Garety et al. Trials
(2021) 22:366
https://doi.org/10.1186/s13063-021-05301-w
STUDY PROTOCOL
Open Access
Optimising AVATAR therapy for people
who hear distressing voices: study protocol
for the AVATAR2 multi-centre randomised
controlled trial
Philippa Garety1,2, Clementine J. Edwards1,2* , Thomas Ward1,2, Richard Emsley1, Mark Huckvale3, Paul McCrone4,
Mar Rus-Calafell5, Miriam Fornells-Ambrojo3,6, Andrew Gumley7,8, Gillian Haddock9,10, Sandra Bucci9,10,
Hamish McLeod7,8, Amy Hardy1,2, Emmanuelle Peters1,2, Inez Myin-Germeys11 and Thomas Craig1,2
Abstract
Background: AVATAR therapy is a novel intervention targeting distressing auditory verbal hallucinations
(henceforth ‘voices’). A digital simulation (avatar) of the voice is created and used in a three-way dialogue between
participant, avatar and therapist. To date, therapy has been delivered over 6 sessions, comprising an initial phase,
focusing on standing up to a hostile avatar, and a second phase in which the avatar concedes and focus shifts to
individualised treatment targets, including beliefs about voices. The first fully powered randomised trial found AVAT
AR therapy resulted in a rapid and substantial fall in voice frequency and associated distress that was superior to
supportive counselling at 12 weeks. The main objective of this AVATAR2 trial is to test the efficacy of two forms of
AVATAR therapy in reducing voice-related distress: AVATAR-brief (standardised focus on exposure, assertiveness and
self-esteem) and AVATAR-extended (phase 1 mirroring AVATAR-brief augmented by a formulation-driven phase 2).
Secondary objectives include the examination of additional voice, wellbeing and mood outcomes, the exploration
of mediators and moderators of therapy response, and examining cost-effectiveness of both forms of therapy
compared with usual treatment (TAU).
Methods: This multi-site parallel group randomised controlled trial will independently randomise 345 individuals to
receive AVATAR-brief (6 sessions) plus TAU or AVATAR-extended (12 sessions) plus TAU or TAU alone (1:1:1
allocation). Participants will be people with a diagnosis of schizophrenia spectrum and other psychotic disorders
who have heard distressing voices for more than 6 months. The primary outcome is the PSYRATS Auditory
Hallucinations Distress dimension score at 16 and 28 weeks, conducted by blinded assessors. Statistical analysis will
follow the intention-to-treat principle and data will be analysed using linear mixed models. Mediation and
moderation analyses using contemporary causal inference methods will be conducted as secondary analyses.
Service costs will be calculated, and cost-effectiveness assessed in terms of quality-adjusted life years accrued.
(Continued on next page)
* Correspondence: clementine.edwards@kcl.ac.uk
1
Institute of Psychiatry, Psychology & Neuroscience, King’s College London,
London, UK
2
South London & Maudsley NHS Foundation Trust, London, UK
Full list of author information is available at the end of the article
© The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,
which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if
changes were made. The images or other third party material in this article are included in the article's Creative Commons
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The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the
data made available in this article, unless otherwise stated in a credit line to the data.
Garety et al. Trials
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(Continued from previous page)
Discussion: This study will clarify optimal therapy delivery, test efficacy in a multi-site study and enable the testing
of the AVATAR software platform, therapy training and provision in NHS settings.
Trial registration: ISRCTN registry ISRCTN55682735. Registered on 22 January 2020. The trial is funded by the
Wellcome Trust (WT).
Keywords: Auditory hallucinations, Psychosis, Psychological intervention, Digital health technology, Randomised
controlled trial
Administrative information
The order of the items has been modified to group similar items (see http://www.equator-network.org/
reporting-guidelines/spirit-2013-statement-definingstandard-protocol-items-for-clinical-trials/).
Title {1}
Trial registration {2a and 2b}.
Optimising AVATAR therapy for
distressing voices: the AVATAR2 multicentre randomised controlled trial.
ISRTCN registry, reference: [ISRC
TN55682735] on 22/01/20.
Protocol version {3}
1.2
Funding {4}
An Innovations Project Award from the
Wellcome Trust.
Author details {5a}
Institute of Psychiatry, Psychology &
Neuroscience, King’s College London.
South London & Maudsley NHS
Foundation Trust
NIHR Biomedical Research Centre
CJE, PAG, TW, TC, EP, AH. RE
Mental Health Research and Treatment
Center
Faculty of Psychology
Ruhr-Universität Bochum
MRC
University of Manchester,
GH, SB
University of Greenwich
PM
KU Leuven
IMG
University College London
MFA, MH
Institute of Health and Wellbeing,
University of Glasgow
HM, AG
Name and contact information Co-Sponsor: King’s College London
for the trial sponsor {5b}
Professor Reza Razavi,
Room 5.31, James Clerk Maxwell
Building, 57 Waterloo Road, London,
SE1 8WA.
02078483224
reza.razavi@kcl.ac.uk
Co-Sponsor: South London & Maudsley
NHS Trust
R&D Department, Room W1.08 Institute
of Psychiatry, Psychology &
Neuroscience (IoPPN) De Crespigny
Park, London, SE5 8AF.
02078480339
slam-ioppn.research@kcl.ac.uk
Role of sponsor {5c}
The sponsor and funders will monitor
the governance of the study and
Administrative information (Continued)
milestones for completion and will
have no other role in the design,
collection, analysis or interpretation of
data or the decision to submit to
report for publication.
Introduction
Background and rationale {6a}
Voices are the most commonly reported form of
auditory hallucinations [1] heard by as many as 70% of
people diagnosed with schizophrenia-spectrum disorders
[2]. They are often associated with high levels of distress
and can have a profound impact on everyday life, with
typical content involving threats, commands, and abusive comments. Voices frequently persist for many years
despite optimal pharmacotherapy, and the currently recommended psychological therapy for voices, cognitive
behavioural therapy for psychosis (CBTp) is effective [3]
but only for just over 50% of people [4]. CBTp also involves delivering a relatively lengthy treatment, which
presents significant barriers to access [5]. Consequently,
there is considerable interest in the development of
novel therapies that are informed by CBTp principles,
but which are both shorter and capable of being delivered by a wider workforce.
Typically, voices have ascribed ‘characterful’ identities
and are experienced as profoundly ‘real’ [6] with three
quarters of people who hear voices reporting an
associated mental image [7]. Cognitive models of voices
highlight the role of beliefs about voices in voice-related
distress (notably relating to omnipotence and malevolence) [8]. Social rank theory [9] has been applied to
voices with evidence that the inferiority and powerlessness people commonly experience in relation to their
voices may mirror key social relationships, which for
some include experiences of trauma [10]. This relational
perspective informs psychological approaches to distressing voices that focus on the interpersonal relationship
between the voice-hearer and the voice [11] and seek to
understand the voice in the broader context of the person’s life [12, 13].
AVATAR therapy is one such relational approach. A
digital representation (avatar) of the person’s main
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distressing voice is created, informed by a detailed
assessment of the voice (including verbatim content,
voice characterisation, the nature of voice-hearer relationship and developmental history). Bespoke software
transforms the voice of the therapist to match the auditory characteristics of the voice. The person then creates
a visual representation of the voice in line with the ascribed identity and character. The two processes are
combined to produce the avatar, through which the
therapist can interact with the voice-hearer using a console to switch between speaking in the transformed avatar voice and their own voice. AVATAR therapy as
delivered to date comprises two phases. In the first
phase, (Exposure and Assertiveness) the avatar delivers
verbatim voice content (including threats and abuse)
and the person practices assertive responding. Over time
the avatar becomes less hostile as the person develops
increased power and control within the dialogue. This
cues a second phase with formulation-driven therapeutic
targets, which can include work on beliefs about voices,
self-concept and trauma [14].
Following a proof-of-concept study [15], we have
conducted a fully powered pragmatic, single blind
single-centre RCT [16] comparing AVATAR therapy
with supportive counselling (SC) delivered over 7 weekly
sessions. This showed that AVATAR therapy resulted in
a rapid and substantial reduction in the frequency and
distress (PSYRATS-AH) and power of voices (BAVQ-R),
that was significantly superior to SC at 12 weeks (the
primary outcome). The observed differences at 12 weeks
were larger than anticipated with a between-group effect
size of 0.8 suggesting that it is a more effective therapy
for voices than the alternatives currently available. At 24
weeks, the differences between the two arms were no
longer statistically significant, although the clinically significant improvements in the AVATAR therapy scores
on primary outcome were sustained.
The lack of a treatment as usual (TAU) arm in this
study made the absence of difference between the two
active treatment groups at 24 weeks hard to interpret.
Similarly, attempts to understand the mechanisms of
action for AVATAR therapy are more challenging in the
context of an active treatment control. With respect to
possible factors which may influence treatment
response, a recent analysis of in-session ratings (collected only in the AVATAR therapy arm) explored selfreported anxiety and the sense of voice presence (i.e. the
extent to which speaking to the avatar was experienced
as like talking to the everyday voice). Whilst sense of
voice presence remained consistently high across all sessions, there was a significant reduction in anxiety which
was driven by a rapid change during sessions 1–3 (phase
1). Notably, improvements in voice frequency and overall severity at follow-up were predicted by an interaction
Page 3 of 17
between overall anxiety reduction and sense of voice
presence [17]. Allied to clinical reports of significant
early improvements [14], this raises the question as to
whether a consistent phase 1 focus on exposure and assertiveness to a valid representation of the voice might
be sufficient for some individuals; for example, where
distress is closely linked to fear, anxiety and relational
submissiveness. There would be fewer barriers to training and dissemination of a standardised phase one-based
AVATAR therapy compared to the extended therapy,
potentially facilitating implementation both across the
UK and in other settings worldwide where therapists
trained in formulation-based psychological therapies are
in short supply.
On the other hand, phase 2 of AVATAR therapy
targets developmental and maintenance (‘here and now’)
processes specific to an individual formulation. The
phase 1 focus on anxiety reduction and assertiveness is
extended in a way that may be necessary for optimally
effective lasting change where distress is associated with
other cognitive, emotional and relational processes.
Notably, phase 2 targets beliefs about voices (relating to
perceived power and malevolent intent) and aims to
facilitate a change in the relationship with the voice
which is grounded in autobiographical context and
personal meaning, e.g. where voices reflect past
experiences of disempowerment and social defeat, the
dialogues target emotional resolution and updated views
of the self. We will examine these key treatment targets
(anxiety and beliefs about voice power and malevolence)
as mediators of treatment effects.
The more complex and personalised phase 2 dialogue
may be particularly relevant for voices that are
experienced as characterful social agents [18–20], i.e.
voices with ascribed attitudes, intentionality, and
personality (their own ‘character’). Ward and colleagues
[21] found that one third of individuals in their AVAT
AR therapy sample reported a highly characterised
dominant voice (e.g. voices associated with a family
member or identifiable ‘stranger’ with a consistent
background and personality). Specifically, these
individuals showed increased interaction (time in
conversation) with the avatar compared to those with
non-complex characterisation (voices with no clear identity or with only ‘one-dimensional’ character, e.g. ‘an
angry, punishing spirit’). Whilst this suggests that the
degree of voice characterisation can affect engagement
in active dialogue, it remains an open question as to
whether it might influence treatment outcome. We plan
to address this question in the current trial design, randomising to the two forms of therapy plus TAU, AVAT
AR-Brief (Phase 1 only) or AVATAR-Extended (phase 1
plus phase 2), or to TAU alone, stratifying by baseline
level of characterisation. We hypothesise that whether
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the voice hearer’s main voice is more or less highly characterised influences (moderates) the treatment effect of
level of therapy compared to TAU. If so, this would provide important information concerning targeted treatment. Additional exploratory moderation analyses will
consider other demographic and clinical factors which
might plausibly influence treatment effects. These include attachment and trauma history, given the relational nature of the AVATAR approach, as well as
clinical characteristics found to affect engagement in
psychological interventions (e.g. negative symptoms [22]
and post-traumatic stress disorder (PTSD) symptomatology [23–25]). Our previous work investigated the costeffectiveness of AVATAR therapy compared to supportive counselling and found favourable results (paper in
preparation). This study will enable us to make a more
robust estimate of cost-effectiveness.
Objectives {7}
The trial will address questions of treatment efficacy and
cost-effectiveness of brief and extended versions of therapy and their implementation in NHS settings, including
testing the provision of the integrated and enhanced
software platform for the delivery of therapy employed
in the clinical trial, together with the operational and
therapy manuals.
Hypotheses
1. AVATAR-brief will be more effective in reducing
voice-related distress, total voice severity and voice
frequency than TAU at post-treatment (16 weeks)
and follow up (28 weeks)
2. AVATAR-extended will be more effective in
reducing voice-related distress, total voice severity
and voice frequency than TAU, at post-treatment
(16 weeks) and follow-up (28 weeks)
3. AVATAR-extended will reduce perceived
omnipotence and malevolence (BAVQ-R) compared
to TAU and these improvements will mediate
change in the primary outcome.
4. In both AVATAR-brief and AVATAR-extended
treatment effects on the primary outcome will be
mediated by anxiety reduction, as measured by
Experience Sampling Methodology (ESM) in daily
life.
5. Greater baseline complexity of voice
characterisation will moderate the treatment effects
of AVATAR-brief and AVATAR-extended
compared to TAU. Other clinical characteristics
will be explored as potential moderators.
6. AVATAR-brief and AVATAR-extended will both
have favourable incremental cost-effectiveness ratios
compared to routine care.
Trial design {8}
A three-arm parallel-group superiority randomised controlled trial, with 1:1:1 allocation and blinded assessors,
to test the efficacy of AVATAR therapy (Brief and Extended forms) in people diagnosed with schizophrenia
spectrum disorders in reducing voice-related distress
when added to treatment as usual (TAU) compared to
TAU alone.
Methods: participants, interventions and
outcomes
Study setting {9}
Four UK research sites will take part in the trial:
Institute of Psychiatry, Psychology & Neuroscience
(KCL), University of Manchester, University of Glasgow
and University College London. At least two local NHS
sites will be attached to each of these research sites and
therapy will take place in community settings.
