Hypotheses
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(1)
A specific, empirically-based treatment model focusing on four core maintenance factors (MANTRA) will be superior to SSCM in producing greater weight gain and greater improvement in eating-disorder related psychopathology in adults with AN at six and twelve months.
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(2)
MANTRA will be more cost-effective than SSCM, showing lower costs at six and twelve months. Specifically, it will be associated with fewer and shorter hospitalizations during treatment and follow-up compared to SSCM.
Research plan
Trial design
This is a multi-center two-arm superiority trial which will evaluate the efficacy and cost-effectiveness of MANTRA compared to SSCM, in consecutive referrals of adult outpatients with AN. Patients will be randomly allocated to either MANTRA or SSCM. More detail regarding the randomization procedure is provided below. Patients in both groups will be offered the same amount of therapy.
The study design is shown in Figure 1.
Outcomes will be measured pre-randomization, at six months (that is, around the end of weekly treatment sessions) and at twelve months follow-up. In addition, mediators of treatment outcome will be assessed mid treatment (three months). Post treatment outcomes will be assessed by researchers who are not involved in the treatment process and steps are undertaken to ensure that researchers remain blind to the patient’s treatment group. Every effort will be made to include patients who drop out of treatment in the follow-up assessments to enable intention-to-treat analysis.
Ethical approval
Ethical approval for the MOSAIC Trial has been obtained from Central London REC 4, National Research Ethics Service, Royal Free Hospital, London, NHS REC Reference: 10/H0714/9. Participants are not exposed to risk, receive verbal and written information before starting and informed written consent is obtained from participants before they enter the study. The research was conducted in compliance with the Helsinki Declaration.
Interventions
Commonalities between both treatments
In both treatments, patients will receive 20 once-weekly individual sessions of therapy together with four follow-up sessions, with monthly spacing. In low-weight patients with a BMI of ≤15 kg/m2, weekly treatment will be extended up to 30 sessions plus four follow-ups. In both treatments two additional sessions with a close other will be offered as well as an assessment from the team’s dietician with follow-up dietetic sessions as needed. Ongoing monitoring of physical risk is an integral part of both treatments. Therapy sessions will last approximately 50 minutes, however in SSCM, from the middle stage of treatment session duration may be reduced to 30 minutes at the therapist’s discretion, as outlined in the original SSCM manual (McIntosh, Jordan, Joyce, McKenzie, Luty, Carter, and Bulik, unpublished). Whilst this means that SSCM patients in our trial will potentially receive somewhat less therapy time than those allocated to MANTRA, we thought that following the original SSCM protocol has the advantage that our study will be comparable to other trials using SSCM.
MANTRA
The MANTRA model [5] proposes that four factors, linked to underlying obsessional and anxious/avoidant personality traits, are central to the maintenance of AN and need to be addressed in treatment.
These are:
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(a)
a thinking style characterized by inflexibility, attention to detail at the expense of the bigger picture and fear of making mistakes;
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(b)
impairments in the socio-emotional domain (such as avoidance of the experience and expression of emotions and the socio-emotional triggers that arouse them);
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(c)
pro-anorexia beliefs (that is, beliefs about the utility of AN in helping the person manage their life). These are one aspect of a broader set of illness beliefs and it is the interaction between beliefs about the illness and other non-illness related beliefs (that is, beliefs about self, others and the world) that gives the illness its own unique meaning for a particular person. Examples of typical pro-AN beliefs include: AN keeps me safe, AN numbs my emotions, AN helps me to express my distress [21–23];
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(d)
the response of close others, including anxiety, worry, blame, criticism, or hostility.
Thus it is hypothesized that MANTRA changes these four putative mediating factors which in turn improve the clinical outcomes (eating disorder symptoms).
MANTRA treatment is centered around a patient-manual (see data supplement DS1 in Schmidt et al. [19] for details), the use of which is tailored to the needs of the individual. The therapist style is that of motivational interviewing [24], that is, reflective, responsive and collaborative. Based on an in-depth physical, psychological, neuropsychological and socio-emotional/relational assessment a collaborative case formulation is developed, which is trait focused and builds on people’s strengths. Feedback, for example, about medical risk, and thinking style is used to increase motivation to change. The principles of behavioral change are used to guide people towards recovery [25, 26]. There is a clear hierarchy of treatment procedures depending on the person’s clinical profile and balancing treatment motivation, level of medical risk, and personal resources and supports available. Close others are invited to participate flexibly in sessions as necessary.
SSCM
This treatment was developed as a comparison treatment in an RCT comparing CBT, IPT and SSCM [18, 27]. SSCM is designed to be delivered by health professionals trained in the treatment of eating disorders and aims ‘to mimic outpatient treatment that could be offered to individuals with AN in usual clinical practice’. This treatment links features of clinical management and supportive psychotherapy. The former emphasizes the therapist’s expertise in providing safe and appropriate patient management and care, including education and support. The latter emphasizes the therapist’s acceptance of the patient and a hopeful, positive stance; a focus on the patient’s strengths, a collaborative, reflective conversational style, using praise, reassurance and advice as appropriate. The abnormal nutritional status and dietary patterns of AN are seen as central to SSCM. The treatment emphasizes the resumption of normal eating and restoration of weight and provides information on weight gain and weight maintenance strategies, energy requirements and relearning to eat normally. The remaining therapy content is determined by the patient. SSCM for AN has three phases. Early on, the patient is oriented towards the treatment, target symptoms are identified and goals for weight gain and normalizing eating are agreed upon. In the middle phase, target symptoms are monitored and the patient is supported and given encouragement in their attainment of the dual goals of weight restoration and normal eating. In the final phase, issues related to the ending of therapy are discussed, including plans for the future and the end of the therapeutic relationship. Further details of this treatment are described in McIntosh et al. [28]. There is also a manual for therapists (McIntosh, Jordan, Joyce, McKenzie, Luty, Carter, and Bulik, unpublished) which contains psycho-educational handouts for patients on topics such as the ineffectiveness of laxatives and the impact of societal beliefs about body shape and weight that are used flexibly throughout treatment.
Therapist training and supervision, treatment fidelity, untoward events and protocol adherence
All therapists will be experienced eating disorder therapists. We will use principles for enhancing treatment fidelity outlined by the NIH Behavior Change Consortium [29]. All therapists will attend two initial training days on MANTRA and SSCM and over the course of the study, update ‘booster’ training days will be held at regular intervals to avoid ‘therapeutic drift’. All therapists will see patients in both conditions. Such a ‘crossed design’ allows for within-therapist assessment of intervention effects and avoids standard error inflation by general therapist effects (see statistical analysis section on how general and therapy-specific therapist effects are modeled). Regular weekly supervision will be provided to therapists by senior clinicians in their team and separately for the two treatment conditions, to avoid contamination across therapies. It is planned that each therapist will see eight or more patients. Patients will be allocated to therapists based on therapist availability. To ensure competent and uniform treatment delivery, psychotherapy sessions will be audiotaped and a random selection of three audiotapes per patient will be reviewed for adherence to the two treatments. An adaptation of the Collaborative Study Psychotherapy Rating Scale will be used to assess whether the two treatments can be reliably distinguished [27]. In addition, we will use the Motivational Interviewing Treatment Integrity (MITI version 2) rating scale [30], and components of the second version of the Motivational Interviewing Skill Code (MISC version 2) [31]. These motivational measures are included as the style of MANTRA is explicitly motivational and that of SSCM has implicit elements of motivational interviewing.
Therapists will keep a case record form for each of their trial patients on which they record each session, briefly describe the session content, session duration, and who attended (including close others involved in the session), note the patient’s eating disorder symptoms, and record any untoward events, according to pre-specified criteria. Any protocol violations, for example, caused by the patient’s admission to hospital will also be recorded here. Criteria for an admission to hospital will be the same as described below under exclusion criteria.
Inclusion/exclusion criteria
Inclusion criteria
Consecutive patients referred to the specialist eating disorder service by their GP will be offered participation if they are:
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(a)
aged between 18 and 60 years;
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(b)
have a BMI of 18.5 or below;
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(c)
have a DSM-IV diagnosis of AN or Eating Disorder Not Otherwise Specified (EDNOS). Our definition of EDNOS is based on that by Thomas et al. [32] and includes people who fulfill all criteria of AN, except the weight criterion; those who fulfill all criteria for AN but still have menses; those without a fat phobia; and those with partial AN (defined as having features of AN but missing at least two of the four diagnostic criteria).
The decision to include EDNOS patients with a BMI cut-off of 18.5 kg/m2 is supported by a recent large meta-analysis of EDNOS which suggests that AN with a more lenient weight criterion and without amenorrhea is very similar to AN as defined currently [32]. We chose a BMI cut-off of 18.5 as this is the WHO cut-off for being underweight. Additionally, this BMI criterion was also used in our previous study and in another large recent AN trial [19, 33].
Exclusion criteria
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(a)
life-threatening AN requiring immediate inpatient treatment as defined in the UK NICE guidelines for eating disorders [17];
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(b)
insufficient knowledge of English to understand the treatment; learning disability; severe mental or physical illness which needs treatment in its own right (for example, psychosis or diabetes mellitus); substance dependence or pregnancy.
