The StoP CDI study will test this idea in a randomized, double-blinded, placebo-controlled trial.
If successful in demonstrating that vancomycin can prevent the disease, the research could save thousands of lives, stop tens of thousands of infections, and save millions of health care dollars.
The Agency for Healthcare Research and Quality recently awarded Dr. Sims with a $2.4 million grant to study a theory that could prevent thousands of C. difficile infections and deaths all over the world. This is one of the largest grants Beaumont Health has ever received.
Ms Post was diagnosed with a Clostridium difficile infection and was treated for it with vancomycin and got better. However, a few days after she stopped the vancomycin, the diarrhea would come back as the infection relapsed. After talking with several doctors she was directed to Matthew Sims, M.D., PhD, director of infectious disease research at Beaumont Hospital, Royal Oak, who enrolled her in a research study and broke the cycle of relapses.
Dr. Sims believes oral vancomycin can keep the C. diff in check when the good bacteria is killed by other antibiotics and should prevent the patient from becoming sick. Participants in the study will be given vancomycin or a placebo along with the antibiotics treating the original infection.
Beaumont Hospital, Royal Oak
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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) infectionrecurrence, 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.
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.
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The study will provide new insights on mechanics of fecal microbiota transplantation with patients being treated for a C. diff. infection.
uBiome and OpenBiome Partner for Microbiome Study in FMT Patients
Study will provide new insights on mechanics of fecal microbiota transplantation in patients treated for a C. difficile infection.
uBiome and OpenBiome announced a new partnership to study the microbiome of patients undergoing fecal microbiota transplantation (FMT) as a treatment for Clostridium difficile infections (C. diff).
Any patient undergoing clinical FMT treatment can request their complimentary mail-order microbiome testing kit at http://ubiome.com/pages/fmt. The kit allows them to swab a sample of their microbiome, which they send back to uBiome for analysis and sequencing. uBiome will use the collected data to conduct a study of FMT’s impact on the body’s microbiota. All study participants will also receive a detailed report on their personal microbiome.
“Because we will be looking at patients before, during, and after FMT we will be able to learn about how the microbiota adjusts to the treatment,” adds OpenBiome Co-Founder and President Dr. Mark Smith. “This has the potential to not only shed light on C. diff, but also open the door to using FMT with patients suffering other conditions.”
C. diff infections can occur when there is a severe imbalance of gut microbiota. Because of this imbalance, the bacterium thrives and causes extreme gastrointestinal distress.
This study will serve to increase awareness and understanding of how FMT affects the human microbiome, which could increase its acceptance in the medical community as a way to treat a potential variety of gastrointestinal conditions.
uBiome (ubiome.com) sequences the microbiome for citizen scientists, researchers, and clinicians, using microbial genomics to help patients benefit from new discoveries in scientific research. uBiome conducts research studies on the microbiome and develops clinical diagnostics based on microbiome research.
OpenBiome (openbiome.org) is a nonprofit stool bank dedicated to expanding safe access to fecal microbiota transplantation (FMT) therapies. Founded by a team of microbiologists, public health advocates, and concerned citizens, OpenBiome aims to significantly reduce the practical barriers for clinicians providing FMTs, while connecting scientists across studies and disciplines.
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