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Trial registered on ANZCTR


Registration number
ACTRN12615001351505
Ethics application status
Approved
Date submitted
2/12/2015
Date registered
14/12/2015
Date last updated
25/11/2019
Date data sharing statement initially provided
4/12/2018
Date results information initially provided
25/11/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Gut Bugs Trial - Gut microbiome transfer for the treatment of adolescent obesity
Scientific title
A randomized double-blind placebo-controlled trial of gut microbiome transfer for the treatment of obesity in adolescents.
Secondary ID [1] 287935 0
Nil
Universal Trial Number (UTN)
U1111-1176-6753
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Obesity (BMI more or equal to 30 kg/m2) 296815 0
Condition category
Condition code
Diet and Nutrition 297043 297043 0 0
Obesity
Metabolic and Endocrine 297044 297044 0 0
Metabolic disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
We will recruit 8 donors (4 males and 4 females), as recipients will only receive gut microbiome from donors of the same sex. Donors will be selected based on a strict inclusion criteria. Each donor is expected to produce a wet stool sample weighing 100-150 g. Stool samples will be collected and immediately processed for encapsulation. Capsules from each sample will be individually coded, so that each recipient will receive an equal number of capsules (n=7) from each of the 4 same sex donors.

Immediately after donation, stools are placed in normal saline, blended, and sieved to remove particulate matter. Samples are then differentially centrifuged to isolate a bacterial pellet. The bacterial pellet is suspended in normal saline (containing 15% glycerol – a cryoprotectant) at 0.5 g wet weight/ml before being dispensed into size 0 DRcapsTM capsules (Capsugel Inc, Sydney, Australia). The size 0 capsules are closed and secondarily sealed in size 00 DRcapsTM capsules. These capsules mask taste, odour, and visual appearance, and are designed to remain intact during passage through the stomach, delivering their contents to the intestine. Capsules are stored frozen at -80°C.

We will recruit 80 obese adolescents aged 14-18 with BMI more or equal 30 kg/m2 randomised into two groups: control (placebo – saline) or treatment (gut microbiome transfer). Participants (recipients) will undergo bowel cleansing with Glycoprep-C® the evening before treatment initiation. The next morning, at the clinical research unit, each recipient in the placebo group will receive saline capsules, while those in the treatment group will receive gut microbiome capsules. Each recipient will receive a total of 28 capsules administered over two consecutive mornings under direct supervision from research staff, specifically 16 capsules on the first morning and 12 capsules on the second morning. Recipients will be fasting overnight for at least 8 hours prior to taking each set of capsules at the clinical research unit. After treatment, all recipients will remain fasting for another 2 hours. Recipients will be advised not to change their diet and physical activity and behaviour during the trial.
Intervention code [1] 293285 0
Treatment: Other
Comparator / control treatment
The control group will receive placebo capsules (with saline solution), in an identical regimen as the treatment group, i.e. 28 capsules in total, over 2 consecutive mornings (16 on first day).
Control group
Placebo

Outcomes
Primary outcome [1] 296645 0
BMI SDS at 6 weeks

Timepoint [1] 296645 0
6 weeks after intervention

Secondary outcome [1] 318983 0
BMI SDS at 12, and 26 weeks
Timepoint [1] 318983 0
at 12 and 26 weeks after intervention

Secondary outcome [2] 318984 0
total body fat percentage [from whole-body dual-energy x-ray absorptiometry (DXA)] at 6, 12, and 26 weeks

Timepoint [2] 318984 0
At 6, 12, and 26 weeks after intervention.
Secondary outcome [3] 350645 0
insulin sensitivity at 6, 12, and 26 weeks

Insulin sensitivity will be assessed in all recipients using the Matsuda index from a 75-g oral glucose tolerance test (OGTT).

Timepoint [3] 350645 0
At 6, 12 and 26 weeks
Secondary outcome [4] 350646 0
gut microbial composition at 6, 12, and 26 weeks

Gut microbial composition will be evaluated via 16S rRNA amplicon sequencing.

Timepoint [4] 350646 0
At 6, 12 and 26 weeks
Secondary outcome [5] 350647 0
liver function at 6, 12, and 26 weeks

Liver function will be assessed by measurement of gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate transaminase (AST) using plasma assays.

