A Randomized Controlled Multicenter Trial of a Five Day Course of Oral Colistin and Neomycin Followed by Restoration of the Gut Microbiota Using Fecal Transplantation to Eradicate Intestinal Carriage of Extended Spectrum Beta-lactamase or Carbapenemase-producing Enterobacteriaceae in High-risk Patients
试验速览
- 阶段
- 2 期
- 发起方
- 入组人数
- 39
- 试验地点
- 4
- 主要终点
- Intestinal carriage of ESBL-E / CRE
研究概览
简要总结
This investigator initiated,international, multicenter open-label, randomized controlled trial aims to assess whether a 5 day course of oral nonabsorbable antibiotics (colistin sulfate 2 million IU per os 4x/day and neomycin sulfate 500 mg (salt) per os 4x/day ) followed by fecal microbiota transplantation (administered either via nasogastric administration or via capsules) is effective at eradicating intestinal carriage of beta-lactamase producing Enterobacteriaceae (ESBL-E) and carbapenemase producing Enterobacteriaceae (CPE). compared to no intervention (current standard of care) in adult non-immunosuppressed patients .
详细描述
In recent years a certain family of bacteria (Enterobacteriaceae) that colonizes the human gastrointestinal tract but can also cause severe infections has increasingly become resistant to antibiotics by acquiring enzymes that can inactivate a wide array of these valuable drugs. Depending on the class of beta-lactam antibiotics that these enzymes can inactivate, these bacteria are either designated as extended spectrum beta-lactamase producing Enterobacteriaceae (ESBL-E) or carbapenemase producing Enterobacteriaceae (CPE).
The R-GNOSIS project which is financed by the European Commission combines five separate international clinical studies (work packages 2 to 6) that examine intervention strategies to reduce carriage, infection and spread of these bacteria. This study (work package 3 of R-GNOSIS) will be conducted in 4 centers in 3 European countries (Switzerland, France, The Netherlands) and Israel. The study will examine whether it is possible to eradicate intestinal carriage with ESBL-E and CPE by administering a 5 day course of oral nonabsorbable antibiotics (colistin sulfate and neomycin sulfate) followed by administration of "healthy" stool flora obtained from a healthy volunteer donor ("fecal microbiota transplantation" or FMT). The "healthy" stool flora for this procedure will be obtained from carefully selected healthy volunteers that have been tested for a wide variety of infectious diseases and do not show any risk factors or risky behavior for transmittable diseases. Once the fecal material has been processed it will be frozen at -80°C for up to six months until administration to patients (via capsules or via a nasogastric tube). FMT has been successfully used to treat recurrent infections with a specific pathogen (Clostridium difficile) and has proven safe and effective for this indication but has never been studied with the aim of eradicating multidrug-resistant organisms.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult patients (>= 18 years at date of inclusion)
- •Ability to provide informed consent
- •Documented intestinal carriage of ESBL-E and / or CPE by stool culture at baseline (visit 0)
- •IF COLONIZED WITH ESBL-E ONLY (WITHOUT CPE): At least one episode of symptomatic infection with ESBL-E requiring systemic antibiotic therapy within the last 180 days before date of inclusion (based on the last day of antibiotic therapy for that infection)
排除标准
- •Pregnancy or planned pregnancy
- •Breastfeeding
- •Difficult / impossible follow-up
- •Allergy or other contraindication to one of the study drugs
- •Recurrent aspirations / chronic dysphagia
- •Resistance to colistin (defined as MIC> 2 mg/l) of any of the ESBL-E or CPE strains isolated at baseline
- •Estimated life expectancy < 6 months
- •Treatment with any systemic antibiotic on the day of inclusion
- •Severe immunodeficiency
- •Systemic chemotherapy ≤30 days from baseline or planned chemotherapy within the next 6 months
- •Human Immunodeficiency Virus (HIV) with CD4 count < 250/mcl
- •Prolonged use of steroids (prednisone equivalent ≥ 60 mg per day for >= 30 days) or other immunosuppressive medications
- •neutropenia with absolute neutrophil count <1000/μL,
- •Solid organ transplant
- •Hematopoeitic stem cell transplant recipients
- •Other causes of severe immunodeficiency
- •Current hospitalization in an Intensive Care Unit
- •Estimated glomerular filtration rate (CKD-EPI) < 15 ml/min/1.73m2
- •Severe food allergy (anaphylaxis, urticaria)
- •Unavailability of compatible FMT preparation (with regard to donor / recipient cytomegalovirus, Epstein-Barr virus and toxoplasma serology)
- •Anatomic contraindication to the placement of a nasogastric tube (only if FMT application via nasogastric tube)
研究组 & 干预措施
colistin + neomycin followed by FMT
CAPSULE APPROACH:
Treatment days 1-5
- Colistin sulphate 2 million IU per os 4x/day (for 5 days)
