Pneumonia, Staphylococcal, Pneumonia, Ventilator-associated
Conditions
Keywords
Pneumonia, S. aureus, Mechanically ventilated
Brief summary
The purpose of this study is the prevention of Staphylococcus aureus pneumonia in mechanically ventilated subjects heavily colonized with S. aureus. Staphylococcus aureus is a human pathogenic bacterium that causes severe infections, including pneumonia and sepsis. Hospital-acquired bacterial pneumonia (HABP) caused by S. aureus, including ventilator-associated bacterial pneumonia (VABP) in mechanically ventilated subjects, is a significant public health threat despite efforts to optimize antibiotic treatment. ASN100 is an investigational monoclonal antibody product that targets the toxins produced by S. aureus to protect subjects from developing S. aureus pneumonia.
Detailed description
This is a double-blind, randomized, single-dose, placebo-controlled study of ASN100 for the prevention of S. aureus pneumonia in mechanically ventilated subjects who are heavily colonized with S. aureus. This will be a global study conducted at approximately 65 sites to assess the safety, tolerability, and efficacy of ASN100. Eligible subjects who meet all of the inclusion criteria and none of the exclusion criteria will be screened by semi-quantitative culture of an endotracheal aspirate (ETA) to identify those who are heavily colonized with S. aureus (3+ to 4+). Upon determination of eligibility, subjects will be randomized in a 1:1 ratio to 1 of 2 treatment groups, ASN100 or placebo.
Interventions
DRUGASN100
monoclonal antibody combination of ASN-1 and ASN-2
DRUGPlacebo
Placebo
Sponsors
Arsanis, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
\- Subject is currently hospitalized and is mechanically ventilated endotracheally (i.e., orotracheal or nasotracheal) and, in the Investigator's opinion, will require ongoing ventilator support for at least 48 hours;
Exclusion criteria
* Subject has a chest X-ray or thoracic computed tomography (CT) scan that is definitive for a diagnosis of pneumonia * Subject has a known and documented ETA culture showing heavy colonization with a -Gram-negative organism at enrollment or at any time during the Screening period; * Significant Neutropenia * Severe non-pulmonary source of infection. * Subjects with a known history or current (suspected) diagnosis of cytokine release syndrome associated with the administration of peptides, proteins, and/or antibodies.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of a Single Intravenous (IV) Dose of ASN100 | Incidence of S. aureus pneumonia up to but not including Day 22 | Percentage of subjects in the MITT population who have or have not developed S. aureus (SA) pneumonia after a single intravenous (IV) dose of ASN100, based on sponsor defined outcome (SDO1). For each arm, the empirical proportion is defined by a ratio, which is the number of SA pneumonia events divided by the total number of subjects in the arm. The inference about the difference of two population rates is based on the empirical counterpart; specifically, the point estimate, 95% confidence interval and p-value for the rate difference. Subjects discontinued from the study due to any cause prior to Day 22 were considered as not developing SA pneumonia for the primary efficacy analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Length of ICU Stay | 21 days | Total length of ICU stay during the first 21 days post-randomization for subjects in the MITT Population |
| 28-day All-cause Mortality | 28 days | 28-day all-cause mortality in the MITT Population |
| ASN-1 and ASN-2 Maximum Serum Concentration (Cmax) | through day 90 | The levels of ASN-1 and ASN-2 measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 (final study visit) in subjects who are hospitalized or are able to return to the clinic for blood sampling. |
| Duration of Mechanical Ventilation | 21 days | Duration of mechanical ventilation during the first 21 days post-randomization for subjects in the Modified Intent-to-Treat (MITT) Population |
| ASN-1 and ASN-2 Area Under the Concentration-time Curve in Serum | through day 90 | The levels of ASN-1 and ASN-2 measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 after completion |
| ASN-1 and ASN-2 Terminal Elimination Half-life (t1/2) in Serum | through day 90 | The levels of ASN-1 and ASN-2 measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 after completion |
| ASN-1 and ASN-2 Time to Maximum Concentration (Tmax) in Serum | through day 90 | The levels of ASN-1 and ASN-2 measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 after completion |
Countries
Austria, Czechia, France, Georgia, Hungary, India, Israel, Poland, Portugal, Romania, Russia, Serbia, South Africa, Spain, Ukraine, United States
Participant flow
Recruitment details
Subjects were randomized at 35 centers in the United States, Austria, Czechia, France, India, Israel, Poland, Portugal, Romania, Serbia, Spain, Rep. of Georgia, and Russian Federation
Pre-assignment details
Eligible subjects underwent daily screening of endotracheal aspirates to determine if they met randomization criteria. Only subjects who were randomized are included in the study analysis and summarized in the Participant Flow. A single subject was randomized/treated in a site-specific pneumonia treatment sub-study.
