Nepal Undifferentiated Febrile Illness Trial

Undifferentiated Febrile Illness Clinical Trial

— NUFIT  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02773407
• Other study ID #: 18NP
• Status: Completed
• Phase: Phase 3
• Start date: May 23, 2016
• Est. completion date: August 4, 2019

Study information

• Verified date: December 2023
• Source: Oxford University Clinical Research Unit, Vietnam
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 330
• Est. completion date: August 4, 2019
• Est. primary completion date: August 4, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Fever
• Hyperthermia
• Undifferentiated Febrile Illness

Intervention

Drug:
• Azithromycin

• Co-trimoxazole

Locations

Country	Name	City	State
Nepal	Nepal Civil Service Hospital	Kathmandu
Nepal	Patan Hospital	Kathmandu

Sponsors (3)

Lead Sponsor	Collaborator
Oxford University Clinical Research Unit, Vietnam	University of Oxford, Wellcome Trust

Country where clinical trial is conducted

Nepal, 

References & Publications (11)

Arjyal A , Basnyat B, Nhan HT, Koirala S, Giri A, Joshi N, et al. A randomised controlled trial of gatifloxacin versus ceftriaxone for the treatment of uncomplicated enteric fever in Nepal. Submitted. 2015;3099(15):1-11

Arjyal A, Basnyat B, Koirala S, Karkey A, Dongol S, Agrawaal KK, Shakya N, Shrestha K, Sharma M, Lama S, Shrestha K, Khatri NS, Shrestha U, Campbell JI, Baker S, Farrar J, Wolbers M, Dolecek C. Gatifloxacin versus chloramphenicol for uncomplicated enteric fever: an open-label, randomised, controlled trial. Lancet Infect Dis. 2011 Jun;11(6):445-54. doi: 10.1016/S1473-3099(11)70089-5. Epub 2011 Apr 29. — View Citation

Chand HJ, Rijal KR, Neupane B, Sharma VK, Jha B. Re-emergence of susceptibility to conventional first line drugs in Salmonella isolates from enteric fever patients in Nepal. J Infect Dev Ctries. 2014 Nov 13;8(11):1483-7. doi: 10.3855/jidc.4228. — 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

Crump JA, Kirk MD. Estimating the Burden of Febrile Illnesses. PLoS Negl Trop Dis. 2015 Dec 3;9(12):e0004040. doi: 10.1371/journal.pntd.0004040. eCollection 2015 Dec. No abstract available. — 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 VV, Nguyen VS, Nguyen TC, Tran TH, Farrar J. A multi-center randomised controlled trial of gatifloxacin versus azithromycin for the treatment of uncomplicated typhoid fever in children and adults in Vietnam. PLoS One. 2008 May 21;3(5):e2188. doi: 10.1371/journal.pone.0002188. — View Citation

Koirala S, Basnyat B, Arjyal A, Shilpakar O, Shrestha K, Shrestha R, Shrestha UM, Agrawal K, Koirala KD, Thapa SD, Karkey A, Dongol S, Giri A, Shakya M, Pathak KR, Campbell J, Baker S, Farrar J, Wolbers M, Dolecek C. Gatifloxacin versus ofloxacin for the treatment of uncomplicated enteric fever in Nepal: an open-label, randomized, controlled trial. PLoS Negl Trop Dis. 2013 Oct 31;7(10):e2523. doi: 10.1371/journal.pntd.0002523. eCollection 2013. — View Citation

Pandit A, Arjyal A, Day JN, Paudyal B, Dangol S, Zimmerman MD, Yadav B, Stepniewska K, Campbell JI, Dolecek C, Farrar JJ, Basnyat B. An open randomized comparison of gatifloxacin versus cefixime for the treatment of uncomplicated enteric fever. PLoS One. 2007 Jun 27;2(6):e542. doi: 10.1371/journal.pone.0000542. — 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-resistant typhoid fever. Antimicrob Agents Chemother. 2007 Mar;51(3):819-25. doi: 10.1128/AAC.00447-06. Epub 2006 Dec 4. — View Citation

Thompson CN, Blacksell SD, Paris DH, Arjyal A, Karkey A, Dongol S, Giri A, Dolecek C, Day N, Baker S, Thwaites G, Farrar J, Basnyat B. Undifferentiated febrile illness in Kathmandu, Nepal. Am J Trop Med Hyg. 2015 Apr;92(4):875-878. doi: 10.4269/ajtmh.14-0709. Epub 2015 Feb 9. — View Citation

Zimmerman MD, Murdoch DR, Rozmajzl PJ, Basnyat B, Woods CW, Richards AL, Belbase RH, Hammer DA, Anderson TP, Reller LB. Murine typhus and febrile illness, Nepal. Emerg Infect Dis. 2008 Oct;14(10):1656-9. doi: 10.3201/eid1410.080236. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Fever failure	defined by fever clearance time (FCT) >7 days post treatment initiation;	over 7 days post treatment initiation
Secondary	Need rescue treatment	Requirement for rescue treatment as judged by the Research Medical Officer (RMO) and Attending Physician (AP)	within 63 days
Secondary	Microbiological failure	Blood culture positivity for S. Typhi or an S. Paratyphi	on day 7 of treatment
Secondary	Relapse	Culture-confirmed or syndromic enteric fever relapse	within 28 days of initiation of treatment
Secondary	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
Secondary	Time-to-treatment failure	the time from the first dose of treatment until the date of the earliest failure event	within 63 days
Secondary	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