Phase II Study of Digitoxin to Treat Cystic Fibrosis

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Pamela L. Zeitlin, MD, PhD, Johns Hopkins University
ClinicalTrials.gov Identifier:
NCT00782288
First received: October 29, 2008
Last updated: January 21, 2016
Last verified: January 2016
  Purpose

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


Condition Intervention Phase
Cystic Fibrosis
Drug: digitoxin
Other: placebo
Phase 2

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by Johns Hopkins University:

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) ] [ 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).


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 ] [ 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.


Enrollment: 24
Study Start Date: August 2010
Estimated Study Completion Date: February 2016
Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 1
low dose 0.05mg digitoxin given once daily for 28 days
Drug: digitoxin
0.05mg tabs, once daily for 28 days
Active Comparator: 2
higher dose 0.1mg digitoxin daily for 28 days
Drug: digitoxin
0.1mg pills, once daily for 28 days.
Placebo Comparator: 3
placebo given daily for 28 days
Other: placebo
pill taken once daily for 28 days

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

Ages Eligible for Study:   18 Years to 45 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00782288

Locations
United States, Maryland
Johns Hopkins Hospital
Baltimore, Maryland, United States, 21287
Sponsors and Collaborators
Pamela L. Zeitlin, MD, PhD
Investigators
Principal Investigator: Pamela L Zeitlin, MD, PhD Johns Hopkins University, School of Medicine, Pediatric Pulmonary
  More Information

Additional Information:
No publications provided

Responsible Party: Pamela L. Zeitlin, MD, PhD, Professor of Pediatrics, Johns Hopkins University
ClinicalTrials.gov Identifier: NCT00782288     History of Changes
Other Study ID Numbers: FD-R-003456-01 
Study First Received: October 29, 2008
Results First Received: October 14, 2015
Last Updated: January 21, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by Johns Hopkins University:
digitoxin
inflammatory markers
cytokines
gene expression

Additional relevant MeSH terms:
Cystic Fibrosis
Fibrosis
Digestive System Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Lung Diseases
Pancreatic Diseases
Pathologic Processes
Respiratory Tract Diseases
Digitoxin
Anti-Arrhythmia Agents
Cardiotonic Agents
Cardiovascular Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on February 08, 2016