Aerosol Liposomal Cyclosporine for Chronic Rejection in Lung Transplant Recipients

• Sponsor: University of Maryland (Other)
• Overall Status: Completed
• CT.gov ID: NCT01650545
• Collaborator: (none)
• Enrollment: 21
• Location: 1
• Arms: 2
• Actual Duration (Months): 37
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

This is a single-center pilot study to investigate the efficacy and safety of aerosolized liposomal cyclosporine A in the treatment of chronic rejection in lung transplant recipients with bronchiolitis obliterans syndrome (BOS).

The primary objective is to evaluate the efficacy of liposomal cyclosporine A in the treatment of chronic rejection. Pulmonary function and changes in BOS grade are the primary end points.

Condition or Disease	Intervention/Treatment	Phase
Disorder Related to Lung Transplantation; Bronchiolitis Obliterans; Decreased Immunologic Activity; Chronic Rejection of Lung Transplant	Drug: Liposomal aerosol cyclosporine; Other: standard immune suppression, oral	Phase 1/Phase 2

Detailed Description

This is a randomized single-center pilot study to investigate the efficacy and safety of aerosolized liposomal cyclosporine A (L-CsA) in the treatment of chronic rejection in lung transplant recipients with Grade 1 or 2 BOS.

The primary endpoints will include:

• Improvement or stabilization of pulmonary function test (FEV1) from baseline

• Stabilization of histology (no deterioration from baseline)

• Safety of the preparation

The secondary endpoints will include:

• Pharmacokinetics and distribution of CsA in blood -

• Change in cytokine levels from BAL specimens.

Study Design

• Study Type: Interventional
• Actual Enrollment: 21 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Masking Description: Open Label
• Primary Purpose: Treatment
• Official Title: A Pilot Study to Demonstrate Efficacy and Safety of Aerosol Liposomal Cyclosporine (L-CsA) in the Treatment of Bronchiolitis Obliterans Syndrome After Lung Transplantation
• Actual Study Start Date: Jul 1, 2012
• Actual Primary Completion Date: Aug 1, 2015
• Actual Study Completion Date: Aug 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Liposomal Aerosol Cyclosporine Arm 1) Aerosol liposomal cyclosporine Open label randomized trial using experimental inhalational therapy with liposomal aerosol cyclosporine in addition to standard immune suppression (tacrolimus , mycophenolate mofetil and prednisone) for 6 month duration at inhalational doses (5mg and 10 mg bid), to be defined by transplant type respectively (single, double lung transplant )	Drug: Liposomal aerosol cyclosporine; inhaled form of immune suppression; Other Names: cyclosporine ; Other: standard immune suppression, oral; conventional drug Conventrional oral immune suppression as standard of care thus consists of tacrolimus, mycophenolate mofetil prednisone and rapamycin; Other Names: tacrolimus rapamycin sirolimus
Active Comparator: Conventional oral immune suppression Arm 2) Standard immune suppression consisting of typical oral immune suppression for lung transplant recipients typically tacrolimus, mycophenolate mofetil and prednisone. Conventrional oral immune suppression as standard of care thus consists of tacrolimus, mycophenolate mofetil prednisone rapamycin described in the subsequent section as well.	Other: standard immune suppression, oral; conventional drug Conventrional oral immune suppression as standard of care thus consists of tacrolimus, mycophenolate mofetil prednisone and rapamycin; Other Names: tacrolimus rapamycin sirolimus

Outcome Measures

Primary Outcome Measures

1. Number Of Participants With Chronic Rejection Who Met Primary Combined End-point [approximately 1 year]

   Treatment failure defined as: BOS progression (> 20% decline lung function), re-transplant, or death

Secondary Outcome Measures

1. Cytokine Analysis From BAL Fluid in Lung [baseline to approximately 1 year]

   Multiple cytokines were assessed as markers of lung inflammation that may be used in addition to biopsy data, collected per patient as clinically indicated during the follow-up interval. Values are reported as mean change from baseline in each group, per week

2. Overall Survival at 5 Years Follow-up [5 years]

   Number of participants surviving at 5 year follow-up

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Chronic rejection

1. Bronchiolitis obliterans diagnosed by bronchiolitis obliterans syndrome and > 20% decline from the individual patient's best FEV1 is observed

2. Recipient of a double or single lung transplant

3. Receiving immunosuppressive treatment according to institutional standards

Exclusion criteria:

1. Active invasive bacterial, viral or fungal infection

2. Current mechanical ventilation

3. Pregnant or breast-feeding woman

4. Known hypersensitivity to cyclosporine A

5. Serum creatinine value of more than 265 μmol/L (3 mg/dL) or chronic dialysis

6. Receipt of an investigational drug as part of a clinical trial

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Maryland Medical Center	Baltimore	Maryland	United States	21201

Sponsors and Collaborators

• University of Maryland

Investigators

• Principal Investigator: Aldo T Iacono, MD, University of Maryland

Study Documents (Full-Text)

None provided.