COVID-19 adaptations to the protocol
In response to the global pandemic, the research team
have made adaptations to the protocol to enable AVAT
AR2 to continue in the event of social distancing
restrictions being in place. These adaptations to the
protocol are detailed in the recruitment, assessment and
therapy delivery sections below. Where possible, the
AVATAR2 team will see participants face-to-face as detailed in this protocol; the changes outlined will be applied when this is required by NHS trust and University
guidance.
Eligibility criteria {10}
The inclusion criteria for the study are as follows: (1)
aged 18 years or over; (2) currently under the care of a
specialist mental health team (inpatient and outpatient
settings); (3) have current frequent and distressing
voices, (as measured by a score of at least 1 on each of
the intensity of distress and frequency items of the PSYR
ATS (Voices) scale), persisting for at least 6 months and
spoken in English; (4) speak and read English to a
sufficient level to provide consent and complete the
assessment procedures; and (5) a clinical diagnosis of
Schizophrenia spectrum disorder (ICD10 F20–29) or
affective disorder with psychotic symptoms (ICD-10
F30–39, subcategories with psychotic symptoms) as
determined through clinical records and additional
consultation with the clinical team if unclear. Criteria
for exclusion are as follows: (1) primary diagnosis of
substance disorder, personality disorder or learning
disability; (2) lacking capacity to consent; (3) profound
visual/hearing impairment or insufficient comprehension
of English to be able to engage in assessment or therapy;
(4) currently undertaking individual psychological
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therapy for voices; and (5) currently experiencing an
acute mental health crisis.
Therapy will be delivered by mental health clinicians,
mostly psychologists, with experience of delivering
psychological therapy to people with psychosis.
Who will take informed consent? {26a}
Potential participants will initially be contacted by a
member of their clinical team in the participating NHS
sites, who believes them to be eligible, inviting them to
learn more about the study. They may also be contacted
if they have indicated they are interested in research
through their NHS Trust (e.g. “Consent for Contact”)
and can also self-refer directly into the study. Once they
have expressed their interest or agreed to be contacted,
they will be approached by a research assistant who will
confirm eligibility criteria and obtain consent to participate in the research.
COVID-19
The information sheet and consent form detail the
changes that will be made to the protocol during social
distancing.
We will continue recruitment of participants as
described above where possible during social restrictions
using remote processes. The research team will maintain
communication with clinical teams remotely and
referrals will be made in the same manner. If face-toface contact is not possible, alternative consent options
will be utilised as follows:
1. Obtaining consent using an electronic signature or
online consent form;
2. Recording verbal consent via video calling or
telephone. These recordings will be stored securely
and linked to the participant code, on university
computers, separate from any identifying details.
Additional consent provisions for collection and use of
participant data and biological specimens {26b}
On the consent form, participants will be asked if they
agree to the use of their data should they choose to
withdraw from the trial. Participants will also be asked
for permission for the research team to share relevant
data with people from the Universities taking part in the
research or from regulatory authorities, where relevant.
This trial does not involve collecting biological
specimens for storage.
Interventions
Explanation for the choice of comparators {6b}
The previous trial of AVATAR therapy showed it was
effective post-treatment at 12 weeks, compared with an
active control treatment (supportive counselling) but the
lack of a TAU only arm meant that it was difficult to interpret the absence of a difference between the two active treatment groups at 24 weeks. The next stage of
treatment evaluation and research therefore calls for a
TAU control comparator before wider dissemination.
Additionally, there are questions about the treatment.
As described above, AVATAR therapy as delivered in
the previous trial comprises two phases. The trial
therapists noted that phase 1 in itself was a powerful
intervention for a sizeable number of people, which was
supported by evidence within the AVATAR therapy arm
of significant anxiety reduction during sessions 1–3 [17].
On the other hand, for some people, anxiety reduction
alone may be insufficient to produce optimally effective
lasting change, and therefore an approach including both
phases may be necessary (see the ‘Introduction’ section).
This trial will therefore include two treatment arms,
AVATAR-brief (6 sessions) and AVATAR-extended (12
sessions), each combined with TAU, to allow an
evaluation and comparison of both these approaches with
TAU alone, with an additional health economics
evaluation of the incremental cost-effectiveness ratios of
each approach compared with TAU.
Intervention description {11a}
AVATAR-brief consists of six individual, face-to-face
sessions (in addition to an initial clinical assessment session including avatar creation), delivered by trained therapists (with previous experience working in psychosis),
assisted by the avatar software described previously.
Therapy focuses on the exposure/assertiveness component and will follow detailed session-by-session guidance
in a written AVATAR clinical manual. At the end of
each interaction with the avatar, the therapist will return
to the room and support the participant to answer questions regarding their experience of the interaction (perceived hostility, anxiety, sense of voice presence)
presented either on the screen or in a booklet (at therapist’s discretion).
AVATAR-extended consists of twelve individual, faceto-face sessions (in addition to the initial assessment and
avatar creation session), delivered by trained therapists,
assisted by the AVATAR therapy software described
previously. It includes both phases of treatment as described earlier and detailed in the AVATAR clinical
manual. The participants will also complete the same
questions at the end of each interaction with the avatar
as described above. In line with the clinical manual, the
number of sessions for both AVATAR-brief or AVAT
AR-extended is permitted to vary by no more than two
sessions added or removed; any such change will be
guided by the clinical judgement of the therapist and in
collaboration with the participant.
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It is necessary to have access to two private rooms to
conduct the therapy; additional equipment includes a
laptop (with a webcam and microphone) and secure
network, the AVATAR therapy software and the
participant must have access to a device on which they
can listen to recordings of the sessions (this will be
provided by the study team as required). Face-to-face
sessions will mostly be conducted at a clinical research
facility or local clinical team settings.
Approximately 20 clinicians will be trained to deliver
AVATAR therapy during the trial. This will include a
core team of 8 trial therapists and clinicians at local
NHS sites who will be trained with a view to delivering a
smaller number of cases and building therapy and
training capacity in the NHS. Training will involve initial
orientation to the clinical and technical manuals
followed by sessions (face-to-face or remote) focusing on
the rationale, therapy targets and delivery of AVATARbrief and AVATAR-extended. Initial pilot cases will be
closely supervised by someone with experience of AVAT
AR therapy delivery. Training cases will be assessed for
treatment fidelity and therapist competence using tools
which have been developed for routine monitoring
throughout the trial (see the ‘Strategies to improve
adherence to interventions {11c}’ section). Therapy
supervision during the trial will include individual and
group-based supervision delivered from the main site
(King’s College London) in addition to individual and
peer-based supervision at each local site.
For both AVATAR-extended and AVATAR-brief
arms, in-session measures assessing anxiety, perceived
hostility, sense of presence and sensed presence will be
completed at the end of each interaction with the avatar
(items adapted from [26, 27]). The Working Alliance Inventory (WAI) Short-Form will be used to assess the
quality of the therapeutic alliance from the perspective
of the participant- this will occur at Session 4 (AVAT
AR-extended and AVATAR-brief) and repeated in Session 10 (AVATAR-extended only) if therapy delivery
changes during the course of intervention (remote or
face to face). Therapy process activities (e.g. between
session phone contact or messaging and clinical team liaison) will be routinely collected to inform future
implementation.
