Clinical trial NCT04349826: The Azithromycin and Cefixime Treatment of Typhoid in South Asia Trial (ACT-South Asia Trial)
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Typhoid Fever
Keywords: Uncomplicated Typhoid Fever
Azithromycin
Cefixime
treatment failure
Lead sponsor: Oxford University Clinical Research Unit, Vietnam
Sponsor class: OTHER
Collaborators: name: University of Oxford
name: Medical Research Council
name: Department for International Development, United Kingdom
name: Wellcome Trust
First posted: 2020-04-16
Enrollment: 1500
Sex: ALL
Minimum age (years): 2
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Treatment Failure
timeFrame: Within 28 days of treatment initiation
Secondary outcomes:
measure: Fever clearance time (FCT) in patients in each treatment arm
timeFrame: at least 2 days
measure: Time from onset of treatment to treatment failure
timeFrame: Within 28 days of treatment initiation
measure: Time from symptom onset to treatment failure
timeFrame: Within 28 days of treatment initiation
measure: Adverse event
timeFrame: Within 90 days
measure: faecal carriage of S.Typhi or S.Paratyphi
timeFrame: One and three month follow-up
measure: cost effectiveness of treatment
timeFrame: Initiation of treatment and one month follow-up visit
Other outcomes:
Locations:
city: Lalitpur
country: Nepal
facility: Patan Hospital
state: Bagmati
Study officials:
affiliation: University of Oxford
name: Buddha Basnyat, MBBS,Msc,MD
role: PRINCIPAL_INVESTIGATOR
References:
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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.
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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-resistant typhoid fever. Antimicrob Agents Chemother. 2007 Mar;51(3):819-25. doi: 10.1128/AAC.00447-06. Epub 2006 Dec 4.
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 Chemother. 1999 Jun;43(6):1441-4. doi: 10.1128/AAC.43.6.1441.
citation: 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.