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

Tracking Information
First Submitted Date ICMJE	January 29, 2011
First Posted Date ICMJE	February 1, 2011
Last Update Posted Date	December 5, 2018
Study Start Date ICMJE	January 29, 2011
Actual Primary Completion Date	August 8, 2018 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: September 1, 2018)	FEV1 improvement or stabilization from study baseline by week 9 or thereafter, for at least two successive measure (efficacy) and the toxicity profile as measured by CTCAE criteria (safety). [ Time Frame: up to 20 weeks ]; Improvement or stabilization of disease
Original Primary Outcome Measures ICMJE; (submitted: January 29, 2011)	The primary endpoint of each study group is FEV1 improvement or stabilization from study baseline by week 9 or thereafter, for at least two successive measures (efficacy) and the toxicity profile as measured by CTCAE criteria (safety)Asses... [ Time Frame: 4 years ]
Change History	Complete list of historical versions of study NCT01287078 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE	Not Provided
Original Secondary Outcome Measures ICMJE; (submitted: January 29, 2011)	Secondary endpoints include PK and lung deposition characteristics improvement in chest CT images, results of cytokine arrays, and functional capacitythe study of pharmacokinetics and lung deposition characteristics of inhaled cyclosporine... [ Time Frame: 4 years ]
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Cyclosporine Inhalation Solution (CIS) in Lung Transplant and Hematopoietic Stem Cell Transplant Recipients for the Treatment of Bronchiolitis Obliterans
Official Title ICMJE	Phase II Trial of Cyclosporine Inhalation Solution (CIS) in Lung Transplant and Hematopoietic Stem Cell Transplant Recipients for Treatment of Bronchiolitis Obliterans
Brief Summary	Background: - Bronchiolitis obliterans or bronchiolitis obliterans syndrome is a lung disorder that occurs as a complication of either lung transplantation or bone marrow/blood stem cell transplantation. In bronchiolitis obliterans, the body s white blood cells or white blood cells from the transplant attack the lungs, which leads to the destruction of lung tissue, and ultimately, scarring or fibrosis of the lung tissues. When a patient develops fibrosis of the lungs or bronchioles, the lungs no longer work properly, which causes difficulties with breathing that lead to a diminished quality of life and an increased risk of death. Treatment typically involves immunosuppressive therapy such as oral cyclosporine or steroid therapy, but these treatments are only marginally effective and can cause significant toxicities and increase the risk of infections. Inhaled cyclosporine (CIS) achieves higher concentrations of cyclosporine in the lungs and lower concentrations of cyclosporine in the blood than oral cyclosporine. Therefore, it could have advantages over conventional oral immunosuppressive therapies used to treat this disorder. Researchers are interested in testing whether inhaled cyclosporine therapy could be used as a safe and effective treatment for bronchiolitis obliterans or bronchiolitis obliterans syndrome occurring after bone marrow/blood stem cell or lung transplants. Objectives: - To evaluate whether inhaled cyclosporine (CIS) can improve or stabilize lung function and quality of life in individuals with bronchiolitis obliterans. Eligibility: - Individuals between 10 and 80 years of age who have been diagnosed with bronchiolitis obliterans or bronchiolitis obliterans syndrome after blood or lung transplants. Design: Participants will be screened with a full medical history and physical examination, as well as blood and urine tests, lung function tests, imaging studies, and quality of life questionnaires.; Participants will take cyclosporine inhalation solution through a nebulizer. The nebulizer generates a mist of cyclosporine inhalation solution (CIS), which is then breathed in through a mouthpiece. The process takes approximately 20 minutes. The solution will be provided in single-use vials.; Participants will continue to take all medications for post-transplant care as required by their doctor and the study researchers. Attempts will be made to reduce the doses and types of immunosuppressants given to participants on the study, as long as the treatment continues to produce improved or stable lung function.; Participants will have study visits every 3 weeks with blood and urine tests, lung function tests, and imaging studies. Participants will also complete quality of life questionnaires as directed. Treatment will continue for a minimum of 18 weeks, followed by a final follow-up visit 2 weeks after the end of the study.; Participants who benefit from the inhaled cyclosporine (CIS) may continue to receive further therapy with inhaled cyclosporine at the end of the study by participation in a separate study extension.
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%. In hematopoietic stem cell transplantation, BO is thought to be a manifestation of chronic graft-vs-host disease (GVHD). Up to 45% 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 safety, efficacy, and pharmacodynamics of inhaled cyclosporine for the treatment of BO. Two distinct patient populations will be offered enrollment in this protocol: hematopoietic transplant recipients with BO (group A) and lung transplant recipients with BO (group B). Study participants will receive CIS at an initial dose of 150mg, three times weekly. Patients will undergo dose titration to a maximum dose of 300mg, three times weekly. Drug deposition and pharmacokinetic analyses will be performed at the initiation of 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 treatment will be recorded. The primary objective is to 1) assess the safety and efficacy of inhaled cyclosporine as a new therapy in hematopoietic transplant patients and lung transplant patients with established BO. Additionally, we seek to promote a better understanding of the pathogenesis of BO in these two transplant groups and to assess the anti-inflammatory effects of inhaled cyclosporine in patients that develop this complication. The primary endpoint of each study group is the best response, FEV1 improvement or stabilization from study baseline at week 18 for two successive measures, at least 1 week apart, no more than 2 weeks apart. Secondary endpoints include the toxicity profile as measured by CTCAE criteria (safety), the study of pharmacokinetics and lung deposition characteristics of inhaled cyclosporine, 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 Type ICMJE	Interventional
Study Phase	Phase 2
Study Design ICMJE	Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Constrictive Bronchiolitis; Bronchiolitis Obliterans; Graft vs Host Disease; Bronchiolitis, Exudative; Bronchiolitis, Proliferative
Intervention ICMJE	Drug: Cyclosporine Inhalation Solution; sterile, clear, colorless, preservative-free solution of cyclosporine (USP) in propylene glycol developed specifically for administration by oral inhalation.
Study Arms	Experimental: 1; Patients receive inhaled drug 3x weekly for 6 months; Intervention: Drug: Cyclosporine Inhalation Solution
Publications *	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.; Boucek MM, Waltz DA, Edwards LB, Taylor DO, Keck BM, Trulock EP, Hertz MI; International Society for Heart and Lung Transplantation. Registry of the International Society for Heart and Lung Transplantation: ninth official pediatric heart transplantation report--2006. J Heart Lung Transplant. 2006 Aug;25(8):893-903.; 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.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: September 1, 2018)	25
Original Estimated Enrollment ICMJE; (submitted: January 29, 2011)	78
Actual Study Completion Date	August 8, 2018
Actual Primary Completion Date	August 8, 2018 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	INCLUSION CRITERIA: History of:<TAB> -Hematopoietic stem cell transplant recipients at least 99 days post transplant (group A) Or; Lung transplant recipients at least 6 months post transplant (Group B); Biopsy proven bronchiolitis obliterans (confirmed by NIH pathology department) or Bronchiolitis Obliterans Syndrome (BOS) as defined by:; FEV1 less than 75 percent predicted and; No evidence of pulmonary infection as a causative etiology to lung dysfunction or other causative etiology; Decline in FEV1 (The FEV1 values used to determine BOS will be the average of 2 measurements of FEV1 taken sequentially at least 3 weeks apart up to 6 months apart) compared to pre-transplant baseline for group A or compared to best post-transplant measurement in group B.; For hematopoietic transplant patients, FEV1 must have declined less than 10 percent from pre-transplant baseline (group A); For lung transplant patients, FEV1 must have declined greater than 20 percent from best post-transplant measurement (group B) And one of the following: FEV1/FVC less than 0.7; Air trapping seen on CT scan or RV greater than 20 percent predicted; Evidence of cGVHD affecting at least one other organ system (group A); Age 10-80 years; Progressive disease or stable disease (active BOS, stable by FEV1 criteria) on immunosuppressants at study entry; Progressive disease at study entry: Diagnosis of BO or BOS with evidence of a progressive decline in FEV1. A documented decline (greater than or equal 10 percent) in FEV1 has occurred within 18 weeks (minimum documentation of 3 weeks) preceding study enrollment; Stable disease at study entry: Diagnosis of BO or BOS on immunosuppressive therapy with evidence of stable disease (active BOS, stable by FEV1 criteria), as documented by a stable FEV1 (increase <5% and decrease <10%) within 18 weeks (minimum documentation of 3 weeks) preceding study enrollment; Patients on calcineurin inhibitors at study entry will be required to be on a stable dose of the calcineurin inhibitor for 4 weeks prior to study enrollment EXCLUSION CRITERIA: Evidence of uncontrolled, pulmonary infection; Patients with unstable coronary insufficiency, severe cardiac arrhythmias, and/or uncontrolled hypertension.; History of hypersensitivity to propylene glycol; History of allergic reaction or hypersensitivity to Technetium- 99m sulfur colloid, used in lung deposition studies; ECOG performance status greater than or equal to 3; Serum creatinine >2.5 mg/dl; Documented allergy or intolerance to cyclosporine; Patient pregnant or breast feeding or not willing to use an approved method of birth control; Inability to comprehend the investigational nature of the study and provide informed consent; Life expectancy less than 18 weeks.; An increase greater than or equal to 5% and an absolute increase greater than or equal to 0.05 in FEV1 in the 18 weeks (minimum documentation of 3 weeks) preceding study enrollment; Subjects who have had prior administration of inhaled cyclosporine.
Sex/Gender	Sexes Eligible for Study: All
Ages	10 Years to 80 Years (Child, Adult, Older Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT01287078
Other Study ID Numbers ICMJE	110068; 11-H-0068
Has Data Monitoring Committee	Not Provided
U.S. FDA-regulated Product	Studies a U.S. FDA-regulated Drug Product: Yes Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement	Not Provided
Responsible Party	National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
Study Sponsor ICMJE	National Heart, Lung, and Blood Institute (NHLBI)
Collaborators ICMJE	Not Provided
Investigators ICMJE	Principal Investigator: Nicole J Gormley, M.D. National Heart, Lung, and Blood Institute (NHLBI)
PRS Account	National Institutes of Health Clinical Center (CC)
Verification Date	August 31, 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP