Bronchiolitis Obliterans Syndrome (BOS), GVHD, Chronic, Stem Cell Transplant Complications
Conditions
Keywords
stem cell, hematopoietic transplant
Brief summary
Primary Objective: The primary objective of this study is to assess the tolerability and safety of two dose levels of aerosolized L-CsA vs placebo in addition to SoC therapy for BOS in adult allo-HSCT recipients. Secondary Objectives: The secondary objectives of this study are to assess PK and exploratory efficacy and quality of life of two dose levels of aerosolized L-CsA vs placebo in addition to SoC therapy for BOS in adult allo-HSCT recipients.
Detailed description
This is a Phase II prospective, multi-center, single-blind, randomized clinical trial evaluating safety and tolerability in adult recipients of an allo-HSCT with BOS. Twenty-four patients were planned for enrollment; but, at the time of the premature termination of this study, a total of 11 patients were screened for the study, of whom 5 patients did not fulfill the inclusion criteria and 6 patients were randomly allocated 1:1:1 in 3 treatment groups (L-CsA 10 mg + SoC, L-CsA 5 mg + SoC, or placebo + SoC). A total of 18 centers in 3 countries (France, Germany, and Spain) in Europe were initiated for this multi-center study. IMP was administered for up to 12 weeks treatment period. With low patient recruitment, the BOSTON-4 safety and tolerability study was terminated early by the sponsor on 18 March 2022. This decision was made after a careful and due diligent analysis performed by Zambon of the study status and considering the impact of coronavirus disease 2019 (COVID-19) pandemic on sites activities. From the beginning of the study, in December 2019, only 6 patients were randomized. So it was estimated that continuing the trial with the current protocol and setting would have taken another 9 years for the study to complete.
Interventions
Liposomal Cyclosporine A is administered at different dosages in the first two arms (10 mg bid and 5 mg bid, respectively) with a new technology of nebulizing liquid drugs, creating an aerosol with a low ballistic momentum and a high percentage of droplets in a respirable size range of 3-5 μm
DRUGLiposomal Placebo
Liposomal Placebo is administered with the same new technology of nebulizing liquid drugs used for L-CsA, creating an aerosol with a low ballistic momentum and a high percentage of droplets in a respirable size range of 3-5 μm
Sponsors
Zambon SpA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Masking description
This was a single-blind trial. Due to the different appearance of the 3 tested strengths of IMP, a full blinding of the study was not possible. Only the randomized study patients were blinded to study treatment assignment.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age \>/= 18 years 2. Patient must have a history of allogeneic HSCT, regardless of source of stem cell or donor or indication for allogeneic HSCT 3. Documented diagnosis of chronic Graft versus Host Disease (cGvHD) in any organ other than the lung. If BOS is the only manifestation of cGvHD, lung biopsy must have been performed before entering the trial to confirm BOS diagnosis. 4. Confirmed diagnosis of BOS Score 1 \[Jagasia et al. 2015\] within \> 6 months and \< 3 years after allo-HSCT: FEV1/FVC \< 0.7 at Screening Visit AND Post-bronchodilator FEV1 \>/= 60 and ≤ 79% predicted at Screening Visit AND * 10% decline of FEV1 % predicted within 24 months prior to Screening Visit AND Absence of acute infection in the respiratory tract. 5. Patient must be capable of understanding the purposes and risks of the study, has given written informed consent, and agrees to comply with the study requirements. 6. Patient is capable of aerosol inhalation. 7. Women of childbearing potential must have a negative serum or urine pregnancy test at screening and at randomization visit.
