Back to resultsA Safety Study of Liposomal Cyclosporine A to Treat Bronchiolitis After Hematopoietic Transplant (BOSTON-4) (BOSTON-4)
Primary Purpose
Bronchiolitis Obliterans Syndrome (BOS), GVHD, Chronic, Stem Cell Transplant Complications
Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Liposomal Cyclosporine A
Liposomal Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Bronchiolitis Obliterans Syndrome (BOS) focused on measuring stem cell, hematopoietic transplant
Eligibility Criteria
Inclusion Criteria:
- Age >/= 18 years
- Patient must have a history of allogeneic HSCT, regardless of source of stem cell or donor or indication for allogeneic HSCT
- 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.
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.
- 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.
- Patient is capable of aerosol inhalation.
- Women of childbearing potential must have a negative serum or urine pregnancy test at screening and at randomization visit.
Exclusion Criteria:
- Active bacterial, viral (as confirmed by multiplex PCR) or fungal infection not successfully resolved at least 4 weeks prior to the Screening Visit.
- Chronic renal dysfunction with serum creatinine >/= 2.5 mg/dL or need for renal dialysis.
- Chronic hepatic dysfunction with serum total bilirubin > 5x upper limit of normal (ULN), transaminases > 5x ULN, or alkaline phosphatase > 5x ULN.
- Evidence of relapse of the primary malignancy which warranted allogeneic bone marrow transplant.
- Use of azithromycin within 4 weeks prior to Randomization (Visit 1).
- Use of zafirlukast during the study period.
- Chronic oxygen use or use of non-invasive ventilation.
- Active smokers (i.e. any kind of inhaled nicotine consumption).
- Pregnant women or women who are unwilling to use appropriate birth control to avoid pregnancy over the course of the clinical trial.
- Women who are currently breastfeeding.
- Known hypersensitivity to L-CsA or to cyclosporine A.
- Patients who do not tolerate administration of inhaled bronchodilators (e.g., salbutamol).
- Patients with life-expectancy of less than 6 months.
- 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.
- Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary procedures.
- 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.
- Pre-scheduled hospitalizations, surgeries or interventions planned to be performed after obtaining Informed Consent for this study.
Sites / Locations
- CHU Hôpital Sud
- Centre Hospitalier Universitaire d'Angers
- Centre Hospitalier Universitaire Grenoble Alpes - Hopital Albert Michallon
- Centre Hospitalier Régional Universitaire de Lille (CHRU) - Hôpital Claude Huriez
- CHU de Nancy, Hopital Brabois
- CHU de Nantes - Hotel-Dieu
- Hopital Saint Louis
- CHU Hopitaux de Bordeaux - Hôpital Haut-Lévêque
- St.-Johannes-Hospital
- Universitätsklinikum Carl Gustav Carus
- Universitätsklinikum Köln
- Universitätsklinikum Münster
- Hospital Clinic i Provincial
- Hospital de la Santa Creu i Sant Pau
- Hospital Universitario Ramón y Cajal
- Hospital Clinico Universitario de Valencia
- Hospital Universitari i Politècnic La Fe
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Placebo Comparator
Arm Label
L-CsA 10 mg plus Standard of Care
L-CsA 5 mg plus Standard of Care
Liposomal Placebo plus Standard of Care
Arm Description
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 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 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
Outcomes
Primary Outcome Measures
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.
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.
Secondary Outcome Measures
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.
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.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04107675
Brief Title
A Safety Study of Liposomal Cyclosporine A to Treat Bronchiolitis After Hematopoietic Transplant (BOSTON-4)
Acronym
BOSTON-4
Official Title
A Phase IIa Multi-Center, Randomized, Single-Blind Safety Study of Liposomal Cyclosporine A to Treat Bronchiolitis Obliterans Syndrome Following Allogeneic Hematopoietic Stem Cell Transplantation
Study Type
Interventional
2. Study Status
Record Verification Date
September 2023
Overall Recruitment Status
Terminated
Why Stopped
Due to the low number of patients recruited and the slow enrollment pace of patients, on 18 March 2022, the sponsor decided to terminate the BOSTON-4 safety and tolerability trial ahead of time.
Study Start Date
February 11, 2020 (Actual)
Primary Completion Date
June 16, 2022 (Actual)
Study Completion Date
December 15, 2022 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Zambon SpA
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bronchiolitis Obliterans Syndrome (BOS), GVHD, Chronic, Stem Cell Transplant Complications
Keywords
stem cell, hematopoietic transplant
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
Participant
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.
Allocation
Randomized
Enrollment
6 (Actual)
8. Arms, Groups, and Interventions
Arm Title
L-CsA 10 mg plus Standard of Care
Arm Type
Experimental
Arm Description
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
Arm Title
L-CsA 5 mg plus Standard of Care
Arm Type
Experimental
Arm Description
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
Arm Title
Liposomal Placebo plus Standard of Care
Arm Type
Placebo Comparator
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Liposomal Cyclosporine A
Other Intervention Name(s)
L-CsA
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Liposomal Placebo
Other Intervention Name(s)
Placebo
Intervention Description
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
Primary Outcome Measure Information:
Title
Number of Local Tolerability Events of Interest From Baseline to Visit 3 (Week 4)
Description
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)
Title
Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment
Description
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
Secondary Outcome Measure Information:
Title
Number of Local Tolerability Events of Interest From Baseline to Week 12
Description
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
Title
Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment
Description
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
Title
CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels
Description
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age >/= 18 years
Patient must have a history of allogeneic HSCT, regardless of source of stem cell or donor or indication for allogeneic HSCT
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.
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.
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.
Patient is capable of aerosol inhalation.
Women of childbearing potential must have a negative serum or urine pregnancy test at screening and at randomization visit.
Exclusion Criteria:
Active bacterial, viral (as confirmed by multiplex PCR) or fungal infection not successfully resolved at least 4 weeks prior to the Screening Visit.
Chronic renal dysfunction with serum creatinine >/= 2.5 mg/dL or need for renal dialysis.
Chronic hepatic dysfunction with serum total bilirubin > 5x upper limit of normal (ULN), transaminases > 5x ULN, or alkaline phosphatase > 5x ULN.
Evidence of relapse of the primary malignancy which warranted allogeneic bone marrow transplant.
Use of azithromycin within 4 weeks prior to Randomization (Visit 1).
Use of zafirlukast during the study period.
Chronic oxygen use or use of non-invasive ventilation.
Active smokers (i.e. any kind of inhaled nicotine consumption).
Pregnant women or women who are unwilling to use appropriate birth control to avoid pregnancy over the course of the clinical trial.
Women who are currently breastfeeding.
Known hypersensitivity to L-CsA or to cyclosporine A.
Patients who do not tolerate administration of inhaled bronchodilators (e.g., salbutamol).
Patients with life-expectancy of less than 6 months.
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.
Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary procedures.
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.
Pre-scheduled hospitalizations, surgeries or interventions planned to be performed after obtaining Informed Consent for this study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Paola Castellani, MD
Organizational Affiliation
Zambon SpA, Chief Medical Officer
Official's Role
Study Director
Facility Information:
Facility Name
CHU Hôpital Sud
City
Amiens
Country
France
Facility Name
Centre Hospitalier Universitaire d'Angers
City
Angers
Country
France
Facility Name
Centre Hospitalier Universitaire Grenoble Alpes - Hopital Albert Michallon
City
La Tronche
Country
France
Facility Name
Centre Hospitalier Régional Universitaire de Lille (CHRU) - Hôpital Claude Huriez
City
Lille
Country
France
Facility Name
CHU de Nancy, Hopital Brabois
City
Nancy
Country
France
Facility Name
CHU de Nantes - Hotel-Dieu
City
Nantes
Country
France
Facility Name
Hopital Saint Louis
City
Paris
Country
France
Facility Name
CHU Hopitaux de Bordeaux - Hôpital Haut-Lévêque
City
Pessac
Country
France
Facility Name
St.-Johannes-Hospital
City
Dortmund
Country
Germany
Facility Name
Universitätsklinikum Carl Gustav Carus
City
Dresden
Country
Germany
Facility Name
Universitätsklinikum Köln
City
Köln
Country
Germany
Facility Name
Universitätsklinikum Münster
City
Münster
Country
Germany
Facility Name
Hospital Clinic i Provincial
City
Barcelona
Country
Spain
Facility Name
Hospital de la Santa Creu i Sant Pau
City
Barcelona
Country
Spain
Facility Name
Hospital Universitario Ramón y Cajal
City
Madrid
Country
Spain
Facility Name
Hospital Clinico Universitario de Valencia
City
Valencia
Country
Spain
Facility Name
Hospital Universitari i Politècnic La Fe
City
Valencia
Country
Spain
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
A Safety Study of Liposomal Cyclosporine A to Treat Bronchiolitis After Hematopoietic Transplant (BOSTON-4)
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