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Whole Blood Bactericidal Activity Against Mycobacterium Tuberculosis of Pyrazinamide Plus Allopurinol in Healthy Volunteers

Primary Purpose

Tuberculosis

Status

Completed

Phase

Phase 1

Locations

Singapore

Study Type

Interventional

Intervention

Pyrazinamide

Allopurinol

About this trial

This is an interventional treatment trial for Tuberculosis

Eligibility Criteria

21 Years - 70 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Aged between 21 and 70 years old
Male or female willing to comply with the study visits and procedures
Willing and able to provide written informed consent

Exclusion Criteria:

Women who are currently pregnant or breastfeeding
Body weight 50kg or below
HLA-B*5801 allele positive
Clinical evidence (symptoms and/or signs) suggestive of active TB
Previous hypersensitivity, intolerance or allergy to pyrazinamide or allopurinol
Current use of any drugs or medication known to have an interaction with pyrazinamide or allopurinol, or known to have anti-TB activity
Evidence of renal or hepatic dysfunction or any clinically significant deviation from normal during screening including laboratory determinations
Known hepatic disease (including chronic hepatitis), recent hepatitis (within last 6 months) or alcohol abuse
Known hyperuricaemia or evidence of hyperuricaemia at screening
History or current episode of gout
Any other significant condition that would, in the opinion of the investigator, compromise the volunteer's safety or outcome in the trial
Current participation in other clinical intervention trial or research protocol

Sites / Locations

National University Hospital, Singapore

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Low dose pyrazinamide

Standard dose pyrazinamide

High dose pyrazinamide

Arm Description

Day 0: Pyrazinamide 10mg/kg, Day 5: Allopurinol 100mg single dose, Day 6: Allopurinol 100mg single dose, Day 7: Pyrazinamide 10mg/kg plus allopurinol 100mg single dose, Day 8: Allopurinol 100mg single dose.

Day 0: Pyrazinamide 25mg/kg single dose, Day 5: Allopurinol 100mg single dose, Day 6: Allopurinol 100mg single dose, Day 7: Pyrazinamide 25mg/kg plus allopurinol 100mg single dose, Day 8: Allopurinol 100mg single dose.

Day 0: Pyrazinamide 35mg/kg single dose, Day 5: Allopurinol 100mg single dose, Day 6: Allopurinol 100mg single dose, Day 7: Pyrazinamide 35mg/kg plus allopurinol 100mg single dose, Day 8: Allopurinol 100mg single dose.

Outcomes

Primary Outcome Measures

Cumulative whole blood bactericidal activity (WBA)

Cumulative bactericidal activity calculated as log change CFU.day

Secondary Outcome Measures

Plasma concentrations of study drugs to determine the Area Under the Curve (AUC)

Plasma concentrations of study drugs to determine the Maximum Plasma Concentration (Cmax)

Plasma concentrations of study drugs to determine the drug half-life (t1/2)

Full Information

NCT ID

NCT02700347

First Posted

February 24, 2016

Last Updated

April 12, 2017

Sponsor

National University Hospital, Singapore

1. Study Identification

Unique Protocol Identification Number

NCT02700347

Brief Title

Whole Blood Bactericidal Activity Against Mycobacterium Tuberculosis of Pyrazinamide Plus Allopurinol in Healthy Volunteers

Official Title

Evaluating Pharmacokinetics and Whole Blood Bactericidal Activity Against Mycobacterium Tuberculosis of Pyrazinamide Boosted With Allopurinol in Healthy Volunteers

Study Type

Interventional

2. Study Status

Record Verification Date

April 2017

Overall Recruitment Status

Completed

Study Start Date

February 2016 (undefined)

Primary Completion Date

April 2016 (Actual)

Study Completion Date

April 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

National University Hospital, Singapore

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

The purpose of this study is to evaluate the bactericidal activity against Mycobacterium tuberculosis of pyrazinamide in combination with allopurinol. Pharmacokinetics (PK) and whole blood bactericidal activity (WBA) will be measured in healthy volunteers following administration of pyrazinamide alone and in combination with allopurinol.

Detailed Description

The whole blood bactericidal activity (WBA) assay is an ex vivo model for measuring the combined effects of administered drugs, host factors and strain factors on mycobacterial sterilisation. If performed in parallel with PK measurements, the method can be used to evaluate the effect of drugs throughout the dosing cycle. The aim of this trial is to assess the WBA activity and PK data of pyrazinamide and its metabolites boosted with allopurinol in healthy volunteers.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Tuberculosis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

12 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Low dose pyrazinamide

Arm Type

Experimental

Arm Description

Arm Title

Standard dose pyrazinamide

Arm Type

Experimental

Arm Description

Arm Title

High dose pyrazinamide

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Pyrazinamide

Intervention Type

Drug

Intervention Name(s)

Allopurinol

Primary Outcome Measure Information:

Title

Cumulative whole blood bactericidal activity (WBA)

Description

Cumulative bactericidal activity calculated as log change CFU.day

Time Frame

48 hours

Secondary Outcome Measure Information:

Title

Plasma concentrations of study drugs to determine the Area Under the Curve (AUC)

Time Frame

48 hours

Title

Plasma concentrations of study drugs to determine the Maximum Plasma Concentration (Cmax)

Time Frame

48 hours

Title

Plasma concentrations of study drugs to determine the drug half-life (t1/2)

Time Frame

48 hours

10. Eligibility

Sex

All

Minimum Age & Unit of Time

21 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Aged between 21 and 70 years old Male or female willing to comply with the study visits and procedures Willing and able to provide written informed consent Exclusion Criteria: Women who are currently pregnant or breastfeeding Body weight 50kg or below HLA-B*5801 allele positive Clinical evidence (symptoms and/or signs) suggestive of active TB Previous hypersensitivity, intolerance or allergy to pyrazinamide or allopurinol Current use of any drugs or medication known to have an interaction with pyrazinamide or allopurinol, or known to have anti-TB activity Evidence of renal or hepatic dysfunction or any clinically significant deviation from normal during screening including laboratory determinations Known hepatic disease (including chronic hepatitis), recent hepatitis (within last 6 months) or alcohol abuse Known hyperuricaemia or evidence of hyperuricaemia at screening History or current episode of gout Any other significant condition that would, in the opinion of the investigator, compromise the volunteer's safety or outcome in the trial Current participation in other clinical intervention trial or research protocol

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Nicholas Paton

Organizational Affiliation

National University Hospital, Singapore

Official's Role

Principal Investigator

Facility Information:

Facility Name

National University Hospital, Singapore

City

Singapore

Country

Singapore

12. IPD Sharing Statement

Citations:

PubMed Identifier

28739782

Citation

Naftalin CM, Verma R, Gurumurthy M, Lu Q, Zimmerman M, Yeo BCM, Tan KH, Lin W, Yu B, Dartois V, Paton NI. Coadministration of Allopurinol To Increase Antimycobacterial Efficacy of Pyrazinamide as Evaluated in a Whole-Blood Bactericidal Activity Model. Antimicrob Agents Chemother. 2017 Sep 22;61(10):e00482-17. doi: 10.1128/AAC.00482-17. Print 2017 Oct.

Results Reference

derived

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Whole Blood Bactericidal Activity Against Mycobacterium Tuberculosis of Pyrazinamide Plus Allopurinol in Healthy Volunteers

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