Back to resultsIV Colistin for Pulmonary Exacerbations: Improving Safety and Efficacy
Primary Purpose
Cystic Fibrosis
Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Colistin
Tobramycin
Sponsored by
About this trial
This is an interventional treatment trial for Cystic Fibrosis
Eligibility Criteria
Inclusion Criteria:
- Male or female ≥ 18 years of age at Visit 1.
Documentation of CF diagnosis as evidenced by one or more clinical features consistent with the CF phenotype and one or more of the following criteria:
- Sweat chloride equal or greater than 60 mEq/L by quantitative pilocarpine iontophoresis test.
- Two well-characterized mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene
- Abnormal nasal potential difference (NPD) as measured by a change in NPD in response to a low chloride solution and isoproterenol of less than -5 mV.
- Documentation of the presence of an acute pulmonary exacerbation, based on CF Foundation guidelines, as diagnosed by a faculty member of the Denver Adult CF Program.
- Respiratory culture(s) demonstrating evidence of Pseudomonas aeruginosa or Achromobacter species airway infection.
- Subject is able to produce sputum, undergo phlebotomy, and provide written consent.
- The subject's treating physician has determined that they should receive either tobramycin or colistin intravenously as one of the designated agents for their APE treatment. Subjects who are able to receive either tobramycin or colistin as part of their antibiotic regimen will be randomized into one of three arms. If a treating physician deems that a subject cannot receive tobramycin due to vestibular toxicity, ototoxicity or bacterial resistance, the subject will be randomized to either standard or PK-adjusted colistin.
Exclusion Criteria:
- Concomitant administration of bactrim (due to effects on creatinine).
- Concomitant administration of inhaled colistin for patients in the colistin PK arm, as this will create inaccuracies in colistin sputum concentration measurements.
- Patients being treated for B. cepacia, due to colistin resistance by the pathogen.
- Presence of chronic renal insufficiency, with abnormal baseline creatinine >1.2mg/dL.
- Presence of a condition or abnormality that in the opinion of the investigator would compromise the safety of the patient or the quality of the data.
- Inability to perform reproducible spirometry.
- Inability to expectorate sputum. -
Sites / Locations
- National Jewish Health
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Active Comparator
Active Comparator
Active Comparator
Arm Label
Standard colistin arm
Modified colistin arm
Standard tobramycin arm
Arm Description
Subjects initially receive IV colistin 2.5 mg/kg/d divided into three times daily (TID) dosing. Subjects receiving colistin will undergo a 2 day up-titration of dose to an ultimate dose of 4-5 mg/kg/day, for a total treatment of 14 days. The drug is infused over 30 minutes on a TID dosing schedule.
Subjects receiving IV colistin undergo a 2 day up-titration to a maximum dose of 5 mg/kg/day, divided into twice daily (BID) dosing, for a total treatment of 14 days. The drug is infused over 30 minutes BID. Steady state plasma concentrations on day 3 of therapy (on 2nd- 3rd dose once at goal dosing) will be measured; specifically, colistin peak (30 minutes after infusion), midpoint (6 hour) and trough (30 minutes prior to next infusion).
Subjects receive IV tobramycin 8-10 mg/kg/day with once daily dosing for 14 days. Peaks and troughs are drawn with the second dose of tobramycin, and the drug is infused over 30 minutes
Outcomes
Primary Outcome Measures
Absolute Change in Forced Expiratory Volume at One Second (FEV1) % Predicted Between Study Arms With Acute Pulmonary Exacerbation (APE) Treatment
absolute change in forced expiratory volume at one second (FEV1) % predicted, or percent predicted FEV1, between study arms with acute pulmonary exacerbation (APE) treatment
Rate of Occurrence of the Development of Acute Kidney Injury (AKI) During APE Treatment
Secondary Outcome Measures
Time to Achievement of Steady State With Pharmacokinetic (PK)-Adjusted Colistin Therapy
Longitudinal Differences in Exacerbation Rates Between Tobramycin and Colistin Use as Seen in Readmission Rate
time to next admission for exacerbation measured in days when comparing of different antibiotic therapies
Differences in Occurrences of Neurotoxicity and Ototoxicity Related Side Effects Between Study Arms as Reported by Treating Physician(s)
absolute occurrences of adverse event rates are being compared between treatment groups using logistic regression, adjusting for age, co-administration of medications such as vancomycin and trimethoprim-sulfamethoxazole, baseline FEV1, admits in the previous year, and diagnosis of CF related diabetes (CFRD) as covariates.
Measurement of Pharmacokinetics of Colistin's Active Metabolites in a Broad CF Population Through Peak, Trough, and Midpoint Blood Draws
Comparison of Plasma Pharmacokinetics of Colistin's Active Metabolites With Levels Achieved in the Sputum, in Order to Calculate Epithelial Lining Fluid Concentrations, Through Mass Spectrometry
Novel Biomarkers of Nephrotoxic AKI, Prior to Serum Creatinine Increases, Based on Urine Protein:Creatinine Ratios
Novel Biomarkers of Nephrotoxic AKI, Prior to Serum Creatinine Increases, Based on the Urine Biomarker Nephrocheck® Point-of-care Assay
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02918409
Brief Title
IV Colistin for Pulmonary Exacerbations: Improving Safety and Efficacy
Official Title
IV Colistin for Pulmonary Exacerbations: Improving Safety and Efficacy
Study Type
Interventional
2. Study Status
Record Verification Date
March 2023
Overall Recruitment Status
Completed
Study Start Date
August 26, 2016 (Actual)
Primary Completion Date
September 10, 2020 (Actual)
Study Completion Date
November 22, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Jewish Health
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The purpose of this study is to find the safest and most effective way to administer IV antibiotics to treat acute pulmonary exacerbations (APEs) in patients with cystic fibrosis (CF) that are caused by pathogens, like Pseudomonas aeruginosa. This study will test the safety and effectiveness of two commonly prescribed IV antibiotics: tobramycin and colistin. Though regularly used, not much is known about how these drugs compare with each other in terms of their toxicities, both during short term treatment of an APE and after many treatment courses with these drugs over many years. There are currently no guidelines on the safest and most effective antibiotics to use when treating APEs. We will study kidney function, sputum cultures, and treatment outcomes in patients receiving routine administration of one of these two IV antibiotics. We will also test these outcomes in patients receiving a less frequent dosing schedule for IV colistin. The hope is that this new schedule for IV colistin, which is twice a day and adjusted based on blood and urine tests, will reduce harmful side effects, such as kidney damage, while still being a powerful treatment against CF microbial pathogens.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cystic Fibrosis
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
51 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Standard colistin arm
Arm Type
Active Comparator
Arm Description
Subjects initially receive IV colistin 2.5 mg/kg/d divided into three times daily (TID) dosing. Subjects receiving colistin will undergo a 2 day up-titration of dose to an ultimate dose of 4-5 mg/kg/day, for a total treatment of 14 days. The drug is infused over 30 minutes on a TID dosing schedule.
Arm Title
Modified colistin arm
Arm Type
Active Comparator
Arm Description
Subjects receiving IV colistin undergo a 2 day up-titration to a maximum dose of 5 mg/kg/day, divided into twice daily (BID) dosing, for a total treatment of 14 days. The drug is infused over 30 minutes BID. Steady state plasma concentrations on day 3 of therapy (on 2nd- 3rd dose once at goal dosing) will be measured; specifically, colistin peak (30 minutes after infusion), midpoint (6 hour) and trough (30 minutes prior to next infusion).
