Nepal Undifferentiated Febrile Illness Trial

Study Overview
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Brief Summary
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The purpose of the study is to determine whether azithromycin or cotrimoxazole is the best empirical treatment for undifferentiated febrile illness in Nepal

Detailed Description
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Fever is one of the most common presenting symptoms of patients presenting to health centers in Nepal. Many of the times, it is difficult to diagnose the cause of the fever by initial history, clinical examination and basic laboratory tests and the patents are treated as presumed enteric fever or fever without focus needing antimicrobials. In fact there are various causes of similarly presenting febrile illnesses including typhoid, paratyphoid, murine typhus, scrub typhus etc. Many of the traditionally used drugs including fluoroquinolones are now resistant against enteric fever in south asia. Oral azithromycin is now commonly used to treat undifferentiated febrile illness and remains effective against enteric fever. Many physicians now also use co-trimoxazole as it was very commonly used in the treatment of enteric fever in the past. Resistance to co-trimoxazole emerged two decades ago, but has subsequently largely disappeared and nearly all Salmonella Typhi and Paratyphi A strains from Nepal are now susceptible. Anecdotal reports claim that it seems to work very well against undifferentiated febrile illness in Nepal; it is largely stocked in government health facilities and is a popular and cheap treatment option. Both azithromycin and co-trimoxazole are available in Nepal and are extensively used in the treatment of undifferentiated febrile illness. Therefore it is important to know the better oral option to treat enteric fever and other febrile illnesses and also to have an alternative oral treatment in case resistance to azithromycin emerges. The investigators purpose to conduct a head to head, parallel group, 1:1, double blinded randomized controlled trial to compare azithromycin and co-trimoxazole for the treatment of undifferentiated febrile illness and determine the best empirical treatment for undifferentiated febrile illness in Nepal.

Official Title
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Parallel Group, Double Blinded, 1:1, Randomized Controlled Phase III Trial of Co-trimoxazole Versus Azithromycin for the Treatment of Undifferentiated Fever In Nepal

Conditions
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Undifferentiated Febrile Illness

Intervention / Treatment
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* Drug: Azithromycin
* Drug: Co-trimoxazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Fever of ≥ 38.0°C and for ≥4 days without a focus of infection ≥ 2 years and <65 years of age Able to take tablets orally Patient residing in Kathmandu Valley Able to come for follow up Can be reached by telephone/mobile phone 24 hours a day. Written informed consent to participate in the study including assent for minors in addition to parental consent. Exclusion Criteria: Fever >14 days Pregnancy Obtundation Shock Visible jaundice Presence of signs of gastrointestinal bleeding History of hypersensitivity to either of the trial drugs Patient requiring intravenous antibiotic or hospital admission for any reason. Contraindication of drug for any reason (e.g. drug interactions). Any patient fulfilling inclusion criteria but already on antimicrobials and responding clinically to the treatment

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group A<br>Azithromycin tablets 20mg/kg/day for 7 days (Maximum dose 1000mg/day) | Drug: Azithromycin<br> <br> |
| Active Comparator: Group B<br>Co-trimoxazole tablets (Trimethoprim 10 mg/kg+Sulphamethoxazole 50 mg/kg) in two divided doses everyday for 7 days (maximum 3000mg/day) | Drug: Co-trimoxazole<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fever clearance time | time from the first dose of a study drug until a temperature ≤37.5°C for at least 2 days | at least 2 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fever failure | defined by fever clearance time (FCT) >7 days post treatment initiation; | over 7 days post treatment initiation | 
| Need rescue treatment | Requirement for rescue treatment as judged by the Research Medical Officer (RMO) and Attending Physician (AP) | within 63 days | 
| Microbiological failure | Blood culture positivity for S. Typhi or an S. Paratyphi | on day 7 of treatment | 
| Relapse | Culture-confirmed or syndromic enteric fever relapse | within 28 days of initiation of treatment | 
| The development of any complication | any complication: e.g. clinically significant bleeding, fall in the Glasgow Coma Score, perforation of the gastrointestinal tract and hospital admission | within 28 days of initiation of treatment | 
| Time-to-treatment failure | the time from the first dose of treatment until the date of the earliest failure event | within 63 days | 
| Adverse events | 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 63 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Undifferentiated febrile illness, Azithromycin, Cotrimoxazole, Efficacy, Enteric fever, Fever clearance time