Timepoint [5] 350647 0
At 6, 12 and 26 weeks
Secondary outcome [6] 350648 0
lipid profile at 6, 12, and 26 weeks

Lipid profile will be assessed by measurement of total cholesterol, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], and triglycerides using plasma assays.

Timepoint [6] 350648 0
At 6, 12 and 26 weeks
Secondary outcome [7] 350649 0
inflammatory markers at 6, 12, and 26 weeks

Inflammatory markers will be assessed by measurement of uric acid and high-sensitivity C-reactive protein (hsCRP) using plasma assays.

Timepoint [7] 350649 0
At 6, 12 and 26 weeks
Secondary outcome [8] 350650 0
blood pressure at 6, 12, and 26 weeks

Clinic resting systolic and diastolic blood pressure will be measured at all assessments using the same oscillometric digital blood pressure monitor (ri-champion® N; Riester, Jungingen, Germany) with an appropriately-sized cuff on the extended non-dominant arm.

Timepoint [8] 350650 0
At 6, 12 and 26 weeks
Secondary outcome [9] 350651 0
health-related quality of life at 6, 12, and 26 weeks

Health-related quality of life will be assessed via questionnaires including EPOCH Measure of Adolescent Well-Being and Pediatric Quality of Life Inventory (PedsQL).
Timepoint [9] 350651 0
At 6, 12 and 26 weeks
Secondary outcome [10] 350652 0
IBS symptoms at 6, 12, and 26 weeks

IBS symptoms will be assessed via the Birmingham IBS symptom questionnaire.
Timepoint [10] 350652 0
at 6, 12, and 26 weeks
Secondary outcome [11] 350653 0
changes in bowel movement at 6, 12, and 26 weeks

Changes in bowel movement will be assessed via the bowel movements questionnaire.
Timepoint [11] 350653 0
at 6, 12, and 26 weeks

Eligibility
Key inclusion criteria
Recipient subjects (40 males and 40 females):
• Age 14-18 years
• Obese (BMI: greater or equal than 30 kg/m2)
• Post-pubertal (Tanner stage 5)

Gut microbiome donors:
• Age 18-28 years
• BMI greater than 18.5 kg/m2 and less than 30.0 kg/m2
• Total body fat percentage: less than or equal to 29% for females; less than or equal to 19% for males
• Regular exercise (moderate to vigorous physical activity for at least 3.5 hours/week)
• Regular Bowel Habit (at least 1 every 2 days)
• Intake greater than or equal to 4 portions of fruit and/or vegetables per day
Minimum age
14 Years
Maximum age
18 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Donors:
• Any transmissible viral or bacterial pathogens, or intestinal parasites
• Multidrug-resistant organisms (e.g. vancomycin-resistant enterococci, extended-spectrum beta-lactamase-producing Enterobacteriaceae, and carbapenem-resistant Enterobacteriaceae)
• Gastrointestinal disease (including symptoms of irritable bowel syndrome, inflammatory bowel disease, or coeliac disease)
• Atopic diseases requiring regular prophylaxis or treatment
• Current or past history of malignancy
• Impaired fasting glucose or impaired glucose tolerance
• Type 1 diabetes, type 2 diabetes, or monogenic diabetes
• Known dyslipidaemia, hypertension, or metabolic syndrome
• Regular use of medications known to influence metabolism or the gut microbiome
• Use of oral antibiotics in the past three months
• Regular 'binge drinking', i.e. consumption of 5 or more standard drinks of alcohol per session, at least once a week
• Any use of recreational drugs or tobacco
• Current or past pregnancy
• Overseas travel in previous 6 months, except for visits to Australia, UK, USA, Canada, Northern Europe, France, and Germany.
• UK residence in 1980–1996 (due to risk of variant Creutzfeldt-Jakob disease)

Recipients:
•Gastrointestinal disease (including inflammatory bowel disease or coeliac disease)
•Use of regular medications that may influence weight, metabolism, or the gut microbiome (including oral oestrogen-containing contraceptives, antidepressants, glucose-lowering drugs, diet drugs, as well as inhaled, topical, or oral steroids)
•Consumption of probiotics
•Type 1 diabetes, type 2 diabetes, or monogenic diabetes
•Chronic diseases that could affect the primary outcome (other than obesity-related conditions)
•Food allergies
•Allergy to macrogol (active ingredient in the bowel preparation product)
•Allergy to any over-the-counter medication
•No antibiotic usage for three months prior to trial treatment

