Clinical trial NCT00350298: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Clostridium Infections
Keywords: Monoclonal antibody,
Clostridium difficile Associated Diarrhea
Lead sponsor: MassBiologics
Sponsor class: OTHER
Collaborators: name: Medarex
First posted: 2006-07-10
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Recurrence of Clostridium Difficile Associated Disease (CDAD)
timeFrame: Day 0 to Day 84
Secondary outcomes:
measure: Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported
timeFrame: Day 0 to Day 84
measure: Time to Resolution of Initial CDAD Episode
timeFrame: Day 0 to Day 84
measure: Number of Patients With Standard of Care Treatment Failure
timeFrame: Day 0 to Day 84
measure: Number of Patients With Severe Initial C. Difficile Disease
timeFrame: Day 0 to Day 84
measure: Antibody Concentrations to Toxin A and to Toxin B Between Treatment Groups
timeFrame: Day 0 to Day 84
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: LAC/USC Medical Center
state: California
city: Los Angeles
country: United States
facility: UCLA CURE Digestive Diseases Center
state: California
city: Oakland
country: United States
facility: Kaiser Permanente Vaccine Study Center
state: California
city: Newark
country: United States
facility: Christiana Care Health Systems
state: Delaware
city: Tampa
country: United States
facility: Dr. Kiran C. Patel Research Institute
state: Florida
city: Idaho Falls
country: United States
facility: Idaho Falls Infectious Diseases, PLLC
state: Idaho
city: Anderson
country: United States
facility: Central Indiana Gastroenterology Group
state: Indiana
city: Des Moines
country: United States
facility: Chest, Infectious Diseases and Critical Care Assoc., PC
state: Iowa
city: Lexington
country: United States
facility: University of Kentucky Medical Center
state: Kentucky
city: West Bloomfield
country: United States
facility: Henry Ford Health System
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Kansas City
country: United States
facility: Saint Luke's Hospital of Kansas City
state: Missouri
city: Butte
country: United States
facility: Saint James Healthcare
state: Montana
city: Neptune
country: United States
facility: Jersey Shore University Medical Center
state: New Jersey
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: Winston-Salem
country: United States
facility: All-Trials Clinical Research, LLC
state: North Carolina
city: Akron
country: United States
facility: Summa Health System
state: Ohio
city: Columbus
country: United States
facility: Remington-Davis Clinical Research
state: Ohio
city: Rapid City
country: United States
facility: Rapid City Regional Hospital
state: South Dakota
city: Houston
country: United States
facility: St. Lukes Episcopal Hospital
state: Texas
city: Temple
country: United States
facility: Scott and White Memorial Hospital
state: Texas
city: Tacoma
country: United States
facility: MultiCare Health System Research Services
state: Washington
city: Calgary
country: Canada
facility: University of Calgary Foothills Medical Center
state: Alberta
city: Victoria
country: Canada
facility: Vancouver Island Health Research Centre
state: British Columbia
city: Winnepeg
country: Canada
facility: Health Sciences Centre, University of Manitoba
state: Manitoba
city: Kingston
country: Canada
facility: Kingston General Hospital
state: Ontario
city: WIndsor
country: Canada
facility: Windsor Regional Hospital
state: Ontario
city: Chicoutimi
country: Canada
facility: Centre de Sante et Services Sociaux de Chicoutimi
state: Quebec
city: Trois-Rivieres
country: Canada
facility: Centre Hospitalier Regional de Trois-Rivieres
state: Quebec
Study officials:
affiliation: Kaiser Permanente
name: Roger Baxter, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: St. Lukes Episcopal Hospital, Houston, TX
name: Herbert DuPont, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Scott and White Memorial Hospital, Temple, TX
name: Joseph White, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: MultiCare Health System Research Services, Tacoma, WA
name: David Chen, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Rapid City Regional Hospital, Rapid City, SD
name: Jorge Reyno, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Mount Sinai Hospital, New York, NY
name: Henry S. Sacks, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Manitoba, Health Sciences Centre, Winnepeg, Manitoba, Canada
name: Charles N. Bernstein, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Summa Health Systems, Akron, Ohio
name: Michael J. Tan, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: All-Trials Clinical Research, LLC, Winston-Salem, NC
name: Michael C. Meadors, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Remington-Davis Clinical Research
name: Ian M. Baird, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Hospitalier Regional de Trois-Rivieres
name: Andre Poirier, MD, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: Idaho Falls Infectious Diseases, PLLC
name: Martha I. Buitrago, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: UCLA CURE Digestive Diseases Research Center
name: Thomas Kovacs, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Christiana Care Health Systems
name: Alfred Bacon, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Jersey Shore University Medical Center
name: Kathleen Casey, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: St. Luke's Hospital, Kansas City, Missouri
name: C. Douglas Cochran, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Vancouver Island Health Research Centre
name: Donald Daly, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Windsor Regional Hospital
name: Anil Dhar, MBBS
role: PRINCIPAL_INVESTIGATOR
affiliation: Kingston Health Sciences Centre
name: Gerald Evans, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Kentucky
name: Richard Greenberg, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Calgary Foothills Medical Center
name: Thomas Louie, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Central Indiana Gastroenterology Group
name: Thomas Nowak, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Dr. Kiran C. Patel Research Institute
name: Jose Prieto, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Chest, Infectious Diseases and Critical Care Assoc., PC
name: Daniel Schroeder, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Henry Ford Health System
name: Ann Silverman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Mercury Street Medical Group
name: John Pullman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: LAC+USC Medical Center
name: Rodney J Mason, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre de Sante et de Services Sociaux de Chicoutimi
name: Doria Grimard, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Mayo Clinic
name: Darrell Pardi, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.