The azithromycin and cefixime treatment of typhoid in South Asia trial
| ISRCTN | ISRCTN18065452 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN18065452 |
| ClinicalTrials.gov number | NCT04349826 |
| Secondary identifying numbers | MR/TOO5033/1 |
- Submission date
- 02/07/2023
- Registration date
- 06/07/2023
- Last edited
- 17/12/2024
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Infections and Infestations
Plain English Summary
Background and study aims
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 a 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 its subsequent international spread, adds urgency to this problem and Salmonella is now listed as a high (Priority 2) pathogen by the World Health Organisation.
Who can participate?
Patients aged 2 years or over (and weighing at least 10 kg) to 65 years with suspected uncomplicated typhoid fever
What does the study involve?
Treatment with combinations of antimicrobials may be more effective for treating typhoid fever and mitigating the problems of resistance. This suggestion is based on expert opinion but is 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 more than 1500 (around 2150) patients with target of 400 blood culture positive cases across sites in Nepal, Bangladesh 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 knows 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-ups. 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 the health system.
What are the possible benefits and risks of participating?
All participants will receive azithromycin which is a standard treatment choice for this disease in South Asia. Half of the patients will, in addition, receive cefixime, which is also a recommended treatment for typhoid in South Asia. For the duration of the study, all participants will have access to free and accurate health assessments and diagnostics at dedicated clinics in the hospitals at each of the study sites. Participants will also have access to medical staff for general health issues for the duration of the study.
Azithromycin and cefixime are widely used antimicrobials with a favorable safety profile. Both antimicrobials have been used in previous clinical trials of typhoid fever with minimal and mild adverse effects only. Safety monitoring will be conducted as a secondary outcome of this study.
Where is the study run from?
Oxford University Clinical Research Unit (Nepal)
When is the study starting and how long is it expected to run for?
November 2019 to December 2025
Who is funding the study?
UK Research and Innovation (UKRI) Joint Global Health Trials Scheme
Who is the main contact?
Buddha Basnyat, buddhabasnyat@gmail.com
Contact information
Public, Scientific, Principal Investigator
Maharjgunj-3
GPO Box 3596
Kathmandu
26500
Nepal
 ORCID ID |
0000-0002-1125-2743 |
|---|---|
| Phone | +977 9851034187 |
| buddhabasnyat@gmail.com |
Study information
| Study design | Randomized participant-and observer-blind multi-centre phase IV study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use contact details to request a participant information sheet |
| Scientific 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 randomized controlled trial (ACT-South Asia Trial) |
| Study acronym | ACT-South Asia trial |
| Study hypothesis | 1. Primary Hypothesis: The combination of azithromycin and cefixime is superior (i.e. it leads to fewer treatment failures) to azithromycin alone for the treatment of clinically suspected or confirmed uncomplicated typhoid fever in South Asia 2. Secondary Hypothesis: The combination of azithromycin and cefixime, when compared to azithromycin alone, for the treatment of clinically suspected or confirmed uncomplicated typhoid fever in South Asia will significantly reduce the fever clearance time, the time to treatment failure, the duration of symptoms, and the occurrence and duration of faecal carriage of S. Typhi and S. Paratyphi. The combination will be more cost-effective than azithromycin alone and will not lead to more adverse events. |
| Ethics approval(s) |
1. Approved 16/07/2020, Oxford Tropical Research Ethics Committee (OxTREC) (Wellington Square, Oxford, OX1 2JD, United Kingdom; +44 (0) 1865 282106; oxtrec@admin.ox.ac.uk), ref: 28-20 2. Approved 02/03/2021, Nepal Health Research Council (NHRC) (Ramshah path, PO Box:7626, Kathmandu, 44600, Nepal; +977 1 4254220; nhrc@nhrc.gov.np), ref: 781/2020 P |
| Condition | The out-patient treatment of clinically suspected or confirmed uncomplicated typhoid fever in South Asia |
| Intervention | Potential participants attending the study site clinics with fever or a history of fever will be identified and approached for possible inclusion in this study. Trial staff will screen potential participants in a fever clinic for eligibility for the study. Those meeting the criteria for the history of illness will be asked for verbal consent to have blood samples taken to complete the eligibility assessment. Participants will be considered eligible for enrolment in the trial if they fulfil all the inclusion criteria and none of the exclusion criteria. Participants will be randomly allocated to one of two treatment arms resulting in a 1:1 final disposition. Before treatment allocation, the patient’s eligibility and informed signed consent will be confirmed and entered into the database. A computer-generated randomization list will use block randomization with stratification by site and age (children (< 16 years) and adults (≥16 years). The recruitment in most sites will take place during working hours as these are uncomplicated typhoid patients. Patients with suspected uncomplicated typhoid fever will be randomized to one of the two interventions: Arm A: Azithromycin 20mg/kg/day oral dose once daily (maximum 1gm/day) and Cefixime 20mg to 30mg/kg/day oral dose in two divided doses (maximum 400mg bd) for 7 days Arm B: Azithromycin 20mg/kg/day oral dose once daily (maximum 1gm/day) for 7 days and Cefixime-matched placebo for 7 days. 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 the health system. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Pharmacoeconomic, Fever clearence time with drugs |