More Information

Publications

• Iacono AT, Johnson BA, Grgurich WF, Youssef JG, Corcoran TE, Seiler DA, Dauber JH, Smaldone GC, Zeevi A, Yousem SA, Fung JJ, Burckart GJ, McCurry KR, Griffith BP. A randomized trial of inhaled cyclosporine in lung-transplant recipients. N Engl J Med. 2006 Jan 12;354(2):141-50.

• Responsible Party: Aldo Iacono, Professor of Medicine Medical Director of Lung Transplantation, University of Maryland
• ClinicalTrials.gov Identifier: NCT01650545
• Other Study ID Numbers: HP-00049596
• First Posted: Jul 26, 2012
• Last Update Posted: Mar 2, 2018
• Last Verified: Mar 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Aldo Iacono, Professor of Medicine Medical Director of Lung Transplantation, University of Maryland: case-control study; aerosolized liposomal cyclosporine A; bronchiolitis obliterans syndrome; Lung Transplantation; Lung function
• Additional relevant MeSH terms: Bronchiolitis; Bronchiolitis Obliterans; Cyclosporine; Sirolimus; Tacrolimus; Cyclosporins

Study Results

Participant Flow

Arm/Group Title	Liposomal Aerosol Cyclosporine	Conventional Oral Immune Suppression
Arm/Group Description	Arm 1) Aerosol liposomal cyclosporine Open label randomized trial using experimental inhalational therapy with liposomal aerosol cyclosporine in addition to standard immune suppression (tacrolimus , mycophenolate mofetil and prednisone) for 6 month duration at inhalational doses (5mg and 10 mg bid), to be defined by transplant type respectively (single, double lung transplant ) Liposomal aerosol cyclosporine: inhaled form of immune suppression standard immune suppression, oral: conventional drug	Arm 2) Standard immune suppression consisting of typical oral immune suppression for lung transplant recipients typically tacrolimus, mycophenolate mofetil and prednisone standard immune suppression, oral: conventional drug
Period Title: Overall Study
STARTED	11	10
COMPLETED	11	10
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Liposomal Aerosol Cyclosporine	Conventional Oral Immune Suppression	Total
Arm/Group Description	Arm 1) Aerosol liposomal cyclosporine Open label randomized trial using experimental inhalational therapy with liposomal aerosol cyclosporine in addition to standard immune suppression (tacrolimus , mycophenolate mofetil and prednisone) for 6 month duration at inhalational doses (5mg and 10 mg bid), to be defined by transplant type respectively (single, double lung transplant ) Liposomal aerosol cyclosporine: inhaled form of immune suppression standard immune suppression, oral: conventional drug	Arm 2) Standard immune suppression consisting of typical oral immune suppression for lung transplant recipients typically tacrolimus, mycophenolate mofetil and prednisone standard immune suppression, oral: conventional drug	Total of all reporting groups
Overall Participants	11	10	21
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	59.1	63.8	61.3
Sex: Female, Male (Count of Participants)
Female	5 45.5%	2 20%	7 33.3%
Male	6 54.5%	8 80%	14 66.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 27.3%	2 20%	5 23.8%
White	8 72.7%	8 80%	16 76.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	11 100%	10 100%	21 100%

Outcome Measures

1. Primary Outcome

Title	Number Of Participants With Chronic Rejection Who Met Primary Combined End-point
Description	Treatment failure defined as: BOS progression (> 20% decline lung function), re-transplant, or death
Time Frame	approximately 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Liposomal Aerosol Cyclosporine	Conventional Oral Immune Suppression
Arm/Group Description	Arm 1) Aerosol liposomal cyclosporine Open label randomized trial using experimental inhalational therapy with liposomal aerosol cyclosporine in addition to standard immune suppression (tacrolimus , mycophenolate mofetil and prednisone) for 6 month duration at inhalational doses (5mg and 10 mg bid), to be defined by transplant type respectively (single, double lung transplant ) Liposomal aerosol cyclosporine: inhaled form of immune suppression standard immune suppression, oral: conventional drug	Arm 2) Standard immune suppression consisting of typical oral immune suppression for lung transplant recipients typically tacrolimus, mycophenolate mofetil and prednisone standard immune suppression, oral: conventional drug
Measure Participants	11	10
Count of Participants [Participants]	2 18.2%	5 50%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Liposomal Aerosol Cyclosporine, Conventional Oral Immune Suppression
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	Log Rank
	Comments

2. Secondary Outcome

Title	Cytokine Analysis From BAL Fluid in Lung
Description	Multiple cytokines were assessed as markers of lung inflammation that may be used in addition to biopsy data, collected per patient as clinically indicated during the follow-up interval. Values are reported as mean change from baseline in each group, per week
Time Frame	baseline to approximately 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Liposomal Aerosol Cyclosporine	Conventional Oral Immune Suppression
Arm/Group Description	Arm 1) Aerosol liposomal cyclosporine Open label randomized trial using experimental inhalational therapy with liposomal aerosol cyclosporine in addition to standard immune suppression (tacrolimus , mycophenolate mofetil and prednisone) for 6 month duration at inhalational doses (5mg and 10 mg bid), to be defined by transplant type respectively (single, double lung transplant ) Liposomal aerosol cyclosporine: inhaled form of immune suppression standard immune suppression, oral: conventional drug	Arm 2) Standard immune suppression consisting of typical oral immune suppression for lung transplant recipients typically tacrolimus, mycophenolate mofetil and prednisone standard immune suppression, oral: conventional drug
Measure Participants	11	10
lL-1beta	-2	3.3
IL-2	-0.9	-0.3
IL-6	-2.0	6.3
IL-8	13.6	37.5
IL-10	0.1	0.1
IL-17	0.4	0.1
TNF-alpha	1.9	-1.7
IFN-gamma	0.5	0

3. Secondary Outcome

Title	Overall Survival at 5 Years Follow-up
Description	Number of participants surviving at 5 year follow-up
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Liposomal Aerosol Cyclosporine	Conventional Oral Immune Suppression
Arm/Group Description	Arm 1) Aerosol liposomal cyclosporine Open label randomized trial using experimental inhalational therapy with liposomal aerosol cyclosporine in addition to standard immune suppression (tacrolimus , mycophenolate mofetil and prednisone) for 6 month duration at inhalational doses (5mg and 10 mg bid), to be defined by transplant type respectively (single, double lung transplant ) Liposomal aerosol cyclosporine: inhaled form of immune suppression standard immune suppression, oral: conventional drug Conventrional oral immune suppression as standard of care thus consists of tacrolimus, mycophenolate mofetil prednisone and rapamycin	Arm 2) Standard immune suppression consisting of typical oral immune suppression for lung transplant recipients typically tacrolimus, mycophenolate mofetil and prednisone. Conventrional oral immune suppression as standard of care thus consists of tacrolimus, mycophenolate mofetil prednisone rapamycin described in the subsequent section as well. standard immune suppression, oral: conventional drug Conventrional oral immune suppression as standard of care thus consists of tacrolimus, mycophenolate mofetil prednisone and rapamycin
Measure Participants	11	10
Count of Participants [Participants]	5 45.5%	0 0%