The AVATAR Therapy software [28] has been CE
marked and registered with the MHRA as a class 1
medical device by Avatar Therapy Ltd. (www.
avatartherapy.co.uk).
manual. Where the participant does not have access to
appropriate equipment at home, the therapist will work
with the person to find a solution that allows therapy to
take place remotely. Where necessary, AVATAR2 will
provide the hardware to the participant (e.g. tablet or
computer), which would be returned to the research
team at the end of the therapy period.
In addition to the protocol as outlined above, there
will be one remote therapy set-up session where the
therapist will explain how the bespoke AVATAR therapy
video call system works and problem solve the set-up of
the remote therapy sessions.
COVID-19
Relevant concomitant care permitted or prohibited
during the trial {11d}
AVATAR therapy, using the same clinical manual, will
be delivered remotely using a bespoke, secure, end-toend encrypted video-call system which will enable the
delivery of the therapy in accordance with the clinical
Criteria for discontinuing or modifying allocated
interventions {11b}
Apart from the change in number of sessions (plus or
minus 2) described above, to take account of clinical
circumstances, the intervention may be discontinued if
the participant requests this or if the clinician judges, in
consultation with the wider supervisory team, that the
intervention is associated with a significant worsening of
mental health. In this case an Adverse Event form would
also be completed. It will be made clear to each
participant that, should they find any aspect of the
research distressing, including the intervention, and/or
no longer wish to continue, they will be able to
withdraw without this impacting on their usual clinical
care in any way.
Strategies to improve adherence to interventions {11c}
The number of active sessions attended (i.e. sessions
involving active avatar dialogue) by the participant will
be measured to assess treatment adherence. Fidelity to
the clinical manual will be assessed by the therapist
completing a session-by-session checklist of specified
components (these will also be used during training and
ongoing supervision- see above). Each session will be
audio recorded with consent. After completion of training, therapist competence will be assessed by an expert
in AVATAR therapy for general/clinical and AVATARspecific skills using ratings adapted from the first AVAT
AR therapy trial and allowing for differing skill requirements for each level of therapy. Each trial therapist will
be rated for competence based on the review of early,
mid and late session therapy delivery for at least one
completed intervention. Ratings will be conducted for
two cases for therapists who deliver completed therapy
with more than five participants.
Participation will not alter clinical treatment decisions
about medication and additional psychological and
psychosocial interventions which remain the responsibility
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of the clinical team. The antipsychotic medication
prescribed to participants in the study and psychological
and psychosocial interventions provided will be recorded.
Provisions for post-trial care {30}
There is no provision for post-trial care in the study and
participants will remain under the care of their usual
mental health services. The trial is covered by the Sponsor’s (King’s College London) indemnity insurance.
Outcomes {12}
The primary outcome for the study is reduction at end
of treatment (16 weeks) and follow up (28 weeks) in the
distress associated with voices, as measured by the
distress dimension of the Psychotic Symptoms Rating
Scale (PSYRATS-AH) [29, 30].
We note the recent CONSORT-SPI guidance which
recommends minimising the distinction between primary and secondary outcomes, therefore all outcomes
will be reported at the end of the trial [31].
All measures are detailed in Table 1.
Participant timeline {13}
Figure 1 shows the participant timeline.
Sample size {14}
We will recruit 345 people in total for the study
(approximately 87 per site and 115 per arm). The
effect size in the sample size calculation is based on
the findings of the previous AVATAR therapy trial
[16] which reported clinically meaningful reduction in
PSYRATS-AH distress dimension post-treatment of
4.8 points, with an effect size of approximately d =
0.8. This has been conservatively reduced for the
current trial, to take into consideration the increase
in the number of centres, the comparison at both
post-treatment and follow-up and a more pragmatic
trial design. We are accounting for two formal comparisons (hypothesis 1 and 2).
The study is powered for an overall treatment effect at
a 5% alpha level, accounting for 2 multiple comparisons
in which the tests are correlated (at r = 0.5), giving an
alpha level for each test of 0.035. Accordingly, a sample
size of 92 per group or 276 in total will have 90% power
to detect a minimum clinically significant difference
(effect size) of 0.5 standard deviations. We will recruit
345 participants in total at baseline, allowing for an
attrition of 20%.
Recruitment {15}
Participants will be recruited from NHS mental health
services linked to each of the four university trial sites
(at least 2 NHS settings per site) with identical
procedures followed at each. Participants will be
identified through close liaison with clinical staff. After
clinical staff have confirmed that a potential participant
is suitable to be approached (i.e. meets study criteria and
no clinical contra-indications), research workers will
meet each potential participant to discuss the study, provide written information and time to consider it, respond to questions and seek written informed consent.
We also intend to use recruitment databases or
consent for contact initiatives where available to
maximise the pool of potential participants. Finally, we
can be approached directly by service users interested in
taking part and intend to place recruitment posters in
the main clinical areas of specialist mental health teams,
as well as promoting the trial through online platforms
(Twitter, trial website) to facilitate this. In all such
instances, we will contact the relevant clinical team and
discuss suitability for participation.
Assignment of interventions: allocation
Sequence generation {16a}
A randomisation list will be prepared independently by
the King’s Clinical Trials Unit using random permuted
blocks, stratified by site and baseline voice
characterisation An allocation sequence (1:1:1) will be
generated, using random permuted blocks of varying
size, and stratified by site (4 sites) and baseline voice
characterisation (more/less) as defined by meeting the
threshold for more highly characterised voice on the
characterisation checklist.
Concealment mechanism {16b}
The allocation sequence will be held independently of
the research team and each participant’s allocation
revealed via a secure web-based service hosted by King’s
Clinical Trials Unit.
Implementation {16c}
Once a participant has completed baseline assessments,
the site trial coordinator will perform the randomisation
utilising the web-based service and inform the
participant.
Assignment of interventions: blinding
Who will be blinded {17a}
Trial coordinators who will not be blind to individual
allocations to allow them to inform participants of
assignment. The research workers who conduct
assessments will remain blinded to the allocation of
participants until after the participant has completed
their involvement in the trial. These research workers
will not be exposed to therapy records whilst they
remain blinded. We will be using a system of web-based
data entry that ensures assessors do not have access to
information in the database that might reveal allocation.
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Table 1 AVATAR2 measures
Measure
Timepointa
Distress, frequency and severity of
voices outcome measures
Psychotic Symptom Rating Scales – Auditory Hallucinations – a dimensional measure of
hallucinations- [27]. Includes Distress dimension (primary outcome), Total score (secondary
outcome), and Frequency dimension (secondary outcome) [28].
Hallucinations Remission Score
Screening,
1, 2, 3
Other voices outcome measures
Beliefs about Voices Revised (BAVQ-R) [30]
Voices acceptance and action scale (VAAS) [31]
First item (power) from the Voice Power Differential Scale [32]
1, 2, 3
Experience sampling methodology
AVATAR2 ESM Questionnaire [33]
1,2,3
Other secondary outcome measures
Health economic outcome measures
Baseline clinical characteristics
AVATAR2 ESM Debrief Questionnaire e.g. [34]
1,2,3
Mood: Beck Depression Inventory-II [35]
1, 2, 3
Anxiety: Depression Anxiety and Stress Scales (DASS-21) [36]
1,2,3
Quality of Life: Warwick-Edinburgh Mental Well-being Scale [37]
1, 2, 3
Delusions: Psychotic Symptoms Rating Scale (PSYRATS-DEL) [27]
1, 2, 3
Service User Led Outcome Measure: Choice of Outcome in CBT for Psychosis (CHOICE) Short
Form [38]
1,2,3
Trauma related symptoms – International Trauma Questionnaire (ITQ) [39]
1, 2
Service use and costs: costs of the intervention (based on staff time, overheads and equipment)
and the costs of other key health and social care services calculated using the [40].
