MODIFY I

Purpose / Objectives

Primary Outcome

The primary endpoint is the proportion of patients with CDI recurrence at Week 12.

To assess for CDI recurrence, 3 clinical variables will be measured:

(1) diarrhea,

(2) stool test for toxigenic C. difficile, and

(3) the type and duration of SOC therapy.

The daily count of loose stools, as recorded by the patient in the stool count log, will be monitored following the infusion through Week 12 (Day 85 ± 5 days) in order to identify a new episode of diarrhea. All new episodes of diarrhea will be tested for toxigenic C. difficile (see Section 3.2.3.8.3) to confirm CDI recurrence.

The type and duration of SOC therapy as well as the reason for any change in SOC therapy will be recorded in the appropriate eCRF.

Secondary Outcomes

To assess the secondary efficacy objectives, the same 3 clinical variables will be measured as planned for the primary efficacy endpoint:

(1) diarrhea (via loose stool counts through Week 12 (Day 85 ± 5 days)),

(2) stool test for toxigenic C. difficile, and

(3) the type and duration of SOC therapy.

Determination of subgroups for the secondary efficacy objectives will be assessed by review of eCRFs (medical history, demographics, and vital signs) and/ or appropriate laboratory results.

To assess the exploratory objective for the proportion of patients with clinical cure 2 clinical variables will be measured

(1) diarrhea (via loose stool counts through Week 12 (Day 85 ± 5 days)) and

(2) the type and duration of SOC therapy.

The remaining exploratory objectives will be measured by assessment of loose stool counts (through Week 12 (Day 85 ± 5 days), WBC results from Day 1 and Day 4 (or Day 11), and review of eCRFs for body temperature from Day 1 and Day 4 (or Day 11).

Exploratory Objective #1: To evaluate the proportion of patients with clinical cure in the treatment group receiving a single infusion of MK-3415A with SOC therapy as compared to the treatment group receiving a single placebo infusion with SOC therapy.

Exploratory Objective #2: To determine if treatment with a single infusion of MK-3415A with SOC therapy reduces the time to resolution of the initial CDI episode as compared to treatment with a single placebo infusion with SOC therapy.

Exploratory Objective #3: To assess the impact of treatment with a single infusion of MK-3415A or placebo with SOC therapy on the median number of loose stools per day for the initial CDI episode (day after infusion [Day 2] through Day 14).

Exploratory Objective #4a: To evaluate the proportion of patients whose elevated baseline WBC (>10,000 cells/mm3) decreases to ≤10,000 cells/mm3 by Day 4 or Day 11 in the treatment group receiving a single infusion of MK-3415A with SOC therapy as compared to the treatment group receiving a single placebo infusion with SOC therapy.

Exploratory Objective #4b: To evaluate the proportion of patients whose elevated baseline body temperature (≥101.0°F [38.4°C]) decreases to <101°F [38.4°C] by Day 4 or Day 11 in the treatment group receiving a single infusion of MK-3415A with SOC therapy as compared to the treatment group receiving a single placebo infusion with SOC
therapy.

Diagnosis

• Clostridium-Diarrhoe (English name missing)
• Gastrointestinale Infektionen (English name missing)
• Infectious diseases in Hematology and Oncology: Bacterial Infections

Target population

Age

18-99

Inclusion criteria

• Patient has a diagnosis of C. difficile infection (CDI) as defined by

a) Presence of diarrhea, as defined by passage of 3 or more loose stools in 24 or fewer hours, AND

b) A positive stool test for toxigenic C. difficile.

NOTE: Diarrhea is not required to be present on the day of infusion. Toxigenic C. difficile positivity should be determined locally by a hospital/clinic/reference microbiology laboratory test using only those methodologies listed in Appendix 6.1; the stool sample with the documented positive result for toxigenic C. difficile must have been collected within 7 days prior to the infusion.

• Patient must be receiving or planning to receive a 10- to 14-day course of SOC therapy for CDI. SOC therapy is defined as the receipt of oral metronidazole, oral vancomycin, intravenous metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with intravenous metronidazole. Oral metronidazole should be administered at a dose of 1200-1500 mg per day (usually 400 to 500 mg every 8 hours [three times a day]). Intravenous metronidazole should be administered at a dose of 1500 mg per day (500 mg every 8 hours [three times a day]). Oral vancomycin should be administered at a dose of 125-500 mg every 6 hours (4 times a day). Oral fidaxomicin should be administered at a dose of 200 mg twice daily.

NOTE: A patient who is planning to initiate SOC therapy on the same day as the infusion is eligible for participation. The first dose of SOC therapy must have been administered prior to or within a few hours following the infusion

Exclusion criteria

• Patient with an active chronic diarrheal illness such as, but not limited to, ulcerative colitis or Crohn’s disease or with a condition such that they routinely pass loose stool (e.g., patients with an ostomy)
• Patient with a planned surgery for CDI within 24 hours
• Patient has previously participated in this study or has previously received MK-3415 or MK-6072 (either alone or in combination)
• Patient has received immune globulin within 6 months prior to receipt of the infusion
  or is planning to receive immune globulin prior to the completion of the 12-Week study period.
• Patient for whom treatment with SOC therapy is planned for longer than 14 days (e.g., planned tapered or pulsed regimen of vancomycin)

Study design

• Phase III
• Double-blind
• Randomized
• Placebo-controlled

Intervention

• A single infusion of the MK-3415 (10 mg/kg of monoclonal antibody to C. difficile toxin A only), or
• A single infusion of MK-6072 (10 mg/kg of monoclonal antibody to C. difficile toxin B only), or
• A single infusion of MK-3415A (combination of 10 mg/kg of monoclonal antibody to C. difficile toxin A [MK-3415] and 10 mg/kg of monoclonal antibody to toxin B [MK-6072]), or
• A single infusion of placebo (0.9% sodium chloride)

Documents (password protected)

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Responsibilities in overall study

Sponsor

Merck & Co

(National) Coordinating Investigator

Univ.-Prof. Dr. med. Oliver A. Cornely