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

• ClinicalTrials.gov Identifier: NCT01273207
• Recruitment Status: Completed
• First Posted: January 10, 2011
• Results First Posted: September 18, 2020
• Last Update Posted: September 18, 2020
• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

Study Description

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; Bronchiolitis, Exudative; Bronchiolitis, Proliferative; Graft-Versus-Host Disease	Drug: Cyclosporine Inhalation Solution (CIS)	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

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 7 participants
• Allocation: N/A
• 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
• Actual Study Start Date: March 2, 2012
• Actual Primary Completion Date: May 10, 2019
• Actual Study Completion Date: May 23, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Inhaled Cyclosporine in HSCT Participants; Hemopoietic Stem Cell transplant (HSCT) subjects with Bronchiolitis Obliterans Syndrome (BOS) received cyclosporine inhalation solution (CIS) at maximum tolerated dose not exceeding 300 mg administered three times per week	Drug: Cyclosporine Inhalation Solution (CIS); CIS is a sterile, clear, colorless, preservative-free solution of cyclosporine (USP) in propylene glycol developed specifically for administration by oral inhalation.

Outcome Measures

Primary Outcome Measures :

1. Improvement in Lung Function - Increase in FEV1 [ Time Frame: 6 Months ]
   Continued improvement in lung function as defined by 10% or more increase in FEV1
2. Disease Stablization - Decrease in FEV1 or Less Than 10% Increase in FEV1 [ Time Frame: 6 Months ]
   Stabilization in Pulmonary Function Test (PFT) as defined by less than 10% increase in FEV1 or less than 10% decline in FEV1
3. Disease Progression - Decrease in FEV1 or Additional/Increase in Immunosuppressive Therapies [ Time Frame: 6 Months ]
   Disease progression as defined by a 20% or more decline in FEV1, or those who require an increase in immunosuppressive therapies by at least 25% or the addition of new immunosuppressive therapies.

Eligibility Criteria

• Ages Eligible for Study: 10 Years to 80 Years (Child, Adult, Older Adult)
• 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 20 percent (sustained for 3 weeks, excluding adjustments made for target drug levels). * The criteria for study entry on this extension protocol are not the same as the criteria for response on the primary protocol to allow for entry of patients on this extension protocol, which is deriving some clinical benefit, but have not met the full response criteria as defined in the primary protocol.

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

Locations

United States, Maryland

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, United States, 20892

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)

  Study Documents (Full-Text)

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

Study Protocol and Statistical Analysis Plan  [PDF] May 10, 2019

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

• Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
• ClinicalTrials.gov Identifier: NCT01273207
• Other Study ID Numbers: 110064; 11-H-0064
• First Posted: January 10, 2011
• Results First Posted: September 18, 2020
• Last Update Posted: September 18, 2020
• Last Verified: August 14, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

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

Additional relevant MeSH terms:

Bronchiolitis; Bronchiolitis Obliterans; Graft vs Host Disease; Respiratory Tract Diseases; Immune System Diseases; Bronchitis; Respiratory Tract Infections; Infections; Bronchial Diseases; Lung Diseases, Obstructive; Lung Diseases; Cyclosporine; Cyclosporins; 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