Clinical trial NCT02564432: Microbiome and Metagenome in Percutaneous Osseointegrated Prostheses (MMPOP)
Official title: Microbiome and Innate Immunity With Percutaneous Osseointegrated Prostheses
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Transfemoral Amputation
Keywords: amputee
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2015-09-30
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: 10 transfemoral amputees selected from Veteran and active military populations

Brief summary: The purpose of this study is to investigate the clinical implementation of a new percutaneous prosthetic attachment system by determining the resident microbial ecology of the implant exit site and to simultaneously study the systemic and local stomal immune responses. This study will follow 10 patients implanted with percutaneous osseointegrated prosthetics (POPs) for a period of one year. Two state-of-the-art, pre- and post-surgery bacterial monitoring technologies will be used; these procedures are intended to facilitate the early prediction, detection, and treatment of infection, as well as to provide follow-up data that can potentially be used to advantageously manipulate the stomal microbial environment in future clinical trials.

Commensal skin bacteria colonize all stomas. Colonization does not necessarily result in infection. Over time, the presence of this skin penetrating foreign object (implant) will cause measurable changes in the bacterial population (microbiota) at and around the POP exit site. It is anticipated that the evolving microbiota, in concert with measurable changes in the local and systemic cytokine responses, will reveal patterns associated with mutualistic-commensal bacteria and/or pathogenic bacteria related to the stages of chronic wound healing. These patterns could be used to determine the presence of a stable uninfected stoma or the progression of a stomal infection. Hopefully, this information will allow timely intervention to prevent infection, i.e. by detecting early stages of infection or discerning common patterns of stable mutualistic-commensal bacterial strains, effective intervention protocols (antibiotics, probiotics or manipulation of the stomal and skin microbiota) may be developed to avoid patient morbidity and assure implant survival.

Detailed description: Percutaneous osseointegrated prosthetic (POP) attachment (i.e., the direct skeletal attachment of artificial limbs) is a rapidly evolving technology. This follows over a decade of successful European trials that largely involved transfemoral amputees. This information together with the translational animal studies have made it possible to commence an Early Feasibility Device Exemption (IDE) Pilot Program under the direction of the Federal Drug Administration (FDA). Ten transfemoral amputees, selected from the Veteran and active military populations will receive a novel POP device. The objective of this study is to follow 10 patients implanted with a POP for a period of one year.

All stomas are colonized by local skin bacteria; colonization does not necessarily result in infection. Over time, the presence of this skin penetrating foreign object (implant) will cause measurable changes in the bacterial population (microbiota) at and around the POP exit site.

It is anticipated that the evolving microbiota, in concert with measurable changes in the local and systemic cytokine responses, will reveal patterns associated with mutualistic-commensal bacteria and/or pathogenic bacteria related to the stages of chronic wound healing. These patterns could be used to determine the presence of a stable uninfected stoma or the progression of a stomal infection. Hopefully, this information will allow timely intervention to prevent infection, i.e. by detecting early stages of infection or discerning common patterns of stable mutualistic-commensal bacterial strains, effective intervention protocols (antibiotics, probiotics or manipulation of the stomal and skin microbiota) may be developed to avoid patient morbidity and assure implant survival.

The study aims will test the following:

Aim 1: Determine and characterize the microbiota in the region surrounding the skin/implant interface. Sampling will take place over all stages of wound healing and stomal maturation and will begin with Stage 1 and Stage 2 surgeries, as well as at defined time points, and collection sites (i.e., the stoma, ipsilateral and contralateral thigh skin) for up to one year post surgery. This will be carried-out by using a specific swabbing technique to collect bacterial and fungal deoxyribonucleic acid (DNA) and to amplify and sequence bacterial 16 Svedberg units ribosomal ribonucleic acid (16S rRNA) and fungal 18 Svedberg units ribosomal ribonucleic acid (18S rRNA) genes.

AIM 2: Compare the expression patterns of the local and systemic inflammatory biomarkers over time and determine if there is a correlation with the microbiota pattern to diagnose the state of wound healing at the skin/implant interface and the systemic response to a potentially life-long chronic wound. The measurements of the pro-inflammatory cytokines, found in the stomal exudate (local biomarkers) and blood serum (systemic biomarkers), along with evolving microbiota profiles (Aim #1) will help to better characterize the homeostatic state of the stoma and subsequent optimum wound care therapies.

The ability to predict infection and to avoid it without the use of antibiotics would be of great value to future clinical trials. Assuming the success of this feasibility pilot trial, it is anticipated that the trial will be expanded to include 200 patients.

Eligibility criteria: Inclusion Criteria:

1. Is a US military Veteran with transfemoral limb loss, that occurred at least 6 months prior to consent, and that the amputation is not a result of dysvascular disease.
2. Is at least 18 years of age or older.
3. Has previously used or is currently using a "socket suspension technology" prosthesis
4. Has, in the opinion of the investigator, normal cognitive function and no physical limitations, addictive diseases, or underlying medical conditions including tobacco use (continued testing for tobacco use will be performed at screening) that may prevent the subject from being an appropriate study candidate.
5. Is willing, able, and committed to participation in baseline and follow-up evaluations for the entire duration of the study.
6. Can provide written informed consent to participate.

Exclusion Criteria:

1. Is currently on active or reserve military duty
2. Has experienced systemic bacterial infection or localized infection at the stump site within the previous 6 months
3. Has had more than 1 limb amputated
4. Has a body mass index (BMI) 30
5. Has insulin dependent diabetes mellitus (IDDM) or has adult onset DM with a glycated hemoglobin (HbA1c) \> 53 mmol/mol (7.0%) at screening
6. Has residual femur bone length of less than 25% of the length of the contralateral femur.
7. Has clinically diagnosed vascular compromise proximal to the surgical site
8. Is pregnant at the time of surgery or plans to become pregnant within the first year of follow-up
9. Has evidence of recent tobacco use (urine cotinine test \> 300 ng/mL \[1703 nmol/L\]) and is not committed to a smoking-cessation program
10. Has renal insufficiency (defined as serum creatinine of 1.8 mg/dL) or is currently receiving renal dialysis
11. Is currently involved in or plans to be involved in high levels of physical activity (competitive sports, heavy physical labor, etc) during the first 12 months of the rehabilitation stage
12. Has muscular, neurologic or vascular deficiencies that may compromise the bone or soft tissue healing of the affected extremity
13. Has anemia characterized by a hemoglobin of 11 g/dL at the time of surgery
14. Is currently on oral anticoagulation (excluding low-dose aspirin for cardiac prophylaxis)

Primary outcomes:
measure: Bacterial Community Types as Determined by Percentage RNA Sequence Reads
timeFrame: On Day 3 after first surgery and day 3 prior to and days, 3, 14 and week 6 and months 3, 6, 9 and 12 after second surgery.
Secondary outcomes:
measure: Time to Equilibrium of the Bacterial Community Types Over the Duration of the Study
timeFrame: On Day 3 after first surgery and day 3 prior to and days, 3, 14 and week 6 and months 3, 6, 9 and 12 after second surgery.
Other outcomes:
Locations:
city: Salt Lake City
country: United States
facility: VA Salt Lake City Health Care System, Salt Lake City, UT
state: Utah
Study officials:
affiliation: VA Salt Lake City Health Care System, Salt Lake City, UT
name: James P Beck, MD
role: PRINCIPAL_INVESTIGATOR
References: