Bronchiolitis Obliterans, Chronic Lung Allograft Dysfunction, Chronic Rejection of Lung Transplant, Lung Transplant; Complications, Lung Transplant Failure and Rejection, Lung Transplant Rejection
Conditions
Brief summary
The objective of this trial is to assess the efficacy and safety of aerosolized liposomal cyclosporine A (L-CsA) as add-on therapy to standard of care (SoC) as compared to SoC alone in single lung transplant recipients with chronic lung allograft dysfunction (CLAD)-bronchiolitis obliterans syndrome (BOS).
Detailed description
BOSTON-1 was a Phase III, prospective, multicenter, randomized, open-label, controlled clinical trial of L-CsA for the treatment of BOS in adults diagnosed with CLAD-BOS following single lung transplant. Eligible patients were randomized to receive either L-CsA (5 mg) via the PARI eFlow® Device (L-CsA eFlow) twice daily plus SoC treatment or SoC alone for a period of 48 weeks. Regardless of treatment allocation, all patients continued to receive their SoC regimen for maintenance of the lung allograft. Maintenance immunosuppressive therapy including tacrolimus, a second agent such as, but not limited to, MMF or azathioprine, and a systemic corticosteroid such as prednisone as third agent was administered according to institutional standards. Up to 11 study visits (screening, V1 through V10) were planned. Spirometry was measured at all visits according to American Thoracic Society/European Respiratory Society 2005 guidelines. Spirometry measurements on-site were performed by pulmonary function technicians, respiratory therapists, or physiotherapists who were blinded to each patient's study treatment assignment. Safety assessments at every study visit included physical examination, vital signs, adverse event (AE) reporting, and clinical laboratory tests. Acute tolerability of L-CsA was assessed by spirometry before and 1 hour and 4 hours after inhalation of L-CsA at initial dosing. All patients who completed the study were eligible to continue in an open-label extension trial of L-CsA (BOSTON-3 \[Study BT-L-CsA-303-FU\]).
Interventions
This formulation is developed for inhalation use and delivered via the PARI eFlow® Device, which is a new technology of nebulizing liquid drugs with a perforated vibrating membrane resulting in an aerosol with a low ballistic momentum and a high percentage of droplets in a respirable size range of 3-5 μm
DRUGstandard of care
Standard of Care Therapy. Eligible patients should be on a maintenance regimen of immunosuppressive agents including tacrolimus, a second agent such as but not limited to MMF or azathioprine, and a systemic corticosteroid such as prednisone as third agent. The regimen must be stable within 4 weeks prior to randomization with respect to the therapeutic agents. Patients receiving azithromycin for prophylaxis or treatment of BOS, must be on a stable regimen for a least 4-weeks prior to randomization and will continue to receive azithromycin during the trial as deemed appropriate by the investigator.
Sponsors
Zambon SpA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
This was an open-label clinical trial. Clinical trial monitors, treating physicians, study nurses, study coordinators, and enrolled patients were not blinded to treatment assignment. However, the pulmonary function technicians, respiratory therapists, or physiotherapists who conducted spirometry on-site were blinded to treatment assignment.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adult patients ≥ 18 years who received a single lung transplant at least 12 months prior to Screening. 2. Patients with BOS diagnosis defined as CLAD-BOS phenotype with: 1. Screening FEV1 between 85-51% of personal best FEV1 value post-transplant OR 2. Screening FEV1 \>85% of personal best FEV1 associated with EITHER a ≥ 200 mL decrease in FEV1 in the previous 12 months OR according to medical history showing BOS progression. 3. Diagnosis of CLAD-BOS must have been made at least 12 months after lung transplantation and 1. within 12 months prior to the screening visit OR 2. more than 12 months from screening and patient must have shown a decline in FEV1 ≥ 200ml in the previous 12 months before screening, which was not due to acute infection or acute organ rejection. 4. Patients in whom the diagnosis of BOS had been confirmed by the elimination of other possible causes of obstructive or restrictive lung disease (CLAD - RAS phenotype, see Protocol Specific Definitions). 5. Patients should have been on a maintenance regimen of immunosuppressive agents including tacrolimus, a second agent such as but not limited to mycophenolate mofetil (MMF) or azathioprine, and a systemic corticosteroid such as prednisone as third agent. The regimen must have been stable within 4 weeks prior to randomization with respect to the therapeutic agents. In case a patient was also receiving concomitant azithromycin for prophylaxis or treatment of BOS in addition to the previously described immunosuppressive regimen, azithromycin must have been on a stable regimen for at least 4 weeks prior to randomization. 6. Patients capable of understanding the purposes and risks of the clinical trial, who had given written informed consent and agreed to comply with the clinical trial requirements/visit schedules, and who were capable of aerosol inhalation. Patients must have consented to retrieve prespecified data from the historic medical record (e.g., information related to the transplant surgery; spirometry data; medication use). 7. Women of childbearing potential must have had a negative serum or urine pregnancy test within 7 days prior to randomization and must agree to use one of the methods of contraception listed in Appendix II of the Protocol through their End of Study (EoS) Visit. 8. Patients had no concomitant diagnoses that were considered fatal within one year (12 months) of Screening.
