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

Typhoid Fever Clinical Trial

— ACT-South Asia  

Official 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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04349826
• Other study ID #: 25NP
• Status: Recruiting
• Phase: Phase 4
• Start date: May 23, 2021
• Est. completion date: December 15, 2024

Study information

• Verified date: December 2023
• Source: Oxford University Clinical Research Unit, Vietnam
• Contact: Buddha Basnyat, MBBS,Msc,MD
• Phone: +977-9851034187
• Email: bbasnyat[@]oucru.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1500
• Est. completion date: December 15, 2024
• Est. primary completion date: July 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Fever
• Typhoid Fever

Intervention

Drug:
• Azithromycin
Azithromycin 20 mg/kg/day for 7 days
• Cefixime
cefixime 20-30 mg/kg/day for 7 days
• Placebo
cefixime-matched placebo for 7 days

Locations

Country	Name	City	State
Nepal	Patan Hospital	Lalitpur	Bagmati

Sponsors (5)

Lead Sponsor	Collaborator
Oxford University Clinical Research Unit, Vietnam	Department for International Development, United Kingdom, Medical Research Council, University of Oxford, Wellcome Trust

Country where clinical trial is conducted

Nepal, 

References & Publications (6)

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. — View Citation

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. — View Citation

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 — View Citation

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 Ch — View Citation

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-r — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Fever clearance time (FCT) in patients in each treatment arm	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
Secondary	Time from onset of treatment to treatment failure	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
Secondary	Time from symptom onset to 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	Within 28 days of treatment initiation
Secondary	Adverse event	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
Secondary	faecal carriage of S.Typhi or S.Paratyphi	Positive culture of faeces sample for S.Typhi or S.Paratyphi	One and three month follow-up
Secondary	cost effectiveness of treatment	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