We will not exclude patients on antidepressants, provided they are on a stable dose, that is, for at least four weeks.
Outcome measures
All outcome measures will be collected at baseline, six and twelve months, except the treatment credibility/acceptability visual analogue scale (VAS) which will be collected only at six and twelve months. Potential mediators of treatment outcome will also be collected at three months (midtreatment).
Primary outcome
Secondary outcomes
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Body Mass Index (kg/m2) at six months.
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Eating Disorders Examination (EDE) global and subscale scores [34]. The EDE is a widely used, semi-structured interview that generates four subscale scores: dietary restraint, eating concern, weight concern and shape concern. The mean of these four subscales is used to create a global score. For patients unwilling/unable to do the EDE interview, the questionnaire form of this assessment (EDE-Q) will be used instead. The EDE-Q has been found to have similar validity to the EDE interview [35].
Other psychopathology
The Depression, Anxiety and Stress Scale - 21 (DASS-21) [36], Obsessive Compulsive Inventory (OCI) [37].
Potential mediators
The Cognitive Flexibility Scale [38], Beliefs about Emotions Scale [39], The Emotion Regulation Questionnaire [40] and a visual analog scale (VAS) assessing motivation and social support.
Treatment credibility/acceptability
Neurocognitive and social-cognitive measures (also potential moderators)
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The Wisconsin Card Sorting Task [41, 42] assesses cognitive flexibility (or set-shifting ability). It is a commonly used task and involves matching stimulus cards with one of four category cards. The stimuli are multidimensional according to color, shape and number.
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The Brixton Spatial Anticipation Task [43]. This also measures set-shifting ability. Participants predict the movement of a blue circle across 10 different positions, adapting their predictions as the pattern of movement changes.
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The Rey-Osterrieth Complex Figure Test [44, 45]. This is a test of central coherence and evaluates ability to plan, organize and assemble complex information. Participants are asked to copy a complex figure design.
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Baron-Cohen’s ‘Reading the Mind in Film’ task [46]. This measures complex Theory of Mind and consists of viewing 22 brief film clips, after which participants are asked to choose which of four words best describes how the given character was feeling at the end of the scene.
Costs and psychosocial impairment
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The Client Services Receipt Interview (CSRI) [47]. This is a self-report inventory of service use which facilitates estimation of support costs. It will be adapted for the current study to cover a wide variety of hospital, mental health, and community-based services as well as medications, impact of employment and additional personal expenditure due to the eating disorder.
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The Clinical Impairment Assessment (CIA) [48]. This is a self-report measure of global psychosocial impairment resulting from the individual’s eating disorder behaviors.
Randomization
The generation and implementation of the randomization sequence is conducted independently from the trial team by the King’s Clinical Trials Unit (CTU). Once the initial assessment has been carried out and the patient recruited to the trial, the researcher enters patient ID and stratifier details into the web-based CTU system. Patients are then allocated to one of the two trial arms using a restricted stratified randomization algorithm. The strata will be (1) severity of weight loss (BMI below or above 15), (2) AN-subtype (restricting or binge/purge) and (3) previous admission within an eating disorder inpatient unit, as these factors are known to affect treatment outcome and rates of possible future hospitalization. The stratification will be implemented by minimized randomization with a random component. The first N cases (N will not be disclosed) will be allocated entirely at random to further enhance allocation concealment.
Blinding and methods for protecting against other sources of bias
It is not possible for patients or therapists to be blind to the type of treatment. The research assessor, however, will be blind to treatment allocation. In order to test whether the researcher has remained blind to the treatment allocation, they will be required to make a judgment at the end of the twelve months assessment as to which treatment they believe the person has received.
Sample size
We observed a mean weight gain of 7.3 kg (standard deviation 4 kg) in an unpublished series of nine pilot patients treated with MANTRA. The mean weight gain for SSCM was previously estimated as 4 kg (McIntosh et al. [18]). We derived a conservative estimate of the group difference by a low estimate of the weight gain under MANTRA (mean – 0.8 × standard error = 6.5 kg) minus the weight gain estimate for SSCM; giving a difference of 2.5 kg. A sample size of n = 55 per group will have 90% power to detect a difference in mean weight gain of 2.5 kg assuming a common weight gain standard deviation of 4 kg (as per unpublished series of the nine pilot patients) and using an independent samples t-test with a significance level of alpha = 0.05. Correcting for 20% attrition (as found in our previous studies), a total of 138 patients will be needed. (The sample size calculation was not inflated for therapist effects because therapists were crossed with treatments, which allows us to take account of general therapist effects in the analysis, and treatment-specific therapist effects were thought to be negligible).
