L-CsA in the Prevention of Bronchiolitis Obliterans Syndrome (BOS) in Lung Transplant (LT) Patients

A Phase II, Multicentre, Randomised, Double-blind, Placebo Controlled Clinical Trial to Investigate the Efficacy and Safety of Aerosolised Liposomal Ciclosporin A Versus Aerosolised Placebo in the Prevention of Bronchiolitis Obliterans Syndrome in Lung Transplant Patients

Immunosuppression is a key intervention in patients with solid organ transplant and is usually achieved by combination therapy with systemic CsA or tacrolimus with azathioprine, mycophenolate mofetil (MMF), or corticoids. However, the outcomes after lung transplantation are poor when compared with those after heart, kidney, or liver transplantation, with a survival rate of only 55% for recipients of lung transplants.

Additional application of aerosolised L-CsA should suppress T-cell activation in the lung tissue and subsequently BOS development. The overall purpose of this phase-II/III study is to obtain efficacy and safety data of L-CsA in the prevention of BOS.

Study Overview

• Status: Terminated
• Conditions: Bronchiolitis Obliterans
• Intervention / Treatment: Drug: Cyclosporine Inhalation Solution

Detailed Description

Preventive therapeutic intervention by L-CsA is primarily aimed to suppress T-lymphocyte suppression and inflammatory responses and secondly to prevent fibrotic effects making it more likely to be effective in early stages of BOS. Early development of BOS, which mostly will not be diagnosed, and acute organ rejections are strongly patho-physiological associated. Prevention of the very early development of chronic rejection by L-CsA post LTX may be the ideal starting point for IMP application.

• Study Type: Interventional
• Enrollment (Actual): 130
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Germany
  • Graefelfing, Germany, 82166
    • PARI Pharma GmbH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patient's written informed consent
2. Received a single lung, bilateral lung or heart/lung transplantation between 6 weeks and 26 weeks prior to first IMP administration.
3. Male or female, 18 years of age
4. Capable of self-administration of medications
5. Capable of understanding the purpose and risk of the clinical trial

6. Received the following immunosuppressive agents and dosages for maintenance therapy:

   1. Tacrolimus and
   2. Mycophenolate mofetil (MMF) 1 to 3 g/day and
   3. Prednisone or any other steroid therapy; tapered down
7. Female patients with childbearing potential must have a negative urine pregnancy test prior to first IMP administration.
8. Estimated life expectancy > 6 month

Exclusion Criteria:

1. Any previous episode of bronchiolitis obliterans (BO) or bronchiolitis obliterans syndrome (BOS) of grade 1 or higher
2. Any active invasive bacterial, viral or fungal infection
3. Received systemic maintenance immunosuppressive therapy other than listed in the inclusion criteria
4. Received any systemic or topical ciclosporin A within
5. Received any systemic or topical Rosuvastatin
6. Current mechanical ventilation
7. Received a lung re-transplantation
8. Pregnant or breast feeding woman
9. Has known hypersensitivity to ciclosporin A
10. Has a serum creatinine value of more than 265 µmol/L (3 mg/dL)
11. Unlikely to comply with visits, inhalation procedures or spirometric measurements
12. Receipt of an investigational drug within 4 weeks prior to first administration of IMP
13. Any co-existing medical condition that in the investigator's judgement
14. Psychiatric disorders or altered mental status
15. Patient was previously enrolled in the present clinical trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: L-CsA; Twice daily inhalation of 2.5 ml/10 mg L-CsA for 96 weeks	Drug: Cyclosporine Inhalation Solution; Cyclosporin for inhalation twice daily
Placebo Comparator: L-CsA placebo; Twice daily inhalation of 2.5 ml aerosolised placebo (carrier) for 96 weeks (24 months)	Drug: Cyclosporine Inhalation Solution; Cyclosporin for inhalation twice daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The primary objective is to compare cumulative BOS-free survival of patients recieving L-CsA or placebo.	BOS stage 1 and higher is considered as BOS for the primary endpoint.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative mean incidence of BOS 12, 18 and 24 months after first IMP administration	Further secondary objectives are to compare further efficacy and safety data from L-CsA versus placebo. Evaluation of IMP pharmacokinetic (PK) data in whole blood samples and bronchoalveolar lavage (BAL)are included in the outcome measure. The main safety evaluation is the incidence of treatment-emergent AEs including clinically relevant laboratory parameters and vital signs	2 years

Collaborators and Investigators

• Sponsor: Pari Pharma GmbH

Study record dates

Study Major Dates

• Study Start: December 1, 2009
• Primary Completion (Actual): July 1, 2013
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: April 11, 2011
• First Submitted That Met QC Criteria: April 12, 2011
• First Posted (Estimate): April 13, 2011

Study Record Updates

• Last Update Posted (Estimate): April 14, 2015
• Last Update Submitted That Met QC Criteria: April 13, 2015
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Bronchitis; Bronchiolitis; Bronchiolitis Obliterans; 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: 12011.201; 2008-003800-73 (EudraCT Number); ISRCTN66069132 (Registry Identifier: ISRCTN66069132)