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NCT Number: NCT04349826

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

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Key information

Conditions

Typhoid Fever Bacterial Infections Bacterial Infections and Mycoses Enterobacteriaceae Infections Gram-Negative Bacterial Infections Infections Salmonella Infections

Age range

2 year–65 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Patan Hospital

Lalitpur, Bagmati, Nepal

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Azithromycin

Drug

Azithromycin 20 mg/kg/day for 7 days

cefixime

Drug

cefixime 20-30 mg/kg/day for 7 days

Placebo

Drug

cefixime-matched placebo for 7 days

Primary outcomes

  1. 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.

Secondary outcomes

  1. 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

  2. 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

  3. 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

  4. 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);

  5. 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

  6. 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.

Sponsors and collaborators

Lead sponsor

Oxford University Clinical Research Unit, Vietnam

Other

Collaborators

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

Registry information

Official study title

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

Acronym: ACT-South Asia

Important dates

Study start
2021
Primary completion
2025
Study completion
2025
First posted
Apr 16, 2020
Registry last updated
Jan 15, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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