1, 2, 3
EQ-5D-5L [41] to measure QALYs
1, 2, 3
Voice Characterisation Checklist: Assesses the complexity in characterisation of the dominant
voice. Rated as more vs. less highly characterised based on presence/absence of ascribed
identity (e.g. known, name), physical characteristics (e.g. age, gender, accent) and psychosocial
characteristics (e.g. intentions, thoughts, relationships)-see [19]. Including two items from the
Voice Phenomenology Interview [42].
1
Fearful Attachment Style Item from Relationships Questionnaire [43].
1
Patient perceived trauma-voice links - Trauma Voice Associations Questionnaire (TVAQ) [44].
1
Trauma history - Mini-Trauma And Life Events (TALE) checklist [45]
1
Clinical Assessment Interview for Negative Symptoms (CAINS) [46]
1
Identification of positive symptoms – Initial items from the Schedules for Clinical Assessment in
Neuropsychiatry (SCAN) 2.1 [47]
1
Detailed assessment of positive symptoms - Scale for the Assessment of Positive Symptoms [48] 1
COVID-19 Impact
COVID-19 Context Questionnaire to assess individual circumstances during pandemic and
change in voice experiences.
1, 2, 3
a
1 = baseline, 2 = 16 weeks post-randomisation, 3 = 28 weeks post-randomisation
Participants will be reminded not to discuss their allocation with research workers when they meet them for the
assessment. The senior trial statistician will be blind
throughout the study; the trial statistician will be unblind at a group level after the first DMEC meeting. The
Statistical Analysis Plan will be prepared before any
unblinding of the trial statistician, and only amended by
the senior trial statistician.
Procedure for unblinding if needed {17b}
There are no pre-determined situations in which blinded
research workers should become unblinded. Breaks in
blindness will be monitored and recorded and where operationally feasible assessments will be allocated to another (blinded) research worker.
Data collection and management
Plans for assessment and collection of outcomes {18a}
Assessments will be completed at baseline, after
treatment at 16 weeks, and at 28-week follow-up. Participants who have consented will also complete an additional ESM assessment at each time point, responding
to questionnaires administered through a smartphone 10
times a day for 6 days. This will be delivered using an
application (M-Path, https://m-path.io/landing/) which
can be downloaded to the participant’s own phone.
Where the participant does not have a smartphone or
has concerns about using their own, a smartphone will
be provided to them. At the end of the 6 days, the research worker will meet the participant again to
complete a debrief questionnaire regarding their
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Fig. 1 Participant Time Schedule
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experiences of the ESM and to collect the smartphone
where this has been provided.
All these assessments will be administered by trained
local research workers, who will be supervised by
experienced research clinical psychologists. Assessments
will be conducted at locations convenient for the
participant (at either NHS, University or residential
locations).
COVID-19
All assessments will take place remotely via a videoconferencing application or telephone, in line with NHS
trust and University guidance. Questionnaires should be
completed online where possible; that is, where the person has a laptop/tablet and a Wi-Fi connection. Where
this is not possible, they will be posted with a stamped
addressed envelope to be returned. In the event of social
distancing restrictions, additional measures will be taken
to manage any distress that occurs with the research
team liaising closely with the clinical team caring for the
person. The content of the assessment will be as described below.
A sub-sample of participants, approximately 20, who
give their consent, will be consecutively recruited across
all sites and from both therapy arms in the study to take
part in a qualitative interview. This will occur in the final
year of the trial, and once those approached have concluded their participation in all assessments in the trial.
This interview and the conduct of this sub-study will be
developed in collaboration with service user consultant
researchers, working with the research team, and will
ask participants for feedback on how they found the
therapy, taking part in the trial and the technology/software involved.
Plans to promote participant retention and complete
follow-up {18b}
Research workers will maximise engagement with
participants and facilitate their completion of followup assessments. This includes flexibility around the
locations of assessments (home visits where risk assessment is completed) and covering travel expenses
for participants. As all outcome measures are through
interviews or self-report measures these cannot be
completed with participants who discontinue their
participation.
Data management {19}
All data are anonymised at source. No patient
identifiable information is recorded on the research
assessment records and the computerised database is
held centrally and managed by the King’s Clinical Trials
Unit. A web-based electronic data capture (EDC) system
will be designed, using the InferMed Macro 4 system.
Page 10 of 17
The EDC will be created in collaboration with the trial
analyst/s and the CI and maintained by the King’s Clinical Trials Unit for the duration of the project. It will be
hosted on a dedicated server within KCL. Experience
sampling data will be uploaded via a secure network to a
Research Electronic Data Capture (REDCap) database
managed by the University of Leuven, Belgium who will
be conducting the ESM data analysis.
Source data will be entered by recruiting site staff,
typically within 7 days of data collection by authorised
staff onto the EDC. A full audit trial of data entry and
any subsequent changes to entered data will be
automatically dated and time-stamped, alongside information about the user making the entry/changes within
the system. Database access will be strictly restricted
through user-specific passwords to the authorised research team members.
The CI team will undertake appropriate reviews of the
entered data, in consultation with the project analyst for
the purpose of data cleaning and will request
amendments as required. No data will be amended
independently of the study site responsible for entering
the data. In order to ensure the accuracy of the data
entered into the database, the primary outcome measure
entry will be checked for every participant by comparing
the paper record with that on the database. An error
rate of no more than 5% is acceptable. This will be
completed once all possible assessments for each time
point have been completed. If the error rate is higher
than 5%, advice will be sought from the trial statisticians
regarding further data checking. At the end of the trial,
there will be a central process of data cleaning and
checking to verify that all the data are complete and
correct. At this point, all data will be formally locked for
analysis.
Audio recording equipment will be used to record
assessments to check fidelity to assessment protocols
and to ensure interrater reliability of the PSYRATS-AH
(primary outcome) and the Voice Characterisation
Checklist (stratification tool). The therapy sessions will
be audio recorded (with participant consent) for
monitoring the intervention in terms of fidelity and
competence. These audio files named with a unique
participant identifier will be stored as computer files on
secure NHS/ University servers.
All personal data will be kept in a locked filing
cabinet in a locked office at the four trial sites and
will be accessible only by researchers. Therapy files
will be kept in a secure office and are not accessible
to the staff collecting the research outcome data.
Audio recordings of the therapy will be stored as
described above, accessible to the patient's trial
therapist and to the senior research clinician
supervising that therapist.
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Confidentiality {27}
All data are anonymised at source. A log of contacts
with participants including address and other contact
details will be kept separate from all the research data.
Details necessary to contact participants, and for
communication with teams will be stored securely in a
locked filing cabinet. A numerical system will be used
for computerised information so that individual
participants will not be identifiable. Participant consent
forms will be retained, kept confidential and stored
securely. All identifiable data will be destroyed following
a period of 7 years (as determined by relevant
information governance policies) after the completion of
the trial.
