Phase II Study of Digitoxin to Treat Cystic Fibrosis
This study will measure the inflammatory effects of digitoxin on IL-8 and neutrophil counts in induced sputum in stable Cystic Fibrosis (CF) patients and the pharmacokinetics of digitoxin in serum.
Funding Source-FDA OOPD
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
|Official Title:||Phase II Study of Digitoxin to Treat Cystic Fibrosis|
- Effect of Digitoxin on IL-8 (Interleukin 8) in Induced Sputum in Stable Cystic Fibrosis (CF) Patients. [ Time Frame: 42 days (Day 1 to Day 42) ] [ Designated as safety issue: No ]The Il-8 measurements of sputum digitoxin levels for each group is shown for 5 days (Days 1, 14, 21, 28 and 42).
- Change in Il-8 (Interleukin 8) Levels From Day 28 Minus Day 1 (Treatment Period). [ Time Frame: 28 days (Day 28 minus Day 1) ] [ Designated as safety issue: No ]Change in Il-8 values are expressed as a change in log 10 Il-8 pg/mL from Day 28 minus Day 1.
- Effect of Digitoxin on Neutrophil Counts in Induced Sputum in Stable Cystic Fibrosis (CF) Patients. [ Time Frame: 42 days (Day 1- Day 42) ] [ Designated as safety issue: No ]The neutrophil counts were measured in the induced sputum of participants in each group on study 5 days (Days 1, 14, 21, 28 and 42).
- Change in Neutrophil Cell Count Day 28 Minus Day 1 (Treatment Period). [ Time Frame: 28 days (Day 28 minus Day 1) ] [ Designated as safety issue: No ]The change in log 10 neutrophil cell count from Day 28 minus Day 1 (during the treatment period) expressed as log (10^4 neutrophil/mL).
- Pharmacokinetics (PK) of Digitoxin in Serum in Stable CF Patients. [ Time Frame: Serum PK on Days 1 (pre-dose), 7, 14, 21 and 42 ] [ Designated as safety issue: No ]Digitoxin serum levels were drawn on Days 1 (pre-dose), 7, 14, 21 and 42. The range of digitoxin levels for each visit is listed and the number of subjects who had that level are marked by group (placebo, low dose and high dose).
- Safety Indices Including Change in FEV1 in Stable CF Patients. [ Time Frame: Baseline and Day 28 ] [ Designated as safety issue: Yes ]Safety indices included changes in FEV1 (forced expiratory volume in 1 second), changes in WBC (white blood cell count), alterations in ECG and sputum microbiology. The median changes in FEV1 are reported.
- Mean Change in Quality of Life Scores, for Each Domain, From Day 1 to Day 42 Using the Cystic Fibrosis Questionnaire Revised (CFQ-R). [ Time Frame: Baseline and Day 42 ] [ Designated as safety issue: No ]
CFQ-R is a disease-specific instrument designed to measure impact on overall health, daily life, perceived well-being and symptoms. Developed specifically for use in patients with a diagnosis of cystic fibrosis. There are 9 Quality of life domains: physical, role/school, vitality, emotion, social, body image, eating, treatment burden, health perceptions and 3 symptom scales: weight, respiratory, and digestion.
Scaling of items is done via 5 distinct 4-point Likert scales. Scores for each domain; after recoding, each item is summed to generate a domain score and standardized. Scores range from 0 to 100, with higher scores indicating better health. Based on clinician judgment of global clinical change, a moderate change was a standardized effect size of 0.50 units and an important change was a standardized effect size of 0.80 units evaluating pre- and post-treatment for CF exacerbation. Mean changes in CFQ-R Scores by Group were evaluated between Visit 6 and Visit 1, by Domain.
- Change in WBC (White Blood Cell) Count by Group During Treatment Period [ Time Frame: Baseline and Day 28 ] [ Designated as safety issue: Yes ]Safety indices included changes in FEV1 (lung function), changes in WBC, alterations in ECG and sputum microbiology. There were no significant alterations in the ECG in any subjects over the course of the study. There were no subjects who acquired multiple resistant changes in microbiology of sputum and no acquisition of B. cepacia in any subjects. Therefore, these data were not analyzed. The median changes in FEV1 and median changes in WBC, ESR and CRP are reported.
- Changes in C Reactive Protein (CRP) During Treatment. [ Time Frame: Baseline and Day 28 ] [ Designated as safety issue: Yes ]Median changes in CRP and IQR were assessed from serum samples collected at Visits 1,3, 4 and 5.
- Changes in Erythrocyte Sedimentation Rate (ESR) During Treatment Period. [ Time Frame: Baseline and Day 28 ] [ Designated as safety issue: Yes ]Median change in serum ESR (mm/hr) and IQR was calculated from Treatment Period (28 days).
- Number of CF Subjects With Microarray Results From Nasal Epithelial Cells to Measure the Effect of Digitoxin on Gene Expression. [ Time Frame: Day 0 and Day 28 ] [ Designated as safety issue: No ]Rhinoprobe was used to collect nasal epithelial cells. The cells were collected pre and post-treatment and placed in Trizol for RNA isolation then used to measure the effect of digitoxin on gene expression. The full set of microarray data has been deposited in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO). The accession number for that data is GSE76347 (data available Dec 2018).
- Clinically Significant Alterations in ECG Readings [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]Safety indices included an assessment for the number of clinically significant alterations in the subjects ECG readings from Day 1 to Day 28.
- Clinically Significant Changes in the Microbiology of Sputum in Subjects [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]Count of clinically significant changes in sputum microbiology during the Treatment phase (Day 1 to Day 28) to include any new acquisition of B. cepacia or new acquisition of any multiple resistant organism.
|Study Start Date:||August 2010|
|Study Completion Date:||August 2016|
|Primary Completion Date:||August 2016 (Final data collection date for primary outcome measure)|
Active Comparator: 1
low dose 0.05mg digitoxin given once daily for 28 days
0.05mg tabs, once daily for 28 days
Active Comparator: 2
higher dose 0.1mg digitoxin daily for 28 days
0.1mg pills, once daily for 28 days.
Placebo Comparator: 3
placebo given daily for 28 days
pill taken once daily for 28 days
Please refer to this study by its ClinicalTrials.gov identifier: NCT00782288
|United States, Maryland|
|Johns Hopkins Hospital|
|Baltimore, Maryland, United States, 21287|
|Principal Investigator:||Pamela L Zeitlin, MD, PhD||Johns Hopkins University, School of Medicine, Pediatric Pulmonary|