Oral Cyclosporine in Chronic Obstructive Pulmonary Disease

A Randomized, Double-Blinded, Placebo-Controlled Protocol of Oral Cyclosporine in Patients With Advanced Stage Chronic Obstructive Pulmonary Disease

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00974142

Enrollment

Registered

2009-09-10

Start date

2009-09-30

Completion date

2016-12-31

Last updated

2025-06-25

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Chronic Obstructive Pulmonary Disease

Keywords

COPD, Chronic Obstructive Pulmonary Disease, Cyclosporine, Oral Immunotherapy, Advanced stage

Brief summary

This is a randomized, double-blinded, placebo-controlled trial of oral Cyclosporine A (CsA) in patients with advanced stage chronic obstructive pulmonary disease. The purpose of the study is to evaluate the safety and effectiveness of CsA as a therapy for the adaptive immune response in advanced stage Chronic Obstructive Pulmonary Disease (COPD). Subjects between 45 and 80 years of age with a confirmed diagnosis of advanced stage COPD, not responsive to conventional inhaler therapy, who meet all the study requirements, will be enrolled in this study. A total of 30 subjects of either sex will be enrolled in this study.

Interventions

DRUGCyclosporine

Fifteen patients will receive cyclosporine at an initial dosing of 3.0 mg/kg/day.

DRUGPlacebo

Fifteen patients will receive will receive placebo.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

45 Years to 80 Years

Healthy volunteers

Inclusion criteria

* Age between 45 and 80 years * A confirmed diagnosis of advanced stage COPD, using current accepted diagnostic criteria, including clinical/laboratory findings, pulmonary function tests, and appropriate history to exclude other disorders that could explain their lung disease. The accepted range of forced expiratory volume at one second will include 25% ≤ forced expiratory volume at one second ≤ 60% * Subjects agree to maintain a stable medication regimen in the absence of a disease flare * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 * carbon dioxide partial pressure \< 45 mm Hg, room air oxyhemoglobin saturation \> 85% * A willingness to participate in all portions of the protocol, including serial bronchoscopy, requisite surveillances, and ancillary immunologic studies in follow-up visits at this institution * For woman of childbearing age, a negative pregnancy test, and a willingness to use two methods of contraception, or abstinence * An ability and willingness to provide written informed consent

Exclusion criteria

* Three, or more exacerbations of lower respiratory disease in the past year requiring systemic corticosteroids, or one exacerbation requiring hospitalization in the past 6 months * Intubation for COPD, or other cause of respiratory failure in the past year * Use of immunosuppressive therapy including oral prednisone \> 10mg per day other than aerosolized corticosteroids, anytime within three months prior to participation * Evidence for an opportunistic infection/colonization of the airways, i.e., non-bacterial * Evidence for systemic illness including hematologic disorders (defined by an absolute neutrophil count (ANC) \< 4000 /mL and platelets \< 120,000/mL), cirrhosis, or hepatic insufficiency (total bilirubin, or alkaline phosphatase \> 1.5 x normal, serum glutamate oxaloacetate transaminase, or serum glutamate pyruvate transaminase \> 1.2 x normal values), or a coagulopathy (INR \> 1.4), seizure disorder * Evidence for renal insufficiency with a calculated creatinine clearance using the Cockcroft and Gault's method of \< 80 ml/min for males and \< 70 ml/min for females, or serum creatinine \> 1.4 mg/dL. * Evidence of coronary artery disease by history, e.g., angina or history of myocardial infarction within the past 12 months, unless corrected by coronary artery bypass graft within \< 5 years, and asymptomatic since * Evidence for systemic abnormal renal function manifested by uncontrolled hypertension (systolic blood pressure \> 160 mmHg or diastolic blood pressure \>90 mmHg), hyperkalemia (serum potassium \> 5.0 meq/dl, and/or elevated serum potassium above the normal range for the subject's age) * Pregnancy or lactation, or inability to take contraception during and for 6 months following treatment * Positive HIV, or hepatitis B or C serology, or another active infection * Current or past history of cancer excluding basal or squamous cell skin cancer * Undiagnosed pulmonary nodule requiring diagnostic evaluation * Weight loss \> 10% usual body weight over the past 6 months or a BMI \< 18 * Known hypersensitivity or allergy to cyclosporine * Concurrent participation in other clinical trials within the prior month * Known medical or psychological condition (severe personality disorder or mental illness) that would not permit the subject to complete the trial or sign informed consent * Autoimmune disorders or other disorders with suspected systemic immune involvement * Active smoking history or urinary cotinine \> 2 * Hypersensitivity to midazolam or narcotics which would not allow bronchoscopy sedation * Concurrent use of drugs with a known interaction with cyclosporine

Design outcomes

Primary

Measure	Time frame	Description
Safety Profile of Oral Cyclosporin A Immunotherapy in Advanced Stage Chronic Obstructive Pulmonary Disease Patients- Nephrotoxicity - Measured by Serum Creatinine	16 weeks	Measurement of nephrotoxicity by monitoring serum creatinine over 16 week treatment interval. Mean serum creatinine values were assessed at Week 2, 4, 6, 8, 10, 12 and 16. The mean values of all measurements for each participant were calculated and then the mean across participants was calculated. Values expressed as mean ± SD.
Safety Profile of Oral Cyclosporin A Immunotherapy in Advanced Stage Chronic Obstructive Pulmonary Disease Patients - Number of Patients That Developed Renal Insufficiency	16 weeks	Development of renal insufficiency defined as \> 30% elevation in serum creatinine above baseline which required dose modification of the cyclosporine over 16 week treatment interval at Week 2, 4, 6, 8, 10, 12 and 16. Outcome measured the number of subjects who developed renal insufficiency during the study treatment interval.
Safety Profile of Oral Cyclosporin A Immunotherapy in Advanced Stage Chronic Obstructive Pulmonary Disease Patients - Number of Patients That Developed Infection Requiring Systemic Antibiotic Therapy	16 weeks	Clinical diagnosis of infection which requires systemic antibiotic therapy during the 16 week study interval at Week 2, 4, 6, 8, 10, 12 and 16. Outcome measured the number of subjects who developed an infection requiring systemic antibiotic therapy during the study treatment interval.

Secondary

Measure	Time frame	Description
Peripheral Blood T Cell Biomarkers Over Treatment Interval - Change in the Percentage of Cluster of Differentiation 8 and Major Histocompatibility Complex II	at Week 8 and Week 16	Outcome measured the change in the percentage of peripheral blood cells expressing biomarker - cluster of differentiation 8 (CD8), major histocompatibility complex (MHC) II at midpoint assessment (Week 8) and at the conclusion of treatment (Week 16). Values expressed as median (full range).
Peripheral Blood T Cell Biomarkers Over Treatment Interval - Change in the Percentage of Cluster of Differentiation 8+ Interferon Gamma	at Week 8 and Week 16	Outcome measured the change in the percentage of peripheral blood T cell biomarkers - CD8+interferon gamma at midpoint assessment (Week 8) and at the conclusion of treatment (Week 16). Values expressed as median (full range).
Peripheral Blood T Cell Biomarkers Over Treatment Interval - Change in the Percentage of Cluster of Differentiation 4+ Interleukin-2	at Week 8 and Week 16	Outcome measured the change in the percentage of peripheral blood T cell biomarkers - cluster of differentiation 4+ interleukin-2 at midpoint assessment (Week 8) and at the conclusion of treatment (Week 16). Values expressed as median (full range).
Peripheral Blood T Cell Biomarkers Over Treatment Interval - Change in the Percentage of Cluster of Differentiation 8+ Tumor Necrosis Factor	at Week 8 and Week 16	Outcome measured the change in the percentage of peripheral blood T cell biomarkers - CD8+ tumor necrosis factor at midpoint assessment (Week 8) and at the conclusion of treatment (Week 16). Values expressed as median (full range).
Pharmacokinetic - Pharmacodynamic Relationship of Oral Cyclosporine and Biomarkers of an Adaptive Immune Response - Cyclosporine Blood Levels	16 weeks	Cyclosporine blood levels on therapy over 16 week treatment interval were measured at Weeks 2, 4, 6, 8, 10, 12 & 16. The median for each participant was found and then the overall median was determined. Values expressed as median (full range).
Effects of Cyclosporin A on Respiratory Function - Change in the Percentage of Post Predicted Value of Forced Expiratory Volume in 1 Second	at Week 8 and Week 16	Outcome measured the change in the percentage of post predicted value of forced expiratory volume in 1 second at midpoint assessment (Week 8) and at the conclusion of treatment (Week 16). Values expressed as median (full range).
Effects of Cyclosporin A on Respiratory Function - Change in Exercise Capacity by a Shuttle Walk Distance Measured in Feet	at Week 8 and Week 16	Measurement of exercise capacity by a shuttle walk distance measured in feet at midpoint assessment (Week 8) and at the conclusion of treatment (Week 16). The purpose of the shuttle walk test is to see how far and fast a patient can walk (without stopping for a rest) by following a series of time signals.Values expressed as median (full range).
Effects of Cyclosporin A on Symptoms - Change in Scores on a Shortness of Breath Scale	at Week 8 and Week 16	Scores on a shortness of breath scale (University of California at San Diego Dyspnea scale): shortness of breath questionnaire scores are summed as a total score ranging from 0-120 with higher scores indicating more severe breathlessness. Assessments were performed at midpoint assessment (Week 8) and at the conclusion of treatment (Week 16). Values expressed as median (full range).
Effects of Cyclosporin A on Respiratory Function - Change in the Percentage of Post Predicted Value of Forced Vital Capacity	at Week 8 and Week 16	Outcome measured the change in the percentage of post predicted value of forced vital capacity at midpoint assessment (Week 8) and at the conclusion of treatment (Week 16). Values expressed as median (full range).
Peripheral Blood T Cell Biomarkers Over 16 Week Treatment Interval - Change in the Percentage of Cluster of Differentiation 4 (CD4)	at Week 8 and Week 16	Outcome measured the change in the percentage of cluster of differentiation 4 (CD4) at midpoint assessment (Week 8) and at the conclusion of treatment (Week 16). Values expressed as median (full range).
Peripheral Blood T Cell Biomarkers Over 16 Week Treatment Interval - Change in the Percentage of Cluster of Differentiation 8 and Cluster of Differentiation 28	at Week 8 and Week 16	Outcome measured the change in the percentage of peripheral blood T cell biomarkers - cluster of differentiation 8 (CD8), cluster of differentiation 28 (CD28) at midpoint assessment (Week 8) and at the conclusion of treatment (Week 16). Values expressed as median (full range).

