Clostridium Infections
Conditions
Keywords
Monoclonal antibody,, Clostridium difficile Associated Diarrhea
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.
Interventions
BIOLOGICALGS-CDA1/MDX-1388
One Intravenous dose
BIOLOGICALnormal saline
One Intravenous dose
Sponsors
Medarex
MassBiologics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Recurrence of Clostridium Difficile Associated Disease (CDAD) | Day 0 to Day 84 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Day 0 to Day 84 | 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 |
| Time to Resolution of Initial CDAD Episode | Day 0 to Day 84 | 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. |
| Number of Patients With Standard of Care Treatment Failure | Day 0 to Day 84 | 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. |
| Number of Patients With Severe Initial C. Difficile Disease | Day 0 to Day 84 | 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. |
| Antibody Concentrations to Toxin A and to Toxin B Between Treatment Groups | Day 0 to Day 84 | 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 |
Countries
Canada, United States
Participant flow
Recruitment details
Inpatients and outpatients diagnosed with laboratory confirmed C. difficile disease whose physicians had opted to treat with standard of care (SOC) antibiotics, metronidazole by mouth (po)/ Intravenous (IV) or vancomycin po. A patient is considered eligible to participate in the study if a stool sample collected within 14 days of enrollment was positive by either the hospital/reference microbiology laboratory test or the rapid diagnostic test.
Pre-assignment details
Prior to enrollment, patients had to meet the study definition of disease which allowed the inclusion of patients with moderate to severe diarrhea or colitis with or without accompanying systemic symptoms/signs (such as fever, nausea, anorexia, leukocytosis, abdominal pain, cramping or discomfort) whose disease was likely to continue for at least a few days after study enrollment.
Participants by arm
| Arm | Count |
|---|---|
| GS-CDA1/MDX-1388 Biological: GS-CDA1/MDX-1388 One Intravenous dose | 101 |
| Placebo Biological: normal saline (0.9% sodium chloride) One Intravenous dose | 99 |
| Total | 200 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 7 | 8 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | GS-CDA1/MDX-1388 | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 63 years STANDARD_DEVIATION 16.24 | 64 years STANDARD_DEVIATION 15.02 | 64 years STANDARD_DEVIATION 15.62 |
| A modified Horn's index for severity of underlying disease | 2 Scores on a severity scale | 2 Scores on a severity scale | 2 Scores on a severity scale |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 6 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 97 Participants | 93 Participants | 190 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 6 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 9 Participants | 13 Participants |
| Race (NIH/OMB) White | 91 Participants | 84 Participants | 175 Participants |
| Sex: Female, Male Female | 61 Participants | 71 Participants | 132 Participants |
| Sex: Female, Male Male | 40 Participants | 28 Participants | 68 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 7 / 101 | 8 / 99 |
| other Total, other adverse events | 100 / 101 | 99 / 99 |
| serious Total, serious adverse events | 18 / 101 | 28 / 99 |
Outcome results
Primary
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.
Time frame: Day 0 to Day 84
Population: 200 subjects who met the eligibility criteria and signed the informed consent and received standard of care treatment randomized 1:1 treatment allocation to receive study treatment: 101 subjects in the GS-CDA1/MDX-1388 (Monoclonal antibody (Mab)) treatment group and 99 subjects in the placebo treatment group
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GS-CDA1/MDX-1388 | Number of Participants With Recurrence of Clostridium Difficile Associated Disease (CDAD) | 7 Participants |
| Placebo | Number of Participants With Recurrence of Clostridium Difficile Associated Disease (CDAD) | 25 Participants |
Secondary
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
Time frame: Day 0 to Day 84
Population: 200 subjects who met the eligibility criteria and signed the informed consent randomized to receive study treatment: 101 in the GS-CDA1 and MDX-1388 (Monoclonal antibody (Mab)) treatment group and 99 in the placebo treatment group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GS-CDA1/MDX-1388 | Antibody Concentrations to Toxin A and to Toxin B Between Treatment Groups | GS-CDA1 (Toxin A) | 115197.1 AUC0-∞ (hours x μg/ml) | Standard Deviation 37546.9 |
| GS-CDA1/MDX-1388 | Antibody Concentrations to Toxin A and to Toxin B Between Treatment Groups | MDX-1388 (Toxin B) | 98540.9 AUC0-∞ (hours x μg/ml) | Standard Deviation 129413.74 |
| Placebo | Antibody Concentrations to Toxin A and to Toxin B Between Treatment Groups | GS-CDA1 (Toxin A) | NA AUC0-∞ (hours x μg/ml) | — |
| Placebo | Antibody Concentrations to Toxin A and to Toxin B Between Treatment Groups | MDX-1388 (Toxin B) | NA AUC0-∞ (hours x μg/ml) | — |
Secondary
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.
Time frame: Day 0 to Day 84
Population: 200 subjects who met the eligibility criteria and signed the informed consent randomized to receive study treatment: 101 in the GS-CDA1 and MDX-1388 (Monoclonal antibody (Mab)) treatment group and 99 in the placebo treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GS-CDA1/MDX-1388 | Number of Patients With Severe Initial C. Difficile Disease | 29 Participants |
| Placebo | Number of Patients With Severe Initial C. Difficile Disease | 37 Participants |
Secondary
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.
Time frame: Day 0 to Day 84
Population: 200 subjects who met the eligibility criteria and signed the informed consent and received standard of care treatment were randomized 1:1 treatment allocation to receive study treatment: 101 subjects in the GS-CDA1/MDX-1388 (Monoclonal antibody (Mab)) treatment group and 99 subjects in the placebo treatment group
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GS-CDA1/MDX-1388 | Number of Patients With Standard of Care Treatment Failure | 21 Participants |
| Placebo | Number of Patients With Standard of Care Treatment Failure | 24 Participants |
Secondary
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
Time frame: Day 0 to Day 84
Population: 200 subjects who met the eligibility criteria and signed the informed consent and received standard of care treatment randomized 1:1 treatment allocation to receive study treatment: 101 subjects in the GS-CDA1/MDX-1388 (Monoclonal antibody (Mab)) treatment group and 99 subjects in the placebo treatment group
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GS-CDA1/MDX-1388 | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Blood And Lymphatic System Disorders | 30 Adverse Events |
| GS-CDA1/MDX-1388 | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Cardiac Disorders | 13 Adverse Events |
| GS-CDA1/MDX-1388 | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Ear and Labyrinth | 3 Adverse Events |
| GS-CDA1/MDX-1388 | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Endocrine Disorders | 0 Adverse Events |
| GS-CDA1/MDX-1388 | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Eye Disorder | 7 Adverse Events |
| GS-CDA1/MDX-1388 | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Gastrointestinal Disorders | 312 Adverse Events |
| GS-CDA1/MDX-1388 | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | General Disorders | 91 Adverse Events |
| GS-CDA1/MDX-1388 | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Hepatobiliary Disorders | 1 Adverse Events |
| GS-CDA1/MDX-1388 | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Immune Disorders | 1 Adverse Events |
| GS-CDA1/MDX-1388 | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Infections And Infestations | 68 Adverse Events |
| GS-CDA1/MDX-1388 | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Injury, Poisoning And Procedural Complications | 9 Adverse Events |
| GS-CDA1/MDX-1388 | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Investigations | 18 Adverse Events |
| GS-CDA1/MDX-1388 | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Metabolism And Nutrition Disorders | 55 Adverse Events |
| GS-CDA1/MDX-1388 | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Musculoskeletal And Connective Tissue Disorders | 37 Adverse Events |
| GS-CDA1/MDX-1388 | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Neoplasms Benign, Malignant And Unspecified (Incl Cysts And Polyps) | 3 Adverse Events |
| GS-CDA1/MDX-1388 | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Nervous System Disorders | 61 Adverse Events |
| GS-CDA1/MDX-1388 | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Psychiatric Disorders | 11 Adverse Events |
| GS-CDA1/MDX-1388 | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Renal And Urinary Disorders | 9 Adverse Events |
| GS-CDA1/MDX-1388 | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Reproductive System And Breast Disorders | 6 Adverse Events |
| GS-CDA1/MDX-1388 | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Respiratory, Thoracic And Mediastinal Disorders | 36 Adverse Events |
| GS-CDA1/MDX-1388 | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Skin And Subcutaneous Tissue Disorders | 27 Adverse Events |
| GS-CDA1/MDX-1388 | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Surgical And Medical Procedures | 4 Adverse Events |
| GS-CDA1/MDX-1388 | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Vascular Disorders | 9 Adverse Events |
| Placebo | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Investigations | 30 Adverse Events |
| Placebo | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Blood And Lymphatic System Disorders | 41 Adverse Events |
| Placebo | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Renal And Urinary Disorders | 9 Adverse Events |
| Placebo | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Cardiac Disorders | 20 Adverse Events |
| Placebo | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Metabolism And Nutrition Disorders | 128 Adverse Events |
| Placebo | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Ear and Labyrinth | 3 Adverse Events |
| Placebo | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Skin And Subcutaneous Tissue Disorders | 17 Adverse Events |
| Placebo | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Endocrine Disorders | 1 Adverse Events |
| Placebo | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Musculoskeletal And Connective Tissue Disorders | 46 Adverse Events |
| Placebo | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Eye Disorder | 7 Adverse Events |
| Placebo | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Reproductive System And Breast Disorders | 1 Adverse Events |
| Placebo | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Gastrointestinal Disorders | 395 Adverse Events |
| Placebo | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Neoplasms Benign, Malignant And Unspecified (Incl Cysts And Polyps) | 1 Adverse Events |
| Placebo | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | General Disorders | 128 Adverse Events |
| Placebo | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Vascular Disorders | 19 Adverse Events |
| Placebo | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Hepatobiliary Disorders | 1 Adverse Events |
| Placebo | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Nervous System Disorders | 79 Adverse Events |
| Placebo | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Immune Disorders | 0 Adverse Events |
| Placebo | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Respiratory, Thoracic And Mediastinal Disorders | 61 Adverse Events |
| Placebo | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Infections And Infestations | 83 Adverse Events |
| Placebo | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Psychiatric Disorders | 36 Adverse Events |
| Placebo | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Injury, Poisoning And Procedural Complications | 19 Adverse Events |
| Placebo | Safety and Tolerability of Study Treatment by the Number of Adverse Events Reported | Surgical And Medical Procedures | 3 Adverse Events |
Secondary
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.
Time frame: Day 0 to Day 84
Population: 200 subjects who met the eligibility criteria and signed the informed consent and received standard of care treatment were randomized 1:1 treatment allocation to receive study treatment: 101 subjects in the GS-CDA1/MDX-1388 (Monoclonal antibody (Mab)) treatment group and 99 subjects in the placebo treatment group
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GS-CDA1/MDX-1388 | Time to Resolution of Initial CDAD Episode | 3 Days |
| Placebo | Time to Resolution of Initial CDAD Episode | 3 Days |