A Randomised Optimisation Study of a Brief Digital Imagery-competing Task Intervention to Support NHS ICU Staff Experiencing Intrusive Memories of Traumatic Events From Working in the COVID-19 Pandemic
Phase: NA
Conditions: Intrusive Memories of Traumatic Event(s)
Sponsor: P1vital Products Limited

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CLINICAL STUDY PROTOCOL 
 
PROTOCOL NUMBER: P1V-GAINS-IN01 
 
 
 
STUDY TITLE: A randomised optimisation study of a brief digital 
imagery-competing task intervention to support NHS ICU staff 
experiencing intrusive memories of traumatic events from working 
in the COVID-19 pandemic  
 
 
 
 
 
 
 
 
Final Protocol Date:  
11 MAR 2022 
Sponsor:  
P1vital Products Ltd, Manor House, Howbery Park, 
Wallingford, Oxfordshire, OX10 8BA 
 
 
 
 
 
 
 
This document is the property of P1vital Products Ltd. 
It may not be used, divulged or published without consent from P1vital Products Ltd. 
[Master Protocol Template, SOP 17, final version 6.0, issued 01 Jun 2020] 

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SIGNATURE PAGE 
 
SPONSOR  
The signature below constitutes approval of this protocol by the signatory and provides the 
necessary assurances that this study will be conducted according to all stipulations of the 
protocol, including all statements regarding regulatory guidelines and confidentiality. 
Signed: 
 
Print name: 
 Jonathan Kingslake 
Job title: 
Chief Executive Officer, P1vital Products Ltd 
Date: 
 
 
INVESTIGATORS 
The signature of the Investigator(s) below constitute approval of this protocol and provides the 
necessary assurances that this study will be conducted according to all stipulations of the 
protocol, including all statements regarding regulatory guidelines and confidentiality. 
CHIEF INVESTIGATOR 
Signed: 
 
Print name: 
Dr Lalitha Iyadurai 
Date: 
 
 
LOCAL INVESTIGATORS 
 
Signed: 
 
Print name: 
 
Date: 
 
 
Signed: 
 
Print name: 
 
Date: 
 
 
 
 
17/03/2022
11/03/2022

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CONTACT LIST 
 
Sponsor:  
P1vital Products Ltd, Manor House, Howbery Park, Wallingford, Oxfordshire, OX10 8BA 
 
Medical Adviser: 
Name: Professor Guy Goodwin 
Address: P1vital Products Limited, Manor House, Howbery Park, Wallingford, Oxfordshire, 
OX10 8BA 
Tel: +44(0)1865 522 030 
Fax: +44(0)1865 597 673 
Email: ggoodwin@p1vital.com 
 
Chief Investigator:  
Name: Dr Lalitha Iyadurai 
Address: P1vital Products Limited, Manor House, Howbery Park, Wallingford, Oxfordshire, 
OX10 8BA 
Tel: +44(0)1865 522 030 
Fax: +44(0)1865 597 673 
Email: liyadurai@p1vital.com 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other key study contacts will be documented on separate contact information pages to be filed 
in the Trial Master File. 
 
 

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Table of Contents 
LIST OF ABBREVIATIONS ................................................................................................................................... 14 
1.0 
INTRODUCTION AND RATIONALE ........................................................................................................ 15 
1.1 
BACKGROUND .............................................................................................................................................15 
1.1.1 
THE MENTAL HEALTH IMPACT OF COVID-19 TRAUMA ON HEALTH CARE STAFF ..........................................................15 
1.2 
RATIONALE .................................................................................................................................................16 
1.2.1 
LIMITATION TO EXISTING INTERVENTIONS AFTER TRAUMA ....................................................................................16 
1.2.2 
A MECHANISM-BASED INTERVENTION TO TARGET INTRUSIVE MEMORIES OF TRAUMA ................................................16 
1.2.3 
CLINICAL TRANSLATION AND APPLICATION.........................................................................................................16 
1.2.4 
AIMS OF THE CURRENT STUDY ........................................................................................................................17 
1.2.5 
MAIN RESEARCH QUESTIONS ..........................................................................................................................17 
1.3 
RISKS AND BENEFITS .....................................................................................................................................18 
1.3.1 
BENEFITS ...................................................................................................................................................18 
1.3.2 
RISKS AND MEASURES TO MINIMISE THEM ........................................................................................................18 
2.0 
STUDY OBJECTIVES .............................................................................................................................. 20 
2.1 
PRIMARY OBJECTIVE .....................................................................................................................................20 
2.2 
SECONDARY OBJECTIVES ...............................................................................................................................20 
2.3 
TERTIARY OBJECTIVES ...................................................................................................................................20 
3.0 
STUDY DESIGN ..................................................................................................................................... 21 
3.1 
OVERVIEW .................................................................................................................................................21 
3.2 
STUDY DESIGN .............................................................................................................................................22 
4.0 
STUDY POPULATION ............................................................................................................................ 25 
4.1 
INCLUSION CRITERIA .....................................................................................................................................25 
4.2 
EXCLUSION CRITERIA ....................................................................................................................................25 
5.0 
STUDY PROCEDURES ............................................................................................................................ 25 
5.1 
RECRUITMENT .............................................................................................................................................25 
5.2 
PRE-SCREENING PROCEDURES & ELIGIBILITY ASSESSMENT ...................................................................................26 
5.3 
INFORMED CONSENT ....................................................................................................................................26 
5.4 
SCREENING VISIT PROCEDURES (RUN-IN-WEEK) ................................................................................................26 
5.4.1 
INTRUSIVE MEMORY DIARY ............................................................................................................................26 
5.4.2 
INTRUSIVE MEMORY RATINGS .........................................................................................................................27 
5.4.3 
RESCREENING .............................................................................................................................................27 
5.5 
RANDOMISATION AND BASELINE PROCEDURES ..................................................................................................27 
5.6 
INTERVENTION PROCEDURES ..........................................................................................................................31 
5.6.1 
DIGITAL INTERVENTION .................................................................................................................................31 
5.6.2 
INTERVENTION ACCESSIBILITY POST TRIAL END DATE ............................................................................................32 
5.7 
IN STUDY PROCEDURES ..................................................................................................................................33 
5.7.1 
WEEK 1 (D1 TO D7) ....................................................................................................................................33 
5.7.2 
WEEK 2&3 (D8 TO D21) .............................................................................................................................33 
5.7.3 
WEEK 4 (D22 TO D28) ................................................................................................................................33 
5.7.4 
WEEK 5,6 & 7 (D29 TO D49) .......................................................................................................................34 
5.7.5 
WEEK 8 (D50 TO D56) ................................................................................................................................34 
5.7.6 
INTERVENTION FEEDBACK ..............................................................................................................................35 
5.7.7 
FEEDBACK QUESTIONNAIRE ............................................................................................................................35 
5.7.8 
OPTIONAL QUALITATIVE INTERVIEW .................................................................................................................35 
5.8 
DEFINITION OF END OF TRIAL .........................................................................................................................35 
5.8.1 
DEBRIEF .....................................................................................................................................................36 
5.9 
COMPLETION AND DISCONTINUATION / WITHDRAWAL .......................................................................................36 
5.10 
STUDY TERMINATION ...................................................................................................................................36 

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6.0 
TRIAL INTERVENTION ........................................................................................................................... 37 
6.1 
DESCRIPTION ..............................................................................................................................................37 
6.2 
INSTRUCTIONS FOR USE ................................................................................................................................37 
6.3 
MANUFACTURER AND DISTRIBUTOR DETAILS ....................................................................................................37 
6.4 
COMPUTER SYSTEM VALIDATION ....................................................................................................................37 
6.5 
SUPPORT AND ASSISTANCE ............................................................................................................................37 
7.0 
RANDOMISATION ................................................................................................................................ 37 
7.1.1 
PROCEDURE TO BE FOLLOWED ........................................................................................................................38 
7.1.2 
BLINDING OF STUDY INTERVENTION.................................................................................................................38 
8.0 
ADVERSE EVENT REPORTING ............................................................................................................... 38 
8.1 
DEFINITIONS ...............................................................................................................................................38 
8.1.1 
ADVERSE EVENT (OR ADVERSE EXPERIENCE) (AE) ...............................................................................................38 
8.1.2 
SERIOUS ADVERSE EVENT (SAE) .....................................................................................................................38 
8.2 
SAFETY REPORTING PROCEDURES ...................................................................................................................39 
8.2.1 
ALL ADVERSE EVENTS ...................................................................................................................................40 
8.2.2 
SERIOUS ADVERSE EVENTS ............................................................................................................................40 
8.2.3 
REPORTING TO RESEARCH ETHICS COMMITTEES AND OTHER BODIES ......................................................................40 
9.0 
PRIMARY AND SECONDARY ENDPOINTS .............................................................................................. 41 
9.1 
PRIMARY ENDPOINT .....................................................................................................................................41 
9.2 
SECONDARY ENDPOINT .................................................................................................................................41 
9.3 
TERTIARY ENDPOINT .....................................................................................................................................41 
10.0 
DATA HANDLING ................................................................................................................................. 42 
10.1 
SOURCE DATA COLLECTION ...........................................................................................................................42 
10.2 
DATA ENTRY / MANAGEMENT .......................................................................................................................43 
10.3 
P1VITAL PRODUCTS DATA SECURITY POLICIES AND PROCEDURES ..........................................................................44 
11.0 
STATISTICAL METHODS AND DATA ANALYSIS ...................................................................................... 44 
11.1 
SAMPLE SIZE ...............................................................................................................................................45 
11.2 
DATA SET FOR ANALYSIS ...............................................................................................................................45 
11.3 
DESCRIPTION OF STATISTICAL METHODS ..........................................................................................................45 
11.3.1 
STUDY DESIGN ANALYSIS ..........................................................................................................................45 
11.3.2 
END OF STUDY ANALYSIS ...........................................................................................................................46 
11.3.3 
ANALYSIS OF PRIMARY OBJECTIVE: .............................................................................................................46 
11.3.4 
ANALYSIS OF SECONDARY OBJECTIVES: ........................................................................................................46 
11.3.5 
ANALYSIS OF TERTIARY OBJECTIVES .............................................................................................................47 
12.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................................................... 48 
13.0 
DATA MONITORING COMMITTEE ........................................................................................................ 48 
14.0 
REGULATORY AND ETHICAL OBLIGATIONS .......................................................................................... 48 
14.1 
REGULATORY FRAMEWORK............................................................................................................................48 
14.2 
APPROVALS ................................................................................................................................................49 
14.3 
STUDY REPORTS ..........................................................................................................................................49 
14.4 
PARTICIPANT CONFIDENTIALITY ......................................................................................................................49 
15.0 
EXPENSES, BENEFITS ............................................................................................................................ 49 
16.0 
FINANCIAL ASPECTS ............................................................................................................................. 49 
17.0 
USE OF INFORMATION AND PUBLICATION .......................................................................................... 49 
18.0 
REFERENCES ......................................................................................................................................... 51 

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APPENDIX 1: TIME AND EVENT SCHEDULE ……………………………………………………………………………………………………..56 
APPENDIX 2: STUDY FLOW CHART .................................................................................................................... 59 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol Synopsis 
Study Title: A randomised optimisation study of a brief digital imagery-competing task 
intervention to support NHS ICU staff experiencing intrusive memories of traumatic events 
from working in the COVID-19 pandemic. 
 
Short Study Title: A brief GAmeplay Intervention for NHS ICU Staff affected by COVID-19 
trauma (GAINS Study) 
Chief Investigator:  Dr Lalitha Iyadurai 
Study Centre(s): Study will be completed remotely in locations of participant’s choosing with 
internet accessibility 
Primary Objective: 
• 
To determine if immediate access to the intervention plus symptom monitoring for 
4 weeks (immediate intervention arm), compared to usual care for 4 weeks 
(delayed intervention arm), can reduce the number of intrusive memories in week 
4 (i.e. between-groups comparison). 
Secondary Objectives: 
• 
To determine if access to the intervention plus symptom monitoring for 4 weeks 
can reduce the number of intrusive memories from run-in week (pre-intervention) 
to week 4 (post intervention; within-group comparison in the immediate 
intervention arm) and from week 4 (pre intervention) to week 8 (post intervention; 
within-group comparison in the delayed intervention arm) 
• 
To determine if immediate access to the intervention plus symptom monitoring for 
4 weeks (immediate intervention arm), compared to usual care for 4 weeks 
(delayed intervention arm), can reduce intrusive memory ratings of distress and 
disruption to concentration/functioning; symptoms of post-traumatic stress, 
anxiety, depression and insomnia; sickness absence; burnout; intention to leave 
job; and improve work engagement, functioning and quality of life at 4 weeks (i.e. 
between-groups comparison). 
• 
To determine if access to the intervention plus symptom monitoring for 4 weeks 
can reduce intrusive memory ratings of distress and disruption to 
concentration/functioning; symptoms of post-traumatic stress, anxiety, depression 
and insomnia; sickness absence; burnout; intention to leave job; and improve work 
engagement, functioning and quality of life from baseline (pre intervention) to 4 
and 8 weeks (post intervention; within-group comparison in the immediate 
intervention arm) and from 4 weeks (pre intervention) to 8 weeks (post 
intervention; within-group comparison in the delayed intervention arm). 
Tertiary Objectives: 
• 
To 
assess 
support 
(from 
managers 
and 
from 
family/friends), 
new 
stressful/traumatic events, new treatments, changes to work 
• 
To obtain feasibility data to improve the intervention implementation. 
• 
To assess the acceptability and perceived value of the intervention from 
participants to optimise the intervention implementation. 
• 
To assess the guidance given by the expert researchers to participants to explain 
how to use the intervention, in order to identify ways to train non-expert 
researchers to give guidance. 

