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

Phase 1

Completed

• Conditions: Tuberculosis
• Interventions: Drug: Pyrazinamide; Drug: Allopurinol

• Registration Number: NCT02700347
• Lead Sponsor: National University Hospital, Singapore

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.

Study Timeline

• Study Start: 2016-02
• Study First Submitted: 2016-02-24
• Study First Submitted QC: 2016-03-01
• Study First Posted: 2016-03-07
• Primary Completion: 2016-04
• Study Completion: 2016-04
• Status Verified: 2017-04
• Last Update Submitted: 2017-04-12
• Last Update Posted: 2017-04-13

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 12

Inclusion Criteria

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

Exclusion Criteria

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Standard dose pyrazinamide	Pyrazinamide	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.
Low dose pyrazinamide	Pyrazinamide	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.
Low dose pyrazinamide	Allopurinol	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.
Standard dose pyrazinamide	Allopurinol	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.
High dose pyrazinamide	Pyrazinamide	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.
High dose pyrazinamide	Allopurinol	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.

Primary Outcome Measures

Name	Time	Method
Cumulative whole blood bactericidal activity (WBA)	48 hours	Cumulative bactericidal activity calculated as log change CFU.day

Secondary Outcome Measures

Name	Time	Method
Plasma concentrations of study drugs to determine the Area Under the Curve (AUC)	48 hours
Plasma concentrations of study drugs to determine the Maximum Plasma Concentration (Cmax)	48 hours
Plasma concentrations of study drugs to determine the drug half-life (t1/2)	48 hours

Trial Locations

Locations (1)

National University Hospital, Singapore; 🇸🇬 Singapore, Singapore