Extension Study (Extended Access) of Cyclosporine Inhalation Solution (CIS) in Lung Transplant and Hematopoietic Stem Cell Transplant Recipients for the Treatment of Bronchiolitis Obliterans

Study Description

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Brief Summary:

Bronchiolitis Obliterans (BO) is an obstructive lung disease that can affect individuals that have undergone a lung or hematopoietic stem cell transplant. BO has been studied most extensively in lung transplant recipients, where it is considered to represent chronic lung rejection. It is the leading cause of death after lung transplant, with mortality rates up to 55 percent. In hematopoietic stem cell transplantation, BO is thought to be a manifestation of chronic graft-vs-host disease (GVHD). Up to 45 percent of patients undergoing hematopoietic stem cell transplantation at the NHLBI develop a decline in pulmonary function. Conventional therapy for patients who develop BO consists of augmentation of systemic immunosuppressants. Systemic immunosuppression has limited efficacy for BO and is associated with deleterious consequences including increased risk of infections and decreased graft-versus tumor/leukemia effects.

Recently, cyclosporine inhalation solution (CIS) in solution with propylene glycol has been shown to improve overall survival and chronic rejection-free survival in lung transplant patients. These findings suggest targeted delivery of immunosuppressive therapy to the diseased organ warrants further investigation as this may minimize the morbidity associated with systemic immunosuppression. However, there currently exists limited data regarding the overall efficacy of inhaled cyclosporine to treat established BO following lung transplantation. Furthermore, inhaled cyclosporine has not been studied in the treatment of BO following hematopoietic stem cell transplantation.

Here, we propose to evaluate the long-term safety and efficacy, of inhaled CIS for the treatment of BO. Enrollment will be offered to subjects who have completed the end of study (week 18 visit) for the initial protocol (Phase II Trial of CIS in lung transplant and hematopoietic stem cell transplant recipients for treatment of Bronchiolitis Obliterans) and who have shown evidence of benefit (either an improvement or stabilization) in BO/BOS with CIS treatment.

Clinical parameters, including pulmonary function tests, will be measured in addition to laboratory markers of the anti-inflammatory response to CIS. Adverse events associated with extended treatment with CIS will be recorded.

The primary objective is to provide long-term safety and efficacy data for the use of CIS in hematopoietic transplant patients and lung transplant patients with established BO.

Secondary objectives include investigation of the inflammatory pathways that lead to chronic BO and ascertainment of the long term anti-inflammatory effects of this CSA preparation ex vivo and in vivo.

Primary endpoint is the efficacy of extended use CIS for BO/BOS. Secondary endpoints include the toxicity profile (adverse events), improvement in high resolution chest CT images, results of peripheral blood and bronchoalveolar cytokine arrays to assess secondary markers of inflammation, and functional capacity measurements using a six-minute walk test.

Condition or disease	Intervention/treatment	Phase
Bronchiolitis Obliterans; Constructive Bronchiolitis; Graft Versus Host Disease	Drug: Inhaled Cyclosporine Solution	Phase 2

Detailed Description:

Bronchiolitis Obliterans (BO) is an obstructive lung disease that can affect individuals that have undergone a lung or hematopoietic stem cell transplant. BO has been studied most extensively in lung transplant recipients, where it is considered to represent chronic lung rejection. It is the leading cause of death after lung transplant, with mortality rates up to 55 percent. In hematopoietic stem cell transplantation, BO is thought to be a manifestation of chronic graft-vs-host disease (GVHD). Up to 45 percent of patients undergoing hematopoietic stem cell transplantation at the NHLBI develop a decline in pulmonary function. Conventional therapy for patients who develop BO consists of augmentation of systemic immunosuppressants. Systemic immunosuppression has limited efficacy for BO and is associated with deleterious consequences including increased risk of infections and decreased graft-versus tumor/leukemia effects.

Recently, cyclosporine inhalation solution (CIS) in solution with propylene glycol has been shown to improve overall survival and chronic rejection-free survival in lung transplant patients. These findings suggest targeted delivery of immunosuppressive therapy to the diseased organ warrants further investigation as this may minimize the morbidity associated with systemic immunosuppression. However, there currently exists limited data regarding the overall efficacy of inhaled cyclosporine to treat established BO following lung transplantation. Furthermore, inhaled cyclosporine has not been studied in the treatment of BO following hematopoietic stem cell transplantation.

Here, we propose to evaluate the long-term safety and efficacy, of inhaled CIS for the treatment of BO. Enrollment will be offered to subjects who have completed the end of study (week 18 visit) for the initial protocol (Phase II Trial of CIS in lung transplant and hematopoietic stem cell transplant recipients for treatment of Bronchiolitis Obliterans) and who have shown evidence of benefit (either an improvement or stabilization) in BO/BOS with CIS treatment.

Clinical parameters, including pulmonary function tests, will be measured in addition to laboratory markers of the anti-inflammatory response to CIS. Adverse events associated with extended treatment with CIS will be recorded.

The primary objective is to provide long-term safety and efficacy data for the use of CIS in hematopoietic transplant patients and lung transplant patients with established BO.

Secondary objectives include investigation of the inflammatory pathways that lead to chronic BO and ascertainment of the long term anti-inflammatory effects of this CSA preparation ex vivo and in vivo.