Countries

United States

Participant flow

Recruitment details

Patients were recruited from local clinics, advertisement, and a disease specific registry

Pre-assignment details

772 patients underwent initial screening and 43 were eligible to sign consent. These patients underwent a second 2 week screening process and 17 subjects met all criteria for randomization

Participants by arm

Arm	Count
Cyclosporine Randomized post 2nd level screen to 3 mg/kg / day oral cyclosporine	8
Placebo Randomized to placebo capsules identical in appearance to cyclosporine	9
Total	17

Baseline characteristics

Characteristic	Placebo	Cyclosporine	Total
Age, Continuous	63 years	68 years	67 years
Blood Urea Nitrogen	13 mg / dL STANDARD_DEVIATION 3.2	16 mg / dL STANDARD_DEVIATION 5.4	13.4 mg / dL STANDARD_DEVIATION 3.9
Cholesterol	193 mg / dL STANDARD_DEVIATION 20	183 mg / dL STANDARD_DEVIATION 30	183 mg / dL STANDARD_DEVIATION 20
Creatinine	0.9 mg / dL STANDARD_DEVIATION 0.2	0.9 mg / dL STANDARD_DEVIATION 0.2	0.9 mg / dL STANDARD_DEVIATION 0.2
Diastolic blood pressure (mm Hg)	78 mm Hg	82 mm Hg	79 mm Hg
Forced Expiratory Volume 1 second (%)	43 % predicted	38 % predicted	39 % predicted
Forced Vital Capacity (%)	77 % predicted	88 % predicted	79 % predicted
Functional Residual Capacity (%)	149 % predicted	146 % predicted	149 % predicted
Glucose	113 mg / dL STANDARD_DEVIATION 29	102 mg / dL STANDARD_DEVIATION 13	111 mg / dL STANDARD_DEVIATION 29
Hemoglobin	13.6 grams / dL STANDARD_DEVIATION 0.9	13.7 grams / dL STANDARD_DEVIATION 1	13.7 grams / dL STANDARD_DEVIATION 1.03
Partial pressure of carbon dioxide (pCO2)	42.6 mm Hg STANDARD_DEVIATION 3.9	40 mm Hg STANDARD_DEVIATION 3.6	41.2 mm Hg STANDARD_DEVIATION 3.7
Partial pressure of oxygen (pO2)	76 mm Hg STANDARD_DEVIATION 20	71 mm Hg STANDARD_DEVIATION 11	74 mm Hg STANDARD_DEVIATION 15
Sex: Female, Male Female	4 Participants	2 Participants	6 Participants
Sex: Female, Male Male	5 Participants	6 Participants	11 Participants
Systolic blood pressure (mm Hg)	133 mm Hg	141 mm Hg	138 mm Hg
Total Lung Capacity (%)	119 % predicted	123 % predicted	119 % predicted
Weight	93 kilograms	83 kilograms	84 kilograms
White blood cell count	6.6 x10E ^09/L STANDARD_DEVIATION 2	7.3 x10E ^09/L STANDARD_DEVIATION 1.3	7.1 x10E ^09/L STANDARD_DEVIATION 2.2

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 8	0 / 9
other Total, other adverse events	6 / 8	5 / 9
serious Total, serious adverse events	0 / 8	0 / 9

Outcome results

Primary

Safety Profile of Oral Cyclosporin A Immunotherapy in Advanced Stage Chronic Obstructive Pulmonary Disease Patients- Nephrotoxicity - Measured by Serum Creatinine

Measurement of nephrotoxicity by monitoring serum creatinine over 16 week treatment interval. Mean serum creatinine values were assessed at Week 2, 4, 6, 8, 10, 12 and 16. The mean values of all measurements for each participant were calculated and then the mean across participants was calculated. Values expressed as mean ± SD.

Time frame: 16 weeks

Arm	Measure	Value (MEAN)	Dispersion
Cyclosporine	Safety Profile of Oral Cyclosporin A Immunotherapy in Advanced Stage Chronic Obstructive Pulmonary Disease Patients- Nephrotoxicity - Measured by Serum Creatinine	0.94 mg / dL	Standard Deviation 0.2
Placebo	Safety Profile of Oral Cyclosporin A Immunotherapy in Advanced Stage Chronic Obstructive Pulmonary Disease Patients- Nephrotoxicity - Measured by Serum Creatinine	0.88 mg / dL	Standard Deviation 0.2

Primary

Safety Profile of Oral Cyclosporin A Immunotherapy in Advanced Stage Chronic Obstructive Pulmonary Disease Patients - Number of Patients That Developed Infection Requiring Systemic Antibiotic Therapy

Clinical diagnosis of infection which requires systemic antibiotic therapy during the 16 week study interval at Week 2, 4, 6, 8, 10, 12 and 16. Outcome measured the number of subjects who developed an infection requiring systemic antibiotic therapy during the study treatment interval.

Time frame: 16 weeks

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Cyclosporine	Safety Profile of Oral Cyclosporin A Immunotherapy in Advanced Stage Chronic Obstructive Pulmonary Disease Patients - Number of Patients That Developed Infection Requiring Systemic Antibiotic Therapy	1 Participants
Placebo	Safety Profile of Oral Cyclosporin A Immunotherapy in Advanced Stage Chronic Obstructive Pulmonary Disease Patients - Number of Patients That Developed Infection Requiring Systemic Antibiotic Therapy	1 Participants

Primary

Safety Profile of Oral Cyclosporin A Immunotherapy in Advanced Stage Chronic Obstructive Pulmonary Disease Patients - Number of Patients That Developed Renal Insufficiency

Development of renal insufficiency defined as \> 30% elevation in serum creatinine above baseline which required dose modification of the cyclosporine over 16 week treatment interval at Week 2, 4, 6, 8, 10, 12 and 16. Outcome measured the number of subjects who developed renal insufficiency during the study treatment interval.

Time frame: 16 weeks

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Cyclosporine	Safety Profile of Oral Cyclosporin A Immunotherapy in Advanced Stage Chronic Obstructive Pulmonary Disease Patients - Number of Patients That Developed Renal Insufficiency	4 Participants
Placebo	Safety Profile of Oral Cyclosporin A Immunotherapy in Advanced Stage Chronic Obstructive Pulmonary Disease Patients - Number of Patients That Developed Renal Insufficiency	1 Participants

Secondary

Effects of Cyclosporin A on Respiratory Function - Change in Exercise Capacity by a Shuttle Walk Distance Measured in Feet

Measurement of exercise capacity by a shuttle walk distance measured in feet at midpoint assessment (Week 8) and at the conclusion of treatment (Week 16). The purpose of the shuttle walk test is to see how far and fast a patient can walk (without stopping for a rest) by following a series of time signals.Values expressed as median (full range).