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TuberculosisPhase 3ACT-TBNCT03545373

Accuracy and Consequences of Using Trial-of-antibiotics for TB Diagnosis (ACT-TB Study)

A Phase 3 study testing Azithromycin and Amoxicillin in people with Tuberculosis and Respiratory Tract Infections, run by London School of Hygiene and Tropical Medicine at 1 site in Malawi.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This is a three-arm, open-label individually randomised controlled clinical trial investigating the benefits of the diagnostic use of broad-spectrum antimicrobials during the diagnostic process for tuberculosis (TB) and the risk of antimicrobial resistance. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Azithromycin and Amoxicillin
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
1,583 participants
Where
1 siteMalawi
Study dates
25 Feb 2019to 14 Apr 2020
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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

Trial locations and contacts

1 site in 1 country.

Malawi1 site

  • University of Malawi College of Medicine

    Blantyre, Southern Region, 00265

Other trials in Malawi

About this study

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)

This is a three-arm, open-label individually randomised controlled clinical trial investigating the benefits of the diagnostic use of broad-spectrum antimicrobials during the diagnostic process for tuberculosis (TB) and the risk of antimicrobial resistance. Adults (≥18 years) presenting to primary care with TB symptoms will, after excluding acute illness, be randomised (1:1:1) to receiving azithromycin, amoxicillin or standard care. Diagnostic accuracy will be ascertained by comparing self-reported response to treatment on Day-8 to results of mycobacteriology tests (MTB culture, smear microscopy and Xpert/MTB/RIF). Antimicrobial resistance will be ascertained by comparing arms with respect to incidence of resistant Streptococcus pneumonia carriage cultured from nasopharyngeal swabs collected on Day-28. Clinical benefit will be ascertained by comparing clinical outcomes by Day-29.

Read the 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

  1. 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.
  2. To determine the overall clinical benefit of giving empirical antibiotic treatment in primary care participants with chronic cough. Secondary
  3. To evaluate using nasopharyngeal Streptococcus pneumonia carriage, the effect of a trial-of-antibiotics on selection for antimicrobial resistance.
  4. 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
  5. 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).

Keywords
antimicrobial resistance, TB, Cough, antibiotics, anti-infective agents
Medical subject headings
Tuberculosis, Respiratory Tract Infections, Pneumonia, Cough

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Study groups in NCT03545373
Study groupRoleWhat they receive
AzithromycinExperimentalAzithromycin 500mg, oral, once daily for 3 days commencing on randomization day.
Receives: Drug: Azithromycin
AmoxicillinExperimentalAmoxicillin 1g, oral, 3 times daily for 5 days commencing on randomization day.
Receives: Drug: Amoxicillin
Standard of careNo interventionThe 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 being measured

The primary outcome is the main question the study is designed to answer.

  1. 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).

    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.

    Measured: Day 1 to Day 8

  2. Clinical impact of trial-of-antibiotics

    We will investigate the overall clinical impact of trial-of-antibiotics by comparing the day 29 risk of any of

    1. death,
    2. hospitalisation, and
    3. 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.

    Measured: Day 1 to Day 29

Secondary outcomes (3)

  1. Impact of trial-of-antibiotics on antimicrobial resistance

    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.

    Measured: Day 1 to Day 29

  2. diagnostic value of trial-of-antibiotics in all patients including those without a valid sputum result

    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%.

    Measured: Day 1 to Day 8

  3. Economic analysis of use of trial-of-antibiotics

    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:

    1. Incremental cost per quality adjusted life year gained
    2. Total direct medical costs per participant
    3. Eq-5D utility score

    Measured: Day 1 to Day 29

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted4 Jun 2018
  2. Study start25 Feb 2019
  3. Primary completion14 Mar 2020
  4. Study completion14 Apr 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Diagnosis
Allocation
Randomised
Intervention model
Parallel groups
Model description
Three treatment arms allocated using computer generated block randomization in a 1:1:1 ratio.
Masking
Single blind
Who is masked
Outcomes assessor
Enrolment
1,583 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03545373
Sponsor's protocol ID
15232
Acronym
ACT-TB
Status last verified
Apr 2021
First submitted
1 May 2018
Last updated
28 Apr 2021
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: 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.

Publications

  • Divala TH, Corbett EL, Kandulu C, Moyo B, MacPherson P, Nliwasa M, French N, Sloan DJ, Chiume L, Ndaferankhande MJ, Chilanga S, Majiga ST, Odland JO, Fielding KL. Trial-of-antibiotics to assist tuberculosis diagnosis in symptomatic adults in Malawi (ACT-TB study): a randomised controlled trial. Lancet Glob Health. 2023 Apr;11(4):e556-e565. doi: 10.1016/S2214-109X(23)00052-9.

    PubMed 36925176

  • Divala TH, Fielding KL, Sloan DJ, French N, Nliwasa M, MacPherson P, Kandulu CC, Chiume L, Chilanga S, Ndaferankhande MJ, Corbett EL. Accuracy and consequences of using trial-of-antibiotics for TB diagnosis (ACT-TB study): protocol for a randomised controlled clinical trial. BMJ Open. 2020 Mar 25;10(3):e033999. doi: 10.1136/bmjopen-2019-033999.

    PubMed 32217561

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Azithromycin and Amoxicillin in people with Tuberculosis and Respiratory Tract Infections, run by London School of Hygiene and Tropical Medicine at 1 site in Malawi.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 28 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Malawi. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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 study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03545373, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Apr 2021.

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