Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618000179235
Ethics application status
Approved
Date submitted
30/01/2018
Date registered
5/02/2018
Date last updated
11/06/2019
Date data sharing statement initially provided
11/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
PRE-BIOTIC: Progressive Resistance Exercise- BIOTa and Inflammation in Crohn’s & colitis
Scientific title
Effect of Progressive Resistance Training on Gut Microbiota and Inflammation in Adults with Crohn’s Disease & Ulcerative Colitis: A Randomized Controlled Trial.
Secondary ID [1] 293911 0
None.
Universal Trial Number (UTN)
U1111-1208-6636
Trial acronym
PRE-BIOTIC (Progressive Resistance Exercise- BIOTa and Inflammation in Crohn’s & colitis)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Crohn's disease 306390 0
Ulcerative colitis 306391 0
Condition category
Condition code
Oral and Gastrointestinal 305476 305476 0 0
Crohn's disease
Oral and Gastrointestinal 305477 305477 0 0
Inflammatory bowel disease
Inflammatory and Immune System 305478 305478 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The experimental group will undergo fully-supervised high intensity PRT 3 days/week for 16 weeks in a small group setting at the University of Sydney Clinic in Lidcombe. One day of rest will be provided between training days. Nine resistance exercises will be performed on Keiser pneumatic resistance machines including chest press, seated row, triceps push down, lat pull-down, leg press, leg extension, leg flexion, hip abduction and hip extension. Participants will be required to perform 3 sets of 8 repetitions @ 80% one-repetition maximum (1RM) for each exercise. Cadence of repetitions will be performed explosively (as rapidly as possible) on the concentric phase and 3 seconds on the eccentric phase. Participants will have 90-second rest between sets. All training sessions over the 16 weeks will be supervised by accredited exercise physiologist (AEP) trainers in a ratio of 1 trainer: 1-4 participants. Participants will be progressed continuously throughout the 16-week intervention by approximately 3% per session, guided and refined by daily ratings of perceived exertion (with a target of 15-18 on the Borg Scale, which approximates 80% of the current peak strength). These ratings will reported by both the trainer (objective assessment) and the trainee (subjective assessment) for each machine when the load is initially presented on each day. In addition, one-repetition maximum (1RM) strength testing will be conducted in lieu of one of the 3 planned sets of exercise every 2 weeks, to maintain training intensity at 80% 1RM. Alterations needed to accommodate musculoskeletal pain or underlying injuries or other health conditions will be prescribed as needed by the AEPs and study physician, Professor Fiatarone Singh. Participants will be asked not to start any other new exercise regimen or intentionally change their habitual diet throughout the entire study and assessment and detraining period. All of the documentation of changes in health care, habitual exercise or diet noted for the control group below will also be recorded in the intervention group.Also, after 16 weeks, participants will be asked to refrain from resistance training for 6 weeks (from 17-22 weeks) to examine whether absence of resistance training over a short period has any effects on changes in disease activity and gut dysbiosis.
Intervention code [1] 300179 0
Lifestyle
Intervention code [2] 300181 0
Other interventions
Comparator / control treatment
Participants will continue to receive usual care as documented at baseline. Any new medical therapy for IBD commenced during the study period will be recorded, as well any change in chronic treatments for IBD, surgeries, other new medical conditions or treatments, or other interventions employed for their known or purported health benefits (e.g., pre-biotics, pro-biotics, acupuncture, counseling, massage, etc.). Participants are asked to maintain their habitual lifestyle regarding diet and exercise throughout the study, but any changes they do make will be recorded.
Control group
Active

Outcomes
Primary outcome [1] 304613 0
Disease activity will be assessed via the Crohn’s Disease Activity Index (CDAI) for participants with Crohn's Disease and via the Mayo Scoring Index for participants with Ulcerative Colitis..
Timepoint [1] 304613 0
Every week from baseline to 22 weeks.
Primary outcome [2] 304614 0
Quality of life will be assessed via Inflammatory Bowel Disease (IBD) Questionnaire.
Timepoint [2] 304614 0
Baseline, 8 weeks, 16 weeks and weekly during weeks 17-22 (detraining period).
Secondary outcome [1] 342542 0
Body composition
Assessed via dual-energy x-ray absorptiometry (DEXA) scan
Timepoint [1] 342542 0
Baseline, 8 weeks, and 16 weeks.
Secondary outcome [2] 342544 0
Faecal calprotectin, Lipopolysaccharide (LPS), C-reactive protein (CRP), tumor necrosis factor and interleukins 1, 6, 10 and 12, full blood count. Serum and plasma aliquots will also be saved for other markers. This is a composite secondary outcome.
Timepoint [2] 342544 0
Baseline, 8, 16, 18, and 20 weeks.
Secondary outcome [3] 342545 0
Muscle strength assessed via one-repetition maximum for the chest press, seated row, triceps push down, lat pull-down, leg press, leg extension, leg flexion, hip abduction and hip extension.
Timepoint [3] 342545 0
Baseline, 2, 4, 6, 8, 10, 12, 14, and 16 weeks.
Secondary outcome [4] 342547 0
Maximal aerobic capacity assessed via:
- treadmill maximal oxygen consumption test
Timepoint [4] 342547 0
Baseline and 16 weeks.
Secondary outcome [5] 342548 0
Neuropsychological profile assessed via: Hospital Anxiety and Depression Scale (HADS), and Patient Health Questionnaire (PHQ-9).
Timepoint [5] 342548 0
Baseline, 8, 16, 18, 20, and 22 weeks.
Secondary outcome [6] 342549 0
Fatigue assessed via the IBD Fatigue Scale.
Timepoint [6] 342549 0
Baseline, 8, 16, 18, 20, and 22 weeks.
Secondary outcome [7] 342550 0
Physical activity level assessed via Axivity monitor and Paffenbarger Physical Activity Questionnaire.
Timepoint [7] 342550 0
Baseline and 16 weeks.
Secondary outcome [8] 342551 0
Sleep will be assessed via axivity accelerometer.
Timepoint [8] 342551 0
Baseline and 16 weeks.
Secondary outcome [9] 342552 0
Nutritional status assessed via food diary or use a free App such as EasyDietDiary
Timepoint [9] 342552 0
Baseline, 8, 16, 18, 20, and 22 weeks.
Secondary outcome [10] 342715 0
Muscle power will be assessed for the chest press, seated row, triceps push down, lat pull-down, leg press, leg extension, leg flexion, hip abduction and hip extension.
Timepoint [10] 342715 0
Baseline, 8, and 16 weeks.
Secondary outcome [11] 371371 0
Gut dysbiosis assessed via: -Gut biome from faecal samples
Timepoint [11] 371371 0
Baseline, 8 weeks, 16 weeks and weekly during weeks 17-22 (detraining period).
Secondary outcome [12] 371372 0
A sigmoidoscopy will be performed on participants with Ulcerative Colitis so that the Total Mayo Scoring Index can be calculated and mucosal inflammation assessed. No sigmoidoscopy will be performed on participants with Crohn’s Disease because unlike Ulcerative Colitis, the inflammation is not confined to colon but can appear anywhere in the digestive tract, from the mouth to the anus. Preparation for the sigmoidoscopy will involve fasting from 6 hours prior to hospital admission and a fleet enema on arrival to clean the left colon. If the participants with Ulcerative Colitis have not had a full colonoscopy in the prior 12 months, then a colonoscopy will be conducted. In preparation for the colonoscopy a low residue diet will be followed for two days, followed by clear fluids with osmotic laxatives on the day prior to the procedure. The participant will then fast from 6 hours prior to their hospital admission. Biopsies will be taken from inflamed mucosa and endoscopic inflammation and disease severity scored by the Mayo index. The Robarts Histology index will be used for assessing histological disease severity. Biopsy samples will be sent to Westmead Hospital for routine histopathology and additional fresh samples will be snap frozen and stored at -80 degrees for later assessment. All procedures (colonoscopies and sigmoidoscopies) will be conducted by investigators who are experienced and accredited endoscopists. These procedures will be performed at either Westmead Hospital, Hospital for Specialist Surgery HSS and HSS Rehabilitation at Baulkham Hills. The sigmoidoscopy will be performed at baseline and after 16 weeks of the study. This is a composite primary outcome (i.e. Total Mayo Scoring Index, Mucosal inflammation and Robarts Histology Index).
Timepoint [12] 371372 0
Baseline and this change was done prior to any enrolments.

Eligibility
Key inclusion criteria
1. Ulcerative Colitis (UC) or Crohn’s Disease (CD) of 3 months or greater duration.
2. Inactive to moderately active disease state based on scores from the Total Mayo Scoring Index for UC (scores of 0 to 10) and Crohn’s Disease Activity Index (CDAI) for CD (scores of 0 to 450). This change was made prior to any enrolments.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Absolute contraindications to exercise testing and training as defined by the American College of Sports Medicine .
2. Planned major surgery within the first 3 months after randomisation.
3. Clinical evidence of any comorbid chronic disease that may interfere with the patient’s ability to enter the trial and undertake the testing and exercise intervention planned
4. Pregnant
5. Female planning pregnancy within the first 4 months after randomisation.
6. Participating in moderate aerobic training equal or greater than 150 minutes per week or vigorous aerobic training equal or greater than 75 minutes per week, or high intensity interval training
7. Those currently practicing resistance training, of any intensity equal or greater than one day per week
8. Participation in another clinical trial for which concurrent participation is deemed inappropriate

Participants will be ineligible for the investigation of gut microbiota changes (therefore not required to give stool samples) if they have the following due to the influence on altering the gut microbiome:

1. Prior or concomitant/planned fecal microbiota transplantation or any rectal preparations for IBD currently
2. Probiotics during the study period or in the preceding 12 weeks
3. Significant prior gastrointestinal surgery (e.g., colon resection, fistula repair, bariatric surgery)

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)
Allocation will be concealed using sealed opaque envelopes given to eligible participants after completion of all baseline testing. Participants will be randomised into an intervention (PRT) group, or a control (usual care) group following completion of baseline assessments.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will involve a concealed, computer-generated sequence of randomly permuted variable blocks of four, stratified for concomitant corticosteroid use. The randomisation sequence will be generated by an online program created by a statistician not otherwise involved in the study.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Currently no experimental trials exist that document exercise effects on gut biome, whereas there have been two studies using PRT that have assessed changes in quality of life in patients with IBD using validated questionnaires [1, 2]. Therefore sample size calculations were based on changes in quality of life. Only one of these two studies that used PRT in patients with IBD had enough information to allow the calculation of effect sizes [1] and therefore this study was used to calculate the required sample size. Hedges’ bias corrected effect sizes were calculated from published means and standard deviations of this single group, pre-post study involving 8 weeks of resistance training in patients with UC. Since this study did not have a control group we have conservatively estimated the effect size at 0.60 (1/3 less than 0.90). Sample sizes were calculated with an alpha of 0.05 and beta of 0.20. Thus, we estimate that a sample size of 90 participants will be required (45 participants per group) for detection of improvement in quality of life following a 16-week PRT intervention.

(1) Tajiri, G.J.d., et al.,(2014). Progressive resistance training improves muscle strength in women with inflammatory bowel disease and quadriceps weakness. J of Crohn’s and Colitis. 8:1749-1750.
(2) Candow D et al., (2002).Effect of resistance training on Crohn’s disease. Can J Appl Physiol. 2002; 27: S7–S8.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
20/02/2019
Actual
20/02/2019
Date of last participant enrolment
Anticipated
1/12/2019
Actual
Date of last data collection
Anticipated
1/05/2020
Actual
Sample size
Target
90
Accrual to date
83
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 10492 0
Westmead Hospital - Westmead

Funding & Sponsors
Funding source category [1] 298535 0
University
Name [1] 298535 0
The University of Sydney
Country [1] 298535 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
Faculty of Health Sciences
East St
Lidcombe NSW 2141
Country
Australia
Secondary sponsor category [1] 297683 0
None
Name [1] 297683 0
Address [1] 297683 0
Country [1] 297683 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299510 0
Western Sydney Local Health District Human Ethics Committee
Ethics committee address [1] 299510 0
Research Office, Level 2, REN Building Westmead Hospital, Hawkesbury & Darcy Roads, Westmead NSW 2145
Ethics committee country [1] 299510 0
Australia
Date submitted for ethics approval [1] 299510 0
26/10/2017
Approval date [1] 299510 0
16/10/2018
Ethics approval number [1] 299510 0
Research Office File No.: 5730; HREC Ref: AU RED HREC/18/WMEAD/238

Summary
Brief summary
PRE-BIOTIC will be the world’s first randomised controlled trial (RCT) of anabolic exercise (high intensity PRT) for patients with active inflammatory bowel disease (IBD) who remain symptomatic despite robust medical treatment. Although current treatment is effective in controlling a number of their symptoms, there is a need for better options to prevent disease, increase response and sustain remission. Exercise is one potential complementary strategy to combat IBD and other diseases, and there is rapidly growing evidence that it may also positively and substantially affect the gut biome, and thus could play a role in both prevention and treatment of IBD. Among exercise modalities, the rationale for resistance training (PRT) in IBD is extremely strong, as it has many of the same benefits of aerobic exercise with regards to cardio-metabolic profile and inflammation, but in addition, due to its anabolic nature, provides unique benefits not seen with aerobic exercise, including increases in muscle strength and mass, bone density and appetite. An anabolic/anti-inflammatory intervention such as PRT is theoretically able to change the underlying pathophysiology of this condition, in addition to addressing important physical and psychological symptoms. The global impact and relief of suffering for these individuals and their loved ones would be unprecedented.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 80662 0
Prof Maria A. Fiatarone Singh, MD, FRACP
Address 80662 0
University of Sydney
K221, Cumberland Campus
75 East Street, Lidcombe, 2141
NSW, Australia
Country 80662 0
Australia
Phone 80662 0
+61 2 9351 9755
Fax 80662 0
+61 2 9351-9204
Email 80662 0
maria.fiataronesingh@sydney.edu.au
Contact person for public queries
Name 80663 0
Dr Daniel Hackett
Address 80663 0
University of Sydney
H106, Cumberland Campus
75 East Street, Lidcombe, 2141
NSW, Australia
Country 80663 0
Australia
Phone 80663 0
+61 2 9351 9294
Fax 80663 0
+61 2 9351-9204
Email 80663 0
daniel.hackett@sydney.edu.au
Contact person for scientific queries
Name 80664 0
Prof Maria A. Fiatarone Singh, MD, FRACP
Address 80664 0
University of Sydney
K221, Cumberland Campus
75 East Street, Lidcombe, 2141
NSW, Australia
Country 80664 0
Australia
Phone 80664 0
+61 2 9351 9755
Fax 80664 0
+61 2 9351-9204
Email 80664 0
maria.fiataronesingh@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
No IPD will be available since we did not include this in our ethics application and therefore do not have approval. The participant data will only be stored on databases available to The University of Sydney staff and is only accessible to our research team (password protected).


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.