Clinical trial NCT03545373: Accuracy and Consequences of Using Trial-of-antibiotics for TB Diagnosis (ACT-TB 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Tuberculosis
Respiratory Tract Infections
Pneumonia
Keywords: antimicrobial resistance
TB
Cough
antibiotics
anti-infective agents
Lead sponsor: London School of Hygiene and Tropical Medicine
Sponsor class: OTHER
Collaborators: name: Kamuzu University of Health Sciences
First posted: 2018-06-04
Enrollment: 1583
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Three treatment arms allocated using computer generated block randomization in a 1:1:1 ratio.
Primary purpose: DIAGNOSTIC

Brief 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. 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.

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).

Eligibility criteria: 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

Primary outcomes:
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).
timeFrame: Day 1 to Day 8
measure: Clinical impact of trial-of-antibiotics
timeFrame: Day 1 to Day 29
Secondary outcomes:
measure: Impact of trial-of-antibiotics on antimicrobial resistance
timeFrame: Day 1 to Day 29
measure: diagnostic value of trial-of-antibiotics in all patients including those without a valid sputum result
timeFrame: Day 1 to Day 8
measure: Economic analysis of use of trial-of-antibiotics
timeFrame: Day 1 to Day 29
Other outcomes:
Locations:
city: Blantyre
country: Malawi
facility: University of Malawi College of Medicine
state: Southern
Study officials:
affiliation: London School of Hygiene and Tropical Medicine
name: Titus H Divala, MBBS MPH MS
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.