Staphylococcal Bacteraemia
Conditions
Keywords
Bacteremia, Dalbavancin, DOTS, Efficacy, Safety, Staphylococcus aureus
Brief summary
This is a Phase 2b clinical study, multicenter, randomized, open-label, assessor-blinded, superiority study. The study will compare dalbavancin to standard of care antibiotic therapy for the completion of therapy in patients with complicated bacteremia or right-sided native valve Infective Endocarditis (IE) caused by S. aureus who have cleared their baseline bacteremia. Approximately 200 subjects will be randomized 1:1 to receive either dalbavancin or a standard of care antibiotic regimen that is based upon the identification and antibiotic susceptibility pattern of the baseline organism. Subjects randomized to the dalbavancin treatment group will receive 2 doses of dalbavancin intravenously (IV) 1 week apart (1500 mg on Day 1 and Day 8 after randomization, with renal dose adjustment if appropriate). Subjects randomized to the standard of care antibiotic therapy treatment group will receive an antibiotic regimen considered to be standard of care based on the methicillin susceptibility pattern of the pathogen isolated at baseline for a duration of 4 to 6 weeks and up to 8 weeks for patients with vertebral osteomyelitis/discitis. The primary objective is to compare the Desirability of Outcome Ranking (DOOR) at Day 70 of dalbavancin to that of standard of care antibiotic therapy used to consolidate therapy for the treatment of subjects with complicated S. aureus bacteremia in the intent-to-treat population (ITT).
Detailed description
This is a Phase 2b clinical study, multicenter, randomized, open-label, assessor-blinded, superiority study. The study will compare dalbavancin to standard of care antibiotic therapy for the completion of therapy in patients with complicated bacteremia or right-sided native valve Infective Endocarditis (IE) caused by S. aureus who have cleared their baseline bacteremia. Approximately 200 subjects will be randomized 1:1 to receive either dalbavancin or a standard of care antibiotic regimen that is based upon the identification and antibiotic susceptibility pattern of the baseline organism. Subjects randomized to the dalbavancin treatment group will receive 2 doses of dalbavancin intravenously (IV) 1 week apart (1500 mg on Day 1 and Day 8 after randomization, with renal dose adjustment if appropriate). Subjects randomized to the standard of care antibiotic therapy treatment group will receive an antibiotic regimen considered to be standard of care based on the methicillin susceptibility pattern of the pathogen isolated at baseline for a duration of 4 to 6 weeks and up to 8 weeks for patients with vertebral osteomyelitis/discitis. The primary objective is to compare the Desirability of Outcome Ranking (DOOR) at Day 70 of dalbavancin to that of standard of care antibiotic therapy used to consolidate therapy for the treatment of subjects with complicated S. aureus bacteremia in the intent-to-treat population (ITT). The secondary objectives are 1) to compare the clinical outcomes of dalbavancin with the standard of care antibiotic therapy at day 70 in the modified intent-to-treat population (mITT). 2) to compare the safety of dalbavancin with that of the standard of care treatment in the modified intent-to-treat population (mITT). 3) to compare each individual component of the Desirability of Outcome Ranking (DOOR) outcome by treatment arm, in the intent-to-treat population.
Interventions
DRUGCefazolin
Cefazolin is a semisynthetic cephalosporin analog with broad-spectrum antibiotic action due to inhibition of bacterial cell wall synthesis. Cefazolin (2 g will be administrated intravenously (IV) every 8 hours for 4-6 weeks)
DRUGDalbavancin
A second-generation lipoglycopeptide antibiotic synthesized from a fermentation product of Nonomuraea species
DRUGDaptomycin
Daptomycin (USA) or Cubicin (Spain) is a cyclic lipopeptide antibiotic that inhibits gram-positive bacteria. Daptomycin (6-10 mg/kg will be administrated intravenously (IV) daily for 4-6 weeks
DRUGNafcillin
Nafcillin is a semi-synthetic antibiotic related to penicillin. Nafcillin (2 g will be administrated intravenously (IV) every 4 hours for 4-6 weeks)
DRUGOxacillin
Oxacillin is an antibiotic used in resistant staphylococci infections. Oxacillin (2 g will be administrated intravenously (IV) every 4 hours for 4-6 weeks
DRUGVancomycin
Vancomycin is a glycopeptide antibiotic product of the organism Amycolatopsis orientalis. Vancomycin (dose per local standard of care × 4-6 weeks)
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
1. Written informed consent obtained from the patient or legally authorized representative before the initiation of any study-specific procedures. 2. Patients \> / = to 18 years old. 3. A diagnosis of complicated Staphylococcus aureus (either Methicillin-sensitive Staphylococcus aureus or Methicillin-resistant Staphylococcus aureus) bloodstream infection. 4. Treated with effective antibiotic therapy for at least 72 hours (maximum 10 days).\* \*Ten consecutive days prior to randomization is the maximum allowed treatment duration. If a subject has received intermittent or incomplete therapy earlier in the treatment course for this episode of S. aureus bacteremia, then discuss with the protocol PI and DMID Medical Officer prior to enrollment. 5. Subsequent defervescence for at least 24 hours and clearance of bacteremia from the qualifying pathogen (at Screening), with negative blood culture incubated for at least 48 hours.\*\* \*\*Two negative blood cultures incubated for 48 hours are preferred. However, if only a single blood culture set is drawn, no growth at 48 hours will be considered adequate to demonstrate clearance. If more than one culture set is drawn, all must show no growth at 48 hours to be considered evidence of clearance (e.g., 1 of 2 positive cultures would still be considered as ongoing bacteremia). 6. Provider willing to treat with either dalbavancin for two doses, or standard of care intravenous monotherapy for at least 4 and no more than 8 weeks from randomization. 7. Patients must be willing and able, if discharged, to return to the hospital or designated clinic for scheduled treatment, laboratory tests, or other procedures as required by the protocol. 8. According to the site Principal Investigator or sub-investigator assessment, patients must be expected to survive with appropriate antibiotic therapy and appropriate supportive care throughout the study.
Exclusion criteria
1. Uncomplicated bacteremia.\* \*Uncomplicated Staphylococcus aureus bacteremia is defined as all of the following: exclusion of endocarditis by echocardiography; catheter-associated bacteremia and removal of catheter; no implanted prostheses; follow-up blood cultures drawn within 48 hours after initial set that do not grow screening pathogen and all follow-up blood cultures thereafter do not grow the screening pathogen; defervescence within 72 hours of initiating effective therapy; and no evidence of metastatic sites of infection. 2. Infectious Central Nervous System events, including septic emboli, ischemic or hemorrhagic stroke, epidural abscess, or meningitis (prior/unrelated Central Nervous System events are not
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Desirability of Outcome Ranking (DOOR) | Day 70 | DOOR is a composite endpoint assessed by: (1) Clinical Failure: Lack of resolution of clinical signs and symptoms of S. aureus bacteremia such that no additional antibiotic therapy is required or anticipated for its treatment; (2) Infectious Complications such as: Endocarditis, New evidence of metastatic foci of infection, relapse - isolation of baseline S. aureus pathogen from a blood culture drawn after randomization, readmission for subsequent care of indication under study, need for additional unplanned source control procedures, or change in antibiotic therapy due to inadequate clinical response; (3) Serious Adverse Events (SAEs); (4) Adverse Events (AEs) Leading to Study Drug Discontinuation; and (5) Death. Clinical failure and infectious complications were assessed by a blinded adjudication committee. Participants missing clinical failure were treated as having clinical failure for calculation of DOOR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Clinical Efficacy | Day 70 | Number of participants that had clinical