Oral Vancomycin vs Placebo in the Prevention of Recurrence of Clostridioides Difficile's Infection

Clostridioides Difficile Infection Clinical Trial

— PREVAN  

Official title:

Phase III,Randomized,Double-blinded Clinical Trial to Evaluate the Effectiveness and Safety of Oral Vancomycin Vs Placebo in the Prevention of Recurrence of C.Difficile Infection in Patients Under Treatment With Systemic Antibiotic Therapy

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05320068
• Other study ID #: PREVAN-ICD
• Status: Recruiting
• Phase: Phase 3
• Start date: August 2, 2022
• Est. completion date: July 2024

Study information

• Verified date: April 2023
• Source: Hospital Universitario 12 de Octubre
• Contact: RAFAEL SAN-JUAN, M.D
• Phone: 0034609488076
• Email: rafael.san[@]salud.madrid.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A phase III randomized clinical trial in proportion 2:1 in favor of oral vancomycin (experimental treatment), multicentric, national, double-blinded, controlled with placebo. The main objective is to evaluate the effectiveness of treatment with oral vancomycin to reduce the incidence of Clostridioides difficile infection (CDI) in patients who suffered previous CDI and who need further hospitalization and treatment with systemic antibiotic therapy in the 90 days after the first CDI.

Description:

As secondary objectives the investigators intend to: - Evaluate the effectiveness of the treatment with oral vancomycin as part of the prophylaxis arsenal to prevent ICD in patients with previous ICD episodes stratified by the number of previous recurrences. - Compare the severity of recurrences in both study groups. - Compare the effectiveness of the treatment with oral vancomycin depending on the type of systemic antibiotic therapy prescribed. - Evaluate the tolerance and the safety of the treatment with oral vancomycin in terms of secondary effects and difficulty in therapeutic compliance. - Evaluate if the treatment with oral vancomycin has an effect in diminishing the severity of ICD recurrences.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 108
• Est. completion date: July 2024
• Est. primary completion date: January 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age equal or superior to 18 years
• Previous history of Clostridioides difficile infection in the 90 days before the study enrolment
• Need for hospitalization and need of antibiotic therapy
• Signature of informed consent

Exclusion Criteria:

• Woman of childbearing age, pregnant woman, or breastfeeding woman
• Hypersensitivity to vancomycin
• Inability to comply with study protocol
• Critically ill condition or life expectancy less than 30 days
• Patients with diagnosed inflammatory bowel disease or with any conditions that produce chronic diarrhea
• Fulfilment of the criteria for diarrhea or diagnosis of CDI at the time of assessment for eligibility or in the previous 3 days
• Therapy with oral vancomycin or any other agent with activity against C. difficile for >48 hours in the previous 3 days;.
• Prophylaxis with oral vancomycin or any other agent with activity against C. difficile within the 70 days before the assessment for eligibility
• Systemic antibiotic therapy for 72 hours or more before the recruitment
• Ongoing enrolment in another RCT evaluating the effectiveness of other drugs
• Estimated use of systemic antibiotic therapy for more than 4 weeks

Related Conditions & MeSH terms

• Clostridioides Difficile Infection
• Clostridium Infections
• Communicable Diseases
• Infections
• Recurrence

Intervention

Drug:
• Oral Vancomycin
A blinded capsule that contains 125mg of vancomycin every 6 hours during 10 days.
• Placebo
A blinded capsule that contains no vancomycin every 6 hours during 10 days.

Locations

Country	Name	City	State
Spain	Rafael San Juan	Madrid

Sponsors (2)

Lead Sponsor	Collaborator
Julia Orígüen	Instituto de Salud Carlos III

Country where clinical trial is conducted

Spain, 

References & Publications (30)

Aldape MJ, Rice SN, Field KP, Bryant AE, Stevens DL. Sub-lethal doses of surotomycin and vancomycin have similar effects on Clostridium difficile virulence factor production in vitro. J Med Microbiol. 2018 Dec;67(12):1689-1697. doi: 10.1099/jmm.0.000852. Epub 2018 Oct 11. — View Citation

Asensio A, Monge D. [Epidemiology of Clostridium difficile infection in Spain]. Enferm Infecc Microbiol Clin. 2012 Jun;30(6):333-7. doi: 10.1016/j.eimc.2011.09.010. Epub 2011 Dec 2. Spanish. — View Citation

Asensio A, Vaque-Rafart J, Calbo-Torrecillas F, Gestal-Otero JJ, Lopez-Fernandez F, Trilla-Garcia A, Canton R; EPINE Working Group. Increasing rates in Clostridium difficile infection (CDI) among hospitalised patients, Spain 1999-2007. Euro Surveill. 2008 Jul 31;13(31):18943. — View Citation

Bauer MP, Kuijper EJ, van Dissel JT; European Society of Clinical Microbiology and Infectious Diseases. European Society of Clinical Microbiology and Infectious Diseases (ESCMID): treatment guidance document for Clostridium difficile infection (CDI). Clin Microbiol Infect. 2009 Dec;15(12):1067-79. doi: 10.1111/j.1469-0691.2009.03099.x. — View Citation

Cadena J, Thompson GR 3rd, Patterson JE, Nakashima B, Owens A, Echevarria K, Mortensen EM. Clinical predictors and risk factors for relapsing Clostridium difficile infection. Am J Med Sci. 2010 Apr;339(4):350-5. doi: 10.1097/MAJ.0b013e3181d3cdaa. — View Citation

Carignan A, Poulin S, Martin P, Labbe AC, Valiquette L, Al-Bachari H, Montpetit LP, Pepin J. Efficacy of Secondary Prophylaxis With Vancomycin for Preventing Recurrent Clostridium difficile Infections. Am J Gastroenterol. 2016 Dec;111(12):1834-1840. doi: 10.1038/ajg.2016.417. Epub 2016 Sep 13. — View Citation

Carpenter BP, Hennessey EK, Bryant AM, Khoury JA, Crannage AJ. Identification of Factors Impacting Recurrent Clostridium difficile Infection and Development of a Risk Evaluation Tool. J Pharm Pharm Sci. 2016 Jul-Sep;19(3):349-356. doi: 10.18433/J32S41. — View Citation

Charlson ME, Sax FL, MacKenzie CR, Braham RL, Fields SD, Douglas RG Jr. Morbidity during hospitalization: can we predict it? J Chronic Dis. 1987;40(7):705-12. doi: 10.1016/0021-9681(87)90107-x. — View Citation

Cheng MP, Parkes LO, Lee TC. Efficacy of Oral Vancomycin in Preventing Recurrent Clostridium difficile Infection in Patients Treated With Systemic Antimicrobial Agents. Clin Infect Dis. 2016 Nov 15;63(10):1391-1392. doi: 10.1093/cid/ciw595. Epub 2016 Aug 27. No abstract available. — View Citation

Cornely OA, Crook DW, Esposito R, Poirier A, Somero MS, Weiss K, Sears P, Gorbach S; OPT-80-004 Clinical Study Group. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis. 2012 Apr;12(4):281-9. doi: 10.1016/S1473-3099(11)70374-7. Epub 2012 Feb 8. — View Citation

Deshpande A, Pasupuleti V, Thota P, Pant C, Rolston DD, Hernandez AV, Donskey CJ, Fraser TG. Risk factors for recurrent Clostridium difficile infection: a systematic review and meta-analysis. Infect Control Hosp Epidemiol. 2015 Apr;36(4):452-60. doi: 10.1017/ice.2014.88. Epub 2015 Jan 28. — View Citation

Eyre DW, Walker AS, Wyllie D, Dingle KE, Griffiths D, Finney J, O'Connor L, Vaughan A, Crook DW, Wilcox MH, Peto TE; Infections in Oxfordshire Research Database. Predictors of first recurrence of Clostridium difficile infection: implications for initial management. Clin Infect Dis. 2012 Aug;55 Suppl 2(Suppl 2):S77-87. doi: 10.1093/cid/cis356. — View Citation

