Cyclosporine Inhalation Solution (CIS) in Lung Transplant and Hematopoietic Stem Cell Transplant Recipients for the Treatment of Bronchiolitis Obliterans
| Status: | Completed |
|---|---|
| Conditions: | Bronchitis, Orthopedic, Pulmonary, Hematology |
| Therapuetic Areas: | Hematology, Pulmonary / Respiratory Diseases, Orthopedics / Podiatry |
| Healthy: | No |
| Age Range: | 10 - 80 |
| Updated: | 1/20/2019 |
| Start Date: | January 29, 2011 |
| End Date: | August 8, 2018 |
Phase II Trial of Cyclosporine Inhalation Solution (CIS) in Lung Transplant and Hematopoietic Stem Cell Transplant Recipients for Treatment of Bronchiolitis Obliterans
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.
- 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.
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.
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.
- INCLUSION CRITERIA:
History of:
-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.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
Phone: 800-411-1222
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