efficacy at Day 70. Clinical efficacy is defined as none of: (1) Clinical Failure: Lack of resolution of clinical signs and symptoms of S. aureus bacteremia such that no additional antibiotic therapy is required or anticipated for its treatment; (2) Infectious Complications such as: Endocarditis, New evidence of metastatic foci of infection, relapse - isolation of baseline S. aureus pathogen from a blood culture drawn after randomization, readmission for subsequent care of indication under study, need for additional unplanned source control procedures, or change in antibiotic therapy due to inadequate clinical response; and (3) Death. Clinical failure and infectious complications are assessed by a blinded adjudication committee. Participants missing clinical failure are treated as not having clinical efficacy. |
| Frequency of SAEs | Day 1 through Day 180 | Number of participants that experience any SAEs from Day 1 to study completion (Day 70 or Day 180 for participants in the osteomyelitis subset). An AE is considered serious if, in the view of either the site principal investigator or sponsor, it results in: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. |
| Frequency of AEs Leading to Study Drug Discontinuation | Day 1 through Day 180 | Number of participants that experience any AEs leading to study drug discontinuation from Day 1 to study completion (Day 70 or Day 180 for participants in the osteomyelitis subset). |
| Frequency of Clinical Failure (A Component of DOOR) | Day 70 | Number of participants who had clinical failure at Day 70, used for DOOR at Day 70. Clinical Failure is defined as lack of resolution of clinical signs and symptoms of S. aureus bacteremia such that no additional antibiotic therapy is required or anticipated for its treatment. Clinical failure is assessed by a blinded adjudication committee. Participants missing clinical failure are treated as having clinical failure. |
| Frequency of SAEs (A Component of DOOR) | Day 1 through Day 70 | Number of participants that experience any SAEs from Day 1 to Day 70, used for DOOR at Day 70. An AE is considered serious if, in the view of either the site principal investigator or sponsor, it results in: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. |
| Frequency of AEs Leading to Study Drug Discontinuation (A Component of DOOR) | Day 1 through Day 70 | Number of participants that experience any AEs leading to study drug discontinuation from Day 1 to Day 70, used for DOOR at Day 70. |
| Frequency of All-Cause Mortality (A Component of DOOR) | Day 1 through Day 70 | Number of participants who passed away from Day 1 to Day 70, used for DOOR at Day 70. |
| Frequency of Infectious Complications (A Component of DOOR) | Day 1 through Day 70 | Number of participants that experience any infectious complications from Day 1 through Day 70, used for DOOR at Day 70. Infectious complications include endocarditis, new evidence of metastatic foci of infection, relapse - isolation of baseline S. aureus pathogen from a blood culture drawn after randomization, readmission for subsequent care of indication under study, need for additional unplanned source control procedures, or change in antibiotic therapy due to inadequate clinical response. Infectious complications are assessed by a blinded adjudication committee. |
Countries
Canada, United States
Participant flow
Recruitment details
Participants were recruited from 23 clinical sites within the United States and Canada. The first participant was enrolled on April 22, 2021, and the last participant was enrolled on July 6, 2023.
Participants by arm
| Arm | Count |
|---|---|
| Dalbavancin Dalbavancin 1500 mg administrated intravenously (IV) over 30 (-/+10) minutes on Day 1 and 1500 mg IV over 30 (-/+10) minutes on Day 8, renally dose-adjusted to 1125 mg for participants with Creatinine Clearance (CrCl) \<30 and not on dialysis.
Dalbavancin: A second-generation lipoglycopeptide antibiotic synthesized from a fermentation product of Nonomuraea species | 100 |
| Standard of Care For Methicillin-sensitive Staphylococcus aureus (MSSA): nafcillin (2 g administrated intravenously (IV) every 4 hours for 4-6 weeks) OR oxacillin (2 g administrated IV every 4 hours for 4-6 weeks OR cefazolin (2 g administrated IV every 8 hours for 4-6 weeks).
For Methicillin-resistant Staphylococcus aureus (MRSA): vancomycin (dose per local standard of care × 4-6 weeks) OR daptomycin (6-10 mg/kg administrated IV daily for 4-6 weeks).
Cefazolin: Cefazolin is a semisynthetic cephalosporin analog with broad-spectrum antibiotic action due to inhibition of bacterial cell wall synthesis.
Daptomycin: Daptomycin (USA) or Cubicin (Spain) is a cyclic lipopeptide antibiotic that inhibits gram-positive bacteria.
Nafcillin: Nafcillin is a semi-synthetic antibiotic related to penicillin.
Oxacillin: Oxacillin is an antibiotic used in resistant staphylococci infections.
Vancomycin: Vancomycin is a glycopeptide antibiotic product of the organism Amycolatopsis orientalis. | 100 |
| Total | 200 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 5 | 4 |
| Overall Study | Lost to Follow-up | 6 | 11 |
| Overall Study | Participant non-compliance | 0 | 1 |
| Overall Study | Protocol Violation | 2 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | Total | Standard of Care | Dalbavancin |
|---|---|---|---|
| Age, Continuous | 54.1 years STANDARD_DEVIATION 16.2 | 54.0 years STANDARD_DEVIATION 16.8 | 54.3 years STANDARD_DEVIATION 15.7 |
| Baseline Pathogen MRSA | 66 Participants | 32 Participants | 34 Participants |
| Baseline Pathogen MSSA | 134 Participants | 68 Participants | 66 Participants |
| Body Mass Index (BMI) | 28.93 kg/m^2 STANDARD_DEVIATION 7.5 | 29.03 kg/m^2 STANDARD_DEVIATION 8.08 | 28.83 kg/m^2 STANDARD_DEVIATION 6.91 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 25 Participants | 14 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 168 Participants | 84 Participants | 84 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 49 Participants | 29 Participants | 20 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 | 6 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) White | 137 Participants | 69 Participants | 68 Participants |
| Region of Enrollment Canada | 2 participants | 0 participants | 2 participants |
| Region of Enrollment United States | 198 participants | 100 participants | 98 participants |
| Sex: Female, Male Female | 62 Participants | 32 Participants | 30 Participants |
| Sex: Female, Male Male | 138 Participants | 68 Participants | 70 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 100 | 4 / 100 |
| other Total, other adverse events | 5 / 100 | 1 / 100 |
| serious Total, serious adverse events | 43 / 100 | 37 / 100 |
Outcome results
Primary
Desirability of Outcome Ranking (DOOR)
DOOR is a composite endpoint assessed by: (1) Clinical Failure: Lack of resolution of clinical signs and symptoms of S. aureus bacteremia such that no additional antibiotic therapy is required or anticipated for its treatment; (2) Infectious Complications such as: Endocarditis, New evidence of metastatic foci of infection, relapse - isolation of baseline S. aureus pathogen from a blood culture drawn after randomization, readmission for subsequent care of indication under study, need for additional unplanned source control procedures, or change in antibiotic therapy due to inadequate clinical response; (3) Serious Adverse Events (SAEs); (4) Adverse Events (AEs) Leading to Study Drug Discontinuation; and (5) Death. Clinical failure and infectious complications were assessed by a blinded adjudication committee. Participants missing clinical failure were treated as having clinical failure for calculation of DOOR.
Time frame: Day 70
Population: The intent-to-treat (ITT) population includes all randomized participants.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dalbavancin | Desirability of Outcome Ranking (DOOR) | Rank 2: Alive with one of clinical failure, infectious comp, or SAE or AE leading to trt discont | 34 Participants |
| Dalbavancin | Desirability of Outcome Ranking (DOOR) | Rank 4: Alive with all of clinical failure, infectious comp, and SAE or AE leading to trt discont | 4 Participants |
| Dalbavancin | Desirability of Outcome Ranking (DOOR) | Rank 3: Alive with two of clinical failure, infectious comp, or SAE or AE leading to trt discont | 9 Participants |
| Dalbavancin | Desirability of Outcome Ranking (DOOR) | Rank 5: Death | 4 Participants |
| Dalbavancin | Desirability of Outcome Ranking (DOOR) | Rank 1: Alive with none of clinical failure, infectious comp, or SAE or AE leading to trt discont | 49 Participants |
| Standard of Care | Desirability of Outcome Ranking (DOOR) | Rank 5: Death | 4 Participants |
| Standard of Care | Desirability of Outcome Ranking (DOOR) | Rank 1: Alive with none of clinical failure, infectious comp, or SAE or AE leading to trt discont | 49 Participants |
| Standard of Care | Desirability of Outcome Ranking (DOOR) | Rank 2: Alive with one of clinical failure, infectious comp, or SAE or AE leading to trt discont | 37 Participants |
| Standard of Care | Desirability of Outcome Ranking (DOOR) | Rank 3: Alive with two of clinical failure, infectious comp, or SAE or AE leading to trt discont | 7 Participants |
| Standard of Care | Desirability of Outcome Ranking (DOOR) | Rank 4: Alive with all of clinical failure, infectious comp, and SAE or AE leading to trt discont | 3 Participants |
Comparison: Null Hypothesis: Probability that a participant in the dalbavancin arm has a better DOOR than a participant in the standard of care arm plus one-half the probability of equal DOOR is 50% (i.e., no difference in DOOR).95% CI: [39.84, 55.68]
Secondary
Frequency of AEs Leading to Study Drug Discontinuation
Number of participants that experience any AEs leading to study drug discontinuation from Day 1 to study completion (Day 70 or Day 180 for participants in the osteomyelitis subset).
Time frame: Day 1 through Day 180
Population: The mITT population includes all randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dalbavancin | Frequency of AEs Leading to Study Drug Discontinuation | 3 Participants |
| Standard of Care | Frequency of AEs Leading to Study Drug Discontinuation | 12 Participants |
Secondary
Frequency of AEs Leading to Study Drug Discontinuation (A Component of DOOR)
Number of participants that experience any AEs leading to study drug discontinuation from Day 1 to Day 70, used for DOOR at Day 70.
Time frame: Day 1 through Day 70
Population: The ITT population includes all randomized participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dalbavancin | Frequency of AEs Leading to Study Drug Discontinuation (A Component of DOOR) | 3 Participants |
| Standard of Care | Frequency of AEs Leading to Study Drug Discontinuation (A Component of DOOR) | 12 Participants |
Secondary
Frequency of All-Cause Mortality (A Component of DOOR)
Number of participants who passed away from Day 1 to Day 70, used for DOOR at Day 70.
Time frame: Day 1 through Day 70
Population: The ITT population includes all randomized participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dalbavancin | Frequency of All-Cause Mortality (A Component of DOOR) | 4 Participants |
| Standard of Care | Frequency of All-Cause Mortality (A Component of DOOR) | 4 Participants |
Secondary
Frequency of Clinical Efficacy
Number of participants that had clinical efficacy at Day 70. Clinical efficacy is defined as none of: (1) Clinical Failure: Lack of resolution of clinical signs and symptoms of S. aureus bacteremia such that no additional antibiotic therapy is required or anticipated for its treatment; (2) Infectious Complications such as: Endocarditis, New evidence of metastatic foci of infection, relapse - isolation of baseline S. aureus pathogen from a blood culture drawn after randomization, readmission for subsequent care of indication under study, need for additional unplanned source control procedures, or change in antibiotic therapy due to inadequate clinical response; and (3) Death. Clinical failure and infectious complications are assessed by a blinded adjudication committee. Participants missing clinical failure are treated as not having clinical efficacy.
Time frame: Day 70
Population: The modified intent-to-treat (mITT) population includes all randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dalbavancin | Frequency of Clinical Efficacy | 73 Participants |
| Standard of Care | Frequency of Clinical Efficacy | 72 Participants |
Comparison: Null Hypothesis: The proportion of clinical efficacy in the dalbavancin arm minus the proportion of clinical efficacy in the standard of care arm is -20%.95% CI: [-12, 14]
Secondary
Frequency of Clinical Failure (A Component of DOOR)
Number of participants who had clinical failure at Day 70, used for DOOR at Day 70. Clinical Failure is defined as lack of resolution of clinical signs and symptoms of S. aureus bacteremia such that no additional antibiotic therapy is required or anticipated for its treatment. Clinical failure is assessed by a blinded adjudication committee. Participants missing clinical failure are treated as having clinical failure.
Time frame: Day 70
Population: The ITT population includes all randomized participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dalbavancin | Frequency of Clinical Failure (A Component of DOOR) | 20 Participants |
| Standard of Care | Frequency of Clinical Failure (A Component of DOOR) | 22 Participants |
Secondary
Frequency of Infectious Complications (A Component of DOOR)
Number of participants that experience any infectious complications from Day 1 through Day 70, used for DOOR at Day 70. Infectious complications include endocarditis, new evidence of metastatic foci of infection, relapse - isolation of baseline S. aureus pathogen from a blood culture drawn after randomization, readmission for subsequent care of indication under study, need for additional unplanned source control procedures, or change in antibiotic therapy due to inadequate clinical response. Infectious complications are assessed by a blinded adjudication committee.
Time frame: Day 1 through Day 70
Population: The ITT population includes all randomized participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dalbavancin | Frequency of Infectious Complications (A Component of DOOR) | 13 Participants |
| Standard of Care | Frequency of Infectious Complications (A Component of DOOR) | 12 Participants |
Secondary
Frequency of SAEs
Number of participants that experience any SAEs from Day 1 to study completion (Day 70 or Day 180 for participants in the osteomyelitis subset). An AE is considered serious if, in the view of either the site principal investigator or sponsor, it results in: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect.
Time frame: Day 1 through Day 180
Population: The mITT population includes all randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dalbavancin | Frequency of SAEs | 43 Participants |
| Standard of Care | Frequency of SAEs | 37 Participants |
Secondary
Frequency of SAEs (A Component of DOOR)
Number of participants that experience any SAEs from Day 1 to Day 70, used for DOOR at Day 70. An AE is considered serious if, in the view of either the site principal investigator or sponsor, it results in: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect.
Time frame: Day 1 through Day 70
Population: The ITT population includes all randomized participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dalbavancin | Frequency of SAEs (A Component of DOOR) | 40 Participants |
| Standard of Care | Frequency of SAEs (A Component of DOOR) | 34 Participants |