Intestinal Lavage for the Treatment of Severe C. Difficile Infections

A Feasibility Randomized Trial of Intestinal Lavage for the Treatment of Severe C. Difficile Infections

Clostridium Difficile infections (CDIs) are treated initially with antibiotic therapy and supportive care, with surgical intervention reserved for patients with significant systemic toxicity or perforation. Severe CDI may be refractory to medical management and require surgical intervention, carrying a mortality of approximately 40%.

Mortality associated with CDI increases significantly as the severity of the infection increases. In patients failing medical management, earlier operation is associated with decreased mortality. However, the lack of validated tools to predict the necessity for surgical intervention, combined with the significant morbidity associated with total colectomy significantly reduces the likelihood of patients receiving early surgical intervention. The purpose of the proposed study is to assess the addition of intestinal PEG lavage via nasojejunal tube to usual care in the treatment of adult patients with severe CDI who have no immediate indication for surgical intervention.

Study Overview

• Status: Unknown
• Conditions: Clostridium Difficile
• Intervention / Treatment: Procedure: Intestinal Lavage; Drug: Vancomycin; Drug: PEG; Drug: Metronidazole

Detailed Description

Despite a lack of definitive evidence, total abdominal colectomy (TAC) is currently recommended as the surgical intervention of choice in the setting of severe-complicated CDI. This recommendation was based on meta-analysis of studies comparing TAC to partial colectomy or other surgery (such as exploratory laparotomy without colectomy, or ostomy formation) or no surgery, which did not find any statistical mortality difference. This recommendation is based on the results of sensitivity analysis and an expert panel consensus that considered the potential for confounding factors such as TAC occurring later in the course of the disease and on sicker patients, and on anticipated patient values that would pace value on a definitive procedure being the initial surgical intervention.

Given the high mortality of fulminant CDI, early surgical intervention is recommended. However, data regarding the optimal timing for surgical intervention is lacking. Meta-analyses and guidelines strongly recommend early surgical management, defined as being before the development of shock or the requirement for vasopressors, based on very low quality evidence, but with the potential for significant mortality reduction.

On the basis of CDI being a toxin mediated inflammatory process of the colonic mucosa, Neal et al hypothesized that surgical diversion of the fecal stream with a loop ileostomy and intraoperative antegrade colonic lavage may effectively treat severe CDI. Widely referred to as the 'Pittsburgh Protocol,' the regimen included colonic lavage with 8 litres of polyethylene glycol (PEG 3350) intra-operatively after formation of a loop ileostomy, followed by antegrade Vancomycin flushes (500mg in 500cc Ringer's Lactate TID) and IV Metronidazole (500mg TID) for 10 days. The study utilized a before-and-after methodology comparing the experimental protocol to historical controls. Forty-two patients were submitted to the regimen over 18 months. Three patients required reoperation for TAC. 30-day mortality was 19% in the intervention cohort, compared to 50% in the control. 79% of survivors went on to ileostomy reversal within 6 months of surgery. One of the potential benefits of this regimen is that given the reduced morbidity compared to TAC, practitioners may have been offering surgical intervention earlier in the management of CDI and not exclusively as a therapy of last resort. Despite the limited sample size and methodological shortcoming of this study, this treatment regime has been adopted in some centres for select cases. A randomized controlled trial to compare this less invasive surgical approach with total abdominal colectomy was closed prematurely given lack of meaningful patient enrolment (clinicaltrials.gov identifier NCT01441271).

Given the positive results of fecal diversion and antegrade lavage and vancomycin flushed proposed by Neal et al, combined with the limited data regarding the benefit of intracolonic vancomycin, a novel treatment was instituted at London Health Sciences Centre (LHSC) to accomplish lavage of the colon and vancomycin flushes in an antegrade fashion using a nasojejunal feeding tube to facilitate delivery in select patients. The protocol allows for lavage and intracolonic antibiotic delivery similar to that provided by the 'Pittsburgh protocol' without surgical fecal diversion.

