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

NCT04107675 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: BT - L-CsA - 201 - SCT2019-000718-13
• Study Type: interventional
• Target: 6
• Locations: 3 countries
• Sites: 17

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.

Conditions

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

Keywords

stem cell; hematopoietic transplant

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (3)

• Number of Local Tolerability Events of Interest From Baseline to Week 12

  at Week 12

• 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

• 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

Study Arms (3)

L-CsA 10 mg plus Standard of Care

EXPERIMENTAL

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

L-CsA 5 mg plus Standard of Care

EXPERIMENTAL

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 Placebo plus Standard of Care

PLACEBO COMPARATOR

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

Interventions

Liposomal Cyclosporine A 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

Also known as: L-CsA

L-CsA 10 mg plus Standard of Care; L-CsA 5 mg plus Standard of Care

Liposomal Placebo 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

Also known as: Placebo

Liposomal Placebo plus Standard of Care

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• % 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Zambon SpA: lead

Study Sites (17)

CHU Hôpital Sud

Amiens, France

Location

Centre Hospitalier Universitaire d'Angers

Angers, France

Location

Centre Hospitalier Universitaire Grenoble Alpes - Hopital Albert Michallon

La Tronche, France

Location

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

Lille, France

Location

CHU de Nancy, Hopital Brabois

Nancy, France

Location

CHU de Nantes - Hotel-Dieu

Nantes, France

Location

Hopital Saint Louis

Paris, France

Location

CHU Hopitaux de Bordeaux - Hôpital Haut-Lévêque

Pessac, France

Location

Universitätsklinikum Köln

Cologne, Germany

Location

St.-Johannes-Hospital

Dortmund, Germany

Location

Universitätsklinikum Carl Gustav Carus

Dresden, Germany

Location

Universitätsklinikum Münster

Münster, Germany

Location

Hospital Clinic i Provincial

Barcelona, Spain

Location

Hospital de la Santa Creu i Sant Pau

Barcelona, Spain

Location

Hospital Universitario Ramón y Cajal

Madrid, Spain

Location

Hospital Clinico Universitario de Valencia

Valencia, Spain

Location

Hospital Universitari i Politècnic La Fe

Valencia, Spain

Location

MeSH Terms

Conditions

Bronchiolitis Obliterans Syndrome

Condition Hierarchy (Ancestors)

Organizing Pneumonia; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Graft vs Host Disease; Immune System Diseases

Limitations and Caveats

From the beginning of the trial, only 6 patients were enrolled. Due to the low number of patients recruited so far and the slow enrolment pace of patients, on 18 March 2022, the sponsor decided to terminate the BOSTON-4 safety and tolerability trial early. This decision was made after the Sponsor performed a careful and due diligent analysis of the current study status and considered the impact of the coronavirus disease 2019 (COVID-19) pandemic on-site activities.

Results Point of Contact

• Title: Ferdinando Ceravolo, MD
• Organization: Zambon SpA

ferdinando.ceravolo@zambongroup.com

02 665241

Study Officials

• Paola Castellani, MD

  Zambon SpA, Chief Medical Officer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 25, 2019
• First Posted: September 27, 2019
• Study Start: February 11, 2020
• Primary Completion: June 16, 2022
• Study Completion: December 15, 2022
• Last Updated: October 3, 2023
• Results First Posted: October 3, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

FR (8); DE (4); ES (5)