Tolevamer Less Effective Than Standard Therapies for C difficile–Associated Diarrhea

Chris Berrie, MA, MPhil, PhD

April 24, 2008

April 24, 2008 (Barcelona) — In a direct head-to-head comparison in the treatment of patients with Clostridium difficile–associated diarrhea (CDAD), metronidazole demonstrated noninferiority to vancomycin, but tolevamer liquid did not satisfy the conditions for noninferiority. However, the flora-sparing approach of tolevamershowed reduced CDAD recurrence rates in these patients.

This study was presented on behalf of the Polymer Alternative for (CDAD) Treatment Investigators by Joanne Donovan, MD, PhD, vice president of clinical research with Genzyme, here during the 18th European Congress of Clinical Microbiology and Infectious Diseases.

C. difficile is a major cause of hospital-acquired infectious diarrhea and colitis, and this spore-forming, gram-positive anaerobic bacillus typically proliferates after antibiotic disruption of the normal enteric bacteria. The standard treatment options to date are for vancomycin or metronidazole, although their effectiveness is suboptimal, and their use is associated with substantial recurrence rates.

With CDAD as a toxin-mediated disease that is restricted to the intestinal lumen, a new approach led to the development of tolevamer liquid, a novel nonantibiotic toxin binder. As Dr. Donovan said, "This would have the advantages of preserving the normal gut flora, potentially reducing the recurrence rate, avoiding systemic antibiotic adverse events, and reducing colonization by antibiotic-resistant bacteria."

Following on the heels of promising data from a recent phase 2 study of tolevamer vs vancomycin, the current noninferiority study was designed as part of a direct head-to-head comparison of the standard treatment options of vancomycin and metronidazole. The treatment protocols were tolevamer 3 g, 3 times a day for 14 days; vancomycin 125 mg, 4 times a day for 10 days; and metronidazole 375 mg, 4 times a day for 10 days.

The primary endpoint was for clinical success, defined as the resolution and absence of severe abdominal discomfort caused by CDAD for 2 contiguous days, including day 10. The secondary endpoints were for time to resolution of diarrhea, and recurrence, as assessed through patients with diarrhea resolution after active treatment.

A total of 544 patients with CDAD were randomly assigned to receive tolevamer (n = 278), vancomycin (n = 126), or metronidazole (n = 140). Their baseline characteristics were similar across these 3 treatment groups for mean age (68.3, 67.3, and 66.6 years, respectively), percentage who were women (55.0%, 46.8%, and 55.0%, respectively), CDAD severity distribution (mild, ~30%; moderate, ~45%; severe, ~25%), and CDAD history (~80% with no prior episode).

According to the study population outcomes, Dr. Donovan said, "A major difference is evident here, in that in the tolevamer population, only about half the patients completed the treatment phase of the study. However, even in the vancomycin and metronidazole sections, 25% and 29% of patients did not complete[, respectively]." In the tolevamer group, 26.6% of patients did not respond to therapy and were withdrawn at the judgment of the principal investigator.

the percentages of patients who met the primary endpoints of clinical success, according to the full-analysis of intent-to-treat patient populations, were similar for vancomycin and metronidazole, with noninferiority for metronidazole being satisfied (81% vs 73%; 95% confidence interval for difference, −18% to 3%;). However, at 42%, the clinical success rate for tolevamer failed to reach noninferiority.

When clinical success was viewed by CDAD severity, in all of the treatment groups there was a decrease in success as the disease severity progressed; similarly, patients with any degree of recurrent disease had lower clinical success rates.

However, the secondary endpoint of CDAD recurrence demonstrated a significant reduction with tolevamer, at 6% recurrence, compared with both vancomycin (18%; P = .009) and metronidazole (19%; P = .006). However, Dr. Donovan did note that with fewer tolevamer patients reaching clinical success, this represented a select population.

For serious adverse events (SAEs), there were no statistical differences seen across the 3 treatment groups (tolevamer, vancomycin, and metronidazole) for deaths (12.0%, 12.0%, and 7.2%, respectively) or for patients with SAEs (27.0%, 32.0%, and 24.5%, respectively), C. difficile colitis (7.7%, 7.2%, and 6.5%, respectively), and sepsis (1.1%, 2.4%, and 0.0%, respectively).

Finally, Dr. Donovan provided a direct comparison of these success and recurrence rates with those from a previous US phase 3 study, noting that metronidazole/vancomycin noninferiority and a decreased recurrence rate for tolevamer were both maintained through both studies.

Dr. Donovan concluded, "Tolevamer did not reach its primary endpoint of noninferiority vs vancomycin, and it was less effective than the standard therapies for achieving clinical success." At the same time, this head-to-head comparison of vancomycin and metronidazole has demonstrated noninferiority for metronidazole, although Dr. Donovan noted the numerically higher success rate for vancomycin.

As a final consideration, she stressed the potential importance of the low level of recurrence of CDAD with patients treated with tolevamer, adding, "This suggests that flora-sparing drugs may help reduce recurrence."

As a cochairman of this session and an investigator in the US trial whose laboratory is involved in the typing of the isolates from this trial, Dale Gerding, MD, from the Hines Veterans Affairs Hospital, Chicago, Illinois, told Medscape Infectious Diseases that, "The study really confirmed the North American trial as far as tolevamer was concerned, but I think that the 1 difference in this trial is that there did not seem to be a difference between metronidazole and vancomycin for the treatment of severe disease, and that's perhaps a little surprising in some respects."

Although he indicated that this could possibly be a result of the evaluations being carried out by 2 different groups of investigators, he added that it could also be caused by a different spectrum of C difficile strains in the 2 studies, particularly because, as Dr. Gerding said, "the frequency of the O27, or BI, epidemic strain is higher in the North American study than it is in the European trial...so that could be 1 factor."

The study was funded by Genzyme, the maker of tolevamer. Dr. Donovan is an employee of Genzyme. Dr. Gerding has disclosed no relevant financial relationships.

18th European Congress of Clinical Microbiology and Infectious Diseases: Abstract O464. Presented April 22, 2008.

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