A Safety Study of Liposomal Cyclosporine A to Treat Bronchiolitis After Hematopoietic Transplant (BOSTON-4) (BOSTON-4)

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

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.

Study Overview

• Status: Terminated
• Conditions: Stem Cell Transplant Complications; GVHD, Chronic; Bronchiolitis Obliterans Syndrome (BOS)
• Intervention / Treatment: Drug: Liposomal Cyclosporine A; Drug: Liposomal Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Amiens, France
    • Chu Hopital Sud
  • Angers, France
    • Centre Hospitalier Universitaire d'Angers
  • La Tronche, France
    • Centre Hospitalier Universitaire Grenoble Alpes - Hopital Albert Michallon
  • Lille, France
    • Centre Hospitalier Régional Universitaire de Lille (CHRU) - Hôpital Claude Huriez
  • Nancy, France
    • CHU de Nancy, Hôpital Brabois
  • Nantes, France
    • CHU de Nantes - Hôtel-Dieu
  • Paris, France
    • Hôpital Saint Louis
  • Pessac, France
    • CHU Hopitaux de Bordeaux - Hôpital Haut-Lévêque
• Germany
  • Dortmund, Germany
    • St.-Johannes-Hospital
  • Dresden, Germany
    • Universitätsklinikum Carl Gustav Carus
  • Köln, Germany
    • Universitätsklinikum Köln
  • Münster, Germany
    • Universitätsklinikum Münster
• Spain
  • Barcelona, Spain
    • Hospital de la Santa Creu i Sant Pau
  • Barcelona, Spain
    • Hospital Clinic I Provincial
  • Madrid, Spain
    • Hospital Universitario Ramón y Cajal
  • Valencia, Spain
    • Hospital Clinico Universitario de Valencia
  • Valencia, Spain
    • Hospital Universitari I Politecnic La Fe

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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	Drug: 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; Other Names: L-CsA
Experimental: 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	Drug: 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; Other Names: L-CsA
Placebo Comparator: 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	Drug: 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; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	at Week 4 (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.	During the first 4 weeks of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	at Week 12
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.	During the first 12 weeks of treatment
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.	Weeks 0 (pre-dose, directly after end of inhalation, 15, 30, 45, 60 min, 1.5 h, 2h, 4h), 2, 4, 8, and 12

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak Plasma Concentration (Cmax)		Day 1 (after receiving the first dose of study drug)
Pharmacokinetic Parameters - CsA Levels	Whole Blood Trough Levels	Weeks 1, 4, 8, and 16
FEV1 Percent Predicted	Change in FEV1 percent predicted	Baseline through Week 16
FEV1/FVC	Change in FEV1/FVC	Baseline through Week 16
Quality of Life Questionnaire	The EuroQoL Health-related Quality of Life tool, Youth Version, is a dimple, generic measure of health.	Baseline through Week 8
Time to Peak Plasma Concentration (Tmax)		Day 1 (after receiving the first dose of study drug)
Area Under the Plasma Concentration versus Time Curve (AUC)		Day 1 (after receiving the first dose of study drug)

Collaborators and Investigators

• Sponsor: Zambon SpA
• Investigators: Study Director: Paola Castellani, MD, Zambon SpA, Chief Medical Officer

Study record dates

Study Major Dates

• Study Start (Actual): February 11, 2020
• Primary Completion (Actual): June 16, 2022
• Study Completion (Actual): December 15, 2022

Study Registration Dates

• First Submitted: September 25, 2019
• First Submitted That Met QC Criteria: September 25, 2019
• First Posted (Actual): September 27, 2019

Study Record Updates

• Last Update Posted (Actual): October 3, 2023
• Last Update Submitted That Met QC Criteria: September 8, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: stem cell; hematopoietic transplant
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Disease; Bronchial Diseases; Lung Diseases, Obstructive; Bronchitis; Organizing Pneumonia; Graft vs Host Disease; Syndrome; Bronchiolitis; Bronchiolitis Obliterans; Bronchiolitis Obliterans Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Antifungal Agents; Calcineurin Inhibitors; Cyclosporine; Cyclosporins
• Other Study ID Numbers: BT - L-CsA - 201 - SCT; 2019-000718-13 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No