Clinical trial NCT00782288: Phase II Study of Digitoxin to Treat Cystic Fibrosis
Official title: Phase II Study of Digitoxin to Treat Cystic Fibrosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cystic Fibrosis
Keywords: digitoxin
inflammatory markers
cytokines
gene expression
Lead sponsor: National Jewish Health
Sponsor class: OTHER
First posted: 2008-10-31
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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).

Eligibility criteria: 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.

Primary outcomes:
measure: Effect of Digitoxin on IL-8 (Interleukin 8) in Induced Sputum in Stable Cystic Fibrosis (CF) Patients.
timeFrame: 42 days (Day 1 to Day 42)
measure: Change in Il-8 (Interleukin 8) Levels From Day 28 Minus Day 1 (Treatment Period).
timeFrame: 28 days (Day 28 minus Day 1)
measure: Effect of Digitoxin on Neutrophil Counts in Induced Sputum in Stable Cystic Fibrosis (CF) Patients.
timeFrame: 42 days (Day 1- Day 42)
measure: Change in Neutrophil Cell Count Day 28 Minus Day 1 (Treatment Period).
timeFrame: 28 days (Day 28 minus Day 1)
Secondary outcomes:
measure: Pharmacokinetics (PK) of Digitoxin in Serum in Stable CF Patients.
timeFrame: Serum PK on Days 1 (pre-dose), 7, 14, 21 and 42
measure: Safety Indices Including Change in FEV1 in Stable CF Patients.
timeFrame: Baseline and Day 28
measure: Mean Change in Quality of Life Scores, for Each Domain, From Day 1 to Day 42 Using the Cystic Fibrosis Questionnaire Revised (CFQ-R).
timeFrame: Baseline and Day 42
measure: Change in WBC (White Blood Cell) Count by Group During Treatment Period
timeFrame: Baseline and Day 28
measure: Changes in C Reactive Protein (CRP) During Treatment.
timeFrame: Baseline and Day 28
measure: Changes in Erythrocyte Sedimentation Rate (ESR) During Treatment Period.
timeFrame: Baseline and Day 28
measure: Number of CF Subjects With Microarray Results From Nasal Epithelial Cells to Measure the Effect of Digitoxin on Gene Expression.
timeFrame: Day 0 and Day 28
measure: Clinically Significant Alterations in ECG Readings
timeFrame: 28 days
measure: Clinically Significant Changes in the Microbiology of Sputum in Subjects
timeFrame: 28 days
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
Study officials:
affiliation: Johns Hopkins University, School of Medicine, Pediatric Pulmonary
name: Pamela L Zeitlin, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zeitlin PL, Diener-West M, Callahan KA, Lee S, Talbot CC Jr, Pollard B, Boyle MP, Lechtzin N. Digitoxin for Airway Inflammation in Cystic Fibrosis: Preliminary Assessment of Safety, Pharmacokinetics, and Dose Finding. Ann Am Thorac Soc. 2017 Feb;14(2):220-229. doi: 10.1513/AnnalsATS.201608-649OC.