Horizon Scanning Research April 2016 & Intelligence Centre Cadazolid for treatment of Clostridium difficile-associated diarrhoea LAY SUMMARY Clostridium difficile is a bacterium that infects the gut and causes diarrhoea. It usually affects people who have recently taken antibiotics and it can cause serious bowel problems if left untreated. The bacterium is easily spread by direct contact with infected people or This briefing is based on surfaces. information available at the time Cadazolid is a new antibiotic that is taken by mouth as a liquid. Some of research and a studies have suggested that this drug can help to treat Clostridium limited literature difficile-associated diarrhoea, and more studies are trying to show how search. It is not well cadazolid works. If cadazolid is licensed for use in the UK, it could intended to be a offer a new treatment option for this patient group. definitive statement on the safety, efficacy or NIHR HSRIC ID: 10123 effectiveness of the health technology covered and should not be used for commercial purposes or commissioning without additional information. This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health. NIHR Horizon Scanning Research & Intelligence Centre, University of Birmingham. Email: [email protected] Web: www.hsric.nihr.ac.uk Horizon Scanning Research & Intelligence Centre TARGET GROUP • Clostridium difficile-associated diarrhoea – treatment of first occurrence and re- occurrence. TECHNOLOGY DESCRIPTION Cadazolid (ACT-179811) is a fluoroquinolone-oxazolidinone, non-absorbable antibiotic that inhibits Clostridium difficile protein synthesis, and leads to suppression of toxin and spore formation1. In a phase III clinical trial, patients with C. difficile-associated diarrhoea (CDAD) are administered cadazolid 250mg oral twice daily for 10 days2. Cadazolid does not currently have a Marketing Authorisation in the EU for any indication. INNOVATION and/or ADVANTAGES If licensed, cadazolid will offer an additional treatment option for this patient group following first occurrence or recurrence. DEVELOPER Actelion. AVAILABILITY, LAUNCH OR MARKETING In phase III clinical trials. PATIENT GROUP BACKGROUND C. difficile is a commensal bacterium that lives harmlessly in the gut of approximately 5% of healthy people. However, wide-spread antibiotic use and immunosuppressive agents change the gut flora, resulting in C. difficile overgrowth3. C. difficile is the most commonly identified infectious cause of antibiotic-associated diarrhoea1. C. difficile produces toxins A and B, which are the main virulence factors. Infection and exotoxin production leads to purulent watery diarrhoea, abdominal cramps, nausea and dehydration3. In severe cases, it can also cause bloody diarrhoea and fever, and may be complicated by pseudomembranous colitis, sepsis, toxic megacolon, colonic rupture and death3. The frequency and severity of C. difficile infections has risen over many years, with increased morbidity and mortality particularly among the elderly1. CLINICAL NEED and BURDEN OF DISEASE Between April 2014 and March 2015, 14,165 cases of CDAD were reported in England, representing an infection rate of 24.8 per 100,000 population, an increase of 6% compared to 2013-144. 2 Horizon Scanning Research & Intelligence Centre Recurrence occurs in about 20% of patients treated initially with metronidazole or vancomycin5. Between 20-50% are thought to be reinfections rather than relapse due to the same strain. Relapses tend to occur in the first two weeks after treatment cessation5. After a first reoccurrence, the risk of reinfections increases to 45-60%5. In 2014-15, there were 4,335 admissions for enterocolitis due to C. difficile (ICD-10 A04.7) in England, resulting in 100,166 bed days and 10,609 finished consultant episodes6. In 2014, there were 522 deaths registered in England and Wales from enterocolitis due to C. difficile7. PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance • NICE guidelines. Antimicrobial stewardship: systems and processed for effective antimicrobial medicine use (NG15). August 2015. • NICE clinical guideline. Infection: prevention and control of healthcare-associated infections in primary and community care (CG139). March 2012. • NICE clinical guideline. Surgical site infection: prevention and treatment of surgical site infection (CG74). October 2008. • NICE quality standard. Healthcare-associated infections (QS113). February 2016. • NICE quality standard. Infection prevention and control (QS61). April 2014 • NICE interventional procedure guidance. Faecal microbiota transplant for recurrent clostridium difficile infection (IPG485). March 2014. • NICE public health guidance. Healthcare-associated infections: prevention and control (PH36). November 2011. Other Guidance • Public Health England. Annual Epidemiological Commentary: Mandatory MRSA, MSSA and E. coli bacteraemia and C. difficile infection data, 2014/15. July 20154. • Public Health England. Updated guidance on the management and treatment of Clostridium difficile infection. May 20135. • American College of Gastroenterology. Guidelines for Diagnosis, Treatment, and Prevention of Clostridium difficile Infections. February 20138. CURRENT TREATMENT OPTIONS The specific treatment of patients with CDAD depends on the severity of disease: mild disease may not require specific antibiotic treatment, although oral metronidazole is recommended for mild to moderate disease4,5,8. Guidelines indicate that severe disease warrants the use of oral vancomycin, and fidaxomicin should also be considered in patients susceptible to recurrence. Surgery (colectomy) may be necessary in severe, worsening cases and to manage serious complications4,5,8. Treatment of recurrent CDAD may require vancomycin tapering/pulse therapy, IV immunoglobulin, or donor stool transplant4,5,8. 3 Horizon Scanning Research & Intelligence Centre EFFICACY and SAFETY Trial NCT01987895, AC- NCT01983683, AC- NCT01222702, AC- 061A301; cadazolid vs 061A302; cadazolid vs 061A201; cadazolid vs vancomycin; phase III. vancomycin; phase III. vancomycin; phase II. Sponsor Actelion. Actelion. Actelion. Status Ongoing. Ongoing. Published. Source of Trial registry2, Trial registry9, Published1, trial registry10. information manufacturer. manufacturer. Location EU (not UK), USA, EU (incl UK), USA, EU (incl UK), USA and Canada, Australia, Brazil Canada and other Canada. and Peru. countries. Design Randomised, active- Randomised, active- Randomised, active- controlled. controlled. controlled. Participants n=640 (planned); aged ≥18 n=640 (planned); aged ≥18 n=81; aged ≥18 years; years; mild, moderate or years; mild, moderate or CDAD (first occurrence or severe CDAD (first severe CDAD (first first recurrence); no occurrence or first occurrence or first concomitant antimicrobial recurrence within 3 recurrence within 3 months treatment for CDAD. months) defined as a defined as: a change in change in bowel habits bowel habits with >3 liquid with >3 liquid or unformed or UBM within 24 hours bowel movements (UBM) prior to randomisation, and within 24 hours prior to a positive C. difficile toxin randomisation, and a test on a stool sample positive C. difficile toxin produced within 72 hours test on a stool sample prior to randomisation; no produced within 72 hours more than 1 previous prior to randomisation; no episode of CDAD in the more than 1 previous previous 3-mths before episode of CDAD in the study; no evidence of life- previous 3-mths; no threatening or fulminant evidence of life-threatening CDAD; no likelihood of or fulminant CDAD; no death within 72 hrs from likelihood of death within any cause; no 72 hrs from any cause; no antimicrobial treatment antimicrobial treatment active against CDAD active against CDAD administered for ˃24 hrs administered for ˃24 hrs except metronidazole for except metronidazole for treatment failure; no treatment failure; no history of inflammatory history of inflammatory colitides, chronic colitides, chronic abdominal pain or chronic abdominal pain or chronic diarrhoea. diarrhoea. Schedule Randomised to Randomised to Randomised to cadazolid cadazolid 250mg oral cadazolid 250mg oral 250mg oral, twice daily; suspension twice daily or suspension twice daily or cadazolid 500mg oral, vancomycin 125mg oral vancomycin 125mg oral twice daily; cadazolid capsules four times daily. capsules four times daily. 1,000mg oral, twice daily or vancomycin 125mg oral, four times daily. Follow-up Active treatment for 10 Active treatment for 10 Active treatment for 10 days, follow-up for up to 32 days, follow-up for up to 32 days, follow-up for up to 4 days. days. weeks. Primary Clinical cure, defined as Clinical cure. Clinical cure. outcome/s resolution of diarrhoea on study treatment that is 4 Horizon Scanning Research & Intelligence Centre maintained for 2 days after end of treatment with no addition treatment against CDAD, including faecal microbiota treatment between first dose of cadazolid and 2 days after end of treatment. Secondary Sustained cure; time to Sustained cure; time to Disease recurrence rate. outcome/s resolution of diarrhoea; resolution of diarrhoea; absolute change from absolute change from baseline in CDAD baseline in CDAD DaySyms patient reported DaySyms PRO daily score. outcomes (PRO) daily score. Key results - - For cadazolid 250mg, 500mg, 1,000mg and vancomycin groups, respectively: primary