Trial Review

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Trial registered on ANZCTR


Registration number
Help: Registration number
ACTRN12626000790347
Ethics application status
Help: Ethics application status
Approved
Date submitted
Help: Date submitted
21/05/2026
Date registered
Help: Date registered
1/07/2026
Date last updated
Help: Date last updated
1/07/2026
Date data sharing statement initially provided
Help: Data sharing statement date
1/07/2026
Type of registration
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Prospectively registered

Titles & IDs
Public title
FERN Study: Fear, Emotion and Reward in Anorexia Nervosa
Scientific title
FERN Study: Fear, Emotion and Reward in Anorexia Nervosa - Understanding Caloric Avoidance in Anorexia Nervosa: the role of neural reward responses, hormones and the gut microbiome.
Additional trial identifiers [1] 317260 0
Nil
Universal Trial Number (UTN)
Trial acronym
FERN
Related trial records

Health condition
Health condition(s) studied:
Anorexia nervosa 341879 0
Condition category
Condition code
Mental Health 337946 337946 0 0
Eating disorders

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of the intervention or exposure
This study aims to better understand why people with anorexia nervosa restrict food intake, by examining how the brain, body, and behaviour work together to influence eating decisions. Participants with anorexia nervosa and healthy individuals will complete tasks such as brain scans, behavioural assessments, and provide biological samples (e.g., blood and faecal samples), allowing us to understand how the brain responds during caloric avoidance.

This is a cross-sectional observational biopsychological sampling study. All assessments and biological samples (see below) are collected at a single time point only, with no intervention administered.
• Physiological measures: a trained researcher will measure participant's height, blind weight (participants won't see their weight) and blood pressure.
• Online questionnaires: participants will be asked to complete a series of questionnaires to assess eating disorder symptoms, mental health and thinking flexibility (all questionnaires are specified under 'outcomes'). This will take approximately 55 minutes to complete.
• Neuroimaging: participants will undergo MRI brain scanning while doing a task where you choose whether to take small sips of a milkshake. This will take approximately 50 minutes.
• Actigraphy and sleep: participants will be asked to wear a smart watch for one week to measure sleep, activity, heart rate and stress.
• Food diary: participants will be asked to keep a food diary for five days.
• Faecal samples: participants will be asked to collect two small faecal samples at home.
• Blood samples: a fasting blood sample will be taken by a qualified blood collector in a clinical setting.

In total, participation in this study will involve approximately 4 hours and 45 minutes of research activities.
Intervention code [1] 334038 0
Not applicable
Description of the comparator or control
Age and sex-matched healthy controls, with no history of eating disorders.
Control group
Active