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• 
To assess the guidance given by both expert and non-expert researchers to 
identify ways to digitise such guidance to establish a fully self-guided version of 
the intervention. 
Hypothesis and Brief Rationale: 
The primary hypothesis is that participants in the immediate intervention arm, compared to 
the delayed intervention arm, will have fewer intrusive memories in week 4 (between-groups 
comparison). 
Study Design: 
This optimisation study uses a two-arm, parallel-group, randomised controlled trial. The 
study’s randomisation method allocates participants using a 1:1 overall ratio to one of two 
arms: 
Immediate intervention arm = immediate access to the brief digital imagery-competing task 
intervention plus symptom monitoring for 4 weeks  
Delayed intervention arm = usual care for 4 weeks followed by access to the intervention plus 
symptom monitoring for 4 weeks 
Study Period:  
Each participant will be in the study for a total of up to 17 weeks. There will be virtual visits 
(i.e., audio or video calls between participant and researcher) at screening, on first 
intervention day, for optional qualitative interview, and to provide support with additional 
intervention sessions or assist the participant (e.g., with outcome completion) when 
appropriate. Remote participant assessments (i.e., typically without researcher; online 
questionnaires only) will take place at Baseline, 4 and 8 weeks. 
Total duration of the study from first participant enrolment to last participant completing the 
study is expected to last approximately 9 months, but will depend on the number enrolled. 
Number of Participants: 
The study will enrol up to approximately 150 participants, 75 per study arm.  
Main Entry Criteria: 
Main Inclusion Criteria: 
• 
Aged 18 or above. 
• 
Able to read, write and speak in English. 
• 
Worked in a clinical role in an NHS Intensive Care Unit or equivalent during the COVID-
19 pandemic (e.g. as a member of ICU staff or deployed to work in the ICU during the 
pandemic). 
• 
Experienced at least one traumatic event related to their work during the COVID-19 
pandemic, meeting criterion A of the Diagnostic and Statistical Manual of Mental 
Disorders, 5th edition (DSM-5) criteria for Post-Traumatic Stress Disorder (PTSD): 
“exposure to actual or threatened death, serious injury, or sexual violence” by "directly 
experiencing the traumatic event(s)" or "witnessing, in person, the event(s) as it occurred 
to others”. 
• 
Experience intrusive memories of the traumatic event(s).  
• 
Experienced at least three intrusive memories in the week prior to screening. 
• 
Have internet access. 
• 
Willing and able to provide informed consent and complete study procedures (including 
briefly listing their intrusive memories (without going into any detail), and playing the 
computer game Tetris® with particular mental rotation instructions, and completing an 
online intrusive memory diary). 

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• 
Willing and able to be contacted by the research team during the study period. 
Main Exclusion Criteria: 
Have fewer than three intrusive memories during the run-in week. We will not exclude those 
undergoing other treatment for PTSD or its symptoms, so the study is as inclusive as possible 
to meet the challenges ICU staff are facing during the COVID-19 pandemic. 
Study Intervention: 
This brief imagery-competing digital task intervention consists of a brief reminder cue to a 
specific intrusive memory, followed by playing the computer game Tetris® for 20 minutes with 
instructions to use mental rotation during game play. The study team will provide a single 
training session on completing the intervention for the first time (guided session). The 
intervention can then be repeated for other intrusive memories. Participants will learn to 
complete the intervention in the initial guided session with the help of a researcher, and 
thereafter use it self-guided for other existing intrusive memories or if intrusive memories from 
a new trauma arise (with the option for researcher support). The intrusive memory diary 
(based on e.g., Holmes et al., 2009; Iyadurai et al., 2018; Kanstrup, Singh et al., 2021; 
Kubickova et al., in prep) helps to indicate when they might benefit from repeating the 
intervention.  
Outline of Study: 
The study is divided into approximately a 1-5 week screening period including one week run-
in period to determine eligibility prior to randomisation followed by approximately 8 weeks in 
the study period and 2 weeks optional, qualitative interview period. 
Participants will be recruited through the Intensive Care Society network membership and 
existing social media followers supplemented by targeted advertisements in social media 
(e.g. Facebook, Twitter).  
Those who are interested in taking part in the study will be asked to complete a brief online 
eligibility questionnaire anonymously, which can be accessed on the study website. 
Participants will be asked to give online consent before completing the questionnaire. Those 
who meet all the inclusion criteria will be asked to provide their contact details (name, 
telephone number and email address). A researcher will then arrange a time to contact them 
by phone or video call to obtain informed consent and go through the study inclusion and 
exclusion criteria. 
All participants will be asked to complete a daily online intrusive memory diary for a run-in 
period of one week to record a simple count of the number of intrusive memories they have 
each day using a secure web-based clinical research system, P1vital® electronic patient 
reported outcome (ePRO) system. Those meeting the study eligibility criteria will then be sent 
a link to complete baseline questionnaires using ePRO. After completing baseline 
questionnaires, participants will be randomised by ePRO to receive either the immediate 
intervention arm or the delayed intervention arm using a 1:1 overall ratio. After randomisation, 
participants will be sent information explaining what will happen next in the study. This 
information will differ according to whether they have been allocated to the immediate 
intervention or delayed intervention arm. Note: to minimise expectation bias, participants are 
not told that the study has two arms or to which arm they have been assigned; participants 
are informed during the consent process that they will have access to an online intervention 
for 4 weeks ‘at some point’ within an 8-week period. 
• 
Participants in the immediate intervention arm will be contacted immediately by a 
researcher to arrange a video call to go through the brief digital intervention for the 
first time with researcher support (the guided session: Day 1). The brief digital 
intervention is a c. 30-minute, single session task completed by the participant on 
their smart phone or other internet enabled device delivered on a secure web platform 

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used for clinical self-management of health in general practice (i-spero®).  Participants 
in this arm will have continuous access to the intervention over the next 4 weeks (Day 
1-28) and can use the intervention either on their own or with the option of researcher 
support. As part of the intervention, participants complete a daily record of their 
intrusive memories in i-spero® to identify which intrusive memories they have had, 
and therefore which to target with the intervention. In week 4 (Day 22-28), they will 
be asked to complete a daily intrusive memory diary and intrusive memory rating 
questionnaire in ePRO (identical to the run-in week) to assess how many intrusive 
memories they had each day. 
• 
Participants in the delayed intervention arm will be asked to complete the online 
intrusive memory diary and intrusive memory rating questionnaire using ePRO during 
week 4 (Day 22 to 28), to assess how many intrusive memories they had each day. 
The online intrusive memory diary completed during week 4 will be the same as the 
intrusive memory diary completed by all participants in the run-in week. After these 
first 4 weeks, they will be contacted by a researcher to arrange a video call to go 
through the brief digital intervention for the first time (as in the immediate intervention 
group, i.e. the guided session: Day 29+7 days1). Participants in the delayed 
intervention arm will have continuous access to the intervention over the next 4 weeks 
(Day 29 to 56+7 days) and can use the intervention either on their own or with the 
option of researcher support. As part of the intervention, participants complete a daily 
record of their intrusive memories to identify which intrusive memories they have had, 
and therefore which to target with the intervention. In week 8 (Day 50 to 56 +7), they 
will be asked to complete a daily intrusive memory diary and intrusive memory rating 
in ePRO (identical to the run-in week) to assess how many intrusive memories they 
had each day. 
Participants in both arms will be asked to complete outcome questionnaires using ePRO at 
4 weeks (Day 28) and 8 weeks (Day 56). They will also be asked to complete an online 
feedback questionnaire about their experience of using the intervention and they will be given 
the option of completing a qualitative interview with a researcher via audio or video call. This 
will be completed after week 4 (Day 28) for participants in the immediate intervention arm 
and after week 8 (Day 56+7 days) for participants in the delayed intervention arm. 
Note: Day 1 in the immediate intervention group is defined as the day on which the participant 
completes the first intervention session with researcher support (guided session). The timing 
of this first intervention session post randomisation may vary slightly from participant to 
participant in the intervention arm. Day 1 for participants in the delayed intervention arm will 
be paired to the timing of Day 1 for participants in the immediate intervention arm, so that the 
timing of the primary outcome assessment post randomisation will be approximately equal 
between the two groups. 
Endpoints / Outcome Measures 
Primary Endpoint: 
• 
Number of intrusive memories of traumatic events recorded by participants in a brief 
daily online intrusive memory diary for 7 days during week 4 (i.e. from Day 22 to 28 
post first intervention session in immediate intervention arm/equivalent timeframe in 
delayed intervention arm). Analysed as between-group comparison (immediate 
 
 
1 A 7-day window, denoted by “+7 days”, is anticipated to allow time to arrange the first intervention 
session with participants in the delayed intervention arm. 

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intervention arm vs. the delayed intervention arm) controlling for the number of 
intrusive memories during the run-in week. 
Secondary Endpoints: 
• 
Number of intrusive memories recorded by participants in a brief daily online intrusive 
memory diary for 7 days during the run-in week (pre intervention) and week 4 (Day 
22 to 28) in the immediate intervention arm; and during week 4 (Day 22 to 28) and 
week 8 (Day 50 to 56+7 days) in the delayed intervention arm (i.e. within-group 
comparisons). 
• 
Intrusive memory ratings (distress, disruption to concentration/functioning: how much 
and how), Impact of Event Scale-Revised (IES-R), PTSD Checklist for DSM-5 (PCL-
5) 4-item, Generalised Anxiety Disorder-2-item questionnaire (GAD-2), Patient Health 
Questionnaire-2-item version (PHQ-2), Sleep Condition Indicator (SCI-08), 
Physiological Outcome Profile Questionnaire (PSYCHLOPS), World Health 
Organization Disability Assessment Schedule (WHODAS), 5-level EQ-5D (EQ-5D-
5L), Number of sick days, Scale of Work Engagement and Burnout (SWEBO), 
Intention to leave job at 4 weeks (i.e. Day 28 post first intervention session in 
immediate intervention arm/equivalent timeframe in delayed intervention arm) in the 
immediate intervention arm vs. the delayed intervention arm (i.e. between-groups 
comparison). 
• 
Intrusive memory ratings (distress, disruption to concentration/functioning: how much 
and how), Impact of Event Scale-Revised (IES-R), PTSD Checklist for DSM-5 (PCL-
5) 4-item, Generalised Anxiety Disorder-2-item questionnaire (GAD-2), Patient Health 
Questionnaire-2-item version (PHQ-2), Sleep Condition Indicator (SCI-08), 
Physiological Outcome Profile Questionnaire (PSYCHLOPS), World Health 
Organization Disability Assessment Schedule (WHODAS), 5-level EQ-5D (EQ-5D-
5L), Number of sick days, Scale of Work Engagement and Burnout (SWEBO), 
Intention to leave job at baseline, 4 weeks (Day 28) and 8 weeks (Day 56) in the 
immediate intervention arm; and at 4 weeks (Day 28) and 8 weeks (Day 56+7 days) 
in the delayed intervention arm (i.e. within-group comparisons). 
Tertiary Endpoint  
• 
8-item questionnaire (changes to health and work) at 4 weeks (Day 28) and 8 weeks 
(Day 56) (both arms). 
• 
Rates of recruitment, intervention use/adherence, outcome measure completion and 
participant attrition. 
• 
Feedback questionnaire at 4 weeks post first intervention session in both arms (i.e. 
Day 28 in the immediate intervention arm and Day 56+7 days in the delayed 
intervention arm). 
• 
Optional qualitative interview at 4 to 6 weeks post first intervention session in both 
arms (i.e. Day 29+14 days in the immediate intervention arm and Day 57+14 days in 
the delayed intervention arm). 
• 
Optional qualitative interview information about guidance given by the expert/non 
expert researchers to help participants to learn how to use the intervention. 
Refer to section 5.7 for specific timings of assessments by day. 
Statistical Methodology: 
Bayesian and frequentist analyses will be used for statistical inference. The Bayesian 
approach will be used throughout data collection to inform on study design. Standard 
(frequentist) statistical approaches will be used at the end of the study to analyse the primary, 
secondary and tertiary data. 
Study Design Analysis 

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• 
Ongoing sequential analysis using Bayesian statistical approaches will be used to 
evaluate the study design based on the primary outcome (difference in the number of 
intrusive memories in week 4 for groups of participants. The analysis will control for 
the number of intrusive memories during the run-in week.  
 
End of Study Analysis 
Primary Analysis 
• 
A between-groups analysis will be used to test the difference in the number of 
intrusive memories in week 4 (i.e. from Day 22 to 28) between the immediate 
intervention and delayed intervention groups. The analysis will control for the number 
of intrusive memories during the run-in week.  
Secondary Analysis 
• 
A within-group analysis will be used to test the change in the number of intrusive 
memories from the run-in week to week 4 (Day 22 to 28) in the immediate intervention 
group.  
• 
A within-group analysis will be used to test the change in the number of intrusive 
memories from week 4 (Day 22 to 28) to week 8 (Day 50 to 56+7 days) in the delayed 
intervention group.  
• 
Between-groups analyses will be used to test for differences in other secondary 
outcomes at 4 weeks (Day 28) between the immediate intervention and delayed 
intervention groups: intrusive memory ratings of distress and disruption to 
concentration / functioning; symptoms of post-traumatic stress, anxiety, depression 
and insomnia; sickness absence; work engagement and burnout; intention to leave 
job; functioning and quality of life.  
• 
Within-group analyses will be used to test the change in other secondary outcomes 
(listed above) from baseline to 4 weeks (Day 28) in the immediate intervention group. 
• 
Within-group analyses will be used to test the change in other secondary outcomes 
(listed above) from 4 weeks (Day 28) to 8 weeks (Day 56) in the delayed intervention 
group. 
• 
Within-group analyses will be used to test if changes in secondary outcome measures 
are maintained at 8 weeks (Day 56) post intervention onset in the immediate 
intervention arm. 
Tertiary Analyses 
• 
Descriptive statistics will be used to summarise support from managers and friends 
family and changes to health and work in the two groups. 
• 
Descriptive statistics will be used to summarise rates of recruitment, intervention 
use/adherence, outcome measure completion and participant attrition. 
• 
Descriptive statistics will be used to summarise quantitative data regarding 
intervention acceptability (feedback questionnaire) 
• 
Qualitative interview data will be thematically analysed using an inductive thematic, 
constant comparison approach based on grounded theory (Glaser and Strauss 1967). 
 
References: 
Holmes, E. A., James, E. L., Coode-Bate, T., & Deeprose, C. (2009). Can playing the 
computer game "Tetris'' reduce the build-up of flashbacks for trauma? A proposal 
from cognitive science. PLoS ONE, 4(1), e4153.  
 
Iyadurai, L., Blackwell, S. E., Meiser-Stedman, R., Watson, P.C., Bonsall, M. B., 
Geddes, J. R., Nobre, A.C., & Holmes, E. A. (2018). Preventing intrusive memories 

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after trauma via a brief intervention involving Tetris computer game play in the 
emergency department: a proof-of-concept randomized controlled trial. Molecular 
Psychiatry. 23(3), 674-682. 
 
Kanstrup, M.*, Singh, L.*, Göransson, K., Widoff, J., Taylor, R., Iyadurai, L., Moulds, 
M. & Holmes, E. A. (2021). Preventing intrusive memories after trauma via a simple 
cognitive intervention in the hospital emergency department: An explorative 
randomised 
controlled 
pilot 
trial. 
Translational 
Psychiatry, 
11(30). 
https://doi.org/10.1038/s41398-020-01124-6. *co-shared first authorship 
 
Kubickova, V., Holmes, E. A. & Iyadurai, L (in preparation). A brief task-based 
intervention to reduce intrusive memories of work-related traumatic events in frontline 
NHS staff: A case series.  

