. This is an error as we are not using the BDI-II in any of the assessments in the trial, so this has been removed from the protocol.
4. The protocol has been updated to include the 6-week follow-up wherever the schedule of follow-ups has been stated in the protocol, reflect the change in the schedule of dispensing study medication to participants, updated to explain the correct treatment procedures for the IMP. There will be no ‘quarter dose’ tablet for citalopram, sertraline and mirtazapine and no ‘half dose’ tablet for fluoxetine. |
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24 Apr 2017 |
Changes to the IMPD had to be made as it was necessary to change the supply of fluoxetine. |
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31 Aug 2017 |
The PHQ9 is a screening tool rather than a diagnostic measure so such discrepancies are to be expected. On reflection, we were using the PHQ9 score to improve the efficiency of the study and to prevent those likely to be excluded because they met the ICD10 depression criterion from having unnecessary further assessments. The important criterion is to ensure that those entering the study are no longer currently depressed according to the ICD10 criteria. |
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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 | |||
