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Trial registered on ANZCTR


Registration number
ACTRN12624001394538
Ethics application status
Approved
Date submitted
1/10/2024
Date registered
26/11/2024
Date last updated
26/11/2024
Date data sharing statement initially provided
26/11/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Dietary Intervention for Eczema
Scientific title
Efficacy of Food Intervention Targeting Salicylates, Histamine and Allergens (FISHA) for Symptom Control in Adults with Moderate-to-Severe Atopic Dermatitis: A Randomised Controlled Trial
Secondary ID [1] 312876 0
Nil known
Universal Trial Number (UTN)
U1111-1312-8735
Trial acronym
FISHA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
atopic dermatitis (eczema) 335025 0
food intolerance 335026 0
Condition category
Condition code
Skin 331534 331534 0 0
Dermatological conditions
Diet and Nutrition 331535 331535 0 0
Other diet and nutrition disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This RCT is a two-arm intervention study design:
Arm 1.
(i) dietary intervention, involving removal of three common food allergens (egg, dairy and wheat), and reduction of dietary salicylates (with each eligible food item containing less than or equal to 0.25 mg/g of free and bound salicylic acid), and histamine, with set menu and recipes, and appropriate supplementation (2 x powdered supplements including calcium) to fill nutritional gaps for 6 weeks, or

Arm2.
(ii) the control group who receive a sham consultation with standard care at baseline, then remain on their habitual diet with no new treatment for 6 weeks.

There are four phases of the trial:
Phase 1: Eighty adults with moderate-to-severe atopic dermatitis are monitored for 2 weeks with no intervention, serving as their own control. All participants record their habitual diet for three days via Photographic Food Record so water and nutrient intakes (Ca, Fe, Zn, K, Na, retinol equivalents, and vitamins C, D and E) can be compared to Australian Estimated Average Requirement (EAR) guidelines. At -2 weeks, participants attend Bond University for in-person assessment. All other contact during phase one occurs remotely via email or phone call.

Phase 2: The dietary intervention has two arms with parallel groups containing 40 participants in the intervention group and 40 participants in the control group (with an anticipated 20% drop out) At baseline, both groups will take part in a sham consultation at Bond University, involving standard care, assessment of skin using the Eczema Severity Score Index (EASI), itch score, and quality of life, measured by the Dermatology Life Quality Index (DLQI). Weight is recorded using scales. Standard care is defined by the management flowchart published by Smith S, et al. (2020) and researchers conducting the sham consultation will be trained by a specialist dermatologist. On exiting the consultation, individuals will be taken to a room on a different floor where an independent researcher will provide a concealed manual (identified only with individual ID) containing instructions on standard care for the control group and a concealed manual containing the diet intervention for the participants.

The participants are randomised to 6 weeks of either (i) dietary intervention, involving removal of three common food allergens (egg, dairy and wheat), and reduction of dietary salicylates (with each eligible food item containing less than or equal to 0.25 mg/g of free and bound salicylic acid), and histamine, with set menu and recipes, and appropriate supplementation (2 x powdered supplements including calcium) to fill nutritional gaps for 6 weeks, or (ii) the control group who receive a sham consultation with standard care at baseline, then remain on their habitual diet with no new treatment for 6 weeks.

Phase 3: In week 6, all subjects attend in person at Bond University (which is within a 1-kilometre radius from Robina Hospital) to assess quality of life (DLQI), disease severity (EASI) and Itch Score, and feasibility and acceptability of the diet using a series of questionnaires. Week 6 also includes Oral Food Challenge involving salicylates for both groups; week 7, histamine challenge; and week 8, milk/egg/wheat challenge, followed by 2-h monitoring with a nurse present. If a participant does not react within 2 hours after oral challenge on site at Bond University, follow up by researchers will occur 24-h and 48-h later (remotely, via email and phone). Follow up involves the participant taking photos of their skin (holding a colour chart beside their skin) at 24-hr and 48-hr after oral challenge for assessment, and then emailing the images to the researchers.

Phase 4: 3-month follow up where participants are asked via email a series of questions including ongoing adherence to the diet. They are asked to provide images of their skin (using a colour card) for EASI skin assessment.

Materials, procedures and processes:
Pre-screening Eligibility Survey will be sent to all interested participants during pre-trial initial screening; consent forms for participants and controls; measuring tape to be used during taking of EASI assessment images to be used by researchers; EASI training information for researchers; training instructions for Research Food Diary app for researchers and participants; instructions by Bird et al. (2020) for oral challenge (for researchers); participant manual (including instructions, menus and recipes) for FISHA intervention participants; standard care manual for the control group; Food Skills Video for participants to enhance their cooking skills; instructional videos for the preparation of 10-15 recipes; Oral Challenge Consent Forms for all participants in the trial who elect to complete the oral challenge involving salicylates, histamine, egg, milk and wheat; scales to measure weight of all participants; and blood vials, needles, and medical gloves for collecting blood samples.

The Australian EAR will be used for assessing nutrient intakes of groups at baseline and week 4. Where EARs are not available, Adequate Intakes (AI) will be used as a benchmark.

The intervention, designed and reviewed by a multidisciplinary team including a qualified nutritionist and dietitian, adheres to Australian Dietary Guidelines, with EAR guidelines used to determine the nutritional needs of participants are met. The intervention will be delivered by the following: a qualified nutritionist with 22 years of clinical experience working with patients with atopic dermatitis and food intolerance including personalised dietary interventions and recipe/menu creation; clinical trial specialist with over 15 years of experience in academic research including managing large scale, complex clinical trials including dietary intervention studies; biostatistician with more than 20 years of experience.

Validated tool, Eczema Area and Severity Index (EASI) will be used for skin assessment to measure atopic dermatitis severity (-2 weeks, baseline, week 6, 7 and 8 and follow-up). Researchers will be trained by local dermatologist in performing skin assessments using EASI. Images will be taken to assist with accurate assessment of atopic dermatitis severity. Eligible participants will have an EASI score between 7.1 to 72.0 (moderate to very severe atopic dermatitis). The minimal clinically important difference is 6.6 EASI points (Schram et al., 2012) so treatment success is a reduction in EASI score by 6.6 points or more. Treatment failure for a participant is defined as inadequate improvement of atopic dermatitis as shown by EASI (less than 6.5-point reduction or an increase in score), or severe adverse event/s, or poor tolerability of the intervention from week 4.

Participants allocated to the diet intervention will be provided with two free compounded powder vitamin and mineral supplements (including calcium as the intervention omits dairy), and approximately 15 pantry items including olive oil and wheat-free oats. Weekly phone calls and text message reminders and check-ins will help to ensure participants stay on track. Weekly online meetings also provide an opportunity to ask questions or report concerns. At baseline participants will be emailed a link to an online 20-minute Food Skills Video for skill development on food purchase and food preparation, allowing people with low cooking skills to participate in the trial. Researchers will call participants on day 1 to check if they can access the videos and to answer any questions or concerns. Adherence is monitored by weekly Photographic Food Records, weekly Zoom/Teams/phone meetings, and face-to-face meetings (weeks 0, 4 and 6).

Blood collection: A trained phlebotomist will collect overnight fasted blood samples via venipuncture at baseline and 6 weeks during intervention to assess circulating proteins by targeted proteomics (Harney 2019). The volume of blood collected will be less than or equal to 20ml. Blood samples will be processed and plasma stored at -80degCel to maintain sample integrity for subsequent analysis.

After a 12-month study intervention period, the intervention and control groups will be compared, following this the control group will receive the dietary intervention as a benefit for participation in the study, but they will not be followed up for assessment of outcomes within this study.

References
Bird JA, Leonard S, Groetch M, et al. Conducting an Oral Food Challenge: An Update to the 2009 Adverse Reactions to Foods Committee Work Group Report. J Allergy Clin Immunol Pract. Jan 2020;8(1):75-90 e17

Smith S, Baker C, Gebauer K, et al. Atopic dermatitis in adults: An Australian management consensus. Australas J Dermatol. Feb 2020;61(1):23-32.

Harney DJ, Hutchison AT, Su Z, Hatchwell L, Heilbronn LK, Hocking S, et al. Small-protein Enrichment Assay Enables the Rapid, Unbiased Analysis of Over 100 Low Abundance Factors from Human Plasma. Mol Cell Proteomics. 2019;18(9):1899-915.
Intervention code [1] 329415 0
Treatment: Other
Comparator / control treatment
Comparator/ control treatment group will be "Standard Care" with no new intervention throughout duration of intervention phase of the trial.
Control group
Active

Outcomes
Primary outcome [1] 339281 0
Atopic dermatitis severity assessed using Eczema Area Severity Index (EASI).

Timepoint [1] 339281 0
baseline and 6 weeks following end of treatment intervention
Secondary outcome [1] 439358 0
Quality of Life assessed using Dermatology Life Quality Index
Timepoint [1] 439358 0
Baseline and 6 weeks following intervention commencement
Secondary outcome [2] 439359 0
Dietary Adherence assessed using weekly Photographic Food Records.
Timepoint [2] 439359 0
weeks 4, 6 and 8 weeks post intervention commencement.
Secondary outcome [3] 440262 0
Feasibility and acceptability of the dietary intervention will be assessed by recruitment and retention numbers, and dietary adherence to the dietary protocol as described above) and qualitative survey questions.

Feasibility will be assessed through the primary outcome of recruitment rate, retention rate, safety and adverse events, compliance to the FISHA protocol, and acceptability attitudes/opinions/barriers). This will be evaluated as a composite primary outcome since no single measure can fully assess feasibility.

Recruitment rate will be assessed by comparing the number of persons screened to the final enrollments; ie. Audit of study pre-screening eligibility survey, recruitment interviews, and participant enrolment logs will be used.

Retention rate will be assessed by comparing the number of participants enrolled to the number of participants who complete the final study measures.. ie. Audit of study enrolment./withdrawal logs will be used.

Safety will be assessed using participant reports of adverse events, such as self-reported gastrointestinal issues, nausea, dizziness, itching, eczema flare or other events resulting from the dietary intervention.

Compliance to the dietary intervention will be assessed using a combination of participant self-reports and photo images of meal times (with time stamps).

Acceptability (attitudes/opinions/barriers) will be assessed through a qualitative questionnaire completed at the end of the intervention (i.e., after 6 weeks of FISHA).
Timepoint [3] 440262 0
6 and 8 weeks after intervention commencement and 3month followup (post-intervention)
Secondary outcome [4] 440264 0
Itch score (change in itch intensity), using the Peak Pruritus Numerical Rating Scale (NRS) which is a validated tool (Yosipovitch, et al. 2019) for use in clinical trials involving adults with moderate-to-severe atopic dermatitis.

Yosipovitch G, Reaney M, Mastey V, et al. Peak Pruritus Numerical Rating Scale: psychometric validation and responder definition for assessing itch in moderate-to-severe atopic dermatitis. Br J Dermatol. Oct 2019;181(4):761-769. doi:10.1111/bjd.17744
Timepoint [4] 440264 0
6 and 8 weeks after intervention commencement (primary timepoint) and 3month followup (post-intervention)
Secondary outcome [5] 440265 0
Prevalence of salicylate intolerance will be assessed by oral food challenge, EASI and self reporting including survey and photos of affected skin areas,

Prevalence of salicylate intolerance will be measured via oral food challenge using an adapted method based on the document by Bird, et al., 2020. Oral food challenge will involve foods high salicylates including sweet potato and curry powder.