Exclusion criteria
1. Active bacterial, viral (as confirmed by multiplex PCR) or fungal infection not successfully resolved at least 4 weeks prior to the Screening Visit. 2. Chronic renal dysfunction with serum creatinine \>/= 2.5 mg/dL or need for renal dialysis. 3. Chronic hepatic dysfunction with serum total bilirubin \> 5x upper limit of normal (ULN), transaminases \> 5x ULN, or alkaline phosphatase \> 5x ULN. 4. Evidence of relapse of the primary malignancy which warranted allogeneic bone marrow transplant. 5. Use of azithromycin within 4 weeks prior to Randomization (Visit 1). 6. Use of zafirlukast during the study period. 7. Chronic oxygen use or use of non-invasive ventilation. 8. Active smokers (i.e. any kind of inhaled nicotine consumption). 9. Pregnant women or women who are unwilling to use appropriate birth control to avoid pregnancy over the course of the clinical trial. 10. Women who are currently breastfeeding. 11. Known hypersensitivity to L-CsA or to cyclosporine A. 12. Patients who do not tolerate administration of inhaled bronchodilators (e.g., salbutamol). 13. Patients with life-expectancy of less than 6 months. 14. Treatments with other Investigational Medicinal Products (IMPs) or previous therapies within four weeks or five times half-life of the drug, whichever is longer prior to screening and during the study. Participation in registries, considering the before, is allowed. 15. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary procedures. 16. Any co-existing medical condition that in the Investigator's judgment will substantially increase the risk associated with the patient's participation in the clinical trial. 17. Pre-scheduled hospitalizations, surgeries or interventions planned to be performed after obtaining Informed Consent for this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Local Tolerability Events of Interest From Baseline to Visit 3 (Week 4) | at Week 4 (visit 3) | The local tolerability events of interest taken into consideration were: Cough, Wheezing, Bronchospasm, Throat irritation and Change from baseline in FEV1 to Visit 3. |
| Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | During the first 4 weeks of treatment | An adverse event (AE) is any untoward medical occurrence after exposure to a medicine, which is not necessarily caused by that medicine. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A serious adverse event is an adverse event that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a birth defect. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Local Tolerability Events of Interest From Baseline to Week 12 | at Week 12 | The local tolerability events of interest taken into consideration were: Cough, Wheezing, Bronchospasm, Throat irritation and Change from baseline in FEV1 to Visit 3. |
| Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | During the first 12 weeks of treatment | An adverse event (AE) is any untoward medical occurrence after exposure to a medicine, which is not necessarily caused by that medicine. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A serious adverse event is an adverse event that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a birth defect. |
| CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | Weeks 0 (pre-dose, directly after end of inhalation, 15, 30, 45, 60 min, 1.5 h, 2h, 4h), 2, 4, 8, and 12 | Whole Blood concentrations (Week 0) are at pre-dose, directly after end of inhalation, 15, 30, and 45 minutes, and 1, 1.5, 2, and 4 hours after end of inhalation, and whole blood trough levels (CsA concentration) at Weeks 2, 4, 8, and 12 were calculated. |
Countries
France, Germany, Spain
Participant flow
Recruitment details
From the start of the trial, only 6 patients were randomized. With low patient recruitment, the BOSTON-4 safety and tolerability study was terminated early on 18 March 2022. This decision was made after a careful and due diligent analysis performed by Zambon of the study status and considering the impact of coronavirus disease 2019 (COVID-19) pandemic on sites activities. So, due to this low recruitment, the Sponsor decided to early terminate the trial, on 18 March 2022.
Participants by arm
| Arm | Count |
|---|---|
| L-CsA 10 mg Plus Standard of Care Liposomal Cyclosporine A 10 mg (10 mg/2.5 mL) bid, once in the morning and once in the evening, for up to 12 weeks.
The inhalations were scheduled to be taken approximately 12 hours (but not less than 6 hours) apart, eg, at 08:00 and 20:00 each day. Nebulization time per inhalation dose was approximately 8 to 13 minutes for the 0- and 10-mg doses.
Standard of care included prophylaxis against common opportunistic infections, immunosuppression, and any other chronic medication
Liposomal Cyclosporine A: Liposomal Cyclosporine A is administered at different dosages in the first two arms (10 mg bid and 5 mg bid, respectively) with a new technology of nebulizing liquid drugs, creating an aerosol with a low ballistic momentum and a high percentage of droplets in a respirable size range of 3-5 μm | 2 |
| L-CsA 5 mg Plus Standard of Care Liposomal Cyclosporine A 5 mg (5 mg/1.25 mL) bid, once in the morning and once in the evening, for up to 12 weeks. The inhalations were scheduled to be taken approximately 12 hours (but not less than 6 hours) apart, eg, at 08:00 and 20:00 each day. Nebulization time per inhalation dose was approximately 5 to 10 minutes for the 5-mg dose.
