Results indicate vaccine generates an immune response against key toxins in volunteers and establish dosing for Phase III
May 19, 2014
Sanofi Pasteur, the vaccines division of Sanofi , presented Phase II trial (H-030-012) results for an investigational vaccine for the prevention of Clostridium difficile (C. diff) infection (CDI) at the 114th General Meeting of the American Society for Microbiology (ASM). The Phase II trial met its primary objectives, reactions were generally mild and of short duration, and the candidate vaccine generated an immune response against C. diff toxins A and B. These toxins are largely responsible for CDI, which can cause potentially life-threatening gut inflammation and diarrhea.
Based on the Phase II results, a high-dose plus adjuvant vaccine formulation administered on days 0, 7 and 30 was selected for further evaluation in the global efficacy program, Cdiffense . This ongoing Phase III trial began in August 2013 with plans to include up to 200 sites in 17 countries.
“C. diff infection threatens the many people who frequently use antibiotics, as well as older hospitalized patients and residents in long-term healthcare facilities,” said Jamshid Saleh, M.D., who participated in Phase II and is currently the principal investigator for the Phase III trial at Northern California Clinical Research Center in Redding, California. “It would be great if we could offer patients a way to help prevent this contagious and debilitating disease versus just treating it after it happens.”
The Phase II vaccine study was a randomized, multi-center trial split into two stages. The first, conducted with 455 volunteers, was placebo-controlled, double-blind and designed for dose and formulation selection. The second, which included 206 additional volunteers, was designed to compare the dose and formulation chosen in the first stage against two alternate dosing schedules. Volunteers in the study were adults aged 40-75 years who were at risk of CDI due to impending hospitalization or residence in a long-term healthcare facility.
“In this trial, we saw a significant increase in antibody production against C. diff toxins, across all dosing schedules and volunteer ages,” said Guy De Bruyn, MBBCh MPH, Director, Clinical Development, Sanofi Pasteur, who presented the data at ASM. “These results provide a strong foundation for our efforts to develop and offer a vaccine to prevent first occurrence CDI.”
In Stage 1 of this trial, volunteers were randomized into one of five study groups: high-dose or low-dose vaccine either with or without adjuvant, or placebo. Each formulation was administered on days 0, 7 and 30. Immune responses were measured using both Enzyme Linked Immunosorbent Assay (ELISA), which assesses anti-toxin A and B immunoglobulin G (IgG) concentrations, and Toxin Neutralization Activity (TNA), which measures anti-toxin A and B neutralizing activity. Composite ELISA ranking analysis determined that the high-dose plus adjuvant vaccine formulation (Group 3) generated the greatest immune response over a 60-day period. ELISA results also showed four-fold increases in the development of detectable antibodies for both toxins A and B.
The high-dose plus adjuvant vaccine formulation was then selected for further study in Stage 2 of the trial, which compared its use across three schedules: days 0, 7 and 30 (Group 3, N=101); days 0, 7 and 180 (Group 6, N=103); and days 0, 30 and 180 (Group 7, N=102). Analysis was conducted on days 0, 7, 14, 30, 60, 180 and 210.
Increased immune responses were observed in all vaccine groups and with each dose, according to ELISA and TNA. Overall, Group 3 demonstrated the most favorable immune profile over the 30-, 60- and 180-day periods, particularly in volunteers aged 65-75 years.
The safety profile of all vaccine doses was deemed acceptable throughout the Phase II study. Reactions were monitored until day 210 and were generally Grade 1 (classified as mild), of short duration, did not lead to study discontinuations, and were not considered clinically significant.
“Sanofi Pasteur’s investigational vaccine stimulates a person’s immune system to fight C. diff toxins upon exposure and, ultimately, may help prevent a future C. diff infection from occurring,” said Dr. Saleh. “Like other toxoid vaccines—such as tetanus, diphtheria and whooping cough—this investigational vaccine targets the symptom-causing toxins generated by C. diff bacteria and could be an important public health measure to help protect individuals from infection.”
About Clostridium difficile Clostridium difficile (C. diff) is a potentially life-threatening, spore-forming bacterium that causes intestinal disease. Despite improvements in reducing some healthcare-associated infections (HAIs), C. diff remains at historically high levels.1 The risk of contracting a C. diff infection (CDI) increases with age, antibiotic treatment and time spent in hospitals or nursing homes, where multiple cases can lead to outbreaks.2 A main source of C. diff bacteria are infected patients who release spores into the environment that subsequently can infect other patients. When antibiotics disrupt the gut’s normal flora and a person has ingested C. diff spores, the C. diff bacteria multiply and release potent toxins that can damage a patient’s intestinal lining and cause CDI.3 Symptoms range from fever to diarrhea and often include dehydration, nausea and abdominal pain. Complications include perforation of the colon, sepsis, life-threatening pseudomembranous colitis and toxic megacolon, a lethal condition.2
Analysis of available data indicates that CDI may have resulted in up to $4.8 billion in excess costs in acute-care facilities in the United States (U.S.) during 2008.4 In 2009, U.S. hospital stays in which CDI was a principal diagnosis averaged 6.9 days and $10,100.When CDI was a complicating factor to already complex principal diagnoses (e.g., septicemia, pneumonia, congestive heart failure, renal failure), hospital stays more than doubled and costs more than tripled (16 days and $31,500, respectively).5
About Sanofi Sanofi, an integrated global healthcare leader, discovers, develops and distributes therapeutic solutions focused on patients’ needs. Sanofi has core strengths in the field of healthcare with seven growth platforms: diabetes solutions, human vaccines, innovative drugs, consumer healthcare, emerging markets, animal health and the new Genzyme. Sanofi is listed in Paris FR:SAN +0.21% and in New York SNY +0.08% .
Sanofi Pasteur, the vaccines division of Sanofi, provides more than 1 billion doses of vaccine each year, making it possible to immunize more than 500 million people across the globe. A world leader in the vaccine industry, Sanofi Pasteur offers a broad range of vaccines protecting against 20 infectious diseases. The company’s heritage, to create vaccines that protect life, dates back more than a century. Sanofi Pasteur is the largest company entirely dedicated to vaccines. Every day, the company invests more than EUR 1 million in research and development. For more information, please visit:www.sanofipasteur.com or www.sanofipasteur.us .