Back to resultsA Single and Repeat Dose PK/PD Study to Characterise Biomarker Response in Healthy Subjects Treated With Azithromycin
Primary Purpose
Autoimmune Diseases
Status
Completed
Phase
Phase 1
Locations
United Kingdom
Study Type
Interventional
Intervention
Azithromycin - 250 mg
Azithromycin - 1000 mg
Azithromycin - 250 mg every other day for 3 weeks
Sponsored by
About this trial
This is an interventional basic science trial for Autoimmune Diseases
Eligibility Criteria
Inclusion Criteria:
- Male or female between 18 and 65 years of age inclusive
- Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy
- Child-bearing potential and agrees to use one of the contraception methods
- Body weight ≥ 50 kg and body mass index (BMI) within the range 18.5 - 30 kg/m2 (inclusive)
- Capable of giving written informed consent, which includes compliance with the requirements and restrictions
- Single QT duration corrected for heart rate by Bazett's formula (QTcB) < 450 msec.
Exclusion Criteria:
- A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
- Current or chronic history of liver disease, or known hepatic or biliary abnormalities
- A positive pre-study drug/alcohol screen
- A positive test for HIV antibody
- History of regular alcohol consumption within 6 months of the study
- The subject has participated in a clinical trial and has received an investigational product within the 3 months
- Exposure to more than four new chemical entities within 12 months prior to the first dosing day
- Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements
- History of sensitivity to any of the study medications, or erythromycin, any macrolide or ketolide antibiotic
- Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period
- The subject has donated blood in the 3 months prior to the study
- Pregnant females as determined by positive serum or urine hCG test at screening or prior to dosing
- Lactating females
- Unwillingness or inability to follow the procedures outlined in the protocol
- Subject is mentally or legally incapacitated
Sites / Locations
- GSK Investigational Site
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Active Comparator
Arm Label
Part A - randomized, open-label parallel group
Part B - repeat dose group
Arm Description
Part A is a randomized, open-label parallel group study evaluating PK/PD of a single azithromycin dose of 250 or 1000 mg. Data from Part A will be used to assess the dose resulting in induction/inhibition of various ex vivo biomarkers relative to a 250 mg dose of azithromycin (the clinical dose used in treatment of neutrophil-induced inflammatory conditions). This information will guide the range of doses to be studied in a FTIH study of a new chemical entity.
Part B is a repeat dose study treating subjects with Azithromycin (250 mg every other day for 3 weeks), the dose approximates that used in the treatment of chronic neutrophil-related inflammatory conditions. This information will provide insight into whether the biomarker effects change over time on repeat dosing and any potential differences observed between single and repeat doses.
Outcomes
Primary Outcome Measures
PK/PD modelling of the time course of concentrations and inhibition/induction of relevant biomarkers including the concentration resulting in 50% induction or inhibition (IC50)
Parameters from PK/PD modelling of the time course of concentrations and inhibition/induction of relevant ex vivo biomarkers (e.g., MDC, GM-CSF and IL-10 with varying levels of LPS stimulation) including the IC50 along with distribution parameters (e.g., kin and kout).
Maximum inhibition/induction of relevant biomarkers and timing of this maximum
Maximum inhibition/induction of relevant ex vivo biomarkers (e.g., MDC, GM-CSF and IL-10) and timing of this maximum
Secondary Outcome Measures
Biomarker:Clinical Dose Ratio for each relevant biomarkers
Biomarker:Clinical Dose Ratio (dose which would result in maximum observed concentration (Cmax) above the concentration resulting in 80% induction or inhibition (IC80) in ≥75% of patients divided by clinical dose of 250 mg) for each relevant ex vivo biomarkers.
Observed maximum inhibition/induction and its coefficient of variation (CV)
For each relevant biomarker, the observed maximum inhibition/induction and its coefficient of variation (CV).
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01416350
Brief Title
A Single and Repeat Dose PK/PD Study to Characterise Biomarker Response in Healthy Subjects Treated With Azithromycin
Official Title
A Single and Repeat Dose Pharmacokinetics/ Pharmacodynamics (PK/PD) Study to Characterise theBiomarker Response in Healthy Subjects Treated With the AntiinflammatoryMacrolide Azithromycin
Study Type
Interventional
2. Study Status
Record Verification Date
July 2017
Overall Recruitment Status
Completed
Study Start Date
March 30, 2011 (Actual)
Primary Completion Date
May 12, 2011 (Actual)
Study Completion Date
May 12, 2011 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
GlaxoSmithKline
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
This is a two part protocol (Parts A and B) in healthy volunteers evaluating the pharmacokinetics/ pharmacodynamics (PK/PD) of azithromycin to investigate the usefulness of various biomarkers (e.g., Interleukin-10 (IL-10), Granulocyte macrophage colony-stimulating factor (GM-CSF), mature dendritic cell (MDC), with and without ex vivo lipopolysaccharide (LPS) stimulation) as markers of macrolide anti-inflammatory activity.
Part A is a randomized, open-label parallel group study evaluating PK/PD of a single azithromycin dose of 250 or 1000 mg. Data from Part A will be used to assess the dose resulting in induction/inhibition of various ex vivo biomarkers relative to a 250 mg dose of azithromycin (the clinical dose used in treatment of neutrophil-induced inflammatory conditions). This information will guide the range of doses to be studied in a first time in humans (FTIH) study of a new chemical entity.
Part B is a repeat dose study treating subjects with Azithromycin (250 mg every other day for 3 weeks), the dose approximates that used in the treatment of chronic neutrophil related inflammatory conditions. This information will provide insight into whether the biomarker effects change over time on repeat dosing and any potential differences observed between single and repeat doses.
