IV Colistin for Pulmonary Exacerbations: Improving Safety and Efficacy

NCT02918409 | Completed Phase 4 Results DMC

• 1 other identifier: SAAVED15A0
• Study Type: interventional
• Target: 51
• Locations: 1 country
• Sites: 1

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.

Conditions

Cystic Fibrosis

Outcome Measures

Primary Outcomes (2)

• 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

  up to 14 days, from beginning to end of APE treatment

• Rate of Occurrence of the Development of Acute Kidney Injury (AKI) During APE Treatment

  up to 14 days, from beginning to end of APE treatment

Secondary Outcomes (2)

• Longitudinal Differences in Exacerbation Rates Between Tobramycin and Colistin Use as Seen in Readmission Rate

  from the beginning of APE treatment to 12 months after APE treatment

• Differences in Occurrences of Neurotoxicity and Ototoxicity Related Side Effects Between Study Arms as Reported by Treating Physician(s)

  up to 14 days, from beginning to end of APE treatment

Study Arms (3)

Standard colistin arm

ACTIVE COMPARATOR

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.

Drug: Colistin

Modified colistin arm

ACTIVE COMPARATOR

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).

Drug: Colistin

Standard tobramycin arm

ACTIVE COMPARATOR

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

Drug: Tobramycin

Interventions

Colistin DRUG

Modified colistin arm; Standard colistin arm

Tobramycin DRUG

Standard tobramycin arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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. -

Sponsors & Collaborators

• National Jewish Health: lead

Study Sites (1)

National Jewish Health

Denver, Colorado, 80206, United States

Location

MeSH Terms

Conditions

Cystic Fibrosis

Interventions

Colistin; Tobramycin

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases

Intervention Hierarchy (Ancestors)

Polymyxins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Lipopeptides; Lipids; Antimicrobial Cationic Peptides; Peptides; Amino Acids, Peptides, and Proteins; Antimicrobial Peptides; Pore Forming Cytotoxic Proteins; Membrane Proteins; Proteins; Nebramycin; Kanamycin; Aminoglycosides; Glycosides; Carbohydrates

Results Point of Contact

• Title: Dr. Milene Saavedra
• Organization: National Jewish Health

saavedram@njhealth.org

303-270-2333

Study Officials

• Milene Saavedra, MD

  National Jewish Health

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 12, 2016
• First Posted: September 29, 2016
• Study Start: August 26, 2016
• Primary Completion: September 10, 2020
• Study Completion: November 22, 2021
• Last Updated: April 28, 2026
• Results First Posted: October 6, 2022

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)