healthmedicinet

Study Design

Phase III efficacy study

The phase III study will consist of a single (researcher) blind parallel-group randomised-controlled
trial (RCT), comparing guided i-RFCBT versus a no-intervention control group, with
this our primary research question.

Quasi-Phase II pilot arm

A separate adjunct arm of unguided i-RFBCT will be included as a quasi-phase II pilot
arm to enable a feasibility study of this intervention. This will be a separate question,
and there will be no direct comparison between unguided i-RFCBT and the guided i-RFCBT
or control arms in the phase III efficacy study.

Setting

The study will be conducted over the internet and by telephone so we will recruit
from around the UK. The intervention will be delivered on the internet, with the guided
version being supported by trained staff at the University of Exeter.

Participant inclusion criteria

Participants will be young adults resident in the UK aged 18 to 24 years and with
elevated RNT, defined as scoring above the 75th percentile on at least one measure
of worry/rumination (?50 on the PSWQ 40] and/or???40 on the RRS 15]). Additionally, participants must be able to understand written English to engage
with the intervention and have private internet access to ensure confidentiality.
In line with standard practice, participants currently receiving antidepressant medication
will be eligible, provided the dosage has been stable for at least the previous month.

Participant exclusion criteria

Because this is a prevention study, participants will be excluded if they meet diagnostic
criteria for a current (within past month) major depressive episode. Additionally,
potential participants will be excluded if they report current and significant substance
abuse or dependence; current symptoms of psychosis or bipolar disorder; current psychological
therapy; or active suicide risk.

Recruitment procedure

The main recruitment pathway involves contacting university departments around the
UK by email and asking them to circulate an advert to their undergraduate students
(as successfully used by Kingston et al. 48]). Generic discipline email addresses, or named individuals within the departmental
administration team where possible, will be obtained using internet searches. Departments
will be asked to circulate an included advert in the form of an attached pdf, containing
a hyperlink to an online trial website that provides information and the initial online
screening measures, to undergraduates within their department. The pdf format ensures
departments can display the advert as a poster if they are not permitted to circulate
by email. The number of emails sent out each week will be modulated depending on the
response rates.

A Facebook and Twitter account will be set up to help circulate the advert, particularly
to non-students. Relevant organisations working with young people and/or mental health
issues will also be asked to advertise a link to the study on their website.

Screening, baseline and consent procedure

Initial Online screening

An online screening website will be used to identify potentially eligible participants.
A brief introduction to the study is included on the introductory page. Consent to
online screening is obtained by informing potential participants that by clicking
continue on this introductory page they are consenting for their responses to be stored
by the researchers and that this data is subject to the Data Protection Act 1998.

A series of short questionnaires is then presented to identify potentially eligible
participants by collecting basic demographic information (age, sex, ethnicity, location,
and how they learned of the study) and screening on shortened versions of the PSWQ
(four items, range 4 to 20, cut-off???12) and RRS (five items, range 5 to 20, cut-off???10)
as used by the Dutch trial to identify individuals with elevated RNT (that is, 75
^th
percentile) and the PHQ-8 49] (PHQ-9 minus the suicidal thought question) to exclude participants who are likely
to meet a diagnosis for current depression (cut-off???15).

Automated feedback informs participants whether they are eligible for further screening.
Those excluded on low worry/rumination are informed that worry and rumination do not
appear to be a significant problem for them and are thanked for their interest. Those
excluded on high PHQ score are given a message explaining that their scores indicate
low mood which is affecting their quality of life and that they may be experiencing
an episode of clinical depression. This message advises them to see their GP and provides
contact details of organisations offering support and advice. Eligible participants
are invited to leave their contact details (name, telephone number and email address)
as consent to be contacted. The full information sheet and consent form are then sent
by email to the participant with an invitation to participate in a telephone interview
with the researcher. The full information sheet (Additional file 1) and consent form (Additional file 2) are then sent by email to the participant with an invitation to participate in a
telephone interview with the researcher.

Telephone screening and baseline assessment

The researcher will provide the interviewee with an overview of the trial, conduct
the clinical interview and ask for verbal consent. Interviews will be audio-recorded,
with the participant’s consent, so that the diagnostic status can be independently
rated. The screening interview consists of brief screening questions on alcohol and
drug use; symptoms of bipolar disorder and psychosis (Psychosis Screening Questionnaire,
PSQ 50]); assessment of any relevant past or current treatments; and the Structured Clinical
Interview for DSM-IV (SCID-I; 43]) sections on current and past depressive episodes, dysthymia and any relevant anxiety
disorders and eating disorders. As the primary objective of this study is to investigate
the prevention of depression, anxiety and eating disorders will be measured, but participants
meeting the criteria for a disorder will not be excluded from this study.