Adverse Events

Time Frame	Serious and non-serious adverse events monitored for one year as described in the IND. All cause mortality monitored out to 5 years.
Arm/Group Title	Liposomal Aerosol Cyclosporine		Conventional Oral Immune Suppression
Arm/Group Description	Arm 1) Aerosol liposomal cyclosporine Open label randomized trial using experimental inhalational therapy with liposomal aerosol cyclosporine in addition to standard immune suppression (tacrolimus , mycophenolate mofetil and prednisone) for 6 month duration at inhalational doses (5mg and 10 mg bid), to be defined by transplant type respectively (single, double lung transplant ) Liposomal aerosol cyclosporine: inhaled form of immune suppression standard immune suppression, oral: conventional drug		Arm 2) Standard immune suppression consisting of typical oral immune suppression for lung transplant recipients typically tacrolimus, mycophenolate mofetil and prednisone standard immune suppression, oral: conventional drug
All Cause Mortality
	Liposomal Aerosol Cyclosporine		Conventional Oral Immune Suppression
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/11 (54.5%)		10/10 (100%)
Serious Adverse Events
	Liposomal Aerosol Cyclosporine		Conventional Oral Immune Suppression
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/11 (72.7%)		8/10 (80%)
Cardiac disorders
Atrial flutter	1/11 (9.1%)		0/10 (0%)
Congestive heart failure	0/11 (0%)		1/10 (10%)
Myocardial infarction	0/11 (0%)		1/10 (10%)
Rapid atrial fibrillation	0/11 (0%)		1/10 (10%)
Gastrointestinal disorders
Cholelithiasis	1/11 (9.1%)		0/10 (0%)
Diarrhea	1/11 (9.1%)		0/10 (0%)
Gastroenteritis	1/11 (9.1%)		0/10 (0%)
Melena	0/11 (0%)		2/10 (20%)
General disorders
Weakness	0/11 (0%)		1/10 (10%)
Immune system disorders
Acute graft rejection	3/11 (27.3%)		1/10 (10%)
Infections and infestations
Bacteremia	1/11 (9.1%)		0/10 (0%)
Bronchitis	1/11 (9.1%)		0/10 (0%)
Herpes zoster exacerbation	1/11 (9.1%)		0/10 (0%)
Influenza	2/11 (18.2%)		0/10 (0%)
Pneumonia	1/11 (9.1%)		4/10 (40%)
Pyrexia	0/11 (0%)		1/10 (10%)
Respiratory syncytial virus	0/11 (0%)		3/10 (30%)
Rhinovirus	0/11 (0%)		1/10 (10%)
Urinary tract infection	1/11 (9.1%)		0/10 (0%)
Metabolism and nutrition disorders
Hypoglycemia	1/11 (9.1%)		0/10 (0%)
Respiratory, thoracic and mediastinal disorders
Aspiration	1/11 (9.1%)		0/10 (0%)
Dyspnea	4/11 (36.4%)		4/10 (40%)
Hypoxic respiratory failure	1/11 (9.1%)		2/10 (20%)
Pneumomediastinum	0/11 (0%)		1/10 (10%)
Pulmonary embolism	1/11 (9.1%)		1/10 (10%)
Skin and subcutaneous tissue disorders
Squamous cell carcinoma (scalp/left cheek)	1/11 (9.1%)		0/10 (0%)
Vascular disorders
Deep vein thrombosis	1/11 (9.1%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Liposomal Aerosol Cyclosporine		Conventional Oral Immune Suppression
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/11 (100%)		10/10 (100%)
Cardiac disorders
Atrial flutter	1/11 (9.1%)		0/10 (0%)
Carotid atherosclerosis	1/11 (9.1%)		0/10 (0%)
Chest pain	1/11 (9.1%)		0/10 (0%)
Congestive heart failure	0/11 (0%)		1/10 (10%)
Myocardial infarction	0/11 (0%)		1/10 (10%)
Rapid atrial fibrillation	0/11 (0%)		1/10 (10%)
Ear and labyrinth disorders
Ear inflammation	1/11 (9.1%)		0/10 (0%)
Eye disorders
Conjunctivitis	1/11 (9.1%)		0/10 (0%)
Gastrointestinal disorders
Anorexia	2/11 (18.2%)		1/10 (10%)
Cholelithiasis	1/11 (9.1%)		0/10 (0%)
