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
Primary Outcome Measures:
- 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) ]
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) ]
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) ]
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) ]
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).
Secondary Outcome Measures:
- Pharmacokinetics (PK) of Digitoxin in Serum in Stable CF Patients. [ Time Frame: Serum PK on Days 1 (pre-dose), 7, 14, 21 and 42 ]
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 ]
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 ]
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 ]
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 ]
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 ]
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 ]
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 ]
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 ]
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:
| Study Completion Date:
| 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
The study will be conducted as a randomized, double blind, placebo-controlled, repeat dosing trial evaluating the effects of 28 days of digitoxin on IL-8 and neutrophil concentrations in induced sputum in subjects with mild to moderate cystic fibrosis lung disease. Twenty-four total patients will be randomized into 3 groups of 8 subjects each (0.05 mg or 0.1 mg digitoxin or a placebo).