Standard of care included prophylaxis against common opportunistic infections, immunosuppression, and any other chronic medication
Liposomal Cyclosporine A: Liposomal Cyclosporine A is administered at different dosages in the first two arms (10 mg bid and 5 mg bid, respectively) with a new technology of nebulizing liquid drugs, creating an aerosol with a low ballistic momentum and a high percentage of droplets in a respirable size range of 3-5 μm | 2 |
| Liposomal Placebo Plus Standard of Care Liposomal Placebo 2.5 mL (0 mg L-CsA/2.5 mL) bid, once in the morning and once in the evening, for up to 12 weeks.
The inhalations were scheduled to be taken approximately 12 hours (but not less than 6 hours) apart, eg, at 08:00 and 20:00 each day. Nebulization time per inhalation dose was approximately 8 to 13 minutes for the 0- and 10-mg doses. Standard of care included prophylaxis against common opportunistic infections, immunosuppression, and any other chronic medication
Liposomal Placebo: Liposomal Placebo is administered with the same new technology of nebulizing liquid drugs used for L-CsA, creating an aerosol with a low ballistic momentum and a high percentage of droplets in a respirable size range of 3-5 μm | 2 |
| Total | 6 |
Baseline characteristics
| Characteristic | L-CsA 10 mg Plus Standard of Care | L-CsA 5 mg Plus Standard of Care | Liposomal Placebo Plus Standard of Care | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 2 Participants | 2 Participants | 6 Participants |
| Age, Continuous | 55.5 years STANDARD_DEVIATION 0.71 | 63.0 years STANDARD_DEVIATION 0 | 46.0 years STANDARD_DEVIATION 12.73 | 54.8 years STANDARD_DEVIATION 9.52 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Region of Enrollment France | 1 participants | 1 participants | 0 participants | 2 participants |
| Region of Enrollment Germany | 1 participants | 0 participants | 1 participants | 2 participants |
| Region of Enrollment Spain | 0 participants | 1 participants | 1 participants | 2 participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 2 | 0 / 2 |
| other Total, other adverse events | 2 / 2 | 1 / 2 | 1 / 2 |
| serious Total, serious adverse events | 1 / 2 | 0 / 2 | 0 / 2 |
Outcome results
Primary
Number of Local Tolerability Events of Interest From Baseline to Visit 3 (Week 4)
The local tolerability events of interest taken into consideration were: Cough, Wheezing, Bronchospasm, Throat irritation and Change from baseline in FEV1 to Visit 3.
Time frame: at Week 4 (visit 3)
Population: The Safety Analysis Set (SAF) was defined as all randomized patients who had received a partial dose of IMP at least once.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| L-CsA 10 mg Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Visit 3 (Week 4) | Any Local Tolerability Event | 1 number of local events |
| L-CsA 10 mg Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Visit 3 (Week 4) | Cough | 0 number of local events |
| L-CsA 10 mg Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Visit 3 (Week 4) | Wheezing | 0 number of local events |
| L-CsA 10 mg Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Visit 3 (Week 4) | Bronchospasm | 0 number of local events |
| L-CsA 10 mg Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Visit 3 (Week 4) | Throat irritation | 1 number of local events |
| L-CsA 10 mg Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Visit 3 (Week 4) | Change in FEV1 | 0 number of local events |
| L-CsA 5 mg Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Visit 3 (Week 4) | Change in FEV1 | 1 number of local events |
| L-CsA 5 mg Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Visit 3 (Week 4) | Any Local Tolerability Event | 5 number of local events |
| L-CsA 5 mg Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Visit 3 (Week 4) | Bronchospasm | 0 number of local events |
| L-CsA 5 mg Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Visit 3 (Week 4) | Throat irritation | 3 number of local events |
| L-CsA 5 mg Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Visit 3 (Week 4) | Cough | 1 number of local events |
| L-CsA 5 mg Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Visit 3 (Week 4) | Wheezing | 0 number of local events |
| Liposomal Placebo Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Visit 3 (Week 4) | Cough | 1 number of local events |
| Liposomal Placebo Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Visit 3 (Week 4) | Wheezing | 0 number of local events |
| Liposomal Placebo Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Visit 3 (Week 4) | Change in FEV1 | 1 number of local events |
| Liposomal Placebo Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Visit 3 (Week 4) | Bronchospasm | 0 number of local events |
| Liposomal Placebo Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Visit 3 (Week 4) | Any Local Tolerability Event | 4 number of local events |
| Liposomal Placebo Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Visit 3 (Week 4) | Throat irritation | 2 number of local events |
Primary
Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment
An adverse event (AE) is any untoward medical occurrence after exposure to a medicine, which is not necessarily caused by that medicine. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A serious adverse event is an adverse event that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a birth defect.
