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Trial registered on ANZCTR


Registration number
ACTRN12614001077651
Ethics application status
Approved
Date submitted
20/08/2014
Date registered
9/10/2014
Date last updated
17/01/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Treating gut flora imbalances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A pilot open label trial examining sex differences and psychological symptoms.
Scientific title
Assessing actigraphic sleep efficiency, Profile of Mood States and Rapid Visual Information Processing for antibiotic and probiotic treatment to reduce gut dysbiosis in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients with high Streptococcus: Comparison between sexes.
Secondary ID [1] 285192 0
Nil
Universal Trial Number (UTN)
Nil
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome 292798 0
Condition category
Condition code
Other 293092 293092 0 0
Conditions of unknown or disputed aetiology (such as chronic fatigue syndrome/myalgic encephalomyelitis)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The Active Treatment Protocol will be combined antibiotic and probiotic therapy for 4 weeks duration.
Week 1 = Erythromycin (EES-400mg) - 2 x daily oral capsules
Week 2 = Pro4 - 50 D-Lactate Free multistrain probiotic (2 x daily oral capsules)
Week 3 = Erythromycin (EES-400mg) - 2 x daily oral capsules
Week 4 = Pro4 - 50 D-Lactate Free multistrain probiotic (2 x daily oral capsules)

Each capsule of Pro4 - 50 D-Lactate Free multistrain contains:
Lactobacillus rhamnosus 25 billion CFUs
Bifidobacterium lactis 15 billion CFUs
Bifidobacterium breve 5 billion CFUs
Bifidobacterium longum 5 billion CFUs
Total CFU Count: 50 billion


Treatment response and compliance will be monitored by weekly phone calls throughout the intervention phase and assessed through participant self-report questions at the end of the study. The second Bioscreen Faecal Microbial Analysis will provide information about any gut flora changes and will be used in conjunction with participant's self-reported treatment adherence.


This treatment protocol is in accordance with current practice at CFSDC. The use of Erythromycin has been TGA approved for Streptococcal infection whilst not specifically indicated for treatment of ME/CFS populations. EES used in this study is not aimed to eradicate faecal streptococcus; but prophylactically to suppress the index organism.
Intervention code [1] 290059 0
Treatment: Drugs
Comparator / control treatment
This is a pilot open label trial with a repeated measures design with no placebo control.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 292955 0
Mean actigraphic sleep efficiency score
Timepoint [1] 292955 0
At baseline and post-intervention (week 5 after conclusion of the 4 week intervention)
Primary outcome [2] 292956 0
Profile of Mood Scale (POMS) mean scores
Timepoint [2] 292956 0
At baseline and post-intervention (week 5 after conclusion of the 4 week intervention)
Primary outcome [3] 292957 0
Mean Rapid Visual Information Processing (RVP) on CANTAB
Timepoint [3] 292957 0
At baseline and post-intervention (week 5 after conclusion of the 4 week intervention)
Secondary outcome [1] 310003 0
Bioscreen Fecal Microbial Analysis results
Timepoint [1] 310003 0
At baseline and post-intervention (week 5 after conclusion of the 4 week intervention)
Secondary outcome [2] 310004 0
Mean scores on the Brain Fog subscale of the Multiple Fatigue Types Questionnaire
Timepoint [2] 310004 0
At baseline and post-intervention (week 5 after conclusion of the 4 week intervention)
Secondary outcome [3] 310005 0
Subjective sleep diary rating of sleep quality and wakefulness
Timepoint [3] 310005 0
At baseline and post-intervention (week 5 after conclusion of the 4 week intervention)
Secondary outcome [4] 310006 0
Symptom Severity and Symptom Hierarchy Profile scores
Timepoint [4] 310006 0
At baseline and post-intervention (week 5 after conclusion of the 4 week intervention)
Secondary outcome [5] 310007 0
Depression, Anxiety and Stress Scale (DASS-21) mean scores
Timepoint [5] 310007 0
At baseline and post-intervention (week 5 after conclusion of the 4 week intervention)
Secondary outcome [6] 310008 0
The Multidimensional Fatigue Inventory (MFI-20) mean scores
Timepoint [6] 310008 0
At baseline and post-intervention (week 5 after conclusion of the 4 week intervention)
Secondary outcome [7] 310009 0
Mean scores on the Pittsburgh Sleep Quality Index (PSQI)
Timepoint [7] 310009 0
At baseline and post-intervention (week 5 after conclusion of the 4 week intervention)
Secondary outcome [8] 310010 0
Mean scores on the Insomnia Severity Index (ISI)
Timepoint [8] 310010 0
At baseline and post-intervention (week 5 after conclusion of the 4 week intervention)
Secondary outcome [9] 310011 0
The Mood Adjectives checklist mean scores
Timepoint [9] 310011 0
At baseline and post-intervention (week 5 after conclusion of the 4 week intervention)
Secondary outcome [10] 310012 0
Mean scores on Attention Switching Task (AST) on CANTAB
Timepoint [10] 310012 0
At baseline and post-intervention (week 5 after conclusion of the 4 week intervention)
Secondary outcome [11] 310013 0
Mean scores on Paired Associate Learning on CANTAB
Timepoint [11] 310013 0
At baseline and post-intervention (week 5 after conclusion of the 4 week intervention)
Secondary outcome [12] 310014 0
Mean scores on Spatial Working Memory (SWM) on CANTAB
Timepoint [12] 310014 0
At baseline and post-intervention (week 5 after conclusion of the 4 week intervention)
Secondary outcome [13] 310015 0
Mean scores on Rey Auditory Verbal Learning Test (RAVLT)
Timepoint [13] 310015 0
At baseline and post-intervention (week 5 after conclusion of the 4 week intervention)
Secondary outcome [14] 310016 0
Mean scores on Weschler Memory Scales (WMS-IV) Logical Memory Subscale
Timepoint [14] 310016 0
At baseline and post-intervention (week 5 after conclusion of the 4 week intervention)
Secondary outcome [15] 310017 0
Mean scores on Controlled Oral Word Association Test (COWAT)
Timepoint [15] 310017 0
At baseline and post-intervention (week 5 after conclusion of the 4 week intervention)
Secondary outcome [16] 313879 0
Urinary D-lactate levels
Timepoint [16] 313879 0
At baseline and post-intervention (week 5 after conclusion of the 4 week intervention).

Eligibility
Key inclusion criteria
Participants will be patients who have voluntarily presented or been referred to CFSDC. Prospective participants will be:
- aged above 18 years
- meet the CCC diagnostic criteria for CFS (Carruthers et al., 2003). The CCC is more commonly used to make a diagnosis of ME/CFS in clinical practice.
- have higher than normal Streptococcus bacteria count levels as indicated by pathology testing (Bioscreen FMA). High levels of Streptococcus are determined by a viable count reference range above 3.00 x 10(exponent 5) cfu/gm and greater than 5% distribution within aerobic microorganisms. Normal levels are below the aforementioned count and distribution levels.
- refrain from taking any other antibiotics for 4 weeks prior and throughout the study period.
- refrain from taking any other probiotics for 2 weeks prior and throughout the study period.
- agree to refrain from substantially altering their current diet and intake of prescription medication or over-the-counter supplements throughout the 6 week study period - or notify the researchers of any changes required at the time of the change.

We will be recruiting equal proportions of male (n = 20) and female (n = 20) participants to evaluate sex-specific treatment responses.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria are individuals with known adverse reactions to antibiotic/probiotic treatment, concurrent contraindicative medication, or significant comorbid physical or psychiatric illnesses that prevent appropriate completion of the study.

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)
1. New patient* presents to first appointment at CFSDC. GP conducts clinical history, sends patients for tests, evaluates appropriateness of ME/CFS diagnosis. Clinic nurse provides brief explanation of research project, distributes VU introductory leaflet. All new patients are informed to contact Bioscreen to order the Fecal Microbial Analysis (FMA) kit to screen for patient eligibility.
2. Patient completes Bioscreen kit and urine sampling (sample collected at same time as stool sample but not an assessment of patient eligibility) in own home and sends direct to Bioscreen as per instructions in the kit.
3. Bioscreen FMA results sent to CFSDC. Results analysed to determine if consistent with inclusion criteria.
4. Clinic nurse contacts patient if they are eligible (i.e., high Streptococcus and no contraindications for treatment protocol) and explains treatment protocol and possible side effects. The clinic nurse explains that the patient can voluntarily choose to temporarily defer the CFSDC whole treatment process and participate in the research or they can continue with treatment as usual at CFSDC. Clinic nurse informs patient to contact VU if interested in participating in the research or the patient can request the clinic nurse to contact VU on their behalf.
5. VU verbally explains the procedures and risks of the research and sends patient the VU Research Pack (including the Information to Participant form, Consent form and screening and background questions).
6. After reading the VU Research Pack in their own time, patients interested in participating completes Consent Form and Screening and Background Questions and returns to VU via reply-plaid postage.
6. Upon receipt of participant forms, VU notifies CFSDC about patient’s participation in the research.
7. CFSDC fax the treatment protocol prescription to the pharmacy and notifies VU that prescription has been faxed.
8. a) VU contacts participant to arrange start date and book Cognitive Testing Session.
8. b) Pharmacist sends treatment package, labelled with ID code number to participant.

*Current patients at CFSDC who continue to present with ME/CFS symptoms and sleep or cognitive difficulties that may indicate a Streptococci overgrowth are eligible to participate in the same screening process outlined for new patients.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
No randomised procedures
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
Efficacy
Statistical methods / analysis
Wrist actigraphy: The data collection program is Phillips Actiware 6.1. Raw data is quantified with this program using standard protocols.

Cognitive Testing: The CANTAB program provides quantitative data. Additional cognitive tests will be manually scored and entered as quantitative data.

The quantitative Wrist Acrigraphy, Cognitive Testing and Survey/Questionnaire data will be analysed using SPSS. After using exploratory data analysis techniques to determine descriptive statistics for each variable, multivariate dependence techniques will be used. Independent samples t-tests and 2 x 2 repeated measures ANOVAs (spilt plot/SPANOVAs) will be used to identify any within- and between-group differences. If variables violate the assumptions of normality, transformations will be applied or within- and between- group differences will be analysed using corresponding non-parametric tests.

Within-group data will include analysis of the a) total sample (n=40; i.e. repeated measures, change across time - baseline and post intervention), the subsamples of b) males (n=20) and c) females (n=20) respectively.

Between-group data will include comparison of a) males vs females, b) total N responders vs non-responders. The results of the previous pilot suggest that there may be a group of individuals who do not respond to antibiotic treatment, i.e. no reduction in Streptococcus level. If this is found during the current study, non-responders will be used as a comparison group.

Bioscreen assessments use a combination of culture-based testing and polymerase chain reaction (PCR) testing to determine the count and percentage of specific microorganisms in the patient's large intestine.

Urinary lactate concentrations will be determined via chiral high performance liquid chromatography. D lactate concentrations will be normalised against urinary creatinine levels.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/05/2015
Actual
29/07/2015
Date of last participant enrolment
Anticipated
13/07/2016
Actual
8/11/2016
Date of last data collection
Anticipated
Actual
26/12/2016
Sample size
Target
40
Accrual to date
Final
44
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment postcode(s) [1] 8623 0
3111 - Donvale

Funding & Sponsors
Funding source category [1] 289804 0
University
Name [1] 289804 0
Victoria University
College of Arts (Psychology)
Country [1] 289804 0
Australia
Funding source category [2] 289805 0
Commercial sector/Industry
Name [2] 289805 0
Bioscreen
Specialist Medical Testing Laboratories
Country [2] 289805 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
CFS Discovery Clinic
Address
90 Mitcham Rd, Donvale VIC 3111
Country
Australia
Secondary sponsor category [1] 288495 0
Commercial sector/Industry
Name [1] 288495 0
Bioscreen
Specialist Medical Testing Laboratories
Address [1] 288495 0
5 Little Hyde Street
Yarraville
Victoria, 3013
Country [1] 288495 0
Australia
Other collaborator category [1] 278102 0
Commercial sector/Industry
Name [1] 278102 0
CFS Discovery Clinic
Address [1] 278102 0
90 Mitcham Rd,
Donvale VIC 3111
Country [1] 278102 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291538 0
Victoria University Human Research Ethics Committee
Ethics committee address [1] 291538 0
Building C, Room 303
Footscray Park Campus
Ballarat Rd,
Footscray
VIC 3011
Ethics committee country [1] 291538 0
Australia
Date submitted for ethics approval [1] 291538 0
27/08/2014
Approval date [1] 291538 0
16/06/2015
Ethics approval number [1] 291538 0
23659

Summary
Brief summary
An imbalance in gut microorganisms (referred to as gut dysbiosis) has been shown to be related to illness and some ME/CFS symptoms. More research is needed to understand the relationship between the gut and the brain to help with understanding possible causes and treatment options for individuals with ME/CFS. This project will examine how treatment to reduce high levels of Streptococcus bacteria (determined by Bioscreen stool analysis and indicative of abnormal gut functioning) is related to improvements in sleep, mood and cognitive symptoms in individuals with ME/CFS. There is also preliminary evidence to suggest sex differences in response to gut bacteria, thus, this research will examine if there is a sex-differential response to treatment.

This is an open-label pilot study that will follow a baseline, treatment and follow-up protocol across 6 weeks. The baseline and follow-up phases are one week each. Possible improvement in sleep, mood and cognition will be measured by using a wrist device (Actiwatch), pen and pencil sleep and day diary, questionnaires and an individual cognitive testing session conducted at Victoria University. A second Bioscreen stool analysis will provide information about changes to gut flora.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 50790 0
Prof Dorothy Bruck
Address 50790 0
College of Arts
Victoria University
Footscray Park Campus
Ballarat Rd,
Footscray
VIC, 3011
Country 50790 0
Australia
Phone 50790 0
+61481008451
Fax 50790 0
Email 50790 0
dorothy.bruck@vu.edu.au
Contact person for public queries
Name 50791 0
Miss Amy Wallis
Address 50791 0
College of Arts
Victoria University
Footscray Park Campus
Ballarat Rd,
Footscray
VIC, 3011
Country 50791 0
Australia
Phone 50791 0
+61 3 99195292
Fax 50791 0
Email 50791 0
amy.wallis1@live.vu.edu.au
Contact person for scientific queries
Name 50792 0
Prof Dorothy Bruck
Address 50792 0
College of Arts
Victoria University
Footscray Park Campus
Ballarat Rd,
Footscray
VIC, 3011
Country 50792 0
Australia
Phone 50792 0
+61481008451
Fax 50792 0
Email 50792 0
Dorothy.Bruck@vu.edu.au

No information has been provided regarding IPD availability


What supporting documents are/will be available?



Results publications and other study-related documents

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

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseOpen-label pilot for treatment targeting gut dysbiosis in myalgic encephalomyelitis/chronic fatigue syndrome: Neuropsychological symptoms and sex comparisons.2018https://dx.doi.org/10.1186/s12967-018-1392-z
N.B. These documents automatically identified may not have been verified by the study sponsor.