Pneumonia Due to Staphylococcus Aureus
Conditions
Keywords
Pneumonia, Monoclonal antibody, Staphylococcus aureus
Brief summary
The objectives of this study are to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and clinical outcome of patients who have severe pneumonia caused by Staphylococcus aureus (S. aureus) after a single intravenous administration of KBSA301 in addition of standard of care antibiotic treatment.
Detailed description
S. aureus is a leading cause of bloodstream, skin, soft tissue, and lower respiratory tract infections worldwide. The frequencies of both nosocomial and community-acquired S. aureus infections have increased steadily over the years and the treatment of these infections has become more challenging due to the emergence of multi-drug resistant strains (e.g. methicillin-resistant Staphylococcus aureus). S. aureus has several virulence factors that contribute to the pathogenesis of the infection. Amongst them, alpha-toxin that is involved in the pathogenesis of pneumonia, as it leads to apoptosis and cell lysis, in particular lymphocytes, macrophages, alveolar epithelial cells, pulmonary endothelium, and thrombocytes. In spite of preventive measures for S. aureus infections and current medical treatment (mostly antibiotic therapy, alone or in combination), there is a clear unmet medical need in the clinic for additional treatment options. Passive immunotherapy with monoclonal antibodies may improve treatment options for severe and life-threatening infections like those caused by S. aureus.
Interventions
DRUGKBSA301
KBSA301 administered as a single intravenous infusion at dose 1, 2, 3 and 4.
DRUGPlacebo
Placebo administered as a single intravenous infusion
Sponsors
Aridis Pharmaceuticals, Inc.
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 80 Years
Healthy volunteers
No
Inclusion criteria
* Adult male or female patients ≥ 18 years and ≤ 70 years of age * Severe pneumonia caused by S. aureus (either methicillin-resistant or methicillin-sensitive) managed in an ICU * APACHE II of ≤30 at the time of diagnosis * Identification of S. aureus * Written informed consent provided by the patient, the relatives or the designated trusted person and/or according to local guidelines
Exclusion criteria
* Women of child bearing potential are excluded from the participation from the study unless they have a negative pregnancy test at baseline and during the course of the study. Postmenopausal women or females that have been surgically sterilized are allowed to participate. * Hypersensitivity to excipients or to any prescribed medication * Severe neutropenia, lymphoma or anticipated chemotherapy * Patients who have long-term tracheostomy * Current or recent investigational drug (within 30 days of enrollment, or 5 half-lives of the investigational compound, whichever is longer) * Presence of meningitis, endocarditis, or osteomyelitis * Acquired immune deficiency syndrome (AIDS) with cluster of differentiation 4 (CD4) count \<200 cells/ml * Known bronchial obstruction or a history of post-obstructive pneumonia. * Active primary lung cancer or another malignancy metastatic to the lungs * Cystic fibrosis, known or suspected Pneumocystis jiroveci pneumonia, or known or suspected active tuberculosis * Immunosuppressive therapy * Liver function deficiency * Moribund clinical condition
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy Endpoint: All-Cause Mortality by Day 28 | At Day 28 post infusion (Day 0) | A summary of the number (%) of patients who died on or before Day 28 (mITT population) is provided, by treatment group and overall. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy: All-Cause Mortality (Day 14) | Patients who died during the specified timepoints (Day 14) | A summary of the number (%) of patients who died on or before timepoints Day 14 visit (mITT population) is provided, by treatment group (overall) and placebo. |
| Efficacy: All-Cause Mortality (Day 7) | Patients who died during the specified timepoints (Day 7) | A summary of the number (%) of patients who died on or before timepoints Day 7 visit (mITT population) is provided, by treatment group (overall) and placebo. |
| Efficacy: All-Cause Mortality (Day 21) | Patients who died during the specified timepoints (Day 21) | A summary of the number (%) of patients who died on or before timepoints Day 21 visit (mITT population) is provided, by treatment group (overall) and placebo. |
| Efficacy: All-Cause Mortality (End Of Study [EOS]) | Patients who died during the specified timepoints (by EOS), up to day 107 | A summary of the number (%) of patients who died on or before timepoints Day EOS (mITT population) is provided, by treatment group (overall) and placebo. |
Countries
Belgium, France, Spain, United States
Participant flow
Recruitment details
Recruitment locations: Intensive Care Units. First subject enrolled: 16-May-2012. Last subject completed: 06-Sep-2016. The study was on administrative hold from 20-Nov-2012 to 24-Dec-2014.
