A Study to Investigate the Safety and Efficacy of Fidaxomicin (Oral Suspension or Tablets) and Vancomycin (Oral Liquid or Capsules) in Pediatric Subjects With Clostridium Difficile-associated Diarrhea (CDAD)

• Fidaxomicin oral suspension (Drug), also known as Dificid, Dificlir: Participants from birth to < 6 years of age received weight based doses of fidaxomicin oral suspension (32 mg/kg/day with a maximum dose of 400 mg/day divided in 2 doses) 2 times daily for 10 days.
• Fidaxomicin tablets (Drug), also known as Dificlir, Dificid: Participants aged ≥ 6 years to < 18 years of age received a 200 mg fidaxomicin tablet 2 times daily for 10 days.
• Vancomycin oral liquid (Drug): Participants from birth to < 6 years of age received weight based doses of vancomycin oral liquid (40 mg/kg/day with a maximum dose of 500 mg/day divided in 4 doses) 4 times daily for 10 days.
• Vancomycin capsules (Drug): Participants aged ≥ 6 years to < 18 years of age received a 125 mg vancomycin capsule 4 times daily for 10 days.

Primary outcomes

• Percentage of Participants With Confirmed Clinical Response (CCR) at End of Treatment (EOT) +2 Days [Up to day 12]: Initial clinical response (ICR) for ages from birth to < 2 years was defined as absence of watery diarrhea for 2 consecutive treatment days, remaining well until study drug discontinuation. ICR for ages ≥ 2 years to < 18 years was defined as improvement in number and character of bowel movements as determined by < 3 unformed bowel movements (UBMs) per day for 2 consecutive treatment days, remaining well until study drug discontinuation. CCR was defined for both age groups as not requiring further CDAD therapy within 2 days after study drug completion, and was reported with a positive (Yes) or negative (No) outcome. Resolution of diarrhea was assessed during interviews of participant/parent/legal guardian, supplemented by review of personal records (if hospitalized) and checked for presence of watery diarrhea (ages from birth to < 2 years) or number of UBMs (for ages ≥ 2 years to < 18 years).

Secondary outcomes

• Percentage of Participants With Sustained Clinical Response (SCR) at EOT +9 Days [Up to day 19]: SCR at EOT + 9 days was defined as CCR (EOT + 2 days) without CDAD recurrence until assessment at EOT +9 days during the follow-up period. Recurrence for ages from birth to < 2 years was defined as re-establishment of watery diarrhea after CCR to an extent that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic Clostridium difficile (C. difficile) in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy. Recurrence for ages ≥ 2 years < 18 years was defined as re-establishment of diarrhea after CCR to an extent (as measured by the frequency of UBMs) that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy.
• Percentage of Participants With Global Cure (GC) at EOT +9 Days [Up to day 19]: GC was reported as a positive (Yes) or negative (No) outcome and was calculated using SCR and ICR/CCR values according to the following conditions: ● if ICR/CCR=Yes and SCR=Yes, then Global Cure was Yes. ● if ICR/CCR=Yes and SCR =No, then Global Cure was No. ● if ICR/CCR=No (SCR not assessed), then Global Cure was No. ● if ICR/CCR=Missing (SCR not assessed), then Global Cure was set to No. No multiple imputation method (MI) was used for global cure at EOT + 9 days.
• Percentage of Participants With Recurrence of CDAD at EOT +9 Days [Up to day 19]: Recurrence for ages from birth to < 2 years was defined as re-establishment of watery diarrhea after CCR to an extent that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy. Recurrence for ages ≥ 2 years < 18 years was defined as re-establishment of diarrhea after CCR to an extent (as measured by the frequency of UBMs) that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy.
• Percentage of Participants With SCR at EOT +16 Days [Up to day 26]: SCR at EOT + 16 days was defined as CCR (EOT + 2 days) without CDAD recurrence until assessment at EOT + 16 days during the follow-up period. Recurrence for ages from birth to < 2 years was defined as re-establishment of watery diarrhea after CCR to an extent that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy. Recurrence for ages ≥ 2 years < 18 years was defined as re-establishment of diarrhea after CCR to an extent (as measured by the frequency of UBMs) that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy.
• Percentage of Participants With GC at EOT +16 Days [Up to day 26]: GC was reported as a positive (Yes) or negative (No) outcome and was calculated using SCR and ICR/CCR values according to the following conditions: ● if ICR/CCR=Yes and SCR=Yes, then Global Cure was Yes. ● if ICR/CCR=Yes and SCR =No, then Global Cure was No. ● if ICR/CCR=No (SCR not assessed), then Global Cure was No. ● if ICR/CCR=Missing (SCR not assessed), then Global Cure was set to No. No multiple imputation method (MI) was used for global cure at EOT + 16 days.
• Percentage of Participants With Recurrence of CDAD at EOT +16 Days [Up to day 26]: Recurrence for ages from birth to < 2 years was defined as re-establishment of watery diarrhea after CCR to an extent that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy. Recurrence for ages ≥ 2 years < 18 years was defined as re-establishment of diarrhea after CCR to an extent (as measured by the frequency of UBMs) that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy.
• Percentage of Participants With SCR at EOT +23 Days [Up to day 33]: SCR at EOT + 23 days was defined as CCR (EOT + 2 days) without CDAD recurrence until assessment at EOT + 16 days during the follow-up period. Recurrence for ages from birth to < 2 years was defined as re-establishment of watery diarrhea after CCR to an extent that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy. Recurrence for ages ≥ 2 years < 18 years was defined as re-establishment of diarrhea after CCR to an extent (as measured by the frequency of UBMs) that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy.
• Percentage of Participants With GC at EOT +23 Days [Up to day 33]: GC was reported as a positive (Yes) or negative (No) outcome and was calculated using SCR and ICR/CCR values according to the following conditions: ● if ICR/CCR=Yes and SCR=Yes, then Global Cure was Yes. ● if ICR/CCR=Yes and SCR =No, then Global Cure was No. ● if ICR/CCR=No (SCR not assessed), then Global Cure was No. ● if ICR/CCR=Missing (SCR not assessed), then Global Cure was set to No. No multiple imputation method (MI) was used for global cure at EOT + 23 days.
• Percentage of Participants With Recurrence of CDAD at EOT +23 Days [Up to day 33]: Recurrence for ages from birth to < 2 years was defined as re-establishment of watery diarrhea after CCR to an extent that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy. Recurrence for ages ≥ 2 years < 18 years was defined as re-establishment of diarrhea after CCR to an extent (as measured by the frequency of UBMs) that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy.
• Percentage of Participants With SCR at End of Study (EOS) (EOT +30 Days) [Up to day 40]: SCR at EOS was defined as CCR (EOT + 2 days) without CDAD recurrence until assessment at EOS (EOT + 30 days) during the follow-up period. Recurrence for ages from birth to < 2 years was defined as re-establishment of watery diarrhea after CCR to an extent that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy. Recurrence for ages ≥ 2 years < 18 years was defined as re-establishment of diarrhea after CCR to an extent (as measured by the frequency of UBMs) that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy.