Time frame: During the first 4 weeks of treatment
Population: The Safety Analysis Set (SAF) was defined as all randomized patients who had received a partial dose of IMP at least once.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| L-CsA 10 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | Severe TEAEs | 0 Participants |
| L-CsA 10 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | Any TEAEs | 1 Participants |
| L-CsA 10 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | Mild TEAEs | 1 Participants |
| L-CsA 10 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | Moderate TEAEs | 0 Participants |
| L-CsA 10 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | Serious TEAEs | 0 Participants |
| L-CsA 10 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | Related TEAEs | 1 Participants |
| L-CsA 10 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | COVID-19 related TEAEs | 0 Participants |
| L-CsA 10 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | Patients discontinued study due to TEAEs | 0 Participants |
| L-CsA 10 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | Patients discontinued treatment due to TEAEs | 0 Participants |
| L-CsA 10 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | TEAEs Leading to Death | 0 Participants |
| L-CsA 5 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | Patients discontinued treatment due to TEAEs | 0 Participants |
| L-CsA 5 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | Related TEAEs | 1 Participants |
| L-CsA 5 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | Patients discontinued study due to TEAEs | 0 Participants |
| L-CsA 5 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | Serious TEAEs | 0 Participants |
| L-CsA 5 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | COVID-19 related TEAEs | 0 Participants |
| L-CsA 5 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | Any TEAEs | 1 Participants |
| L-CsA 5 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | Moderate TEAEs | 0 Participants |
| L-CsA 5 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | TEAEs Leading to Death | 0 Participants |
| L-CsA 5 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | Mild TEAEs | 1 Participants |
| L-CsA 5 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | Severe TEAEs | 0 Participants |
| Liposomal Placebo Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | Mild TEAEs | 1 Participants |
| Liposomal Placebo Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | Moderate TEAEs | 0 Participants |
| Liposomal Placebo Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | Severe TEAEs | 0 Participants |
| Liposomal Placebo Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | Patients discontinued study due to TEAEs | 0 Participants |
| Liposomal Placebo Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | Serious TEAEs | 0 Participants |
| Liposomal Placebo Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | Related TEAEs | 1 Participants |
| Liposomal Placebo Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | Patients discontinued treatment due to TEAEs | 0 Participants |
| Liposomal Placebo Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | Any TEAEs | 1 Participants |
| Liposomal Placebo Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | COVID-19 related TEAEs | 0 Participants |
| Liposomal Placebo Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment | TEAEs Leading to Death | 0 Participants |
Secondary
CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels
Whole Blood concentrations (Week 0) are at pre-dose, directly after end of inhalation, 15, 30, and 45 minutes, and 1, 1.5, 2, and 4 hours after end of inhalation, and whole blood trough levels (CsA concentration) at Weeks 2, 4, 8, and 12 were calculated.
Time frame: Weeks 0 (pre-dose, directly after end of inhalation, 15, 30, 45, 60 min, 1.5 h, 2h, 4h), 2, 4, 8, and 12
Population: The Full Analysis Set (FAS) was defined as all randomized patients for whom at least~1 post-baseline measurement of an efficacy outcome measure (ie, spirometry or quality of life measures) was available. For spirometry measures, baseline corresponded to the assessment at randomization visit (Visit 1) prior to inhalation of IMP.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| L-CsA 10 mg Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | Whole Blood Trough Levels - Week 8 | 18.7280 ng/ml | Standard Deviation 26.48539 |
| L-CsA 10 mg Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | 4 hours | 33.3425 ng/ml | Standard Deviation 35.73506 |
| L-CsA 10 mg Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | 1 hour | 117.8030 ng/ml | — |
| L-CsA 10 mg Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | 15 min | 73.5110 ng/ml | Standard Deviation 59.82123 |
| L-CsA 10 mg Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | 2 hours | 67.0700 ng/ml | Standard Deviation 71.46587 |
