Tag Archives: C diff recurrence

Fecal Microbiota Transplantation From A Donor To Treat Recurrent C.difficle Infection

Fecal microbiota transplantation (FMT) from a donor (heterologous) to treat recurrent Clostridium difficile infection (CDI) is safe and more effective than self (autologous) transplantation, according to data from a randomized controlled, double-blind clinical trial.

However, the results, published online August 23 in the Annals of Internal Medicine, also show that the treatment success rate in the control group varied substantially between two study locations, which suggests there are subtleties not yet understood with the approach.

The efficacy of FMT using donor stool to treat recurrent CDI has made headlines, but so far it has largely been tested only in open-label clinical trials and case series.

 

To complement these studies, Colleen R. Kelly, MD, from the Women’s Medicine Collaborative, The Miriam Hospital, Providence, Rhode Island, and coworkers enrolled 46 patients who had had at least three recurrences of CDI and who were treated with vancomycin for the most recent infection and randomly assigned them to receive donor or self stool preparations by colonoscopy.

The researchers assessed adverse events for 6 months after FMT, defining efficacy as cessation of diarrhea without the need for further antibiotics during the 8 weeks after the intervention. All stool was subject to microbiota analysis before and after FMT.

Twenty of the 22 patients in the donor FMT group (90.9%; 95% confidence interval [CI],69.2% – 97.8%) were clinically cured compared with

15 of the 24 (62.5%; 95% CI, 41.6% – 79.6%) patients who received self FMT (P = .042).

The nine patients who developed CDI after self FMT were then given donor FMT and were cured.

Microbiome analysis revealed no improvement in gut microbial diversity after self FMT, but restoration of a normal microbiota with donor FMT, including increases in Bacteroidetes and Firmicutes and decreases in Proteobacteria and Verrucomicrobia populations.

An unexpected finding was that patients treated autologously at Montefiore Medical Center in the Bronx, New York had a much higher cure rate than those treated autologously at The Miriam Hospital in Providence. Specifically, for Rhode Island, cure rate with donor FMT was 90.0% (CI, 51.8% – 98.7%) vs 42.9% (CI, 20.1% – 69.0%) with self FMT. For New York, cure rate with donor FMT was 91.7% (CI, 57.2% – 98.9%) compared with 90.0% (CI, 51.8% – 98.7%) with self FMT.

The researchers list clinical differences among the patients at the two sites that could explain the different responses to self FMT:

  • NY patients were infected longer, had more recurrences, and had more courses of fidaxomicin than did Rhode Island patients.
  • NY patients waited longer to be treated and took antibiotics longer before entering the study, and may have been cured at that time.
  • Fecal microbiomes among NY patients had more Clostridia species, which may have occupied niches for C difficile.

Limitations of the study include lack of inclusion of baseline antibody titers and infection severity, small sample size attributed partly to unwillingness of participants to risk assignment to the autologous group, and nonuniform stool doses. In addition, the researchers mention that some patients may be infected according to polymerase chain reaction (PCR)-based identification of the pathogen, but be asymptomatic, and that some patients may have diarrhea resulting from undiagnosed irritable bowel syndrome but also be infected with C difficile, according to PCR testing.

In an accompanying editorial, Elizabeth L. Hohmann, MD, from Massachusetts General Hospital in Boston, points out another limitation, that “the population enrolled in this trial was younger (mean age, 50 years) and seemed healthier and more adventurous than most patients with recurrent CDI.” In contrast, about 60% of her patients with whom she discusses FMT are older than 60 years, and 30% are older than 75 years. However, the investigators had to recruit patients younger than 75 years to comply with FDA regulations to consider FMT as an investigational new drug.

No serious adverse events were reported. The researchers conclude, “FMT using fresh donor stool administered via colonoscopy after a course of vancomycin was effective at preventing further CDI episodes in patients with multiply recurrent infection.” They call for additional investigation to identify types of patients most likely to benefit from FMT using donor stool.

Dr Hohmann regards the differing response rates to autologous FMT at the two study sites as instructive, underscoring the value of conducting a rigorous controlled trial even when the tested technology has proven itself in other types of investigations. “Their results prompt us to ask again whether microbial manipulation has any as-yet unappreciated health benefits or risks and whether there are preferred microbiomes for specific human populations or locales,” she concludes.

To read this article in its entirety:

http://www.medscape.com/viewarticle/867727?nlid=108986_2981&src=wnl_dne_160823_mscpedit&uac=206986BK&impID=1183588&faf=1

 

Merck’s Phase 3 Studies of Bezlotoxumab, its Investigational Antitoxin to Prevent C. difficile Recurrence Met Primary Endpoint

NewspaperIIIN THE NEWS

Merck  known as MSD outside the United States and Canada, announced that the two pivotal Phase 3 clinical studies for bezlotoxumab, its investigational antitoxin for prevention of Clostridium difficile (C. difficile) infection recurrence, met their primary efficacy endpoint: the reduction in C. difficile recurrence through week 12 compared to placebo, when used in conjunction with standard of care antibiotics for
the treatment of C. difficile.

Based on these results, the company plans to submit new drug applications seeking regulatory approval of bezlotoxumab in the U.S., EU and Canada in 2015. Currently, there are no therapies approved for the prevention of recurrent disease caused by C. difficile.

“These results were also demonstrated in patient subgroups known to be at
high risk for C. difficile recurrence.”

Results from the studies were presented for the first time at the Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC) and International Congress of Chemotherapy and Infection (ICC) joint meeting in San Diego, Sept. 17-21.

“Results of these studies showed that a single, one-time infusion of the antitoxin bezlotoxumab given with standard of care C. difficile antibiotic treatment significantly reduced the recurrence of C. difficile infection compared to standard of care alone, and demonstrated this benefit over a 12-week period,” said Dr. Mark Wilcox, Leeds Teaching Hospitals and University of Leeds, U.K., and a lead investigator for the studies. “These results were also demonstrated in patient subgroups known to be at high risk for C. difficile recurrence.”

Bezlotoxumab is not an antibiotic. It is a selective, fully-human, monoclonal antibody designed to
neutralize C. difficile toxin B, a toxin that can damage the gut wall and cause inflammation, leading to the symptoms of C. difficile enteritis, which include abdominal pain and watery diarrhea.

Bezlotoxumab was developed by researchers at the University of Massachusetts Medical School’s MassBiologics Laboratory in conjunction with Medarex (now part of Bristol-Myers Squibb), and licensed to Merck in 2009 for development as a potential
therapeutic for C. difficile infection.

“Recurrence is a major challenge with C. difficile infection, and novel approaches are
needed to help prevent the cycle of C. difficile recurrence,” said Dr. Dale Gerding, professor of medicine, Loyola University Chicago Stritch School of Medicine, Maywood, Ill., and a lead investigator for the studies.

About the pivotal Phase 3 studies

Two global, Phase 3, double-blind studies were conducted to evaluate bezlotoxumab, either alone or in combination with actoxumab (a fully human monoclonal antibody against C. difficile toxin A), compared to placebo for the prevention of recurrent C. difficile infection in patients on standard of care antibiotics for a primary or recurrent C. difficile infection. The MODIFY I study (MONOCOLONAL ANTIBODIES FOR C. DIFFICILE THERAPY) enrolled 1452 patients (median age 65 years) in 19 countries and the MODIFY II study enrolled 1203 patients (median age 67 years) in 17 countries. The studies were conducted in both hospital and outpatient settings, and the primary endpoint for each study was evaluated through 12 weeks following study drug administration.

In the MODIFY I study, patients receiving standard of care antibiotics for C. difficile were randomized to receive a single, one-time infusion of either bezlotoxumab (10 mg/kg) (n=403), actoxumab (10 mg/kg) (n=242), the combination of bezlotoxumab and actoxumab (10 mg/kg each) (n=403) or placebo (n=404). The actoxumab arm was stopped for efficacy and safety reasons after an interim analysis. In the MODIFY II study, patients receiving standard of care antibiotics for C. difficile were randomized to receive a single, one-time infusion of either bezlotoxumab (10 mg/kg) (n=407), bezlotoxumab and actoxumab (10 mg/kg each) (n=397) or placebo (n=399).

In both MODIFY I and MODIFY II, the rate of C. difficile infection recurrence through week 12, the primary efficacy endpoint, was significantly lower in the bezlotoxumab arms (17.4%, p=0.0003) and (15.7%; p=0.0003), and the combination bezlotoxumab and actoxumab arms (15.9%, p<0.0001) and (14.9%, p<0.0001), compared to the placebo arms (27.6%) and (25.7%), respectively. In MODIFY I and MODIFY II, 1396 and 1163 patients were evaluated in the full analysis sets, respectively.

In both studies, the rate of C. difficile infection recurrence was lower in the bezlotoxumab arms compared to the placebo arms in patient subgroups known to be at high
risk for C. difficile recurrence, including patients with any prior
episode(s) of C. difficile infection within the previous six months, patients infected with the BI/NAP1/027 strain, patients with severe C. difficile infection (Zar score ≥ 2), patients 65 years of age or older, and patients with compromised immunity. These subpopulation analyses were pre-specified in the protocol for each study.

In the studies, the adverse reaction rates were comparable across the bezlotoxumab and placebo arms. In MODIFY I, the most common adverse reactions through four weeks after infusion (nausea, diarrhea and pyrexia) occurred at similar rates in the bezlotoxumab group (7.4%, 6.7% and 5.6%) and the placebo group (6.5%, 5.0% and 2.8%). In MODIFY II, the most common adverse reactions through four weeks after infusion (nausea, diarrhea and urinary tract infection) occurred at similar rates in the bezlotoxumab group (5.8%, 5.3% and 4.5%) and the placebo group (3.4%, 6.6% and 4.2%). Additionally, rates of serious adverse reactions and deaths assessed through 12 weeks after infusion were comparable across these treatment arms.

Treatment with the combination of bezlotoxumab and actoxumab did not provide added efficacy over bezlotoxumab alone. Furthermore, actoxumab alone provided no benefit in the prevention of C. difficile recurrence compared with placebo. Based on these results, bezlotoxumab alone was selected for the marketing authorization application.

About Merck

Today’s Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside of the United States and Canada. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

 

To read the article in its entirety click on the following link:

http://www.businesswire.com/news/home/20150920005053/en/Pivotal-Phase-3-Studies-Bezlotoxumab-Merck%E2%80%99s-Investigational#.VgFWTpftVQs

 

*Please note – The C Diff Foundation does not endorse this product or any product and this posting is strictly for informational purposes only.