A small preliminary cohort of patients completing this protocol at LHSC is being assessed retrospectively, comparing outcomes to a group undergoing the Pittsburgh protocol and initial total colectomy. The study was approved by the Western University Research Ethics Board (REB File # 104944). Interim analysis of the past 24 months includes 13 patients undergoing the study protocol, 9 undergoing the Pittsburgh protocol and 17 undergoing initial colectomy. Despite significant limitations of the study methodology, the results are encouraging and further study is warranted, especially given the significant mortality associated with fulminant CDI.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Tina E Mele, MD PhD; Phone Number: 519-663-3970; Email: tina.mele@lhsc.on.ca

Study Locations

• Canada
  • Ontario
    • London, Ontario, Canada, N6A 5A5
      • Recruiting
      • London Health Sciences Centre
      • Contact: Tina Mele, MD, PhD; Phone Number: 519-663-3970; Email: tina.mele@lhsc.on.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adult (>= 18 years) inpatients at LHSC with symptomatic CDI (diarrhea or colonic ileus)
• CDI confirmed by standard hospital microbiology lab testing
• Patients must meet criteria for severe CDI, defined as either: white blood cell > 15,000 or Serum Creatinine > 1.5 times the pre-morbid level

• Patients must have at least one additional risk factor for severity:

  i. Fever >38.5 (if no other source of fever suspected) ii. Vasopressor requirement iii. Mechanical ventilation requirement iv. Serum lactate >5 mmol/L v. Colonic distension (>6cm transverse colon diameter on abdominal Xray or CT) vi. Colonic wall thickening, on abdominal Xray or CT, as reported by radiology. vii. Calculated ATLAS score ≥ 4

Exclusion Criteria:

• The patient is deemed to have an immediate indication for surgery related to the diagnosis of CDI by the on call General Surgery service.
• Pre-existing bowel discontinuity (e.g. ileostomy).
• General Surgery service or most responsible care team deem the patient to have a contraindication to nasojejunal tube or fecal management system
• Patients anticipated to be intolerant of the study regimen (e.g. severe ileus, unable to tolerate oral intake, etc.)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intestinal Lavage; A nasojejunal tube and fecal management system will be inserted. Intestinal lavage with PEG is initiated and increased to a goal rate of 400cc/hour to a total of 8L of PEG. In the absence of an ileus, lavage should be initiated at 200cc/hr. Tolerance is confirmed if the rectal effluent volume is ≥50% of the lavage volume over the first 6 hours and no emesis has developed. If the consulting surgical service suspects a significant ileus, the lavage is initiated at 100cc/hr. If tolerance is confirmed the lavage rate is increased in a stepwise fashion. Antibiotic regimen will consist of Vancomycin 500mg via nasojejunal every 6 hours and Metronidazole 500 mg IV three times daily for 14 days. PEG will be held for 2 hours after administration of Vancomycin.	Procedure: Intestinal Lavage; A nasojejunal tube and fecal management system will be inserted. Intestinal lavage with PEG is initiated and increased to a goal rate of 400cc/hour to a total of 8L of PEG. In the absence of an ileus, lavage should be initiated at 200cc/hr. Tolerance is confirmed if the rectal effluent volume is ≥50% of the lavage volume over the first 6 hours and no emesis has developed. If the consulting surgical service suspects a significant ileus, the lavage is initiated at 100cc/hr. If tolerance is confirmed the lavage rate is increased in a stepwise fashion. Antibiotic regimen will consist of Vancomycin 500mg via nasojejunal every 6 hours and Metronidazole 500 mg IV three times daily for 14 days. PEG will be held for 2 hours after administration of Vancomycin.; Other Names: PEG Lavage; Drug: Vancomycin; Patients will receive standard antibiotic treatment for severe CDI. This includes an antibiotic regimen of Vancomycin 500mg orally every 6 hours and Metronidazole 500mg IV three times daily for 14 days. The standard medical care group (active comparator group) will receive the same antibiotic doses as the experimental arm of the study For both arms, indications to escalate treatment to surgical intervention will ultimately be based on the clinical assessment by the surgical service. An absolute indication for surgery is perforation. Other indications such as toxic megacolon, worsening peritonitis or biochemical profile lavage are relative indications that vary according to clinician and individual patient characteristics.; Other Names: Antibiotic-V; Drug: PEG; Polyethylene glycol 3350, 8L in 48 hours, via a nasojejunal tube will be used to facilitate intestinal lavage.; Other Names: Polyethylene glycol 3350; Drug: Metronidazole; Patients will receive standard antibiotic treatment for severe CDI. This includes an antibiotic regimen of Vancomycin 500mg orally every 6 hours and Metronidazole 500mg IV three times daily for 14 days. The standard medical care group (active comparator group) will receive the same antibiotic doses as the experimental arm of the study For both arms, indications to escalate treatment to surgical intervention will ultimately be based on the clinical assessment by the surgical service. An absolute indication for surgery is perforation. Other indications such as toxic megacolon, worsening peritonitis or biochemical profile lavage are relative indications that vary according to clinician and individual patient characteristics.; Other Names: Antibiotic-M
Active Comparator: Usual Care; Patients will receive usual care for severe CDI. This includes an antibiotic regimen of Vancomycin 500mg orally every 6 hours and Metronidazole 500mg IV three times daily for 14 days. The usual care group will receive the same antibiotic doses as the experimental arm of the study. For both arms, indications to escalate treatment to surgical intervention will ultimately be based on the clinical assessment by the surgical service. An absolute indication for surgery is perforation. Other indications such as toxic megacolon, worsening peritonitis or biochemical profile lavage are relative indications that vary according to clinician and individual patient characteristics.	Drug: Vancomycin; Patients will receive standard antibiotic treatment for severe CDI. This includes an antibiotic regimen of Vancomycin 500mg orally every 6 hours and Metronidazole 500mg IV three times daily for 14 days. The standard medical care group (active comparator group) will receive the same antibiotic doses as the experimental arm of the study For both arms, indications to escalate treatment to surgical intervention will ultimately be based on the clinical assessment by the surgical service. An absolute indication for surgery is perforation. Other indications such as toxic megacolon, worsening peritonitis or biochemical profile lavage are relative indications that vary according to clinician and individual patient characteristics.; Other Names: Antibiotic-V; Drug: Metronidazole; Patients will receive standard antibiotic treatment for severe CDI. This includes an antibiotic regimen of Vancomycin 500mg orally every 6 hours and Metronidazole 500mg IV three times daily for 14 days. The standard medical care group (active comparator group) will receive the same antibiotic doses as the experimental arm of the study For both arms, indications to escalate treatment to surgical intervention will ultimately be based on the clinical assessment by the surgical service. An absolute indication for surgery is perforation. Other indications such as toxic megacolon, worsening peritonitis or biochemical profile lavage are relative indications that vary according to clinician and individual patient characteristics.; Other Names: Antibiotic-M

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of eligible participants recruited into the study	Recruited participants	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants meeting study inclusion criteria	Included participants	12 months
Number of participants who complete the assigned study protocol	Completed study participants	12 months
Number of participants who complete the treatment protocol without an adverse event	Participants with no adverse events	12 months
Number of participants with a complication or adverse event	Participants with adverse events	12 months
Number of participants who require initiation of mechanical ventilation following protocol initiation	Participants requiring mechanical ventilation	12 months
Number of participants who require operative intervention for CDI treatment	Participants requiring operative intervention	12 months
Surgeons' indication for operative intervention	Surgeons will indicate the indication for operative intervention for any patient that is taken to the operating theatre for CDI treatment	12 months
30-day all-cause mortality	Mortality within 30 days	12 months

Collaborators and Investigators

• Sponsor: Lawson Health Research Institute
• Collaborators: London Health Sciences Centre
• Investigators: Principal Investigator: Tina E Mele, MD PhD, London Health Sciences Centre

Publications and helpful links

General Publications

• McCreery G, Jones PM, Kidane B, DeMelo V, Mele T; ERASE C. difficile (Early Rescue from Acute SEvere Clostridium difficile) Trials Group. Polyethylene glycol intestinal lavage in addition to usual antibiotic treatment for severe Clostridium difficile colitis: a randomised controlled pilot study. BMJ Open. 2017 Jul 31;7(7):e016803. doi: 10.1136/bmjopen-2017-016803.

Study record dates

Study Major Dates

• Study Start: August 1, 2016
• Primary Completion (Anticipated): August 1, 2019
• Study Completion (Anticipated): August 1, 2019

Study Registration Dates

• First Submitted: June 4, 2015
• First Submitted That Met QC Criteria: June 8, 2015
• First Posted (Estimate): June 9, 2015

Study Record Updates

• Last Update Posted (Actual): August 13, 2018
• Last Update Submitted That Met QC Criteria: August 9, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Colectomy; Surgical Procedures, Operative
• Additional Relevant MeSH Terms: Infections; Anti-Infective Agents; Gastrointestinal Agents; Antiprotozoal Agents; Antiparasitic Agents; Antitubercular Agents; Laxatives; Vancomycin; Metronidazole; Anti-Bacterial Agents; Antibiotics, Antitubercular; Polyethylene glycol 3350
• Other Study ID Numbers: 106184

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-dentified data available upon reasonable request after publication of study results
• IPD Sharing Time Frame: Data will be available for sharing after publishing the study.
• IPD Sharing Access Criteria: A direct request from PI.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL