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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04349826
Recruitment Status : Recruiting
First Posted : April 16, 2020
Last Update Posted : October 6, 2022
Sponsor:
Collaborators:
University of Oxford
Medical Research Council
Department for International Development, United Kingdom
Wellcome Trust
Information provided by (Responsible Party):
Oxford University Clinical Research Unit, Vietnam

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.


Condition or disease Intervention/treatment Phase
Typhoid Fever Drug: Azithromycin Drug: Cefixime Drug: Placebo Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1500 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double Blind
Primary Purpose: Treatment
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
Actual Study Start Date : May 23, 2021
Estimated Primary Completion Date : September 1, 2023
Estimated Study Completion Date : April 15, 2024


Arm Intervention/treatment
Active Comparator: Azithromycin+Cefixime
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
Azithromycin 20 mg/kg/day for 7 days

Drug: Cefixime
cefixime 20-30 mg/kg/day for 7 days

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

Drug: Placebo
cefixime-matched placebo for 7 days




Primary Outcome Measures :
  1. Treatment Failure [ Time Frame: Within 28 days of treatment initiation ]
    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. Fever clearance time (FCT) in patients in each treatment arm [ Time Frame: at least 2 days ]
    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

  2. Time from onset of treatment to treatment failure [ Time Frame: Within 28 days of treatment initiation ]
    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. Time from symptom onset to treatment failure [ Time Frame: Within 28 days of treatment initiation ]
    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 event [ Time Frame: Within 90 days ]
    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);

  5. faecal carriage of S.Typhi or S.Paratyphi [ Time Frame: One and three month follow-up ]
    Positive culture of faeces sample for S.Typhi or S.Paratyphi

  6. cost effectiveness of treatment [ Time Frame: Initiation of treatment and one month follow-up visit ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04349826


Contacts
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Contact: Buddha Basnyat, MBBS,Msc,MD +977-9851034187 bbasnyat@oucru.org
Contact: Samita Rijal, Master's in Pharmacy +977-9840509767 srijal@oucru.org

Locations
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Nepal
Patan Hospital Recruiting
Lalitpur, Bagmati, Nepal
Contact: Buddha Basnyat         
Sponsors and Collaborators
Oxford University Clinical Research Unit, Vietnam
University of Oxford
Medical Research Council
Department for International Development, United Kingdom
Wellcome Trust
Investigators
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Principal Investigator: Buddha Basnyat, MBBS,Msc,MD University of Oxford
Publications of Results:
Other Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Oxford University Clinical Research Unit, Vietnam
ClinicalTrials.gov Identifier: NCT04349826    
Other Study ID Numbers: 25NP
First Posted: April 16, 2020    Key Record Dates
Last Update Posted: October 6, 2022
Last Verified: October 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: 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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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Oxford University Clinical Research Unit, Vietnam:
Uncomplicated Typhoid Fever
Azithromycin
Cefixime
treatment failure
Additional relevant MeSH terms:
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Typhoid Fever
Fever
Body Temperature Changes
Salmonella Infections
Enterobacteriaceae Infections
Gram-Negative Bacterial Infections
Bacterial Infections
Bacterial Infections and Mycoses
Infections
Azithromycin
Cefixime
Anti-Bacterial Agents
Anti-Infective Agents