Ghantoji SS, Sail K, Lairson DR, DuPont HL, Garey KW. Economic healthcare costs of Clostridium difficile infection: a systematic review. J Hosp Infect. 2010 Apr;74(4):309-18. doi: 10.1016/j.jhin.2009.10.016. Epub 2010 Feb 12. — View Citation

Hu MY, Katchar K, Kyne L, Maroo S, Tummala S, Dreisbach V, Xu H, Leffler DA, Kelly CP. Prospective derivation and validation of a clinical prediction rule for recurrent Clostridium difficile infection. Gastroenterology. 2009 Apr;136(4):1206-14. doi: 10.1053/j.gastro.2008.12.038. Epub 2008 Dec 13. — View Citation

Johnson S, Louie TJ, Gerding DN, Cornely OA, Chasan-Taber S, Fitts D, Gelone SP, Broom C, Davidson DM; Polymer Alternative for CDI Treatment (PACT) investigators. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis. 2014 Aug 1;59(3):345-54. doi: 10.1093/cid/ciu313. Epub 2014 May 5. — View Citation

Johnson SW, Brown SV, Priest DH. Effectiveness of Oral Vancomycin for Prevention of Healthcare Facility-Onset Clostridioides difficile Infection in Targeted Patients During Systemic Antibiotic Exposure. Clin Infect Dis. 2020 Aug 22;71(5):1133-1139. doi: 10.1093/cid/ciz966. — View Citation

Kelly CP. Can we identify patients at high risk of recurrent Clostridium difficile infection? Clin Microbiol Infect. 2012 Dec;18 Suppl 6:21-7. doi: 10.1111/1469-0691.12046. — View Citation

Larrainzar-Coghen T, Rodriguez-Pardo D, Puig-Asensio M, Rodriguez V, Ferrer C, Bartolome R, Pigrau C, Fernandez-Hidalgo N, Pumarola T, Almirante B. First recurrence of Clostridium difficile infection: clinical relevance, risk factors, and prognosis. Eur J Clin Microbiol Infect Dis. 2016 Mar;35(3):371-8. doi: 10.1007/s10096-015-2549-9. Epub 2016 Jan 11. — View Citation

Leav BA, Blair B, Leney M, Knauber M, Reilly C, Lowy I, Gerding DN, Kelly CP, Katchar K, Baxter R, Ambrosino D, Molrine D. Serum anti-toxin B antibody correlates with protection from recurrent Clostridium difficile infection (CDI). Vaccine. 2010 Jan 22;28(4):965-9. doi: 10.1016/j.vaccine.2009.10.144. Epub 2009 Nov 24. — View Citation

Louie TJ, Miller MA, Mullane KM, Weiss K, Lentnek A, Golan Y, Gorbach S, Sears P, Shue YK; OPT-80-003 Clinical Study Group. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011 Feb 3;364(5):422-31. doi: 10.1056/NEJMoa0910812. — View Citation

Magill SS, Edwards JR, Bamberg W, Beldavs ZG, Dumyati G, Kainer MA, Lynfield R, Maloney M, McAllister-Hollod L, Nadle J, Ray SM, Thompson DL, Wilson LE, Fridkin SK; Emerging Infections Program Healthcare-Associated Infections and Antimicrobial Use Prevalence Survey Team. Multistate point-prevalence survey of health care-associated infections. N Engl J Med. 2014 Mar 27;370(13):1198-208. doi: 10.1056/NEJMoa1306801. Erratum In: N Engl J Med. 2022 Jun 16;386(24):2348. — View Citation

McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin SE, Dubberke ER, Garey KW, Gould CV, Kelly C, Loo V, Shaklee Sammons J, Sandora TJ, Wilcox MH. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018 Mar 19;66(7):e1-e48. doi: 10.1093/cid/cix1085. — View Citation

McDonald LC, Owings M, Jernigan DB. Clostridium difficile infection in patients discharged from US short-stay hospitals, 1996-2003. Emerg Infect Dis. 2006 Mar;12(3):409-15. doi: 10.3201/eid1205.051064. — View Citation

Ooijevaar RE, van Beurden YH, Terveer EM, Goorhuis A, Bauer MP, Keller JJ, Mulder CJJ, Kuijper EJ. Update of treatment algorithms for Clostridium difficile infection. Clin Microbiol Infect. 2018 May;24(5):452-462. doi: 10.1016/j.cmi.2017.12.022. Epub 2018 Jan 6. — View Citation

Pepin J, Alary ME, Valiquette L, Raiche E, Ruel J, Fulop K, Godin D, Bourassa C. Increasing risk of relapse after treatment of Clostridium difficile colitis in Quebec, Canada. Clin Infect Dis. 2005 Jun 1;40(11):1591-7. doi: 10.1086/430315. Epub 2005 Apr 25. — View Citation

Rauseo AM, Olsen MA, Reske KA, Dubberke ER. Strategies to prevent adverse outcomes following Clostridioides difficile infection in the elderly. Expert Rev Anti Infect Ther. 2020 Mar;18(3):203-217. doi: 10.1080/14787210.2020.1717950. Epub 2020 Jan 27. — View Citation

Rodriguez-Pardo D, Almirante B, Bartolome RM, Pomar V, Mirelis B, Navarro F, Soriano A, Sorli L, Martinez-Montauti J, Molins MT, Lung M, Vila J, Pahissa A; Barcelona Clostridium difficile Study Group. Epidemiology of Clostridium difficile infection and risk factors for unfavorable clinical outcomes: results of a hospital-based study in Barcelona, Spain. J Clin Microbiol. 2013 May;51(5):1465-73. doi: 10.1128/JCM.03352-12. Epub 2013 Feb 27. — View Citation

Van Hise NW, Bryant AM, Hennessey EK, Crannage AJ, Khoury JA, Manian FA. Efficacy of Oral Vancomycin in Preventing Recurrent Clostridium difficile Infection in Patients Treated With Systemic Antimicrobial Agents. Clin Infect Dis. 2016 Sep 1;63(5):651-3. doi: 10.1093/cid/ciw401. Epub 2016 Jun 17. — View Citation

Weiss K, Allgren RL, Sellers S. Safety analysis of fidaxomicin in comparison with oral vancomycin for Clostridium difficile infections. Clin Infect Dis. 2012 Aug;55 Suppl 2(Suppl 2):S110-5. doi: 10.1093/cid/cis390. — View Citation

Zilberberg MD, Reske K, Olsen M, Yan Y, Dubberke ER. Risk factors for recurrent Clostridium difficile infection (CDI) hospitalization among hospitalized patients with an initial CDI episode: a retrospective cohort study. BMC Infect Dis. 2014 Jun 4;14:306. doi: 10.1186/1471-2334-14-306. — View Citation

* Note: There are 30 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Effectiveness of treatment with oral vancomycin in the prevention of Clostridioides difficile	Absolute difference in the rate of C. difficile infection recurrences with vancomycin Vs placebo.	60 days after the beginning of the intervention
Secondary	Effectiveness of treatment with oral vancomycin according to the number of previous recurrences	The absolute difference in the rate of C. difficile infection recurrences with vancomycin vs placebo stratified by index CDI episode (first episode or recurrence)	60 days after the beginning of the intervention
Secondary	Effectiveness of treatment with oral vancomycin in diminishing the severity of the recurrence	The absolute difference in the rate of severe C. difficile infection recurrences with vancomycin vs placebo	60 days after the beginning of the intervention
Secondary	Effectiveness of treatment with oral vancomycin depending on antibiotic therapy	The absolute difference in the rate of C. difficile infection recurrences with vancomycin vs placebo stratified by the type of systemic antibiotic therapy prescribed.	60 days after the beginning of the intervention
Secondary	Tolerance and safety of treatment with oral vancomycin	Rate of major adverse events and drug-related adverse events.	60 days after the beginning of the intervention