Further MT for AntIbiotic-Resistant Bacterial Colonization in Inpatients

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to better understand the effectiveness and safety of microbiome therapies (MT) as a treatment for patients with Multidrug Resistant Organism (MDRO) colonization after an infection. Limited data from prior studies suggest that MT may be an effective treatment to reduce intestinal MDRO colonization Although shedding of MDROs from patients to their surrounding environment is a recognized pathway of transmission, the potential effect of MT on the transmission of MDRO to other patients in the hospital environment is unclear. This study will test the safety and efficacy of MT for this use in hospitalized patients. This study will also help design larger studies. The MT may help reduce MDROs that colonize the gut. By reducing colonization before infections happen, this could help doctors avoid using last resort antibiotics that can have serious side effects like kidney damage. The reduction in MDROs after MT was originally identified in patients treated with MT for recurrent Clostridioides difficile (often called C. diff) diarrhea. It has been shown that a type of MT called fecal microbiota transplant (FMT) can eliminate both C. difficile and other resistant bacteria.

Detailed Description
-----------------
Antimicrobial resistance (AR) has been declared by the World Health Organization to be one of the greatest threats to global health. Every year, at least 2 million people are infected with antibiotic-resistant bacteria, and over 23,000 dies from such infections. This study aims to take initial steps to directly address these public health priorities and clinical threats of MDRO by estimating the safety of the IP in reducing patient-level intestinal MDRO colonization as well as the effect of the IP on environmental contamination. FAIR is a phase 2, randomized, placebo-controlled, double-blind, parallel, clinical trial of the IP for the treatment of MDRO colonization. The hypothesis is that lyophilized human intestinal microbiota will safely and efficaciously reduce MDRO colonization. This is a randomized, controlled, clinical trial with two arms: a placebo arm and an intervention arm. The target population will include 40 adult inpatients with the colonization of a multi-drug resistant organism (MDRO) after infection. Target MDRO colonization is defined as a positive clinical microbiology bacterial culture and antibiotic susceptibility result that includes one or more of the following: carbapenem-resistant Enterobacteriaceae (CRE), vancomycin-resistant Enterococcus spp (VRE), extended-spectrum β-lactamase (ESBL) producing Enterobacteriaceae, multidrug-resistant (MDR) Acinetobacter and/or MDR Pseudomonas

Official Title
-----------------
A Randomized Controlled Trial to Further Microbiota Therapy for AntIbiotic-Resistant Bacterial Colonization in Inpatients.