Bird JA, Leonard S, Groetch M, et al. Conducting an Oral Food Challenge: An Update to the 2009 Adverse Reactions to Foods Committee Work Group Report. J Allergy Clin Immunol Pract. Jan 2020;8(1):75-90 e17. doi:10.1016/j.jaip.2019.09.029
Timepoint [5] 440265 0
6 weeks after intervention commencement
Secondary outcome [6] 441407 0
Prevalence of histamine intolerance assessed by oral food challenge, EASI and self reporting including survey and photos of affected skin areas,

Prevalence of histamine intolerance, measured via oral food challenge using an adapted method based on the document by Bird, et al., 2020. Oral food challenge will involve foods high in histamine including sauerkraut.

Bird JA, Leonard S, Groetch M, et al. Conducting an Oral Food Challenge: An Update to the 2009 Adverse Reactions to Foods Committee Work Group Report. J Allergy Clin Immunol Pract. Jan 2020;8(1):75-90 e17. doi:10.1016/j.jaip.2019.09.029
Timepoint [6] 441407 0
7 weeks post intervention commencement
Secondary outcome [7] 441408 0
Prevalence of food allergen (cow's milk, hen's egg, wheat) intolerance assessed by oral food challenge, EASI and self reporting including survey and photos of affected skin areas,

Prevalence of hypersensitivity to milk, egg and wheat, measured via oral food challenge (within a baked muffin) following a standardised protocol by Bird, et al., 2020.

Bird JA, Leonard S, Groetch M, et al. Conducting an Oral Food Challenge: An Update to the 2009 Adverse Reactions to Foods Committee Work Group Report. J Allergy Clin Immunol Pract. Jan 2020;8(1):75-90 e17. doi:10.1016/j.jaip.2019.09.029
Timepoint [7] 441408 0
Week 8 post intervention commencement
Secondary outcome [8] 441933 0
Blood biochemistry- changes in circulating proteins in blood (plasma) will be assessed by proteomics as described in Harney et al. 2019.

Harney DJ, Hutchison AT, Su Z, Hatchwell L, Heilbronn LK, Hocking S, et al. Small-protein Enrichment Assay Enables the Rapid, Unbiased Analysis of Over 100 Low Abundance Factors from Human Plasma. Mol Cell Proteomics. 2019;18(9):1899-915.

Additionally, systemic inflammation will be assessed by measuring C-Reactive Protein by Afinion CRP - Abbott Point of Care.
Timepoint [8] 441933 0
Week 6 post-intervention commencement and changes will be expressed relative to baseline

Eligibility
Key inclusion criteria
We will recruit 80 adults (40 in each group), aged 20-60yo, with moderate to severe atopic dermatitis (EASI, Eczema Area and Severity Index). Aiming for an equal sex distribution (1:1). Justification for age range: adults aged >20 are more likely to have improved nutritional intakes on an elimination diet, compared to children and adolescents. Ageing populations have reduced appetites, resulting in lower energy intakes so we have restricted the age bracket to <60.
Minimum age
20 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Unwell in the past four weeks, severe asthma (uncontrolled), anaphylaxis, Celiac disease, anaemia (iron deficiency anaemia), anorexia or other eating disorder, topical steroid withdrawal (red skin syndrome), topical steroid dependence, cancer or any life-threatening disease, irritable bowel syndrome (IBS) or any chronic bowel issues, or people taking blood thinning medications (FISHA is a low salicylate diet, and anticoagulants are usually high in salicylates), antibiotics, steroid injections/oral or immunosuppressants, or intolerance to FODMAPs (FISHA is high in prebiotic fibre which is not well tolerated in people with FODMAP-related issues). Smoking and frequent alcohol consumption (more than 10 standard drinks a week as per Australian guidelines), as they are risk factors for AD. Children and teenagers are excluded. Vegans and vegetarians and persons who avoid red meat (as red meat and white fish are a part of the program). Persons unwilling or unlikely to make dietary changes, who are operationally defined as eating outside of the home more than five times per week, or incapability to comply with the study protocol. Adults will be excluded from the study protocol if food diaries during intervention period show non-compliance with the specific dietary recommendations, diaries are missed for more than 1 week, severe adverse reaction occurs, or presentation of other severe diseases that require additional therapy.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Randomisation will be performed by computer generation by independent researcher

Allocation will involve contacting the holder of the allocation schedule who will be "off-site" or at central administration site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?

The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample Size Calculation
Participant sample size calculation of 80 is based on previous research which has reported that around 50% of individuals with atopic dermatitis have pharmacological food intolerance (Greenlees, 1998). The study power of the trial is 80% and the level of significance is 5%. The study is powered for a 35% absolute increase (from expected 15% in the control group) in participants with a reduction in EASI by a minimum of 6.6 points. The expected proportion of participant dropout in the trial is around 20%.

Greenlees N. Food intolerance in children with eczema. Thesis, University of Sydney. 1998

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
20/01/2025
Actual
Date of last participant enrolment
Anticipated
31/12/2027
Actual
Date of last data collection
Anticipated
31/12/2028
Actual
Sample size
Target
80
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD

Funding & Sponsors
Funding source category [1] 317317 0
University
Name [1] 317317 0
Bond University
Country [1] 317317 0
Australia
Primary sponsor type
University
Name
Bond University
Address
Country
Australia
Secondary sponsor category [1] 319599 0
None
Name [1] 319599 0
Address [1] 319599 0
Country [1] 319599 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 316050 0
Bond University Human Research Ethics Committee
Ethics committee address [1] 316050 0
https://bond.edu.au/ethics
Ethics committee country [1] 316050 0
Australia
Date submitted for ethics approval [1] 316050 0
10/11/2023
Approval date [1] 316050 0
24/01/2024
Ethics approval number [1] 316050 0
HO01016

Summary
Brief summary
Atopic dermatitis (eczema), is an inflammatory skin disease, presenting with an intense itch-scratch cycle, lesions, pain, sleep loss and lowered quality of life.

The complex nature of atopic dermatitis, with chronic and often relapsing disease course, makes treatment difficult.

Elimination diets have been used as a medical tool for atopic dermatitis and food allergy for decades, but current strategies are outdated. This is a new dietary study based on new research.

The overall aim of this study is to evaluate the efficacy and safety of a novel dietary elimination protocol for the management of moderate to severe atopic dermatitis to reduce the severity of symptoms in affected individuals and improve the quality of life.

Specifically, this study aims to investigate whether temporary elimination of dietary allergens (milk, egg and wheat), salicylates and histamine is an effective therapeutic strategy for adults with moderate-to-severe atopic dermatitis.

General public statement
We hypothesise that a temporary elimination of dietary allergens (milk, egg, and wheat), salicylates, and histamine will effectively reduce the severity of symptoms and improve the quality of life in adults with moderate-to-severe atopic dermatitis (eczema).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 62606 0
Dr Hayley O'Neill
Address 62606 0
Bond University, Faculty of Health Sciences and Medicine, 14 University Drive, Varsity Lakes, QLD 4229 Australia
Country 62606 0
Australia
Phone 62606 0
+61 7 5595 1273
Fax 62606 0
Email 62606 0
[email protected]
Contact person for public queries
Name 62607 0
Hayley O'Neill
Address 62607 0
Bond University, Faculty of Health Sciences and Medicine, 14 University Drive, Varsity Lakes, QLD 4229 Australia
Country 62607 0
Australia
Phone 62607 0
+61 7 5595 1273
Fax 62607 0
Email 62607 0
[email protected]
Contact person for scientific queries
Name 62608 0
Hayley O'Neill
Address 62608 0
Bond University, Faculty of Health Sciences and Medicine, 14 University Drive, Varsity Lakes, QLD 4229 Australia
Country 62608 0
Australia
Phone 62608 0
+61 7 5595 1273
Fax 62608 0
Email 62608 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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.