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

NCT01287078 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 11006811-H-0068
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

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. One of the complications of transplant is the occurrence of graft versus host disease (in hematopoietic stem cell transplants) and host versus graft disease (in lung transplantation). In these diseases, the cells attack the lungs and cause irreversible small airway fibrosis referred to as bronchiolitis obliterans syndrome. 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, bronchoalveolar lavage samples, 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 undergo repeat bronchoalveolar sample at week 9 and 18. 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.

Conditions

Constrictive Bronchiolitis; Bronchiolitis Obliterans; Graft vs Host Disease; Bronchiolitis, Exudative; Bronchiolitis, Proliferative

Keywords

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

Outcome Measures

Primary Outcomes (8)

• Overall Response to Treatment Based on Positive Response to Cyclosporine Inhalation Solution (CIS)

  Participants who responded to treatment with cyclosporine inhalation solution (CIS)

  18 weeks

• Overall Non-response to Treatment

  Participants who did not respond to treatment with cyclosporine inhalation solution (CIS)

  18 weeks

• Stable or Progressive Disease at Baseline With Improvement of FEV1

  Participants with stable or progressive disease at baseline with improvement of FEV1

  18 weeks

• Disease Progression at Baseline With Stablization of FEV1

  Participants with progressive disease at baseline with stablization of FEV1

  18 weeks

• Disease Stability at Baseline With Stablization in FEV1 and Greater Than 25% Decline in Systemic Immunosuppression

  Participants with stable disease at baseline with stablization in FEV1 and greater than 25% decline in systemic immunosuppression

  18 weeks

• Stable or Progressive Disease at Baseline With Greater Than 20% of Decline in FEV1

  Participants with stable or progressive disease at baseline with greater than 20% of decline in FEV1

  18 weeks

• Stable Disease at Baseline With Stablization of FEV1 and no Change or Increase in Systemic Immunosuppresion

  Participants with stable disease at baseline with stablization of FEV1 and no change or increase in systemic immunosuppresion

  18 weeks

• Disease Progression at Baseline With Decline in FEV1 Greater Than 10%

  Participants with progressive disease at baseline with decline in FEV1 greater than 10%

  18 weeks

Study Arms (1)

Inhaled Cyclosporine in Lung Transplant and HSCT Recipients

EXPERIMENTAL

Subjects with Bronchiolitis Obliterans Syndrome (BOS) received cyclosporine inhalation solution (CIS) 150 mg, three times weekly during weeks 1-5. Dose escalated to 300 mg three times weekly from weeks 6-8. Study drug administration ended at week 19.

Drug: Cyclosporine Inhalation Solution

Interventions

Cyclosporine Inhalation Solution DRUG

sterile, clear, colorless, preservative-free solution of cyclosporine (USP) in propylene glycol developed specifically for administration by oral inhalation.

Inhaled Cyclosporine in Lung Transplant and HSCT Recipients

Eligibility Criteria

• Age: 10 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• History of:\<TAB\>
• Hematopoietic stem cell transplant recipients at least 99 days post transplant (group A)
• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• 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. doi: 10.1038/sj.bmt.1703142.

  PMID: 11593314 BACKGROUND

• 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. doi: 10.1016/j.healun.2006.05.014. No abstract available.

  PMID: 16890109 BACKGROUND

• 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. doi: 10.1016/j.bbmt.2006.07.016.

  PMID: 17162207 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Bronchiolitis Obliterans; Graft vs Host Disease

Condition Hierarchy (Ancestors)

Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Immune System Diseases

Results Point of Contact

• Title: Dr Richard Childs
• Organization: National Heart Lung and Blood Institute

childsr@nhlbi.nih.gov

301-451-7128

Study Officials

• Nicole J Gormley, M.D.

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 29, 2011
• First Posted: February 1, 2011
• Study Start: January 29, 2011
• Primary Completion: August 8, 2018
• Study Completion: August 8, 2018
• Last Updated: September 24, 2020
• Results First Posted: September 24, 2020

Record last verified: 2018-08-31

Locations

US (1)