Accuracy and Consequences of Using Trial-of-antibiotics for TB Diagnosis (ACT-TB Study) (ACT-TB)
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|ClinicalTrials.gov Identifier: NCT03545373|
Recruitment Status : Completed
First Posted : June 4, 2018
Last Update Posted : April 28, 2021
|Condition or disease||Intervention/treatment||Phase|
|Tuberculosis Respiratory Tract Infections Pneumonia||Drug: Azithromycin Drug: Amoxicillin||Phase 3|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||1583 participants|
|Intervention Model:||Parallel Assignment|
|Intervention Model Description:||Three treatment arms allocated using computer generated block randomization in a 1:1:1 ratio.|
|Masking:||Single (Outcomes Assessor)|
|Masking Description:||All laboratory forms for mycobacteriology and nasopharyngeal pneumococcal work will have no reference to participant treatment allocation. On Day-8, assessment of improvement from baseline symptoms will utilize audio computer-assisted self-interview (ACASI) to minimise potential for social-mediated reporting and ascertainment biases. On Day-29, clinical outcome assessment forms will bear no reference to treatment arm. Participants, research coordinators, and routine care staff will not be masked to ensure safety of the participants and allow appropriate patient management decision-making which may be related to the trial interventions.|
|Official Title:||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)|
|Actual Study Start Date :||February 25, 2019|
|Actual Primary Completion Date :||March 14, 2020|
|Actual Study Completion Date :||April 14, 2020|
Azithromycin 500mg, oral, once daily for 3 days commencing on randomization day.
Azithromycin tablet taken orally
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)
- 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.
- 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
- hospitalisation, and
- missed tuberculosis
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.
- 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.
- 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%.
- 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:
- Incremental cost per quality adjusted life year gained
- Total direct medical costs per participant
- Eq-5D utility score
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03545373
|University of Malawi College of Medicine|
|Blantyre, Southern, Malawi, 00265|
|Principal Investigator:||Titus H Divala, MBBS MPH MS||London School of Hygiene and Tropical Medicine|