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

NCT04349826 | Completed Phase 4 DMC

• 1 other identifier: 25NP
• Study Type: interventional
• Target: 2,150
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Typhoid Fever

Keywords

Uncomplicated Typhoid Fever; Azithromycin; Cefixime; treatment failure

Outcome Measures

Primary Outcomes (1)

• Treatment Failure

  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 Outcomes (6)

• Fever clearance time (FCT) in patients in each treatment arm

  at least 2 days

• Time from onset of treatment to treatment failure

  Within 28 days of treatment initiation

• Time from symptom onset to treatment failure

  Within 28 days of treatment initiation

• Adverse event

  Within 90 days

• faecal carriage of S.Typhi or S.Paratyphi

  One and three month follow-up

Study Arms (2)

Azithromycin+Cefixime

ACTIVE COMPARATOR

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; Drug: Cefixime

Azithromycin+placebo

PLACEBO COMPARATOR

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

Drug: Azithromycin; Drug: Placebo

Interventions

Azithromycin DRUG

Azithromycin 20 mg/kg/day for 7 days

Azithromycin+Cefixime; Azithromycin+placebo

Cefixime DRUG

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

Azithromycin+Cefixime

Placebo DRUG

cefixime-matched placebo for 7 days

Azithromycin+placebo

Eligibility Criteria

• Age: 2 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Oxford University Clinical Research Unit, Vietnam: lead
• University of Oxford: collaborator
• Medical Research Council: collaborator
• Department for International Development, United Kingdom: collaborator
• Wellcome Trust: collaborator

Study Sites (1)

Patan Hospital

Lalitpur, Bagmati, Nepal

Location

Related Publications (7)

• Butler T, Sridhar CB, Daga MK, Pathak K, Pandit RB, Khakhria R, Potkar CN, Zelasky MT, Johnson RB. Treatment of typhoid fever with azithromycin versus chloramphenicol in a randomized multicentre trial in India. J Antimicrob Chemother. 1999 Aug;44(2):243-50. doi: 10.1093/jac/44.2.243.

  PMID: 10473232 BACKGROUND

• Chinh NT, Parry CM, Ly NT, Ha HD, Thong MX, Diep TS, Wain J, White NJ, Farrar JJ. A randomized controlled comparison of azithromycin and ofloxacin for treatment of multidrug-resistant or nalidixic acid-resistant enteric fever. Antimicrob Agents Chemother. 2000 Jul;44(7):1855-9. doi: 10.1128/AAC.44.7.1855-1859.2000.

  PMID: 10858343 BACKGROUND

• Trivedi NA, Shah PC. A meta-analysis comparing the safety and efficacy of azithromycin over the alternate drugs used for treatment of uncomplicated enteric fever. J Postgrad Med. 2012 Apr-Jun;58(2):112-8. doi: 10.4103/0022-3859.97172.

  PMID: 22718054 RESULT

• Dolecek C, Tran TP, Nguyen NR, Le TP, Ha V, Phung QT, Doan CD, Nguyen TB, Duong TL, Luong BH, Nguyen TB, Nguyen TA, Pham ND, Mai NL, Phan VB, Vo AH, Nguyen VM, Tran TT, Tran TC, Schultsz C, Dunstan SJ, Stepniewska K, Campbell JI, To SD, Basnyat B, Nguyen VV, Nguyen VS, Nguyen TC, Tran TH, Farrar J. A multi-center randomised controlled trial of gatifloxacin versus azithromycin for the treatment of uncomplicated typhoid fever in children and adults in Vietnam. PLoS One. 2008 May 21;3(5):e2188. doi: 10.1371/journal.pone.0002188.

  PMID: 18493312 RESULT

• Parry CM, Ho VA, Phuong le T, Bay PV, Lanh MN, Tung le T, Tham NT, Wain J, Hien TT, Farrar JJ. Randomized controlled comparison of ofloxacin, azithromycin, and an ofloxacin-azithromycin combination for treatment of multidrug-resistant and nalidixic acid-resistant typhoid fever. Antimicrob Agents Chemother. 2007 Mar;51(3):819-25. doi: 10.1128/AAC.00447-06. Epub 2006 Dec 4.

  PMID: 17145784 RESULT

• Girgis NI, Butler T, Frenck RW, Sultan Y, Brown FM, Tribble D, Khakhria R. Azithromycin versus ciprofloxacin for treatment of uncomplicated typhoid fever in a randomized trial in Egypt that included patients with multidrug resistance. Antimicrob Agents Chemother. 1999 Jun;43(6):1441-4. doi: 10.1128/AAC.43.6.1441.

  PMID: 10348767 RESULT

• Giri A, Karkey A, Dongol S, Arjyal A, Maharjan A, Veeraraghavan B, Paudyal B, Dolecek C, Gajurel D, Phuong DNT, Thanh DP, Qamar F, Kang G, Hien HV, John J, Lawson K, Wolbers M, Hossain MS, Sharifuzzaman M, Luangasanatip N, Maharjan N, Olliaro P, Rupali P, Shakya R, Shakoor S, Rijal S, Qureshi S, Baker S, Joshi S, Ahmed T, Darton T, Bao TN, Lubell Y, Kestelyn E, Thwaites G, Parry CM, Basnyat B. 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 protocol. Wellcome Open Res. 2021 Nov 12;6:207. doi: 10.12688/wellcomeopenres.16801.2. eCollection 2021.

  PMID: 35097222 DERIVED

MeSH Terms

Conditions

Typhoid Fever

Interventions

Azithromycin; Cefixime

Condition Hierarchy (Ancestors)

Salmonella Infections; Enterobacteriaceae Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals; Cefotaxime; Cephacetrile; Cephalosporins; beta-Lactams; Lactams; Amides; Thiazines; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Buddha Basnyat, MBBS,Msc,MD

  University of Oxford

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double Blind
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 6, 2020
• First Posted: April 16, 2020
• Study Start: May 23, 2021
• Primary Completion: December 31, 2025
• Study Completion: December 31, 2025
• Last Updated: January 15, 2026

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will share

Locations

NE (1)