Clostridium difficile	1/11 (9.1%)		1/10 (10%)
Constipation	1/11 (9.1%)		0/10 (0%)
Diarrhea	2/11 (18.2%)		1/10 (10%)
Emesis	1/11 (9.1%)		0/10 (0%)
Gastroenteritis	1/11 (9.1%)		0/10 (0%)
Gastrointestinal discomfort	1/11 (9.1%)		0/10 (0%)
Melena	1/11 (9.1%)		2/10 (20%)
General disorders
Allergic rhinitis	0/11 (0%)		1/10 (10%)
Ankle edema	1/11 (9.1%)		1/10 (10%)
Ankle pain	1/11 (9.1%)		0/10 (0%)
Back pain	3/11 (27.3%)		3/10 (30%)
Bilateral ankle edema	1/11 (9.1%)		1/10 (10%)
Bilateral foot edema	1/11 (9.1%)		2/10 (20%)
Bilateral knee pain	0/11 (0%)		1/10 (10%)
Bilateral leg edema	1/11 (9.1%)		2/10 (20%)
Elevated creatinine level	1/11 (9.1%)		0/10 (0%)
Elevated tacrolimus level	1/11 (9.1%)		0/10 (0%)
Fall	0/11 (0%)		1/10 (10%)
Fatigue	1/11 (9.1%)		0/10 (0%)
Generalized pain (in joints)	1/11 (9.1%)		0/10 (0%)
Left knee pain	1/11 (9.1%)		0/10 (0%)
Leg edema	1/11 (9.1%)		0/10 (0%)
Low back pain	3/11 (27.3%)		0/10 (0%)
Malaise	6/11 (54.5%)		1/10 (10%)
Motor vehicle crash	1/11 (9.1%)		0/10 (0%)
Muscle spasms	1/11 (9.1%)		0/10 (0%)
Neck edema	0/11 (0%)		2/10 (20%)
Pain	0/11 (0%)		1/10 (10%)
Paresthesia (lower legs)	0/11 (0%)		2/10 (20%)
Right leg weakness	0/11 (0%)		1/10 (10%)
Shoulder and back pain	0/11 (0%)		1/10 (10%)
Weakness	0/11 (0%)		1/10 (10%)
Infections and infestations
Bacteremia	1/11 (9.1%)		0/10 (0%)
Bronchitis	2/11 (18.2%)		0/10 (0%)
Cytomegalovirus	1/11 (9.1%)		0/10 (0%)
Herpes zoster exacerbation	1/11 (9.1%)		0/10 (0%)
Influenza	3/11 (27.3%)		0/10 (0%)
Lower respiratory infection	0/11 (0%)		1/10 (10%)
Pharyngitis	1/11 (9.1%)		0/10 (0%)
Pneumonia	1/11 (9.1%)		5/10 (50%)
Pyrexia	1/11 (9.1%)		1/10 (10%)
Respiratory syncytial virus	0/11 (0%)		3/10 (30%)
Rhinitis	1/11 (9.1%)		1/10 (10%)
Rhinovirus	0/11 (0%)		1/10 (10%)
Upper respiratory infection	4/11 (36.4%)		1/10 (10%)
Urinary tract infection	3/11 (27.3%)		0/10 (0%)
Viral infection	1/11 (9.1%)		0/10 (0%)
Metabolism and nutrition disorders
Hypoglycemia	2/11 (18.2%)		0/10 (0%)
Nervous system disorders
Confusion	1/11 (9.1%)		0/10 (0%)
Hallucinations	1/11 (9.1%)		0/10 (0%)
Tremor	0/11 (0%)		1/10 (10%)
Reproductive system and breast disorders
Uterine pain	0/11 (0%)		1/10 (10%)
Respiratory, thoracic and mediastinal disorders
Acute rejection	4/11 (36.4%)		1/10 (10%)
Aspiration	1/11 (9.1%)		0/10 (0%)
Cough	2/11 (18.2%)		0/10 (0%)
Dyspepsia	1/11 (9.1%)		0/10 (0%)
Dyspnea	7/11 (63.6%)		5/10 (50%)
Hypoxic respiratory failure	1/11 (9.1%)		2/10 (20%)
Pneumomediastinum	0/11 (0%)		1/10 (10%)
Productive cough	0/11 (0%)		3/10 (30%)
Pulmonary embolism	1/11 (9.1%)		1/10 (10%)
Skin and subcutaneous tissue disorders
Abscess (right axillary)	1/11 (9.1%)		0/10 (0%)
Anterior tongue lesion	0/11 (0%)		1/10 (10%)
Foot rash	1/11 (9.1%)		0/10 (0%)
Herpes zoster (left scalp, ear, face)	1/11 (9.1%)		0/10 (0%)
Skin hyperpigmentation	0/11 (0%)		1/10 (10%)
Skin rash	0/11 (0%)		1/10 (10%)
Squamous cell carcinoma (chest, temple)	1/11 (9.1%)		0/10 (0%)
Squamous cell carcinoma (scalp/left cheek)	1/11 (9.1%)		0/10 (0%)
Squamous cell carcinoma (left ear)	0/11 (0%)		1/10 (10%)
Squamous cell carcinoma (left hand)	0/11 (0%)		1/10 (10%)
Urticarial (left cheek)	1/11 (9.1%)		0/10 (0%)
Vascular disorders
Deep vein thrombosis	1/11 (9.1%)		0/10 (0%)
Hypertension	3/11 (27.3%)		2/10 (20%)
Postural hypotension	0/11 (0%)		1/10 (10%)
Pulmonary hypertension	1/11 (9.1%)		0/10 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.