Exclusion criteria
1. Patients with confirmed other causes for loss of lung function, such as acute infection, acute rejection, restrictive allograft syndrome (CLAD - RAS phenotype, see Protocol Specific Definition ), etc. 2. Patients with acute antibody-mediated rejection at Screening. In this context, clinically stable patients (as judged by the Investigator) with detectable levels of donor specific antibodies (DSA) at the Screening Visit were eligible for the study. 3. Active acute bacterial, viral, or fungal infection not successfully resolved at least 4 weeks prior to the Screening Visit. Patients with chronic infection or colonization who were clinically stable as per judgement of the Investigator are eligible for the study. 4. Mechanical ventilation (including CPAP) within 12 weeks prior to Randomization. 5. Patients with uncontrolled hypertension. 6. Patient had baseline resting oxygen saturation of \< 89% on room air or use of supplemental oxygen at rest. 7. Evidence of functional airway stenosis (e.g., bronchomalacia/tracheomalacia, airway stents, or airways requiring balloon dilatations to maintain patency) with onset after the initial diagnosis of BOS and ongoing at Screening and/or Baseline Visit. 8. Known hypersensitivity to L-CsA or to cyclosporine A. 9. Patients with chronic renal failure, defined as serum creatinine \> 2.5 mg/dL at screening, or requiring chronic dialysis. 10. Patients with liver disease and serum bilirubin \> 3-fold upper limit of normal range or transaminases \> 2.5 upper limit of normal range. 11. Patients with active malignancy within the previous 2 years, including post-transplant lymphoproliferative disorder, with the exception of treated, localized basal and squamous cell carcinomas. 12. Pregnant women or women who were unwilling to use appropriate birth control to avoid pregnancy through their End of Study (EoS) Visit. 13. Women who were currently breastfeeding. 14. Receipt of an investigational drug as part of a clinical trial within 4 weeks prior to the Screening Visit. This was defined as any treatment that was implemented under an Investigational New Drug (IND) or compassionate use. 15. Patients who had received extracorporeal photophoresis (ECP) for treatment of BOS within 1 month prior to Randomization. 16. Patients who were currently participating in an interventional clinical trial. 17. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary procedures. 18. Any co-existing medical condition that in the Investigator's judgment would substantially increase the risk associated with the patient's participation in the clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in FEV1 (L) From Baseline to Week 48 | Week 48 (V9) | FEV1 is the Forced Expiratory Volume in One Second. For FEV1 were considered primary the data collected from the on site COMPACT study spirometer. Baseline is the mean of the best FEV1 obtained with the study spirometer at Screening Visit and the pre-randomization best FEV1 obtained at the Baseline Visit (V1).The primary efficacy analysis was carried out using a Linear Mixed Model (LMM) for repeated measures, using all observed available FEV1 measurements. In case of death or re-transplantation events, FEV1 was imputed as zero at each nominal day post event. PS: Estimates are from a LMM on the response variable with factors for time splines, treatment, the interactions of time splines by treatment, baseline FEV1, the interactions of time splines with baseline FEV1, region, underlying indication for lung transplant (COPD vs all others), use of azithromycin at randomization, and time as random effect. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in FEV1/FVC From Baseline to Week 48 | Week 48 | Forced Expiratory Volume in One Second on Forced Vital Capacity. It was analysed in the FAS using a LMM for repeated measurements and COMPACT data, with baseline FEV1/FVC among covariates. In case of death or re- transplantation events, FEV1/FVC was imputed as zero at each nominal day post event. FEV1/FVC is a calculated ratio used to diagnose obstructive and restrictive lung disease. It represents the proportion of a patient's vital capacity that he/she is able to expire in the first second of forced expiration to the full forced vital capacity. |
| Time to Progression of Bronchiolitis Obliterans Syndrome (BOS) | From date of randomization until the date of first documented progression of BOS, or date of retransplantation, or date of death from respiratory failure, whichever came first, assessed up to 48 weeks. | The progression of BOS is defined as the earliest of the following: * Absolute decrease from baseline in FEV1 by at least 10% or 200 mL and a decrease in FEV1/FVC by at least 5% (if a patient had an event that met this criterion for progression of BOS, progression of BOS must have been confirmed by measurements that were taken with COMPACT spirometer at least 2 weeks apart) OR * Worsening of BOS grade, OR * Re-transplantation, OR * Death from respiratory failure. Rules for censoring progression of BOS are set. More than one type of event might correspond to the event of BOS progression (even those occurring on the same date). In case progression of BOS was defined by more than one criterion on different dates, the earliest event date was considered, i.e., the date closer to randomization was used as the progression date. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Adverse Events (AE) | Baseline through study completion (week 48) | An AE is an untoward medical occurrence after exposure to a medicine, which is not necessarily caused by that medicine. |
| Acute Tolerability of L-CsA: Change From Pre-dose to 1 hr and 4h Post-dose | Baseline through study completion Week 48 | Acute tolerability of IMP (L-CsA) during initial dosing was determined by measuring spirometry 1 hour and 4 hours after treatment. The FEV1 was measured prior to dosing with L-CsA. A decline of ≥20% associated with symptoms could have warranted IMP discontinuation. Parameters reflecting acute tolerability of IMP were: spirometry, cough, or dyspnea. |
Countries
Belgium, France, Germany, Israel, Spain, United Kingdom, United States
Participant flow
Recruitment details
The study randomized 62 patients globally from 26Mar2019 to 16Apr2024.
Pre-assignment details
Of the 97 patients screened (up to 4 weeks screening period prior to Visit 1), 62 patients were enrolled, randomized, and treated.
Participants by arm
| Arm | Count |
|---|---|
| L-CsA treatment plus SoC (SAF) Liposomal Cyclosporine A 5 mg twice daily for 48 weeks + Standard of Care Therapy
Liposomal Cyclosporine A: This formulation is developed for inhalation use and delivered via the PARI eFlow® Device, which is a new technology of nebulizing liquid drugs with a perforated vibrating membrane resulting in an aerosol with a low ballistic momentum and a high percentage of droplets in a respirable size range of 3-5 μm | 32 |
| SoC alone (SAF) In this control arm only the standard of care is administered. Standard of care is a maintenance regimen of immunosuppressive agents.
standard of care: Standard of Care Therapy. Eligible patients should be on a maintenance regimen of immunosuppressive agents including tacrolimus, a second agent such as but not limited to MMF or azathioprine, and a systemic corticosteroid such as prednisone as third agent. The regimen must be stable within 4 weeks prior to randomization with respect to the therapeutic agents. Patients receiving azithromycin for prophylaxis or treatment of BOS, must be on a stable regimen for a least 4-weeks prior to randomization and will continue to receive azithromycin during the trial as deemed appropriate by the investigator. | 30 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event, including SAE/Death | 6 | 3 |
| Overall Study | PATIENT WITHDRAWN BY THE SPONSOR DUE TO USE OF CYCLOSPORINE A DURING TRIAL (NOT ALLOWED) | 1 | 0 |
| Overall Study | PI WITHDREW PATIENT DUE TO THE HIS/HER UNSTABLE CLINICAL CONDITION | 1 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 4 |
Baseline characteristics
| Characteristic | L-CsA treatment plus SoC (SAF) | SoC alone (SAF) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 23 Participants | 25 Participants | 48 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 5 Participants | 14 Participants |
| Age, Continuous | 66.9 years STANDARD_DEVIATION 7.2 | 69.3 years STANDARD_DEVIATION 5.28 | 68.0 years STANDARD_DEVIATION 6.41 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 1 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants | 29 Participants | 58 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 | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 6 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 | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 28 Participants | 25 Participants | 53 Participants |
| Region of Enrollment Germany | 3 participants | 0 participants | 3 participants |
| Region of Enrollment Israel | 2 participants | 4 participants | 6 participants |
| Region of Enrollment Spain | 5 participants | 4 participants | 9 participants |
| Region of Enrollment United Kingdom | 1 participants | 2 participants | 3 participants |
| Region of Enrollment United States | 21 participants | 20 participants | 41 participants |
| Sex: Female, Male Female | 10 Participants | 13 Participants | 23 Participants |
| Sex: Female, Male Male | 22 Participants | 17 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 32 | 3 / 30 |
| other Total, other adverse events | 28 / 32 | 17 / 30 |
| serious Total, serious adverse events | 20 / 32 | 14 / 30 |
Outcome results
Primary
Mean Change in FEV1 (L) From Baseline to Week 48
FEV1 is the Forced Expiratory Volume in One Second. For FEV1 were considered primary the data collected from the on site COMPACT study spirometer. Baseline is the mean of the best FEV1 obtained with the study spirometer at Screening Visit and the pre-randomization best FEV1 obtained at the Baseline Visit (V1).The primary efficacy analysis was carried out using a Linear Mixed Model (LMM) for repeated measures, using all observed available FEV1 measurements. In case of death or re-transplantation events, FEV1 was imputed as zero at each nominal day post event. PS: Estimates are from a LMM on the response variable with factors for time splines, treatment, the interactions of time splines by treatment, baseline FEV1, the interactions of time splines with baseline FEV1, region, underlying indication for lung transplant (COPD vs all others), use of azithromycin at randomization, and time as random effect.
