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

Study Overview
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Brief Summary
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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.

Detailed Description
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An extended 9-month follow-up to assess for CDI recurrence through Month 12 will be conducted in a subset of participants.

Official Title
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A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy, Safety and Tolerability of a Single Infusion of MK-6072 (Human Monoclonal Antibody to Clostridium Difficile Toxin B), and MK-3415A (Human Monoclonal Antibodies to Clostridium Difficile Toxin A and B) in Patients Receiving Antibiotic Therapy for Clostridium Difficile Infection (MODIFY II)

Conditions
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Clostridium Difficile Infection

Intervention / Treatment
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* Biological: MK-6072
* Biological: MK-3415A
* Biological: Placebo
* Drug: SOC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has a diagnosis of CDI defined as: a) presence of diarrhea (passage of 3 or more loose stools in 24 or fewer hours); and b) positive test for toxigenic C. difficile from a stool collected no more than 7 days before study infusion. Participant is receiving SOC therapy (i.e., oral metronidazole, oral vancomycin, IV metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with IV metronidazole) for CDI. Participant is highly unlikely to become pregnant or to impregnate a partner by meeting at least one of the following criteria: a) females not of reproductive potential (i.e., one who has either (1) reached natural menopause, defined as 6 months of spontaneous amenorrhea with serum follicle stimulating hormone [FSH] levels in the postmenopausal range, or 12 months of spontaneous amenorrhea not including cases with an underlying disease, such as anorexia nervosa, that causes amenorrhea; (2) 6 weeks post surgical bilateral oophorectomy with or without hysterectomy; or (3) bilateral tubal ligation); or b) participants of reproductive potential who agree to remain abstinent or use (or have their partner use) two acceptable methods of birth control (i.e., intrauterine device [IUD], diaphragm with spermicide; contraceptive sponge, condom, vasectomy and any registered and marketed hormonal contraceptives that contain an estrogen and/or progestational agent including oral, subcutaneous, intrauterine, or intramuscular agents) starting at enrollment and throughout the 12-week study. Exclusion Criteria: Participant with an uncontrolled chronic diarrheal illness such that their normal 24-hour bowel movement habit is 3 or more loose stools. Participant with planned surgery for CDI within 24 hours. Female participant with a positive pregnancy test in the 48 hours before infusion and pre-menopausal females who are not sterilized and therefore have the potential to bear a child who are unwilling to undergo pregnancy testing. Female participant breast feeding or planning to breast feed before completion of the 12-week study. Female participant planning to donate ova before completion of the 12-week study and male participants planning to impregnate or donate sperm before completion of the 12-week study. Participant has previously participated in this study, has previously received MK-3415 or MK-6072 (either alone or in combination), has received a C. difficile vaccine, or has received another experimental monoclonal antibody against C. difficile toxin A or B. Participant plans to donate blood and/or blood products within 6 months after infusion. Participant has received immune globulin within 6 months before infusion or is planning to receive immune globulin before completion of the 12-week study. Treatment with SOC therapy is planned for longer than 14 days. Participant has received more than a 24-hour regimen of cholestyramine, colestimide, rifaximin, or nitazoxanide within 14 days before infusion or plans to receive these medication before completion of the 12-week study period. Participant plans to take medications that are given to decrease gastrointestinal peristalsis, such as loperamide (Imodium™) or diphenoxylate hydrochloride/atropine sulfate (Lomotil™) any time during the 14 days after infusion. Participants receiving opioid medications at the onset of diarrhea may be included if they are on a stable dose or if there is anticipation of a dose decrease or cessation of use. Participant plans to take the probiotic Saccaromyces boulardii or plans to receive fecal transplantation therapy, or any other therapies that have been demonstrated to decrease CDI recurrence at any time after infusion (Day 1) and through completion of the 12-week study period. Participant has received another investigational study agent within the past 30 days or is currently participating in or scheduled to participate in any other clinical study with an investigational agent during the 12-week study. Participant is not expected to survive for 72 hours. Participant has any other condition that, in the opinion of the investigator, would jeopardize the safety or rights of the participant, would make it unlikely for the participant to complete the study, or would confound the results of the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-6072 + SOC<br>Single intravenous (IV) infusion of 10 mg/kg MK-6072 + Standard of Care (SOC) for CDI | Biological: MK-6072<br>* Single IV infusion of MK-6072 (10 mg/kg of monoclonal antibody to C. difficile Toxin B)<br>Drug: SOC<br>* SOC for CDI will be prescribed for 10 to 14 days and can begin on the day of study drug infusion; but the first dose must have been administered prior to or within a few hours following study drug infusion. SOC is defined as the receipt of oral metronidazole, oral vancomycin, IV metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with IV metronidazole.<br>|
| Experimental: MK-3415A + SOC<br>Single IV infusion of 10 mg/kg MK-3415A + SOC for CDI | Biological: MK-3415A<br>* Single IV infusion of MK-3415A (10 mg/kg of monoclonal antibody to C. difficile Toxin A and 10 mg/kg of monoclonal antibody to C. difficile Toxin B)<br>Drug: SOC<br>* SOC for CDI will be prescribed for 10 to 14 days and can begin on the day of study drug infusion; but the first dose must have been administered prior to or within a few hours following study drug infusion. SOC is defined as the receipt of oral metronidazole, oral vancomycin, IV metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with IV metronidazole.<br>|
| Placebo Comparator: Placebo + SOC<br>Normal saline IV infusion (0.9% sodium chloride) + SOC for CDI | Biological: Placebo<br>* Single IV infusion of normal saline (0.9% sodium chloride)<br>Drug: SOC<br>* SOC for CDI will be prescribed for 10 to 14 days and can begin on the day of study drug infusion; but the first dose must have been administered prior to or within a few hours following study drug infusion. SOC is defined as the receipt of oral metronidazole, oral vancomycin, IV metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with IV metronidazole.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With CDI Recurrence | CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile after clinical cure of the initial CDI episode. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen. | 12 weeks | 
| Percentage of Participants With One or More Adverse Events During 4 Weeks Following Infusion Treatment | An adverse event (AE) is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an adverse event. | Up to 4 weeks | 
| Percentage of Participants With One or More Drug-related Adverse Events During 4 Weeks Following Infusion Treatment | An adverse event (AE) is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an adverse event. A drug-related adverse event is determined by the investigator to be related to the drug. | Up to 4 weeks | 
| Percentage of Participants With One or More Serious Drug-related Adverse Events During 4 Weeks Following Infusion Treatment | A serious adverse event (SAE) is any AE occurring at any dose or during any use of the medicinal product that results in death; or is life threatening; or results in a persistent or significant disability/incapacity; or results in or prolongs an existing inpatient hospitalization; or is a congenital anomaly/birth defect; or other important medical events. A serious drug-related adverse event is determined by the investigator to be related to the drug. | Up to 4 weeks | 
| Percentage of Participants Who Discontinued Study Medication Due to an Adverse Event During 4 Weeks Following Infusion Treatment | An adverse event (AE) is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an adverse event. | Up to 4 weeks | 
| Percentage of Participants With One or More Infusion-specific Adverse Events on the Day of Infusion or the Day After Infusion | An adverse event (AE) is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an adverse event. | Up to 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Global Cure | Global cure is defined as the clinical cure of the initial CDI episode with no CDI recurrence through Week 12. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen. | 12 weeks | 
| Percentage of Participants With CDI Recurrence in Those With Clinical Cure of the Initial CDI Episode | CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen. | 12 weeks | 
| Percentage of Participants With CDI Recurrence in Those With a History of CDI in the 6 Months Prior to Enrollment | CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen. | 12 weeks | 
| Percentage of Participants With CDI Recurrence in Those With the 027 Ribotype | CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen. The 027 ribotype is a more virulent, epidemic strain responsible for several outbreaks of disease associated with an increased risk of severity and mortality. | 12 weeks | 
| Percentage of Participants With CDI Recurrence in Those With an Epidemic Strain | CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen. An epidemic strain includes ribotypes 027, 014, 002, 001, 106 or 020. | 12 weeks | 
| Percentage of Participants With CDI Recurrence in Those With Clinically Severe CDI | CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen. Participants with clinically severe CDI have a Zar Score greater than or equal to 2 points based on the presence of 1 or more of the following: 1) age >60 years old (1 point); 2) body temperature >38.3°C (>100°F) (1 point); 3) albumin level ˂2.5 mg/dl (1 point); 4) peripheral white blood cell count >15,000 cells/mm^3 within 48 hours (1 point); 5) endoscopic evidence of pseudomembranous colitis (2 points); and 6) treatment in Intensive Care Unit (2 points). | 12 weeks | 
| Percentage of Participants With CDI Recurrence in Those 65 Years and Older | CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen. | 12 weeks | 
| Percentage of Participants With CDI Recurrence in Those With Compromised Immunity | CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen. Compromised immunity is an active hematological malignancy (including leukemia, lymphoma, multiple myeloma), an active malignancy requiring recent cytotoxic chemotherapy, receipt of a prior hematopoietic stem cell transplant, receipt of a prior solid organ transplant, asplenia, or neutropenia/pancytopenia due to other conditions. | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Clostridium difficile, Clostridium difficile infection (CDI), recurrent Clostridium difficile, vancomycin, metronidazole, monoclonal antibody