MODIFY I and II
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.?
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.
Clostridium difficile infection (CDI) may recur in up to one-third of patients after completing initial therapy. 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). However, its cost-effectiveness has been debated. As discussed in a recent review, the recurrence rate associated with fidaxomicin treatment remains suboptimal (>10%). Recent reviews and guidelines have concluded that there are insufficient data to recommend the use of probiotics for prevention of recurrent CDI. FMT has also demonstrated efficacy in reducing recurrence rates, however many questions including administration route, and candidate selection remains to be addressed. The annual economic burden of CDI is estimated to be more than $496 million in the US. A study in 2014 also showed that C. difficile was the most common pathogen isolated in healthcare-associated infections (12.1%). 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.
As of March 2018, the latest IDSA / SHEA guidelines do not comment on the use of these agents.
- Multicenter, double-blind, randomized, placebo-controlled, phase 3 trials
- 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
- 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)
- 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
From the bezlotoxumab+actoxumab group
- Demographics: Age ≥65 years 57%, female 55%
- ≥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%
- 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.
Comparisons are monoclonal antibodies vs. placebo
- 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)
- 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
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%
- 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.
- 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.
- The selection of standard antibiotic was at the discretion of the trial investigators.
- The cost-effectiveness of bezlotoxumab remains to be determined.
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