• Percentage of Participants With GC at EOS (EOT +30 Days) [Up to day 40]: GC was reported as a positive (Yes) or negative (No) outcome and was calculated using SCR and ICR/CCR values according to the following conditions: ● if ICR/CCR=Yes and SCR=Yes, then Global Cure was Yes. ● if ICR/CCR=Yes and SCR =No, then Global Cure was No. ● if ICR/CCR=No (SCR not assessed), then Global Cure was No. ● if ICR/CCR=Missing (SCR not assessed), then Global Cure was set to No. Global Cure at EOT +30 days was derived using MI in case ICR/CCR=Missing (SCR not assessed) following Rubin's multiple imputation method.
• Percentage of Participants With Recurrence of CDAD at EOS (EOT +30 Days) [Up to day 40]: Recurrence for ages from birth to < 2 years was defined as re-establishment of watery diarrhea after CCR to an extent that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy. Recurrence for ages ≥ 2 years < 18 years was defined as re-establishment of diarrhea after CCR to an extent (as measured by the frequency of UBMs) that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy.
• Time to Resolution of Diarrhea (TTROD) [Up to day 10]: TTROD for ages from birth < 2 years was defined as time elapsing (hours rounded up from minutes > 30) from treatment start (time of first study drug dose) to diarrhea resolution (time of last episode of watery diarrhea the day prior to the first of 2 consecutive days without watery diarrhea sustained through EOT). TTROD for ages ≥ 2 years to < 18 years was defined as time elapsing (hours rounded up from minutes > 30) from treatment start (time of first dose) to diarrhea resolution (time of the last UBM the day prior to the first of 2 consecutive days of < 3 UBMs sustained through EOT). TTROD by Kaplan-Meier Method. Those who completed treatment but did not show diarrhea resolution until EOT were censored at Day 10/240 hours. Those who did not complete treatment, discontinued earlier but did not show diarrhea resolution until disc. day were censored at disc. (days converted to hours). Those whose diarrhea did not continue after first dose were included with a TTROD of 1 hour.
• Time to Recurrence of CDAD for Participants With CCR at EOT +2 Days [Up to day 40]: Time to recurrence was defined as the time (days) from CCR until the onset of recurrence. Time to recurrence of CDAD by Kaplan-Meier Method. Data for median was estimated and the 95% CI could not be estimated due to low event rate. Data not estimable denoted as NA. Participants with CCR at EOT+2 days, who completed the follow-up period but did not experience a recurrence of CDAD were censored at EOT+30 days and those who did not complete the follow-up period and discontinued during this period and did not experience a recurrence of CDAD were censored at day of discontinuation.
• Number of Participants With Adverse Events (AEs) [From the first dose of study drug administration up to 30 days after EOT (up to day 40)]: An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a study drug or who had undergone study procedures which did not necessarily have a causal relationship with this treatment. This included abnormal laboratory tests, vital signs, electrocardiogram data or physical examinations that were defined as AEs if the abnormality induced clinical signs or symptoms, required active intervention, interruption or discontinuation of study drug or was clinically significant in the investigator's opinion. The following standard with 3 grades was used to measure the severity of AEs, including abnormal clinical laboratory values: ● Mild: No disruption of normal daily activities ● Moderate: Affected normal daily activities ● Severe: Inability to perform daily activities. A treatment-emergent adverse event (TEAE) was defined as an AE observed after starting administration of the test drug/comparative drug.
• Plasma Concentrations of Fidaxomicin [Within 30 minutes predose and 1 to 5 hours postdose taken between day 5 and day 10]: Drug concentration was derived from the blood samples collected.
• Plasma Concentrations of Metabolite OP-1118 [Within 30 minutes predose and 1 to 5 hours postdose taken between day 5 and day 10]: Drug concentration was derived from the blood samples collected.
• Metabolite-to-Parent Ratio (MPRconc) [Within 30 minutes predose and 1 to 5 hours postdose taken between day 5 and day 10]: Drug concentration was derived from the blood samples collected.
• Fecal Concentrations of Fidaxomicin [Within 24 hours of a dose taken between day 5 and day 10]: Drug concentration was derived from the stool samples collected.
• Fecal Concentrations of Metabolite OP-1118 [Within 24 hours of a dose taken between day 5 and day 10]: Drug concentration was derived from the stool samples collected.
• MPRconc Within 24 Hours of a Dose [Within 24 hours of a dose taken between day 5 and day 10]: Drug concentration was derived from the stool samples collected.
• Acceptance of Formulation (Palatability Assessment) in All Participants at First Administration of Study Drug and at Day 7 [Days 1 and 7]: Acceptance of formulation was evaluated in all participants who received fidaxomicin oral suspension and vancomycin oral liquid (i.e., participants from birth to =< 6 years and participants > 6 years unable to swallow tablets) by means of a five-point rating scale (awful, poor, fair, good, excellent) by unblinded staff if hospitalized, and by the participant/parents/legal guardian when at home.

Sex: All, ages: any to 17 Years

Inclusion Criteria:

* Subject is diagnosed with CDAD according to local diagnostic criteria. As a minimum there must be positive detection, within 72 hours prior to randomization, of either toxin A and/or toxin B in stool or positive detection of toxigenic C. difficile in stool and:

  * Subject from Birth to < 2 years: watery diarrhea in the 24 hours prior to screening.
  * Subject ≥ 2 years to < 18 years: ≥ 3 unformed bowel movements in the 24 hours prior to screening.
  * Male and female subjects aged from birth to < 18 years: Note that in the United States of America subjects can only be included if aged ≥ 6 months to < 18 years.
* For subjects < 5 years: Negative rotavirus test.
* Female subject of childbearing potential:

  * must have a negative urine pregnancy test at Screening, and
  * must abstain from sexual activity for the duration of the study, or
  * must use two forms of birth control (at least one of which must be a barrier method) starting at Screening and throughout the study period and for 28 days after the final study drug administration.
* Female subject must not be breastfeeding at Screening or during the study period, and for 28 days after the final study drug administration.
* Female subject must not donate ova starting at Screening and throughout the study period, and for 28 days after the final study drug administration.
* Subject agrees not to participate in another interventional study while in the study (with the exception of studies as described in exclusion criteria below).

Exclusion Criteria:

* Concurrent use of metronidazole, oral vancomycin or any other antibiotic treatments for CDAD. If the investigator feels the clinical imperative is to begin treatment before knowing the laboratory result for toxigenic C. difficile, up to four doses but no more than 24 hours of treatment with metronidazole, oral vancomycin or any other effective treatment for CDAD are allowed.
* Subject has pseudomembranous colitis, fulminant colitis, toxic megacolon or ileus.
* Subject has a history of inflammatory bowel disease (e.g., ulcerative colitis or Crohn's disease etc.).
* Subject has diarrhea caused by an agent other than C. difficile (e.g. infections, infestations, drugs etc.).
* Subject has known hypersensitivity to fidaxomicin, vancomycin or their excipients or to teicoplanin.
* Subject has received an investigational therapy within 28 days, prior to Screening, with the exception of studies with primary treatment for cancer without novel Investigational Medicinal Product (IMP) and which do not affect the assessment of diarrhea.

