A Study of MK-3415, MK-6072, and MK-3415A in Participants Receiving Antibiotic Therapy for Clostridium Difficile Infection (MK-3415A-001 AM2) (MODIFY I)
Treatment with monoclonal antibodies against Clostridium difficile toxins (Lowy et al. N Eng J Med 2010 Jan 21;362(3):197-205)
A new adjunctive approach to the treatment of CDI is the use of monoclonal antibodies directed against the toxins. Results from the Phase II clinical study of a single infusion of the combination of monoclonal antibodies directed against toxins A and B (MK-3415A) demonstrated a significant difference (p = 0.001) in CDI recurrence between recipients of the monoclonal antibodies (7% [7/101]) and those who received placebo (25% [25/99]). The safety of MK-3415A was comparable to placebo.
This is a randomized, double-blind, placebo-controlled, multicentre, Phase III study evaluating the efficacy, safety, and tolerability of monoclonal antibodies to C. difficile exotoxins. Participants receiving standard of care (SOC) therapy will be randomised equally into 1 of 4 treatment groups. On Day 1 participants will receive MK-3415 (toxin A only), MK-6072 (toxin B only), MK-3415A or placebo.
This study will investigate whether:
- treatment with MK-3415A (Human Monoclonal Antibodies to Clostridium Difficile Toxin A and Toxin B) in addition to standard of care (SOC) antibiotic therapy will decrease Clostridium difficile infection (CDI) recurrence as compared to treatment with MK-6072 or MK-3415,
- treatment with MK-3415A, MK-6072 (Human Monoclonal Antibody to Clostridium Difficile Toxin B), or MK-3415 (Human Monoclonal Antibody to Clostridium Difficile Toxin A), in addition to SOC antibiotic therapy will decrease CDI recurrence as compared to placebo, and
- MK-3415A, MK-6072, and MK-3415 will be generally well tolerated in participants receiving SOC therapy for CDI as compared to placebo.
- participant must be 18 years of age or older.
- participant has a diagnosis of 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.
- participant must be receiving SOC therapy for CDI. SOC therapy 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.
- participant is highly unlikely to become pregnant or to impregnate a partner since they meet at least one of the following criteria: a. A female participant who is not of reproductive potential is eligible without requiring the use of contraception. A female participant who is not of reproductive potential is defined as: 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 as determined by the local laboratory, or 12 months of spontaneous amenorrhea); (2) 6 weeks post surgical bilateral oophorectomy with or without hysterectomy; or (3) bilateral tubal ligation. Spontaneous amenorrhea does not include cases for which there is an underlying disease that causes amenorrhea (e.g. anorexia nervosa). b. A participant who is of reproductive potential agrees to remain abstinent or use (or have their partner use) 2 acceptable methods of birth control starting at enrollment and through the 12 Week study period. Acceptable methods of birth control are: intrauterine device (IUD), diaphragm with spermicide, contraceptive sponge, condom, vasectomy and any registered and marketed hormonal contraceptives that contain an estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents)
- participant or legal representative must have voluntarily agreed to participate by providing written informed consent after the nature of the study has been fully explained.
- participant with an active chronic diarrheal illness such as, but not limited to, ulcerative colitis or Crohn’s disease or with a condition that causes routine passage of loose stool (e.g., an ostomy).
- participant with a planned surgery for CDI within 24 hours.
- participant has a positive pregnancy test in the 48 hours before the infusion or is unwilling to undergo pregnancy testing if a pre-menopausal female who is not sterilized and therefore has the potential to bear a child.
- participant is breast-feeding or plans to breast-feed prior to the completion of the 12-week study period.
- A female participant who plans to donate ova prior to the completion of the 12-week study period, or a male participant who is planning to impregnate or provide sperm donation prior to the completion of the 12-week study period.
- participant has previously participated in this study or has previously received MK-3415 or MK- 6072 (either alone or in combination).
- participant plans to donate blood and/or blood products within 6 months following the infusion.
- participant 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.
- Treatment with SOC therapy is planned for longer than 14 days
- participant has received cholestyramine, rifaximin, or nitazoxanide within 14 days prior to receipt of the infusion or is planning to receive these medications prior to the completion of the 12-week study period.
- participant plans to take antiperistaltic agents, such as loperamide (Imodium™) or diphenoxylate hydrochloride/atropine sulfate (LOMOTIL™), at any time during the 14 days following 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 Saccharomyces boulardii at any time following infusion (Day 1) and through the completion of the 12-week study period.
- participant has received another investigational study agent within the previous 30 days, or is currently participating in or scheduled to participate in any other clinical trial during the 12-week study period.
- 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 participating in the study, would make it unlikely for the participant to complete the study, or would confound the results of the study.
Primary Outcome Measures
Proportion of participants with Clostridium difficile infection (CDI) recurrence [ Time Frame: 12 weeks ]
Secondary Outcome Measures
Proportion of participants with Global Cure [ Time Frame: 12 weeks ]
Proportion of participants with CDI recurrence in those with clinical cure of the initial CDI episode [ Time Frame: 12 weeks ]