Outcomes
Primary outcome [1] 345386 0
Task-based functional brain activity during the Sip or Skip task.
Timepoint [1] 345386 0
The duration of the sip or skip task will be 50 minutes and will be assessed at one timepoint only
Primary outcome [2] 345655 0
Behavioural choice preferences during the Sip or Skip task, defined as the percentage of trials in which the “Sip” option is selected, calculated overall and across different experimental reward conditions.
Timepoint [2] 345655 0
The duration of the sip or skip task will be 50 minutes and will be assessed at one timepoint only
Secondary outcome [1] 461476 0
Frequency of movement
Timepoint [1] 461476 0
Data will be collected for 5-9 days only between appointment 1 and 2
Secondary outcome [2] 461477 0
Sleep patterns
Timepoint [2] 461477 0
Data will be collected for 5-9 days only between appointment 1 and 2
Secondary outcome [3] 461478 0
Heart rate
Timepoint [3] 461478 0
Data will be collected for 5-9 days only between appointment 1 and 2
Secondary outcome [4] 461479 0
Stress
Timepoint [4] 461479 0
Data will be collected for 5-9 days only between appointment 1 and 2
Secondary outcome [5] 461480 0
Average daily caloric intake, macronutrient intake, and pattern and timing of meals. This will be assessed as a composite outcome.
Timepoint [5] 461480 0
Data will be collected for 5 days only between appointment 1 and 2
Secondary outcome [6] 461481 0
Taxonomic profile of the gut microbiome
Timepoint [6] 461481 0
Two faecal samples at one timepoint will be collected 2-3 days apart to account for natural variability
Secondary outcome [7] 461482 0
Body mass index
Timepoint [7] 461482 0
Collected at one timepoint only
Secondary outcome [8] 461483 0
Eating disorder symptoms
Timepoint [8] 461483 0
Collected at one timepoint only
Secondary outcome [9] 461484 0
Quality of life
Timepoint [9] 461484 0
Collected at one timepoint only
Secondary outcome [10] 461521 0
Food restriction behaviour in eating disorders
Timepoint [10] 461521 0
Collected at one timepoint only
Secondary outcome [11] 461523 0
Fear of Food
Timepoint [11] 461523 0
Collected at one timepoint only
Secondary outcome [12] 461524 0
Depression
Timepoint [12] 461524 0
Collected at one timepoint only
Secondary outcome [13] 461525 0
Anxiety
Timepoint [13] 461525 0
Collected at one timepoint only
Secondary outcome [14] 461527 0
Cognitive flexibility
Timepoint [14] 461527 0
Collected at one timepoint only
Secondary outcome [15] 461531 0
Desire for thinness perceptions and behaviours
Timepoint [15] 461531 0
Collected at one timepoint only
Secondary outcome [16] 461532 0
Sleep quality
Timepoint [16] 461532 0
Collected at one timepoint only
Secondary outcome [17] 461535 0
Addiction
Timepoint [17] 461535 0
Collected at one timepoint only
Secondary outcome [18] 461536 0
Emotional response to rewards
Timepoint [18] 461536 0
Collected at one timepoint only
Secondary outcome [19] 461543 0
Avoidance and sensitivity to reward. This will be assessed as a composite outcome
Timepoint [19] 461543 0
Collected at one timepoint only
Secondary outcome [20] 461551 0
Blood pressure
Timepoint [20] 461551 0
Collected at one timepoint only
Secondary outcome [21] 461556 0
Appetite
Timepoint [21] 461556 0
Collected at one timepoint only
Secondary outcome [22] 461558 0
Stress
Timepoint [22] 461558 0
Collected at one timepoint only
Secondary outcome [23] 461559 0
Inflammatory markers: TNF-a, IL-6. This will be assessed as a composite outcome.
Timepoint [23] 461559 0
Collected at one timepoint only
Secondary outcome [24] 461560 0
Genetic profile
Timepoint [24] 461560 0
Collected at one timepoint only
Secondary outcome [25] 462706 0
Altered homeostasis
Timepoint [25] 462706 0
Collected at one timepoint only

Eligibility
Key inclusion criteria
Inclusion Criteria for Anorexia Nervosa (AN) participants
• Current diagnosis of AN (restrictive, binge-purge or OSFED atypical-AN (subthreshold AN))
• Age 18 - 60 years
• Willing and able to comply with all study requirements, including timing and/or nature of required assessments

Inclusion Criteria for Healthy Controls (HC)
• Age 18 - 60 years
• Body mass index 18.5 - 30
• Weight stability for past 3 months
Minimum age
18 Years
Maximum age
60 Years
Sex
Both males and females
Healthy volunteers
Yes
Key exclusion criteria
Exclusion Criteria for Anorexia Nervosa (AN) participants and Healthy Controls (HC)
• Inability to undergo MRI examination due to physical (implants or devices) or psychological reasons
• Unable to access study location
• Use of medications that affect appetite, weight or metabolism e.g. Insulin, Metformin, Ozempic, Seroquel, Vyvanse, GLP-1 agonists, steroids
• Antibiotic use in the past 3 months
• Active suicidality
• Active psychosis
• Pregnancy
• Diabetes
• Unable to speak or read English

Study design
Purpose
Natural history
Duration
Cross-sectional
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Sample Size Calculation

Power analyses were conducted to ensure adequate sample sizes:

For aim 1, using the PWR package in R (v1.3.0), assuming a correlation of r = 0.41, 80% power, and a = 0.05 (two-sided), the required sample was n = 23 per group to detect between-group differences in nucleus accumbens activation.

For aim 2, using the blavaan package in R, simulations assuming moderate collinearity (r = 0.4) indicated that a sample of n = 120 (90 AN, 30 controls) achieved 86.6% power. Accounting for a conservative 10% data loss, power remains acceptable (~79%).

Groups are intentionally unbalanced, as the primary focus is on mechanisms within the group with Anorexia Nervosa (AN), with controls serving as a normative comparison.

Analysis Plan

For Aim 1: Determine the nature of reward circuitry activation in response to caloric avoidance in AN relative to controls.

Neural responses during reward processing are analysed using voxelwise general linear models (GLMs). At the subject level, Blood Oxygen Level Dependent (BOLD) signals are modelled with phase-specific regressors (decision, anticipation, consumption), generating contrast images (e.g., anticipation > baseline). At the group level, between-group and group-by-phase effects are tested within predefined regions of interest and across the whole brain. Significant clusters from corrected whole-brain analyses are carried forward into region-level and hierarchical linear models to estimate effect sizes and associations with clinical variables. Robustness is evaluated through sensitivity analyses including exclusion criteria, ANCOVA-style covariate adjustment, alternative preprocessing pipelines, and linear mixed-effects models where repeated data exist.

For Aim 2: Build a mechanistic understanding of brain circuitry and peripheral inputs underpinning self-feeding behaviour in AN.

A Bayesian structural equation modelling (bSEM) framework is used to quantify relationships between biological variables (blood, microbiome), neural activation/connectivity, and clinical outcomes. Latent constructs (e.g., reward anticipation/consumption) are modelled using factor structures, with directed paths capturing hypothesised mechanisms. Dynamic causal modelling (DCM) provides subject-level connectivity parameters incorporated into the SEM. Model adequacy is assessed using posterior predictive checks, while model comparison (BIC, WAIC/LOO) informs selection of optimal specifications. MCMC diagnostics (R-hat, ESS, trace plots) ensure convergence. To address overparameterisation, penalised regression (LASSO) and dimensionality reduction are used. Indirect (mediated) effects are estimated within the Bayesian framework, with posterior intervals quantifying uncertainty. Sensitivity analyses test robustness to priors, influential observations, and predictor sets.

Aim 3: Explore subgroups with distinct biological mechanisms underlying caloric avoidance in AN

Bayesian Gaussian mixture modelling (BGMM) is used to identify latent subgroups within AN using multivariate inputs (neural, biological, genetic, clinical). The model estimates class-specific distributions and posterior probabilities of class membership, explicitly accounting for uncertainty. Subgroup differences are characterised and compared using logistic or multinomial regression models. Stability is assessed via alternative priors, covariance structures, and feature sets, with additional comparison to non-Bayesian clustering approaches. Inference emphasises posterior intervals and pattern consistency rather than significance testing due to small class sizes.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
3/08/2026
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
120
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 29523 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 45841 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 321834 0
Government body
Name [1] 321834 0
NHMRC
Country [1] 321834 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
Country
Australia
Secondary sponsor category [1] 324777 0
None
Name [1] 324777 0
Address [1] 324777 0
Country [1] 324777 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 320376 0
SLHD Human Research Ethics Commttee (RPAH Zone)
Ethics committee address [1] 320376 0
Ethics committee country [1] 320376 0
Australia
Date submitted for ethics approval [1] 320376 0
31/03/2026
Approval date [1] 320376 0
20/05/2026
Ethics approval number [1] 320376 0
Protocol No. X26-0123 & 2026/ETH00290

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 150278 0
Dr Kristi Griffiths
Address 150278 0
Charles Perkins Centre (D17), John Hopkins Drive, The University of Sydney, NSW, 2006
Country 150278 0
Australia
Phone 150278 0
+61 457055400
Fax 150278 0
Email 150278 0
[email protected]
Contact person for public queries
Name 150279 0
Talia Palacios
Address 150279 0
Charles Perkins Centre (D17), John Hopkins Drive, The University of Sydney, NSW, 2006
Country 150279 0
Australia
Phone 150279 0
+61 2 9562 5384
Fax 150279 0
Email 150279 0
[email protected]
Contact person for scientific queries
Name 150280 0
Kristi Griffiths
Address 150280 0
Charles Perkins Centre (D17), John Hopkins Drive, The University of Sydney, NSW, 2006
Country 150280 0
Australia
Phone 150280 0
+61 457055400
Fax 150280 0
Email 150280 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
Yes
Will there be any conditions when requesting access to individual participant data?
Persons/groups eligible to request access:
• Researchers
Conditions for requesting access:
• Yes, conditions apply:
• Requires review on a case-by-case basis by the trial custodian, sponsor or data sharing committee
• Requires a scientifically sound proposal or protocol
• Requires approval by an ethics committee
• Requires a data sharing agreement between data requester and trial custodian or sponsor
What individual participant data might be shared?
• All de-identified individual participant data
What types of analyses could be done with individual participant data?
• Research closely related to the original project or the general area of eating disorders, which may include genetic studies.

When can requests for individual participant data be made (start and end dates)?
From:
After publication of main results
To:
No end date
Where can requests to access individual participant data be made, or data be obtained directly?
• Access to study data could be obtained by contacting the study team ([email protected]) or via the ENIGMA consortium, where deidentified, pre-processed imaging data can be shared in order to combine with other similar datasets (https://enigma.ini.usc.edu/).

Are there extra considerations when requesting access to individual participant data?
Yes: University of Sydney Research Data Management Policy and the InsideOut Institute Data Management SOP.



What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.