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

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

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

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.

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.

Azithromycin 20mg/kg/day oral dose once daily (Max 1gm/day) for 7 days AND Cefixime-matched placebo for 7 days.

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.

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

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

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

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);

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.

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.

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.

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