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List of Abbreviations  
 
AE  
Adverse Event 
COVID-19 
Coronavirus Disease 2019 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
GAD-2 
Generalised Anxiety Disorder – 2-item questionnaire 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
ePRO 
Electronic Patient Reported Outcomes 
EQ-5D-5L 
5-level EQ-5D 
ICF 
Informed Consent Form 
ICU 
Intensive Care Unit 
IES-R 
Impact of Event Scale-Revised 
NHS 
National Health Service 
PCL-5 
PTSD Checklist for DSM-5 
PHQ-2 
Patient Health Questionnaire – 2-item version 
PI 
Principal Investigator 
PIS 
Participant Information Sheet 
PSYCHLOPS 
Psychological Outcome Profiles Questionnaire 
PTSD 
Post-traumatic Stress Disorder 
REC 
Research Ethics Committee 
SCI 
Sleep Condition Indicator 
SWEBO 
Scale of Work Engagement and Burnout 
WHO 
World Health Organization 
WHODAS 
World Health Organization Disability Assessment Schedule 
 

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1.0 
Introduction and Rationale 
1.1 Background  
1.1.1 The mental health impact of covid-19 trauma on health care staff 
The mental health of frontline healthcare staff who are delivering care to 
COVID-19 patients is a major priority internationally (Holmes et al., 2020), for 
two reasons: 
1. Frontline healthcare staff are at elevated risk of post-traumatic stress 
disorder (PTSD) and other mental health symptoms due to increased 
exposure to occupational trauma and require prompt access to 
effective interventions.  
2. Retaining healthcare staff in their jobs and preventing work dropout is 
necessary for delivering critical care to COVID-19 patients.  
During the COVID-19 pandemic, frontline healthcare staff are experiencing 
extreme exposure to potentially traumatic events, e.g. traumatic or tragic 
death of a patient (Adriaenssens et al., 2012; Jonsson & Segesten, 2003; 
Laposa et al., 2003; Michael & Jenkins, 2001), or heightened risk of infection 
(Kang et al., 2020; Zhang et al., 2020).  
After a trauma, it is common to experience intrusive memories (or 
“flashbacks”) of the event. Even before COVID-19, 65% of emergency nurses 
reported having intrusive memories of work-related traumatic events (Kleim et 
al., 2015) – emotional, intrusive and primarily visual memories of the traumatic 
event that pop suddenly into mind. For some individuals, intrusive memories 
persist, and become a core symptom of post-traumatic stress disorder (PTSD) 
(American Psychiatric Association, 2013). 
Around 40% of healthcare staff in UK hospitals reported a level of symptoms 
consistent with a diagnosis of PTSD as of June/July 2020 (Greenberg et al., 
2021)- five times higher than in 2015 (Colville et al., 2015). Of this sample of 
almost 3000 respondents, approximately one quarter report “Repeated, 
disturbing memories, thoughts of images related to the current pandemic” 
(i.e., intrusive memories) have been bothersome (scores of 3=moderately to 
5=extremely on the PCL-6; (Lang et al., 2012) Greenberg on our Expert 
Advisory Panel, personal communication (Greenberg, 2021)).  
Recent studies from China report that between 24% and 35% of healthcare 
workers reported PTSD symptoms during the COVID-19 pandemic (Tan et 
al., 2020; Lai et al., 2020; Kang et al., 2020).  
PTSD has a major impact on an individual’s functioning and incurs great cost 
for both the individual and society. PTSD symptoms can impair work 
performance: 27% of healthcare workers who reported PTSD symptoms said 
they interfered with their work functioning (Laposa & Alden, 2003) and 20% 
considered changing their job (Laposa, Alden & Fullerton, 2003). Mental 
health problems are the leading cause of sickness absence in the NHS (NHS 
Digital, 2020). 

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1.2 Rationale 
1.2.1 Limitation to existing interventions after trauma  
Whilst there are effective treatments for PTSD, such as talking therapies like 
trauma-focused cognitive behavioural therapy (NICE, 2018), uptake in 
frontline staff is limited by difficulty finding time to attend fixed therapy 
sessions and mental health stigma. Moreover, we lack evidence-based 
interventions to target sub-clinical symptoms and prevent full-blown PTSD 
from developing - which is critical to keeping frontline staff working well. We 
urgently need psychological interventions for healthcare staff that are brief, 
remotely-delivered (digital), low stigma and scalable. 
1.2.2 A mechanism-based intervention to target intrusive memories of 
trauma 
Intrusive memories of trauma may be a potential target for early and 
preventative interventions post-trauma (Iyadurai et al., 2019). Intrusive 
memories are centrally linked to other symptoms of the disorder, both at an 
early and later period post-trauma (Bryant et al, 2017). This has led to the 
suggestion that targeting intrusive memories may prevent PTSD from 
developing (McNally, 2017). 
Almost two decades of laboratory and clinical studies within Prof Holmes’ 
research group has led to the development of a brief mechanism-driven 
behavioural intervention to reduce intrusive trauma memories (e.g. Holmes, 
James, Coode-Bate, & Deeprose, 2009; James et al., 2015).  
This brief imagery-competing task intervention consists of a brief reminder cue 
to orient to the traumatic event, followed by playing the computer game Tetris 
for 20 minutes with instructions to use mental rotation during game play. The 
principles of the intervention are informed by the (neuro)science of memory 
consolidation and cognitive task interference. The hypothesis is that the 
memory consolidation process of a traumatic event can be disrupted by 
engaging in visuospatial demanding tasks, e.g. Tetris, and reduce the 
frequency of the intrusive memories. However, the ability to voluntarily recall 
the memories does not appear to be affected in laboratory studies.  
1.2.3 Clinical translation and application  
The intervention is thought to be effective across different types of traumatic 
events. A number of pilot and proof-of-concept clinical studies have been 
carried out – three randomised controlled trials and three case series studies. 
An initial randomised controlled trial compared the intervention to usual care 
in woman who had an emergency caesarean section (traumatic childbirth). 
The results showed that the frequency of intrusive memories decreased 
during the following week for the intervention group in comparison to the 
control group (Horsch et al, 2017). Similar results were found in a randomised 
controlled study with participants admitted to a UK emergency department 
after a traumatic motor vehicle accident. Those who received the intervention, 

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compared to an attention-placebo control, reported fewer intrusive memories 
over the next week (Iyadurai et al., 2018). In a pilot replication trial in a 
Swedish emergency department, reduction in intrusive memory frequency 
was maintained (and in fact even greater) at 5 weeks post intervention 
(Kanstrup, Singh et al., 2021). In all of these trials, feedback from participants 
indicated that the intervention was acceptable. Finally, the intervention has 
also been found to reduce intrusive memories in case series studies with 
patients with chronic PTSD (Kessler et al, 2018), refugees (Kanstrup et al., 
2020), and most recently NHS staff exposed to work-related trauma including 
during the COVID-19 pandemic (Kubickova et al., in prep). 
Our game-based intervention is an ‘early intervention’ that aims to reduce and 
prevent the recurrence of intrusive memories during the COVID-19 pandemic. 
The intervention can be delivered within the timeframes of early prevention 
(within 1 month after the traumatic event), early preventative treatment (1-3 
months after the event), delayed preventative treatment (>3 months after the 
event), or during ongoing trauma exposure (NICE evidence reviews for PTSD 
prevention, 2018). Within the NICE evidence reviews for PTSD prevention 
(2018), the intervention would be considered as self-help with or without 
support. 
1.2.4 Aims of the current study  
The current study aims to investigate if the effects of the intervention a) extend 
to ICU staff who have experienced work-related traumatic events during the 
COVID-19 pandemic, and b) impact key secondary outcomes such as other 
mental health symptoms, work functioning, sickness absence and intention to 
leave the job. 
The intervention holds particular promise for overcoming some of the 
challenges of implementing mental health interventions for healthcare staff as 
it is brief (one guided intervention session of approximately 30 minutes), can 
be used flexibly in different locations (e.g. on a smartphone during a 
commute), and is non-stigmatising (involves a digital task including a 
computer game rather than talking to a trained therapist). Participants can 
then use it self-guided for additional different intrusive memories they may be 
experiencing. It can also be delivered following each new traumatic event, and 
for new intrusive memories as they arise, so is well-suited for healthcare staff 
facing repeated or ongoing trauma in their jobs during the pandemic. 
Participants do not need to talk about the traumatic event in detail, which 
minimises distress. 
Results of the study will be relevant globally to healthcare staff affected by 
traumatic events during the COVID-19 pandemic. 
1.2.5 Main research questions  
1. Can a brief digital imagery-competing task intervention for national health 
service (NHS) intensive care unit (ICU) staff who have experienced work-
related traumatic events during COVID-19:  

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a) Reduce the number of intrusive memories in week 4 (Day 22 to D28) 
(primary outcome)? 
b) Reduce symptoms of PTSD, anxiety, depression and insomnia (secondary 
outcomes)? 
c) Improve work functioning and engagement, and reduce sickness absence, 
burnout and intention to leave the profession (secondary outcomes)? 
2. Is the intervention feasible and acceptable to NHS ICU staff? (tertiary 
outcomes) 
3. How can we optimise the intervention for guided delivery by non-expert 
researchers and inform non-guided delivery? (tertiary outcomes)  
1.3 Risks and benefits 
1.3.1 Benefits 
The study holds the following potential benefits to NHS ICU staff and COVID-
19/other patients: 
1. Immediate clinical benefit to NHS ICU staff participants, by reducing 
distressing intrusive memories and other mental health symptoms. 
2. Immediate benefit to staff job performance and delivery of care to COVID-
19/other patients, by reducing disruption to concentration and work 
performance caused by intrusive memories.  
3. Longer-term/preventative impact on staff participants’ mental health, by 
reducing the persistence of PTSD symptoms and other mental health 
symptoms. 
4. Longer-term impact on staff sickness absence, burnout and intention to 
leave the job. 
5. Longer-term impact on the delivery of care to COVID-19/other patients, due 
to improved staff retention. 
Previous studies show that participants rate the intervention as easy, helpful, 
minimally distressing/burdensome and acceptable (Horsch et al, 2017; 
Iyadurai et al, 2018; Kanstrup, Singh et al, 2021). Moreover, participants 
reported that the intervention took their mind off the traumatic event (e.g. 
Iyadurai et al, 2018) and was fun and relaxing (Kanstrup, Singh et al, 2021). 
All participants will be given information on how to seek help for any ongoing 
mental health concerns at the end of the study, and individuals who are not 
eligible for the study will be signposted to NHS/Every Mind Matters and other 
support websites.  
1.3.2 Risks and measures to minimise them 
The study has no anticipated long-term risks to participants, and no adverse 
events related to study procedures have been reported by participants in 
previous trials of the intervention (Horsch et al., 2017; Iyadurai et al., 2018; 
Kanstrup, Singh et al., 2021).  

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However, the study procedures may be associated with the following risks and 
measures to minimise each risk are also described: 
1. Briefly listing image-based intrusive memories of traumatic events and 
bringing them to mind as part of the intervention (memory reminder) may be 
unpleasant or distressing for some participants. 
This procedure has been tested in several previous studies (Iyadurai et al., 
2018; Kanstrup et al, 2020; Kanstrup, Singh et al., 2021) with no adverse 
consequences. The procedure is very brief, and participants are only asked 
to write a few words for each intrusion, before moving on quickly to the next. 
Participants are only asked to bring to mind the image very briefly, before 
moving immediately on to playing Tetris. Participants are not required to recall 
or describe the traumatic event(s) in detail. 
2. Some participants may find playing the computer game Tetris difficult or 
stressful. 
Tetris is a simple and popular computer game, and whilst most participants in 
previous studies have reported finding it fun and distracting, participants 
occasionally find it difficult or stressful. All participants will be given 
instructions on how to play Tetris, and in this study the difficulty of the game 
adapts to the skill of the player. The researcher will be present to help the 
participant the first time they do the intervention. Many healthcare staff already 
use computer games for distraction and recreation (BBC News, 2020). 
3. Completing outcome measures may be perceived as burdensome by some 
participants. 
We have tried to minimise participant burden by limiting the number of 
outcome measures, and wherever possible using shortened versions of 
measures (e.g. 4-item PTSD Checklist for DSM-5). We have selected 
measures with the specific needs and demands of healthcare staff in mind. 
All outcome measures will be administered online, meaning that participants 
can complete them at a time and place that suits them. 
4. Some staff who do not meet the eligibility criteria may still be experiencing 
difficulties. 
To address this, we will ensure that all potential participants who do not meet 
the initial screening criteria will be signposted to the NHS/Every Mind Matters 
and other support website.   
The research team includes qualified Clinical Psychologists and Psychiatrists 
with extensive experience in running clinical research studies in mental health. 
These include previous studies testing this intervention, trials of other digital 
mental health interventions, and studies with healthcare staff and students. 
The study has been designed in line with Good Clinical Practice (GCP) 
guidance, and all investigators are GCP trained. Dr Lalitha Iyadurai and 
Professor Emily Holmes (clinical psychologists) have expertise in treating 

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traumatised individuals and will be involved in the training and monitoring of 
the study team. 
2.0 
Study Objectives 
2.1 Primary Objective      
• 
To determine if immediate access to the intervention plus symptom monitoring for 4 
weeks (immediate intervention arm), compared to usual care for 4 weeks (delayed 
intervention arm), can reduce the number of intrusive memories in week 4 (i.e. 
between-groups comparison). 
2.2 Secondary Objectives     
• 
To determine if access to the intervention plus symptom monitoring for 4 weeks can 
reduce the number of intrusive memories from run-in week (pre-intervention) to week 
4 (post intervention; within-group comparison in the immediate intervention arm) and 
from week 4 (pre intervention) to week 8 (post intervention; within-group comparison 
in the delayed intervention arm) 
 
• 
To determine if immediate access to the intervention plus symptom monitoring for 4 
weeks (immediate intervention arm), compared to usual care for 4 weeks (delayed 
intervention arm), can reduce intrusive memory ratings of distress and disruption to 
concentration/functioning; symptoms of post-traumatic stress, anxiety, depression 
and insomnia; sickness absence; burnout; intention to leave job; and improve work 
engagement, functioning and quality of life  at 4 weeks(i.e. between-groups 
comparison). 
 
• 
To determine if access to the intervention plus symptom monitoring for 4 weeks, can 
reduce 
intrusive 
memory 
ratings 
of 
distress 
and 
disruption 
to 
concentration/functioning; symptoms of post-traumatic stress, anxiety, depression 
and insomnia; sickness absence; burnout; intention to leave job; and improve work 
engagement, functioning and quality of life from baseline (pre intervention) to 4 and 
8 weeks (post intervention; within-group comparison in the immediate intervention 
arm) and from 4 weeks (pre intervention) to  8 weeks (post intervention; within-group 
comparison in the delayed intervention arm).  
 