Primary endpoint is the efficacy of extended use CIS for BO/BOS. Secondary endpoints include the toxicity profile (adverse events), improvement in high resolution chest CT images, results of peripheral blood and bronchoalveolar cytokine arrays to assess secondary markers of inflammation, and functional capacity measurements using a six-minute walk test.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	78 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Extension Study (Extended Access) of Cyclosporine Inhalation Solution (CIS) in Lung Transplant and Hematopoietic Stem Cell Transplant Recipients for the Treatment of Bronchiolitis Obliterans
Study Start Date :	February 1, 2011
Estimated Primary Completion Date :	June 30, 2025
Estimated Study Completion Date :	June 30, 2025

Arms and Interventions

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Outcome Measures

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Primary Outcome Measures :

1. Primary endpoints include the toxicity profile (adverse events) and efficacy of extended use CIS for BO/BOS [ Time Frame: 3 years ]

Secondary Outcome Measures :

1. Secondary endpoints include improvement in chest CT images, results of peripheral blood and bronchoalveolar cytokine arrays, and functional capacity measurements [ Time Frame: 3 years ]
2. Toxicity profile (adverse events) [ Time Frame: 3 years ]

Eligibility Criteria

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Ages Eligible for Study:	10 Years to 80 Years (Child, Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

• INCLUSION CRITERIA:

  1. Completed the End of Study visit (week 19) on the initial protocol (Phase II Trial of Cyclosporine Inhalation Solution (CIS) in Lung Transplant and Hematopoietic Stem Cell Transplant Recipients for Treatment of Bronchiolitis Obliterans) in the preceding 12 weeks
  2. Patients have shown evidence for a clinical benefit to CIS as evidenced by one or more of the following:
• Improvement in pulmonary function defined by a 10 percent or more increase in the FEV1 at week 18, confirmed with repeat PFTs at least 1 week apart.
• In patients with progressive disease at study entry on the initial protocol (Phase II Trial of Cyclosporine Inhalation Solution (CIS) in Lung Transplant and Hematopoietic Stem Cell Transplant Recipients for Treatment of Bronchiolitis Obliterans), stabilization in pulmonary function, defined as less than a 10 percent improvement in FEV1 or less than 10 percent decline in FEV1 at week 18, confirmed with repeat PFTs at least 1 week apart.
• In patients with stable disease (active BOS stable by FEV1 criteria) at study entry on the initial protocol (Phase II Trial of Cyclosporine Inhalation Solution (CIS) in Lung Transplant and Hematopoietic Stem Cell Transplant Recipients for Treatment of Bronchiolitis Obliterans), stabilization in pulmonary function, defined as less than a 10 percent improvement in their FEV1 or less than 10 percent decline in FEV1, and a decrease in the dose of one or more systemic immunosuppressants by at least 25 percent (sustained for 3 weeks, excluding adjustments made for target drug levels)

EXCLUSION CRITERIA:

1. More than a 12 week gap in study drug administration (CIS)
2. Evidence of uncontrolled, pulmonary infection
3. ECOG performance status greater than or equal to 3
4. Patient pregnant or breast feeding or not willing to continue the use of an approved method of birth control
5. Life expectancy less than 18 weeks
6. History of hypersensitivity reaction to propylene glycol
7. Documented allergy or intolerance to CIS
8. History of untreated coronary insufficiency, severe cardiac arrhythmias, and/or uncontrolled hypertension.
9. Serum creatinine greater than 2.5 mg/dl
10. Inability to comprehend the investigational nature of the study and provide informed consent

Contacts and Locations

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Contacts

Contact: Catalina Ramos, R.N.	(301) 451-1173	cramos@mail.nih.gov
Contact: Nicole J Gormley, M.D.	(240) 402-0210	nicole.gormley@nih.gov

Locations

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike	Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 ext TTY8664111010 prpl@cc.nih.gov

Sponsors and Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

Principal Investigator:	Nicole J Gormley, M.D.	National Heart, Lung, and Blood Institute (NHLBI)

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

Publications:

Trulock EP, Edwards LB, Taylor DO, Boucek MM, Keck BM, Hertz MI; International Society for Heart and Lung Transplantation. Registry of the International Society for Heart and Lung Transplantation: twenty-third official adult lung and heart-lung transplantation report--2006. J Heart Lung Transplant. 2006 Aug;25(8):880-92.

Savani BN, Montero A, Srinivasan R, Singh A, Shenoy A, Mielke S, Rezvani K, Karimpour S, Childs R, Barrett AJ. Chronic GVHD and pretransplantation abnormalities in pulmonary function are the main determinants predicting worsening pulmonary function in long-term survivors after stem cell transplantation. Biol Blood Marrow Transplant. 2006 Dec;12(12):1261-9.

Afessa B, Litzow MR, Tefferi A. Bronchiolitis obliterans and other late onset non-infectious pulmonary complications in hematopoietic stem cell transplantation. Bone Marrow Transplant. 2001 Sep;28(5):425-34. Review.

Responsible Party:	National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier:	NCT01273207 History of Changes
Other Study ID Numbers:	110064; 11-H-0064
First Posted:	January 10, 2011
Last Update Posted:	March 29, 2018
Last Verified:	November 22, 2017

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) ):

Peripheral Blood Stem Cell Transplant; Inhaled Cyclosporine; Graft-Versus-Host Disease; Bone Marrow Transplant	Lung Transplantation; Bronchiolitis Obliterans; Graft Versus Host Disease

Additional relevant MeSH terms:

Graft vs Host Disease; Bronchiolitis; Bronchiolitis Obliterans; Immune System Diseases; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Infections; Pharmaceutical Solutions; Cyclosporins	Cyclosporine; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antifungal Agents; Anti-Infective Agents; Dermatologic Agents; Antirheumatic Agents; Calcineurin Inhibitors