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Clinical Trial Results:
Treating Anxiety to PrevEnt Relapse in Psychosis (TAPERS): a feasibility trial

Summary
EudraCT number	2019-001408-39
Trial protocol	GB
Global end of trial date	31 Jul 2022

Results information
Results version number	v1(current)
This version publication date	25 Jan 2024
First version publication date	25 Jan 2024
Other versions
Summary report(s)	TAPERS HRA Report

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

SPON1720-19

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Other trial identifiers

Eudract: 2019-001408-39

Sponsor organisation name

Cardiff University

Sponsor organisation address

30-36 Newport Road, Cardiff, United Kingdom, CF24 0DE

Public contact

Dr Eleri Owen-Jones, Cardiff University, owen-jonesce@cardiff.ac.uk

Scientific contact

Professor Jeremy Hall, Cardiff University, HallJ10@cardiff.ac.uk

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

31 Jul 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

31 Jul 2022

Global end of trial reached?

Yes

Global end of trial date

31 Jul 2022

Was the trial ended prematurely?

Main objective of the trial

To establish the feasibility (including recruitment, retention, adherence, acceptability) of the addition of antidepressant medication to antipsychotic treatment in patients with early psychotic illness to prevent relapse.

Protection of trial subjects

Participants were adults who had received a diagnosis of psychosis within the last seven years and were being treated by the NHS. All trial participants would continue with their usual care (typically antipsychotic medication). Participants were followed-up either face-to-face or by telephone (T) at weeks-1(T), -4, -8, -12, -16, -18, -20, -22(T) and -24. Vital signs (heart rate, blood pressure, respiratory rate, body temperature) were assessed at Baseline, and weeks-4, -18 and -20.

Background therapy

The question of whether the addition of antidepressant medication to treatment as usual (typically antipsychotic medication) is an effective secondary prevention measure was the focus of this trial.

Evidence for comparator

N/A, comparator used in this trial was placebo.

Actual start date of recruitment

14 Jun 2021

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 4

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Recruitment was supported by research nurses already employed by 2 Health Boards (C&V and AB) and initially focused on specialist first episode psychosis teams and early intervention services. Trial staff worked with clinical teams to help identify eligible patients from early intervention and community mental health teams within the last 7 years.

Screening details

We maintained detailed screening logs of patients’ eligibility and success in recruitment to inform our trial objectives.

Number of subjects started

285 ^[1]

Intermediate milestone: Number of subjects

Excluded: 219

Number of subjects completed

Reason: Number of subjects

Eligibility not confirmed: 19

Reason: Number of subjects

Eligible but not recruited: 43

Reason: Number of subjects

Excluded at Screening: 219

Notes
[1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: The pre-assignment period involved eligibility assessments before participants were enrolled and randomised into the trial. Therefore, more participants entered the pre-assignment period (n = 285) than were enrolled i.e., worldwide number enrolled - n = 4.

Period 1 title

Baseline visit

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst, Carer, Assessor

Blinding implementation details

Participants, clinical staff, Chief Investigator, Principal Investigator, research nurses and the trial statisticians remained blinded to treatment allocation throughout the trial. The trial medication allocation was known to key members of the trial team (the study lead, senior trial manager, trial manager and data manager) during the trial.

Are arms mutually exclusive

Yes

Sertraline

Arm description

50mg/day of IMP (sertraline) for 18 weeks, then 50mg every other day for 4 weeks (weeks 19 to 22), then no IMP in weeks 23 and 24.

Arm type

Experimental

Investigational medicinal product name

Sertraline

Investigational medicinal product code

Active

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Treatment was either a) 50mg/day of IMP (sertraline) for 18 weeks, then 50mg every other day for 4 weeks (weeks 19 to 22), then no IMP in weeks 23 and 24 (a tapered design), or b) placebo to match for an equivalent period.

Placebo

Arm description

Placebo to match

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

N/A

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo to match Active for an equivalent period (daily dose from randomisation till end of week 22).

Number of subjects in period 1	Sertraline	Placebo
Started	2	2
Completed	2	2

Period 2 title

Overall Trial

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst, Carer, Assessor

Blinding implementation details

Are arms mutually exclusive

Yes

Sertraline

Arm description

50mg/day of IMP (sertraline) for 18 weeks, then 50mg every other day for 4 weeks (weeks 19 to 22), then no IMP in weeks 23 and 24.

