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Trial registered on ANZCTR

Registration number

ACTRN12621001504808

Ethics application status

Approved

Date submitted

16/09/2021

Date registered

4/11/2021

Date last updated

10/12/2023

Date data sharing statement initially provided

4/11/2021

Type of registration

Prospectively registered

Titles & IDs

Public title

Gut Bugs in Anorexia Nervosa

Scientific title

An open-label pilot trial of faecal microbiome transfer to restore the gut microbiome in anorexia nervosa

Secondary ID [1]

None

Universal Trial Number (UTN)

U1111-1268-2837

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Anorexia nervosa

Condition category

Condition code

Mental Health

Eating disorders

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Participants will receive 20 capsules containing the gut microbiota derived from four healthy, clinically-screened female stool donors. Each capsule contains 0.5 grams concentrated gut microbiota suspended in a cryoprotective solution (0.9% saline + 15% glycerol). Capsules will be swallowed with a glass of water under direct supervision from a research clinician or nurse. The dose will be split over two or four consecutive mornings depending on participant preference (i.e. 10 capsules/day or 5 capsules/day, all taken at the same time).

Intervention code [1]

Treatment: Other

Comparator / control treatment

No control group.

Control group

Uncontrolled

Outcomes

Primary outcome [1]

Gut microbiome structure (assessed with faecal samples and using Bray Curtis Dissimilarity)

Timepoint [1]

3-weeks pre-treatment, baseline (i.e. day before treatment), 3-weeks post-treatment

Secondary outcome [1]

Gut microbiome composition and functional potential (composite outcome) assessed with faecal samples using bioBakery tools

Timepoint [1]

3-weeks pre-treatment, baseline (i.e. day before treatment), 3-weeks, 6-weeks, 12-weeks post-treatment.

Secondary outcome [2]

Adverse events associated with treatment
(assessed by study-specific questionnaire based on Common Terminology Criteria for
Adverse Events (CTCAE) manual v4.; specifically, participants will be asked to report on the following events: any changes in bowel movements, loose or bloody stools, abdominal pain, vomiting, nausea, fever, malodorous burps, fatigue, or any other symptom/s they have experienced.)

Timepoint [2]

24 hours after each capsule dose, 1-week, 3-weeks, 6-weeks, 12-weeks post-treatment.

Secondary outcome [3]

Tolerability 1: Proportion of participants who complete treatment. (based on study records)

Timepoint [3]

Day 4 (after final capsule dose).

Secondary outcome [4]

Eating disorder symptoms (assessed using the Eating Disorder Examination Questionnaire, version 6.0)

Timepoint [4]

baseline, 6-weeks, 12-weeks post-treatment.

Secondary outcome [5]

Nutritional blood markers (including sodium, potassium, creatinine, ferritin, total protein, albumin, alkaline phosphatase, alanine aminotransferase, aspartate transaminase, gamma-glutamyl transferase, folate, vitamin B12, cortisol, free thyroxine, thyroid stimulating hormone, and serotonin)

Timepoint [5]

baseline, 6-weeks, 12-weeks post-treatment.

Secondary outcome [6]

Faecal biomarkers of gut inflammation and permeability (composite outcome).
(test include: Calprotectin, Lactoferrin, M2-pyruvate kinase, and S100A12 assays)

Timepoint [6]

baseline, 3-weeks, 6-weeks, 12-weeks post-treatment

Secondary outcome [7]

BMI (provided by DXA scan)

Timepoint [7]

baseline, 12-weeks post-treatment

Secondary outcome [8]

Body composition (DXA scan)

Timepoint [8]

baseline, 12-weeks post-treatment

Secondary outcome [9]

Donor strain engraftment (assessed with faecal samples using strain profiling methods)

Timepoint [9]

baseline, 3-weeks, 6-weeks, 12-weeks post-treatment

Secondary outcome [10]

Tolerability 2: Proportion of participants who would consider having the treatment again if it was later proven to be beneficial in treating anorexia nervosa (assessed by Treatment Tolerability questionnaire).

Timepoint [10]

Day 4 (after final capsule dose)

Secondary outcome [11]

Depression symptoms (assessed using the Patient Health Questionnaire-9)

Timepoint [11]

baseline, 6-weeks, 12-weeks post-treatment.

Secondary outcome [12]

Anxiety symptoms (assessed using the Generalised Anxiety Disorder Assessment 7 questionnaire)

Timepoint [12]

baseline, 6-weeks, 12-weeks post-treatment.

Eligibility

Key inclusion criteria

Participants:
- Biological female
- Age 16 – 32 years
- BMI 13 - 19 kg/m2
- formal diagnosis of anorexia nervosa by an eating disorder specialist (meets the DSM-5 criteria, 307.1)
- Medically stable
- Be able and willing to swallow treatment capsules and comply with the clinical assessments.

Donors:
- Female
- Age 18-32 years
- BMI 18.5 - 25.0 kg/m2
- Total body fat less than or equal to 33%
- Healthy diet (greater than or equal to 4 portions of fruit and vegetables per day)
- Regular exercise (moderate to vigorous physical activity for at least 3.5 hours per week)
- Regular bowel habit (at least once every two days)

Minimum age

16 Years

Maximum age

32 Years

Sex

Females

Can healthy volunteers participate?

Yes

Key exclusion criteria

Participants:
- Known allergies to food and/or common medications
- Use of antibiotics or probiotics in the month prior to treatment
- Regular oral steroid treatment or daily application of potent topical steroids extensively to the body
- Compromised immune system
-Any chronic illness affecting gut or metabolic health
- Thoughts of self-harm and/or suicide ideation (assessed by PHQ-9)
- Current or planned pregnancy during the course of the study

Donors:
- Positive screening test for any transmissible pathogen or multi-drug resistant organism
- Gastrointestinal disease (e.g. inflammatory bowel disease, irritable bowel syndrome, coeliac disease, eosinophilic oesophagitis)
- Metabolic disorder (e.g. diabetes, metabolic syndrome, hypertension, dyslipidemia, dysglycemia)
- Impaired fasting glucose (>5.9 mmol/l) or elevated HbA1c (>41 mmol/mol)
- Asthma or eczema requiring regular prophylaxis or treatment
- Autism spectrum conditions
- Previous diagnosis of mental health issues including eating disorders
- Current or past history of malignancy
- Use of oral antibiotics or probiotics in the past 3 months
- Regular binge drinking (>5 standard alcoholic units/session at least once a week)
- Past or present use of recreational drugs, tobacco, or vaping
- Current or past pregnancy
- Overseas travel in the past 2 weeks
- UK residence in 1980-1996 for 6 months or longer

Study design

Purpose of the study

Treatment

Allocation to intervention

Non-randomised trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Single group

Other design features

Phase

Not Applicable

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

Primary Outcome
The primary outcome was powered for a shift in gut microbiome structure from baseline that is above the natural drift of the gut microbiome over a 3-week period without intervention. To assess this we will need a minimum of 18 participants (80% power, alpha = 0.05). To account for a potential drop-out rate of 10%, we aim to recruit 20 participants.

Gut microbiome profiling will be performed on stool samples collected from participants 3-weeks before treatment, just before treatment (baseline), and 3-, 6-, and 12-weeks after treatment. Gut microbiome shifts will be assessed by calculating the Bray Curtis dissimilarity to baseline. To assess the primary outcome, a paired t-test will compare the shift in gut microbiome structure 3-weeks before treatment, to the shift in gut microbiome structure 3-weeks after treatment. No imputation will be performed for missing data.

Secondary Outcomes
Gut Microbiome
Changes in alpha-diversity and microbial gene richness will be assessed using paired t-tests (parametric) or Wilcoxon signed rank tests (non-parametric) as appropriate. Multivariate Association with Linear Models (MaAsLin2) will be used to identify any significant changes in microbiome features (e.g. microbial taxa, metabolic pathways) in response to treatment. The genetic similarity of donor and recipient strains (before and after treatment) will be compared to assess the proportion and stability of donor strain engraftment.

Demographics & Clinical Outcomes
Baseline demographics and clinical characteristics will be summarized using descriptive statistics. Changes in clinical and nutritional features from baseline will be assessed using paired t-tests (parametric) or Wilcoxon signed rank tests (non-parametric) as appropriate.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

22/08/2022

Actual

22/08/2022

Date of last participant enrolment

Anticipated

1/06/2023

Actual

6/11/2023

Date of last data collection

Anticipated

1/09/2023

Actual

27/11/2023

Sample size

Target

Accrual to date

Final

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Auckland

Funding & Sponsors

Funding source category [1]

Other

Name [1]

The Rockfield Trust

Address [1]

Castle Drive
Epsom
Auckland 1023
New Zealand

Country [1]

