Oral Cyclosporine in Chronic Obstructive Pulmonary Disease

Phase 1

Completed

Conditions: Chronic Obstructive Pulmonary Disease

Interventions: Drug: Cyclosporine
Drug: Placebo

Registration Number: NCT00974142

Lead Sponsor: Michael Donahoe

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 43

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cyclosporine	Cyclosporine	-
Placebo	Placebo	-

Primary Outcome Measures

Name	Time	Method
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.
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- 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.

Secondary Outcome Measures

Name	Time	Method
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).
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 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).
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).
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).
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).
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).
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).
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 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).