Assessment and therapy sessions will be recorded,
with consent, using password-protected smartphone or
equivalent devices and data will be transferred to secure
central storage as soon as possible. When not in use, devices will be stored in a locked cabinet within a locked
office.
Plans for collection, laboratory evaluation and storage of
biological specimens for genetic or molecular analysis in
this trial/future use {33}
See above {26b}, there will be no biological specimens
collected.
Statistical methods
Statistical methods for primary and secondary outcomes
{20a}
We will report all participant flow in the study in
accordance with the CONSORT principles, with the
2018 extension for reporting social and psychological
intervention trials ((CONSORT SPI) [31]). Descriptive
statistics will be used to summarise assessments of
recruitment, drop-out and completeness of therapy.
The primary outcome of voice-related distress as measured by PSYRATS-AH distress dimension score will be
analysed using a mixed effects model including data
from all time points. Fixed effects will be site, characterisation, baseline assessment for the outcome under investigation, random allocation, time and time*random
allocation interactions. Participant and therapist will be
included as random intercepts, with the participants in
the TAU arm considered as being in individual clusters
of size 1. Marginal treatment effects for each pairwise
comparison will be estimated for outcomes at each time
point and reported separately as mean adjusted differences in scores between the respective randomised
groups with 96.5% confidence intervals and two-sided p
values (to account for correlated multiple comparisons).
For continuous secondary outcomes, the same approach
will be followed, and for binary secondary outcomes,
logistic mixed models will be used.
The random effect structure will account for repeated
measures and clustering due to the partially nested
design and allow estimates of separate ICCs in both
randomised arms.
Cohen’s d effect sizes at 16 and 28 weeks will be
calculated as the adjusted mean difference divided by
the sample standard deviation of the outcome at
baseline and displayed in a forest plot.
Interim analyses {21b}
There are no planned interim analyses.
Methods for additional analyses (e.g. subgroup analyses)
{20b}
Causal mediation analysis will be based on parametric
regression models [50]. For each mediator separately,
this involves estimating a linear model for each mediator
with random allocation, baseline outcome, baseline
mediator, site and characterisation as covariates, and
separately estimating a linear model for each outcome
with the mediator, random allocation, baseline outcome,
baseline mediator, site and characterisation as covariates.
The effect of random allocation on the mediator is
multiplied by the effect of mediator on the outcome to
estimate the indirect effect, and the effect of random
allocation on outcome in the model including mediator
is an estimate of the direct effect. The indirect and
direct effects sum to the total effect and bootstrapping
with 1000 replications will be used to obtain valid
standard errors for the causal effects.
For the moderation analyses, these will be conducted
by adding interaction terms between random allocation,
time and the respective moderators. The difference in
treatment effect between unit levels of the moderator
can be interpreted as the difference in the estimated
treatment effect between a participant with a moderator
value at baseline of a+ 1 and a participant with a
moderator value at baseline of a.
For analyses involving ESM variables as outcome, an
additional level of nesting will be included, with multiple
ESM observations (level 1) being nested within time
points (level 2) and time points as nested within subjects
(level 3).
Methods in analysis to handle protocol non-adherence
and any statistical methods to handle missing data {20c}
The main efficacy analysis will be via intention to treat
with data from all participants included in the analysis
including those who do not complete therapy. Every
effort will be made to follow up all participants for
research assessments, and the analysis will use, where
appropriate, statistical techniques for handling missing
data. All models will be estimated using maximum
likelihood estimation, which allows for missing outcome
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data under the missing at random assumption; we may
also use inverse probability weighting to adjust for nonadherence to allocated treatment and other intermediate
outcomes as predictors of future loss to follow-up.
Health economic analyses
The use of services at baseline, 16 weeks and 28 weeks
will be measured with the Client Service Receipt
Inventory. Service costs will be calculated by combining
these data with appropriate unit cost information
(including NHS Reference Costs and figures from the
University of Kent). These costs will be added to the
costs of the therapy (based on staff time, overheads and
activity levels). Costs will be compared between the
three arms at 16 and 28 weeks using regression models
adjusting for baseline differences. (The 28-week comparison will be of the cumulative costs to that time
point.) Bootstrap methods will be used to generate confidence intervals around the cost differences. Qualityadjusted life years (QALYs) will be generated using the
EQ-5D-5L along with cross-walk method recommended
by NICE. We will assume linear change between time
points and use area under the curve methods. QALY
comparisons will make adjustment for baseline EQ-5D5L tariffs. Cost-effectiveness will be assessed by generating incremental cost-effectiveness ratios (in the event of
non-dominated arms) and uncertainty addressed using
cost-effectiveness planes and acceptability curves.
Missing cost and EQ-5D-5L data will be imputed using
multiple imputation methods on 1000 bootstrapped
resamples. We will assume that data are missing at
random. The imputation will be conducted on each
bootstrapped resample in turn and cost-effectiveness
estimates made on each.
Plans to give access to the full protocol, participant leveldata and statistical code {31c}
The datasets generated and/or analysed during the
current study will be available in anonymised form, and
the corresponding statistical code, from the research
team on reasonable request, subject to review, following
the publication of trial results.
Oversight and monitoring
Composition of the coordinating centre and trial steering
committee {5d}
The trial has been carefully designed to ensure
compliance with Good Clinical Practice and scientific
integrity. The research programme development, design
and implementation will be managed by the Chief
Investigator (CI) and the co-applicants, in consultation
with service-user consultants and other expert research
collaborators from within and outside of the CI's institution. A dedicated Trial coordinator post will assist in the
day-to-day management of the project reporting to the
(CI). A trial management committee (TMC) will meet
monthly, its membership will include the investigators
and the Trial coordinator and site coordinators. It will
be chaired by the CI and will manage the day–to-day
running of the study and ensure good communication
between trial sites, receiving monthly reports from each
site on recruitment, therapy completion, adverse events,
reviewing progress against milestones and finding solutions to problems as they arise. It will oversee the preparation of reports to the Trial Steering Committee
(TSC) and Data Monitoring and Ethics Committee
(DMEC).
The Clinical Trial Steering Committee (TSC) will
meet at least every 6 months. Its purpose is to provide
overall supervision of the trial, approving the protocol
and amendments, monitoring adherence to the protocol
and providing independent advice on all aspects of the
trial. A senior clinical academic, independent of the trial
team, will be nominated as the chair. The TSC will
include senior clinicians, clinical academics and two
service users of mental health services with lived
experience of psychosis. The principal investigator (the
co-applicant lead at each site), co-applicant investigators,
trial coordinator and representatives for each clinical site
may join the meetings as observers. The Wellcome Trust
may appoint up to two representatives who shall have
the right to attend TSC meetings in person, by
telephone or by other electronic means as observers.
Wellcome observers have no right to participate in the
decisions of the TSC.
Patient and Public Involvement (PPI) strategy
Each of the four sites will have a local PPI reference
group who will attend regular meetings and be asked to
contribute to the delivery of the trial in a range of ways,
e.g. reviewing materials, supporting recruitment and
dissemination and piloting assessment protocols. These
local reference groups will be brought together in
annual whole trial PPI meetings with input from expert
consultants to ensure effective PPI in AVATAR2. We
will also develop and deliver the quantitative interviews
with input from these consultants and in collaboration
with members of the local PPI reference groups.