2.3 Tertiary Objectives 
 
• 
To assess support (from managers and family/friends), new stressful/traumatic 
events, new treatments, changes to work. 
 
• 
To obtain feasibility data to improve the intervention implementation. 
 
• 
To assess the acceptability and perceived value of the intervention from participants 
to optimise the intervention implementation.  
 

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• 
To assess the guidance given by the expert researchers to participants to explain 
how to use the intervention, in order to identify ways to train non-expert researchers 
to give guidance. 
 
• 
To assess the guidance given by both expert and non-expert researcher to identify 
ways to digitise such guidance to establish a fully self-guided version of the 
intervention. 
 
Primary, secondary, tertiary endpoints and outcome measures are outlined in 
section 9 of the protocol. 
3.0 
Study Design 
3.1 Overview  
 
The study is a randomised optimisation study of a brief digital imagery-competing 
task intervention to support NHS ICU staff experiencing intrusive memories of 
traumatic events from working in the COVID-19 pandemic.  
Participants will be randomised to one of two study arms: 
The Immediate intervention arm = immediate access to the brief digital imagery-
competing task intervention plus symptom monitoring for 4 weeks  
Delayed intervention arm = usual care for 4 weeks followed by access to the 
intervention plus symptom monitoring for 4 weeks 
The study will enrol up to approximately 150 participants, 75 participants per study 
arm (see sample size calculation, section 11.1).   
The study will enrol NHS ICU staff (e.g. doctors, nurses, paramedics and clinical 
support staff) aged 18 and over who: a) have experienced one or more work-related 
traumatic events during the COVID-19 pandemic (e.g. a patient death), and b) have 
intrusive memories of the event(s). 
The study is divided into a 1-5 week screening period, randomisation into an 
immediate intervention or delayed intervention arm using a 1:1 overall ratio, 8 week 
in-study period, followed by two weeks optional qualitative interview period. Each 
participant will be in the study for a total of up to 17 weeks. All of the study visits will 
be completed by participants remotely on their smart phone or other internet 
enabled device. 
During the in-study period participants will complete the intervention for a period of 
4 weeks and will collect self-reported questionnaires at Baseline, 4 and 8 weeks 
digitally and remotely. 
Optional qualitative interviews will be performed 4 weeks post intervention onset to 
assess the feasibility, acceptability and perceived value of the intervention. 
Information on the guidance provided by researchers to participants to explain how 
to use the intervention will be collected to help identify ways to train non-expert 
researchers to give guidance and/or digitise such guidance to establish a fully self-
guided version of the intervention. 

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Total duration of the study from first participant enrolment to last participant 
completing the study is expected to last approximately 6 months. 
The brief imagery-competing task intervention will be delivered on a secure web 
platform used for clinical self-management of health in general practice (i-spero®). 
A secure web-based clinical research system, P1vital® ePRO will be used to: 
• 
Randomise participants and will issue email/text reminders to participants 
and study researchers when study-related activities are due. 
• 
Collect intrusive memory diary and intrusive memory rating data during the 
run-in week and at week 4 (Day 22 to 28) for all participants and at week 8 
(Day 50 to 56) for participants in the delayed intervention arm. 
• 
Collect self-reported outcome measurement data at baseline, 4 weeks (Day 
28) and 8 weeks (Day 56) in both arms. 
The primary comparison will be a between-groups comparison of the number of 
intrusive memories recorded during week 4 (i.e. from day 22 to 28; which is post 
intervention in arm 1 and pre-intervention in arm 2), controlling for the number of 
intrusive memories recorded during the run-in week. Secondary comparisons will 
be within-group comparisons of the number of intrusive memories in the run-in week 
(pre-intervention) and week 4 (Day 22 to 28) (post intervention; immediate 
intervention arm only) and week 4 (Day 22 to 28) (pre-intervention) and week 8 (Day 
50 to 56 +7 days) (post intervention; delayed intervention arm only). After the first 
intervention session, both arms will have continued access to the intervention for 
the duration of the study period. 
3.2 Study design 
Participants will be recruited through the Intensive Care Society network 
membership and existing social media followers supplemented by targeted 
advertisements in social media (e.g. Facebook, Twitter).  
 
Those who are interested in taking part in the study will be asked to complete a brief 
online eligibility questionnaire anonymously, which can be accessed on the study 
website. Participants will be asked to give online consent before completing the 
questionnaire. Those who meet all the inclusion criteria will be asked to provide their 
contact details (name, telephone number and email address). A researcher will then 
arrange a time to contact them by phone or video call to obtain informed consent 
and go through the study inclusion and exclusion criteria. 
All participants will be asked to complete a daily online intrusive memory diary for a 
run-in period of one week where participants will be asked to record a simple count 
of the number of intrusive memories they have each day followed by an intrusive 
memory rating at the end of the week using ePRO.  
 
Those meeting the study entry criteria will be sent a link to complete baseline 
questionnaires using ePRO, after completing the baseline questionnaires 
participants will be randomised by ePRO to receive either the immediate 
intervention arm or the delayed intervention arm using a 1:1 overall ratio. After 

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randomisation, participants will be sent information explaining what will happen next 
in the study. This information will differ according to whether they have been 
allocated to the immediate intervention or delayed intervention arm. 
 
Participants in the immediate intervention arm will be contacted immediately by a 
researcher to arrange a time (e.g. via video call using Microsoft Teams) to go 
through the intervention for the first time (guided session: Day 1). The intervention 
is a 30 minute, single session task completed by the participant on their smart phone 
or other internet enabled device delivered on a secure web platform used for clinical 
self-management of health in general practice (i-spero®).  
 
Participants in this arm will have continuous access to the intervention over the next 
8 weeks and can use the intervention either on their own or with the option of 
researcher support. As part of the intervention, participants complete a daily record 
of their intrusive memories using i-spero® to identify which intrusive memories they 
have had, and therefore which to target with the intervention. In week 4, they will be 
asked to complete an intrusive memory diary during week 4 (Day 22 to 28) and 
intrusive memory rating at the end of week 4 (Day 28) using ePRO to assess how 
many intrusive memories they had each day. 
 
Participants in the delayed intervention arm will be asked to complete the daily 
online intrusive memory diary during week 4 (Day 22 to 28) and intrusive memory 
rating at the end of week 4 (Day 28) using ePRO, to assess how many intrusive 
memories they had each day. The online intrusive memory diary/rating completed 
during week 4 will be the same as the intrusive memory diary/rating completed by 
all participants in the run-in week. After these first 4 weeks, they will be contacted 
by a researcher to arrange a video call to go through the intervention for the first 
time (as for the immediate intervention arm: Day 29+7 days. Participants in the 
delayed arm will have continuous access to the intervention over the next 4 weeks 
(Day 29 to 56+7 days) and can use the intervention either on their own or with the 
option of researcher support. As part of the intervention, participants complete a 
daily record of their intrusive memories using i-spero® during the 4 week period (Day 
29 to 56+7 days) to identify which intrusive memories they have had, and therefore 
which to target with the intervention. 
 
All participants will complete self-reported outcome questionnaires using ePRO at 
Baseline (prior to randomisation), 4 weeks (Day 28) and 8 weeks (Day 56). 
 
Four to six weeks after participants started to use the intervention (and who agreed 
to an interview) in depth qualitative interviews with a researcher via audio or video 
call will be conducted.  
 
Note: Day 1 in the immediate intervention group is defined as the day on which the 
participant completes the first intervention session with researcher support (guided 
session). The timing of this first intervention session post randomisation may vary 
slightly from participant to participant in the intervention arm. Day 1 for participants 

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in the delayed intervention arm will be paired to the timing of Day 1 for participants 
in the immediate intervention arm, so that the timing of the primary outcome 
assessment post randomisation will be approximately equal between the two 
groups. 
This randomised optimisation study uses an adaptive Bayesian design for speed 
under pandemic conditions. Recent advances in trial design and methodology oﬀer 
more eﬃcient alternatives to traditional RCTs to speed up the testing and thus 
implementation of evidence-based treatments (ACE CONSORT Extension; Dimairo 
et al. 2020). Adaptive designs enable smaller, more efficient trials without loss of 
scientific integrity, and allow a trial to be modified on the basis of interim analysis, 
thereby making optimal use of data for decision-making.   
Interim analyses at a group level (immediate intervention vs delayed intervention) 
start at e.g. n=20 and are conducted sequentially approximately between every 4-
10 participants thereafter, up to a maximum of approximately n=150. Prespecified 
thresholds are used to trigger a potential modification of the intervention (e.g. 
assessed using Bayes factors which compare different hypotheses. Potential 
aspects of the intervention that may be tweaked for optimisation include: (i) memory 
reactivation procedure (e.g., to promote sufficient reactivation whilst keeping 
distress low); (ii) mental rotation instructions (e.g., to promote sufficient training and 
checking of participant understanding prior to the gameplay component); (iii) Tetris 
gameplay with mental rotation (e.g., to boost engagement or encourage users to 
self-administer the intervention more regularly).    
If on the other hand we find that the intervention is working sufficiently well when 
delivered by the clinical psychologists on our team (Drs Lalitha Iyadurai and 
Veronika Kubickova), we may test the intervention with different levels of 
researcher-guidance; for example, delivered by a less trained individual (not a 
qualified clinical psychologist); and with no human guidance (non-guided). We thus 
include the possibility to recruit and train for intervention delivery individuals who are 
not clinically qualified, as we have done in previous clinical studies (e.g. Kanstrup, 
Singh et al. 2021). Intervention delivery by less trained individuals or without human 
guidance would promote scalability in the future, minimising time and resources 
required for rapid rollout to respond to the pandemic. Decisions around when and 
what to optimise in the intervention will ultimately be guided by incoming participant 
data and feedback; consultation with our collaborators in the Intensive Care Society 
Expert Advisory Panel and Data Monitoring Committee; and what is clinically 
sensible for the target population at the time in this pandemic. 
If the intervention is shown to be significantly more effective than control (assessed 
using Bayes factors which compare different hypotheses) before reaching the max 
n=150 participants, then the optimisation study may conclude early and a follow-up 
pragmatic RCT, testing clinical effectiveness of the optimised intervention, can be 
initiated (a separate ethics application will be submitted for such a study). Precise 
probability thresholds will be registered prior to data analysis and after consultation 
with Prof Thomas Jaki on our Expert Advisory Panel. Our thinking around this has 
been informed by initial power estimates based on an effect size of d= 0.63 for the 

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primary outcome, pooled from three RCTs of this intervention Horsch et al, 2017; 
Iyadurai et al., 2018: Kanstrup, Singh et al. 2021). Our simulations estimate 
approximately 84% power to find strong evidence for the intervention by the time 
the maximum sample size (n=150) is reached. 
4.0 
Study Population 
4.1 Inclusion Criteria 
Potential participants will be included if they meet the following criteria: 
• 
Aged 18 or above 
• 
Able to read, write and speak in English 
• 
Worked in a clinical role in an NHS Intensive Care Unit or equivalent during the 
COVID-19 pandemic (e.g. as a member of ICU staff or deployed to work in the 
ICU during the pandemic). 
• 
Experienced at least one traumatic event related to their work during the COVID-
19 pandemic, meeting criterion A of the DSM-5 criteria for PTSD: “exposure to 
actual or threatened death, serious injury, or sexual violence” by "directly 
experiencing the traumatic event(s)" or "witnessing, in person, the event(s) as it 
occurred to others" 
• 
Have intrusive memories of the traumatic event(s)  
• 
Experienced at least three intrusive memories in the week prior to screening 
• 
Have internet access 
• 
Willing and able to provide informed consent and complete study procedures 
(including briefly listing their intrusive memories (without going into any detail), 
and playing the computer game Tetris® with particular mental rotation 
instructions and completing an online intrusive memory diary). 
• 
Willing and able to be contacted by the research team during the study period 
4.2 Exclusion Criteria 
Potential participants will be excluded if they meet the following criteria:  
• 
Have fewer than three intrusive memories in the run-in week 
We will not exclude those undergoing other treatment for PTSD or its symptoms, so 
the study is as inclusive as possible to meet the challenges ICU staff are facing 
during the COVID-19 pandemic. 
5.0 
Study Procedures 
Activities taking place during the study are shown in the Time and Events table in 
Appendix 1. 
5.1 Recruitment 
Participants will be recruited through the Intensive Care Society network 
membership and existing social media followers supplemented by targeted 
advertisements in social media (e.g. Facebook, Twitter). The advertisements email 

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will contain a link to the study website, where potential participants will be able to 
read a summary of the study information including the participant information sheet 
and watch a video explaining what intrusive memories of traumatic events are. 
Study web site will also include a link to the pre-screening eligibility questionnaire.  
5.2 Pre-Screening Procedures & Eligibility Assessment 
Those who are potentially interested in taking part in the study will be asked to 
complete an online eligibility questionnaire, which can be accessed via the study 
website. Participants will be asked to give online consent before completing the 
questionnaire. The brief questionnaire is completed anonymously. Those who are 
not eligible to take part in the study will be sent information signposting them to NHS 
staff and mental health support websites, such as the NHS Every Mind Matters 
website. Those who meet all the inclusion criteria will be asked to provide their 
contact details (name, telephone number and email address). A researcher will send 
them a participant information sheet with full information about the study. The 
participant information sheet will include: the nature and purpose of the study; the 
study eligibility criteria; what it will involve for the participant; any risks and benefits 
involved in taking part; and researcher contact details in case they have any 
questions. It will be clearly stated that the participant is free to withdraw from the 
study at any time for any reason, and with no obligation to give the reason for 
withdrawal. The participant will be allowed as much time as wished to consider the 
information, and the opportunity to question the Investigator, their GP or other 
independent parties to decide whether they will participate in the study. If they are 
still interested in taking part in the study, a researcher will then arrange a time to 
contact them by phone or video call to obtain informed consent. 
5.3 Informed Consent 
Informed consent will be obtained during a phone or video call to ensure safety and 
adherence to the current social distancing guidelines in the pandemic. The 
participant and researcher will complete, sign and date the consent form using a 
simple electronic signature via email. Participants will be emailed a copy of the 
consent form.  This will take place before any baseline measures or study specific 
procedures commence. The researcher obtaining informed consent will be GCP 
trained and authorised to do so by the Principal Investigator. During this meeting, 
the researcher will also verbally collect and record additional personal details for the 
participant, the NHS Trust organisation they have worked in during the COVID-19 
pandemic and will go through the study inclusion and exclusion criteria with 
participants.  These two forms will also be retained electronically in a secure format. 
Participants will be asked to indicate how they would prefer to be contacted during 
the study (e.g. by text or email). 
5.4 Screening Visit Procedures (Run-in-week) 
5.4.1 Intrusive memory diary  
After obtaining informed consent, participants will be asked to complete a daily 
online intrusive memory diary for a run-in period of one week. Participants will 
be asked to record a simple count of the number of intrusive memories they 

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have each day. The intrusive memory diary is based on that used in previous 
studies of the brief behavioural intervention (e.g. Holmes et al., 2009; James 
et al., 2015; Iyadurai et al., 2018), and adapted for digital delivery using ePRO. 
Participants will be a sent a link to create a personal, password-protected user 
account to access ePRO. Each day they will receive a reminder (by text/email) 
to log in and complete their intrusive memory count. Intrusive memories are 
defined as “mental images from a traumatic event that pop suddenly into your 
mind when you don’t want them to” and instructions will include a link to a 
video explaining what intrusive memories are. Each day, the participant is 
asked to indicate if they have had any intrusive memories (yes/no) and if so, 
how many. This type of daily online intrusive memory diary has already been 
piloted with NHS staff with high (99.4%) completion rates (Kubickova et al., in 
prep). At the end of the week, they will be asked to rate how accurately they 
think they completed the diary over the last week (on an 11-point scale from 
0 = not at all accurately to 10 = extremely accurately). 
5.4.2 Intrusive memory ratings 
At the end of the run-in-week, participants will be asked to rate 8 items to 
assess the following characteristics of their intrusive memories over the last 
week: frequency, distress, disruption to concentration, interference with what 
they were doing (how much and for how long), duration of interference, impact 
on work functioning (how much and how) and impact on functioning in other 
areas of life (how much and how). Two additional items will assess the number 
of days worked and number of night shifts worked in the last week. 
After completing the run-in-week diary, participants will be informed by the 
researcher if they are eligible to continue to the next stage of the study.  
5.4.3 Rescreening 
The study permits the re-screening (after the end of the screening period) of 
participants who have consented to participate in the study but are not 
subsequently randomised into the study for any reason (e.g. the participant 
had fewer than 3 intrusive memories during the run-in week, but may have 
more intrusive memories at a later time). The participant will be assigned a 
new participant identification number, and the screening procedures must be 
performed again. 
5.5 Randomisation and Baseline Procedures 
Participants who meet the eligibility criterion of having 3 or more intrusive memories 
in the run-in week will be allocated to either the immediate intervention arm or the 
delayed intervention arm using a 1:1 overall ratio. Participants will have a 85% 
(rather than 50%) chance of being allocated to the arm with the fewest participants, 
to minimise the difference in group sizes between the two arms. This approach leads 
to relatively balanced groups sizes, even with small samples (Hagino et al., 2004). 
The randomisation program will be incorporated into ePRO to ensure that allocation 
cannot be influenced by the research team (i.e., randomisation is computerised and 
automated to ensure allocation concealment). The program will be validated by the 

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independent statistician. Refer to section 7.1.2 of the CSP for more information on 
the blinding procedures. 
Before randomisation, participants will complete baseline questionnaires using 
ePRO.  They will be asked to complete the following self-report measures: 
Credibility/Expectancy Questionnaire (Devilly & Borkovec, 2000) 
This 6-item questionnaire will assess participants’ belief that the intervention will 
help reduce their intrusive memories. Wording is adapted for the current 
intervention: for example, the word “therapy” is changed to “intervention” and 
“trauma symptoms” is changed to “intrusive memories”. 
Demographic information 
The following information is collected: age, gender identity, education level, marital 
status, ethnicity, employment status, number of hours per week currently working 
and number of years working as a healthcare professional. 
Health background 
A 6-item questionnaire will be used to assess current physical health problems, 
current treatments/medication for physical health problems, current/past mental 
health problems, current treatments/medication for mental health problems, family 
history of mental health problems and prior traumatic events. 
Checklist of work-related traumatic events 
Participants are asked to select from a list the types of traumatic events they have 
experienced or witnessed during the COVID-19 pandemic, for which they have 
intrusive memories. The list contains traumatic events previously reported by 
healthcare professionals in research literature, including a traumatic or tragic death 
of a patient, increased risk of COVID-19 infection, and severe or unsuccessful 
resuscitation. 
Perceived threat to self/other 
Participants are asked to rate “to what extent did you feel your life was in danger?” 
and “to what extent did you think that someone else’s life was in danger?” on a 10-
point Likert scale from 0 (not at all) to 10 (extremely). This is based on the 
assessment of perceived life threat used in previous prospective studies following 
trauma (Blanchard et al., 1995), as used in Iyadurai et al. (2018). 
Peritraumatic Distress Inventory (PDI; Brunet et al., 2001)  
This 13-item measure assesses the extent to which participants experienced a 
number of emotional reactions during the trauma. Items are rated on a 5-point Likert 
scale from 0 (not at all) to 4 (extremely) and a total score is calculated. The measure 
is internally consistent, with good test-retest reliability and good convergent and 
divergent validity. Peritraumatic distress was found to be one of the strongest 
predictors of PTSD symptoms in first responders (Marmar et al., 2006). 
Impact of Event Scale-Revised (IES-R; Weiss & Marmer, 1997) 

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This 22-item questionnaire assesses subjective distress after a traumatic event 
(with reference to the events for which participants are taking part in the study). 
Items are rated for how distressing they have been during the past 7 days on a 5-
point scale ranging from 0 ("not at all") to 4 ("extremely"). Scores are calculated for 
the intrusion, avoidance and hyperarousal subscales and total score. The measure 
has good reliability and validity, and is widely used as an outcome measure in 
randomised controlled trials of interventions after trauma (e.g. Bryant et al., 2008).   
PTSD Checklist for DSM-5 (PCL-5) 4-item version (Price et al., 2016) 
This shortened 4-item version of the PCL-5 assesses symptoms of PTSD over the 
last month. Items are rated on a 5-point scale ranging from 0 ("not at all") to 4 
("extremely"). Scores are summed to give a total severity score (ranging 0 to 16), 
and a cut-off score of 10 indicates a probable diagnosis of PTSD. The measure is 
highly correlated with the full 20-item PCL-5 and has comparable diagnostic utility. 
Generalized Anxiety Disorder (GAD-2; Kroenke et al., 2007) 
This 2-item short-form self-report measure assesses the severity of anxiety 
symptoms. Items are rated for how often they have bothered the respondent over 
the last two weeks, from 0 (“not at all”) to 3 (“nearly every day”). The total score 
ranges 0-6, with a cut-off score of 3 indicating a probable diagnosis of generalised 
anxiety disorder. The measure has comparable performance to the full 7-item 
version as a screening tool. 
Patient Health Questionnaire (PHQ-2; Kroenke, Spitzer & Williams, 2003) 
This 2-item short-form self-report measure assesses symptoms of depression. 
Items are rated for how often they have bothered the respondent over the last two 
weeks, from 0 (“not at all”) to 3 (“nearly every day”). The total score ranges 0-6, with 
a cut-off score of 3 indicating a probable diagnosis of depression. The measure has 
adequate construct validity with a sensitivity of 83% and a specificity of 92% for 
detecting major depression. 
Sleep Condition Indicator (SCI; Espie et al., 2014) 
This 8-item scale measures sleep problems against the DSM-5 criteria for insomnia 
disorder. Item responses are each scored 0-4, with scores from 0 to 2 indicating 
threshold criteria for insomnia disorder. Total score ranges 0-32, with a higher score 
indicating better sleep. The SCI is valid, reliable and sensitive to change (Espie et 
al, 2014; Luik et al, 2017). 
Psychological Outcome Profiles Questionnaire (PSYCHLOPS; adapted by 
WHO, 2018) 
This measure consists of 4 questions designed to assess the impact of a person’s 
problems. Here it will be used in relation to the impact of intrusive memories. The 
measure has been adapted in the World Health Organisaton (WHO) intervention 
package “Problem Management Plus” from Version 5 of the Psychological Outcome 
Profiles Questionnaire (PSYCHLOPS). The adapted version used in the WHO 
publication (a) does not ask when the person became concerned about the problem; 
(b) asks how people have felt this last week rather than how they have felt in 

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themselves this last week (Q4); (c) probes for a problem description; and (d) uses 
the word “intervention” rather than “therapy”. 
World Health Organization Disability Assessment Schedule (WHODAS) 2.0 
The 12-item, self-report version of the WHODAS 2.0 will be used to assess 
difficulties in relation to the impact of intrusive memories. Respondents rate how 
much difficulty they have had in each area in the past 30 days, from 0 (none) to 4 
(extreme or cannot do). The measure showed high internal consistency (Cronbach 
alpha=.83-.92), 
high 
2-week 
test-retest 
reliability 
(intraclass 
correlation 
coefficient=.83), adequate construct validity, and was sensitive to change when 
administered online to individuals with anxiety and stress disorders (Axelsson et al., 
2017). 
EQ-5D-5L (Herdman et al., 2011) 
The 5-level version of the EuroQol-5D (EQ-5D-5L) is a brief measure for assessing 
general quality of life and health status. Items assess mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression each on a 5-point scale. 
Respondents rate their overall health today from 0 (the worst health you can 
imagine) to 100 (the best health you can imagine).  
Sickness absence (Revicki et al., 1994) 
A single item will assess the number of sick days taken from work during the past 4 
weeks. 
Scale of work engagement and burnout (SWEBO; Hultell & Gustavsson, 2010) 
This 18-item self-report measure assesses work engagement and burnout. The 
work engagement subscale consists of 9 items assessing three dimensions (vigour, 
attentiveness, dedication). The burnout subscale also consists of 9 items assessing 
with three dimensions (exhaustion, disengagement and inattentiveness). 
Respondents rate how often they have felt each descriptive in the past two weeks, 
from 1 (not at all) to 4 (all the time). The mean score is calculated for each subscale. 
Support from managers and from family/friends 
A 2 item questionnaire asks “During the COVID-19 pandemic, how well supported 
have you been by your supervisors/managers?” The response is rated as “not at 
all”, “quite a bit”, “moderately”, “quite a bit”, or “extremely” (Greenberg, 2021, 
personal communication). The second questionnaire items asks “how well 
supported have you been by your family/friends?” rated using the same response 
format. 
Intention to leave job (Cohen, 1998) 
3 items are used to assess participants’ intention to leave their job e.g. “I think a lot 
about leaving the job”, each rated from 1 (strongly agree) to 5 (strongly disagree). 
The total score ranges 3 to 15, with a lower score indicating stronger intention to 
leave the job. 
Changes to health and work 

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At week 4 and 8 participants in both arms complete a 6-item questionnaire. This 
questionnaire will be used to assess the occurrence of any new traumatic events, 
any additional stressful life events (e.g. relationship problems, financial problems), 
new treatments received, social support received, changes to the job, or changes 
to the number of hours worked per week since the last assessment. 
Note: Changes to health and work questionnaire is not required to be completed at 
baseline. 
5.6 Intervention procedures 
After completing baseline questionnaires, participants will be sent information 
explaining what will happen next in the study. This information will differ according 
to whether they have been allocated to the immediate intervention or delayed 
intervention arm. Participants in the immediate intervention arm will be contacted to 
arrange a time to go through the digital intervention instructions with them for the 
first time (see below). They will then have access to the digital intervention for 4 
weeks. Participants in the delayed intervention arm will be asked to complete the 
online intrusive memory diary and intrusive memory ratings using ePRO (as for the 
run-in week, section 5.4), at week 4. They will then be contacted by a researcher to 
arrange a time to go through the digital intervention instructions with them (as in the 
immediate intervention group). They will have access to the digital intervention for 
the next 4 weeks. 
5.6.1 Digital intervention  
The brief, digital intervention is a 30-minute, single-session task completed by 
the participant on their smart phone or other internet-enabled device. It 
includes animated videos to explain what the intervention is and how to do it, 
and takes participants through each step one at a time. The intervention will 
be delivered on a secure web platform used for clinical self-management of 
health in general practice (i-spero®). Participants will be a sent a unique 
registration code to create a personal, password-protected user account to 
access the intervention. 
Participants will be contacted by the researcher to arrange a video call to run 
through the intervention with them for the first time. The investigator team may 
audio-record the guided intervention sessions using Microsoft Teams for 
training and treatment fidelity assessment purposes. For those in the 
immediate intervention arm, this will be as soon as possible after completing 
baseline questionnaires. For those in the delayed intervention arm, this will be 
approximately 4 weeks after completing baseline questionnaires. During this 
session, the participant will be asked to briefly list the different intrusive 
memories they have and choose the one they wish to target first (“list of 
intrusive memories (hotspots)” – see below). They will then be asked to 
complete the intervention, which includes several key components: a) the 
participant is asked to briefly bring to mind the intrusive image as a reminder 
to the specific memory, b) they receive instruction on how to play the computer 
game Tetris using “mental rotation”, and c) they are asked to play Tetris using 
mental rotation for at least 20 minutes. During the intervention, participants 

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are asked to rate how distressed they are feeling on 3 occasions (“distress 
rating” – see below), to rate the vividness of the image that is brought to mind 
("reactivation vividness rating” – see below), and to rate how much they were 
able to follow mental rotation instructions (“mental rotation rating” – see 
below), to assess adherence to the instructions. After this first session, 
participants may use the intervention as many times as they like over the next 
4 weeks (e.g. to target other intrusive memories or those that recur), either on 
their own or with the option of researcher support. Intervention use and 
compliance will be assessed and monitored. 
Within-intervention measures: 
List of intrusive memories (hotspots) 
Participants are asked to briefly list the content of the different intrusive 
memories they are having i.e. a few words to describe the image that pops up 
for each e.g. “seeing the patient’s face”. They are asked to move quickly from 
one to the next, and not to think about their memories in any detail. 
Distress rating 
Participants are asked to rate how distressed they are feeling right now, on a 
11-point rating scale from 0 = not at all distressed to 10 = extremely 
distressed. This measure is given before the memory reminder cue, after the 
memory reminder cue, and after playing Tetris. 
Reactivation vividness rating 
After the memory reminder cue, participants are asked to rate how vividly they 
saw the intrusive memory in their mind, rated as 1 = no image at all, 2 = vague 
and dim, 3 = moderately clear and vivid, 4 = clear and reasonably vivid and 5 
= perfectly clear and as vivid as normal vision.  
Mental rotation rating 
After playing Tetris, participants are asked to rate how closely they were able 
to follow instructions i.e. plan ahead and visualise where to play the blocks 
coming up next, on a 11-point rating scale from 0 = not at all closely to 10 = 
extremely closely. 
Record of intrusive memories 
During the 4-week period participants have access to the intervention, they 
will be asked to complete a daily record of their intrusive memories using the 
same web platform as the intervention (i-spero®), to identify which intrusive 
memories they have had (in addition to how many). The purpose of recording 
intrusive memories in this way is to identify when participants might benefit 
from repeating the intervention, i.e. when they have intrusive memories. If they 
record the occurrence of intrusive memories, they will be given the option of 
repeating the intervention to target those intrusive memories.  
5.6.2 Intervention accessibility post trial end date  

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The digital intervention will be made available to all participants who have 
requested to keep having continued access to the intervention after the trial’s 
end date (please refer to section 5.8 of the protocol for more information on 
end of trial definition). Those participants who have requested to keep their 
access will have continued access to non-guided version of the intervention 
for a period of 12 months after they have completed the trial. 
 
