A Phase 1 interventional study of Colistimethate sodium and Colistimethate sodium in Pathogen Resistance, Pneumococcal Infection and Pneumonia, sponsored by National Institute of Allergy and Infectious Diseases (NIAID). Terminated at 2 sites in United States. Open to participants aged 18 Years to 45 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2020-03-02.
Sponsored by National Institute of Allergy and Infectious Diseases (NIAID) · Phase 1, Interventional, and Treatment
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.
"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.
2,044 studies on the registry are indexed under Pneumonia; 283 are open to participants now.
This study's enrollment of 27 is below the median of 106 across 1,247 interventional studies indexed under Pneumonia.
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Exclusion Criteria:
9 Subjects
Drug: Colistimethate sodium
9 Subjects
Drug: Colistimethate sodium
9 Subjects
Drug: Colistimethate sodium
12 Subjects
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.
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.
The occurrence of solicited and unsolicited adverse events, including symptoms, physical findings, laboratory testing (hematology, chemistries, urinalysis), and ECG changes
Time frame: Enrollment through to 2 weeks after end of dosing period 3
Pharmacokinetic effect of colistimethate sodium: measure of bronchoalveolar lavage (BAL) colistimethate sodium, colistin A, and colistin B levels.
Time frame: BAL: 3hrs after completion of each dose, (in 3 of 9 subjects per cohort)
Pharmacokinetics: measure of plasma colistimethate sodium, colistin A, and colistin B levels at multiple time points. Parameters: Cmax, AUC 0-t, Tmax, T1/2, Kel, clearance. Cohort 3 only.
Time frame: Cohorts 3: Prior to first dose (less than and equal to 10 min); 30 minutes after the first dose in dosing periods 1 and 2; 30 minutes after the first IV and aerosol doses have both finished in dosing period 3
Pharmacokinetics: measure of plasma colistimethate sodium, colistin A, and colistin B levels at multiple time points. Parameters: Cmax, AUC 0-t, Tmax, T1/2, Kel, clearance. Cohort 4 only.
Time frame: Cohorts 4: Prior to first dose (less than and equal to 10 min); 30 minutes after doses 7 and 13 in dosing period 1; 30 minutes after doses, 9 and 17 in dosing period 2; 30 minutes after doses 16 and 30 in dosing period 3
Pharmacokinetics: measure of plasma colistimethate sodium, colistin A, and colistin B levels at multiple time points. Parameters: Cmax, AUC 0-t, Tmax, T1/2, Kel, clearance. Cohorts 1-4.
Time frame: Cohort 1-4: Prior to first dose (less than and equal to 10 min), immediately after (less than and equal to 10 min), 0.5, 1, 1.5, 2, 4, 8, 12 & 24 hours after the last dose in each dosing periods
This study is terminated, as verified in Feb 2020. You cannot join it, but the record below documents what was studied.
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National Institute of Allergy and Infectious Diseases (NIAID)