- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03545373
Accuracy and Consequences of Using Trial-of-antibiotics for TB Diagnosis (ACT-TB Study) (ACT-TB)
Randomised Controlled Clinical Trial Investigating Benefits of Using Response to Broad Spectrum Antibiotics as an Exclusion Diagnostic for Tuberculosis (TB) in Primary Care Adult Patients Versus Risk of Antimicrobial Resistance (AMR)
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
BACKGROUND
Antimicrobial resistance (AMR) is a growing public health threat that is in part fuelled by empirical antibiotic usage. Empirical antibiotic use is often motivated by lack of point of care diagnostics a common problem in infectious diseases most of which are life-threatening. Tuberculosis (TB), the leading cause of infectious disease mortality, is one of the life-threatening illnesses without adequate diagnostics. Just over 50% of TB cases reported to WHO annually have confirmed mycobacteriological diagnosis. To complement the diagnostic gap, standard diagnostic algorithms include empirical antibiotic use. The antibiotic course, referred to as "trial-of-antibiotics", given to mycobacteriology-negative but symptomatic adults, is often broad-spectrum aiming to provide treatment for pneumonia. The goal is to treat infectious causes of respiratory symptoms other than TB, effectively performing the role of a "rule-out" diagnostic test for TB.
RATIONALE
Approximately 26.5 million antibiotics courses are prescribed in the course of diagnosis of the 5.3 million smear negative TB registrations per annum. Despite this widespread use, there is no randomised controlled trial (RCT) evidence supporting the diagnostic accuracy of antibiotic trials and their impact on AMR. It is also unknown whether this usage of antibiotics can improve clinical outcomes considering that in settings of high HIV prevalence, bacterial infection associated mortality just before and during TB treatment is high.
OBJECTIVES
Primary
- To establish the diagnostic value of trial-of-antibiotics for excluding pulmonary tuberculosis (PTB) in adults with prolonged cough (and have a valid sputum test result) at primary care level in Malawi.
To determine the overall clinical benefit of giving empirical antibiotic treatment in primary care participants with chronic cough.
Secondary
- To evaluate using nasopharyngeal Streptococcus pneumonia carriage, the effect of a trial-of-antibiotics on selection for antimicrobial resistance.
- To establish the diagnostic value of trial-of-antibiotics for excluding pulmonary tuberculosis (PTB) in primary care presenting Malawian adults with prolonged cough including those without a successful sputum
- To estimate the incremental cost-effectiveness of trial-of-antibiotics using azithromycin and trial-of-antibiotics using amoxicillin in comparison to standard of care, and to each other.
METHODS To address the evidence gaps related to a) accuracy, b) antimicrobial resistance, and c) impact on clinical outcomes), a randomised controlled clinical trial recruiting adult patients (≥18 years) presenting to primary care centres in Blantyre, Malawi with history of cough for at least 2 weeks, will be conducted. After excluding those with danger signs participants will be randomised to receiving or not receiving trial-of-antibiotics (azithromycin or amoxicillin) from Day-1 to determine diagnostic accuracy (specificity) against mycobacteriology reference standard (smear microscopy, Xpert/MTB/RIF and culture).
Differences in antimicrobial resistance and clinical outcomes [1)death, 2)hospitalisation, 3)missed TB diagnosis] will be compared between treatment arms by Day-29.
To adequately address these objectives, 388 sputum-TB-negative participants will be required for each of the three arms (azithromycin, amoxicillin and standard of care).
FUNDING
Funding was provided by Commonwealth Scholarship Commission (Titus Divala), Helse Nord RHF (Titus Divala), Wellcome Trust Senior Research Fellowship in Clinical Science (WT200901, Liz Corbett), and the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) (MR/K012126/1, Katherine Fielding).
Study Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
-
-
Southern
-
Blantyre, Southern, Malawi, 00265
- University of Malawi College of Medicine
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Ambulatory clinic attendees presenting with cough
- Unwell for at least 14 days
- Aged at least 18 years
- Reside in Blantyre and willing to return to the same clinic for follow up visits over the entire study period.
Exclusion Criteria:
- Self-reported allergy to study medications
- WHO/Malawi National tuberculosis Program (NTP) danger signs: respiratory rate > 30/min, temperature >39oC, Heart rate >120/minute, confused/agitated, respiratory distress, systolic blood pressure <90 mmHg, inability to walk unassisted
- Treated with antibiotics other than co-trimoxazole prophylaxis within the past 14 days
- Tuberculosis treatment or isoniazid preventive therapy within the last 6 months
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Diagnostic
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Azithromycin
Azithromycin 500mg, oral, once daily for 3 days commencing on randomization day.
|
Azithromycin tablet taken orally
|
Experimental: Amoxicillin
Amoxicillin 1g, oral, 3 times daily for 5 days commencing on randomization day.
|
Amoxicillin tablets taken orally
|
No Intervention: Standard of care
The standard of care in current national guidelines for patients presenting with cough and without danger signs (No treatment, re-evaluate with sputum results)
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Diagnostic accuracy of trial-of-antibiotics: proportion of patients without tuberculosis (by sputum tests) who report improvement of their baseline illness when asked 7 days after randomisation (Day 8 study visit).
Time Frame: Day 1 to Day 8
|
The proportion of patients without tuberculosis (by sputum tests) who report improvement of their baseline illness when asked 7 days after randomisation (Day 8 study visit). This can be thought of as diagnostic specificity if you take sputum test results as a reference standard and change in symptoms at Day 8 as the investigational test. In this case the possible results of the investigational test are improvement and no improvemet (no change or worsened) in response to the question: on day 1, you reported that you were unwell; compared to that day, has your illness worsened, remained the same, or improved? The mycobacteriology reference standard will be defined in participants with at least one valid sputum test result on days 1 and 8 as sputum-test-positive if there is at least one positive of smear microscopy, Xpert/MTB/RIF, or MTB culture; and as sputum-test-negative if none of the tests is positive. |
Day 1 to Day 8
|
Clinical impact of trial-of-antibiotics
Time Frame: Day 1 to Day 29
|
We will investigate the overall clinical impact of trial-of-antibiotics by comparing the day 29 risk of any of
The connection between trial-of-antibiotics and risk of hospitalisation and death assumes a protective effect of antibiotics. In patients presenting with chronic cough at primary care in high HIV prevalence settings, frequencies of mortality and hospitalization over a two months period are similar, ranging from 2 to 6%. We have included missed tuberculosis diagnosis because this too can lead to death. We are defining "missed tuberculosis" as participants who meet standard mycobacteriological and radiological tuberculosis definitions but are incorrectly classified as tuberculosis-negative and not yet on tuberculosis treatment by Day 29. |
Day 1 to Day 29
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Impact of trial-of-antibiotics on antimicrobial resistance
Time Frame: Day 1 to Day 29
|
We will use Streptococcus pneumoniae isolated from swabs of the nasopharynx as the indicator pathogen for AMR evaluation. An ecological niche for many bacterial species, the upper respiratory tract also presents a convenient window for investigating antimicrobial resistance. We will define AMR positive as having nasopharyngeal isolates of Streptococcus pneumoniae that are resistant to any of the following commonly used antibiotics: ceftriaxone, amoxycillin, cefoxitin, azithromycin, and erythromycin as determined using disc diffusion technique; and AMR negative as either (1) not isolating any Streptococcus pneumoniae or (2) isolating any Streptococcus pneumoniae that is not resistant to any of the assessed antibiotics. For each arm, and at both baseline and day 29, we will report proportion of AMR positive participants. The study outcome will be the proportion of AMR positive participants at day 29. |
Day 1 to Day 29
|
diagnostic value of trial-of-antibiotics in all patients including those without a valid sputum result
Time Frame: Day 1 to Day 8
|
In this analysis, all will remain as described for primary outcome 1 except for the denominator, which will now include those without a valid sputum test result. The mycobacteriology reference standard for secondary outcome 2 will be defined as sputum test positive if at least one positive of smear microscopy, Xpert/MTB/RIF, or MTB culture from samples collected on days 1 and 8. The reference test will be sputum-test-negative if none of the tests is positive and where there is no valid sputum test result available. The most likely reason for not having a valid sputum result will be inability to produce sputum, but other explanations will be: lost sample before laboratory analysis, an invalid laboratory reading, or contamination. We have opted to analyse this population because in symptomatic adults of the study setting, failure to produce sputum can be as high as 13%. |
Day 1 to Day 8
|
Economic analysis of use of trial-of-antibiotics
Time Frame: Day 1 to Day 29
|
To estimate the incremental cost-effectiveness of trial-of-antibiotics using azithromycin and trial-of-antibiotics using amoxicillin in comparison to standard of care, and to each other using a combination of information from the following data:
|
Day 1 to Day 29
|
Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Titus H Divala, MBBS MPH MS, London School of Hygiene and Tropical Medicine
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 15232
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Data sharing of all data with any group requesting access to individual records will be ensured within 12 months of completion of publication related analyses, with all data and study tools made available by that time through the institutional research data repository established by London School of Hygiene & Tropical Medicine(LSHTM) Research Data Management Support Service..
Anonymised data will be held for sharing as original databases stored with a soft copy of the fully annotated questionnaires and the STATA files used for recoding and analysis. Personal identifiers, such as names, will not be held, with ID numbers used instead.
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- Study Protocol
- Statistical Analysis Plan (SAP)
- Informed Consent Form (ICF)
- Clinical Study Report (CSR)
- Analytic Code
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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