MODIFY I and II

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Tavazzi L, et al. "Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection". New England Journal of Medicine. 2017. 376(4):305-317.
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Clinical Question

Among patients receiving oral antibiotics for primary or recurrent C. difficile infection, does actoxumab or bezlotoxumab reduce the rate of recurrent infection as compared to placebo.?

Bottom Line

Among patients receiving oral antibiotics for primary or recurrent C. difficile infection, bezlotoxumab, but not actoxumab, reduces the rate of recurrent infection as compared to placebo.

Major Points

Clostridium difficile infection (CDI) may recur in up to one-third of patients after completing initial therapy.[1][2] Different therapies have been evaluated for the prevention of CDI recurrence, including probiotics, fidaxomicin and fecal microbiota transplantation (FMT). Fidaxomicin has been shown to reduce recurrence rate as compared to vancomycin (16.9% vs 29.2%; P = 0.048).[3] However, its cost-effectiveness has been debated.[4] As discussed in a recent review, the recurrence rate associated with fidaxomicin treatment remains suboptimal (>10%).[5] Recent reviews and guidelines have concluded that there are insufficient data to recommend the use of probiotics for prevention of recurrent CDI.[6][7][8][9] FMT has also demonstrated efficacy in reducing recurrence rates, however many questions including administration route, and candidate selection remains to be addressed.[10][11][5] The annual economic burden of CDI is estimated to be more than $496 million in the US.[12] A study in 2014 also showed that C. difficile was the most common pathogen isolated in healthcare-associated infections (12.1%).[13] Given the burden of CDI, there is an urgent need to identify effective additional effective therapies for its secondary prevention.

The MODIFY I and MODIFY II phase 3 trials evaluated the efficacy of the monoclonal antibodies actoxumab and bezlotoxumab that bind and neutralize C. difficile toxins A and B, respectively, for the prevention of recurrent CDI. A total of 2,655 adults receiving standard oral antibiotics for primary or recurrent CDI were randomized to receive bezlotoxumab, actoxumab, bezlotoxumab plus actoxumab, or placebo. The primary outcome was recurrent CDI within 12 weeks after treatment.

Among the participants, 781 received bezlotoxumab, 232 received actoxumab, 773 received bezlotoxumab plus actoxumab, and 773 received placebo. Treatment with actoxumab alone was discontinued after interim analysis in MODIFY I showed a lack of efficacy. In both trials, bezlotoxumab significantly reduced the recurrence rate as compared to placebo (MODIFY I: 17% vs. 28%; 95% CI −15.9 to −4.3; P<0.001; MODIFY II: 16% vs. 26%; 95% CI −15.5 to −4.3; P<0.001). The combination of actoxumab plus bezlotoxumab also reduced the recurrence rate as compared to placebo (MODIFY I: 16% vs. 28%; 95% CI −17.4 to −5.9; P<0.001; MODIFY II: 15% vs. 26%; 95% CI −16.4 to −5.1; P<0.001).

The most frequent adverse reactions were nausea and diarrhea. The adverse event rates were comparable between the bezlotoxumab, bezlotoxumab plus actoxumab, and placebo groups. However, the actoxumab group observed higher mortality and serious adverse event rates. The authors concluded that a causal association between actoxumab and death could not be confirmed or excluded.

Guidelines

As of March 2018, the latest IDSA / SHEA guidelines do not comment on the use of these agents.[14]

Design

  • Multicenter, double-blind, randomized, placebo-controlled, phase 3 trials
  • N=2,655
    • Bezlotoxumab (n=781)
    • Actoxumab (n=232)
    • Bezlotoxumab plus actoxumab (n=773)
    • Placebo (n=773)
  • Setting: 322 centers in 30 countries
  • Enrollment: 2011-2015
  • Follow-up: 12 weeks
  • Analysis: Intention-to-treat
  • Primary outcome: Recurrent C. difficile infection (a new episode of infection after initial clinical cure of the baseline episode) during follow-up

Population

Inclusion Criteria

  • Age ≥18 years
  • C. difficile infection diagnosed by fulfilling both criteria:
    • Diarrhea- passage of ≥3 loose stools in ≤24 hours
    • Positive stool test for toxigenic C. difficile
  • Receiving standard therapy for CDI (oral metronidazole, oral vancomycin or intravenous metronidazole with oral vancomycin at recommended dose)

Exclusion Criteria

  • Active chronic diarrheal illness (eg, Crohn's disease)
  • Surgery for CDI planned within 24 hours
  • Pregnancy or lactation
  • Previously received study treatment
  • Plan to donate blood within 6 months post-infusion
  • Treatment with IVIG 6 months prior to the infusion or planning to receive IVIG during the study period
  • Treatment with cholestyramine, rifaximin, nitazoxanide, or fidaxomicin14 days prior to the infusion or planned to receive these treatments during the study period
  • Plan to take antiperistaltic agents during the 14 days following infusion
  • Plan to take the probiotic Saccharomyces boulardii during the study period
  • Expected survival <72 hours
  • Pre-existing condition which may compromise the safety or right to participate in the study, or would confound the study results

Baseline Characteristics

From the bezlotoxumab+actoxumab group

  • Demographics: Age ≥65 years 57%, female 55%
  • CDI:
    • ≥1 episode in previous 6 months: 26%
    • ≥2 episodes ever: 13%
    • Severe disease: 18%
    • Diagnosis-related: Positive culture 62%, among which: common strains 46%; 027, 078, or 244 strains 19%; 027 strain 16%
    • Current treatment: Metronidazole 47%; vancomycin 47%; fidaxomicin 3%
  • Comorbidities: Renal impairment 12%; hepatic impairment 7%; immunocompromised 21%

Interventions

  • Participants receiving standard antibiotic treatment were randomized to receive bezlotoxumab (10 mg/kg), actoxumab alone (10 mg/kg; in MODIFY I only), actoxumab plus bezlotoxumab (10 mg/kg each), placebo (0.9% sodium chloride).
  • Treatment with actoxumab only was not evaluated in MODIFY II due to lack of efficacy in interim analysis in MODIFY I.
  • Treatment was administered as an IV infusion over 1 hour; these agents have a half-life of approximately 19 days hence only 1 dose was required.
  • Participants recorded bowel movement; telephone contact was established to monitor for new-onset diarrhea.

Outcomes

Comparisons are monoclonal antibodies vs. placebo

Primary Outcome

Recurrent CDI
Bezlotoxumab vs. placebo:
MODIFY I: 17% vs. 28%; adjusted difference −10.1 percentage points; 95% CI −15.9 to −4.3; P<0.001
MODIFY II: 16% vs. 26%; adjusted difference −9.9 percentage points; 95% CI −15.5 to −4.3; P<0.001
Actoxumab+bezlotoxumab vs. placebo:
MODIFY I: 16% vs. 28%; adjusted difference −11.6 percentage points; 95% CI −17.4 to −5.9; P<0.001
MODIFY II: 15% vs. 26%; adjusted difference −10.7 percentage points; 95% CI −16.4 to −5.1; P<0.001)

Secondary Outcomes

Recurrent CDI in participants who had an initial clinical cure
Bezlotoxumab vs. placebo:
MODIFY I: 22% vs. 33%; adjusted difference −10.8 percentage points; 95% CI −17.7 to −3.8; P=0.003
MODIFY II: 19% vs. 33%; adjusted difference −13.7 percentage points; 95% CI −20.4 to −6.9; P<0.001
Actoxumab+bezlotoxumab vs. placebo:
MODIFY I: 21% vs. 33%; adjusted difference, −11.7 percentage points; 95% CI −18.6 to −4.7; P=0.001;
MODIFY II: 21% vs. 33%; adjusted difference −11.9 percentage points; 95% CI −19.0 to −4.7; P=0.001)
Recurrent CDI in participants ≥65 years
Bezlotoxumab vs. placebo: 15.4% vs. 31.4%; absolute difference −16 percentage points
Actoxumab+bezlotoxumab vs. placebo: 17.2% vs. 31.4%; absolute difference −14.1 percentage points
Recurrent CDI in participants with no CDI in the past 6 month
Bezlotoxumab vs. placebo: 13.5% vs. 20.91%; absolute difference −7.4 percentage points
Actoxumab+bezlotoxumab vs. placebo: 12.9% vs. 20.9%; absolute difference −8 percentage points
Recurrent CDI in participants with ≥1 CDI episodes in the past 6 month
Bezlotoxumab vs. placebo: 25% vs. 41.1%; absolute difference −16.1 percentage points
Actoxumab+bezlotoxumab vs. placebo: 22.5% vs. 41.1%; absolute difference −18.6 percentage points
Recurrent CDI in participants with ≥2 CDI episodes ever
Bezlotoxumab vs. placebo: 29% vs. 42.1%; absolute difference −13.1 percentage points
Actoxumab+bezlotoxumab vs. placebo: 23.3% vs. 42.1%; absolute difference −18.8 percentage points
Recurrent CDI in immunocompromised patients
Bezlotoxumab vs. placebo: 14.6% vs. 27.5%; absolute difference −12.8 percentage points
Actoxumab+bezlotoxumab vs. placebo: 14.1% vs. 27.5%; absolute difference −13.3 percentage points
Recurrent CDI in participants with severe CDI
Bezlotoxumab vs. placebo: 10.7% vs. 22.4%; absolute difference −11.7 percentage points
Actoxumab+bezlotoxumab vs. placebo: 12% vs. 22.4%; absolute difference −10.4 percentage points
Recurrent CDI in participants with 027, 078, or 244 strains infection
Bezlotoxumab vs. placebo: 21.6% vs. 32.2%; absolute difference −10.6 percentage points
Actoxumab+bezlotoxumab vs. placebo: 14.4% vs. 32.2%; absolute difference −17.7 percentage points
Recurrent CDI in participants with 027 strain infection
Bezlotoxumab vs. placebo: 23.6% vs. 34%; absolute difference −10.4 percentage points
Actoxumab+bezlotoxumab vs. placebo: 11.8% vs. 34%; absolute difference −22.2 percentage points

Adverse Events

Comparisons are actoxumab+bezlotoxumab vs. bezlotoxumab vs. actoxumab vs. placebo

Infusion reactions within 24 hours post-infusion
8.0% vs. 10.3% vs. 11.1% vs. 7.6%
Within 4 weeks post-infusion
Adverse events: 58.6% vs. 61.7% vs. 67.2% vs. 61.2%
Serious adverse events: 15.8% vs. 19.8% vs. 27.7% vs. 21.4%
Drug-related: 6.4% vs. 7.5% vs. 7.2% vs. 5.9%
Serious drug-related: 0.6% vs. 0.5% vs. 1.3% vs. 0.3%
Abdominal pain: 4.1% vs. 4.3% vs. 6.4% vs. 4.4%
Diarrhea: 5.9% vs. 6 vs. 5.5 vs. 5.8%
Nausea: 6% vs. 6.6% vs. 11.9% vs. 5%
Vomiting: 3.1% vs. 3.9% vs. 4.3% vs. 2.7%
Fatigue: 2.7% vs. 2.3% vs. 4.3% vs. 2.7%
Pyrexia: 4% vs. 4.6% vs. 4.7% vs. 3.5%
CDI: 3.5% vs. 2.9% vs. 9.5% vs. 6.1%
UTI: 3.1% vs. 4.1% vs. 5.5% vs. 4.5%
Headache: 4.2% vs. 4.5% vs. 6% vs 3.1%
Mortality: 3.6% vs. 4.1% vs. 6% vs. 4.1%
12 weeks post-infusion
Serious adverse events: 27.3% vs. 29.4% vs. 44.3% vs. 32.7%
Mortality: 6.6% vs. 7.1% vs. 11.5% vs. 7.6%

Criticisms

  • The primary outcome is not robust and could have been driven by false negative c diff tests due to antibody binding -- no outcomes measuring diarrhea or rehospitalization to confirm endpoint
  • The number of participants with severe CDI may have been underestimated as patients were already on antibiotic treatment when the severity assessment was done.[15]
  • Therapies that are currently used for the prevention of CDI recurrence (eg, fidaxomicin) were excluded from the study, hence the combined effect with these therapies was not evaluated.[15][16]
  • The selection of standard antibiotic was at the discretion of the trial investigators.[15]
  • The cost-effectiveness of bezlotoxumab remains to be determined.[16]

Funding

  • Merck

Further Reading

  1. Cornely OA et al. Treatment of first recurrence of Clostridium difficile infection: fidaxomicin versus vancomycin. Clin. Infect. Dis. 2012. 55 Suppl 2:S154-61.
  2. Marsh JW et al. Association of relapse of Clostridium difficile disease with BI/NAP1/027. J. Clin. Microbiol. 2012. 50:4078-82.
  3. Mullane KM, Miller MA, Weiss K, et al. Efficacy of fidaxomicin versus vancomycin as therapy for Clostridium difficile infection in individuals taking concomitant antibiotics for other concurrent infections. Clin Infect Dis. 2011 Sep;53(5):440-7. doi: 10.1093/cid/cir404.
  4. Bartsch SM, Umscheid CA, Fishman N, et al. Is fidaxomicin worth the cost? An economic analysis. Clin Infect Dis. 2013 Aug;57(4):555-61. doi: 10.1093/cid/cit346. Epub 2013 May 23.
  5. 5.0 5.1 Kociolek LK, Gerding DN. Breakthroughs in the treatment and prevention of Clostridium difficile infection. Nat Rev Gastroenterol Hepatol. 2016 Mar;13(3):150-60. doi: 10.1038/nrgastro.2015.220. Epub 2016 Feb 10.
  6. Crow JR et al. Probiotics and Fecal Microbiota Transplant for Primary and Secondary Prevention of Clostridium difficile Infection. Pharmacotherapy 2015. 35:1016-25.
  7. Evans CT & Johnson S Prevention of Clostridium difficile Infection With Probiotics. Clin. Infect. Dis. 2015. 60 Suppl 2:S122-8.
  8. Surawicz CM et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am. J. Gastroenterol. 2013. 108:478-98; quiz 499.
  9. Fehér C, Mensa J. Comparison of current guidelines of five international societies on Clostridium difficile infection management Infect Dis Ther. 2016 Sep;5(3):207-30. doi: 10.1007/s40121-016-0122-1. Epub 2016 Jul 28.
  10. Kelly CR, Khoruts A, Staley C, et al. Effect of Fecal Microbiota Transplantation on Recurrence in Multiply Recurrent Clostridium difficile Infection: A Randomized Trial. Ann Intern Med. 2016 Nov 1;165(9):609-616. doi: 10.7326/M16-0271. Epub 2016 Aug 23.
  11. Youngster I, Sauk J, Pindar C, et al. Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study. Clin Infect Dis. 2014 Jun;58(11):1515-22. doi: 10.1093/cid/ciu135. Epub 2014 Apr 23.
  12. McGlone SM, Bailey RR, Zimmer SM, et al. The economic burden of Clostridium difficile. Clin Microbiol Infect. 2012 Mar;18(3):282-9. doi: 10.1111/j.1469-0691.2011.03571.x. Epub 2011 Jun 10.
  13. Magill SS, Edwards JR, Bamberg W, et al. Multistate point-prevalence survey of health care-associated infections. N Engl J Med. 2014 Mar 27;370(13):1198-208. doi: 10.1056/NEJMoa1306801.
  14. McDonald LC et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin. Infect. Dis. 2018. 66:987-994.
  15. 15.0 15.1 15.2 Wilcox MH, Gerding DN, Poxton IR, et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med 2017;376:305-317
  16. 16.0 16.1 Bartlett JG. Bezlotoxumab — A New Agent for Clostridium difficile Infection. N Engl J Med 2017; 376:381-382January 26, 2017DOI: 10.1056/NEJMe1614726