Arm Title
Standard tobramycin arm
Arm Type
Active Comparator
Arm Description
Subjects receive IV tobramycin 8-10 mg/kg/day with once daily dosing for 14 days. Peaks and troughs are drawn with the second dose of tobramycin, and the drug is infused over 30 minutes
Intervention Type
Drug
Intervention Name(s)
Colistin
Intervention Type
Drug
Intervention Name(s)
Tobramycin
Primary Outcome Measure Information:
Title
Absolute Change in Forced Expiratory Volume at One Second (FEV1) % Predicted Between Study Arms With Acute Pulmonary Exacerbation (APE) Treatment
Description
absolute change in forced expiratory volume at one second (FEV1) % predicted, or percent predicted FEV1, between study arms with acute pulmonary exacerbation (APE) treatment
Time Frame
up to 14 days, from beginning to end of APE treatment
Title
Rate of Occurrence of the Development of Acute Kidney Injury (AKI) During APE Treatment
Time Frame
up to 14 days, from beginning to end of APE treatment
Secondary Outcome Measure Information:
Title
Time to Achievement of Steady State With Pharmacokinetic (PK)-Adjusted Colistin Therapy
Time Frame
up to 14 days, from beginning to end of APE treatment
Title
Longitudinal Differences in Exacerbation Rates Between Tobramycin and Colistin Use as Seen in Readmission Rate
Description
time to next admission for exacerbation measured in days when comparing of different antibiotic therapies
Time Frame
from the beginning of APE treatment to 12 months after APE treatment
Title
Differences in Occurrences of Neurotoxicity and Ototoxicity Related Side Effects Between Study Arms as Reported by Treating Physician(s)
Description
absolute occurrences of adverse event rates are being compared between treatment groups using logistic regression, adjusting for age, co-administration of medications such as vancomycin and trimethoprim-sulfamethoxazole, baseline FEV1, admits in the previous year, and diagnosis of CF related diabetes (CFRD) as covariates.
Time Frame
up to 14 days, from beginning to end of APE treatment
Title
Measurement of Pharmacokinetics of Colistin's Active Metabolites in a Broad CF Population Through Peak, Trough, and Midpoint Blood Draws
Time Frame
up to 14 days, from beginning to end of APE treatment
Title
Comparison of Plasma Pharmacokinetics of Colistin's Active Metabolites With Levels Achieved in the Sputum, in Order to Calculate Epithelial Lining Fluid Concentrations, Through Mass Spectrometry
Time Frame
up to 14 days, from beginning to end of APE treatment
Title
Novel Biomarkers of Nephrotoxic AKI, Prior to Serum Creatinine Increases, Based on Urine Protein:Creatinine Ratios
Time Frame
up to 14 days, from beginning to end of APE treatment
Title
Novel Biomarkers of Nephrotoxic AKI, Prior to Serum Creatinine Increases, Based on the Urine Biomarker Nephrocheck® Point-of-care Assay
Time Frame
up to 14 days, from beginning to end of APE treatment
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Male or female ≥ 18 years of age at Visit 1.
Documentation of CF diagnosis as evidenced by one or more clinical features consistent with the CF phenotype and one or more of the following criteria:
Sweat chloride equal or greater than 60 mEq/L by quantitative pilocarpine iontophoresis test.
Two well-characterized mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene
Abnormal nasal potential difference (NPD) as measured by a change in NPD in response to a low chloride solution and isoproterenol of less than -5 mV.
Documentation of the presence of an acute pulmonary exacerbation, based on CF Foundation guidelines, as diagnosed by a faculty member of the Denver Adult CF Program.
Respiratory culture(s) demonstrating evidence of Pseudomonas aeruginosa or Achromobacter species airway infection.
Subject is able to produce sputum, undergo phlebotomy, and provide written consent.
The subject's treating physician has determined that they should receive either tobramycin or colistin intravenously as one of the designated agents for their APE treatment. Subjects who are able to receive either tobramycin or colistin as part of their antibiotic regimen will be randomized into one of three arms. If a treating physician deems that a subject cannot receive tobramycin due to vestibular toxicity, ototoxicity or bacterial resistance, the subject will be randomized to either standard or PK-adjusted colistin.
Exclusion Criteria:
Concomitant administration of bactrim (due to effects on creatinine).
Concomitant administration of inhaled colistin for patients in the colistin PK arm, as this will create inaccuracies in colistin sputum concentration measurements.
Patients being treated for B. cepacia, due to colistin resistance by the pathogen.
Presence of chronic renal insufficiency, with abnormal baseline creatinine >1.2mg/dL.
Presence of a condition or abnormality that in the opinion of the investigator would compromise the safety of the patient or the quality of the data.
Inability to perform reproducible spirometry.
Inability to expectorate sputum. -
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Milene Saavedra, MD
Organizational Affiliation
National Jewish Health
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Jewish Health
City
Denver
State/Province
Colorado
ZIP/Postal Code
80206
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
IV Colistin for Pulmonary Exacerbations: Improving Safety and Efficacy
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