Time frame: Week 48 (V9)
Population: FAS: The FAS is defined as all randomized patients. Patients were analyzed according to the treatment group to which they were randomized. All primary and secondary endpoints were performed using the FAS, unless otherwise specified. n=25 is the number of patients with data available, not the number of patients in the analysis set (N).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| L-CsA treatment plus SoC (FAS) | Mean Change in FEV1 (L) From Baseline to Week 48 | -0.186 liters | Standard Error 0.3093 |
| SoC alone (FAS) | Mean Change in FEV1 (L) From Baseline to Week 48 | -0.090 liters | Standard Error 0.2879 |
Comparison: at V9.p-value: 0.73195% CI: [-0.405, 0.214]Mixed Models Analysis
Secondary
Mean Change in FEV1/FVC From Baseline to Week 48
Forced Expiratory Volume in One Second on Forced Vital Capacity. It was analysed in the FAS using a LMM for repeated measurements and COMPACT data, with baseline FEV1/FVC among covariates. In case of death or re- transplantation events, FEV1/FVC was imputed as zero at each nominal day post event. FEV1/FVC is a calculated ratio used to diagnose obstructive and restrictive lung disease. It represents the proportion of a patient's vital capacity that he/she is able to expire in the first second of forced expiration to the full forced vital capacity.
Time frame: Week 48
Population: FAS: The FAS is defined as all randomized patients. Patients were analyzed according to the treatment group to which they were randomized. All primary and secondary endpoints were performed using the FAS, unless otherwise specified. n=25 is the number of patients with data available, not the number of patients in the analysis set (N).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| L-CsA treatment plus SoC (FAS) | Mean Change in FEV1/FVC From Baseline to Week 48 | 0.093 ratio | Standard Error 0.2353 |
| SoC alone (FAS) | Mean Change in FEV1/FVC From Baseline to Week 48 | 0.157 ratio | Standard Error 0.2433 |
Comparison: Estimates were from a Linear Mixed Model on the response variable change from baseline in FEV1/FVC with factors for time splines, treatment, the interactions of time splines by treatment, baseline FEV1/FVC, the interactions of time splines with baseline FEV1/FVC, region (North America versus all other countries together), underlying indication for lung transplant (COPD versus all others), use of azithromycin at randomization, and time as random effect.p-value: 0.804195% CI: [-0.212, 0.084]Mixed Models Analysis
Secondary
Time to Progression of Bronchiolitis Obliterans Syndrome (BOS)
The progression of BOS is defined as the earliest of the following: * Absolute decrease from baseline in FEV1 by at least 10% or 200 mL and a decrease in FEV1/FVC by at least 5% (if a patient had an event that met this criterion for progression of BOS, progression of BOS must have been confirmed by measurements that were taken with COMPACT spirometer at least 2 weeks apart) OR * Worsening of BOS grade, OR * Re-transplantation, OR * Death from respiratory failure. Rules for censoring progression of BOS are set. More than one type of event might correspond to the event of BOS progression (even those occurring on the same date). In case progression of BOS was defined by more than one criterion on different dates, the earliest event date was considered, i.e., the date closer to randomization was used as the progression date.
Time frame: From date of randomization until the date of first documented progression of BOS, or date of retransplantation, or date of death from respiratory failure, whichever came first, assessed up to 48 weeks.
Population: FAS: The FAS is defined as all randomized patients. Patients were analyzed according to the treatment group to which they were randomized. All primary and secondary endpoints were performed using the FAS, unless otherwise specified.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| L-CsA treatment plus SoC (FAS) | Time to Progression of Bronchiolitis Obliterans Syndrome (BOS) | NA Weeks |
| SoC alone (FAS) | Time to Progression of Bronchiolitis Obliterans Syndrome (BOS) | NA Weeks |
p-value: 0.155995% CI: [0.408, 16.585]Regression, Cox
Other Pre-specified
Acute Tolerability of L-CsA: Change From Pre-dose to 1 hr and 4h Post-dose
Acute tolerability of IMP (L-CsA) during initial dosing was determined by measuring spirometry 1 hour and 4 hours after treatment. The FEV1 was measured prior to dosing with L-CsA. A decline of ≥20% associated with symptoms could have warranted IMP discontinuation. Parameters reflecting acute tolerability of IMP were: spirometry, cough, or dyspnea.