Arm type

Experimental

Investigational medicinal product name

Sertraline

Investigational medicinal product code

Active

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo

Arm description

Placebo to match

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

N/A

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo to match Active for an equivalent period (daily dose from randomisation till end of week 22).

Number of subjects in period 2	Sertraline	Placebo
Started	2	2
Week 4 follow-up	1	2
Week 8 follow-up	1	2
Week 12 follow-up	1	2
Week 16 follow-up	1	2
Week 18 follow-up	1	2
Week 20 follow-up	1	2
Week 22 follow-up	1	2
Week 24 follow-up	0	1
Completed	0	1
Not completed	2	1
Consent withdrawn by subject	1	-
Physician decision	1	1

Baseline characteristics

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Reporting group title

Baseline visit

Reporting group description

Reporting group values	Baseline visit	Total
Number of subjects	4	4
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	4	4
From 65-84 years	0	0
85 years and over	0	0
Gender categorical
Units: Subjects
Female	0	0
Male	4	4
Concomitant medication
All four patients at baseline were using concomitant medication at baseline. One participant in the sertraline arm was using Clozapine and Amisulpride for Schizophrenia, Bisoprolole for hypertension, Itraconozole for fungal infection. Three participants were using Olanzapine, two participants (one in the sertraline arm and one in the placebo arm) were using it for psychosis, whilst the third participant (in the placebo arm) was using Olanzapine, but the disease was missing.
Units: Subjects
No concomitant medication	0	0
Taking concomitant medication	4	4
Heart rate
The vital signs measured were Heart rate (BPM), Systolic blood pressure (mmHg), Diastolic blood pressure (mmHg), Respiratory rate (Breaths/min) and Body temperature ( ̊C). These were measured to monitor for serotonin syndrome or neuroleptic malignant syndrome and were also measured at weeks 4, 18 and 20. Since no measurement was made at the primary endpoint (week 24), the "primary outcome" value represents the measurement made at the week 20 timepoint.
Units: bpm
arithmetic mean (standard deviation)	78.3 ( 14.8 )	-
Systolic blood pressure
The vital signs measured were Heart rate (BPM), Systolic blood pressure (mmHg), Diastolic blood pressure (mmHg), Respiratory rate (Breaths/min) and Body temperature ( ̊C). These were measured to monitor for serotonin syndrome or neuroleptic malignant syndrome and were also measured at weeks 4, 18 and 20. Since no measurement was made at the primary endpoint (week 24), the "primary outcome" value represents the measurement made at the week 20 timepoint.
Units: mmHg
arithmetic mean (standard deviation)	128.8 ( 9.3 )	-
Diastolic blood pressure
The vital signs measured were Heart rate (BPM), Systolic blood pressure (mmHg), Diastolic blood pressure (mmHg), Respiratory rate (Breaths/min) and Body temperature ( ̊C). These were measured to monitor for serotonin syndrome or neuroleptic malignant syndrome and were also measured at weeks 4, 18 and 20. Since no measurement was made at the primary endpoint (week 24), the "primary outcome" value represents the measurement made at the week 20 timepoint.
Units: mmHg
arithmetic mean (standard deviation)	72.8 ( 5.4 )	-
Respiratory rate
The vital signs measured were Heart rate (BPM), Systolic blood pressure (mmHg), Diastolic blood pressure (mmHg), Respiratory rate (Breaths/min) and Body temperature ( ̊C). These were measured to monitor for serotonin syndrome or neuroleptic malignant syndrome and were also measured at weeks 4, 18 and 20. Since no measurement was made at the primary endpoint (week 24), the "primary outcome" value represents the measurement made at the week 20 timepoint.
Units: Breaths/min
arithmetic mean (standard deviation)	12.5 ( 1.0 )	-
Body temperature
The vital signs measured were Heart rate (BPM), Systolic blood pressure (mmHg), Diastolic blood pressure (mmHg), Respiratory rate (Breaths/min) and Body temperature ( ̊C). These were measured to monitor for serotonin syndrome or neuroleptic malignant syndrome and were also measured at weeks 4, 18 and 20. Since no measurement was made at the primary endpoint (week 24), the "primary outcome" value represents the measurement made at the week 20 timepoint.
Units: ̊C
arithmetic mean (standard deviation)	36.5 ( 0.4 )	-

Subject analysis set title

Demographics

Subject analysis set type

Intention-to-treat

Subject analysis set description

All four patients recruited were single males, three British and one African. Three were living with their parents while one had the living arrangement missing.

Subject analysis set title

Primary Outcome

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis sets values	Demographics	Primary Outcome
Number of subjects	4	4
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	4	4
From 65-84 years	0	0
85 years and over	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	( )	( )
Gender categorical
Units: Subjects
Female
Male
Concomitant medication
All four patients at baseline were using concomitant medication at baseline. One participant in the sertraline arm was using Clozapine and Amisulpride for Schizophrenia, Bisoprolole for hypertension, Itraconozole for fungal infection. Three participants were using Olanzapine, two participants (one in the sertraline arm and one in the placebo arm) were using it for psychosis, whilst the third participant (in the placebo arm) was using Olanzapine, but the disease was missing.
Units: Subjects
No concomitant medication	0	0
Taking concomitant medication	4	4
Heart rate
The vital signs measured were Heart rate (BPM), Systolic blood pressure (mmHg), Diastolic blood pressure (mmHg), Respiratory rate (Breaths/min) and Body temperature ( ̊C). These were measured to monitor for serotonin syndrome or neuroleptic malignant syndrome and were also measured at weeks 4, 18 and 20. Since no measurement was made at the primary endpoint (week 24), the "primary outcome" value represents the measurement made at the week 20 timepoint.
Units: bpm
arithmetic mean (standard deviation)	78.3 ( 14.8 )	78.7 ( 15 )
Systolic blood pressure
The vital signs measured were Heart rate (BPM), Systolic blood pressure (mmHg), Diastolic blood pressure (mmHg), Respiratory rate (Breaths/min) and Body temperature ( ̊C). These were measured to monitor for serotonin syndrome or neuroleptic malignant syndrome and were also measured at weeks 4, 18 and 20. Since no measurement was made at the primary endpoint (week 24), the "primary outcome" value represents the measurement made at the week 20 timepoint.
Units: mmHg
arithmetic mean (standard deviation)	128.8 ( 9.3 )	133 ( 8.2 )
Diastolic blood pressure
The vital signs measured were Heart rate (BPM), Systolic blood pressure (mmHg), Diastolic blood pressure (mmHg), Respiratory rate (Breaths/min) and Body temperature ( ̊C). These were measured to monitor for serotonin syndrome or neuroleptic malignant syndrome and were also measured at weeks 4, 18 and 20. Since no measurement was made at the primary endpoint (week 24), the "primary outcome" value represents the measurement made at the week 20 timepoint.
Units: mmHg
arithmetic mean (standard deviation)	72.8 ( 5.4 )	71.7 ( 8.5 )
Respiratory rate
The vital signs measured were Heart rate (BPM), Systolic blood pressure (mmHg), Diastolic blood pressure (mmHg), Respiratory rate (Breaths/min) and Body temperature ( ̊C). These were measured to monitor for serotonin syndrome or neuroleptic malignant syndrome and were also measured at weeks 4, 18 and 20. Since no measurement was made at the primary endpoint (week 24), the "primary outcome" value represents the measurement made at the week 20 timepoint.
Units: Breaths/min
arithmetic mean (standard deviation)	12.5 ( 1.0 )	12.7 ( 1.2 )
Body temperature
The vital signs measured were Heart rate (BPM), Systolic blood pressure (mmHg), Diastolic blood pressure (mmHg), Respiratory rate (Breaths/min) and Body temperature ( ̊C). These were measured to monitor for serotonin syndrome or neuroleptic malignant syndrome and were also measured at weeks 4, 18 and 20. Since no measurement was made at the primary endpoint (week 24), the "primary outcome" value represents the measurement made at the week 20 timepoint.
Units: ̊C
arithmetic mean (standard deviation)	36.5 ( 0.4 )	36.5 ( 0.4 )

End points

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Reporting group title

Sertraline

Reporting group description

50mg/day of IMP (sertraline) for 18 weeks, then 50mg every other day for 4 weeks (weeks 19 to 22), then no IMP in weeks 23 and 24.

Reporting group title

Placebo

Reporting group description

Placebo to match

Reporting group title

Sertraline

Reporting group description

50mg/day of IMP (sertraline) for 18 weeks, then 50mg every other day for 4 weeks (weeks 19 to 22), then no IMP in weeks 23 and 24.

Reporting group title

Placebo

Reporting group description

Placebo to match

Subject analysis set title

Demographics

Subject analysis set type

Intention-to-treat

Subject analysis set description

All four patients recruited were single males, three British and one African. Three were living with their parents while one had the living arrangement missing.

Subject analysis set title

Primary Outcome

Subject analysis set type

Intention-to-treat

Subject analysis set description

Primary: Week 24 Follow-up

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End point title

Week 24 Follow-up ^[1]

End point description

Due to the exploratory nature of this feasibility trial no formal statistical hypothesis testing was performed. Primary feasibility outcomes (rates of recruitment, retention, and adherence) overall and per outcome assessment time point (retention and adherence only) are presented as point estimates with 95% exact binomial confidence intervals. These outcomes have been assessed against the ‘traffic light system’ to guide decisions to progress to definitive evaluations.

End point type

Primary

End point timeframe

24 weeks

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: The low numbers recruited into this trial did not allow for statistical analysis of the data from 4 participants. Some of the feasibility outcomes were reported using a traffic light system.

End point values	Primary Outcome
Number of subjects analysed	4
Units: 1
Recruitment into the trial	4
Retention over a 24-week period	3
Adherence to antidepressant medication	1

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events were monitored from Baseline till follow-up at week-24.

Adverse event reporting additional description

Adverse Events (AEs) were planned to be collected throughout the trial. This included events deemed to be classed as ‘hypomania’ or ‘mania’. An overdose was not considered an AE and may not have resulted in any noticeable effect on the participant.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

Sertraline

Reporting group description

Includes participants randomised to receive Sertraline.

Reporting group title

Placebo

Reporting group description

This includes all participants randomised to the placebo group.

Serious adverse events	Sertraline	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Sertraline	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	1 / 2 (50.00%)	1 / 2 (50.00%)
Psychiatric disorders
Mood altered
Additional description: Mood changes for 2 subjects: Week 20: mood changes for both did not meet study withdrawal criteria Week 22: risk to self for 1 of the 2 subject and justified withdrawal After week 22: second subject withdrawn (mental state and mood concerns)
subjects affected / exposed	1 / 2 (50.00%)	1 / 2 (50.00%)
occurrences all number	1	1

More information

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Were there any global substantial amendments to the protocol? Yes

07 May 2020

Addressing comments to the MHRA upon their grounds for non-acceptance. These were as follows: i. Tapering the trial design to include a half dose for 4 weeks and no dose for the last 2 weeks; ii. Amend the unblinding process to enable the delegated trial clinician to unblind; iii. Amend wording re: summary of product characteristics (SmPC) in relation to the reference safety information; iv. Addition of details about qualification of research nurses (footnote to inclusion/exclusion criteria amended); v. Addition of two exclusion criteria (inclusion/exclusion criteria); vi. Addition of pregnancy tests and contraception wording (inclusion/exclusion criteria); vii. Renaming a section from Prohibited medication and interaction with other drugs to General Precautions; viii. Addition of Linezolid as a prohibited therapy; ix. Vital signs added to trial schema, and assessments; x. Item 10 of MADRS questionnaire added to the monthly research nurse follow-ups; xi. End of trial wording amended; xii. Treatment prescribing and dispensing amended to simplify the process.

13 Jan 2021

The Information Sheet for Family Member / Partner interviews (this was not submitted with initial approval paperwork).

10 May 2021

Adjustment to the timing of the secondary outcomes to bring them in line with the end of the main IMP treatment period, including updating the Participant Information Sheet; update to the Reference Safety Information; and the option of posting IMP to trial participants due to the covid-19 pandemic.

26 Jul 2021

Change to first eligibility criteria from three to seven years. Clarification to source data being used.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

High ineligibility (many already on SSRIs); very demanding trial regime (staff resourcing & assessments) maximise inclusion with more pragmatic design in future; Covid-19 negatively impacted the trial; treatment misallocation – no sertraline received

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Clinical trials

Clinical Trial Results:
Treating Anxiety to PrevEnt Relapse in Psychosis (TAPERS): a feasibility trial

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Week 24 Follow-up

Primary: Week 24 Follow-up

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: Treating Anxiety to PrevEnt Relapse in Psychosis (TAPERS): a feasibility trial

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Week 24 Follow-up

Primary: Week 24 Follow-up

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Treating Anxiety to PrevEnt Relapse in Psychosis (TAPERS): a feasibility trial