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)
Participants will be randomized in a 1:1 ratio to either treatment or placebo group, stratified by sex, using block randomisation with variable block sizes of 2 and 4. Randomisation sequences will be computer generated, and overseen by the biostatistician. To maintain the integrity of the trial evaluation, statistical analyses will be performed at the completion of the study on encoded data (i.e. Group A vs Group B), so that the biostatistician will be blinded to treatment allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer-generated randomisation sequences, stratified by sex.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
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
Treatment evaluation will be performed on the principle of intention to treat, using data collected from all randomized participants. Baseline demographics and clinical characteristics of participants will be summarised by randomized group. The distribution of outcome measures will be first evaluated at scheduled visits using descriptive statistics. Generalised linear regression models will be used to assess treatment effects between groups, adjusting for the baseline outcome value and sex. Model-adjusted estimates and the differences between the two groups will be calculated with 95% confidence intervals. Random effects mixed models will be used to evaluate the outcomes measured repeatedly over time, controlling for correlated data collected from the same participant. Planned subgroup analysis by sex will be conducted on primary and key secondary outcomes to evaluate the consistency of main treatment effects in males and females. Missing data on the primary outcome will be imputed using multiple imputations. Per-protocol analyses will be carried out on those participants without major protocol violations. Data analyses will be performed in SAS v.9.4 (SAS Institute, Cary, NC, USA), SPSS v24 (IBM Corp, Armonk, NY, USA), and/or Minitab v.16 (Pennsylvania State University, State College, PA, USA). All statistical tests will be two-sided at p<0.05, with no adjustments for multiple comparisons. The CONSORT 2010 guidelines will be followed in reporting the main trial results.

Power calculation was based on data from a cohort of 50 obese adolescents in Australia aged 14–18 years, with a pooled mean BMI SDS of 2.5 and standard deviation of 0.27 at baseline. A study with 32 participants per group will have 80% power at 5% significance level (two-sided) to detect a group difference of 0.19 in BMI SDS at 6 weeks after gut microbiome transfer. To account for an approximate 20% loss to follow up, we aim to recruit 40 treatment and 40 control participants.

Recruitment
Recruitment status
Completed
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] 7345 0
New Zealand
State/province [1] 7345 0
Auckland

Funding & Sponsors
Funding source category [1] 292416 0
Other
Name [1] 292416 0
The Rockfield Trust
Address [1] 292416 0
Castle Drive
Epsom
Auckland 1023
New Zealand
Country [1] 292416 0
New Zealand
Funding source category [2] 300395 0
Government body
Name [2] 300395 0
A Better Start National Science Challenge
Address [2] 300395 0
Liggins Institute
85 Park Road, Grafton, Auckland 1023, New Zealand
Country [2] 300395 0
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] 291106 0
None
Name [1] 291106 0
Address [1] 291106 0
Country [1] 291106 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293935 0
Northern A Health and Disability Ethics Committee
Ethics committee address [1] 293935 0
Health and Disability Ethics Committees
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington
6011
Ethics committee country [1] 293935 0
New Zealand
Date submitted for ethics approval [1] 293935 0
05/10/2016
Approval date [1] 293935 0
08/11/2016
Ethics approval number [1] 293935 0
16/NTA/172

Summary
Brief summary
Hypothesis:
Gut microbiome transfer will lead to weight reduction and improvement in metabolism in obese adolescents.

Aims:
To determine whether gut microbiome transfer in severely obese adolescents will:
(i) reduce body mass index (BMI) adjusted for age and sex
(ii) improve body composition
(iii) improve insulin sensitivity

Background
Gut microbiome transfer (GMT) in mice demonstrates the critical role of gut bacteria (i.e. the gut microbiome) in weight regulation at many levels: increased calorie absorption from non-digestible carbohydrates; impairment of the gut mucosal barrier; and production of bacterial products that pass into the host circulation (which are pro-inflammatory, promote adipogenesis, and have an effect on appetite). In humans, an association has been found between obesity and gut microbiome dysbiosis, with reduced bacterial diversity and over-abundance of obesogenic bacteria from the Firmicutes phylum. GMT is the first-line treatment for recurrent chronic Clostridium difficile colitis, curing ~90% of cases with remarkably few adverse events. In addition, a small pilot study showed that GMT improved insulin action in adults with type 2 diabetes. GMT has not been evaluated for the treatment of human obesity. We propose to perform a novel gold-standard clinical trial using encapsulated material to demonstrate the effectiveness of GMT for the treatment of severe obesity in adolescents.

Subjects
We will recruit 4 male and 4 female gut microbiome donors who are fit lean adults aged 18-28 years. These donors will provide fresh stools throughout the trial to be encapsuled for treatment.

We will recruit 80 obese (BMI more or equal 30 kg/m2) adolescents (14-18 years), who will be randomly allocated into two groups: 40 control (placebo – capsules containing saline solution) or 40 treatment (capsules containing GMT). Recipients will undergo bowel cleansing with Glycoprep-C the evening before the GMT to optimise donor bacterial colonisation. Subsequently, recipients will receive 28 capsules of placebo or treatment over two consecutive mornings (16 on first day and 12 on second day).
Clinical assessments will be performed at baseline, 6, 12, and 26 weeks.
Trial website
n/a
Trial related presentations / publications
n/a
Public notes
n/a

Contacts
Principal investigator
Name 61670 0
Prof Wayne Cutfield
Address 61670 0
Liggins Institute
University of Auckland
85 Park Road
Grafton
Auckland 1023
New Zealand
Country 61670 0
New Zealand
Phone 61670 0
+64 9 3737599 Ext 84476
Fax 61670 0
Email 61670 0
w.cutfield@auckland.ac.nz
Contact person for public queries
Name 61671 0
Prof Wayne Cutfield
Address 61671 0
Liggins Institute
University of Auckland
85 Park Road
Grafton
Auckland 1023
New Zealand
Country 61671 0
New Zealand
Phone 61671 0
+64 9 3737599 Ext 84476
Fax 61671 0
Email 61671 0
w.cutfield@auckland.ac.nz
Contact person for scientific queries
Name 61672 0
Prof Wayne Cutfield
Address 61672 0
Liggins Institute
University of Auckland
85 Park Road
Grafton
Auckland 1023
New Zealand
Country 61672 0
New Zealand
Phone 61672 0
+64 9 3737599 Ext 84476
Fax 61672 0
Email 61672 0
w.cutfield@auckland.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Data from the clinical trial cannot be made publicly available, as per the conditions of the ethics approval.
What supporting documents are/will be available?
Study protocol
Statistical analysis plan
Informed consent form
Clinical study report
Ethical approval
Analytic code
How or where can supporting documents be obtained?
Type [1] 5838 0
Study protocol
Citation [1] 5838 0
Leong, Karen SW, et al. "Protocol for the Gut Bugs Trial: a randomised double-blind placebo-controlled trial of gut microbiome transfer for the treatment of obesity in adolescents." BMJ open 9.4 (2019): e026174.
Email [1] 5838 0
w.cutfield@auckland.ac.nz
Other [1] 5838 0
N/A
Type [2] 5839 0
Statistical analysis plan
Citation [2] 5839 0
Link [2] 5839 0
Email [2] 5839 0
w.cutfield@auckland.ac.nz
Other [2] 5839 0
The statistical analysis plan will be uploaded once it is finalised.
Attachment [2] 5839 0
Type [3] 5840 0
Informed consent form
Citation [3] 5840 0
Link [3] 5840 0
Email [3] 5840 0
w.cutfield@auckland.ac.nz
Other [3] 5840 0
Attachment [3] 5840 0
Type [4] 5841 0
Clinical study report
Citation [4] 5841 0
Link [4] 5841 0
Email [4] 5841 0
w.cutfield@auckland.ac.nz
Other [4] 5841 0
Attachment [4] 5841 0
Type [5] 5842 0
Ethical approval
Citation [5] 5842 0
Link [5] 5842 0
Email [5] 5842 0
w.cutfield@auckland.ac.nz
Other [5] 5842 0
Attachment [5] 5842 0
Type [6] 5843 0
Analytic code
Citation [6] 5843 0
Link [6] 5843 0
Email [6] 5843 0
w.cutfield@auckland.ac.nz
Other [6] 5843 0
Attachment [6] 5843 0
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary