A Study of MK-6072 and MK-3415A in Participants Receiving Antibiotic Therapy for Clostridium Difficile Infection (MK-3415A-002)

Summary

MK-3415A is the combination of monoclonal antibodies to Clostridium (C.) difficile toxin A (MK-3415) and toxin B (MK-6072). This study will investigate whether: 1) treatment with MK-6072 or MK-3415A in addition to standard of care (SOC) antibiotic therapy will decrease Clostridium Difficile Infection (CDI) recurrence compared with placebo; and 2) MK-6072 and MK-3415A will be generally well tolerated in participants receiving SOC therapy for CDI compared with placebo.

Timeline

Start

2012-02-01

Primary completion

2015-05-22

Completion

2015-05-22

Outcome

Met primary endpoint

registry NUMBER MK-3415A + SOC: 14.9 Percentage of participants NUMBER MK-6072 + SOC: 15.7 Percentage of participants NUMBER Placebo + SOC: 25.7 Percentage of participants NCT01513239 ↗

registry analysis (superiority or other test); MK-3415A + SOC vs Placebo + SOC; p <0.0001; Adjusted Difference -10.7 (95% CI -16.4 to -5.1) NCT01513239 ↗

registry analysis (superiority or other test); MK-6072 + SOC vs Placebo + SOC; p = 0.0003; Adjusted Difference -9.9 (95% CI -15.5 to -4.3) NCT01513239 ↗

Publications

• de Almeida C, Wong M, Kleijn HJ, Wrishko RE. Predicted Bezlotoxumab Exposure in Patients Who Have Received a Hematopoietic Stem Cell Transplant. Clin Ther. 2023 Apr;45(4):356-362. doi: 10.1016/j.clinthera.2023.02.006. Epub 2023 Mar 9.
• Zhang H, Mehrotra DV, Shen J. AWOT and CWOT for genotype and genotype-by-treatment interaction joint analysis in pharmacogenetics GWAS. Bioinformatics. 2023 Jan 1;39(1):btac834. doi: 10.1093/bioinformatics/btac834.
• Bouza E, Cornely OA, Ramos-Martinez A, Plesniak R, Ellison MC, Hanson ME, Dorr MB. Analysis of C. difficile infection-related outcomes in European participants in the bezlotoxumab MODIFY I and II trials. Eur J Clin Microbiol Infect Dis. 2020 Oct;39(10):1933-1939. doi: 10.1007/s10096-020-03935-3. Epub 2020 Jun 6.
• Shen J, Mehrotra DV, Dorr MB, Zeng Z, Li J, Xu X, Nickle D, Holzinger ER, Chhibber A, Wilcox MH, Blanchard RL, Shaw PM. Genetic Association Reveals Protection against Recurrence of Clostridium difficile Infection with Bezlotoxumab Treatment. mSphere. 2020 May 6;5(3):e00232-20. doi: 10.1128/mSphere.00232-20.
• Zhang H, Zhao N, Mehrotra DV, Shen J. Composite Kernel Association Test (CKAT) for SNP-set joint assessment of genotype and genotype-by-treatment interaction in Pharmacogenetics studies. Bioinformatics. 2020 May 1;36(10):3162-3168. doi: 10.1093/bioinformatics/btaa125.
• Cornely OA, Mullane KM, Birch T, Hazan-Steinberg S, Nathan R, Bouza E, Calfee DP, Ellison MC, Wong MT, Dorr MB. Exploratory Evaluation of Bezlotoxumab on Outcomes Associated With Clostridioides difficile Infection in MODIFY I/II Participants With Cancer. Open Forum Infect Dis. 2020 Jan 31;7(2):ofaa038. doi: 10.1093/ofid/ofaa038. eCollection 2020 Feb.
• Goldstein EJC, Citron DM, Gerding DN, Wilcox MH, Gabryelski L, Pedley A, Zeng Z, Dorr MB. Bezlotoxumab for the Prevention of Recurrent Clostridioides difficile Infection: 12-Month Observational Data From the Randomized Phase III Trial, MODIFY II. Clin Infect Dis. 2020 Aug 14;71(4):1102-1105. doi: 10.1093/cid/ciz1151.
• Zeng Z, Zhao H, Dorr MB, Shen J, Wilcox MH, Poxton IR, Guris D, Li J, Shaw PM. Bezlotoxumab for prevention of Clostridium difficile infection recurrence: Distinguishing relapse from reinfection with whole genome sequencing. Anaerobe. 2020 Feb;61:102137. doi: 10.1016/j.anaerobe.2019.102137. Epub 2019 Dec 14.
• Kelly CP, Poxton IR, Shen J, Wilcox MH, Gerding DN, Zhao X, Laterza OF, Railkar R, Guris D, Dorr MB. Effect of Endogenous Clostridioides difficile Toxin Antibodies on Recurrence of C. difficile Infection. Clin Infect Dis. 2020 Jun 24;71(1):81-86. doi: 10.1093/cid/ciz809.
• Montgomery DL, Matthews RP, Yee KL, Tobias LM, Dorr MB, Wrishko RE. Assessment of Bezlotoxumab Immunogenicity. Clin Pharmacol Drug Dev. 2020 Apr;9(3):330-340. doi: 10.1002/cpdd.729. Epub 2019 Aug 14.
• Basu A, Prabhu VS, Dorr MB, Golan Y, Dubberke ER, Cornely OA, Heimann SM, Pedley A, Xu R, Hanson ME, Marcella S. Bezlotoxumab Is Associated With a Reduction in Cumulative Inpatient-Days: Analysis of the Hospitalization Data From the MODIFY I and II Clinical Trials. Open Forum Infect Dis. 2018 Nov 15;5(11):ofy218. doi: 10.1093/ofid/ofy218. eCollection 2018 Nov.
• Yee KL, Kleijn HJ, Kerbusch T, Matthews RP, Dorr MB, Garey KW, Wrishko RE. Population Pharmacokinetics and Pharmacodynamics of Bezlotoxumab in Adults with Primary and Recurrent Clostridium difficile Infection. Antimicrob Agents Chemother. 2019 Jan 29;63(2):e01971-18. doi: 10.1128/AAC.01971-18. Print 2019 Feb.
• Kelly CP, Wilcox MH, Glerup H, Aboo N, Ellison MC, Eves K, Dorr MB. Bezlotoxumab for Clostridium difficile Infection Complicating Inflammatory Bowel Disease. Gastroenterology. 2018 Oct;155(4):1270-1271. doi: 10.1053/j.gastro.2018.06.080. Epub 2018 Sep 15. No abstract available.
• Prabhu VS, Cornely OA, Golan Y, Dubberke ER, Heimann SM, Hanson ME, Liao J, Pedley A, Dorr MB, Marcella S. Thirty-Day Readmissions in Hospitalized Patients Who Received Bezlotoxumab With Antibacterial Drug Treatment for Clostridium difficile Infection. Clin Infect Dis. 2017 Oct 1;65(7):1218-1221. doi: 10.1093/cid/cix523.
• Birch T, Golan Y, Rizzardini G, Jensen E, Gabryelski L, Guris D, Dorr MB. Efficacy of bezlotoxumab based on timing of administration relative to start of antibacterial therapy for Clostridium difficile infection. J Antimicrob Chemother. 2018 Sep 1;73(9):2524-2528. doi: 10.1093/jac/dky182.
• Gerding DN, Kelly CP, Rahav G, Lee C, Dubberke ER, Kumar PN, Yacyshyn B, Kao D, Eves K, Ellison MC, Hanson ME, Guris D, Dorr MB. Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection in Patients at Increased Risk for Recurrence. Clin Infect Dis. 2018 Aug 16;67(5):649-656. doi: 10.1093/cid/ciy171.
• Wilcox MH, Gerding DN, Poxton IR, Kelly C, Nathan R, Birch T, Cornely OA, Rahav G, Bouza E, Lee C, Jenkin G, Jensen W, Kim YS, Yoshida J, Gabryelski L, Pedley A, Eves K, Tipping R, Guris D, Kartsonis N, Dorr MB; MODIFY I and MODIFY II Investigators. Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection. N Engl J Med. 2017 Jan 26;376(4):305-317. doi: 10.1056/NEJMoa1602615.

Drugs

Evaluation	Drug	Modality	Dose	Route
Subject	Bezlotoxumab	Monoclonal antibody	10 mg/kg	Intravenous
Subject	MK-3415	Monoclonal antibody	10 mg/kg	Intravenous
Background	Fidaxomicin	Other / unclassified	—	Oral
Background	Metronidazole	Small molecule	—	Oral
Background	Vancomycin	Other / unclassified	—	Oral

Indications