Study of the Clinical Effectiveness of a Human Monoclonal Antibody to C. Difficile Toxin A and Toxin B in Patients With Clostridium Difficile Associated Disease

Study Overview
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Brief Summary
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Patients with Clostridium difficile associated disease who fulfill the eligibility criteria will be approached to participate. All study patients must receive standard of care treatment for Clostridium difficile associated disease. Enrolled patients will be randomized to receive a single intravenous solution of a human monoclonal antibody (huMab) to C. difficile toxin A (GS-CDA1) combined with a human monoclonal antibody to C. difficile toxin B (MDX-1388) or 0.9% sodium chloride as placebo in a 1:1 treatment allocation. Patients will be evaluated for safety and clinical outcomes through day 84 +/- 10 days. Occurrence of adverse events, use of concomitant medications, and stool output will be assessed at scheduled phone contacts and study visits. Some patients enrolled will have a subsequent visit on day 168 ± 14 days.

Detailed Description
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This study is a phase II, randomized, double-blind, placebo-controlled study in patients diagnosed with Clostridium difficile associated disease. Patients with Clostridium difficile associated disease will be identified either from stool test results or by physician referral, and those who fulfill the eligibility criteria will be approached to participate. All study patients must receive standard of care treatment for Clostridium difficile associated disease. Enrolled patients will be randomized to receive a single intravenous solution of a human monoclonal antibody to C. difficile toxin A (GS-CDA1) combined with a human monoclonal antibody to C. difficile toxin B (MDX-1388) or 0.9% sodium chloride as placebo in a 1:1 treatment allocation. One hundred patients will be enrolled in the combination monoclonal antibody treated arm and 100 patients will be enrolled in the placebo arm. Patients will be evaluated through day 84 ± 10 days after receipt of study infusion for safety and clinical outcomes. Blood samples for safety analyses, anti-toxin A and anti-toxin B antibody measurements and human anti-human antibody (HAHA) titers will be collected at scheduled times. Study visits will occur on days 3 ± 1, 10 ± 2, 28 ± 3, 56 ± 7 and on day 84 ± 10 days. Occurrence of adverse events, use of concomitant medications, and record of stool output will be assessed at scheduled phone contacts and study visits. The first 20 patients enrolled will have a subsequent visit on day 168 ± 14 days for an additional blood collection for HAHA analysis.

Official Title
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A Phase II Randomized, Double-Blind, Placebo-Controlled Study of the Clinical Effectiveness of a Human Monoclonal Antibody to Clostridium Difficile Toxin A (GS-CDA1) and a Human Monoclonal Antibody to Clostridium Difficile Toxin B (MDX-1388) in Patients Being Treated for Clostridium Difficile Associated Disease

Conditions
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Clostridium Infections

Intervention / Treatment
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* Biological: GS-CDA1/MDX-1388
* Biological: normal saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient > 18 years of age with diarrhea associated with a positive stool test for C. difficile toxin(s). Patients may be diagnosed with C. difficile by hospital/clinic/reference microbiology laboratory test or by a rapid diagnostic test performed by the study staff and positive test result must be within 14 days of enrollment. Patient must receive standard of care treatment for C. difficile associated disease. Standard of care treatment should include either metronidazole by mouth or intravenously or vancomycin by mouth. Patient or legal representative must have read, understood, and provided written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization after the nature of the study has been fully explained. Exclusion Criteria: History of chronic diarrheal illness such as ulcerative colitis or Crohn's disease. Score of 4 on modified Horn's index Severe C. difficile colitis with planned surgery in less than 24 hours. Positive pregnancy test within 24 hours of study infusion or an unwillingness to undergo pregnancy testing in females of child-bearing potential. Females capable of child-bearing must agree not to become pregnant from the time of study enrollment until at least 3 months after completion of study infusion. If a woman is sexually active and has no history of hysterectomy or tubal ligation, she must agree to use hormonal or barrier birth control with spermicidal gel. Breastfeeding. Receipt of other investigational study agent within previous 30 days. Any other condition that in the opinion of the investigator would jeopardize the safety or rights of the patient participating in the study or make it unlikely the patient could complete 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GS-CDA1/MDX-1388<br>Biological: GS-CDA1/MDX-1388 One Intravenous dose | Biological: GS-CDA1/MDX-1388<br>* One Intravenous dose<br>|
| Placebo Comparator: Placebo<br>Biological: normal saline (0.9% sodium chloride) One Intravenous dose | Biological: normal saline<br>* One Intravenous dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Recurrence of Clostridium Difficile Associated Disease (CDAD) | Determine if the addition of C. difficile toxin A and toxin B human monoclonal anti-toxin antibodies to standard of care treatment reduces the number of subjects with recurrent CDAD compared to standard of care and placebo. Standard of care treatment is defined as receipt of either metronidazole by mouth or parenterally or receipt of vancomycin by mouth with a standard duration of treatment defined as 10 - 14 days (+ 2 days)). Recurrence of CDAD is defined as the development of a new episode of C. difficile disease associated with a positive C. difficile stool toxin(s) test after the resolution of prior episode and after discontinuation of SOC treatment. | Day 0 to Day 84 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Safety and tolerability of a C. difficile toxin A human monoclonal antibody combined with a human monoclonal antibody to C. difficile toxin B in patients receiving standard of care treatment for C. difficile associated disease (CDAD) compared to those patients receiving standard of care and placebo reporting system organ class (SOC) MedDRA V.9.0 | Day 0 to Day 84 | 
| Time to Resolution of Initial CDAD Episode | Determine if the addition of a C. difficile toxin A human monoclonal antibody combined with C. difficile toxin B human monoclonal antibody to standard of care treatment reduces the time to resolution of diarrhea in patients with CDAD compared to those patients receiving standard of care and placebo. Resolution of CDAD is defined as the cessation of diarrhea for at least two consecutive days. | Day 0 to Day 84 | 
| Number of Patients With Standard of Care Treatment Failure | Determine if the addition of a C. difficile toxin A human monoclonal antibody combined with C. difficile toxin B human monoclonal antibody to standard of care treatment reduces the number of patients who experience standard of care treatment failure compared to those patients receiving standard of care and placebo. Standard of care treatment failure is defined as (i) recurrence of diarrhea (after it had initially resolved) while on SOC treatment during the first 14 days, or (ii) change in SOC treatment (i.e., antibiotics given), or (iii) diarrhea episode lasting ≥14 days while on SOC treatment. | Day 0 to Day 84 | 
| Number of Patients With Severe Initial C. Difficile Disease | Determine if the addition of a C. difficile toxin A human monoclonal antibody combined with C. difficile toxin B human monoclonal antibody to standard of care treatment reduces the number of patients with severe C. difficile disease compared to those patients receiving standard of care and placebo. Severe initial disease is defined as ≥ 5 unformed stools/day for 2 consecutive days from day 1 to the end of the initial episode of diarrhea and discontinuation of SOC. | Day 0 to Day 84 | 
| Antibody Concentrations to Toxin A and to Toxin B Between Treatment Groups | Antibody concentrations to Toxin A and to Toxin B in those patients receiving C. difficile toxin A human monoclonal antibody combined with C. difficile toxin B human monoclonal antibody and standard of care treatment to those patients receiving standard of care and placebo | Day 0 to Day 84 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Monoclonal antibody,, Clostridium difficile Associated Diarrhea