| L-CsA 10 mg Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | 1.5 hours | 115.4350 ng/ml | — |
| L-CsA 10 mg Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | Week 0 - predose | 12.2115 ng/ml | Standard Deviation 17.26967 |
| L-CsA 10 mg Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | Directly after end of inhalation | 84.6510 ng/ml | Standard Deviation 69.82821 |
| L-CsA 10 mg Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | Whole Blood Trough Levels - Week 4 | 16.2465 ng/ml | Standard Deviation 17.33048 |
| L-CsA 10 mg Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | 30 min | 68.3640 ng/ml | Standard Deviation 60.56228 |
| L-CsA 10 mg Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | Whole Blood Trough Levels - Week 12 | 23.0195 ng/ml | Standard Deviation 32.55449 |
| L-CsA 10 mg Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | Whole Blood Trough Levels - Week 2 | 48.6725 ng/ml | Standard Deviation 64.65148 |
| L-CsA 10 mg Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | 45 min | 70.1555 ng/ml | Standard Deviation 64.88483 |
| L-CsA 5 mg Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | 1.5 hours | 16.0300 ng/ml | Standard Deviation 13.34876 |
| L-CsA 5 mg Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | Week 0 - predose | 0.0000 ng/ml | Standard Deviation 0 |
| L-CsA 5 mg Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | Directly after end of inhalation | 19.3420 ng/ml | Standard Deviation 15.9198 |
| L-CsA 5 mg Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | 15 min | 30.0500 ng/ml | Standard Deviation 24.34003 |
| L-CsA 5 mg Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | 30 min | 26.9400 ng/ml | Standard Deviation 22.19184 |
| L-CsA 5 mg Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | 45 min | 23.2780 ng/ml | Standard Deviation 18.52761 |
| L-CsA 5 mg Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | 1 hour | 19.4395 ng/ml | Standard Deviation 18.15638 |
| L-CsA 5 mg Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | 2 hours | 13.4045 ng/ml | Standard Deviation 10.8053 |
| L-CsA 5 mg Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | 4 hours | 8.3950 ng/ml | Standard Deviation 8.0992 |
| L-CsA 5 mg Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | Whole Blood Trough Levels - Week 2 | 4.6365 ng/ml | Standard Deviation 3.62534 |
| L-CsA 5 mg Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | Whole Blood Trough Levels - Week 4 | 16.8475 ng/ml | Standard Deviation 21.28745 |
| L-CsA 5 mg Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | Whole Blood Trough Levels - Week 8 | 9.0405 ng/ml | Standard Deviation 3.16855 |
| L-CsA 5 mg Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | Whole Blood Trough Levels - Week 12 | 0.0000 ng/ml | — |
| Liposomal Placebo Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | 4 hours | 7.6615 ng/ml | Standard Deviation 10.835 |
| Liposomal Placebo Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | 30 min | 13.1780 ng/ml | Standard Deviation 18.63651 |
| Liposomal Placebo Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | Whole Blood Trough Levels - Week 8 | 4.9500 ng/ml | Standard Deviation 7.00036 |
| Liposomal Placebo Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | Whole Blood Trough Levels - Week 2 | 6.0500 ng/ml | Standard Deviation 8.55599 |
| Liposomal Placebo Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | 15 min | 11.2440 ng/ml | Standard Deviation 15.90142 |
| Liposomal Placebo Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | Week 0 - predose | 11.7750 ng/ml | Standard Deviation 16.65236 |
| Liposomal Placebo Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | Whole Blood Trough Levels - Week 4 | 6.3000 ng/ml | Standard Deviation 8.90955 |
| Liposomal Placebo Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | 1.5 hours | 13.0425 ng/ml | Standard Deviation 18.44488 |
| Liposomal Placebo Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | 1 hour | 14.0835 ng/ml | Standard Deviation 19.91708 |
| Liposomal Placebo Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | Directly after end of inhalation | 12.1760 ng/ml | Standard Deviation 17.21946 |
| Liposomal Placebo Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | 2 hours | 10.9615 ng/ml | Standard Deviation 15.5019 |
| Liposomal Placebo Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | 45 min | 13.3145 ng/ml | Standard Deviation 18.82955 |
| Liposomal Placebo Plus Standard of Care | CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | Whole Blood Trough Levels - Week 12 | 4.9500 ng/ml | Standard Deviation 7.00036 |
Secondary
Number of Local Tolerability Events of Interest From Baseline to Week 12
The local tolerability events of interest taken into consideration were: Cough, Wheezing, Bronchospasm, Throat irritation and Change from baseline in FEV1 to Visit 3.