Composition of the data monitoring committee, its role and
reporting structure {21a}
A DMEC will be convened and will meet at least
annually and report to the TSC. It will have access to all
unblinded trial data and will receive regular reports on
adverse events. The DMEC will be notified of any
serious adverse events as they occur and will consider
whether any interim analyses are warranted, review data
(including numbers of participants stratified at each
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level) and advise the TSC on any ethical or safety
reasons why the trial should be prematurely ended. The
DMEC chair will be responsible for confirming
judgements on the likelihood of any SAE’s relatedness to
Clinical Trial involvement as well as the SAE’s intensity
and unexpectedness. Membership of the DMEC will be
independent of the applicants and of the TSC. An
independent senior clinical academic will be appointed
as chair and the group will also comprise another
independent senior clinical academic and a senior
statistician. The CI, trial coordinator and the trial
statistician will attend parts of the DMEC meeting to
provide reports but will not be members of the DMEC
or be present when unblinded data is discussed.
Adverse event reporting and harms {22}
The occurrence of adverse events (AEs) will be
monitored actively and systematically, following
guidance from the Consolidated Standards of Reporting
Trials (CONSORT) with the extension for social and
psychological interventions, and the extension for
reporting of harms. Medical Research Council
Guidelines for Good Practice in Clinical Trials will also
be followed to ensure good governance of the trial for
integrity and participants’ safety and wellbeing.
AEs are defined as any untoward medical occurrence,
unintended disease or injury, or untoward clinical signs
in service user/patient participants, whether or not
related to the therapy or device which require additional
support or input from health professionals.
Adverse events will be initially assessed at three levels
of intensity: mild, moderate and severe, which reflect the
impact of the event on the person at the time. Please
note there is a distinction between ‘severe’ and ‘serious’.
Seriousness is the criteria for defining regulatory
reporting obligations and the following will be
considered as serious adverse events (SAE, categories
A–C): All deaths (category A), incidents which acutely
jeopardise the health or psychological wellbeing of the
individual, resulting in immediate hospital admission
and/or permanent disability (category B), or resulting in
injury requiring immediate medical attention (category
C). These SAEs will include but are not limited to (1)
hospital admissions; (2) home treatment team
involvement; (3) suicide attempts; (4) any violent
incident necessitating police involvement (whether
victim or accused); (5) self-harming behaviour; and (6)
all deaths. In order to ensure active surveillance of
harms, at each assessment point, research workers will
utilise the interview to actively check for the occurrence
of specific AEs. At the completion of the trial, all medical notes will be checked, for the total duration of enrolment, for any previously undisclosed record of AEs.
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Reasons for withdrawal from the study will also be
recorded.
The chair of the DMEC will determine relatedness of
the event to the research assessment, therapy or device
based on a temporal relationship, and consideration of
whether there were insufficient or inadequate
instructions for use, deployment, installation, or
operation, or any malfunction of the AVATAR software.
An adverse event may also be device-related if it was the
result of user error or intentional misuse of AVATAR
therapy software. The DMEC chair will confirm whether
the event is unexpected or unexplained given the participant’s clinical course, previous conditions and history,
and concomitant treatments. As detailed in the risk analysis conducted for the CE-marking of AVATAR therapy
software, we do not anticipate any serious adverse device
effects. We do not anticipate any serious therapy or
assessment-related adverse events; this expectation is
based on the safety data from the previous AVATAR
trial.
All SAEs will be reported immediately to the Chief
Investigator and Principal Investigators (for the relevant
site) and the independent chair of the Data Monitoring
and Ethics Committee (DMEC). At each meeting of the
DMEC, or at any time at the request of the DMEC
Chair, a full report of AEs will be reviewed.
COVID-19 In addition to our recording of adverse
events as described above, we will add a category for
identification of adverse events as remote-deliveryrelated. This will ensure we capture any adverse events
that may be specifically related to the delivery of assessments or therapy remotely.
Frequency and plans for auditing trial conduct {23}
The roles of the TSC and the DMEC are to ensure the
trial is conducted to a high standard; these committees
are independent from the investigators and sponsor. The
DMEC will receive open reports showing summary
measures of the data across the sample and will be the
only committee to receive closed reports displaying
summary measures of the data split by treatment group.
Plans for communicating important protocol amendments
to relevant parties (e.g. trial participants, ethical
committees) {25}
Any important protocol amendments will be submitted
for approval to the research ethics committee and the
Trial steering Committee for approval, subsequent
changes will then be made and recorded in the trial
protocol and the ISRTCN registration.
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Dissemination plans {31a}
It is intended that the results of the study will be
reported and disseminated at international conferences
and in peer-reviewed scientific journals and will be made
available to participants and clinical teams in an accessible format and on the study website. It will also be accessible in print and digital media and presented at
stakeholder events. The trial is intended as an important
step towards the dissemination of the therapy into routine care, if efficacy is established. If the success of earlier trials is replicated and we can demonstrate that it is
feasible to train a larger workforce, next steps would include licensed provision of the AVATAR therapy software and training in therapy to interested parties both in
the UK and elsewhere.
Discussion
AVATAR therapy is a relational therapy for distressing
voices involving direct dialogue with a digital
representation of the main voice the person hears.
Encouraging pilot work [15] led to a fully powered RCT
in which AVATAR Therapy was found to be superior to
an active control post-therapy with a large effect size of
0.8 [16]. Delivery of AVATAR Therapy in this recent
trial resulted in an evolution in our understanding of the
core therapy processes and how these might, in
principle, differ between a standardised phase 1 focusing
on exposure and assertiveness, and a formulation-driven
phase 2 incorporating a broader range of treatment targets [14]. Data from the previous trial suggest that anxiety reduction is especially prominent during phase 1,
but that other processes during phase 2, including
changes in the perceived omnipotence and malevolence
of the voice, may contribute to improved treatment outcomes, at least for some participants [17]. The new trial
develops these insights and aims to make progress towards increased availability of AVATAR therapy in routine mental health care. In addition to testing efficacy of
AVATAR-brief and AVATAR-extended, our examination of mediation will also provide understanding of the
mechanisms of therapeutic change. The trial will also
provide important information on whether, if the therapy is shown to be effective, this is influenced by the
complexity of characterisation of the voice. Other clinical characteristics which might plausibly influence
AVATAR treatment effectiveness (e.g. trauma experiences and negative symptoms) will be included in exploratory moderation analyses. In AVATAR2 we will
harness the ecological validity of ESM to capture
changes in anxiety and the relationship with the voice in
daily life at each time-point. Finally, the incremental
cost-effectiveness of both AVATAR-brief and AVATARextended compared to TAU will also inform future
strategies for therapist training and wider provision.
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The trial will also allow testing of the AVATAR
software platform across multiple sites with participants
and therapists recruited from several NHS settings
serving both urban and rural populations. It is likely that
a proportion of participants will be recruited, assessed
and indeed receive therapy remotely. At the time of
writing this protocol, the UK is experiencing a second
surge in COVID-19 cases. As a result, many clinical services have reduced face-to-face contact for all but urgent
purposes and a range of social distancing and other restrictions are periodically imposed in localities or UK nations. Recruitment strategies including meetings with
clinicians will be carried out virtually, as required, as will
procedures for obtaining consent and data capture. Previously, AVATAR therapy was delivered in clinic settings
and although the therapist conducted the dialogue from
a separate room, he/she was nevertheless available in
person at any point during the therapy. Although remote
delivery of therapy is now technically feasible, there are
anticipated to be challenges in terms of recruitment and
the practical feasibility of delivering sessions increasing
the importance of careful monitoring of treatment adherence and fidelity. Whilst we have the technology to
deliver therapy via a secure, encrypted system and we
can supply the necessary hardware to participants, the
extensive geography of the new trial may bring challenges of connectivity and other in-session technical difficulties. The fact that the therapist is not immediately
on hand may also be a barrier to recruitment or continued participation especially in the anxiety-provoking
early sessions and brief therapy. Communication with
the participant’s usual clinical team may also be delayed.
Given these potential challenges, detailed standard operating procedures for remote recruitment, assessment
and therapy delivery have been developed, the latter informed by recent evidence of successful remote delivery
of psychological therapy including trauma-focused work
which shares AVATAR therapy’s approach to working
in the context of high affect [51]. We anticipate the possibility of conducting sub-analyses that take account of
whether data collection and/or therapy were delivered
remotely and of the wider covid-19 context.
AVATAR therapy is multifaceted and therapy delivery
requires skill, sensitivity, and effective training and
supervision [14]. Therapists on the previous trial were
four doctoral-level psychologists and one senior consultant psychiatrist, all experienced clinicians with prior
expertise in working within a cognitive-behavioural
therapy approach for psychosis. The majority of the
therapy-specific interventions were developed and refined in the earlier trial. Whilst interest in the approach
is growing; for example, with independent pilot work
conducted by other research groups [52], the small number of therapists who have delivered AVATAR therapy
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as pioneered by Julian Leff and developed within our
team remains a significant barrier to wider dissemination. The present study extends training to approximately 20 clinicians across at least 8 NHS settings with
planned assessments of fidelity and competence in delivering the therapy.
The findings of this trial will provide further data on
efficacy and cost-effectiveness across multiple clinical
settings, and lead to the optimisation and increased personalisation of the AVATAR therapy approach. This will
pave the way, should the findings be positive, to wider
therapy training and implementation in the future.
Prof Richard Emsley). Prof Emsley is supported by an NIHR Research
Professorship, (NIHR300051).
Dr Mar Rus-Calafell acknowledges individual funding from the Sofja Kovalevskaja Award (Alexander von Humbold Foundation and Ministry of Education
and Research, Germany).
Professor Gillian Haddock acknowledges individual funding from an NIHR
Senior Investigator Award (NIHR201393).
Trial status
Protocol Version Number: 1.2, Date: 28/10/20.
Recruitment will begin in January 2021 and will be
completed in November 2022 with the final follow-up
data collected in March 2023.
Ethics approval and consent to participate {24}
This study has been submitted to London – Camberwell St Giles Research
Ethics Committee (REC) and has received REC/HRA ethical approval (20/LO/
0657). Written informed consent will be gained from each participant before
any study procedures are initiated.
Abbreviations
AE: Adverse event; AVH: Auditory verbal hallucinations; AVATAR: Audio Visual
Assisted Therapy Aid for Refractory auditory hallucinations; BAVQ-R: Beliefs
about Voices Questionnaire Revised version; BDI-II: Beck Depression
Inventory–II; CAINS: Clinical Assessment Interview for Negative Symptoms;
CBTp: Cognitive behavioural therapy for psychosis; CHOICE: The Choice of
Outcome in CBT for Psychosis; CI: Chief Investigator; CONSORT: Consolidated
Standards of Reporting Trials; CSRI: Clinical Service Receipt Inventory;
CTU: Clinical Trials Unit; DASS-21: Depression Anxiety and Stress Scale;
DMEC: Data Monitoring and Ethics Committee; EDC: Electronic data capture;
ESM: Experience Sampling Methodology; GDPR: General Data Protection
Regulation; NHS: National Health Service; ICD: International Classification of
Diseases; ISRTCN: International Standard Registered Clinical/soCial sTudy
Number; ITQ: International Trauma Questionnaire; KCL: King’s College
London; PSYRATS: Psychotic Symptoms Rating Scale; PTSD: Post-traumatic
stress disorder; QALY: Quality-adjusted life year; RCT: Randomised controlled
trial; REDCap: Research Electronic Data Capture; RQ: Relationships
Questionnaire; SAE: Serious adverse event; SAPS: Scale for Assessment of
Positive Symptoms; SC: Supportive counselling; SCAN: Schedules for Clinical
Assessment in Neuropsychiatry; Mini-TALE: Mini-Trauma and Life Events
Checklist; TAU: Treatment as usual; TMC: Trial Management Committee;
TVAQ: Trauma Voice Associations Questionnaire; TSC: Trial Steering
Committee; VAAS: Voice Acceptance and Action Scale; VPDS: Voice Power
Differential Scale; WAI: Working Alliance Inventory; WEMWBS: Warwick
Edinburgh Mental Wellbeing Scale; WT: Welcome Trust
Acknowledgements
Not applicable.
Intellectual property
The AVATAR therapy software is patented, intellectual property for the AVAT
AR therapy software system and therapy manuals is owned by the
universities in collaboration between KCL, UCL and UCLB, arising from
research funded by the Wellcome Trust.
Authors’ contributions {31b}
PAG, CE, TW, TC, RE and PM drafted the manuscript. All authors read and
approved the final manuscript.
Funding {4}
This study is funded by The Wellcome Trust Ltd., through an Innovations
Project award (grant reference 215471/Z/19/Z).
The funding body has no role in the design of the study or the collection,
analysis and interpretation of data or the writing of the manuscript.
The work was also supported in part by the National Institute for Health
Research (NIHR) Biomedical Research Centre at South London and Maudsley
NHS Foundation Trust and King’s College London (Prof Philippa Garety and
Availability of data and materials {29}
The datasets generated and/or analysed during the current study will be
available in anonymised form, and the corresponding statistical code, from
the research team on reasonable request, subject to review, following the
publication of trial results. The Avatar Therapy software will be made
available for licence at the end of the trial.
Declarations
Consent for publication {32}
Not applicable.
Competing interests {28}
Professor Sandra Bucci is the Director of Affigo, a not-for-profit community
interest company designed to make apps/ digital health technologies commercially available in the NHS (http://www.affigo.io/).
Author details
1
Institute of Psychiatry, Psychology & Neuroscience, King’s College London,
London, UK. 2South London & Maudsley NHS Foundation Trust, London, UK.
3
University College London, London, UK. 4University of Greenwich, London,
UK. 5Mental Health Research and Treatment Center, Faculty of Psychology,
Ruhr-Universität Bochum, Bochum, Germany. 6South London & Maudsley
NHS Foundation Trust, London, UK. 7University of Glasgow, Glasgow, UK.
8
NHS Greater Glasgow & Clyde, Glasgow, UK. 9University of Manchester and
the Manchester Academic Health Sciences Centre, Manchester, UK. 10Greater
Manchester Mental Health NHS Foundation Trust and the Manchester
Academic Health Sciences Centre, Manchester, UK. 11KU Leuven, Leuven,
Belgium.
Received: 18 February 2021 Accepted: 28 April 2021
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