Pre-assignment details
Eligible patients were randomized based on evidence of severe pneumonia caused by S. aureus. All patients enrolled were intubated.
Participants by arm
| Arm | Count |
|---|---|
| KBSA301, a Monoclonal Antibody Dose 1 1 mg/kg KBSA301
KBSA301: KBSA301 administered as a single intravenous infusion at dose 1, 2, 3 and 4. | 6 |
| KBSA301, a Monoclonal Antibody Dose 2 3 mg/kg KBSA301
KBSA301: KBSA301 administered as a single intravenous infusion at dose 1, 2, 3 and 4. | 8 |
| KBSA301, a Monoclonal Antibody Dose 3 10 mg/kg KBSA301
KBSA301: KBSA301 administered as a single intravenous infusion at dose 1, 2, 3 and 4. | 10 |
| KBSA301, a Monoclonal Antibody Dose 4 20 mg/kg KBSA301
KBSA301: KBSA301 administered as a single intravenous infusion at dose 1, 2, 3 and 4. | 8 |
| Placebo KBSA301-placebo
Placebo: Placebo administered as a single intravenous infusion | 16 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Death | 1 | 2 | 2 | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 | 2 | 3 | 0 |
Baseline characteristics
| Characteristic | KBSA301, a Monoclonal Antibody Dose 2 | KBSA301, a Monoclonal Antibody Dose 3 | KBSA301, a Monoclonal Antibody Dose 4 | KBSA301, a Monoclonal Antibody Dose 1 | Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 5 Participants | 4 Participants | 3 Participants | 4 Participants | 17 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 5 Participants | 4 Participants | 3 Participants | 12 Participants | 31 Participants |
| Age, Continuous | 49.1 years STANDARD_DEVIATION 17.02 | 61.5 years STANDARD_DEVIATION 10.3 | 60.6 years STANDARD_DEVIATION 13.62 | 64.7 years STANDARD_DEVIATION 9.97 | 52.1 years STANDARD_DEVIATION 16.23 | 56.6 years STANDARD_DEVIATION 14.77 |
| APACHE II Score | 21.5 units on a scale (score) STANDARD_DEVIATION 5.21 | 17.9 units on a scale (score) STANDARD_DEVIATION 4.15 | 19.5 units on a scale (score) STANDARD_DEVIATION 3.7 | 18.3 units on a scale (score) STANDARD_DEVIATION 3.01 | 17.5 units on a scale (score) STANDARD_DEVIATION 4.9 | 18.7 units on a scale (score) STANDARD_DEVIATION 4.48 |
| BMI | 28.1 kg/m^2 STANDARD_DEVIATION 7.3 | 31.1 kg/m^2 STANDARD_DEVIATION 6.15 | 29.1 kg/m^2 STANDARD_DEVIATION 3.88 | 32.6 kg/m^2 STANDARD_DEVIATION 9.14 | 26.8 kg/m^2 STANDARD_DEVIATION 5.39 | 29.0 kg/m^2 STANDARD_DEVIATION 6.32 |
| CPIS Score | 9.6 units on a scale (score) STANDARD_DEVIATION 2.26 | 9.6 units on a scale (score) STANDARD_DEVIATION 2.26 | 9.6 units on a scale (score) STANDARD_DEVIATION 3.7 | 8.3 units on a scale (score) STANDARD_DEVIATION 1.63 | 9.8 units on a scale (score) STANDARD_DEVIATION 1.28 | 9.6 units on a scale (score) STANDARD_DEVIATION 1.58 |
| Pa02/Fi02 Ratio | 173.7 ratio STANDARD_DEVIATION 38.36 | 138.8 ratio STANDARD_DEVIATION 53.56 | 148.4 ratio STANDARD_DEVIATION 34.49 | 146.7 ratio STANDARD_DEVIATION 30.7 | 140.7 ratio STANDARD_DEVIATION 40.7 | 147.8 ratio STANDARD_DEVIATION 41.32 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 8 Participants | 9 Participants | 8 Participants | 6 Participants | 15 Participants | 46 Participants |
| Region of Enrollment Belgium | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Region of Enrollment France | 8 participants | 9 participants | 6 participants | 4 participants | 16 participants | 43 participants |
| Region of Enrollment Spain | 0 participants | 0 participants | 0 participants | 2 participants | 0 participants | 2 participants |
| Region of Enrollment United Kingdom | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Region of Enrollment United States | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Sex: Female, Male Female | 0 Participants | 4 Participants | 1 Participants | 2 Participants | 3 Participants | 10 Participants |
| Sex: Female, Male Male | 8 Participants | 6 Participants | 7 Participants | 4 Participants | 13 Participants | 38 Participants |
| SOFA Score | 8.8 units on a scale (score) STANDARD_DEVIATION 3.45 | 5.6 units on a scale (score) STANDARD_DEVIATION 1.51 | 6.8 units on a scale (score) STANDARD_DEVIATION 1.72 | 6.8 units on a scale (score) STANDARD_DEVIATION 1.64 | 6.8 units on a scale (score) STANDARD_DEVIATION 2.86 | 6.9 units on a scale (score) STANDARD_DEVIATION 2.62 |
| Type of Pneumonia CABP | 3 Participants | 0 Participants | 1 Participants | 1 Participants | 4 Participants | 9 Participants |
| Type of Pneumonia HABP | 1 Participants | 3 Participants | 2 Participants | 0 Participants | 7 Participants | 13 Participants |
| Type of Pneumonia VABP | 4 Participants | 7 Participants | 5 Participants | 5 Participants | 5 Participants | 26 Participants |
| Type of S. aureus Infection MRSA | 0 Participants | 0 Participants | 2 Participants | 2 Participants | 2 Participants | 6 Participants |
| Type of S. aureus Infection MSSA | 8 Participants | 9 Participants | 6 Participants | 4 Participants | 14 Participants | 41 Participants |
| Type of S. aureus Infection Not confirmed | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 6 | 2 / 8 | 2 / 10 | 0 / 8 | 1 / 16 |
| other Total, other adverse events | 6 / 6 | 8 / 8 | 10 / 10 | 7 / 8 | 15 / 16 |
| serious Total, serious adverse events | 3 / 6 | 4 / 8 | 5 / 10 | 1 / 8 | 5 / 16 |
Outcome results
Primary
Efficacy Endpoint: All-Cause Mortality by Day 28
A summary of the number (%) of patients who died on or before Day 28 (mITT population) is provided, by treatment group and overall.
Time frame: At Day 28 post infusion (Day 0)
Population: The modified intent to treat (mITT) population corresponded to the safety (ITT) population minus one patient for which infection by S. aureus was not confirmed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| KBSA301, a Monoclonal Antibody Dose 1 | Efficacy Endpoint: All-Cause Mortality by Day 28 | 1 Participants |
| KBSA301, a Monoclonal Antibody Dose 2 | Efficacy Endpoint: All-Cause Mortality by Day 28 | 2 Participants |
| KBSA301, a Monoclonal Antibody Dose 3 | Efficacy Endpoint: All-Cause Mortality by Day 28 | 2 Participants |
| KBSA301, a Monoclonal Antibody Dose 4 | Efficacy Endpoint: All-Cause Mortality by Day 28 | 0 Participants |
| Placebo | Efficacy Endpoint: All-Cause Mortality by Day 28 | 0 Participants |
| All Treatment Group | Efficacy Endpoint: All-Cause Mortality by Day 28 | 5 Participants |
Secondary
Efficacy: All-Cause Mortality (Day 14)
A summary of the number (%) of patients who died on or before timepoints Day 14 visit (mITT population) is provided, by treatment group (overall) and placebo.
