The BLAST- 1 Trial - Cephalexin+Amoxicillin-clavulanate for Tuberculosis (BLAST)

Early Bactericidal Activity of Cephalexin and Amoxicillin-clavulanate for Susceptible Tuberculosis - BLAST 1 Trial

The goal of this randomized controlled trial is to study the early bactericidal activity in adult patients with smear-positive pulmonary tuberculosis.

The main question it aims to answer are if cephalexin, in combination with amoxicillin-clavulanate, is effective in the treatment of tuberculosis.

Participants with smear-positive tuberculosis will be randomized to either of two groups:

Intervention group: cephalexin and amoxicillin-clavulanate. Control group: Standard of care TB treatment. The study period is 2 weeks and participants will be asked to submit multiple sputum samples to measure the bacterial sputum load. They will also submit saliva samples for estimation of drug concentrations in the body.

Researchers will compare the intervention group with the control group to see if the trial drugs result in a reduced bacterial sputum load

Overall aim: To study the early bactericidal activity of cephalexin, in combination with amoxicillin-clavulanate, in comparison to standard treatment in patients with active pulmonary tuberculosis during the first 2 weeks of treatment.

Primary aim:

1. To evaluate the early bactericidal activity (measured as 'time to culture positivity') of cephalexin-clavulanate in comparison, to standard TB treatment (rifampicin, isoniazid, pyrazinamide, and ethambutol).

   Secondary aim:

2. To asses safety and tolerability of cephalexin together with amoxicillin-clavulanate.
3. To determine key pharmacokinetic (PK) parameters of cephalexin, especially half-life and drug exposure (maximal concentration; Cmax and area under the concentration versus time curve, AUC).

Study Overview

• Status: Recruiting
• Conditions: Tuberculosis, Pulmonary
• Intervention / Treatment: Other: Standard of care treatment of tuberculosis; Drug: Cephalexin; Drug: Amoxicillin-Clavulanate 500 Mg-125 Mg Oral Tablet

Detailed Description

Given the need for alternative and well-tolerated tuberculosis (TB) treatment options, there is scope to re-assess the potential value of already approved drugs that are known to be safe, cheap and widely available. Cephalexin, in combination with amoxicillin-clavulanate, have shown high in vitro efficacy against the TB bacteria. Both cephalexin and amoxicillin-clavulanate are Therapeutic Goods Administration (TGA) approved and are widely used in Australia for common infections.

In order to compare the bacterial killing effect of cephalexin, in combination with amoxicillin-clavulanate, with current standard of care TB treatment, we will perform an open-label randomized controlled trial.

Eligible and consenting study participants with bacteriologically confirmed sputum-smear positive pulmonary TB will be randomised to an intervention or control arm in a 1:1 ratio (15 patients in each arm) for the two weeks duration of the trial.

• Intervention arm: cephalexin 1g thrice daily + amoxicillin-clavulanate 500/125 mg thrice daily.
• Control arm: standard of care treatment for TB (rifampicin, isoniazid, ethambutol and pyrazinamide) The primary outcome is the fall in bacterial load measured by 'time to positive culture' using the BACTEC MGIT system with automated detection. Multiple sputum samples (10 in total) will be collected during the first 2 weeks of TB treatment. Six saliva samples will be collected after 4 days of treatment, in order to estimate the drug concentrations of cephalexin in the body (intervention arm only).

For a small subset of patients receiving cephalexin (n=5), a more intensive simultaneous blood and saliva sampling will be done in order to calculate the saliva:plasma ratio, in order to facilitate the estimation of plasma drug concentrations from saliva samples.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jan-Willem Alffenaar, Professor; Phone Number: +61 (0)286270019; Email: johannes.alffenaar@nsw.health.gov.au
• Study Contact Backup: Name: Lina Davies Forsman, MD, PhD; Phone Number: +61 (0)478384977

Study Locations

• Australia
  • Sydney, Australia
    • Not yet recruiting
    • Royal Prince Alfred Hospital
    • Contact: Gregory Fox, Professor
  • Sydney, Australia
    • Not yet recruiting
    • Blacktown Hospital
    • Contact: Tasnim Hasan, MD
  • Sydney, Australia
    • Recruiting
    • Western Sydney Health District
    • Contact: Jin-Gun Cho, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Consenting adults (≥18 years)
• ≥40 kg
• Smear-positive patients with active tuberculosis, confirmed by sputum smear, TB PCR and/or GeneXpert.