5.7 In study procedures 
5.7.1 Week 1 (D1 to D7) 
Immediate Intervention Arm: 
• 
On Day 1 the participant meets with the researcher (virtual visit) to 
complete the intervention for the first time. Each time the participant 
completes the intervention they will choose an intrusive memory to 
work on, complete distress ratings (x3), play Tetris® using mental 
rotation, complete a reactivation vividness rating and a mental rotation 
rating (for further detail of the intervention see section 5.6.1 Digital 
intervention).  Following the completion of the first intervention, 
participants in this arm will have continued access to the intervention 
for 4 more weeks (D28).   
All participants in the immediate intervention arm will use i-spero® to complete 
a daily record of intrusive memories for 4 weeks and access the intervention.  
Delayed Intervention Arm: 
• 
During week 1 participants in the delayed intervention arm are not 
required to complete any procedures. 
5.7.2 Week 2&3 (D8 to D21) 
Immediate Intervention Arm: 
• 
During week 2 and 3 participants in the immediate intervention arm 
will have continuous access to the intervention on i-spero®. 
 
Delayed Intervention Arm: 
• 
During week 2 and 3 participants in the delayed intervention arm are 
not required to complete any procedures. 
5.7.3 Week 4 (D22 to D28) 
Immediate Intervention Arm: 
• 
All participants in the immediate intervention arm will be asked to 
complete the online questionnaires at the end of week 4 (D28), 
including IES-R, PCL-5 4-item version, GAD-2, PHQ-2, SCI, 
PSYCHLOPS, WHODAS, EQ-5D-5L, Number of sick days, Scale of 
Work Engagement and Burnout (SWEBO), Intention to leave job, in 
addition to changes to health and work on ePRO.  

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• 
All participants in the immediate intervention arm will have continuous 
access to the intervention and at the end of week 4 (D28) will be asked 
to complete the daily intrusive memory diary during week 4 (D22 to 
D28) on a daily basis followed by intrusive memory ratings at the end 
of week 4 (D28) on ePRO. 
Delayed Intervention Arm: 
• 
All participants in the delayed intervention arm will be asked to 
complete the daily intrusive memory diary during week 4 (D22 to D28) 
on a daily basis followed by intrusive memory rating at the end of week 
4 (D28) on ePRO. 
• 
All participants in the delayed intervention arm will be asked to 
complete the online questionnaires at the end of week 4 (D28) 
including IES-R, PCL-5 4-item version, GAD-2, PHQ-2, SCI, 
PSYCHLOPS, WHODAS, EQ-5D-5L, Number of sick days, Scale of 
Work Engagement and Burnout (SWEBO), Intention to leave job, in 
addition to changes to health and work on ePRO. 
5.7.4 Week 5,6 & 7 (D29 to D49)  
Immediate Intervention Arm: 
• 
All participants in the immediate intervention arm are not required to 
complete any procedures during week 5, 6 and 7, but continue to have 
access to the intervention on i-spero® (for optional use). 
Delayed Intervention Arm: 
• 
On Day 1 of Week 5 (D29+7 days), the participant meets with the 
researcher (virtual visit) to complete the intervention for the first time. 
Each time the participant completes the intervention they will choose 
an intrusive memory to work on, complete distress ratings (x3), play 
Tetris® using mental rotation, complete a reactivation vividness rating 
and a mental rotation rating (for further detail of the intervention see 
section 5.6.1 Digital intervention).  Following the completion of the first 
intervention, participants in this arm will have continued access to the 
intervention for 4 more weeks (D56+7 days).All participants in the 
delayed intervention arm will use i-spero® to complete a daily record 
of intrusive memories for 4 weeks (from Week 5 to 8+7 days inclusive) 
and access the intervention.   
5.7.5 Week 8 (D50 to D56) 
Immediate Intervention Arm: 
• 
All participants in the immediate intervention arm will be asked to 
complete the intrusive memory rating at the end of week 8 (D56). 
• 
All participants in the immediate intervention arm will be asked to 
complete the online questionnaires at the end of week 8 (D56), 
including IES-R, PCL-5 4-item version, GAD-2, PHQ-2, SCI, 
PSYCHLOPS, WHODAS, EQ-5D-5L, Number of sick days, Scale of 

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Work Engagement and Burnout (SWEBO), Intention to leave job in 
addition to changes to health and work on ePRO.  
Delayed Intervention Arm: 
• 
All participants in the delayed intervention arm will be asked to 
complete the online questionnaires at the end of week 8 (D56+7 days), 
including IES-R, PCL-5 4-item version, GAD-2, PHQ-2, SCI, 
PSYCHLOPS, WHODAS, EQ-5D-5L, Number of sick days, Scale of 
Work Engagement and Burnout (SWEBO), Intention to leave job, in 
addition to changes to health and work on ePRO.  
• 
All participants in the delayed intervention arm will have continuous 
access to the intervention and the record of intrusive memories at the 
end of week 8 (D56+7 days) will be asked to complete the daily 
intrusive memory diary during week 8 (D50 to D56) on a daily basis 
followed by  intrusive memory ratings at the end of week 8 (D56) on 
ePRO. 
5.7.6 Intervention feedback  
After the 4-week intervention period, participants in both arms will be asked to 
complete an online feedback questionnaire about their experience of using 
the intervention, as well as an optional qualitative interview. 
5.7.7 Feedback questionnaire 
A 12-item questionnaire will assess participants’ experience of using the 
intervention. The first ten items assess how easy, helpful, distressing, 
burdensome and acceptable participants found the intervention, how willing 
they would be to use it in the future, how confident they would be in 
recommending it to a friend and how much they feel it could be used to support 
staff within NHS ICUs, each rated from 0 (not at all) to 10 (very). The last two 
items ask how the intervention could be improved, for any other comments or 
suggestions about the intervention, and for the occurrence of any adverse 
events, all with an open response. 
5.7.8 Optional qualitative interview 
Participants will be given the option of completing a qualitative interview with 
a researcher via audio or video call. This semi-structured interview will consist 
of a number of questions designed to gain an in-depth understanding of 
participants’ experience of using the intervention and, including acceptability, 
improvement suggestions, training/psychoeducation materials, potential 
barriers/facilitators to recruitment and uptake, and support needed for remote 
intervention delivery. The interview will be audio-recorded (using a password-
protected digital voice recorder) and will last approximately 30 minutes. 
5.8 Definition of End of Trial 
The end of the study is defined as the date that the last participant completes their 
final online assessment (8 weeks post intervention in the immediate intervention 

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arm / equivalent timeframe in the delayed intervention arm) and final qualitative 
interview has been completed. 
As described above (section 3.2 Study design), a strength of this adaptive Bayesian 
design is that interim analyses can guide decision-making, such as when to adjust 
aspects of the intervention to optimise its effect, and when sufficient evidence has 
been collected to end this optimisation trial and proceed to follow-up confirmatory 
testing. In the event that the probability that the intervention is more effective than 
control exceeds e.g. 90% at any point (i.e., before reaching the max n=150), this 
optimisation study may conclude early and a follow-up pragmatic RCT, testing 
clinical effectiveness of the optimised intervention, can be initiated (a separate 
ethics application will be submitted for such a study). Precise probability thresholds 
will be registered prior to data analysis and after consultation with statisticians Dr 
David Moreau and Prof Thomas Jaki on our Expert Advisory Panel. 
5.8.1 Debrief 
Following the end of the final outcome assessment (8 weeks post 
intervention), participants will be sent information by email about the overall 
study design, how they can access further information about the study once 
published, and where they can access further mental health information online 
if needed. They will be given details on how they can contact the research 
team if they have any questions, concerns or comments about the study. 
5.9 Completion and Discontinuation / Withdrawal 
A participant will be considered to have completed the study if they have completed 
all study procedures up to and including the assessments.   
Each participant has the right to withdraw from the study at any time.  In addition, 
the Investigator may discontinue a participant from the study at any time if the 
Investigator considers it necessary for any reason including: 
• 
Ineligibility (either arising during the study or retrospectively having been 
overlooked at screening) 
• 
An adverse event that results in participant no longer being able to comply 
with study procedures. 
• 
Significant protocol deviation 
• 
Withdrawal of consent 
In all cases, the reason for withdrawal will be recorded.  
5.10 Study Termination 
The Sponsor reserves the right to terminate the study at any time.  Reasons for the 
early termination of a study by the Sponsor, may include but are not limited to:  
• Failure of the Investigator to comply with the protocol, the Sponsor’s procedures, 
or GCP guidelines; 
• Safety concerns; 

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• Inadequate recruitment of participants.   
We note that if the Investigators choose to end the study before reaching the 
maximum sample size of approximately n=150, based on strong evidence for an 
effect of the intervention, this would not be considered as “Study Termination” but 
would reflect a potential outcome of this optimisation study design. 
6.0 
Trial Intervention 
6.1 Description 
This brief imagery-competing task intervention consists of a brief reminder cue to 
the specific intrusive memory, followed by playing the computer game Tetris for 20 
minutes with instructions to use mental rotation during game play. The study team 
will provide a single training session on completing the intervention for the first time 
(guided session). The intervention can then be repeated for other intrusive 
memories. 
Refer to section 5.6.1 for more information about the digital intervention. 
The brief digital intervention will be delivered using a secure web platform used for 
clinical self-management of health in general practice (i-spero®).   
The intervention is not a medical device as it does not have a medical purpose.  
6.2 Instructions for Use 
Instructions for use are included within the intervention itself, both digitally (e.g. via 
videos) and through researcher guidance (virtual visit). Participants will receive 
instructions on how to identify and list their intrusive memories, how to select and 
reactivate an intrusive memory, and how to play the computer game Tetris using 
“mental rotation”. They are asked to play Tetris using mental rotation for at least 20 
minutes. 
6.3 Manufacturer and Distributor Details 
The brief digital intervention on i-spero® is owned and manufactured by P1vital 
Products Ltd.  Tetris® has been licenced for use within i-spero® from The Tetris 
Company. 
6.4 Computer System Validation 
ePRO, i-spero® and the brief digital intervention have been developed following a 
formal computerised system validation methodology which complies with GCP, FDA 
21CFR Part 11 and ISO13485 Quality Management System. 
6.5 Support and Assistance 
In the event that difficulties are experienced with ePRO or i-spero®, researcher or 
participants should notify P1vital Products Ltd. (telephone number +44 
(0)1865522088; email itsupport@p1vital.com). Any Adverse Device Effects or 
device deficiencies must be reported in accordance with Section 10.2. 
7.0 
Randomisation  

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7.1.1 Procedure to be followed  
Participants who meet the entry criteria during the screening visit and after the 
run in week will be randomised into one of two study arms.  
After randomisation, the study researcher will not tell the participant which 
study arm they are assigned. 
The study researcher will contact the participant at the appropriate time based 
on which arm they have been allocated to schedule a virtual meeting to 
support the participant completing the brief digital intervention for the first time.  
The study researcher will provide information for the participant to set up a 
user account on i-spero® to access the intervention. 
After the first time the intervention has been completed participants will have 
the option of being contacted by a researcher to complete the intervention 
again and/or complete the intervention on their own. 
7.1.2 Blinding of Study Intervention 
Statisticians will be blinded to allocation, and all assessments are self-report 
questionnaires administered digitally, eliminating assessor bias (i.e., to 
ensure blinding of outcome assessment). As all eligible participants are 
randomised to receive the intervention, but at two different time points, all will 
be told that they will receive the intervention and have access to it for 4 weeks 
at some point over the next 8 weeks. They will also all be informed that they 
will be asked to complete an online daily intrusive memory diary for some of 
those weeks. Researchers involved in contacting the participants and 
facilitating the conduct of intervention will not be blinded: however, as both 
arms receive the same intervention but at different time points (and the same 
clinicians will be administering the intervention in both arms), clinician 
motivation is likely to be unbiased (thereby minimising performance bias on 
part of the clinician). The remaining principal investigator’s delegated study 
members will also be unblinded during the length of the trial. 
8.0 
Adverse Event Reporting 
8.1 Definitions 
8.1.1 Adverse Event (or adverse experience) (AE)  
Any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs in subjects, users or other persons, whether or not related to the 
brief digital intervention.  
NOTE 1: This definition includes events related to the procedures involved. 
8.1.2 Serious Adverse Event (SAE)  
Any adverse event, respectively, that: 
• 
results in death. 
• 
is life-threatening. 

