Vancomycin, Metronidazole, or Tolevamer for Clostridium difficile Infection: Results From Two Multinational, Randomized, Controlled Trials

Incomplete

Johnson S, et al. "Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials". Clinical Infectious Diseases. 2014. 59(3):345-354.
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Clinical Question

In patients with Clostridium difficile infection (CDI), is treatment with the toxin-binding polymer tolevamer non-inferior to antibiotic agents vancomycin or metronidazole in clearing CDI and resolution of symptoms?

Bottom Line

When comparing the efficacy of tolevamer with vancomycin and metronidazole, tolevamer was found to be inferior to both metronidazole and vancomycin for treatment of CDI, and metronidazole was inferior to vancomycin.

Major Points

Clostridium difficile is a toxin-secreting bacteria that causes diarrhea and can result from previous antibotic therapy, among other causes. Typical treatment for CDI involves the use of more antibiotics, such as metronidazole or oral vancomycin. Two trials were conducted to study the efficacy of tolevamer, a polymer meant to bind toxins, comparing it to traditional antibiotic therapy.

Between two studies, 1071 patients with CDI were randomly assigned in a 2:1:1 ratio to oral tolevamer, vancomycin, or metronidazole. The primary endpoint was clinical success, defined as resolution of diarrhea and absence of severe abdominal discomfort for more than 2 consecutive days including day 10. 81.1% of patients in the vancomycin arm and 72.7% of patients in the metronidazole arm saw clinical success, while only 44.2% of patients in the tolevamer arm saw clinical success. In both studies, time to resolution of diarrhea (TTROD) was significantly longer in the tolevamer arm compared with the metronidazole and vancomycin arms.

Based on the results of this study, non-antibiotic toxin-binding polymer tolevamer was shown to be inferior to antibiotic agents vancomycin and metronidazole. If the patient is able to use either vancomycin or metronidazole, they would be more effective choices at resolving their CDI than tolevamer.

Guidelines

ISDA/SHEA (2018, adapted)

• “Discontinue therapy of the inciting antibiotic agent(s) as soon as possible”
• “Either vancomycin or fidaxomicin is recommended over metronidazole for an initial episode of CDI. The dosage is vancomycin 125 mg orally 4 times per day or fidaxomicin 200 mg twice daily for 10 days”
• “In settings where access to vancomycin or fidaxomicin is limited… [use] metronidazole for an initial episode of nonsevere CDI only. The suggested dosage is metronidazole 500 mg orally 3 times per day for 10 days”
• “Treat a first recurrence of CDI with oral vancomycin as a tapered and pulsed regimen rather than a second standard 10-day course of vancomycin”

Design

• Trial type: phase 3, multicenter, randomized, double-dummy, double-blind, active-controlled, parallel-design efficacy studies
• Number of patients randomized: 1118 patients were randomly assigned to treatment in the 2 studies, 574 patients in the 301 study and 544 patients in the 302 study
• Experimental/standard arms:
  • 301 study: Tolevamer n=266, metronidazole n=143, vancomycin n=134
  • 302 study: Tolevamer n=268, metronidazole n=135, vancomycin n=125
• Setting: Protocol 301 included 91 study sites in Canada and United States, and protocol 302 had 109 study sites in Australia, Austria, Belgium, Canada, Czech Republic, Denmark, France, Germany, Ireland, Norway, Portugal, Spain, Sweden, Switzerland, and the United Kingdom.
• Enrollment years: 2005-2007
• Mean follow-up: After the 2-week treatment period, patients were followed for 4 weeks
• Analysis:
  • Safety analysis set including all randomized patients who received any treatment.
  • Full analysis set including all randomized patients who received any treatment and had any post-dose evaluation.
  • Per-protocol set including patients from the full analysis set who had> 7 days of treatment, met all CDI diagnostic criteria, no previous diagnosis of active chronic diarrhea unrelated to CDI or enteritis from pathogens other than C. difficile causing diarrhea at screening, ≤48 hours of antibacterial therapies specific for CDI within the 5 days preceding enrollment, and were compliant with study medication.
• Primary outcome: Clinical success- Resolution of diarrhea and absence of severe abdominal discomfort for greater than 2 consecutive days

Population

Inclusion Criteria

• Hospitalized or ambulatory patients with non–life-threatening medical conditions and confirmed primary CDI or presumed or confirmed recurrent CDI were screened
  • CDI was defined as greater than 3 bowel movements within a 24-hour period with a watery or loose consistency, a positive C. difficile toxin assay result, or pseudomembranes on endoscopy
• Patients aged ≥18 years
• Patients with toxin confirmation within 72 hours prior to enrollment, except for patients who had been treated for a prior CDI episode within 30 days of enrollment.

Exclusion Criteria

• Fulminant CDI
• Intestinal ileus
• Vomiting more than twice in 24 hours
• Inability to swallow oral medication
• Hypokalemia (serum K+ < 3.0 mEq/L or serum K+ < 3.5 mEq/L and a history of cardiac arrhythmias or currently receiving digoxin)
• Continued exposure to CDI-inducing antibiotic(s) for more than 7 days
• Hepatic failure and biliary obstruction
• Diarrhea of other known cause
• Existence of active chronic diarrhea unrelated to CDI
• Greater than 48 hours of oral vancomycin or intravenous or oral metronidazole or other effective alternative treatment for CDI within 5 days of enrollment
• Allergy to vancomycin or metronidazole
• Participation in an investigational drug study within 30 days
• Pregnancy or lactation
• Inability to abstain from alcohol during the 14-day treatment period
• Prior treatment with tolevamer
• Presence of an acute life-threatening condition that would preclude completion of the study

Baseline Characteristics

From the Study 301 Tolevamer group - There was a statistical significant difference between age, body weight, inpatient status and concomitant antibiotic use between the two groups.

• Demographics: Age 62, 53% female
• Vitals: Weight 76 kg
• Treatment Naive: 47%
• CDI History:
  • Primary Infection: 68%
  • First recurrence: 20%
  • Multiple recurrence: 11%
  • Missing: 1 (0.38%)
• CDI Severity:
  • Mild: 29%
  • Moderate: 36%
  • Severe: 36%
• Concomitant antibiotic use: 22%
• Antibiotic use during follow-up: 56%
• CD Strain:
  • BI: 26%
  • Non-BI: 47%
  • Unknown: 27%

Interventions

• Tolevamer arm received 9 grams loading dose followed by 3 grams every 8 hours for 14 days
• Vancomycin arm received 125 mg every 6 hours for 10 days
• Metronidazole arm received 375 mg every 6 hours for 10 days

Outcomes

Presented as Tolevamer vs. Vancomycin vs. Metronidazole

Primary Outcomes

Clinical Success

Defined as resolution of diarrhea and absence of severe abdominal discomfort due to CDI for more than 2 consecutive days including day 10. Resolution of diarrhea was defined as attainment of bowel movements with a hard or formed consistency on average or 2 or fewer BM/day with a loose or watery consistency on average

44.2% vs. 81.1% vs. 72.7% (P<0.001, NNT 3 vs. 2 vs. 2)

Secondary Outcomes

Time to Resolution of Diarrhea (TTROD)

Defined as the beginning of diarrhea resolution that was sustained for the treatment period (10 days for metronidazole and vancomycin and 14 days for tolevamer)

12 days vs. 4-5 days vs. 4-5 days (P<0.001, NNT at 6 days 4 vs. 2 vs. 2)

Recurrence of CDI

Defined as a confirmed CDI diagnosis during the 4-week follow-up period according to the criteria listed above in patients who had previously met the criteria for resolution of diarrhea

4.5% vs. 20.6% vs. 23.0% (P<0.001, NNH 22 vs. 4 vs. 4)

Subgroup Analysis

• Vancomycin vs. Metronidazole, Odds ratio 1.681 (CI 1.114-2.537 P=.013)
• Treatment Naive vs. Treatment Experienced, Odds ratio: 1.817 (CI 1.206-2.737 P=.0043)
• Primary Disease vs. Recurrent Disease, 1.616 (CI 1.024-2.55 P=.039)
• Mild/Moderate Disease vs. Severe Disease, 1.545 (CI 1.009-2.367 P=.045)

Adverse Events

• Number of patients who discontinued study medication because of an adverse event related to study medication
  • 12.2% vs. 2.7% vs. 6.3% (P<0.001 tolevamer/vancomycin, P<0.01 tolevamer/metronidazole, P=0.044 metronidazole/vancomycin; NNH 8 vs. 37 vs. 15)
• Mortality
  • 9.3% vs. 8.8% vs. 5.6% (NNH 10 vs. 11 vs. 17, statistically insignificant)
• One or more serious adverse event related to study medication
  • 2.9% vs. 1.2% vs. 1.0% (NNH 34 vs. 83 vs. 100, statistically insignificant)

Criticisms

• No specifics given for what the study classifies an adverse event
• CDIs were defined in this study as “3 or more bowel movements in a 24-hour period with a ‘loose or watery consistency.’” This criteria is subjective because it is not being evaluated on a more definitive, objective scale
• Metronidazole was administered as 375 mg four times daily, instead of 500 mg three times daily

Funding

• Studies were sponsored by Genzyme
• Data analysis was funded by Genzyme and ViroPharma Incorporated