Time frame: Patients who died during the specified timepoints (Day 14)
Population: The modified intent to treat (mITT) population corresponded to the safety (ITT) population minus one patient for which infection by S. aureus was not confirmed.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| KBSA301, a Monoclonal Antibody Dose 1 | Efficacy: All-Cause Mortality (Day 14) | Died on or before Day 14 | 1 Participants |
| KBSA301, a Monoclonal Antibody Dose 1 | Efficacy: All-Cause Mortality (Day 14) | Survived on or before Day 14 | 5 Participants |
| KBSA301, a Monoclonal Antibody Dose 2 | Efficacy: All-Cause Mortality (Day 14) | Died on or before Day 14 | 1 Participants |
| KBSA301, a Monoclonal Antibody Dose 2 | Efficacy: All-Cause Mortality (Day 14) | Survived on or before Day 14 | 7 Participants |
| KBSA301, a Monoclonal Antibody Dose 3 | Efficacy: All-Cause Mortality (Day 14) | Died on or before Day 14 | 0 Participants |
| KBSA301, a Monoclonal Antibody Dose 3 | Efficacy: All-Cause Mortality (Day 14) | Survived on or before Day 14 | 9 Participants |
| KBSA301, a Monoclonal Antibody Dose 4 | Efficacy: All-Cause Mortality (Day 14) | Survived on or before Day 14 | 8 Participants |
| KBSA301, a Monoclonal Antibody Dose 4 | Efficacy: All-Cause Mortality (Day 14) | Died on or before Day 14 | 0 Participants |
| Placebo | Efficacy: All-Cause Mortality (Day 14) | Died on or before Day 14 | 0 Participants |
| Placebo | Efficacy: All-Cause Mortality (Day 14) | Survived on or before Day 14 | 16 Participants |
Secondary
Efficacy: All-Cause Mortality (Day 21)
A summary of the number (%) of patients who died on or before timepoints Day 21 visit (mITT population) is provided, by treatment group (overall) and placebo.
Time frame: Patients who died during the specified timepoints (Day 21)
Population: The modified intent to treat (mITT) population corresponded to the safety (ITT) population minus one patient for which infection by S. aureus was not confirmed.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| KBSA301, a Monoclonal Antibody Dose 1 | Efficacy: All-Cause Mortality (Day 21) | Died on or before Day 21 | 1 Participants |
| KBSA301, a Monoclonal Antibody Dose 1 | Efficacy: All-Cause Mortality (Day 21) | Survived on or before Day 21 | 5 Participants |
| KBSA301, a Monoclonal Antibody Dose 2 | Efficacy: All-Cause Mortality (Day 21) | Died on or before Day 21 | 2 Participants |
| KBSA301, a Monoclonal Antibody Dose 2 | Efficacy: All-Cause Mortality (Day 21) | Survived on or before Day 21 | 6 Participants |
| KBSA301, a Monoclonal Antibody Dose 3 | Efficacy: All-Cause Mortality (Day 21) | Died on or before Day 21 | 1 Participants |
| KBSA301, a Monoclonal Antibody Dose 3 | Efficacy: All-Cause Mortality (Day 21) | Survived on or before Day 21 | 8 Participants |
| KBSA301, a Monoclonal Antibody Dose 4 | Efficacy: All-Cause Mortality (Day 21) | Survived on or before Day 21 | 8 Participants |
| KBSA301, a Monoclonal Antibody Dose 4 | Efficacy: All-Cause Mortality (Day 21) | Died on or before Day 21 | 0 Participants |
| Placebo | Efficacy: All-Cause Mortality (Day 21) | Died on or before Day 21 | 0 Participants |
| Placebo | Efficacy: All-Cause Mortality (Day 21) | Survived on or before Day 21 | 16 Participants |
Secondary
Efficacy: All-Cause Mortality (Day 7)
A summary of the number (%) of patients who died on or before timepoints Day 7 visit (mITT population) is provided, by treatment group (overall) and placebo.