Conditions
-----------------
Multi-drug Resistant Organism

Intervention / Treatment
-----------------
* Drug: Microbiome Therapeutic
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Be able to (or have an available Legal Authorized Representative who is able to) understand and be willing to sign a written informed consent document. Be at least 18 years old at the time of consent. Be able and willing to comply with all study protocol requirements, including the ability to swallow capsules. Be colonized with a target MDRO (CRE, VRE, ESBL, MDR Acinetobacter, and/or MDR Pseudomonas) as detected by bacterial culture of stool or perianal/rectal swab. Be willing to discontinue antibiotics, probiotics, or other microbiota restoration therapies, and proton pump inhibitors (PPIs) at least one day prior to study Day 0 and throughout the study. The effects of the IP on the developing human fetus are unknown. For this reason, women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. If the potential participant is male, and the partner is of childbearing potential, the subject agrees to practice at least one effective method of birth control for the duration of the study. Exclusion Criteria: Be pregnant, breastfeeding, lactating, or planning a pregnancy during the study duration (through 4 weeks after the last dose of investigational product, or IP), if women of childbearing potential (WOCBP). Have known uncontrolled intercurrent illness(es) such as, but not limited to: Symptomatic congestive heart failure, acute coronary syndrome, cardiac arrhythmia, untreated in situ colorectal cancer, toxic megacolon or ileus, use of medications that decrease GI motility and increase broncho-aspiration risk (e.g. loperamide, diphenoxylate/atropine, cholestyramine), or history of positive stool studies or cultures in the last 30 days for ova, parasites, Salmonella, Shigella, Campylobacter, or other enteropathogens other than those detected by screening MDRO stool cultures for inclusion. Have any other intercurrent acute illness that in the opinion of the investigator will preclude the subject from entering the study. Be on systemic antibiotics for any reason other than if the MDRO infection was recent or the potential participant is still taking antibiotics for target MDRO at the time of screening. If the latter, then the participant must complete the planned antibiotic course by study Day -1. Inability to discontinue PPI therapy. Have a compromised immune system, defined as AIDS with a cluster of differentiation 4 (CD4)+ T-cell count <200, Absolute neutrophil count (ANC) <1,000 neutrophils / mL on the day of enrollment, active malignancy requiring intensive induction chemotherapy, radiotherapy, or biologic treatment within 2 months of enrollment or history of hematopoietic cell transplantation, either allogeneic or autologous in the last 1 year. Have a history of significant food allergy that led to anaphylaxis or hospitalization. Have a life expectancy of 24 weeks or less Have any condition that, in the opinion of the investigator, might interfere with study objectives or limit compliance with study requirements, including but not limited to: Known active intravenous drug or alcohol abuse, psychiatric illness, and/or social situation Participated in an investigational study that also meets one of the following criteria: Received an interventional agent (drug, device, or procedure) in the last 28 days or enrollment in any other interventional study for MDROs.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: microbiome therapeutic<br>The study intervention is manufactured from a healthy screened donor as an investigational product (IP) and delivered via swallowed capsule after room reset of the patient's hospital room. | Drug: Microbiome Therapeutic<br>* Participants will receive a single course of study treatment (IP, Encapsulated Microbiota): Orally delivered, non-frozen, encapsulated investigational intestinal microbiota, consisting of 16 capsules. One dose (8 capsules) is administered daily (QD) for 2 days. The capsules are to be taken orally with water on an empty stomach.<br>* Other names: Intervention Group;|
| Placebo Comparator: Placebo<br>The control arm will remain in routine contact precautions per standard of care, take placebo capsules, and have a room reset. | Drug: Placebo<br>* Participants will receive a single course of study treatment (Color-matched placebo capsules containing microcrystalline cellulose (MCC) powder), consisting of 16 capsules. One dose (8 capsules) is administered daily (QD) for 2 days. The capsules are to be taken orally with water on an empty stomach.<br>* Other names: Control Group;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the MDRO colony-forming unit (CFU) densities | MDRO colony-forming unit (CFU) densities from quantitative stool cultures in placebo vs IP-treated participants. | Day 0, day 14, and 24 weeks | 
| Change in proportion of participants MDRO colonized after the investigational product (IP) | Proportion of stool cultures positive for any target MDRO will be compared in IP-treated vs placebo-treated participants. | Day 0, day 14, and 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimate safety of the of the IP for MDRO colonization after infection | The frequency of adverse events from IP efficacy for reducing recurrent MDRO infection will be assessed by the frequency of MDRO infections at 24 weeks | Day 0, 24 weeks | 
| Severity of adverse events caused by administration of the investigational product | Severity of adverse events after administration of MT will be graded as mild, moderate or severe, form the time of MT administration up to 24 weeks. | Day 0, 24 weeks | 
| Estimate efficacy of the IP for reducing recurrent MDRO infection | Efficacy will be measured by the frequency of MDRO infections from Day 0 of the first cycle until 24 weeks | Day 0, 24 weeks | 
| Time to recurrent MDRO infection after IP administration | Time to recurrent MDRO infection from Day 0 of first cycle censored at last final safety visit, or death. | Day 0, 24 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Carbapenem-resistant Enterobacteriaceae (CRE), Vancomycin-Resistant Enterococcus (VRE), Extended Spectrum Beta-Lactamase (ESBL), Multi-Drug Resistant (MDR) Acinetobacter, Multi-Drug Resistant (MDR) Pseudomonas