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

NCT03545373 | Completed Phase 3 DMC

• 1 other identifier: 15232
• Study Type: interventional
• Target: 1,583
• Locations: 1 country
• Sites: 1

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.

Conditions

Tuberculosis; Respiratory Tract Infections; Pneumonia

Keywords

antimicrobial resistance; TB; Cough; antibiotics; anti-infective agents

Outcome Measures

Primary Outcomes (2)

• 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.

  Day 1 to Day 8

• 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.

  Day 1 to Day 29

Secondary Outcomes (3)

• Impact of trial-of-antibiotics on antimicrobial resistance

  Day 1 to Day 29

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

  Day 1 to Day 8

• Economic analysis of use of trial-of-antibiotics

  Day 1 to Day 29

Study Arms (3)

Azithromycin

EXPERIMENTAL

Azithromycin 500mg, oral, once daily for 3 days commencing on randomization day.

Drug: Azithromycin

Amoxicillin

EXPERIMENTAL

Amoxicillin 1g, oral, 3 times daily for 5 days commencing on randomization day.

Drug: Amoxicillin

Standard of care

NO INTERVENTION

The standard of care in current national guidelines for patients presenting with cough and without danger signs (No treatment, re-evaluate with sputum results)

Interventions

Azithromycin DRUG

Azithromycin tablet taken orally

Azithromycin

Amoxicillin DRUG

Amoxicillin tablets taken orally

Amoxicillin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• London School of Hygiene and Tropical Medicine: lead
• Kamuzu University of Health Sciences: collaborator

Study Sites (1)

University of Malawi College of Medicine

Blantyre, Southern Region, 00265, Malawi

Location

Related Publications (2)

• 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.

  PMID: 36925176 DERIVED

• 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.

  PMID: 32217561 DERIVED

MeSH Terms

Conditions

Tuberculosis; Respiratory Tract Infections; Pneumonia; Cough

Interventions

Azithromycin; Amoxicillin

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Diseases; Lung Diseases; Respiration Disorders; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals; Ampicillin; Penicillin G; Penicillins; beta-Lactams; Lactams; Amides; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Titus H Divala, MBBS MPH MS

  London School of Hygiene and Tropical Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Three treatment arms allocated using computer generated block randomization in a 1:1:1 ratio.

Study Record Dates

• First Submitted: May 1, 2018
• First Posted: June 4, 2018
• Study Start: February 25, 2019
• Primary Completion: March 14, 2020
• Study Completion: April 14, 2020
• Last Updated: April 28, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: After publishing study main papers.
• Access Criteria: Through the London School of Hygiene \& Tropical Medicine data repository.

Locations

MA (1)