| Phase | Phase IV |
| Drug / device / biological / vaccine name(s) | Azithromycin, cefixime |
| Primary outcome measure | 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 outcome measures | 1.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 for at least 48 h; 2.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.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 events will be graded(grade3/4 adverse events, serious adverse events, adverse events of any grade leading to modification of study drug dose or interruption/early discontinuation); 5.Postive culture of faeces sample for S.Typhi or S.Paratyphi 6. 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 GDP/capita, in each of the four countries to establish the cost- Effectiveness of the combination regimen. |
| Overall study start date | 01/11/2019 |
| Overall study end date | 30/12/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Mixed |
| Lower age limit | 2 Years |
| Upper age limit | 65 Years |
| Sex | Both |
| Target number of participants | 2150 |
| Participant inclusion criteria | 1. A history of fever at presentation for >48 hours and a documented fever(≥37.5oC (axillary)) 2. Aged ≥2 years (and ≥10 kg) to 65 years old 3. No clear focus of infection on initial clinical evaluation 4. Malaria RDT negative; dengue NS1 RDT negative; scrub typhus RDT negative; CRP rapid test ≥10 mg/L. Able to take oral treatment ( Exception case if any Of RDT is positive or CRP< 10, but blood/stool culture positive case). 5. Able to attend for follow-up and can be contacted by telephone 6. Written fully informed consent to participate in the study including assent for children in addition to parental/legal guardian consent |
| Participant exclusion criteria | 1. History of fever for >14 days 2. Pregnant or positive pregnancy test or breast-feeding 3. Presence of clinical symptoms or signs indicating a focal infection such as pneumonia; urinary infection, meningitis, eschar 4. Obtundation, haemodynamic shock, visible jaundice, gastrointestinal bleeding or any signs of severe disease that may require immediate hospitalization 5. Being treated for TB or HIV or severe acute malnutrition 6. Patients with cardiac disease 7. Patient requiring intravenous antibiotics for any reason 8. Previous history of hypersensitivity to any of the treatment options 9. Either of the trial drugs are contraindicated for any reason (e.g. drug interactions) 10. Has received azithromycin or cefixime in the last 5 days 11. Receiving another antimicrobial and responding clinically to the treatment as judged by the attending clinician. 12. Being on another drug (for example certain kinds of anti-depressants, or anticonvulsants) that may also cause prolonged QT interval 13. COVID-19 PCR/antigen positive |
| Recruitment start date | 09/05/2021 |
| Recruitment end date | 30/08/2025 |
Locations
Countries of recruitment
- Bangladesh
- Nepal
- Pakistan
Study participating centres
Kathmandu
26500
Nepal
kathmandu
44600
Nepal
Bhaktapur
44600
Nepal
Dharan
44600
Nepal
Kathmandu
44600
Nepal
Putalisadak
Kathmandu
44600
Nepal
Karachi
411102
Pakistan
Garden east Karachi
Karachi
411102
Pakistan
Gulberg town
Karachi
411102
Pakistan
Karachi
75510
Pakistan
Dhaka
16340
Bangladesh
Dhaka
807
Bangladesh
Dhaka
807
Bangladesh
Sponsor information
University/education
University of Oxford
Research Services
University Offices
Wellington Square
Oxford
OX1 2JD
England
United Kingdom
| Phone | +44 (0) 1865 282106 |
|---|---|
| oxtrec@admin.ox.ac.uk | |
| Website | http://www.ox.ac.uk/ |
"ROR" |
https://ror.org/052gg0110 |
Funders
Funder type
Research council
Government organisation / National government
- Alternative name(s)
- UKRI
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 30/07/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal |
| IPD sharing plan | The datasets generated during and/or analyzed during the current study are/will be available on request from Dr Buddha Basnyat at ctu-nepal@oucru.org/buddhabasnyat@gmail.com |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | 12/11/2021 | 03/07/2023 | Yes | No |
Editorial Notes
17/12/2024: The following changes were made to the trial record:
1. The overall end date was changed from 30/12/2024 to 30/12/2025.
2. The target number of participants was changed from 1500 to 2150.
3. The recruitment start date was changed from 23/05/2021 to 09/05/2021.
4. The recruitment end date was changed from 30/07/2024 to 30/08/2025.
5. The intention to publish date was changed from 30/07/2025 to 30/07/2026.
6. The plain English summary was updated to reflect these changes.
06/07/2023: Trial's existence confirmed by the Oxford Tropical Research Ethics Committee (OxTREC) (UK).
