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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03545373
Recruitment Status : Completed
First Posted : June 4, 2018
Last Update Posted : April 28, 2021
Sponsor:
Collaborator:
University of Malawi College of Medicine
Information provided by (Responsible Party):
London School of Hygiene and Tropical Medicine

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.

Condition or disease Intervention/treatment Phase
Tuberculosis Respiratory Tract Infections Pneumonia Drug: Azithromycin Drug: Amoxicillin Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1583 participants
Allocation: Randomized
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.
Primary Purpose: Diagnostic
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


Arm Intervention/treatment
Experimental: Azithromycin
Azithromycin 500mg, oral, once daily for 3 days commencing on randomization day.
Drug: Azithromycin
Azithromycin tablet taken orally

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



Primary Outcome Measures :
  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). [ 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.


  2. 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

    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.



Secondary Outcome Measures :
  1. 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.


  2. 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%.


  3. 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:

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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

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


Locations
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Malawi
University of Malawi College of Medicine
Blantyre, Southern, Malawi, 00265
Sponsors and Collaborators
London School of Hygiene and Tropical Medicine
University of Malawi College of Medicine
Investigators
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Principal Investigator: Titus H Divala, MBBS MPH MS London School of Hygiene and Tropical Medicine
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: London School of Hygiene and Tropical Medicine
ClinicalTrials.gov Identifier: NCT03545373    
Other Study ID Numbers: 15232
First Posted: June 4, 2018    Key Record Dates
Last Update Posted: April 28, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: After publishing study main papers.
Access Criteria: Through the London School of Hygiene & Tropical Medicine data repository.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by London School of Hygiene and Tropical Medicine:
antimicrobial resistance
TB
Cough
antibiotics
anti-infective agents
Additional relevant MeSH terms:
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Tuberculosis
Respiratory Tract Infections
Infections
Respiratory Tract Diseases
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Bacterial Infections and Mycoses
Amoxicillin
Azithromycin
Anti-Bacterial Agents
Anti-Infective Agents