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Note: the term “life-threatening” refers to an event in which the 
participant was at risk of death at the time of the event; it does not refer 
to an event which hypothetically might have caused death if it were more 
severe;  
• 
requires hospitalisation or prolongation of existing hospitalisation. 
Note: any event that may not be immediately life-threatening or result 
in death or hospitalisation, but may jeopardise the participant or may 
require intervention to prevent one of these outcomes; 
• 
results in persistent or significant disability or incapacity 
Note: any event that seriously disrupts the ability of the participant to 
lead a normal life, in other words leads to a persistent or permanent 
significant change, deterioration, injury or perturbation of the 
participant's body functions or structure, physical activity and / or quality 
of life; 
• 
consists of a congenital anomaly or birth defect 
Important medical events that may not be immediately life-threatening or 
result in death or hospitalisation but may jeopardise the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above 
should also be considered serious.   
8.2 Safety Reporting Procedures  
No major risks are expected in association with any part of the study methodology 
or intervention. The brief behavioural intervention is non-invasive, minimally 
distressing, and no study-related adverse events have been reported in any 
previous trials or studies testing the intervention. In this trial, any adverse events will 
be self-reported at 4-week and 8-week assessment. In the event that any adverse 
events are reported by participants, this will be reviewed by the Chief Investigator 
in the first instance, and with a clinical colleague in the research team as necessary. 
If a serious adverse event is identified (i.e. meeting the definition in section 8.1.2 
above), this will be reported to the REC (in line with section 8.2.2 below). 
As in any study, and unrelated to the study methodology, there may be participants 
for whom significant risk to themselves or others becomes apparent during the study 
period, e.g. through spontaneously reporting suicidal intent during contact with the 
research team or in open-response questionnaire items. In these cases, the 
research team will encourage the participant to seek help e.g. contact their GP or 
other relevant healthcare provider. Any such instances will be discussed within the 
research team and recorded appropriately.  
At the end of the study, all participants will be sent information about access to 
mental health support, such as the NHS/Every Mind Matters website, the Intensive 
Care Society Wellbeing Hub webpage and advice to contact their GP/occupational 
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Additionally, if at any point during the study the participant reveals information that 
may suggest professional malpractice, they will be encouraged by the researcher to 
report this to their Hospital’s Freedom To Speak Up (FTSU) Guardian and/or to 
follow their Trust Whistleblowing Policy.  
8.2.1 All Adverse Events  
All adverse events will be reported from the time a signed and dated informed 
consent form is obtained until completion of the last study-related procedure.   
All adverse events, regardless of seriousness, severity, or presumed 
relationship to study intervention (if applicable), must be recorded on the 
paper AE forms designed for this study. 
8.2.2 Serious Adverse Events  
Research staff must record SAEs that meets the criteria described in section 
8.2 on the serious adverse event form and report that to the Chief Investigator 
immediately (maximum within 24 hours of their knowledge of the event).  The 
initial report of an SAE may be made by telephone and this must be followed 
up by written confirmation (for example by facsimile (fax) or e-mail). 
The Chief Investigator will report SAEs immediately to the study Sponsor 
(maximum within 24 hours of research staff knowledge of the event). 
SAE and Incident reporting numbers: 
Telephone: 44(0)1865 522 030 
Facsimile: +44(0)1865 597 673 
Email: admin@p1vital.com 
The initial report may be made by telephone and this must be followed up by 
written confirmation.  
Note: P1vital Products Ltd and the Chief Investigator have the same contact 
details. Safety information will be circulated internally within 24 hours of 
receipt. 
8.2.3 Reporting to Research Ethics Committees and other bodies 
An SAE occurring to a research participant should be reported to the main 
Research Ethics Committee where, in the opinion of the Chief Investigator, 
the event was: 
• 
Related – that is, it resulted from administration of any of the research 
procedures or intervention. 
• 
Unexpected – that is, the type of event is not listed in the protocol as an 
expected occurrence. 
The Chief Investigator will report all related, unexpected SAEs to the  
Research Ethics Committee within 15 days of their becoming aware of the 
event.  The report must be made using the appropriate national/international 
SAE report forms (e.g. SAE report form for non-Clinical Trials of Medicinal 

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Products, available from the Health Research Authority (HRA) website in the 
UK).   
9.0 
Primary and Secondary Endpoints 
9.1 Primary Endpoint 
• 
Number of intrusive memories of traumatic events recorded by participants in a 
brief daily online intrusive memory diary for 7 days during week 4 (i.e. from Day 
22 to 28 post first intervention session in immediate intervention arm/equivalent 
timeframe in delayed intervention arm). Analysed as between-group comparison 
(immediate intervention arm vs. the delayed intervention arm) controlling for the 
number of intrusive memories during the run-in week. 
9.2 Secondary Endpoint 
• 
Number of intrusive memories recorded by participants in a brief daily online 
intrusive memory diary for 7 days during the run-in week (pre-intervention) and 
week 4 (Day 22 to 28) in the immediate intervention arm; and during week 4 (Day 
22 to 28) and week 8 (Day 50-56+7 days) in the delayed intervention arm (i.e. 
within-group comparisons). 
• 
Intrusive memory ratings (distress, disruption to concentration/functioning: how 
much and how), Impact of Event Scale-Revised (IES-R), PTSD Checklist for 
DSM-5 (PCL-5) 4-item, Generalised Anxiety Disorder-2-item questionnaire 
(GAD-2), Patient Health Questionnaire-2-item version (PHQ-2), Sleep Condition 
Indicator (SCI-08), Physiological Outcome Profile Questionnaire (PSYCHLOPS), 
World Health Organization Disability Assessment Schedule (WHODAS), 5-level 
EQ-5D (EQ-5D-5L), Number of sick days, Scale of Work Engagement and 
Burnout (SWEBO), Intention to leave job at week 4 (i.e. Day 28 post first 
intervention session in immediate intervention arm/equivalent timeframe in 
delayed intervention arm) in the immediate intervention arm vs. the delayed 
intervention arm (i.e. between-groups comparison). 
• 
Intrusive memory ratings (distress, disruption to concentration/functioning: how 
much and how), Impact of Event Scale-Revised (IES-R), PTSD Checklist for 
DSM-5 (PCL-5) 4-item, Generalised Anxiety Disorder-2-item questionnaire 
(GAD-2), Patient Health Questionnaire-2-item version (PHQ-2), Sleep Condition 
Indicator (SCI-08), Physiological Outcome Profile Questionnaire (PSYCHLOPS), 
World Health Organization Disability Assessment Schedule (WHODAS), 5-level 
EQ-5D (EQ-5D-5L), Number of sick days, Scale of Work Engagement and 
Burnout (SWEBO), Intention to leave job at baseline,  4 weeks (Day 28) and 8 
weeks (Day 56) in the immediate intervention arm; and at 4 weeks (Day 28) and 
8 weeks (Day 56+7 days) in the delayed intervention arm (i.e. within-group 
comparisons). 
 
9.3 Tertiary Endpoint 
• 
8-item questionnaire (changes to health and work) at4 weeks (Day 28) and 8 
weeks (Day 56) (both arms). 

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• 
Rates of recruitment, intervention use/adherence, outcome measure completion 
and participant attrition. (examples of adherence include how long they played 
Tetris for; mental rotation compliance rating; and if the participant experienced 
an intrusive memory in the diary, whether they then engaged in the intervention 
and focussed it on that memory specifically rather than a different memory)  
 
• 
Feedback questionnaire at 4 weeks post first intervention session in both arms 
(i.e. Day 28 in the immediate intervention arm and Day 56 in the delayed 
intervention arm). 
• 
Optional qualitative interview at 4 to 6 weeks post first intervention session in 
both arms (i.e. Day 29+14 days in the immediate intervention arm and Day 
57+14 days in the delayed intervention arm). 
• 
Optional qualitative interview information about guidance given by the 
expert/non expert researchers to help participants to learn how to use the 
intervention. 
10.0 Data Handling 
10.1 Source Data Collection 
Source documents are original documents, data and records. These include, but 
are not limited to, study related documents e.g. Informed consent form, ePRO 
questionnaire data, i-spero® intervention data, Adverse events. 
The following data will be recorded in the study file (paper source): 
• 
Participant information sheet 
• 
Eligibility Questionnaire 
• 
Consent form  
• 
Contact details 
• 
Inclusion/Exclusion Criteria 
• 
Intrusive memory daily and weekly data (missed during electronic source 
entry) 
The following data will be recorded directly into the ePRO system by participant 
(electronic source): 
• 
Intrusive memory diary (daily) 
• 
Intrusive memory rating (end of week) 
• 
Randomisation 
• 
Credibility/Expectancy Questionnaire  
• 
Demographics 
• 
Health background 
• 
Checklist of traumatic events  
• 
Perceived threat to self/other 
• 
Peritraumatic Distress Inventory  
• 
Support from managers and from family/friends 
• 
Impact of Event scale-Revised (IES-R) 
• 
PTSD Checklist for DSM-5 (PCL-5) 
• 
Generalised Anxiety Disorder (GAD-2) 

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• 
Patient Health Questionnaire (PHQ-2) 
• 
Sleep Condition Indicator 
• 
Psychological Outcome Profiles Questionnaire (PSYCHLOPS) 
• 
World Health Organisation Disability Assessment Schedule (WHODAS) 2.0 
• 
EQ-5D-5L (5-LEVEL EuroQol 5D) 
• 
Sickness absence 
• 
Scale of Work Engagement and Burnout (SWEBO) 
• 
Intention To Leave Job 
• 
Changes to health and work 
The following intervention data will be recorded directly into the i-spero® system 
(electronic source). 
• 
Intervention: List of intrusive memories (hotspots) 
• 
Intervention: Distress rating (x3) 
• 
Intervention: Reactivation vividness rating 
• 
Intervention: Mental rotation rating 
• 
Intervention: Record of intrusive memories (daily) 
• 
Feedback Questionnaire 
The following data will be recorded directly on audio files and stored in the study file 
(electronic source). 
• 
Qualitative interviews 
 
10.2 Data Entry / Management 
Questionnaire and intervention task data will be collected and stored electronically 
in the P1vital® ePRO and i-spero® systems. These two systems will be set up, 
hosted and managed by P1vital Products Ltd, and have been developed, validated 
and qualified in accordance with regulatory requirements for computerised systems 
used in clinical research/practice (see further details below). Data will be collected 
using a unique study-specific ID code for each participant, and the only personal 
identifiable data collected using these systems will be the participant’s first name, 
email address and mobile phone number, to send them automated emails/texts and 
reminders about the study procedures. Data will be stored securely on their server 
until deletion is requested by the research group after the study has terminated and 
all relevant data has been transferred to the research team. Personal identifiable 
data will be deleted automatically once a participant completes the study, of if they 
are not eligible after completing the baseline count of their intrusive memories. 
Anonymised datasets, sent in encrypted files in a .csv/.xlsx file format, will be 
securely transferred to the research team for statistical analysis. Participants will be 
identified by an ID code in any database, and their name and any other identifying 
details will NOT be included in any study data electronic file. During screening, 
potential participants are asked to complete an anonymous eligibility questionnaire 
on the study website. Eligible participants will be asked to provide their name, 
telephone number and/or email address. These data will be deleted as soon as they 

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are no longer needed to contact the participant. Anonymous consent data will be 
downloaded from the study website. Electronic data will be stored on a secure file 
server which is firewall and password protected. Study data (including consent 
forms) will be kept for at least 3 years after final publication/public release, and de-
identified data may be archived in an online repository. 
Documents containing personal information (e.g. consent form and participant 
contact details) and audio-recordings will be stored separately from other study 
data, in password-protected files on secure file servers, and only accessible by 
study staff and authorised personnel. (Note, personal data will not be stored on 
paper documents due to remote working during the COVID-19 pandemic). Personal 
data (apart from consent forms) will be kept for a maximum of 6 months after the 
end of the study, after which time it will be destroyed (files will be deleted). If 
participants give consent to be contacted about future research, their contact details 
will be held in a password-protected database, until they are no longer required. 
 
10.3 P1vital Products Data Security Policies and Procedures 
P1vital Products Ltd is fully compliant with the UK Data Protection Act 2018 and has 
appropriate data security policies and procedures in place. The P1vital® ePRO and 
i-spero® systems are hosted by Amazon Web Services, EU West 1 region (Ireland). 
The P1vital® ePRO and i-spero® systems administration and support is provided by 
a third party, Elysium Ltd, who are ISO27001 and ISO9001 certified. P1vital 
Products Ltd and Elysium Ltd are registered with the Information Commissioners 
Office, who are responsible for the enforcement of UK data protection.  
The P1vital® ePRO and i-spero® systems are only accessible through a secure 
encrypted web address (https//: web access), via a unique user ID and secure 
password. All non-study participant users must complete a security access request 
form to be registered and authorised to use the system. All personal identifiable data 
is stored in an encrypted form in the application database. The encryption key is 
only known by 3 system administrators (one primary and two backup personnel) at 
Elysium Ltd who support the P1vital® ePRO and i-spero® systems. No employees 
of P1vital Products can access the database or the encryption key. 
11.0 Statistical Methods and Data Analysis 
This randomised optimisation study uses an adaptive Bayesian design for speed 
under pandemic conditions. Recent advances in trial design and methodology oﬀer 
more eﬃcient alternatives to traditional RCTs to speed up the testing and thus 
implementation of evidence-based treatments (ACE CONSORT Extension; Dimairo 
et al. 2020). Adaptive designs enable smaller, more efficient trials without loss of 
scientific integrity, and allow a trial to be modified on the basis of interim analysis, 
thereby making optimal use of all data for decision-making.   
A brief statistical analysis plan (optimisation SAP) will be prepared prior to the first 
interim analysis, based on the primary outcome (number of intrusive memories at 
week 4) that will guide trial adaptation and optimisation.  

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A second statistical analysis plan for independent analysis of the complete trial data 
will be prepared prior to database lock (standard SAP - end of Study Analysis. Using 
standard statistical methods). Below is an outline of the sample size calculations 
and the main statistical analyses to be performed on the complete trial data. 
11.1 Sample Size 
Interim analyses at a group level (immediate intervention vs delayed intervention) 
start with a small number of participants (e.g. n=20) and are conducted sequentially 
every approximately between 4-10 participants thereafter, up to a maximum of 
approximately n=150. Prespecified thresholds are used to trigger a potential 
modification of the intervention (e.g. assessed using Bayes factors which compare 
different hypotheses. If the intervention is shown to be significantly more effective 
than control (assessed using Bayes factors which compare different hypotheses) 
before reaching the max n=150 participants, then the optimisation study may 
conclude early and a follow-up pragmatic RCT, testing clinical effectiveness of the 
optimised intervention, can be initiated (a separate ethics application will be 
submitted for such a study). Our thinking around this has been informed by initial 
power estimates based on an effect size of d= 0.63 for the primary outcome, pooled 
from three RCTs of this intervention Horsch et al, 2017; Iyadurai et al., 2018: 
Kanstrup, Singh et al. 2021). Our simulations estimate 84% power to find strong 
evidence for the intervention by the time the maximum sample size (n=150) is 
reached. 
11.2 Data Set for Analysis 
All analyses will be conducted on an intention to treat (ITT) basis. The ITT is defined 
as all randomised participants. 
11.3 Description of Statistical Methods   
Prof Emily A Holmes, and Dr Lalitha Iyadurai will work with collaborators and 
statisticians (Prof Mike Bonsall and Varsha Ramineni, Prof Thomas Jaki and Dr 
Boliang Guo to develop the statistical analysis plan and to analyse the data. A pre-
specified analysis script will be preregistered prior to data analysis (e.g., on the 
Open Science Framework).  
11.3.1 
Study Design Analysis 
Ongoing sequential analysis using Bayesian statistical approaches will 
be used to evaluate the study design based on the primary outcome 
(difference in the number of intrusive memories in week 4 for groups of 
participants. The analysis will control for the number of intrusive 
memories during the run in week. Exploratory data analysis will be used 
to investigate the distribution of the primary outcome measure. Patterns 
of missing data will be explored and will be imputed as necessary. In the 
case where we see excess zeros (i.e., zero inflation) we will explore 
treating this with the use of an alternative statistical model (e.g., zero 
inflated Poisson GLM, negative binominal). This is further explained in 
the statistical analysis plan for designing the study.  

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11.3.2 
End of study Analysis 
Standard statistical methods will be used to analyse the complete trial 
data. The sections below (11.3.3 – 11.3.5) give a brief overview of these 
planned analyses.  
Outcome measures will be tested for assumptions of the planned 
analyses, and where assumptions are violated (e.g., normality of 
residuals), data will be either transformed or analysed using a non-
parametric test.  
Sensitivity analyses will be conducted to examine whether analytical 
decisions (e.g., the exclusion of outliers or inclusion of covariates in 
analyses) influences the results.  
For tertiary analyses (section 11.3.3 below), a combination of descriptive 
and qualitative analyses will be used. This end of study analysis will be 
conducted by the University of Nottingham.  
11.3.3 
Analysis of Primary Objective:  
A between-groups analysis will be used to test the difference in the 
number of intrusive memories in week 4 (i.e. from Day 22 to 28) between 
the immediate intervention and delayed intervention groups. The analysis 
will control for the number of intrusive memories during the run-in week. 
11.3.4 
Analysis of Secondary Objectives:  
As all measures will be repeatedly measured, multilevel modelling will be 
used to examine the group comparison at 4th week and derive the 
change estimate from baseline to each follow-up time, with patient as 
level two analytical unit, baseline measure, treatment arm, following up 
time and the interaction of arm × time as covariate. 
 
A within-group analysis will be used to test the change in the number of 
intrusive memories from the run-in week to week 4 (Day 22 to 28) in the 
immediate intervention group.  
A within-group analysis will be used to test the change in the number of 
intrusive memories from week 4(Day 22 to 28) to week 8 (Day 50 to 56+7 
days) in the delayed intervention group. 
Between-groups analyses will be used to test for differences in other 
secondary outcomes at 4 weeks between the immediate intervention and 
delayed intervention groups: intrusive memory ratings of distress and 
disruption to concentration / functioning; symptoms of post-traumatic 
stress, anxiety, depression and insomnia; sickness absence; work 
engagement and burnout; intention to leave job; functioning and quality 
of life.  

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Within-group analyses will be used to test the change in other secondary 
outcomes (listed above) from baseline to 4 weeks in the immediate 
intervention group. 
Within-group analyses will be used to test the difference in other 
secondary outcomes (listed above) from 4 weeks and 8 weeks in the 
delayed intervention group. 
Within-group analyses will be used to test if changes in secondary 
outcome measures are maintained at 8 weeks post intervention onset in 
the immediate intervention arm. 
11.3.5 
Analysis of Tertiary Objectives 
Acceptability questionnaires will be reported using descriptive statistics. 
Free text comments will be analysed thematically. Questionnaire and 
demographic data will be used to guide sampling for the semi-structured 
interviews.  
Interview data will initially be thematically analysed using an inductive 
thematic, constant comparison approach based on grounded theory 
(Glaser and Strauss 1967). Once a thematic analysis has been carried 
out and key themes identified, data will be explored for suitability in 
relation to normalisation process theory (or an alternative framework 
drawn from implementation science, addressing key aspects such as the 
intervention’s design and fit within clinical practice, if more suitable). This 
will be complemented by the questionnaire data, which will provide 
quantitative data that includes aspects of normalisation process theory. 
Normalisation process theory is a sociological theory developed and 
tested to understand the implementation of new ways of working 
(including technology) in health care, including depression and in primary 
care (May et al. 2009). It is likely that we will use normalisation process 
theory to explore implementation of the intervention. However, using a 
predetermined analytical framework precludes a more inductive 
approach and risks the exclusion of relevant insight that is not discernible 
through that particular analytical lens. For this reason, choice of analytical 
framework will be informed by its appropriateness to the data 
(MacFarlane and O’Reilly de Brun 2012).   
Both the questionnaire and interview data will be used to develop an 
inductive analysis of the value and implementation of the intervention. 
This type of inductive analysis will further our understanding of how the 
intervention is used and if changes could be made to enhance its 
implementation and facilitate its adoption. 
Descriptive statistics will be used to summarise data regarding support 
from managers and family/friends and changes to health and work in the 
two groups. 
Descriptive statistics will be used to summarise rates of recruitment, 
intervention 
use/adherence, 
outcome 
measure 
completion 
and 

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participant attrition. 
Descriptive statistics will be used to summarise quantitative data 
regarding intervention acceptability (feedback questionnaire) 
Qualitative interview data will be thematically analysed using an inductive 
thematic, constant comparison approach based on grounded theory 
(Glaser and Strauss 1967). 
 
12.0 Quality Control and Quality Assurance 
Regular monitoring will be performed to verify that the study is conducted and data are 
generated, documented and reported in compliance with the protocol, GCP and the 
applicable regulatory requirements.  The Investigator will allow the monitor to carry out 
study monitoring at regular intervals, depending on the recruitment rate, and at times 
arranged by mutual agreement.   
Quality assurance representatives from the Sponsor or P1vital may visit to carry out an 
audit of the study in compliance with regulatory guidelines and relevant standard 
operating procedures.   
The Investigator will allow monitors and other persons responsible for audits to: 
• meet all members of his / her team involved in the study, 
• consult all of the documents relevant to the study, 
• directly access source documents to check, 
• verify that the study is carried out in compliance with the protocol and local regulatory 
requirements. 
All information dealt with during these visits will be treated as strictly confidential. 
 
13.0 Data Monitoring Committee 
An independent data monitoring committee including a psychologist, clinician, 
statistician and other appropriate members from the expert advisory panel will be 
appointed. The Data Monitoring Committee will review trial data and will advise the 
Sponsor whether changes to the protocol are advisable in light of safety, optimisation, 
recruitment and retention of participants and/or sample size.  
 
Any changes to optimise the intervention procedures will be decided by members of the 
Data Monitoring Committee. 
14.0 Regulatory and Ethical Obligations 
14.1 Regulatory Framework 
The trial will be conducted in compliance with the principles of the Declaration of 
Helsinki (1996 – the author should confirm which version is preferred by the sponsor 
at the time of writing), the principles of GCP and in accordance with all applicable 

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national and international regulatory requirements, including but not limited to the 
Research Governance Framework and the Medicines for Human Use (Clinical Trial) 
Regulations 2004, and any subsequent amendments.   
14.2 Approvals 
The study protocol, informed consent form, participant information sheet and any 
proposed advertising material will be submitted to an appropriate Research Ethics 
Committee (REC) for written approval. Any subsequent updates to these documents 
will also be sent to the REC for their approval prior to use in the study. 
14.3 Study Reports 
Annual progress reports and a final report at conclusion of the study will be 
submitted to the Research Ethics Committee within the required timelines.   
14.4 Participant Confidentiality 
The study researchers will ensure that the participants’ anonymity is maintained.  
The participants will be identified by a study participant number on the P1vital® 
ePRO and i-spero® systems. Only the participant consent form and contact details 
form will include the participant’s name, and these will be stored separately from 
other study data. All documents will be stored securely and only accessible by study 
staff and authorised personnel. The study will comply with the UK Data Protection 
Act 2018 which requires data to be anonymised as soon as it is practical to do so. 
15.0 Expenses, Benefits 
Participants will not be reimbursed financially for doing the intervention, for the following 
reasons: 
• 
All participants may potentially benefit clinically, as participants in both arms will 
receive the intervention (either immediately or after a delay of 4 weeks). 
• 
We wish for uptake of the intervention to be motivated by clinical benefit (a 
reduction in intrusive trauma memories) rather than financial benefit, to indicate 
naturalistic uptake in preparation for roll-out of the intervention. 
• 
No travel expenses are incurred, as the study is run entirely remotely using 
digital platforms that participants can access from their own home or another 
preferred location. 
However, as an incentive to complete follow-up measures, participants will be offered a 
£10 online voucher at the end of the study. 
16.0 Financial Aspects 
The study is funded by Wellcome Trust discretionary project grant award 
(223016/Z/21/Z) in mental health. 
17.0 Use of Information and Publication 
All information, including but not limited to scientific research data, generated as a result 
of this study, are considered confidential and remain the sole property of P1vital and its 

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academic and pharmaceutical company collaborators.  The results of the primary, 
secondary and tertiary analysis will be reported in a Study Report generated by P1vital 
Products Ltd (or delegate). 
Any anonymised data collected from the intervention use after participants have 
completed the trial, will only be used to optimise the intervention, and will not be 
considered research data. 
Study results will be also published in peer-reviewed journals and presented at scientific 
conferences. Study subject identifiers will not be used in any publications. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Experimental Trauma via Reconsolidation-Update Mechanisms. Psychological 
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APPENDIX 1: TIME AND EVENT SCHEDULE 
 
Virtual Visit Name  
Items 
Screening 
Run-in week 
Baseline 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Week 7 
Week 8 
Follow Up 
Day 
 
 
 
D1 
D1 to D7 
D8 to 
D14 
D15 to 
D21 
D22 to D28 
D29 to 
D35 
D36 to 
D42 
D43 to 
D49 
D50 to 
D56 
D57 to D70 
Visit Window 
 
D-35 
D-35 to D-21  
D-28 to D1 
 
 
 
 
D29 + 
7days 
(Del) 
+7 days 
(Del) 
+7 days 
(Del) 
+7 days 
(Del) 
+7 days 
(Del) 
Procedures and Assessment Tasks 
Participant information 
sheet 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Eligibility questionnaire 
9 
x 
 
 
 
 
 
 
 
 
 
 
 
Consent form 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Contact details 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Intrusive memory diary 
(daily) 
 
 
x x x x x x x 
 
 
 
 
x x x x x x x  
 
 
 
x x x x x x 
x (Del) 
 
Intrusive memory ratings 
10 
 
x1 
 
 
 
 
x1 
 
 
 
x1 
 
Randomisation 
 
 
 
x 
 
 
 
 
 
 
 
 
 
Credibility/Expectancy 
Questionnaire 
6 
 
 
x 
 
 
 
 
 
 
 
 
 
Demographics 
10 
 
 
x 
 
 
 
 
 
 
 
 
 
Health background 
6 
 
 
x 
 
 
 
 
 
 
 
 
 
Checklist of traumatic 
events 
4 
 
 
x 
 
 
 
 
 
 
 
 
 
Perceived threat to 
self/other 
2 
 
 
x 
 
 
 
 
 
 
 
 
 
Peritraumatic Distress 
Inventory 
13 
 
 
x 
 
 
 
 
 
 
 
 
 
Impact of Event Scale – 
Revised (IES-R) 
22 
 
 
x 
 
 
 
x2 
 
 
 
x2 
 
PTSD Checklist for DSM-5 
(PCL-5) 
4 
 
 
x 
 
 
 
x2 
 
 
 
x2 
 

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Generalized Anxiety 
Disorder (GAD-2) 
2 
 
 
x 
 
 
 
x2 
 
 
 
x2 
 
Patient Health 
Questionnaire (PHQ-2) 
2 
 
 
x 
 
 
 
x2 
 
 
 
x2 
 
Sleep Condition Indicator 
(SCI-08) 
8 
 
 
x 
 
 
 
x2 
 
 
 
x2 
 
Psychological Outcome 
Profiles Questionnaire 
(PSYCHLOPS) 
4 
 
 
x 
 
 
 
x2 
 
 
 
x2 
 
World Health 
Organization Disability 
Assessment Schedule 
(WHODAS) 2.0 
12 
 
 
x 
 
 
 
x2 
 
 
 
x2 
 
EQ- 5D-5L (5-level 
EuroQol 5D) 
5 
 
 
x 
 
 
 
x2 
 
 
 
x2 
 
Sickness absence 
1 
 
 
x 
 
 
 
x2 
 
 
 
x2 
 
Scale of Work 
Engagement and Burnout 
(SWEBO) 
18 
 
 
x 
 
 
 
x2 
 
 
 
x2 
 
Support from managers 
And friend/family 
2 
 
 
x 
 
 
 
 
 
 
 
 
 
Intention To Leave Job 
3 
 
 
x 
 
 
 
x2 
 
 
 
x2 
 
Changes to health and 
work 
9 
 
 
 
 
 
 
x2 
 
 
 
x2 
 
Intervention: List of 
intrusive memories 
(hotspots) 
 
 
 
 
x..x(Imm) 
x..x(Del) 
 
Intervention: Distress 
rating (x3) 
1 
 
 
 
x..x(Imm) 
x..x(Del) 
 
Intervention: 
Reactivation Vividness 
rating 
1 
 
 
 
x..x(Imm) 
x..x(Del) 
 
Intervention: Playing the 
computer game Tetris (at 
least for 20 minutes) 
 
 
 
 
x..x(Imm) 
x..x(Del) 
 
Intervention: mental 
rotating rating 
1 
 
 
 
x..x(Imm) 
x..x(Del) 
 

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Record of intrusive 
memories (daily) 
 
 
 
 
x..x(Imm) 
x..x(Del) 
 
Feedback questionnaire 
11 
 
 
 
 
 
 
𝐱𝟒(Imm) 
 
 
 
𝐱𝟒(Del) 
 
Qualitative interview 
(Optional) 
 
 
 
 
 
 
 
 
x3 
 
 
 
x3 
 
Note: measures in bold are in i-spero; measures not in bold are in ePRO; Del = delayed-intervention arm, Imm = immediate-intervention arm, X = all participants  
(immediate and delayed intervention arms) 
 
1. 
To be completed by participants at the end of the week (7th day) 
 
2. 
Participant for both arms will have a +7 days window to complete week 4 and week 8 outcome measures. 
3. 
Optional qualitative interview for immediate and delayed intervention arm can be completed within 14 days of day 29 and 57 respectively. 
4. 
Feedback questionnaire can be completed within 14 days of days 28 and 56 for delayed and immediate intervention arm participants respectively. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX 2: STUDY FLOW CHART 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continued 
optional access 
to Intervention 
+ intrusive 
memory diary 
(weeks 5-8) 
 
 
 
 
 
Screening 
Baseline questionnaires 
Immediate intervention: access to 
intervention + symptom monitoring for 4 
weeks 
Delayed intervention: usual care for 4 weeks then 
access to intervention + symptom monitoring for 
4 weeks 
Number of intrusive memories  
(run in week) 
Intervention + 
intrusive 
memory diary 
(weeks 1-4) 
 
 
 
 
Number of intrusive memories 
(week 4) 
Usual care 
(weeks 1-4) 
 
 
 
 
 
Number of intrusive memories 
(week 4) 
4 week follow-up questionnaires 
8 week follow-up questionnaires 
4 week follow-up questionnaires 
Informed consent 
Secondary 
comparison 
Primary 
comparison 
Eligible 
Intervention + 
intrusive 
memory diary 
(weeks 5-8)  
 
 
 
 
 
Number of intrusive memories 
(week 8) 
8(+4) week follow-up 
questionnaires 

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