Time frame: Patients who died during the specified timepoints (Day 7)
Population: The modified intent to treat (mITT) population corresponded to the safety (ITT) population minus one patient for which infection by S. aureus was not confirmed.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| KBSA301, a Monoclonal Antibody Dose 1 | Efficacy: All-Cause Mortality (Day 7) | Died on or before Day 7 | 0 Participants |
| KBSA301, a Monoclonal Antibody Dose 1 | Efficacy: All-Cause Mortality (Day 7) | Survived on or before Day 7 | 6 Participants |
| KBSA301, a Monoclonal Antibody Dose 2 | Efficacy: All-Cause Mortality (Day 7) | Died on or before Day 7 | 1 Participants |
| KBSA301, a Monoclonal Antibody Dose 2 | Efficacy: All-Cause Mortality (Day 7) | Survived on or before Day 7 | 7 Participants |
| KBSA301, a Monoclonal Antibody Dose 3 | Efficacy: All-Cause Mortality (Day 7) | Died on or before Day 7 | 0 Participants |
| KBSA301, a Monoclonal Antibody Dose 3 | Efficacy: All-Cause Mortality (Day 7) | Survived on or before Day 7 | 9 Participants |
| KBSA301, a Monoclonal Antibody Dose 4 | Efficacy: All-Cause Mortality (Day 7) | Survived on or before Day 7 | 8 Participants |
| KBSA301, a Monoclonal Antibody Dose 4 | Efficacy: All-Cause Mortality (Day 7) | Died on or before Day 7 | 0 Participants |
| Placebo | Efficacy: All-Cause Mortality (Day 7) | Died on or before Day 7 | 0 Participants |
| Placebo | Efficacy: All-Cause Mortality (Day 7) | Survived on or before Day 7 | 16 Participants |
Secondary
Efficacy: All-Cause Mortality (End Of Study [EOS])
A summary of the number (%) of patients who died on or before timepoints Day EOS (mITT population) is provided, by treatment group (overall) and placebo.
Time frame: Patients who died during the specified timepoints (by EOS), up to day 107
Population: The modified intent to treat (mITT) population corresponded to the safety (ITT) population minus one patient for which infection by S. aureus was not confirmed.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| KBSA301, a Monoclonal Antibody Dose 1 | Efficacy: All-Cause Mortality (End Of Study [EOS]) | Died on or before EOS | 1 Participants |
| KBSA301, a Monoclonal Antibody Dose 1 | Efficacy: All-Cause Mortality (End Of Study [EOS]) | Survived on or before EOS | 5 Participants |
| KBSA301, a Monoclonal Antibody Dose 2 | Efficacy: All-Cause Mortality (End Of Study [EOS]) | Died on or before EOS | 2 Participants |
| KBSA301, a Monoclonal Antibody Dose 2 | Efficacy: All-Cause Mortality (End Of Study [EOS]) | Survived on or before EOS | 6 Participants |
| KBSA301, a Monoclonal Antibody Dose 3 | Efficacy: All-Cause Mortality (End Of Study [EOS]) | Died on or before EOS | 2 Participants |
| KBSA301, a Monoclonal Antibody Dose 3 | Efficacy: All-Cause Mortality (End Of Study [EOS]) | Survived on or before EOS | 7 Participants |
| KBSA301, a Monoclonal Antibody Dose 4 | Efficacy: All-Cause Mortality (End Of Study [EOS]) | Survived on or before EOS | 8 Participants |
| KBSA301, a Monoclonal Antibody Dose 4 | Efficacy: All-Cause Mortality (End Of Study [EOS]) | Died on or before EOS | 0 Participants |
| Placebo | Efficacy: All-Cause Mortality (End Of Study [EOS]) | Died on or before EOS | 1 Participants |
| Placebo | Efficacy: All-Cause Mortality (End Of Study [EOS]) | Survived on or before EOS | 15 Participants |
Comparison: The number (%) of patients who died on or before end of study (EOS) was compared among all 5 groups. The mITT population was used.p-value: 0.3962Fisher Exact