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

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

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.

Study Overview

• Status: Completed
• Conditions: Clostridium Infections
• Intervention / Treatment: Biological: GS-CDA1/MDX-1388; Biological: normal saline

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 200
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • University of Calgary Foothills Medical Center
  • British Columbia
    • Victoria, British Columbia, Canada, V8R 1J8
      • Vancouver Island Health Research Centre
  • Manitoba
    • Winnepeg, Manitoba, Canada, R3A 1R9
      • Health Sciences Centre, University of Manitoba
  • Ontario
    • Kingston, Ontario, Canada, K7L 2V7
      • Kingston General Hospital
    • WIndsor, Ontario, Canada, N8W 1L9
      • Windsor Regional Hospital
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 5H6
      • Centre de Sante et Services Sociaux de Chicoutimi
    • Trois-Rivieres, Quebec, Canada, G8Z 3R9
      • Centre Hospitalier Regional de Trois-Rivieres
• United States
  • California
    • Los Angeles, California, United States, 90033
      • LAC/USC Medical Center
    • Los Angeles, California, United States, 90095
      • UCLA CURE Digestive Diseases Center
    • Oakland, California, United States, 94612
      • Kaiser Permanente Vaccine Study Center
  • Delaware
    • Newark, Delaware, United States, 19718
      • Christiana Care Health Systems
  • Florida
    • Tampa, Florida, United States, 33613
      • Dr. Kiran C. Patel Research Institute
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Idaho Falls Infectious Diseases, PLLC
  • Indiana
    • Anderson, Indiana, United States, 46016
      • Central Indiana Gastroenterology Group
  • Iowa
    • Des Moines, Iowa, United States, 50325
      • Chest, Infectious Diseases and Critical Care Assoc., PC
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Medical Center
  • Michigan
    • West Bloomfield, Michigan, United States, 48322
      • Henry Ford Health System
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Saint Luke'S Hospital of Kansas City
  • Montana
    • Butte, Montana, United States, 59701
      • Saint James Healthcare
  • New Jersey
    • Neptune, New Jersey, United States, 07754
      • Jersey Shore University Medical Center
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai Hospital
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27103
      • All-Trials Clinical Research, LLC
  • Ohio
    • Akron, Ohio, United States, 44304
      • SUMMA Health System
    • Columbus, Ohio, United States, 43214
      • Remington-Davis Clinical Research
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
      • Rapid City Regional Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • St. Lukes Episcopal Hospital
    • Temple, Texas, United States, 76508
      • Scott and White Memorial Hospital
  • Washington
    • Tacoma, Washington, United States, 98405
      • MultiCare Health System Research Services

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 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.
2. 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.
3. 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:

1. History of chronic diarrheal illness such as ulcerative colitis or Crohn's disease.
2. Score of 4 on modified Horn's index
3. Severe C. difficile colitis with planned surgery in less than 24 hours.
4. 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.
5. Breastfeeding.
6. Receipt of other investigational study agent within previous 30 days.
7. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: MassBiologics
• Collaborators: Medarex
• Investigators: Principal Investigator: Roger Baxter, MD, Kaiser Permanente; Principal Investigator: Herbert DuPont, MD, St. Lukes Episcopal Hospital, Houston, TX; Principal Investigator: Joseph White, MD, Scott and White Memorial Hospital, Temple, TX; Principal Investigator: David Chen, MD, MultiCare Health System Research Services, Tacoma, WA; Principal Investigator: Jorge Reyno, MD, Rapid City Regional Hospital, Rapid City, SD; Principal Investigator: Henry S. Sacks, MD, PhD, Mount Sinai Hospital, New York, NY; Principal Investigator: Charles N. Bernstein, MD, University of Manitoba, Health Sciences Centre, Winnepeg, Manitoba, Canada; Principal Investigator: Michael J. Tan, MD, Summa Health Systems, Akron, Ohio; Principal Investigator: Michael C. Meadors, MD, All-Trials Clinical Research, LLC, Winston-Salem, NC; Principal Investigator: Ian M. Baird, MD, Remington-Davis Clinical Research; Principal Investigator: Andre Poirier, MD, MSc, Centre Hospitalier Regional de Trois-Rivieres; Principal Investigator: Martha I. Buitrago, MD, Idaho Falls Infectious Diseases, PLLC; Principal Investigator: Thomas Kovacs, MD, UCLA CURE Digestive Diseases Research Center; Principal Investigator: Alfred Bacon, MD, Christiana Care Health Systems; Principal Investigator: Kathleen Casey, MD, Jersey Shore University Medical Center; Principal Investigator: C. Douglas Cochran, MD, Saint Luke'S Hospital of Kansas City; Principal Investigator: Donald Daly, MD, Vancouver Island Health Research Centre; Principal Investigator: Anil Dhar, MBBS, Windsor Regional Hospital; Principal Investigator: Gerald Evans, MD, Queen's University; Principal Investigator: Thomas Louie, MD, University of Calgary Foothills Medical Center; Principal Investigator: Thomas Nowak, MD, Central Indiana Gastroenterology Group; Principal Investigator: Jose Prieto, MD, Dr. Kiran C. Patel Research Institute; Principal Investigator: Daniel Schroeder, MD, Chest, Infectious Diseases and Critical Care Assoc., PC; Principal Investigator: Ann Silverman, MD, Henry Ford Health System; Principal Investigator: John Pullman, MD, Mercury Street Medical Group; Principal Investigator: Rodney J Mason, MD, LAC+USC Medical Center; Principal Investigator: Doria Grimard, MD, Centre de sante et de services sociaux de Chicoutimi; Principal Investigator: Darrell Pardi, MD, Mayo Clinic

Publications and helpful links

General Publications

• Montgomery DL, Matthews RP, Yee KL, Tobias LM, Dorr MB, Wrishko RE. Assessment of Bezlotoxumab Immunogenicity. Clin Pharmacol Drug Dev. 2020 Apr;9(3):330-340. doi: 10.1002/cpdd.729. Epub 2019 Aug 14.
• Gupta SB, Mehta V, Dubberke ER, Zhao X, Dorr MB, Guris D, Molrine D, Leney M, Miller M, Dupin M, Mast TC. Antibodies to Toxin B Are Protective Against Clostridium difficile Infection Recurrence. Clin Infect Dis. 2016 Sep 15;63(6):730-734. doi: 10.1093/cid/ciw364. Epub 2016 Jun 30.
• Lowy I, Molrine DC, Leav BA, Blair BM, Baxter R, Gerding DN, Nichol G, Thomas WD Jr, Leney M, Sloan S, Hay CA, Ambrosino DM. Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med. 2010 Jan 21;362(3):197-205. doi: 10.1056/NEJMoa0907635.

Study record dates

Study Major Dates

• Study Start (Actual): July 20, 2006
• Primary Completion (Actual): June 25, 2008
• Study Completion (Actual): June 25, 2008

Study Registration Dates

• First Submitted: July 7, 2006
• First Submitted That Met QC Criteria: July 7, 2006
• First Posted (Estimate): July 10, 2006

Study Record Updates

• Last Update Posted (Actual): February 9, 2021
• Last Update Submitted That Met QC Criteria: January 21, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Clostridium difficile Associated Diarrhea; Monoclonal antibody,
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Clostridium Infections
• Other Study ID Numbers: CA-GCDX-06-02