Phase II Study of Digitoxin to Treat Cystic Fibrosis

Study Overview
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Brief Summary
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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

Detailed Description
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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).

Official Title
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Phase II Study of Digitoxin to Treat Cystic Fibrosis

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: digitoxin
* Drug: digitoxin
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Male or female 18-45 years of age Confirmed diagnosis of CF based on the following criteria:positive sweat chloride > or = 60 mEq/liter (by pilocarpine iontophoresis) and/or a genotype with two identifiable mutations consistent with CF FEV1 > or = 40% predicted value at screening Weight > 45 kg at Screening and Visit 1 (dosing) Clinically stable with no evidence of acute upper or lower respiratory tract infection or current pulmonary exacerbation (see Appendix II) or treatment of a pulmonary exacerbation within the 14 days prior to Screen Visit. Subject may rescreen 14 days after they complete treatment for a pulmonary exacerbation, if healthy at that time. Ability to perform Spirometry. Ability to understand and sign a written informed consent and comply with the requirements of the study. Exclusion Criteria: Use of an investigational agent within the 4-week period prior to Screen visit. Use of a medication with anti-neutrophil or anti-inflammatory effect or those known to have an effect on inflammatory outcomes [azithromycin, gentamicin, amikacin, colistin, ibuprofen, celecoxib, or other NSAIDs, prednisone or other corticosteroids(systemic or inhaled), such as Advair, cromolyn (Intal®), montelukast (Singulair®), zafirlukast (Accolate®), zileuton (Zyflo®), and any immunosuppressive agent within the 4 weeks prior to Visit #1, Day 1 and until their participation in the study ends (after Visit 6). See NOTE at end of exclusionary criteria for subjects on oral antibiotic therapy. Use of topical nasal steroid products for at least 2 weeks prior to study drug administration and discontinued use until after the nasal cell collection at Day 28. Inability or unwillingness to stop macrolide antibiotics 4 weeks prior to Day 1 until their participation in the study ends. Prior use of macrolide antibiotics, including those for maintenance therapy will not exclude the subject from participation. History of significant cardiac disease or cardiac arrhythmia Presence of an arrhythmia identified on screening ECG or 24 hour holter monitor Pulmonary hypertension History of significant cardiac disease or cardiac arrhythmia Presence of a clinically significant arrhythmia identified on screening ECG or 24 hour holter monitor. Pulmonary hypertension Burkholderia species in sputum within 2 years or at Screen visit Drugs known to interact with digitoxin including phenobarbital, amphotericin B, rifampicin, diltiazem, and verapamil or drugs that would potentiate potassium loss (certain diuretics or excessive laxative use, defined as more than twice daily use of miralax). Unwillingness to use beta-agonists (or levalbuterol) prior to induced sputum procedures. Oxygen saturation < 92% on room air at Screen visit Pregnant, breastfeeding, or unwilling to use an effective form of birth control for the duration of the study History of significant hemoptysis > or = 60cc per episode during the 30 days prior to Screening visit Significant history of hepatic, cardiovascular, renal, neurological, hematologic, or peptic ulcer disease SGOT (ALT) or SGPT (AST) > 3 times the upper limit of normal at Screen, documented biliary cirrhosis, or portal hypertension Creatinine > 1.8 mg/dL at Screen Inability to swallow pills Potassium, serum <3.3 mEq/L at screening Known inability to produce sputum (if unable to expectorate, must be able to produce an induced sputum sample at screening). Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the subject or the quality of the data NOTE: For subjects on continuous antibiotic therapy for at least 6 months one continuous antibiotic or alternating two different antibiotics, they can maintain their current therapy. If the subject is alternating between two different inhaled antibiotics each month, Visit 1 should coincide with the on cycle of one of the inhaled antibiotics for consistency during the treatment period. For subjects on alternate month TOBI®, colistin or Cayston therapy, the off cycle must coincide with the Treatment Phase of the study. Subjects should be scheduled for Screening Visit during their one-month on period, and may resume taking TOBI®, colistin or Cayston after completion of Visit 6 (Day 42) or early termination.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>low dose 0.05mg digitoxin given once daily for 28 days | Drug: digitoxin<br>* 0.05mg tabs, once daily for 28 days<br>|
| Active Comparator: 2<br>higher dose 0.1mg digitoxin daily for 28 days | Drug: digitoxin<br>* 0.1mg pills, once daily for 28 days.<br>|
| Placebo Comparator: 3<br>placebo given daily for 28 days | Other: placebo<br>* pill taken once daily for 28 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of Digitoxin on IL-8 (Interleukin 8) in Induced Sputum in Stable Cystic Fibrosis (CF) Patients. | The Il-8 measurements of sputum digitoxin levels for each group is shown for 5 days (Days 1, 14, 21, 28 and 42). | 42 days (Day 1 to Day 42) | 
| Change in Il-8 (Interleukin 8) Levels From Day 28 Minus Day 1 (Treatment Period). | Change in Il-8 values are expressed as a change in log 10 Il-8 pg/mL from Day 28 minus Day 1. | 28 days (Day 28 minus Day 1) | 
| Effect of Digitoxin on Neutrophil Counts in Induced Sputum in Stable Cystic Fibrosis (CF) Patients. | 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). | 42 days (Day 1- Day 42) | 
| Change in Neutrophil Cell Count Day 28 Minus Day 1 (Treatment Period). | 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). | 28 days (Day 28 minus Day 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) of Digitoxin in Serum in Stable CF Patients. | 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). | Serum PK on Days 1 (pre-dose), 7, 14, 21 and 42 | 
| Safety Indices Including Change in FEV1 in Stable CF Patients. | 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. | Baseline and Day 28 | 
| Mean Change in Quality of Life Scores, for Each Domain, From Day 1 to Day 42 Using the Cystic Fibrosis Questionnaire Revised (CFQ-R). | 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. | Baseline and Day 42 | 
| Change in WBC (White Blood Cell) Count by Group During Treatment Period | 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. | Baseline and Day 28 | 
| Changes in C Reactive Protein (CRP) During Treatment. | Median changes in CRP and IQR were assessed from serum samples collected at Visits 1,3, 4 and 5. | Baseline and Day 28 | 
| Changes in Erythrocyte Sedimentation Rate (ESR) During Treatment Period. | Median change in serum ESR (mm/hr) and IQR was calculated from Treatment Period (28 days). | Baseline and Day 28 | 
| Number of CF Subjects With Microarray Results From Nasal Epithelial Cells to Measure the Effect of Digitoxin on Gene Expression. | 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). | Day 0 and Day 28 | 
| Clinically Significant Alterations in ECG Readings | Safety indices included an assessment for the number of clinically significant alterations in the subjects ECG readings from Day 1 to Day 28. | 28 days | 
| Clinically Significant Changes in the Microbiology of Sputum in Subjects | 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. | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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digitoxin, inflammatory markers, cytokines, gene expression