Clinical Trial Results:
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.
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Summary
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EudraCT number |
2019-000718-13 |
Trial protocol |
DE ES FR |
Global end of trial date |
16 Jun 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
05 Jul 2023
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First version publication date |
05 Jul 2023
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Other versions |
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Summary report(s) |
Boston 4 - Termination Letter |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
BT–L-CsA–201–SCT
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04107675 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Zambon S.p.A.
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Sponsor organisation address |
Via Lillo del Duca, 10 , Bresso, Milan, Italy, 20091
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Public contact |
Sponsor Contact Point, Zambon SpA, Zambon S.p.A., +39 02 66524513, clinicaltrials@zambongroup.com
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Scientific contact |
Sponsor Contact Point, Zambon SpA, Zambon S.p.A., +39 02 66524513, clinicaltrials@zambongroup.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
15 Dec 2022
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
16 Jun 2022
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Global end of trial reached? |
Yes
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Global end of trial date |
16 Jun 2022
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
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 the treatment of BOS in adult allo-HSCT recipients.
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.
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Protection of trial subjects |
This study was conducted in compliance with the protocol and amendments approved by the appropriate EC and health authorities, according to International Committee for Harmonisation and applicable good clinical practice standards, and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
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Background therapy |
Standard of care (SoC). SoC included prophylaxis against common opportunistic infections, immunosuppression, and any other chronic medication. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
11 Feb 2020
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Spain: 2
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Country: Number of subjects enrolled |
France: 2
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Country: Number of subjects enrolled |
Germany: 2
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Worldwide total number of subjects |
6
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EEA total number of subjects |
6
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
6
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
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 fulfil the inclusion criteria and 6 patients were randomized into 3 treatment groups (L-CsA 10 mg + SoC, L-CsA 5 mg + SoC, or placebo + SoC). | ||||||||||||
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Pre-assignment
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Screening details |
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. | ||||||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Single blind | ||||||||||||
Roles blinded |
Subject | ||||||||||||
Blinding implementation details |
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. The members of the DMC were unblinded.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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L-CsA 10 mg + SoC | ||||||||||||
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. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Liposomal Cyclosporine A
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Investigational medicinal product code |
L-CsA
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Other name |
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Pharmaceutical forms |
Nebuliser solution
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Routes of administration |
Inhalation use
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Dosage and administration details |
Liposomal Cyclosporine A is administered at 10 mg bid 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. 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.
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Arm title
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L-CsA 5 mg + SoC | ||||||||||||
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. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Liposomal Cyclosporine A
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Investigational medicinal product code |
L-CsA
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Other name |
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Pharmaceutical forms |
Nebuliser solution
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Routes of administration |
Inhalation use
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Dosage and administration details |
Liposomal Cyclosporine A is administered at 5 mg bid 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. 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.
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Arm title
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Liposomal Placebo + SoC | ||||||||||||
Arm description |
Liposomal Placebo 2.5 mg (0 mg L-CsA/2.5 mL) bid, once in the morning and once in the evening, for up to 12 weeks. | ||||||||||||
Arm type |
Placebo | ||||||||||||
Investigational medicinal product name |
Liposomal placebo
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Investigational medicinal product code |
placebo
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Other name |
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Pharmaceutical forms |
Nebuliser solution
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Routes of administration |
Inhalation use
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Dosage and administration details |
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. 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.
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Baseline characteristics reporting groups
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Reporting group title |
L-CsA 10 mg + SoC
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Reporting group 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
L-CsA 5 mg + SoC
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Reporting group 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Liposomal Placebo + SoC
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Reporting group description |
Liposomal Placebo 2.5 mg (0 mg L-CsA/2.5 mL) bid, once in the morning and once in the evening, for up to 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
L-CsA 10 mg + SoC
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Reporting group 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. | ||
Reporting group title |
L-CsA 5 mg + SoC
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Reporting group 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. | ||
Reporting group title |
Liposomal Placebo + SoC
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Reporting group description |
Liposomal Placebo 2.5 mg (0 mg L-CsA/2.5 mL) bid, once in the morning and once in the evening, for up to 12 weeks. | ||
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End point title |
Number of Local Tolerability Events of Interest From Baseline to Visit 3 (week 4) [1] | ||||||||||||||||||||||||||||||||||||
End point 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.
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End point type |
Primary
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End point timeframe |
at Week 4 (visit 3)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analyses are possible with only 2 subjects per arm. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
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End point title |
Number of Participants With AE and sAE of Different Level of Severity During the First 4 Weeks of Treatment [2] | ||||||||||||||||||||||||||||||||||||||||||||||||||||
End point 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.
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End point type |
Primary
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End point timeframe |
During the first 4 weeks of treatment
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analyses are possible with only 2 subjects per arm. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Number of Local Tolerability Events of Interest from baseline to week 12 | ||||||||||||||||||||||||||||||||||||
End point 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.
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End point type |
Secondary
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End point timeframe |
at Week 12
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
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End point title |
Number of Participants With AE and sAE of Different Level of Severity During the First 12 Weeks of Treatment | ||||||||||||||||||||||||||||||||||||||||||||||||||||
End point 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.
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End point type |
Secondary
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End point timeframe |
During the first 12 weeks of treatment
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
CsA Whole Blood Concentrations and CsA Whole Blood Trough Levels | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point 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.
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End point type |
Secondary
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End point timeframe |
Weeks 0 (pre-dose, directly after end of inhalation, 15, 30, 45, 60 min, 1.5 h, 2h, 4h), 2, 4, 8, and 12
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Throughout the complete clinical trial period, i.e. up to week 14 (visit 6 / EoS).
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Adverse event reporting additional description |
Please note that if a patient has multiple occurrences of an AE, the patient is presented only once in the respective patient count
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.1
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Reporting groups
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Reporting group title |
L-CsA 10 mg + SoC
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Reporting group 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
L-CsA 5 mg + SoC
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Reporting group 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Liposomal Placebo + SoC
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Reporting group description |
Liposomal Placebo 2.5 mg (0 mg L-CsA/2.5 mL) bid, once in the morning and once in the evening, for up to 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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30 Sep 2020 |
COVID-19 specific considerations were implemented following the sponsor
risk-benefit assessment, and the request from French CA, asking to amend
the protocol to include actions in response to COVID-19 emergency. The
below details were added and clarified, including but not limited to:
o Screening and Visits 1, 2 and 5 were mandatory on-site visits while
remote visits were possible for other visits due to COVID-19
restrictions. In case the planned on-site visit could not be performed due
to COVID-19 restrictions, a remote visit via telephone would be
performed to assess any potential AEs and to confirm the patient’s
status and well-being.
o Full amount of assigned IMP would be dispensed during Visit 1 to
cover the entire treatment period of 12 weeks to guarantee IMP supply
for the patient, in case a site visit could not be performed due to
COVID-19 restrictions. IMP availability check was added to be
performed at Visit 2 through Visit 5.
o Drug accountability check would be performed at Visit 5 only instead
of at Visit 2 though Visit 5.
o The CGI was specified to be assessed on-site only, as CGI required
evaluation of a physician.
o COVID-19 related AEs would be reported as SAEs.
o Schedule of assessments table was modified accordingly to clarify
remove visit activities.
• As this was a safety study, an additional investigator’s tolerability
assessment was added at Visit 5.
• Other administrative changes and minor edits were made |
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30 Apr 2021 |
Study title was amended and certain wording in the protocol was changed or
added to add clarification and ensure consistency throughout the protocol.
• Five inclusion criteria were modified to allow suitable patients to be
identified and enrolled in a reasonable period of time.
• One exclusion criterion was added to ensure exclusion of other confounding
pulmonary diseases.
• Two exclusion criteria were deleted as 1 was mentioned elsewhere and 1
was no longer applicable.
• “Changes in the dose of corticosteroids and immunosuppressive therapy
administered throughout trial duration” was added as an exploratory endpoint.
• Wording was added to justify single-blind study scheme.
• The concomitant medication section was updated to clarify that patients
who had received the vaccination against SARS-CoV-2 were still eligible to
participate and those already randomized could continue with clinical study
program, and to add further clarification on concurrent treatments included.
• Wording was added and changed for clarification as it was decided to
evaluate the L-CsA PK measurements centrally only.
• Other administrative changes and minor edits were made. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| From the beginning of the trial, in December 2019, only 6 pts were enrolled. Due to the low number of pts recruited and the slow enrollment pace of pts, on 18 March 2022, the sponsor decided to terminate this safety/tolerability trial early. | |||
