NCT01863719

Aerosolized and Intravenous Colistin in Healthy Adults

A Phase 1, Open-Label Study of the Safety, Tolerability and Pharmacokinetics of Aerosolized Colistimethate Sodium After Multiple Doses Administered Separately or in Combination With Intravenous Colistimethate Sodium in Healthy Adults

• Status: Terminated
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 27 (actual)
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) · NIH
• Sex: All
• Age: 18 Years – 45 Years
• Healthy volunteers: Accepted

Summary

Colistin is amphipathic, cannot be absorbed from the gastrointestinal tract and is administered intramuscularly, intravenously (IV) or via inhalation. In the case of pneumonia, aerosolized route of administration is favorable as it presumably delivers a high concentration of drug directly to the infection site. Colistimethate sodium is an FDA approved drug, however, its aerosolized use represents a new method of administration not currently FDA-approved in the United States. In this proposal, the inactive prodrug colistimethate sodium has been selected to use for aerosolization as it is better tolerated than colistin sulphate. It is a randomized, open-labeled Phase 1 trial of aerosolized and/or IV formulations of colistin as multiple doses over seven days. The primary objective of this trial is to evaluate the safety and tolerability of multiple doses of aerosolized and intravenous colistimethate sodium separately or in combination in healthy adult subjects.

Detailed description

"Colistin" (the first breakdown product colistimethate sodium, also known as polymyxin E) is comprised of approximately 30 different polymyxins, with colistin A (polymyxin E1) and colistin B (polymyxin B) accounting for upwards of 85% of the mass. It is amphipathic, cannot be absorbed from the gastrointestinal tract and is administered intramuscularly, intravenously (IV) or via inhalation. While approved for aerosolized use in the United Kingdom, and used in Europe for decades as such, aerosolized colistin is not FDA-approved in the United States. The intravenous formulation is approved for use in the U.S., but due to the age of the drug, it did not undergo rigorous studies of safety prior to FDA-approval. Thus, detailed pharmacokinetic data are limited and dosing is not standardized, although the maximum IV dose should not exceed 5mg/kg/day, divided into two to four equal doses. In the United Kingdom, the recommended dosing of nebulized colistin for adults is one million units (1MIU) twice daily. Despite the paucity of dosing and safety guidelines, aerosolized colistin is being prescribed regularly out of necessity given the emergence of multi-drug resistant organisms (MDROs). MDROs are strongly associated with nosocomial pneumonia and several strains are only susceptible to this older drug, thus there is an urgent need for clarification on the safe use of colistin, including in aerosolized form as this delivers a high concentration of drug directly to the infection site. This is a randomized, open-labeled Phase 1 trial of aerosolized and/or IV formulations of colistin as multiple doses over seven days. 39 healthy male and female subjects, 18-45 years of age will be admitted for an inpatient study with outpatient follow-up. The primary objective of this trial is to evaluate the safety and tolerability of multiple doses of aerosolized and intravenous colistimethate sodium separately or in combination in healthy adult subjects. The secondary objective of this trial is to determine the pharmacokinetics of multiple daily doses of aerosolized and intravenous colistimethate sodium separately or in combination in healthy adult subjects. Subjects will participate for up to 25 days plus a screening and a follow-up appointment. The duration of this study shall be for two years, including screening, study conduct (including scheduled SMC reviews), study follow-up and preparation of all reports.

Conditions

• Pathogen Resistance
• Pneumococcal Infection
• Pneumonia

Interventions

Type	Name	Description
DRUG	Colistimethate sodium	Aerosol: In Dosing period 2 subjects receive 75mg colistin base activity via aerosol every 6 hours x 4 doses, followed by a washout period of at least 3 days. In Dosing period 3 subjects receive 75mg colistin base activity via aerosol every 6 hours x 4 doses in combination with 3.3mg/kg colistin base activity IV every 8 hours x 3 doses.
DRUG	Colistimethate sodium	Intravenous: In Dosing period 1 subjects receive 3.3mg/kg colistin base activity every 8 hours x 3 doses (total exposure 10mg/kg) intravenously (IV) followed by a washout period of at least 3 days. In Dosing period 3 subjects receive 3.3mg/kg colistin base activity IV every 8 hours x 3 doses in combination with 75mg colistin base activity via aerosol every 6 hours x 4 doses.

Timeline

• Start date: 2013-08-06
• Primary completion: 2017-05-04
• Completion: 2017-05-04
• First posted: 2013-05-29
• Last updated: 2020-03-02

Locations

2 sites across 1 country: United States

Regulatory

• FDA-regulated drug study