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

NCT ID: NCT04107675

Last Updated: 2023-10-03

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 6 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-02-11
• Study Completion Date: 2022-12-15

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.

Conditions

Bronchiolitis Obliterans Syndrome (BOS); GVHD, Chronic; Stem Cell Transplant Complications

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

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

Group Type: EXPERIMENTAL

Liposomal Cyclosporine A

Intervention Type: DRUG

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

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

Group Type: EXPERIMENTAL

Liposomal Cyclosporine A

Intervention Type: DRUG

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

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

Group Type: PLACEBO_COMPARATOR

Liposomal Placebo

Intervention Type: DRUG

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

Interventions

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

Intervention Type: 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

Intervention Type: DRUG

Other Intervention Names

L-CsA; Placebo

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Zambon SpA

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Paola Castellani, MD

Role: STUDY_DIRECTOR

Zambon SpA, Chief Medical Officer

Locations

CHU Hôpital Sud

Amiens, , France

Centre Hospitalier Universitaire d'Angers

Angers, , France

Centre Hospitalier Universitaire Grenoble Alpes - Hopital Albert Michallon

La Tronche, , France

Centre Hospitalier Régional Universitaire de Lille (CHRU) - Hôpital Claude Huriez

Lille, , France

CHU de Nancy, Hopital Brabois

Nancy, , France

CHU de Nantes - Hotel-Dieu

Nantes, , France

Hopital Saint Louis

Paris, , France

CHU Hopitaux de Bordeaux - Hôpital Haut-Lévêque

Pessac, , France

Universitätsklinikum Köln

Cologne, , Germany

St.-Johannes-Hospital

Dortmund, , Germany

Universitätsklinikum Carl Gustav Carus

Dresden, , Germany

Universitätsklinikum Münster

Münster, , Germany

Hospital Clinic i Provincial

Barcelona, , Spain

Hospital de la Santa Creu i Sant Pau

Barcelona, , Spain

Hospital Universitario Ramón y Cajal

Madrid, , Spain

Hospital Clinico Universitario de Valencia

Valencia, , Spain

Hospital Universitari i Politècnic La Fe

Valencia, , Spain

Countries

France; Germany; Spain

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2019-000718-13

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

BT - L-CsA - 201 - SCT

Identifier Type: -

Identifier Source: org_study_id