Detailed Description
This is a two part protocol (Parts A and B) in healthy volunteers evaluating the pharmacokinetics/ pharmacodynamics (PK/PD) of azithromycin to investigate the usefulness of various biomarkers (e.g., IL-10, GM-CSF, MDC, with and without ex vivo lipopolysaccharide (LPS) stimulation) as markers of macrolide anti-inflammatory activity.
Part A is a randomized, open-label parallel group study evaluating PK/PD of a single azithromycin dose of 250 or 1000 mg. Data from Part A will be used to assess the dose resulting in induction/inhibition of various ex vivo biomarkers relative to a 250 mg dose of azithromycin (the clinical dose used in treatment of neutrophil-induced inflammatory conditions). This information will guide the range of doses to be studied in a FTIH study of a new chemical entity.
Part B is a repeat dose study treating subjects with Azithromycin (250 mg every other day for 3 weeks), the dose approximates that used in the treatment of chronic neutrophil related inflammatory conditions. This information will provide insight into whether the biomarker effects change over time on repeat dosing and any potential differences observed between single and repeat doses.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Autoimmune Diseases
7. Study Design
Primary Purpose
Basic Science
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
20 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Part A - randomized, open-label parallel group
Arm Type
Active Comparator
Arm Description
Part A is a randomized, open-label parallel group study evaluating PK/PD of a single azithromycin dose of 250 or 1000 mg. Data from Part A will be used to assess the dose resulting in induction/inhibition of various ex vivo biomarkers relative to a 250 mg dose of azithromycin (the clinical dose used in treatment of neutrophil-induced inflammatory conditions). This information will guide the range of doses to be studied in a FTIH study of a new chemical entity.
Arm Title
Part B - repeat dose group
Arm Type
Active Comparator
Arm Description
Part B is a repeat dose study treating subjects with Azithromycin (250 mg every other day for 3 weeks), the dose approximates that used in the treatment of chronic neutrophil-related inflammatory conditions. This information will provide insight into whether the biomarker effects change over time on repeat dosing and any potential differences observed between single and repeat doses.
Intervention Type
Drug
Intervention Name(s)
Azithromycin - 250 mg
Intervention Description
Part A - A single azithromycin dose of 250 mg.
Intervention Type
Drug
Intervention Name(s)
Azithromycin - 1000 mg
Intervention Description
Part A - A single azithromycin dose of 1000 mg.
Intervention Type
Drug
Intervention Name(s)
Azithromycin - 250 mg every other day for 3 weeks
Intervention Description
Part B - Repeat dose study treating subjects with Azithromycin (250 mg every other day for 3 weeks), the dose approximates that used in the treatment of chronic neutrophil-related inflammatory conditions.
Primary Outcome Measure Information:
Title
PK/PD modelling of the time course of concentrations and inhibition/induction of relevant biomarkers including the concentration resulting in 50% induction or inhibition (IC50)
Description
Parameters from PK/PD modelling of the time course of concentrations and inhibition/induction of relevant ex vivo biomarkers (e.g., MDC, GM-CSF and IL-10 with varying levels of LPS stimulation) including the IC50 along with distribution parameters (e.g., kin and kout).
Time Frame
For Part A Day 1 to 15
Title
Maximum inhibition/induction of relevant biomarkers and timing of this maximum
Description
Maximum inhibition/induction of relevant ex vivo biomarkers (e.g., MDC, GM-CSF and IL-10) and timing of this maximum
Time Frame
For Part A Day 1 to 15
Secondary Outcome Measure Information:
Title
Biomarker:Clinical Dose Ratio for each relevant biomarkers
Description
Biomarker:Clinical Dose Ratio (dose which would result in maximum observed concentration (Cmax) above the concentration resulting in 80% induction or inhibition (IC80) in ≥75% of patients divided by clinical dose of 250 mg) for each relevant ex vivo biomarkers.
Time Frame
For Part B Day 1 to 35
Title
Observed maximum inhibition/induction and its coefficient of variation (CV)
Description
For each relevant biomarker, the observed maximum inhibition/induction and its coefficient of variation (CV).
Time Frame
For Part B Day 1 to 35
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Male or female between 18 and 65 years of age inclusive
Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy
Child-bearing potential and agrees to use one of the contraception methods
Body weight ≥ 50 kg and body mass index (BMI) within the range 18.5 - 30 kg/m2 (inclusive)
Capable of giving written informed consent, which includes compliance with the requirements and restrictions
Single QT duration corrected for heart rate by Bazett's formula (QTcB) < 450 msec.
Exclusion Criteria:
A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
Current or chronic history of liver disease, or known hepatic or biliary abnormalities
A positive pre-study drug/alcohol screen
A positive test for HIV antibody
History of regular alcohol consumption within 6 months of the study
The subject has participated in a clinical trial and has received an investigational product within the 3 months
Exposure to more than four new chemical entities within 12 months prior to the first dosing day
Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements
History of sensitivity to any of the study medications, or erythromycin, any macrolide or ketolide antibiotic
Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period
The subject has donated blood in the 3 months prior to the study
Pregnant females as determined by positive serum or urine hCG test at screening or prior to dosing
Lactating females
Unwillingness or inability to follow the procedures outlined in the protocol
Subject is mentally or legally incapacitated
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
GSK Clinical Trials
Organizational Affiliation
GlaxoSmithKline
Official's Role
Study Director
Facility Information:
Facility Name
GSK Investigational Site
City
London
ZIP/Postal Code
NW10 7EW
Country
United Kingdom
12. IPD Sharing Statement
Learn more about this trial
A Single and Repeat Dose PK/PD Study to Characterise Biomarker Response in Healthy Subjects Treated With Azithromycin
We'll reach out to this number within 24 hrs