New Zealand

Primary sponsor type

University

Name

University of Auckland

Address

Liggins Institute
University of Auckland
85 Park Road
Grafton 1023
Auckland
New Zealand

Country

New Zealand

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Central Health and Disability Ethics Committee

Ethics committee address [1]

Health and Disability Ethics Committees
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington
6011

Ethics committee country [1]

New Zealand

Date submitted for ethics approval [1]

04/08/2021

Approval date [1]

24/08/2021

Ethics approval number [1]

21/CEN/212

Summary

Brief summary

Background
Individuals with anorexia nervosa harbour distinct gut microbiomes compared to healthy individuals, which are sufficient to induce weight loss and anxiety-like behaviours when transplanted into germ-free mice. 

Hypothesis
We hypothesise that faecal microbiome transfer (FMT) from healthy donors will help restore the gut microbiomes of individuals with anorexia nervosa which may aid patient recovery. 

Study design and aims
We plan to conduct an open-label pilot study to assess the safety, tolerability, and efficacy of FMT to restore the gut microbiome in adolescents and young adults with anorexia nervosa. 

Participants
We aim to recruit 20 females, aged 16-32 years, who meet the DSM-5 criteria for anorexia nervosa and have a BMI 13-19 kg/m2.

Donors
We will also recruit four healthy, lean, female “super-donors”, aged 18-32 years, who will undergo extensive clinical screening prior to stool donation. 

Intervention
Faecal microbiota will be harvested from four donors and double encapsulated in delayed release, acid-resistant capsules. All participants will receive a single course of 20 FMT capsules which they can choose to take over two or four consecutive days.

Assessments
Stool and blood samples will be collected from participants over a period of 3 months to monitor changes in their gut microbiome profile, gut inflammation/permeability, and nutritional/metabolic status. Our primary outcome is a shift in the gut microbiome composition at 3 weeks post-FMT (shotgun metagenomic sequencing). We will also measure changes in participants body composition (DXA-scan), eating disorder psychopathology (EDEQ questionnaire), mental health (PHQ9 & GAD-7 questionnaires), and assess their views and tolerability to treatment. All adverse events will be recorded and reviewed by a data monitoring committee.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Justin O'Sullivan

Address

Liggins Institute
University of Auckland
85 Park Road
Grafton
Auckland 1023
New Zealand

Country

New Zealand

Phone

+64 9 923 9868

Fax

justin.osullivan@auckland.ac.nz

Contact person for public queries

Name

Brooke Wilson

Address

Liggins Institute
University of Auckland
85 Park Road
Grafton
Auckland 1023
New Zealand

Country

New Zealand

Phone

+64 9 923 6691

Fax

b.wilson@auckland.ac.nz

Contact person for scientific queries

Name

Brooke Wilson

Address

Liggins Institute
University of Auckland
85 Park Road
Grafton
Auckland 1023
New Zealand

Country

New Zealand

Phone

+64 9 923 6691

Fax

b.wilson@auckland.ac.nz

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

Yes

What data in particular will be shared?

1. de-identified post-filtered metagenomic sequencing data will be shared on NCBI's sequence read archive (SRA)

2. de-identified clinical data may be made available for future research upon valid requests to the Liggins Institute Clinical Data Research Hub Data Access Committee.

When will data be available (start and end dates)?

Upon publication of the study findings with no end date.

Available to whom?

Metagenomic sequencing data will be accessible to the public via NCBI's SRA.

Clinical data will only be made available to researchers who meet the the data access requirements set out by the Liggins Institute's data access committee.

Available for what types of analyses?

Gut microbiome characterisation
FMT meta-analyses

How or where can data be obtained?

metagenomic sequencing data will be shared on NCBI's Sequence Read Archive (SRA)

clinical data access requests to be sent to the Liggins Institute's Clinical Data Research Hub Data Access Committee (email: researchhub@auckland.ac.nz)

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
13233	Study protocol			b.wilson@auckland.ac.nz	Planning to publish the trial protocol in a scient... [More Details]

Results publications and other study-related documents

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Documents added automatically

Source	Title	Year of Publication	DOI
Embase	An open-label pilot trial of faecal microbiome transfer to restore the gut microbiome in anorexia nervosa: protocol.	2023	https://dx.doi.org/10.1136/bmjopen-2022-070616

N.B. These documents automatically identified may not have been verified by the study sponsor.

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