Title

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
  • Phase

    Phase 2
  • Study Type

    Interventional
  • Study Participants

    200
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.
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 Started
Jul 20
2006
Primary Completion
Jun 25
2008
Study Completion
Jun 25
2008
Results Posted
Feb 09
2021
Last Update
Feb 09
2021

Biological GS-CDA1/MDX-1388

One Intravenous dose

Biological normal saline

One Intravenous dose

Placebo Placebo Comparator

Biological: normal saline (0.9% sodium chloride) One Intravenous dose

GS-CDA1/MDX-1388 Experimental

Biological: GS-CDA1/MDX-1388 One Intravenous dose

Criteria

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.

Summary

GS-CDA1/MDX-1388

Placebo

All Events

Event Type Organ System Event Term GS-CDA1/MDX-1388 Placebo

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.

GS-CDA1/MDX-1388

Placebo

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

GS-CDA1/MDX-1388

Blood And Lymphatic System Disorders

30.0
Adverse Events

Cardiac Disorders

13.0
Adverse Events

Ear and Labyrinth

3.0
Adverse Events

Endocrine Disorders

Eye Disorder

7.0
Adverse Events

Gastrointestinal Disorders

312.0
Adverse Events

General Disorders

91.0
Adverse Events

Hepatobiliary Disorders

1.0
Adverse Events

Immune Disorders

1.0
Adverse Events

Infections And Infestations

68.0
Adverse Events

Injury, Poisoning And Procedural Complications

9.0
Adverse Events

Investigations

18.0
Adverse Events

Metabolism And Nutrition Disorders

55.0
Adverse Events

Musculoskeletal And Connective Tissue Disorders

37.0
Adverse Events

Neoplasms Benign, Malignant And Unspecified (Incl Cysts And Polyps)

3.0
Adverse Events

Nervous System Disorders

61.0
Adverse Events

Psychiatric Disorders

11.0
Adverse Events

Renal And Urinary Disorders

9.0
Adverse Events

Reproductive System And Breast Disorders

6.0
Adverse Events

Respiratory, Thoracic And Mediastinal Disorders

36.0
Adverse Events

Skin And Subcutaneous Tissue Disorders

27.0
Adverse Events

Surgical And Medical Procedures

4.0
Adverse Events

Vascular Disorders

9.0
Adverse Events

Placebo

Blood And Lymphatic System Disorders

41.0
Adverse Events

Cardiac Disorders

20.0
Adverse Events

Ear and Labyrinth

3.0
Adverse Events

Endocrine Disorders

1.0
Adverse Events

Eye Disorder

7.0
Adverse Events

Gastrointestinal Disorders

395.0
Adverse Events

General Disorders

128.0
Adverse Events

Hepatobiliary Disorders

1.0
Adverse Events

Immune Disorders

Infections And Infestations

83.0
Adverse Events

Injury, Poisoning And Procedural Complications

19.0
Adverse Events

Investigations

30.0
Adverse Events

Metabolism And Nutrition Disorders

128.0
Adverse Events

Musculoskeletal And Connective Tissue Disorders

46.0
Adverse Events

Neoplasms Benign, Malignant And Unspecified (Incl Cysts And Polyps)

1.0
Adverse Events

Nervous System Disorders

79.0
Adverse Events

Psychiatric Disorders

36.0
Adverse Events

Renal And Urinary Disorders

9.0
Adverse Events

Reproductive System And Breast Disorders

1.0
Adverse Events

Respiratory, Thoracic And Mediastinal Disorders

61.0
Adverse Events

Skin And Subcutaneous Tissue Disorders

17.0
Adverse Events

Surgical And Medical Procedures

3.0
Adverse Events

Vascular Disorders

19.0
Adverse Events

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.

GS-CDA1/MDX-1388

3.0
Days (Median)
Full Range: 0.0 to 84.0

Placebo

3.0
Days (Median)
Full Range: 0.0 to 58.0

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.

GS-CDA1/MDX-1388

21.0
Participants

Placebo

24.0
Participants

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.

GS-CDA1/MDX-1388

29.0
Participants

Placebo

37.0
Participants

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

GS-CDA1/MDX-1388

GS-CDA1 (Toxin A)

115197.1
AUC0-∞ (hours x μg/ml) (Mean)
Standard Deviation: 37546.90

MDX-1388 (Toxin B)

98540.9
AUC0-∞ (hours x μg/ml) (Mean)
Standard Deviation: 129413.74

Placebo

GS-CDA1 (Toxin A)

MDX-1388 (Toxin B)

Total

200
Participants

Age, Continuous

64
years (Mean)
Standard Deviation: 15.62

A modified Horn's index for severity of underlying disease

2
Scores on a severity scale (Median)
Full Range: 1.0 to 4.0

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Sex: Female, Male

Overall Study

GS-CDA1/MDX-1388

Placebo

Drop/Withdrawal Reasons

GS-CDA1/MDX-1388

Placebo