The Azithromycin and Cefixime Treatment of Typhoid in South Asia Trial (ACT-South Asia Trial) (ACT-South Asia)

December 5, 2023 updated by: Oxford University Clinical Research Unit, Vietnam

Azithromycin and Cefixime Combination Versus Azithromycin Alone for the Out-patient Treatment of Clinically Suspected or Confirmed Uncomplicated Typhoid Fever in South Asia; a Randomised Controlled Trial

Typhoid and paratyphoid (enteric) fever affects more than 11 million children and adults globally each year including 7 million in South Asia. Up to 1% of patients who get typhoid may die of the disease and, in those that survive, a prolonged period of ill health and catastrophic financial cost to the family may follow. In the last 20 years, treatment of typhoid fever with a 7-day course of a single oral antimicrobial, such as ciprofloxacin, cefixime or azithromycin, given in an out-patient setting has led to patient recovery in 4 to 6 days without the need for expensive hospitalization. Increasing antimicrobial resistance in Asia and sub-Saharan Africa, threatens the effectiveness of these treatments and increases the risk of prolonged illness and severe disease. The recent emergence of a particularly resistant typhoid strain in Pakistan, and subsequent international spread, adds urgency to this problem and Salmonella is now listed as a high (Priority 2) pathogen by world health organisation.

Treatment with combinations of antimicrobials may be more effective for treating typhoid fever and mitigate the problems of resistance. This suggestion is based on expert opinion but not backed up by good quality evidence. The ACT-South Asia study aims to compare a combination of azithromycin and cefixime with azithromycin alone in the outpatient treatment of clinically suspected and confirmed uncomplicated typhoid fever. The total recruitment will be 1500 patients across sites in Bangladesh, India, Nepal and Pakistan. A placebo (sugar pill) will be used instead of cefixime in the single drug arm so that neither the patient nor the study team know which patient is receiving which treatment.Investigators will assess whether treatment outcomes are better with the combination after one week of treatment and at one and three month follow-up. Both antimicrobials are widely used and have excellent safety profiles. If the combination treatment is better than the single antibiotic treatment, this will be an important result for patients across South Asia and other typhoid endemic areas. This study will additionally investigate the financial implications for families and health system.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

1500

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Buddha Basnyat, MBBS,Msc,MD
  • Phone Number: +977-9851034187
  • Email: bbasnyat@oucru.org

Study Contact Backup

  • Name: Samita Rijal, Master's in Pharmacy
  • Phone Number: +977-9840509767
  • Email: srijal@oucru.org

Study Locations

  • Nepal
    • Bagmati
      • Lalitpur, Bagmati, Nepal
        • Recruiting
        • Patan Hospital
        • Contact:
          • Buddha Basnyat

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

2 years to 65 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • A history of fever at presentation for ≥ 72 hours and a documented fever (≥37.5oC (axillary) or ≥38oC (oral))
  • Age ≥ 2 years (and ≥ 10kg) to 65 years
  • No clear focus of infection on initial clinical evaluation
  • Malaria rapid Diagnostic test( RDT) negative; dengue nonstructural protein(NS) 1 RDT negative; scrub typhus RDT negative; c-reactive protein(CRP) rapid test ≥10 mg/L
  • Able to take oral treatment
  • Able to attend for follow-up and can be contacted by telephone
  • Written fully informed consent to participate in the study including assent for children in addition to parental/legal guardian consent.

Exclusion Criteria:

  • History of fever for >14 days
  • Pregnant or positive pregnancy test or breast-feeding
  • Presence of clinical symptoms or signs indicating a focal infection such as pneumonia; urinary infection, meningitis, eschar
  • Obtundation, haemodynamic shock, visible jaundice, gastrointestinal bleeding or any signs of severe disease that may require immediate hospitalisation
  • Being treated for TB or HIV or severe acute malnutrition
  • Patients with cardiac disease
  • Patient requiring intravenous antibiotics for any reason
  • Previous history of hypersensitivity to any of the treatment options
  • Either of the trial drugs are contraindicated for any reason (e.g. drug interactions)
  • Has received azithromycin or cefixime in the last five days
  • Receiving another antimicrobial and responding clinically to the treatment as judged by the attending clinician.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Azithromycin+Cefixime
Azithromycin 20mg/kg/day oral dose once daily (maximum 1gm/day) AND Cefixime 20-30mg/kg/day oral dose in two divided doses (maximum 400mg bd) for 7 days.
Drug: Azithromycin
Azithromycin 20 mg/kg/day for 7 days
Drug: Cefixime
cefixime 20-30 mg/kg/day for 7 days
Placebo Comparator: Azithromycin+placebo
Azithromycin 20mg/kg/day oral dose once daily (Max 1gm/day) for 7 days AND Cefixime-matched placebo for 7 days.
Drug: Azithromycin
Azithromycin 20 mg/kg/day for 7 days
Drug: Placebo
cefixime-matched placebo for 7 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Treatment Failure
Time Frame: Within 28 days of treatment initiation
A composite outcome of treatment failure by the 28th day after the initiation of treatment will be defined by either of the following events: 1.Clinical failure: persistence of fever on day 7 (168 h) post treatment initiation OR The need for rescue treatment as judged by the Trial Clinician OR The development of any complication (e.g., clinically significant bleeding, fall in the Glasgow Coma Scale score, perforation of the gastrointestinal tract) OR Syndromic enteric fever relapse within 28 days of initiation of treatment. 2.Microbiological failure: a positive blood-culture for S. Typhi or S. Paratyphi on day 7 of treatment regardless of the presence of fever (microbiological failure) OR blood culture-confirmed typhoid fever relapse within 28 days of initiation of treatment.
Within 28 days of treatment initiation

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Fever clearance time (FCT) in patients in each treatment arm
Time Frame: at least 2 days
The FCT will be the time from the first dose of a study drug until a temperature of < 37.5°C (axillary); < 38.0°C (oral) has been achieved
at least 2 days
Time from onset of treatment to treatment failure
Time Frame: Within 28 days of treatment initiation
The time to treatment failure will be the time from the first dose of a study drug until an event occurs defined as a treatment failure
Within 28 days of treatment initiation
Time from symptom onset to treatment failure
Time Frame: Within 28 days of treatment initiation
The time to treatment failure will be the time from the day of the first symptom until an event occurs defined as a treatment failure
Within 28 days of treatment initiation
Adverse event
Time Frame: Within 90 days
Adverse events will be graded (grade 3/4 adverse events, serious adverse events, adverse events of any grade leading to modification of study drug dose or interruption/early discontinuation);
Within 90 days
faecal carriage of S.Typhi or S.Paratyphi
Time Frame: One and three month follow-up
Positive culture of faeces sample for S.Typhi or S.Paratyphi
One and three month follow-up
cost effectiveness of treatment
Time Frame: Initiation of treatment and one month follow-up visit
The incremental cost-effectiveness ratio (ICER) will comprise of the total costs per case, real outpatient and in-patient costs, total direct and indirect costs for the family and healthcare system and health outcomes converted to Disability Adjusted Life Years (DALYs). The cost per DALY averted will be compared against multipliers of the gross domestic product/capita in each of the four countries to establish the cost-effectiveness of the combination regimen.
Initiation of treatment and one month follow-up visit

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Oxford University Clinical Research Unit, Vietnam

Collaborators

Medical Research Council
University of Oxford
Wellcome Trust
Department for International Development, United Kingdom

Investigators

  • Principal Investigator: Buddha Basnyat, MBBS,Msc,MD, University of Oxford

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 23, 2021

Primary Completion (Estimated)

July 30, 2024

Study Completion (Estimated)

December 15, 2024

Study Registration Dates

First Submitted

April 6, 2020

First Submitted That Met QC Criteria

April 14, 2020

First Posted (Actual)

April 16, 2020

Study Record Updates

Last Update Posted (Estimated)

December 6, 2023

Last Update Submitted That Met QC Criteria

December 5, 2023

Last Verified

December 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 25NP

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Anonymised individual participant data will be made available to researcher and public as supporting material via open access journal and /or upon request by qualified research group.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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