Exclusion Criteria:

• On TB treatment for >1 day
• Condition affecting ability of an informed consent (i.e. dementia, delirium etc).
• Pregnancy or breast-feeding
• HIV
• Known allergy or sensitivity to any of the study drugs
• Drug-resistant TB (resistance to rifampicin and/or isoniazid)
• Poor general condition or severe infection such that, in the opinion of the investigator at screening, any delay in initiation of definitive TB treatment cannot be tolerated
• TB with concomitant central nervous system and/or cardiac involvement.
• Any condition as determined by physical examination, medical history, laboratory data, or chest x-ray which, in the opinion of the investigator, would interfere with safety or endpoint assessments in the study.
• Use of metformin, probenecid or allopurinol
• Known previous Clostridium difficile infection due to the risk of colitis. (In case no medical records are available, it should be suspected in elderly patients reporting severe gastrointestinal infections in relation to courses of antibiotics)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard of care TB; Standard of care treatment for TB (rifampicin, isoniazid, ethambutol and pyrazinamide according to WHO)	Other: Standard of care treatment of tuberculosis; The control group will be given standard of care treatment of tuberculosis consisting of rifampicin, isoniazid, pyrazinamide and ethambutol; Other Names: HREZ
Experimental: Cephalexin + amoxicillin-clavulanate; Intervention arm: cephalexin 1g thrice daily + amoxicillin-clavulanate 500/125 mg thrice daily.	Drug: Cephalexin; Participants in intervention group will receive a combination of cephalexin and amoxicillin-clavulanate for the first 2 weeks of TB treatment; Other Names: Keflex; Drug: Amoxicillin-Clavulanate 500 Mg-125 Mg Oral Tablet; Participants in the intervention group will receive a combination of cephalexin and amoxicillin-clavulanate for the first 2 weeks of TB treatment; Other Names: Augmentin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to positivity (TTP)	Early bactericidal activity measured as fall in time to positivity (TTP) 1. The primary outcome is fall in bacterial load in sputum, measured as the rate of change in Time to Sputum Culture Positivity (TTP). TTP is the time to a positive culture when sputum samples are incubated in BACTEC MGIT for automated detection of M. tuberculosis. Measuring the fall in bacterial load is standard choice of outcome for studies evaluating the effect (kill) of drug on TB bacteria.	2 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events	Tolerability - frequency, categorization and grade of adverse events according to CTCAE (Common Terminology Criteria for Adverse Events)	2 weeks
Area under the concentration versus time curve (AUC) of cephalexin	Estimation of the pharmacokinetic parameter area under the concentration versus time curve (AUC) of cephalexin in saliva.	2 weeks
Cmax of cephalexin	Estimation of the pharmacokinetic parameter maximum concentration (Cmax) of cephalexin saliva.	2 weeks

Collaborators and Investigators

• Sponsor: Western Sydney Local Health District
• Collaborators: Centre Of Research Excellence in Tuberculosis Control
• Investigators: Principal Investigator: Jan-Willem Alffenaar, Professor, WSLHD, Department of Pharmacy, Westmead hospital, NSW, Australia

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2023
• Primary Completion (Estimated): July 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: November 2, 2022
• First Submitted That Met QC Criteria: December 15, 2022
• First Posted (Actual): December 23, 2022

Study Record Updates

• Last Update Posted (Actual): June 26, 2023
• Last Update Submitted That Met QC Criteria: June 22, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Randomized controlled trial; Cephalosporin; Early bactericidal activity; Smear-positive TB; Betalactam antibiotics; Time to positivity
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Amoxicillin; Cephalexin; Clavulanic Acid; Clavulanic Acids; Amoxicillin-Potassium Clavulanate Combination
• Other Study ID Numbers: 2022/PID01942

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No