Excluded participants are given feedback including advice to visit their GP and contact
details of organisations for further support. Additionally, any risk reported during
the interview is assessed using a well-established protocol to ensure that appropriate
clinical support is obtained. Eligible participants are then asked to complete baseline
measures, assessing episodic stress (the Episodic Life Event Interview, part of the
UCLA Life Stress Interview 51]); levels of worry and rumination (PSWQ and RRS); symptom severity of depression and
generalized anxiety (PHQ-9 and GAD-7); neuroticism (Eysenck Personality Questionnaire-Revised
Neuroticism sub-scale (EPQ-R; 52]) and history (family history of depression, experience of abuse in childhood). With
the exception of the episodic stress interview, which is always completed during the
interview, baseline measures can be completed during the telephone interview, or returned
by email/post.

Consent to trial

All eligible participants will then be invited to enter the trial and asked to return
the written consent to participate. Once consent is received, the participant will
be randomised (see Fig. 1).

Fig. 1. CONSORT diagram

Randomisation and allocation concealment

Independent computer-generated block randomisation to the guided i-RFCBT, unguided
i-RFCBT or the no-intervention control group will be used. Randomisation will be stratified
by sex and by past history of depression (presence or absence of past depressive episodes)
to assess the effect of sex on outcomes and to examine potential differences between
prevention of first onset and relapse prevention. The randomisation uses blocks of
three to ensure close parity of randomisation across the intervention arms across
time. Because of the two levels of stratification by sex and by level of depression,
with blocks of three, the researcher would not be able to anticipate or determine
allocation easily, and the use of varying block sizes was therefore deemed unnecessary.
In order to preserve blinding of the study researcher, randomisation will be conducted
by a third party not involved in assessing or treating the participants, and this
third party will also inform the therapist, who will be responsible for informing
participants of their allocation.

Sample size calculation for phase III efficacy trial

Power and sample size calculations were based on testing the primary question of the
efficacy of guided internet-RFCBT in terms of reducing the onset of major depression
relative to the no-intervention control. For our primary comparison of guided i-RFCBT
versus the no-intervention control, the Topper et al. study using the binary outcome
of number of individuals meeting caseness for depression at 12 months, reported 13.1 %
incidence of depression in guided i-RFCBT and 32.2 % incidence in the no-intervention
control (hazard ratio?=?0.41). Assuming similar effect sizes to the Topper et al.
study for our intended time-to-outcome survival analysis over 12 months, then to detect
the hazard ratio of 0.41 between these arms at the two-tailed 5 % alpha level, 75
participants must be recruited to each arm to provide 86 % power.

Estimates for change in depressive symptoms pre-to-post intervention for the guided
i-RFCBT relative to the waiting list control indicate that 78 participants per arm
provide a power of 80 % to detect the observed effect size of d?=?0.51 from the Dutch
trial at the two-tailed 5 % alpha level, allowing for the 20 % follow-up drop-out
attrition observed in the Dutch study.

Sample for quasi-phase II pilot arm

In the absence of any data on the unguided i-RFCBT, no power and sample size calculation
was conducted for this arm. We will therefore aim to recruit the same number of participants
for this arm as the other arms (n?=?78), giving a total sample size of 234. The inclusion
of this intervention arm is to explore the feasibility of this unguided intervention
with respect to attrition, acceptability and estimates of incident rate and effect
size.

Interventions

Guided i-RFCBT

The guided intervention is an English version of i-RFCBT (called MindReSolve). RFCBT
is derived from theoretical models 11] and experimental findings, which propose the existence of distinct types of repetitive
thought (RT) with distinct consequences: constructive RT is characterized by a concrete,
specific and action-oriented mode of processing, focusing on how events happen, whereas
unconstructive RT is characterised by an abstract and evaluative processing mode,
focusing on the meaning and implications of events and difficulties 11]. In experimental studies, relative to the abstract mode, the concrete mode improved
problem-solving 53], 54] and reduced emotional reactivity in response to failure 55]. Underpinning RFCBT is the idea that shifting individuals into the concrete mode
will reduce unconstructive rumination; consistent with this, repeated training of
dysphoric and depressed participants to become more concrete reduces depression and
rumination in both a proof-of-principle study and a randomised controlled trial 31], 33]. RFCBT therefore involves experiential and imagery exercises to adaptively shift
processing mode (including concreteness, absorption and compassion), as well as functional
analysis to help patients spot when rumination starts, distinguish between helpful
versus unhelpful RT, and learn more functional responses. RFCBT seeks to change the
process of thinking as opposed to the content of thoughts as in standard CBT 30]. In addition, rumination is conceptualised as a form of avoidance 11], 56], which is targeted on behavioural activation principles 57] with avoidance behaviour being replaced with more appropriate approach behaviours.

I-RFCBT consists of six modules, each taking around an hour to complete in session
and 1 to 2 weeks to practise. It includes psycho-education, mood diaries, on-line
experiential exercises using audio-recordings, pictures and video vignettes of students’
experiences of the therapy. The modules each follow the same basic structure: reflection
on the previous session, introduction of a new technique, practical exercises and
planning how to practise or implement the technique in daily life. The specific behaviour-change
techniques are drawn from the following groups in the BCT Taxonomy (v1) 58]: goals and planning (goal setting, action planning, review behaviour and behavioural
contract), feedback and monitoring (self-monitoring of behaviour and outcomes), shaping
knowledge (information about antecedents), natural consequences (information about
social and environmental consequences and monitoring of emotional consequences), associations
(prompts/cues and associative learning), repetition and substitution (behavioural
practice/rehearsal, behaviour substitution, and habit formation), antecedents (restructuring
physical and social environment, avoiding/reducing cues for the behaviour), and self-belief
(mental rehearsal of successful performance, focus on past success, and self-talk).
The key strategies include coaching participants to spot warning signs for rumination
and worry, and then to make IF-THEN plans in which an alternative strategy is repeatedly
practised in response to the warning signs. These strategies include being more active,
slowing things down, breaking tasks down, opposite action, relaxation, concrete thinking,
becoming absorbed, self-compassion and assertiveness.

The intervention is accessed through a secure website, with each participant having
a password protected account. Participants’ log-ins are automatically recorded by
the programme, allowing for an automated measure of treatment compliance. Reminder
emails will be sent to participants after 2 weeks if they have not completed the module.

The participant can work through each module at his own pace but can only move from
one module to the next after the coach has provided feedback. The coach will provide
feedback on these responses within 2 working days, in particular highlighting any
positive steps made and encouraging participants to sustain these as well as pointing
out areas to focus on over the next module. Participants will also be able to send
questions to their assigned therapist throughout the programme if they are having
difficulty with a specific exercise.

The intervention will be supported by qualified clinicians who have received specific
training in the rumination-focused CBT approach. Treatment fidelity is ensured through
the use of fixed modules in the platform, ensuring that all participants receive identical
content. Detailed template responses for each module provide the coach with constrained
feedback faithful with the treatment model, which they can then tailor to individual
client responses. All responses from both the client and coach are automatically saved
by the online platform, and a random sample will be checked against the templates
to ensure they are faithful to the treatment. Furthermore, coaches will be provided
with ongoing supervision with the developer of RFCBT to encourage fidelity. Supervision
meetings will involve a brief overview of all clients and a more in-depth discussion
of cases deemed to be more complex or where there is risk or non-response to the intervention.

Unguided i-RFCBT

The unguided version of the therapy contains the same six modules as the guided version,
with almost identical content, adapted for self-help, including some conditional feedback
on common difficulties with exercises. Participants are able to move freely from one
module to the next, but are advised to spend 1 to 2 weeks on each to allow time for
practice. Participants in the unguided version will be made aware that there is no
coach monitoring their responses. However, they will be told that their questionnaire
scores will be monitored on a weekly basis to check for any risk reported.

Control condition

Participants in the control condition will be informed that they have been allocated
to carry on as usual. In order to ensure participants’ welfare, participants are permitted
to access any other treatments throughout the course of the study, as necessary. They
will also be able to access the unguided i-RFCBT at the end of the study if they so
wish.

Blinding

This is a single blind study, with the researcher conducting outcome measures while
blind to allocation. Participants will be asked at the end of the screening interview
not to disclose their allocation to the researcher in any of their future correspondence
with the researcher and reminded of the importance of this prior to and during each
follow-up interview. Due to the intervention, participants and therapists cannot be
blinded.

Follow-up assessments and outcome measures

The primary outcome of interest of this study is the onset of a major depressive episode
over a 12-month period, which we will assess with the SCID-I at 3 (post-intervention),
6 and 15 months after randomisation. The use of the SCID-I will allow for the ascertainment
of depressive episodes that may have occurred between assessments (continuous time-to-onset
and occurrence) and will also enable us to assess clinically significant symptoms
of anxiety (particularly generalized anxiety disorder) that may have arisen in isolation
or comorbid with depression. The severity of the depressive symptoms is measured using
the PHQ-9 and of the anxiety symptoms using the GAD-7. The effect of the intervention
on levels of worry and rumination will be assessed using the PSWQ and RRS. A number
of potential confounding variables are also measured: stressful life events, using
the Episodic Life Event Interview and any treatments received outside the trial (medication,
therapy and use of self-help materials). Each assessment will take place via a telephone
interview, with the option of the questionnaire measures being returned by email or
post. To increase participant retention and completion of follow-ups, multiple attempts
and multiple means (email, telephone and post) will be used to contact participants.
Additionally, to increase motivation to complete the follow-up measures, lottery draws
for £50 in vouchers will be held, with each participant receiving one ticket per completed
follow-up.

Feasibility and acceptability outcome measures (quasi-phase II pilot arm)

With respect to the unguided intervention, feasibility and acceptability of data collection
procedures, levels of attrition, effect size and acceptability of the unguided internet
RFCBT intervention will be measured to aid planning for a fully powered, definitive,
phase III trial. The feasibility of data collection procedures will be assessed by
measuring the missing items on the clinical outcome measures, the number and timing
of drop-outs and whether these vary across arms. The acceptability of the intervention
will be assessed using a behavioural index, which will measure the number of modules
completed, the time spent logged into the site and which modules are completed more
easily or frequently than others.

Statistical analysis plan for phase III efficacy trial

Data cleaning will follow the protocol set out by Tabachnick and Fidell 59]. Statistical analysis will follow the CONSORT standards 60]. Unplanned missing data will be handled via multiple imputation (MI). Sensitivity
analysis, assuming a variety of MI models (Missing at Random; Missing Not at Random),
will verify the likely impact of missing data. Auxiliary variables will be used to
improve the estimation of missing data. Primary analyses will be conducted on the
intention-to-treat (ITT) sample.

Subsequent analyses will use the Complier Average Causal Effect (CACE) analysis 61], 62]. CACE assumes that randomisation has no direct effect on outcome variable; instead
it assumes that the effect of treatment depends on the compliance to treatment (operationalized
in terms of completing four out of six modules), which in turn is dependent on randomisation.
Therefore, CACE provides estimates of a treatment effect whilst taking into account
adherence and compliance with the treatment and whilst also retaining the benefits
of randomisation. This model is thus an exemplar of using an Instrumental Variable
(IV) where randomisation is the instrument, which is correlated with compliance to
the treatment, and directly unrelated to the outcome. In simple terms, CACE finds
the difference in the outcome variable between the compliers in the treatment arm
and the compliers in the control arm had they been offered the treatment, assuming
that the rates of compliance are similar in both arms as a consequence of randomisation.

As a prevention study, the main outcome of interest is the occurrence and time to
onset of any depressive episode. Cox regression survival analyses will be performed
to examine the effect of the preventive intervention on episode onsets of major depression.
Participants will be censored upon measurement dropout or end of study. Although condition
will be the main independent variable included in the model, we will also consider
sex and history of past depression (the stratification variables).

The secondary outcome of occurrence/time to onset of generalized anxiety disorder
will also be assessed using Cox regression survival analyses. Symptom severity and
levels of rumination/worry will be examined using mixed model ANCOVAs: between group
(ITT/CACE) and repeated measures (3 to 15-month follow-ups), with baseline symptom
levels and stratification variables as covariates.

Mediation and moderation analysis

Mediational analyses will be used to test the hypothesis that rumination acts as mediator
of the treatment effects of condition on onset of major depression using the approach
outlined by Kraemer et al. 63]. Potential moderators (for example, stratification variables and baseline characteristics)
will also be investigated using this approach.

Ethical approval

Ethical and professional guidelines will be followed at all times, in line with Good
Clinical Practice guidelines. Ethical approval has been obtained from the Ethics Committee
of the School of Psychology, University of Exeter (Ref: 2012/554). Any possible adverse
events witnessed by the researcher or the therapist will be discussed as soon as possible
with the supervisor. If this is deemed to be an adverse event, an adverse event report
will be completed. In the case of serious adverse events, the University of Exeter,
as sponsor, will also be notified using the same report and a follow-up phone call.