Recruitment
Patients will be recruited from several centers: South London and Maudsley NHS Foundation Trust (catchment area: two million); North East London Foundation Trust Eating Disorders Service (catchment area 650,000); Barnet, Enfield & Haringey Mental Health NHS Trust (catchment area five million); Oxford Health NHS Foundation Trust (catchment area 1.1 million for Oxfordshire and Buckinghamshire).
Data management
Data will be checked for entry errors by performing double data entry for 10% of the data. Quality of the data will be tested by examining the data for impossible values by looking at data ranges. No post treatment data will be released until the database is locked. Statistical analysis will be blind to treatment arm.
Statistical analysis
Outcomes will be analyzed on an intention-to-treat (ITT) basis, that is, participants will be analyzed in the group to which they were randomized irrespective of their compliance with the assigned scheme.
Primary outcome analysis
BMI at pretreatment (baseline), posttreatment (six months) and follow-up (twelve months) will be analyzed using a linear mixed effects model. In this model, the explanatory variables with fixed effects are treatment (MANTRA or SSCM), time (six months or twelve months), the treatment x time interaction, baseline BMI and randomization stratifiers (severity of weight loss, AN-subtype, and previous hospitalization). Correlation due to seeing the same therapist will be modeled by random effects that vary at the level of the therapist (accounting for general therapist effects) and a second set of random effects that vary at the level of the therapist within a specific treatment (a therapist x treatment interaction accounting for therapy-specific therapist effects). Correlation due to repeated measures will be accounted for by subject-varying random effects. Models will be fitted using maximum likelihood [49]. Model fitting will produce treatment effects estimates at posttreatment (secondary BMI outcome) and twelve months (primary BMI outcome). In the case of missing values in posttreatment BMI, the analysis is valid under the missing at random (MAR) assumption which stipulates that missingness is only driven by variables included in the mixed model. We will summarize the relation between demographic and clinical variables at baseline and study drop-out by twelve months (that is, those lost to follow-up or who actively withdrew from the study). Any baseline variables found to be predictive of missingness will be included as further explanatory variables in the mixed model.
Adherence with allocated treatment will be measured by the number of sessions attended and patients classified as ‘MANTRA completers’, ‘SSCM completers’ or ‘non-completers. Treatment completion will be defined as attending a minimum of 15 out of 20 weekly sessions [50]. In the case of non-adherence with randomized treatments, the ITT estimate no longer provides an efficacy assessment (only effectiveness under the current setting) and we will estimate the outcome difference between those receiving SSCM and MANTRA (relative efficacy, or more specifically the complier average causal effects or CACE) using instrumental variables methods (see for example, Dunn et al. [51]).
Secondary outcome analyses
Secondary outcome variables are all continuous and will be analyzed in the same way as the BMI variables. There are a considerable number of assessments of treatment effects on secondary outcomes. Thus interpretation of these treatment effect estimates will need to take into account the impact of multiple inferences.
Exploratory mediation assessment
Four of the secondary outcomes were chosen since they measure the core maintenance factors targeted by the MANTRA intervention. In other words these variables are putative mediators of the effect of MANTRA on patient ED outcomes. We will use the Baron and Kenny regression approach [52] to assess the potential of each of these four variables as mediators of patient ED outcomes (BMI and EDE global score). Such analyses make restrictive assumptions; the most important being that there is no hidden confounding of the effect of the mediator on the outcome. Thus we only use this as an exploratory approach to empirically re-formulate our basic (theoretical) MANTRA process model. The parameters of this model will yet have to be estimated without bias from future studies that have been designed for mediation analysis.
Exploratory moderation assessment
The study was not powered to detect treatment effect modification by baseline variables. We will carry out exploratory moderator analyses by including interactions between treatment and putative moderators (see potential moderators’ list above) in respective linear mixed models. The results will suggest moderation hypotheses to be investigated in future trials.
All analyses will be carried out in Stata 12 [53].
Economic analysis
Service use patterns will be described and service costs calculated using a well-established compendium of unit costs [54] or those specifically estimated for this study, using a comparable estimation method. Use of MANTRA and SSCM will be recorded by therapists on the case record form noting the number of sessions each participant attended, the duration of each session and details of staff involved in providing the intervention. From these data, the cost of the intervention will be estimated.
Cost-effectiveness analysis will then be conducted for the period from baseline to twelve months follow-up using the primary outcome measures, and the CIA.
Reporting of trial
The trial data will be reported in line with the extension of CONSORT guidance for trials assessing non-pharmacological treatments [55, 56].