Time frame: Baseline through study completion Week 48
Population: SAF: The SAF was defined as all randomized patients receiving SoC and/or at least one dose of L-CsA, independently of the treatment allocation at randomization. All safety and tolerability data were summarized and analyzed using the SAF.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| L-CsA treatment plus SoC (FAS) | Acute Tolerability of L-CsA: Change From Pre-dose to 1 hr and 4h Post-dose | 1 hr Post-dose | -0.022 Liters | Standard Deviation 0.0663 |
| L-CsA treatment plus SoC (FAS) | Acute Tolerability of L-CsA: Change From Pre-dose to 1 hr and 4h Post-dose | 4 hr Post-dose | -0.019 Liters | Standard Deviation 0.0701 |
Other Pre-specified
Number of Patients With Adverse Events (AE)
An AE is an untoward medical occurrence after exposure to a medicine, which is not necessarily caused by that medicine.
Time frame: Baseline through study completion (week 48)
Population: SAF: The SAF was defined as all randomized patients receiving SoC and/or at least one dose of L-CsA, independently of the treatment allocation at randomization. All safety and tolerability data were summarized and analyzed using the SAF.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| L-CsA treatment plus SoC (FAS) | Number of Patients With Adverse Events (AE) | No of patients with any AE | 32 Participants |
| L-CsA treatment plus SoC (FAS) | Number of Patients With Adverse Events (AE) | No. of patients with any TEAE leading to discontinuation of study treatment | 8 Participants |
| L-CsA treatment plus SoC (FAS) | Number of Patients With Adverse Events (AE) | No. of patients with any TEAE leading to study discontinuation | 6 Participants |
| L-CsA treatment plus SoC (FAS) | Number of Patients With Adverse Events (AE) | No. of patients with any TEAE leading to death | 6 Participants |
| L-CsA treatment plus SoC (FAS) | Number of Patients With Adverse Events (AE) | No. of patients with any TEAE of Grade 1 severity (Mild) | 22 Participants |
| L-CsA treatment plus SoC (FAS) | Number of Patients With Adverse Events (AE) | No. of patients with any TEAE of Grade 2 severity (Moderate) | 14 Participants |
| L-CsA treatment plus SoC (FAS) | Number of Patients With Adverse Events (AE) | No. of patients with any TEAE of Grade 3 severity (severe) | 15 Participants |
| L-CsA treatment plus SoC (FAS) | Number of Patients With Adverse Events (AE) | No. of patients with any study treatment-related TEAE | 11 Participants |
| L-CsA treatment plus SoC (FAS) | Number of Patients With Adverse Events (AE) | No. of patients with any serious TEAE | 20 Participants |
| L-CsA treatment plus SoC (FAS) | Number of Patients With Adverse Events (AE) | No. of patients with any serious treatment-related TEAE | 3 Participants |
| SoC alone (FAS) | Number of Patients With Adverse Events (AE) | No. of patients with any study treatment-related TEAE | NA Participants |
| SoC alone (FAS) | Number of Patients With Adverse Events (AE) | No of patients with any AE | 25 Participants |
| SoC alone (FAS) | Number of Patients With Adverse Events (AE) | No. of patients with any TEAE of Grade 2 severity (Moderate) | 12 Participants |
| SoC alone (FAS) | Number of Patients With Adverse Events (AE) | No. of patients with any TEAE leading to discontinuation of study treatment | 2 Participants |
| SoC alone (FAS) | Number of Patients With Adverse Events (AE) | No. of patients with any serious treatment-related TEAE | NA Participants |
| SoC alone (FAS) | Number of Patients With Adverse Events (AE) | No. of patients with any TEAE leading to study discontinuation | 3 Participants |
| SoC alone (FAS) | Number of Patients With Adverse Events (AE) | No. of patients with any TEAE of Grade 3 severity (severe) | 8 Participants |
| SoC alone (FAS) | Number of Patients With Adverse Events (AE) | No. of patients with any TEAE leading to death | 3 Participants |
| SoC alone (FAS) | Number of Patients With Adverse Events (AE) | No. of patients with any serious TEAE | 14 Participants |
| SoC alone (FAS) | Number of Patients With Adverse Events (AE) | No. of patients with any TEAE of Grade 1 severity (Mild) | 22 Participants |