Case study: Modify
Clostridium difficile, also known as C. difficile, or ‘C diff’, is a bacterium which can live harmlessly in the gut of many people. However these bacteria can make toxins (poisons) which cause very severe diarrhoea with complications that can lead to death. The aim of the Modify study was to test whether new monoclonal antibody drugs (drugs which were designed to neutralise the C. difficile toxins), would reduce the recurrence of the infection when used alongside standard antibiotic treatment.Find out more
Bezlotoxumab for the Prevention of Recurrent Clostridium difficile Infection
• July 2012 - August 2014
• The NIHR met its recruitment target of 37 patients
• Eight sites across the UK conducted the study
• The study was funded by Merck Sharp and Dohme Limited
• UK Chief Investigator: Dr Jane Minton, Leeds Teaching Hospitals NHS Trust
• A novel approach using monoclonal antibody drugs in the treatment of C. difficile
Clostridium difficile, also known as C. difficile, or ‘C diff’, is a bacterium which can live harmlessly in the gut of many people. About three per cent of healthy adults and as many as seventy per cent of healthy babies have C. difficile bacteria living in their gut. However these bacteria can make toxins (poisons) which cause very severe diarrhoea with complications that can lead to death. C. difficile particularly affects frail, elderly people and those who have been treated with broad-spectrum antibiotics (antibiotics that work against several types of bacteria) or several different antibiotics at the same time.
C. difficile infection has caused outbreaks in hospitals and care home settings and it can reoccur in up to 35 per cent of patients who have already had the infection. Such relapses can occur multiple times and are very debilitating and distressing. C. difficile is diagnosed by laboratory tests on diarrhoea samples to look for the toxins which are made by the bacterium.
There are antibiotics available which are effective against C. difficile infection, but quite often they do not fully clear the infection from the body and only provide a temporary improvement before the diarrhoea symptoms recur. The aim of the Modify study was to test whether new monoclonal antibody drugs (drugs which were designed to neutralise the C. difficile toxins), developed by the pharmaceutical company Merck Sharp & Dohme Limited, would reduce the recurrence of the infection when used alongside standard antibiotic treatment.
Outcomes and findings
A randomised, controlled trial was conducted in 19 countries and recruited a total of 1,452 patients to the Modify study. The NIHR supported the study from eight sites across the UK and met its recruitment target of 37 patients in the allocated time. Patients were randomised to four arms of the study, group one would receive both the new Actoxumab and Bezlotoxumab monoclonal antibodies with the standard antibiotic treatment, group two would receive Bezlotoxumab with the standard antibiotic treatment, group three would receive Actoxumab and the standard antibiotic treatment and group four would receive the placebo (dummy drug) and the standard antibiotic treatment.
Patients received the drugs through a drip at the beginning of their 12 week assessment period. They were monitored for safety and to see if there was a recurrence of the C. difficile infection during that time. The results of the study showed that Bezlotoxumab alone was significantly more effective in preventing a recurrence in C. difficile in patients compared to the placebo. A combination of Bezlotoximab and Actoxumab was not any more effective than Bezlotoximab alone.
“The results of the study are a really exciting development in the treatment of C. difficile. Using monoclonal antibody drugs to treat difficult infections is a novel approach and signifies a step-change in the treatment options available to patients.”
Dr Jane Minton, UK Chief Investigator, Leeds Teaching Hospitals NHS Trust
Value to the NHS
The drug Bezlotoxumab reduces recurrent infection by nearly 40 per cent compared with standard treatment of antibiotics alone and could have far-reaching impacts for patients who suffer with recurrent C. difficile infections. Fewer recurrent infections would mean much less distress to the patients affected, fewer hospital admissions and reduced costs for NHS. Bezlotoxumab has recently been licensed for use in the UK, but it is an expensive treatment option and so is reserved for patients at particular risk for whom other types of therapy are not effective.
• Publication details: New England Journal of Medicine N Engl J Med 2017; 376:305-317