Safety and Efficacy of Fidaxomicin Versus Placebo for Prophylaxis Against Clostridium Difficile-Associated Diarrhea in Adults Undergoing Hematopoietic Stem Cell Transplantation (MK-5119-001)

• fidaxomicin (Drug), also known as DIFICID, DIFICLIR, OPT-80, PAR-101: Fidaxomicin 200 mg tablet once daily from the start (+/- 2 days) of condition (prior to transplantation) or at the time of Fluoroquinolone initiation. Study drug treatment will continue until 7 days after either neutrophil engraftment or the completion of any Fluoroquinolone antibiotic regimen (whichever occurs later). Study drug treatment will stop at onset of CDAD or no longer than 40 days of duration, even if other antibiotics are still administered or neutrophil engraftment extends beyond 40 days.
• Placebo (Drug): Placebo tablet once daily from the start (+/- 2 days) of condition (prior to transplantation) or at the time of Fluoroquinolone initiation. Treatment will continue until 7 days after either neutrophil engraftment or the completion of any Fluoroquinolone antibiotic regimen (whichever occurs later). Treatment will stop at onset of CDAD or no longer than 40 days of duration, even if other antibiotics are still administered or neutrophil engraftment extends beyond 40 days.

Primary outcomes

• Percentage of Participants With Occurrence of CDAD From Start of Study Treatment up to 30 Days Post-treatment Follow-up. [Up to 30 days post-treatment]: CDAD is defined as follows: Diarrhea: (change in bowel habits with >3 unformed bowel movements in a 24 hour period) and the presence of either toxin A and/or B (or their respective genes, tcdA and/or tcdB) of C. difficile in the stool determined by C. difficile toxin assay. Wald 95% Confidence Intervals (CI) are presented.

Secondary outcomes

• Percentage of Participants With Occurrence of CDAD From Start of Study Treatment up to 60 Days Post-treatment. [Up to 60 days post-treatment]: CDAD is defined as follows: Diarrhea: (change in bowel habits with >3 unformed bowel movements in a 24 hour period) and the presence of either toxin A and/or B (or their respective genes, tcdA and/or tcdB) of C. difficile in the stool determined by C. difficile toxin assay. Wald 95% Confidence Intervals (CI) are presented.
• Percentage of Participants With Occurrence of CDAD From Start of Study Treatment up to Day 70 of Study. [Up to Day 70 of study]: CDAD is defined as follows: Diarrhea: (change in bowel habits with >3 unformed bowel movements in a 24 hour period) and the presence of either toxin A and/or B (or their respective genes, tcdA and/or tcdB) of C. difficile in the stool determined by C. difficile toxin assay. Wald 95% Confidence Intervals (CI) are presented.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Male or female 18 years of age or older.
* Females of childbearing potential must be using an adequate and reliable method of contraception (e.g., abstinence, barrier with additional spermicide foam or jelly, intrauterine device, hormonal contraception). Males and females must agree to avoid conception during treatment and for four weeks following the end of study treatment.
* Is undergoing HSCT with planned Fluoroquinolone prophylaxis.
* Informed consent is provided.

Exclusion Criteria:

* Ongoing active CDAD infection (as evidenced by clinical signs of diarrhea along with the presence of either toxin A and/or B \[or their respective genes, tcdA and/or tcdB\] of C. difficile in the stool) or current treatment for CDAD.
* Undergoing cord blood transplants.
* Has fulminant colitis, toxic megacolon, or ileus.
* A history of inflammatory bowel disease (ulcerative colitis or Crohn's disease).
* Women who are pregnant or are actively breast feeding (all women of childbearing potential must have a negative pregnancy test result prior to dosing study drug).
* Use of any drugs potentially useful in the treatment of CDAD (e.g. oral Vancomycin, Metronidazole, oral Bacitracin, Fusidic Acid, Rifaximin, and Nitazoxanide).
* Any other condition that, in the opinion of the investigator, would jeopardize the safety or rights of the participant in the study, would make it unlikely for the participant to complete the study, or would confound the results of the study.
* Participation in other clinical research studies utilizing an investigational agent within one month prior to screening and during the study treatment period.

Participant flow

Outcome results

• Percentage of Participants With Occurrence of CDAD From Start of Study Treatment up to 30 Days Post-treatment Follow-up. (Primary), Number, Percentage of participants: Fidaxomicin 28.6 (23.5 to 33.7); Placebo 30.8 (25.5 to 36.0) (p 0.2778)
• Percentage of Participants With Occurrence of CDAD From Start of Study Treatment up to 60 Days Post-treatment. (Secondary), Number, Percentage of participants: Fidaxomicin 35.2 (29.8 to 40.6); Placebo 35.8 (30.4 to 41.2) (p 0.4420)
• Percentage of Participants With Occurrence of CDAD From Start of Study Treatment up to Day 70 of Study. (Secondary), Number, Percentage of participants: Fidaxomicin 29.2 (24.1 to 34.4); Placebo 31.1 (25.9 to 36.4) (p 0.3091)

Adverse events

Time frame: Non-serious adverse events (AEs) up to 32 days post treatment. Serious AEs (SAEs) up to 62 days post treatment.

Serious adverse events by term

104 more terms not shown.

Other adverse events by term

7 more terms not shown.

• Results publication: 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. PMID 36906440
• Results publication: Mullane KM, Winston DJ, Nooka A, Morris MI, Stiff P, Dugan MJ, Holland H, Gregg K, Adachi JA, Pergam SA, Alexander BD, Dubberke ER, Broyde N, Gorbach SL, Sears PS. A Randomized, Placebo-controlled Trial of Fidaxomicin for Prophylaxis of Clostridium difficile-associated Diarrhea in Adults Undergoing Hematopoietic Stem Cell Transplantation. Clin Infect Dis. 2019 Jan 7;68(2):196-203. doi: 10.1093/cid/ciy484. PMID 29893798

• Medical Director, Study director, Merck Sharp & Dohme LLC