- Neomycin sulphate 500 mg (salt) per os 4x/day (for 5 days) Treatment day 6: no treatment
Treatment days 7 and 8:
-15 capsules of capsulized Fecal microbiota transplantation (FMT) per os per day
NASOGASTRIC TUBE APPROACH:
Treatment days 1-5
- Colistin sulphate 2 million IU per os 4x/day (for 5 days)
- Neomycin sulphate 500 mg (salt) per os 4x/day (for 5 days)
Treatment day 6 and 7:
- Omeprazole 20 mg per os 1 dose on the evening of day 6 and on the morning of day 7
Treatment day 7:
- Infusion of 80 ml of a standardized stool suspension through a nasogastric tube - Fecal microbiota transplantation (FMT)
干预措施: Colistin (Drug)
colistin + neomycin followed by FMT
CAPSULE APPROACH:
Treatment days 1-5
- Colistin sulphate 2 million IU per os 4x/day (for 5 days)
- Neomycin sulphate 500 mg (salt) per os 4x/day (for 5 days) Treatment day 6: no treatment
Treatment days 7 and 8:
-15 capsules of capsulized Fecal microbiota transplantation (FMT) per os per day
NASOGASTRIC TUBE APPROACH:
Treatment days 1-5
- Colistin sulphate 2 million IU per os 4x/day (for 5 days)
- Neomycin sulphate 500 mg (salt) per os 4x/day (for 5 days)
Treatment day 6 and 7:
- Omeprazole 20 mg per os 1 dose on the evening of day 6 and on the morning of day 7
Treatment day 7:
- Infusion of 80 ml of a standardized stool suspension through a nasogastric tube - Fecal microbiota transplantation (FMT)
干预措施: Neomycin (Drug)
colistin + neomycin followed by FMT
CAPSULE APPROACH:
Treatment days 1-5
- Colistin sulphate 2 million IU per os 4x/day (for 5 days)
- Neomycin sulphate 500 mg (salt) per os 4x/day (for 5 days) Treatment day 6: no treatment
Treatment days 7 and 8:
-15 capsules of capsulized Fecal microbiota transplantation (FMT) per os per day
NASOGASTRIC TUBE APPROACH:
Treatment days 1-5
- Colistin sulphate 2 million IU per os 4x/day (for 5 days)
- Neomycin sulphate 500 mg (salt) per os 4x/day (for 5 days)
Treatment day 6 and 7:
- Omeprazole 20 mg per os 1 dose on the evening of day 6 and on the morning of day 7
Treatment day 7:
- Infusion of 80 ml of a standardized stool suspension through a nasogastric tube - Fecal microbiota transplantation (FMT)
干预措施: Fecal microbiota transplantation (FMT) (Drug)
colistin + neomycin followed by FMT
CAPSULE APPROACH:
Treatment days 1-5
- Colistin sulphate 2 million IU per os 4x/day (for 5 days)
- Neomycin sulphate 500 mg (salt) per os 4x/day (for 5 days) Treatment day 6: no treatment
Treatment days 7 and 8:
-15 capsules of capsulized Fecal microbiota transplantation (FMT) per os per day
NASOGASTRIC TUBE APPROACH:
Treatment days 1-5
- Colistin sulphate 2 million IU per os 4x/day (for 5 days)
- Neomycin sulphate 500 mg (salt) per os 4x/day (for 5 days)
Treatment day 6 and 7:
- Omeprazole 20 mg per os 1 dose on the evening of day 6 and on the morning of day 7
Treatment day 7:
- Infusion of 80 ml of a standardized stool suspension through a nasogastric tube - Fecal microbiota transplantation (FMT)
干预措施: Omeprazole (Drug)
结局指标
主要结局
Intestinal carriage of ESBL-E / CRE
时间窗: 35 to 48 days after randomization
Intestinal carriage of ESBL-E / CRE (absence / presence by stool culture of any ESBL-E and / or CRE with enrichment independent of type of carriage at baseline) 35 to 48 days after randomization
次要结局
- Occurrence of any adverse event(6 months)
- Occurrence of any gastrointestinal adverse event(6 months)
- Occurrence of any serious adverse event(6 months)
- Comparison of the global microbiota composition and diversity between the groups with FMT from the same donor and the groups with FMT from different donors(6 months)
- Intestinal carriage of ESBL-E / CRE(6 months after randomization)
- Occurrence of any adverse drug reaction(6 months)
- Isolation of any not intrinsically colistin resistant strain of Enterobacteriaceae during follow-up (MIC> 2mg/l)(6 months)
- Comparison between treatment groups of the change (relative to baseline) in the proportion of bacterial taxa and antibiotic resistance genes over time(6 months)
- Assess the stability of the microbiome of donor stools after 3 months of frozen storage(3 months of freezing (donor stools))
- Assess the stability of the microbiome of donor stools after 6 months of frozen storage(6 months of freezing (donor stools))
- Use of any antibiotics active against all of the colonizing ESBL-E / CRE strains(6 months)
- Assess the stability of the microbiome of donor stools after 18 months of frozen storage(18 months of freezing (donor stools))
- Assess the stability of the microbiome of donor stools after 24months of frozen storage(24 months of freezing (donor stools))
- ESBL-E and CRE infections per 100 patient months at risk (first infection with either)(6 months)
- Use of any antibiotics active against at least one of the colonizing ESBL-E / CRE strains(6 months)
- Assess the stability of the microbiome of donor stools after 12 months of frozen storage(12 months of freezing (donor stools))
研究者
Stephen Harbarth
Professor
University Hospital, Geneva