Gut Microbiome in Orthopaedics (GUMBO)

Gut Microbiome in Orthopaedics: Effect of Probiotics on Initial Implant Migration and Joint Inflammation After Total Knee Replacement

Patients having knee replacement surgery regularly experience joint pain and compromised bone quality leading to implant loosening and periprosthetic fractures. The role of the gut microbiome, which is the collection of bacteria and other microbes within the human gastrointestinal tract, is just beginning to be recognized, including its potential effects on pain, infection, and loosening after total joint replacement. Antibiotics are regularly used in orthopaedic surgery to reduce the risk of infection, but they also harm gut microbiota and reduce their potentially beneficial effects. Probiotics may have a role to play in enhancing bone quality and decreasing synovial inflammation after joint replacement surgery, and this study will explore the potential relationship of probiotic use with implant migration, bone density, and patient outcomes.

This study is a randomized, controlled, double-blinded trial comparing probiotic use with placebo in post-menopausal women undergoing primary total knee replacement. The main questions it aims to answer are:

• to compare implant migration between groups from baseline to six weeks post-surgery
• to compare bone density and joint inflammation between groups from baseline to six weeks post-surgery
• to compare gut microbiome composition and patient-reported outcome measures between groups from baseline to six weeks post-surgery

Study Overview

• Status: Withdrawn
• Conditions: Inflammation; Total Knee Arthroplasty; Gastrointestinal Health
• Intervention / Treatment: Other: Placebo; Dietary supplement: Probiotic Formula Bacillus subtilis

Detailed Description

Participants will take a daily probiotic (DE111®) or placebo once daily starting 3 weeks prior to surgery until six weeks after surgery. The following will be completed at baseline and 6 weeks:

• Bloodwork
• Fecal sample collection
• MRSA swab
• Patient-reported outcome measures
• CT imaging scan

In addition, the following will be done:

• Intraoperative fluid and tissue collection
• Positron Emission Tomography-Magnetic Resonance Imaging (PET-MRI) scan at 6 weeks post-surgery

Researchers will compare the probiotic and placebo groups for any significant differences in implant stability, bone quality, inflammation, gut microbiome composition, and pain.

• Study Type: Interventional
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • London, Ontario, Canada, N6A 5A5
      • London Health Sciences Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Signed informed consent obtained prior to any study-related activities
• Postmenopausal female patients of London Health Sciences Centre (LHSC) aged 55-75 years
• Scheduled to undergo primary total knee replacement for osteoarthritis

Exclusion Criteria:

• Unable to understand and respond to the provided questionnaires
• Male sex
• Inflammatory arthritis
• Periprosthetic infection
• Prior surgery with hardware insertion in the target knee
• Metabolic syndrome
• Inflammatory bowel disease
• Body mass index <18.5 kg/m2
• Immune-compromised condition (e.g. AIDS, lymphoma, patients undergoing long-term corticosteroid treatment)
• Any contraindications for PET-MRI
• Allergy to cephalosporin antibiotics

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Probiotic DE111®; 1 capsule of probiotic DE111® containing 5 billion CFU Bacillus subtilis, to be taken once daily starting 3 weeks prior to surgery until 6 weeks after surgery.	Dietary supplement: Probiotic Formula Bacillus subtilis; 5 billion colony forming units (CFU) per day for 9 weeks (3 weeks before surgery to six weeks after surgery); Other Names: DE111®
Placebo Comparator: Placebo; 1 capsule of placebo, to be taken once daily starting 3 weeks prior to surgery until 6 weeks after surgery.	Other: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Implant Migration	Tibial component migration over time calculated by measuring the position of the component compared to the bone using CT imaging.	baseline, 6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bone Density	Volumetric bone mineral density over time measured in the anteromedial, anterolateral, posteromedial, and posterolateral regions surrounding the tibial component using CT imaging.	baseline, 6 weeks
Magnitude of 18-F-Fluoroethyl(2-(2-fluoroethoxy)phenyl)-proprionate ([¹⁸F]FEPPA) Tracer Uptake	Magnitude of standardized uptake values (SUV) of the [¹⁸F]FEPPA tracer uptake in the synovium as measured by PET-MRI. SUV will be calculated using the mean signal intensity, body weight, and decay-corrected injected dose.	6 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Veterans Rand 12-Item Health Survey (VR-12)	Patient-reported outcome measure observing physical and mental health status of patient. Contains 12 questions about 8 health domains: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health. For each domain, the scores range from 0 to 100, with higher scores indicating better health-related quality of life. The minimum score is 0, indicating the lowest level of health or well-being, and the maximum score is 100, indicating the highest level of health or well-being.	pre-operative, 6 weeks
EuroQol-5D (EQ-5D)	Patient-reported outcome measure to assess quality of life on a scale of 0 (worst) to 100 (best). Higher scores indicate better quality of life.	pre-operative, 6 weeks
Western Ontario McMaster Osteoarthritis Index (WOMAC)	Patient-reported outcome measure to assess function, pain and stiffness on a scale of 0 (better function/pain/stiffness) to 100 (worse function/pain/stiffness). Higher scores indicate worse pain, stiffness, and functional limitations.	pre-operative, 6 weeks
Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP)	Patient-reported questionnaire to assess experience with constant and intermittent pain on a scale of 0 (no pain) to 4 (extreme pain). A higher score indicates worse pain.	pre-operative, 6 weeks
Patient Global Assessment (PGA)	Patient-reported scale question to measure global disease activity on a range of 0 (doing very well) to 10 (doing very poorly). A higher score indicates worse condition.	pre-operative, 6 weeks
University of California, Los Angeles (UCLA) Activity Score	Patient-reported outcome measure assessing activity level of patient. Contains a 10-level scale with 1 representing a patient who is inactive and dependent on others, to 10 representing a patient who regularly participates in impact sports. A higher score indicates a greater activity level.	pre-operative, 6 weeks
Oxford Knee Score - English for Canada	Patient-reported outcome measure to assess level of function, activities of daily living, and effects of pain over preceding four weeks, measured with 12 questions each on a scale from 0 (worst outcome) to 4 (best outcome). A higher score represents a better outcome, with total score range from 0-48	pre-operative, 6 weeks
Knee Society Score (KSS)	Functional outcome measure. Contains 5 sections measuring patient symptoms (none to severe), satisfaction (very satisfied to very dissatisfied), expectation (too high to too low), functional activities, and discretionary knee activities. Functional activities are split into walking and standing (with or without aids and the duration), standard activities (no bother to cannot do), and advanced activities (no bother to cannot do). Discretionary knee activities measure difficulty with the three most important activities for the patient (no bother to cannot do). Higher scores indicate greater patient outcomes.	pre-operative, 6 weeks
Presence of MRSA	Participants will provide a Methicillin-Resistant Staphylococcus Aureus (MRSA) swab sample. Presence of MRSA will be compared over time and between groups.	pre-operative, 6 weeks
Microbial Diversity - Taxonomic Differences	Participants will provide a fecal sample. Microbial DNA will be extracted from the samples for 16S ribosomal ribonucleic acid (rRNA) sequencing so taxonomy can be assigned. The Shannon index for microbial diversity will be calculated and used to determine taxonomic differences in composition and diversity within and between samples.	pre-operative, 6 weeks
Microbial Diversity - Taxonomic Correlation	Participants will provide a fecal sample. Microbial DNA will be extracted from the samples for 16S ribosomal ribonucleic acid (rRNA) sequencing so taxonomy can be assigned. Taxonomic correlations to other clinical and metadata in the study will be determined.	pre-operative, 6 weeks
Diet and Supplement Questionnaire	Patient-reported questionnaire collecting probiotic and supplement consumption habits and gastrointestinal symptoms. Consumption of fermented foods or drinks containing live bacteria will be scored from 0 (no consumption) to 3 (daily consumption) with a higher score indicating greater consumption of live bacteria. Consumption of vitamins and probiotics will be scored from 0 (no consumption) to 3 (daily consumption) with a higher score indicating greater consumption of vitamins and probiotics. Seven gastrointestinal symptoms will be scored from 0 (none) to extreme (4), with a maximum score of 28. A higher score indicates worse gastrointestinal symptoms.	pre-operative
Histopathology	Synovial and tibial plateau samples will be collected intraoperatively and graded for synovitis. Intimal hyperplasia, sub-synovial infiltrate, fibrosis, fibrin deposition, perivascular edema, and vascularization will be graded on a scale of 0 (none) to 3 (severe). A higher score indicates greater synovial inflammation, with a total score range from 0 to 18.	intraoperative
Immunohistochemistry	Synovial and tibial plateau samples will be collected intraoperatively, and the number of macrophages per mm² will be determined. A higher number indicates greater synovial inflammation.	intraoperative
Inflammatory Blood Marker: C-Reactive Protein	Participants will provide a blood sample. Levels of C-Reactive Protein (CRP) will be measured (mg/mL) and compared over time and between groups. Elevated CRP levels are an indicator of inflammation.	pre-operative, 6 weeks
Inflammatory Blood Marker: Interleukin-1B	Participants will provide a blood sample. Levels of Interleukin-1B (IL-1β) will be measured (pg/mL) and compared over time and between groups. Elevated IL-1β levels are an indicator of inflammation.	pre-operative, 6 weeks
Inflammatory Blood Marker: Interleukin-6	Participants will provide a blood sample. Levels of Interleukin-6 (IL-6) will be measured (pg/mL) and compared over time and between groups. Elevated IL-6 levels are an indicator of inflammation.	pre-operative, 6 weeks
Inflammatory Blood Marker: Interleukin-8	Participants will provide a blood sample. Levels of Interleukin-8 (IL-8) will be measured (pg/mL) and compared over time and between groups. Elevated IL-8 levels are an indicator of inflammation.	pre-operative, 6 weeks
Inflammatory Blood Marker: Tumor Necrosis Factor Alpha	Participants will provide a blood sample. Levels of Tumor Necrosis Factor Alpha (TNF-α) will be measured (pg/mL) and compared over time and between groups. Elevated TNF-α levels are an indicator of inflammation.	pre-operative, 6 weeks
Inflammatory Blood Marker: Erythrocyte Sedimentation Rate	Participants will provide a blood sample. The Erythrocyte Sedimentation Rate (ESR) will be measured (mm/hr) and compared over time and between groups. Elevated ESR is an indicator of inflammation.	pre-operative, 6 weeks
Inflammatory Blood Marker: Alkaline Phosphatase	Participants will provide a blood sample. Levels of Alkaline Phosphatase (ALP) will be measured (units/L) and compared over time and between groups. Elevated ALP levels can indicate inflammation, and may occur during periods of increased bone remodeling or tissue regeneration.	pre-operative, 6 weeks
Inflammatory Blood Marker: Calcium	Participants will provide a blood sample. Levels of calcium will be measured (mmol/L) and compared over time and between groups. Lower calcium levels are an indicator of inflammation.	pre-operative, 6 weeks
Inflammatory Blood Marker: Albumin	Participants will provide a blood sample. Levels of albumin will be measured (g/L) and compared over time and between groups. Decreased levels of albumin are often observed in conditions associated with inflammation.	pre-operative, 6 weeks
Inflammatory Blood Marker: Urate	Participants will provide a blood sample. Levels of urate will be measured (μmol/L) and compared over time and between groups. Elevated urate levels are an indicator of inflammation.	pre-operative, 6 weeks
Inflammatory Blood Marker: Total Protein	Participants will provide a blood sample. Levels of total protein will be measured (g/L) and compared over time and between groups. Elevated protein levels can indicate inflammation.	pre-operative, 6 weeks
Inflammatory Blood Marker: Creatinine	Participants will provide a blood sample. Levels of creatinine will be measured (μmol/L) and compared over time and between groups. Elevated creatinine levels can indicate inflammation.	pre-operative, 6 weeks
Inflammatory Blood Marker: Vitamin D	Participants will provide a blood sample. Levels of Vitamin D will be measured (nmol/L) and compared over time and between groups. Decreased Vitamin D levels are an indicator of inflammation.	pre-operative, 6 weeks
Inflammatory Blood Marker: White Blood Cell Count	Participants will provide a blood sample. Levels of white blood cells (WBC) will be measured (cells/μL) and compared over time and between groups. Elevated WBC levels are an indicator of inflammation.	pre-operative, 6 weeks
Inflammatory Blood Marker: Red Blood Cell Count	Participants will provide a blood sample. Levels of red blood cells (RBC) will be measured (cells/μL) and compared over time and between groups. Decreased RBC levels are an indicator of inflammation.	pre-operative, 6 weeks
Inflammatory Blood Marker: Hemoglobin Concentration	Participants will provide a blood sample. Hemoglobin concentration (Hgb) will be measured (g/L) and compared over time and between groups. Decreased Hgb concentration is an indicator of inflammation.	pre-operative, 6 weeks
Inflammatory Blood Marker: Hematocrit Percentage	Participants will provide a blood sample. Hematocrit (Hct) percentage will be measured (%) and compared over time and between groups. Decreased Hct percentage is an indicator of inflammation.	pre-operative, 6 weeks
Inflammatory Blood Marker: Platelet Count	Participants will provide a blood sample. Platelet counts will be measured (cells/μL) and compared over time and between groups. Elevated platelet counts are an indicator of inflammation	pre-operative, 6 weeks

Collaborators and Investigators

• Sponsor: London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's
• Investigators: Principal Investigator: Brent Lanting, BESc, MD, London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2025
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2028

Study Registration Dates

• First Submitted: February 27, 2024
• First Submitted That Met QC Criteria: April 12, 2024
• First Posted (Actual): April 17, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 13, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation
• Other Study ID Numbers: 123608

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No