Time frame: at Week 12
Population: The Safety Analysis Set (SAF) was defined as all randomized patients who had received a partial dose of IMP at least once.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| L-CsA 10 mg Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Week 12 | Bronchospasm | 0 number of events |
| L-CsA 10 mg Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Week 12 | Wheezing | 0 number of events |
| L-CsA 10 mg Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Week 12 | Change in FEV1 | 0 number of events |
| L-CsA 10 mg Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Week 12 | Any Local Tolerability Event | 1 number of events |
| L-CsA 10 mg Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Week 12 | Cough | 0 number of events |
| L-CsA 10 mg Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Week 12 | Throat irritation | 1 number of events |
| L-CsA 5 mg Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Week 12 | Any Local Tolerability Event | 7 number of events |
| L-CsA 5 mg Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Week 12 | Bronchospasm | 0 number of events |
| L-CsA 5 mg Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Week 12 | Throat irritation | 4 number of events |
| L-CsA 5 mg Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Week 12 | Wheezing | 0 number of events |
| L-CsA 5 mg Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Week 12 | Change in FEV1 | 1 number of events |
| L-CsA 5 mg Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Week 12 | Cough | 2 number of events |
| Liposomal Placebo Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Week 12 | Change in FEV1 | 1 number of events |
| Liposomal Placebo Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Week 12 | Cough | 2 number of events |
| Liposomal Placebo Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Week 12 | Any Local Tolerability Event | 6 number of events |
| Liposomal Placebo Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Week 12 | Wheezing | 0 number of events |
| Liposomal Placebo Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Week 12 | Throat irritation | 3 number of events |
| Liposomal Placebo Plus Standard of Care | Number of Local Tolerability Events of Interest From Baseline to Week 12 | Bronchospasm | 0 number of events |
Secondary
Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment
An adverse event (AE) is any untoward medical occurrence after exposure to a medicine, which is not necessarily caused by that medicine. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A serious adverse event is an adverse event that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a birth defect.
Time frame: During the first 12 weeks of treatment
Population: The Safety Analysis Set (SAF) was defined as all randomized patients who had received a partial dose of IMP at least once.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| L-CsA 10 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | COVID-19 related TEAEs | 0 Participants |
| L-CsA 10 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | Severe TEAEs | 0 Participants |
| L-CsA 10 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | Mild TEAEs | 2 Participants |
| L-CsA 10 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | Related TEAEs | 1 Participants |
| L-CsA 10 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | Serious TEAEs | 1 Participants |
| L-CsA 10 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | TEAEs Leading to Death | 0 Participants |
| L-CsA 10 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | Any TEAEs | 2 Participants |
| L-CsA 10 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | Patients discontinued study due to TEAEs | 0 Participants |
| L-CsA 10 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | Moderate TEAEs | 1 Participants |
| L-CsA 10 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | Patients discontinued treatment due to TEAEs | 1 Participants |
| L-CsA 5 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | Serious TEAEs | 0 Participants |
| L-CsA 5 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | TEAEs Leading to Death | 0 Participants |
| L-CsA 5 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | Any TEAEs | 1 Participants |
| L-CsA 5 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | Mild TEAEs | 1 Participants |
| L-CsA 5 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | Moderate TEAEs | 0 Participants |
| L-CsA 5 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | Severe TEAEs | 0 Participants |
| L-CsA 5 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | Related TEAEs | 1 Participants |
| L-CsA 5 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | COVID-19 related TEAEs | 0 Participants |
| L-CsA 5 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | Patients discontinued study due to TEAEs | 0 Participants |
| L-CsA 5 mg Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | Patients discontinued treatment due to TEAEs | 0 Participants |
| Liposomal Placebo Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | Moderate TEAEs | 0 Participants |
| Liposomal Placebo Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | TEAEs Leading to Death | 0 Participants |
| Liposomal Placebo Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | COVID-19 related TEAEs | 0 Participants |
| Liposomal Placebo Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | Mild TEAEs | 1 Participants |
| Liposomal Placebo Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | Patients discontinued treatment due to TEAEs | 0 Participants |
| Liposomal Placebo Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | Patients discontinued study due to TEAEs | 0 Participants |
| Liposomal Placebo Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | Serious TEAEs | 0 Participants |
| Liposomal Placebo Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | Severe TEAEs | 0 Participants |
| Liposomal Placebo Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | Any TEAEs | 1 Participants |
| Liposomal Placebo Plus Standard of Care | Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | Related TEAEs | 1 Participants |