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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01449838




Registration number
NCT01449838
Ethics application status
Date submitted
8/09/2011
Date registered
10/10/2011
Date last updated
21/07/2017

Titles & IDs
Public title
Phase I Study of Colistin Methanesulfonate Sodium
Scientific title
Phase I Study of Colistin Methanesulfonate Sodium (CMS-Na) -A Randomized, Double Blind, Placebo Controlled, Single and Repeat Dose Study to Investigate the Safety, Tolerability, and Pharmacokinetics of CMS-Na in Healthy Japanese Male Subjects -
Secondary ID [1] 0 0
114490
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Infections, Pseudomonas 0 0
Condition category
Condition code
Infection 0 0 0 0
Other infectious diseases
Infection 0 0 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Colistimethate sodium
Treatment: Drugs - Saline

Placebo Comparator: Saline - Subjects were administered single dose or twice daily for 2.5 days repeat dose of placebo by the intravenous route.

Experimental: Colistimethate sodium - 2.5 milligrams (mg)/kilogram (kg) of CMS-NA (as colistin activity or 75,000 International Unit/kg) was administered as single dose or twice daily for 2.5 days repeat dose by the intravenous route.


Treatment: Drugs: Colistimethate sodium
active

Treatment: Drugs: Saline
placebo

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Profile of pharmacokinetics (PK) - Maximum drug concentration (Cmax), Time of occurrence of Cmax (tmax), Terminal phase half-life(t1/2), Area under the concentration-time curve: AUC(0-inf), AUC(0-12), AUC(0-last), Clearance (CL), Fraction of urinary excretion (fe), Accumulation ratio (Ro and Rs).
Timepoint [1] 0 0
Single dose and repeat dose day 3: pre-dose, 15min (m), 30m, 35m, 1,2,4,6,8,12,16,24,36 and 48h after the start of infusion. Repeat dose day 1 and day 2: pre-dose and 12h after the start of infusion.
Primary outcome [2] 0 0
Profile of safety (single) - Vital signs, ECGs, clinical laboratory test and adverse events.
Timepoint [2] 0 0
Vital: -24h, pre-dose, 2,4,8,12,24,36,48h after the start of infusion. ECGs: -24h, pre-dose, 12, 24, 36 and 48h after the start of infusion. Clinical lab: pre-dose, 24 and 48h after the start of infusion. Adverse event: All study period.
Primary outcome [3] 0 0
Profile of renal function - Urinary ß2-microglobulin, N-acetyl-ß-D-glucosaminidase and creatinine clearance (CLcr).
Timepoint [3] 0 0
Single and repeat dose day 3: Pre-dose, 12, 24 36 and 48h after the start of infusion. Repeat dose day 1 and day 2:Pre-dose and 12h after the start of infusion. CLcr urine sampling: -24-0h of start of single dose and 24-36, 36-48h after d3 repeat dose
Primary outcome [4] 0 0
Profile of safety (repeat day1 and 2) - Vital signs, ECGs, clinical laboratory test and adverse events.
Timepoint [4] 0 0
Vital: pre-dose, 2,4,8,12 and14h after the start of infusion. ECGs: pre-dose and 12h after the start of infusion. Clinical lab: pre-dose. Adverse event: All study period.
Primary outcome [5] 0 0
Profile of safety (repeat day 3) - Vital signs, ECGs, clinical laboratory test and adverse events.
Timepoint [5] 0 0
Vital: pre-dose, 2,4,8,12,24,36,48h after the start of infusion. ECGs: pre-dose, 12, 24, 36 and 48h after the start of infusion. Clinical lab: pre-dose, 24 and 48h after the start of infusion. Adverse event: All study period.
Secondary outcome [1] 0 0
Profile of urinary PK - Urinary recovery (Ae) and Renal clearance (CLr)
Timepoint [1] 0 0
Single dose and repeat dose day 3: 0-2, 2-4, 4-6, 6-12, 12-18, 18-24, 24-30, 30-36, 36-42, 42-48h. Repeat dose day 1 and day 2: Every 6 hours.
Secondary outcome [2] 0 0
Profile of other PK - AUC(0-24), %AUCex, rambda_z, Volume of destribution based on the terminal phase (Vz) and volume of distribution at steady state (Vss)
Timepoint [2] 0 0
Single dose and repeat dose day 3: pre-dose, 15m, 30m, 35m, 1,2,4,6,8,12,16,24,36 and 48h after the start of infusion. Repeat dose day 1 and day 2: pre-dose and 12h after the start of infusion.

Eligibility
Key inclusion criteria
<Inclusion Criteria>

A subject will be eligible for inclusion in this study only if all of the following
criteria apply:

1. Healthy as determined by a responsible and experienced physician, based on a medical
evaluation including medical history, physical examination, laboratory tests and
cardiac monitoring. A subject with a clinical abnormality or laboratory parameters
outside the reference range for the population being studied may be included only if
the Investigator and the GSK Medical Monitor agree that the finding is unlikely to
introduce additional risk factors and will not interfere with the study procedures.

2. Japanese ethnic origin defined as having been born in Japan, having four ethnic
Japanese grandparents, holding a Japanese passport or identity papers and being able
to speak Japanese. Subjects should also have lived outside Japan for less than 10
years at the time of screening.

3. Male between 20 and 55 years of age inclusive, at the time of signing the informed
consent.

4. Subjects must agree to use one of the contraception methods listed in Section 8.1.
This criterion must be followed from the time of the first dose of study medication
until completion of the follow-up visit.

5. Body weight 50 kg(inclusive) and BMI (body mass index)within the range 18.5 - 25 kg/m2
inclusive.

6. AST, ALT, alkaline phosphatase and bilirubin less than 1.5(inclusive)xULN (isolated
bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin
<35%).

7. Subjects with no clinically significant value of CLcr, NAG and beta-2 microglobulin
judged by the investigator.

8. Average QTcB or QTcF < 450 msec; or QTc < 480 msec in subjects with Bundle Branch
Block taken from triplicate assessments at screening.

9. No clinically active and relevant abnormality on 12-lead ECG at screening.

10. Non-smokers (never smoked or not smoking for >6 months with <10 pack years history
[Pack years = (cigarettes per day smoked/20) x number of years smoked])

11. A signed and dated written informed consent is obtained from the subject

12. The subject is capable of giving informed consent, which includes compliance with the
requirements and restrictions listed in the consent form

13. Able to complete all study procedures and planned treatment periods. <
Minimum age
20 Years
Maximum age
55 Years
Gender
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
Exclusion
Criteria>

A subject will not be eligible for inclusion in this study if any of the following criteria
apply:

1. The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs that
will be screened for include amphetamines, barbiturates, cocaine, opiates and
benzodiazepines. The detection of drugs with a legitimate medical use would not
necessarily be an exclusion to study participation.

2. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody
result within 3 months of screening.

3. Current or chronic history of liver disease, or known hepatic or biliary abnormalities
(with the exception of Gilbert's syndrome or asymptomatic gallstones).

4. A positive test for HIV antibody.

5. History of regular alcohol consumption within 3months of the study defined as:

an average weekly intake of greater than 21 units or an average daily intake of
greater than 3 units. One unit is equivalent to a 285 mL glass of full strength beer
or 425 mL schooner of light beer or 1 (30 mL) measure of spirits or 1 glass (100 mL)
of wine (NHMRC Guidelines [NHMRC, 2001])

6. The subject has participated in a clinical trial and has received an investigational
product within the following time period prior to the first dosing day in the current
study: 30 days, 5 half-lives or twice the duration of the biological effect of the
investigational product (whichever is longer).

7. Exposure to more than four new chemical entities within 12 months prior to the first
dosing day.

8. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary
supplements (including St John's Wort) within 7 days (or 14 days if the drug is a
potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first
dose of study medication, unless in the opinion of the Investigator and GSK Medical
Monitor the medication will not interfere with the study procedures or compromise
subject safety.

9. History of sensitivity to any of the study medications, or components thereof or a
history of drug or other allergy that, in the opinion of the investigator or GSK
Medical Monitor, contraindicates their participation.

10. Where participation in the study would result in donation of blood or blood products
in excess of 500 mL within a 56 day period.

11. Unwillingness or inability to follow the procedures outlined in the protocol.

12. Urinary cotinine levels indicative of smoking or history of regular use of tobacco- or
nicotine-containing products prior to screening.

13. The subject has a known allergy or hypersensitivity to colistin or derived components.

14. Subject is kept under regulatory of judicial order in an institution.

15. Subject is mentally or legally incapacitated.

16. The subject's systolic blood pressure is outside the range of 90-140 mmHg or diastolic
blood pressure is outside the range of 45-90 mmHg.

17. Consumption of red wine, seville oranges, grapefruit or grapefruit juice from 7 days
prior to the first dose of study medication.

<Other Eligibility Criteria Considerations> To assess any potential impact on subject
eligibility with regard to safety, the investigator must refer to the Prescribing
Information (see Appendix 2, 3 and 4) for detailed information regarding warnings,
precautions, contraindications, adverse events, and other significant data pertaining to
the investigational product being used in this study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
GSK Investigational Site - Randwick
Recruitment postcode(s) [1] 0 0
2031 - Randwick

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
GlaxoSmithKline
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This is a clinical study protocol for a single centre, randomized, double blind, placebo
controlled, single and repeat dose study to investigate the safety, tolerability and
pharmacokinetics of intravenous dosing of Colistin Methanesulfonate Sodium (CMS-Na) in
healthy Japanese male subjects.

Eighteen subjects will receive CMS-Na 2.5mg/kg (as colistin activity or 75,000 IU/kg) or
placebo as a single dose and twice daily for 2.5 days by intravenous infusion.

Blood and urine samples for pharmacokinetics analysis will be taken at regular intervals
after dosing. Safety will be assessed by measurement of vital signs, Echocardiogram (ECGs),
safety laboratory data, renal function and review of adverse events.
Trial website
https://clinicaltrials.gov/show/NCT01449838
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
GSK Clinical Trials
Address 0 0
GlaxoSmithKline
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications