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Trial registered on ANZCTR


Registration number
ACTRN12620001337965
Ethics application status
Approved
Date submitted
28/09/2020
Date registered
11/12/2020
Date last updated
11/12/2020
Date data sharing statement initially provided
11/12/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
The FIDGIT Study. Exploring the relationship between Fibromyalgia, Digestive Markers and the Gastrointestinal Tract in adult women.
Scientific title
The FIDGIT Study; A prospective observational study investigating functional gastrointestinal disorders, the gut microbiome and markers thereof in adult women with fibromyalgia, compared to healthy controls.
Secondary ID [1] 302685 0
None
Universal Trial Number (UTN)
U1111-1258-5108
Trial acronym
The FIDGIT Study.
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Fibromyalgia 319141 0
Functional gastrointestinal disorders 319142 0
Condition category
Condition code
Musculoskeletal 317103 317103 0 0
Other muscular and skeletal disorders
Oral and Gastrointestinal 317104 317104 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Neurological 317493 317493 0 0
Other neurological disorders

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Adult women with fibromyalgia and matched controls.
All data will be gathered over a two-three week period for each participant.

All participants will be required to:
1. Collect samples of faeces for microbiome testing. This sample can be collected at home, and is to be collected before presenting for hydrogen-methane breath testing. Equipment for collection and detailed instructions are provided.
Microbiome analysis conducted using 16S rRNA or metagenomic analysis.
Helicobacter pylori antigen assessed using chemiluminescent immunoassay (CLIA) or Enzyme immunoassay (EIA)

2. Undergo hydrogen-methane breath testing on 3 separate occasions. Each is following a one-day low residue diet and 12 hour overnight (water-only) fast. The following substrates will be administered, in the order indicated, with a minimum of 2 days between each test:
a. Glucose 75g (or 1g/kg less than 50kg body weight): breath samples collected at 15 minute intervals for 120 minutes
b. Lactulose 10g: breath samples collected at 20 minute intervals for 180 minutes
c. Fructose 25g: breath samples collected at 20 minute intervals for 180 minutes

Breath testing will be conducted by one of two methods:
a. In-house. Whereby the participant attends the research centre, samples are collected and analysed by a research assistant. Baseline breath gases will be calculated from the average of three breath samples (collected over a maximum periodof 5 minutes) .All participants with an average hydrogen or methane gas concentration of 10ppm or higher at baseline will be instructed to conduct a mouthwash. Three repeat breath samples are taken within 5 minutes after the mouthwash. Where a significant reduction (at least -10ppm or 25%) in breath gas or gases is recorded, participants will also be invited to contribute to the OMG Study (Trial No: 380620)
b. Remotely, using the test kit provided by the manufacturer (Quintron). Guidance and support for correct collection is provided by a research assistant. All participants conducting breath tests remotely will conduct a single mouthwash after the initial breath sample, and then collect a further breath sample before consuming the substrate.
A link to an explanatory video is provided to guide the collection process for at-home participants.

All breath samples will be analysed on the same equipment (with test-tube extraction adaptor for remotely collected samples), by a research assistant trained in the use of the analyser.
All symptoms reported during breath testing are also recorded.

In-house participants may have an oral swab collected during the first breath test (prior to ingestion of the test substrate). In-house participants will also have capillary blood samples collected for a) blood sugar monitoring during the glucose challenge, and b) for FORT/FORD testing (free radical and antioxidant defence measure)

3. Collect 4 urine samples over a single 24-hour period, not to be collected during menstruation.
Urine collections are done by the participant, at home, at least 48 hours after completion of breath testing. At breath testing appointment, the procedure is explained by the study coordinator or research assistant. Detailed written instructions and all collection equipment is provided.
Participants are advised to avoid the following foods for 24 hours prior to commencing collection of the urine samples: Celery, onions, pumpkin, mushrooms, snow peas, sweet potato, peaches, chocolate, any substance with artificial sweetener (e.g., cough drops, sweets, chewing gum), fermented foods and probiotics (including yoghurt)
Day of testing:
- Fast (no food, water intake as specified) from arising until 4 hours after starting the test.
- Collect 2x 10mL samples from first morning urination (1 as control for Lactulose-mannitol recovery, 1 for histamine measurement).
- Ingest 100 ml water with 10 g lactulose and 5 g mannitol
- No water consumption for the following 2 hours
- Continue collecting urine, with aliquoted samples at 2- and 4-hours post ingestion (to evaluate recovery of these saccharides in urine as a marker of intestinal hyperpermeability)
- 250mL water at 2 hours and 3 hours post-ingestion
- Remain without food until the 4-hour collection is complete. Avoid fermented foods and probiotics until the full 24-hour collection is complete.
- Continue collecting urine until 24 hours after initial sample, (to evaluate 24-hour urine histamine excretion)

4. Make a single visit to a community laboratory for blood testing within one week of completion of all breath testing (to collect blood samples for measurement of serum ferritin, full blood count, electrolytes, creatinine, C-reactive protein)

5. All participants complete a single, integrated online questionnaire (hosted in REDCap) which merges the following tools:
• American College of Rheumatology fibromyalgia diagnostic criteria (ACR) 2016. (Wolfe et al. 2016)
• Revised Fibromyalgia Impact Questionnaire (FIQR) (Bennett et al. 2009; Burckhardt, Clark, and Bennett 1991)
• Rome IV (Drossman and Hasler 2016; Palsson et al. 2016)
• Functional Bowel Disorder Severity Index (FBDSI) (Drossman et al. 1995; Sperber et al. 2000)
• Headache Symptom Questionnaire (HSQ) (van der Meer et al. 2019; (IHS) 2013)
• Medical Outcomes Study Sleep Scale (SSS) (Williams and Arnold 2011)
• Short Form Survey -36 (SF36) (McHorney et al. 1994; Hays, Sherbourne, and Mazel 1995)
• Oral Health Questionnaire (OHQ) (Petersen, Baez, and World Health 2013)
The questionnaire is to be submitted before all testing is completed.
Intervention code [1] 318649 0
Not applicable
Comparator / control treatment
The control group are matched by gender and age, and the absence of fibromyalgia. All questionnaires and testing procedures are the same as for the study group.
Control group
Active

Outcomes
Primary outcome [1] 325188 0
Obtain measures of gastrointestinal bacteria from oral and faecal swabs. For measuring Helicobacter pylori status, a separate stool sample is required.
Timepoint [1] 325188 0
Single oral and faecal swabs will be obtained at baseline.
Primary outcome [2] 325189 0
Measure breath hydrogen and methane gas (and hydrogen sulphide if equipment becomes available) on three occasions:
1. Oral glucose challenge: up to 75g glucose [or 1g/kg if less than 50kg body weight], Breath gases measured every 15 minutes for 120 mins
2. Oral lactulose challenge: 10g lactulose, Breath gases measured every 20 mins for 3 hours
3. Oral fructose challenge: 25g fructose in 300ml water. Breath gases measured every 20 minutes for 180 mins.
Timepoint [2] 325189 0
At baseline, each test conducted on a separate occasions, at least 2 days apart.
Primary outcome [3] 325571 0
Measure symptoms of fibromyalgia, as assessed by American College of Rheumatology (ACR) 2106 criteria.
Timepoint [3] 325571 0
At baseline.
Secondary outcome [1] 387126 0
Evaluate presence of functional gastrointestinal disorders as determined by Rome IV questionnaire,
Timepoint [1] 387126 0
At baseline
Secondary outcome [2] 387127 0
Measure headache prevalence and intensity using the Headache Symptom Questionnaire (HSQ)
Timepoint [2] 387127 0
At baseline.
Secondary outcome [3] 388428 0
Measure sleep quality and quantity using the Medical Outcomes Study Sleep Scale (SSS)
Timepoint [3] 388428 0
At baseline.
Secondary outcome [4] 388429 0
Assess quality of life measures using the Rand Short Form Survey -36 (SF36)
Timepoint [4] 388429 0
At baseline.
Secondary outcome [5] 388432 0
Measure free radical oxidative stress via capillary blood sample collected by the study coordinator or research assistant, Sample will be evaluated using a dedicated spectrophotometer for free oxygen radicals (FORT), based on the Fenton reaction. This procedure is outlined in Kovac 2019 (https://doi.org/10.1155/2019/5063565)
This test will only be conducted on those presenting to the research centre for hydrogen-methane breath testing. Those conducting breath testing at home will not be included.
Timepoint [5] 388432 0
At baseline
Secondary outcome [6] 388457 0
Measure blood antioxidant concentration via capillary blood sample collected by the study coordinator or research assistant, Sample will be evaluated using a dedicated spectrophotometer for an estimation of free oxygen radicals defense (FORD). This procedure is outlined in Kovac 2019 (https://doi.org/10.1155/2019/5063565)
This test will only be conducted on those presenting to the research centre for hydrogen-methane breath testing. Those conducting breath testing at home will not be included.
Timepoint [6] 388457 0
At baseline.
Secondary outcome [7] 389611 0
H.pylori status assessed by stool antigen testing
Timepoint [7] 389611 0
At baseline
Secondary outcome [8] 389612 0
Anion gap as determined by serum measurement of sodium, potassium, chloride and bicarbonate.
Timepoint [8] 389612 0
At baseline
Secondary outcome [9] 389616 0
Measure circulating histamine via 24-hour urine sample collection
Timepoint [9] 389616 0
At baseline.
Secondary outcome [10] 389618 0
Assess oral health using the WHO Oral Health Questionnaire.
Timepoint [10] 389618 0
At baseline.
Secondary outcome [11] 389784 0
Measure intestinal permeability by recovery of lactulose and mannitol in urine following oral lactulose & mannitol challenge.
Timepoint [11] 389784 0
At baseline

Eligibility
Key inclusion criteria
Adult women meeting ACR2016 criteria for fibromyalgia and age & gender-matched controls.
Must be willing to provide biological samples that will be sent overseas for analysis with microbiome data potentially becoming part of a larger biobank.
Minimum age
18 Years
Maximum age
75 Years
Gender
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Diabetes or any other condition precluding fasting for 15 hours, pregnancy, any major comorbid illness (e.g. malignancy, active inflammatory or metabolic
disease), taking chronic analgaesics (and unable to cease for 3 days prior to sample collection),or immune-modifying medication. Antibiotic use within previous 4 weeks (deferral is an option). Unable to provide informed consent or complete questionnaires in English. Participants unwilling to submit biological samples in accordance with the study protocol.

Study design
Purpose
Screening
Duration
Cross-sectional
Selection
Case control
Timing
Prospective
Statistical methods / analysis
Using estimated prevalence of IBS (as benchmark for FGID) in fibromyalgia of 48% (as per systematic review) & estimated prevalence of IBS in general population 15%.
- Alpha of 0.05, CI 95% = Sample size minimum of 48,
= minimum of 55 participants & 55 controls, which allows ~10% attrition.
If data is normally distributed the prevalence of co-morbidities is compared to controls using Student’s paired T-test; otherwise the Wilcoxen signed-rank test will be used.
Relationships between each of the variables will be examined, and compared to controls.
Data will be evaluated using a range of statistical analyses: anthropometrics, symptom prevalance, scores & co-morbidities compared using ANOVA (univariate) & MANOVA (multivariate). For microbiome analyses:correction for multiple comparisons (eg using Benjamini–Hochberg FDR) and normalised operational taxonomy units (OTUs) evaluated using Pearson's correlations. Strength of associations with clinical variables tested using Spearman's Rho.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 23007 0
New Zealand
State/province [1] 23007 0
All of country

Funding & Sponsors
Funding source category [1] 306801 0
Commercial sector/Industry
Name [1] 306801 0
QuinTron Instrument Company
Address [1] 306801 0
2208 South 38th St
Milwaukee, WI 53215
Country [1] 306801 0
United States of America
Funding source category [2] 306802 0
Commercial sector/Industry
Name [2] 306802 0
House of Health Ltd
Address [2] 306802 0
888 New North Road
Mt Albert
Auckland 1025
Country [2] 306802 0
New Zealand
Primary sponsor type
University
Name
The University of Sydney
Address
The University of Sydney
Private Bag
NSW 2006
Country
Australia
Secondary sponsor category [1] 307341 0
None
Name [1] 307341 0
Address [1] 307341 0
Country [1] 307341 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306950 0
Health & Disability Ethics Committee
Ethics committee address [1] 306950 0
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington 6011
Ethics committee country [1] 306950 0
New Zealand
Date submitted for ethics approval [1] 306950 0
07/08/2020
Approval date [1] 306950 0
29/10/2020
Ethics approval number [1] 306950 0
20/CEN/197

Summary
Brief summary
Fibromyalgia remains a poorly understood chronic disorder associated with a range of comorbidities. There are limited treatment options, with variable efficacy.

Hypothesis: Functional gastrointestinal disorders (FGID) in people with fibromyalgia are associated with alterations in the microbiome. Such alterations and metabolic by-products thereof contribute to symptoms, reduced quality of life and other comorbidities in people with fibromyalgia.
In women with fibromyalgia, we aim to:
1. Determine the relationship between the gastrointestinal microbiome and markers thereof and functional gastrointestinal disorders
2. Evaluate relationships between markers of the gastrointestinal microbiome, symptoms and comorbidities,
3. Examine relationships between functional gastrointestinal disorders, symptoms and comorbidities.
Each will be compared with matched healthy controls.
The outcomes of this study will inform future research directions including exploration of new treatment options/management strategies to support people living with fibromyalgia.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 105554 0
Dr Joanna Harnett
Address 105554 0
The University of Sydney School of Pharmacy
Faculty of Medicine and Health
The University of Sydney
NSW 2006
Country 105554 0
Australia
Phone 105554 0
+61 2 9351 7009
Fax 105554 0
+61 2 9036 0000
Email 105554 0
joanna.harnett@sydney.edu.au
Contact person for public queries
Name 105555 0
Mrs Sharon Erdrich
Address 105555 0
House of Health
888 New North Road
Mt Albert
Auckland 1025
Country 105555 0
New Zealand
Phone 105555 0
+64 9 8465566
Fax 105555 0
+64 9 846 5567
Email 105555 0
sharon.erdrich@sydney.edu.au
Contact person for scientific queries
Name 105556 0
Mrs Sharon Erdrich
Address 105556 0
House of Health
888 New North Road
Mt Albert
Auckland 1025
Country 105556 0
New Zealand
Phone 105556 0
+64 9 8465566
Fax 105556 0
+64 9 846 5567
Email 105556 0
sharon.erdrich@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
IPD will not be available
What supporting documents are/will be available?
Informed consent form
Ethical approval
How or where can supporting documents be obtained?
Type [1] 9597 0
Ethical approval
Citation [1] 9597 0
Link [1] 9597 0
Email [1] 9597 0
Other [1] 9597 0
Type [2] 9598 0
Informed consent form
Citation [2] 9598 0
Link [2] 9598 0
Email [2] 9598 0
Other [2] 9598 0
Summary results
No Results