Participant flow

Outcome results

• Percentage of Participants With Confirmed Clinical Response (CCR) at End of Treatment (EOT) +2 Days (Primary), Number, percentage of participants: Fidaxomicin 77.6 (68.0 to 85.4); Vancomycin 70.5 (54.8 to 83.2)
• Percentage of Participants With Sustained Clinical Response (SCR) at EOT +9 Days (Secondary), Number, percentage of participants: Fidaxomicin 94.7 (87.1 to 98.5); Vancomycin 77.4 (58.9 to 90.4)
• Percentage of Participants With Global Cure (GC) at EOT +9 Days (Secondary), Number, percentage of participants: Fidaxomicin 75.5 (65.8 to 83.6); Vancomycin 54.5 (38.8 to 69.6)
• Percentage of Participants With Recurrence of CDAD at EOT +9 Days (Secondary), Number, percentage of participants: Fidaxomicin 5.3 (1.5 to 12.9); Vancomycin 22.6 (9.6 to 41.1)
• Percentage of Participants With SCR at EOT +16 Days (Secondary), Number, percentage of participants: Fidaxomicin 89.5 (80.3 to 95.3); Vancomycin 71.0 (52.0 to 85.8)
• Percentage of Participants With GC at EOT +16 Days (Secondary), Number, percentage of participants: Fidaxomicin 71.4 (61.4 to 80.1); Vancomycin 52.3 (36.7 to 67.5)
• Percentage of Participants With Recurrence of CDAD at EOT +16 Days (Secondary), Median, percentage of participants: Fidaxomicin 7.9 (3.0 to 16.4); Vancomycin 25.8 (11.9 to 44.6)
• Percentage of Participants With SCR at EOT +23 Days (Secondary), Number, percentage of participants: Fidaxomicin 85.5 (75.6 to 92.5); Vancomycin 71.0 (52.0 to 85.8)
• Percentage of Participants With GC at EOT +23 Days (Secondary), Number, percentage of participants: Fidaxomicin 68.4 (58.2 to 77.4); Vancomycin 50.0 (34.6 to 65.4)
• Percentage of Participants With Recurrence of CDAD at EOT +23 Days (Secondary), Number, percentage of participants: Fidaxomicin 11.8 (5.6 to 21.3); Vancomycin 29.0 (14.2 to 48.0)
• Percentage of Participants With SCR at End of Study (EOS) (EOT +30 Days) (Secondary), Number, percentage of participants: Fidaxomicin 85.5 (75.6 to 92.5); Vancomycin 71.0 (52.0 to 85.8)
• Percentage of Participants With GC at EOS (EOT +30 Days) (Secondary), Number, percentage of participants: Fidaxomicin 68.4 (58.2 to 77.4); Vancomycin 50.0 (34.6 to 65.4)
• Percentage of Participants With Recurrence of CDAD at EOS (EOT +30 Days) (Secondary), Number, percentage of participants: Fidaxomicin 11.8 (5.6 to 21.3); Vancomycin 29.0 (14.2 to 48.0)
• Time to Resolution of Diarrhea (TTROD) (Secondary), Median, hours: Fidaxomicin 58 (29.0 to 122.0); Vancomycin 97 (42.0 to 146.0) (p 0.579)
• Time to Recurrence of CDAD for Participants With CCR at EOT +2 Days (Secondary), Median, days: Fidaxomicin 25 (NA to NA); Vancomycin 26 (NA to NA) (p 0.023)
• Number of Participants With Adverse Events (AEs) (Secondary), Count of participants, Participants: Fidaxomicin 72; Vancomycin 33
• Plasma Concentrations of Fidaxomicin (Secondary), Mean, ng/mL: Fidaxomin All Formulations 20.17 +/- 40.16; Fidaxomicin Oral Suspension 15.26 +/- 20.43; Fidaxomicin Tablets 30.16 +/- 63.27
• Plasma Concentrations of Metabolite OP-1118 (Secondary), Mean, ng/mL: Fidaxomin All Formulations 63.04 +/- 171.97; Fidaxomicin Oral Suspension 42.18 +/- 76.76; Fidaxomicin Tablets 105.54 +/- 277.67
• Metabolite-to-Parent Ratio (MPRconc) (Secondary), Mean, ratio: Fidaxomin All Formulations 3.18 +/- 1.42; Fidaxomicin Oral Suspension 3.24 +/- 1.46; Fidaxomicin Tablets 3.05 +/- 1.35
• Fecal Concentrations of Fidaxomicin (Secondary), Mean, μg/g: Fidaxomin All Formulations 2685.56 +/- 2476.92; Fidaxomicin Oral Suspension 2969.87 +/- 2713.58; Fidaxomicin Tablets 2190.63 +/- 1948.68
• 3 more outcome measures not shown.

Adverse events

Time frame: From the first dose of study drug administration up to 30 days after EOT (up to day 40)

Serious adverse events by term

Other adverse events by term

• Results publication: Wolf J, Kalocsai K, Fortuny C, Lazar S, Bosis S, Korczowski B, Petit A, Bradford D, Croos-Dabrera R, Incera E, Melis J, van Maanen R. Safety and Efficacy of Fidaxomicin and Vancomycin in Children and Adolescents with Clostridioides (Clostridium) difficile Infection: A Phase 3, Multicenter, Randomized, Single-blind Clinical Trial (SUNSHINE). Clin Infect Dis. 2020 Dec 17;71(10):2581-2588. doi: 10.1093/cid/ciz1149. PMID 31773143
• Results publication: Borali E, De Giacomo C. Clostridium Difficile Infection in Children: A Review. J Pediatr Gastroenterol Nutr. 2016 Dec;63(6):e130-e140. doi: 10.1097/MPG.0000000000001264. PMID 27182626

• Study Protocol (PDF, 2015-07-21)
• Statistical Analysis Plan (PDF, 2018-04-20)

• Clinical Research Physician, Study director, Astellas Pharma Europe B.V.