Participants by arm
| Arm | Count |
|---|---|
| ASN100 ASN100 administered as 2 separate intravenous (IV) infusions
ASN100 3600 mg: monoclonal antibody combination of ASN-1(1800 mg) and ASN-2(1800 mg) \[administered once\] | 76 |
| Placebo Placebo administered as 2 separate intravenous (IV) infusions
Placebo: Placebo \[administered once\] | 76 |
| Total | 152 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 40 | 32 |
| Overall Study | Lost to Follow-up | 5 | 2 |
| Overall Study | Prohibited Concomitant Medication | 0 | 1 |
| Overall Study | Transfer to Hospice Care | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Total | ASN100 | Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 69 Participants | 36 Participants | 33 Participants |
| Age, Categorical Between 18 and 65 years | 83 Participants | 40 Participants | 43 Participants |
| Age, Continuous | 62.5 years | 63.5 years | 62 years |
| Body Mass Index Category | 27.07 kg/m^2 STANDARD_DEVIATION 5.209 | 26.98 kg/m^2 STANDARD_DEVIATION 5.985 | 27.17 kg/m^2 STANDARD_DEVIATION 4.335 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 141 Participants | 70 Participants | 71 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 2 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 | 4 Participants | 0 Participants |
| Race (NIH/OMB) White | 145 Participants | 71 Participants | 74 Participants |
| Region of Enrollment Austria | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Czechia | 1 participants | 1 participants | 0 participants |
| Region of Enrollment France | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Georgia | 63 participants | 34 participants | 29 participants |
| Region of Enrollment India | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Israel | 4 participants | 1 participants | 3 participants |
| Region of Enrollment Poland | 9 participants | 4 participants | 5 participants |
| Region of Enrollment Portugal | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Romania | 3 participants | 1 participants | 2 participants |
| Region of Enrollment Russia | 42 participants | 19 participants | 23 participants |
| Region of Enrollment Serbia | 3 participants | 2 participants | 1 participants |
| Region of Enrollment Spain | 2 participants | 1 participants | 1 participants |
| Region of Enrollment United States | 21 participants | 10 participants | 11 participants |
| Sex: Female, Male Female | 52 Participants | 26 Participants | 26 Participants |
| Sex: Female, Male Male | 100 Participants | 50 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 41 / 77 | 32 / 77 |
| other Total, other adverse events | 74 / 77 | 69 / 77 |
| serious Total, serious adverse events | 49 / 77 | 38 / 77 |
Outcome results
Primary
Efficacy of a Single Intravenous (IV) Dose of ASN100
Percentage of subjects in the MITT population who have or have not developed S. aureus (SA) pneumonia after a single intravenous (IV) dose of ASN100, based on sponsor defined outcome (SDO1). For each arm, the empirical proportion is defined by a ratio, which is the number of SA pneumonia events divided by the total number of subjects in the arm. The inference about the difference of two population rates is based on the empirical counterpart; specifically, the point estimate, 95% confidence interval and p-value for the rate difference. Subjects discontinued from the study due to any cause prior to Day 22 were considered as not developing SA pneumonia for the primary efficacy analysis.
Time frame: Incidence of S. aureus pneumonia up to but not including Day 22
Population: MITT: There are 2 SDO definitions. SDO1 meets either respiratory OR signs/symptoms requirements while SDO2 must meet BOTH. Individual assessments for each randomized subject were collapsed to assign a SDO1/SDO2 of Yes, No, Indeterminate (insufficient data to assign a SDO of Yes or No), or Censored (subject died prior to the Day 22 assessment).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ASN100 | Efficacy of a Single Intravenous (IV) Dose of ASN100 | Censored | 20 Participants |
| ASN100 | Efficacy of a Single Intravenous (IV) Dose of ASN100 | Indeterminate | 9 Participants |
| ASN100 | Efficacy of a Single Intravenous (IV) Dose of ASN100 | Did Not Develop S. aureus Pneumonia | 42 Participants |
| ASN100 | Efficacy of a Single Intravenous (IV) Dose of ASN100 | Developed S. aureus Pneumonia | 5 Participants |
| Placebo | Efficacy of a Single Intravenous (IV) Dose of ASN100 | Indeterminate | 4 Participants |
| Placebo | Efficacy of a Single Intravenous (IV) Dose of ASN100 | Developed S. aureus Pneumonia | 7 Participants |
| Placebo | Efficacy of a Single Intravenous (IV) Dose of ASN100 | Did Not Develop S. aureus Pneumonia | 48 Participants |
| Placebo | Efficacy of a Single Intravenous (IV) Dose of ASN100 | Censored | 17 Participants |
Comparison: Subjects were analyzed for efficacy in the group to which they randomized. Sponsor defined outcomes were based on review of microbiology results from samples tested at the central lab. If sample was not sent to the central lab., determination was based on results from the local microbiology lab. In cases where both local \& central lab results were available, concordance was confirmed for S. aureus. Therefore, the analysis used local microbiology data in order to utilize a more complete dataset.p-value: 0.547Wald Test on equality of proportions
Secondary
28-day All-cause Mortality
28-day all-cause mortality in the MITT Population
Time frame: 28 days
Population: Modified Intent to treat (MITT): includes all subjects in the ITT Population (randomized subjects) who receive study drug and who are heavily colonized with S. aureus as determined by quantitative or semi-quantitative culture of an ETA specimen. Exclusion from the MITT Population was determined programmatically for each ITT subject.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ASN100 | 28-day All-cause Mortality | 30 Participants |
| Placebo | 28-day All-cause Mortality | 25 Participants |
Secondary
ASN-1 and ASN-2 Area Under the Concentration-time Curve in Serum
The levels of ASN-1 and ASN-2 measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 after completion
Time frame: through day 90
Population: Pharmacokinetic (PK) Population: All subjects in the MITT population with at least 1 serum PK sample collected post-dose. Of the 76 subjects who received ASN100, 74 were included in the PK analysis as a result of 2 not having sufficient data. Additional reductions in the number of participants analyzed is due to missing or out of window samples.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ASN100 | ASN-1 and ASN-2 Area Under the Concentration-time Curve in Serum | 44192.3 μg*h/mL | Standard Deviation 25080.9 |
| Placebo | ASN-1 and ASN-2 Area Under the Concentration-time Curve in Serum | 49366.7 μg*h/mL | Standard Deviation 29337.9 |
Secondary
ASN-1 and ASN-2 Maximum Serum Concentration (Cmax)
The levels of ASN-1 and ASN-2 measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 (final study visit) in subjects who are hospitalized or are able to return to the clinic for blood sampling.
Time frame: through day 90
Population: Pharmacokinetic (PK) Population: All subjects in the MITT population with at least 1 serum PK sample collected post-dose. Of the 76 subjects who received ASN100, 74 were included in the PK analysis as a result of 2 not having sufficient data. Additional reductions in the number of participants analyzed is due to missing or out of window samples.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ASN100 | ASN-1 and ASN-2 Maximum Serum Concentration (Cmax) | 414.43 μg/mL | Standard Deviation 125.55 |
| Placebo | ASN-1 and ASN-2 Maximum Serum Concentration (Cmax) | 460.88 μg/mL | Standard Deviation 149.76 |
Secondary
ASN-1 and ASN-2 Terminal Elimination Half-life (t1/2) in Serum
The levels of ASN-1 and ASN-2 measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 after completion
Time frame: through day 90
Population: Pharmacokinetic (PK) Population: All subjects in the MITT population with at least 1 serum PK sample collected post-dose. Of the 76 subjects who received ASN100, 74 were included in the PK analysis as a result of 2 not having sufficient data. Additional reductions in the number of participants analyzed is due to missing or out of window samples.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ASN100 | ASN-1 and ASN-2 Terminal Elimination Half-life (t1/2) in Serum | 178.9 Hours | Standard Deviation 101.13 |
| Placebo | ASN-1 and ASN-2 Terminal Elimination Half-life (t1/2) in Serum | 185.1 Hours | Standard Deviation 136.09 |
Secondary
ASN-1 and ASN-2 Time to Maximum Concentration (Tmax) in Serum
The levels of ASN-1 and ASN-2 measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 after completion
Time frame: through day 90
Population: Pharmacokinetic (PK) Population: All subjects in the MITT population with at least 1 serum PK sample collected post-dose. Of the 76 subjects who received ASN100, 74 were included in the PK analysis as a result of 2 not having sufficient data. Additional reductions in the number of participants analyzed is due to missing or out of window samples.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ASN100 | ASN-1 and ASN-2 Time to Maximum Concentration (Tmax) in Serum | 6.34 Hours (from end of infusion) | Standard Deviation 10.25 |
| Placebo | ASN-1 and ASN-2 Time to Maximum Concentration (Tmax) in Serum | 4.52 Hours (from end of infusion) | Standard Deviation 5.77 |
Secondary
Duration of Mechanical Ventilation
Duration of mechanical ventilation during the first 21 days post-randomization for subjects in the Modified Intent-to-Treat (MITT) Population
Time frame: 21 days
Population: Modified Intent to Treat (MITT): Includes All subjects in ITT Population (randomized) who received study drug and were heavily colonized with S. aureus determined by quantitative or semi-quant. culture of an ETA specimen. Exclusion from the MITT was determined programmatically. Subjects on MV \< 2 days post treatment were excluded from analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ASN100 | Duration of Mechanical Ventilation | 11.6 Days | Standard Deviation 7.47 |
| Placebo | Duration of Mechanical Ventilation | 10.1 Days | Standard Deviation 6.93 |
Secondary
Length of ICU Stay
Total length of ICU stay during the first 21 days post-randomization for subjects in the MITT Population
Time frame: 21 days
Population: Modified Intent to Treat (MITT): Includes all subjects in ITT Population (randomized) who received study drug and were heavily colonized with S. aureus determined by quantitative/semi-quant. culture of an ETA specimen. Exclusion from the MITT determined programmatically. Subjects not listed as being in ICU post treatment were excluded from analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ASN100 | Length of ICU Stay | 13.7 Days | Standard Deviation 6.69 |
| Placebo | Length of ICU Stay | 13.6 Days | Standard Deviation 7.21 |