Commercial Typhoid Tests Validation Trial

NCT ID: NCT04801602

Last Updated: 2022-05-24

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 3091 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2020-10-25
• Study Completion Date: 2021-12-31

Brief Summary

Typhoid fever (typhoid) is an enteric bacterial infection caused by Salmonella enterica serovar Typhi (Salmonella Typhi; S. Typhi). It is one of the most common bacterial causes of acute febrile illness in the developing world, with an estimated 10.9 million new cases worldwide and 116.8 thousand deaths in 2017. Like many febrile illnesses, typhoid presents with non-specific symptoms and signs, especially in its early stages. In routine healthcare settings in low- and middle-income countries (LMIC), typhoid fever is commonly suspected and treated empirically with antibiotics. This overuse of antibiotics creates a selective pressure for the development of antimicrobial resistance (AMR), that has resulted in the emergence and spread of typhoid strains that are resistant to all first-line antibiotics. Similarly, the low specificity of current rapid diagnostic tests (RDTs) can lead to an over diagnosis of typhoid fever that may result in the overuse of antibiotics and delay the proper treatment for underlying conditions. FIND in collaboration with international typhoid experts developed a target product profile outlining the ideal characteristics of point of care tests. As part of this activity it became apparent that no quality data are available that systematically compare all available commercially point of care tests against the same set of reference standards used in multiple populations (e.g. Africa vs Asia). This lack of benchmarking data significantly impedes health provider's ability to decide on the utility of commercial tests in different settings, ultimately restricting use and access. Further the lack of well characterized samples reduces the ability for targeted innovation in the typhoid space.

The current study aims to benchmark different commercial typhoid tests against a defined reference standard applied in multiple population and simultaneously develop a sample set that can be used in future evaluations of emerging technologies and/or to support innovative test development.

Detailed Description

Typhoid is an enteric disease caused by the bacterium Salmonella Typhi; it is estimated that 11 to 20 million people contract typhoid each year and 128 000 to 161 000 die from the disease; children under 5 are at higher risk of contracting the disease.

Typhoid endemic areas are located mainly in South Asia and Sub-Saharan Africa and is transmitted through contaminated water and food. The disease is treatable with a specific antibiotics regimen, however antimicrobial resistance has been reported in several countries, particularly in Pakistan.Several vaccines have been developed but their uptake has been low, partly due to limited information on the exact burden of the disease in endemic countries.

The symptoms of typhoid are similar to other undifferentiated febrile illnesses and typhoid can be mistaken with vector borne febrile illnesses such as scrub typhus.

Blood and bone marrow cultures are considered the gold standard for the diagnosis of typhoid. Those methods require specific infrastructure and skilled staff that are not always available in LMICs and are not adequate for rapid patient management. In addition, although very specific, blood culture sensitivity is impacted by misuse of antibiotics that lower the bacterial load to undetectable levels in patients' blood.

As a consequence, alternatives to blood culture have been used in LMIC. The Widal test is the most used test despite a low performance (sensitivity range: 57-34%; specificity range: 43-83%;reported in several studies. Other options in typhoid diagnosis are rapid diagnostic tests; among them, three tests (Typhidot, Tubex and Test-it™ Typhoid IgM) have been evaluated in several studies. It has been reported a variability of tests performance in different studies and according to the geographical regions. Variability in the test performance reported so far in the literature has hampered WHO to recommend any of these rapid tests in the EDL. FIND in collaboration with international typhoid experts developed a target product profile outlining the ideal characteristics of point of care tests. As part of this activity it became apparent that no quality data are available that systematically compare all available commercially point of care tests against the same set of reference standards used in multiple populations (e.g. Africa vs Asia). These lack of benchmarking data significantly impedes health providers' ability to decide on the utility of commercial tests in different settings, ultimately restricting use and access. Further the lack of well characterized samples reduces the ability for targeted innovation in the typhoid space. A second gap that was identified was the lack of a simple well-performing gold standard suggesting Latent class modelling as a solution used for other pathogens with an imperfect gold standard.

The current study aims to benchmark different commercial typhoid tests against a defined reference standard applied in multiple population and simultaneously develop a sample set that can be used in future evaluations of emerging technologies and/or to support innovative test development.

Conditions

Typhoid Fever

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Interventions

Rapid diagnostic tests

To evaluate different RDTs that are commercially available internationally for detecting antigens or antibodies to Salmonella Typhi and use blood culture as standard for comparison.

Intervention Type: DIAGNOSTIC_TEST

Eligibility Criteria

Inclusion Criteria

• - Individuals aged 8 years of age to 65 years of age
• Body weight equals to or more than 8kgs
• History of fever or axillary temperature of >37.50C for at least 3 consecutive days within the last 7 days prior to enrolment
• Clinical suspicion of enteric fever
• One of the following scenarios:

• Presents to outpatient department or Emergency Department
• Admitted to hospital within last 12 hours
• Able and willing to provide informed consent (and assent when required)

Exclusion Criteria

• Unwillingness to participate in the study

• Inability to provide the required volume of blood
• Unwillingness to provide blood
• Known non-infectious / Non typhoid Infectious causes of fever or other alternate diagnosis of fever
• Taking anticoagulant drugs
• Unconscious

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Department for International Development, United Kingdom

OTHER_GOV

Sponsor Role: collaborator

Foundation for Innovative New Diagnostics, Switzerland

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Rumina Hasan, M.D

Role: PRINCIPAL_INVESTIGATOR

AKU

Robert S Onsare, PhD

Role: PRINCIPAL_INVESTIGATOR

Kenya Medical Research Institute

Locations

KEMRI

Nairobi, , Kenya

Aga Khan University

Karachi, Sindh, Pakistan

Countries

Kenya; Pakistan

References

Sapkota J, Hasan R, Onsare R, Arafah S, Kariuki S, Shakoor S, Qamar F, Mundalo S, Njeru F, Too R, Ndegwa E, Andrews JR, Dittrich S. Comparative Analysis of Commercially Available Typhoid Point-of-Care Tests: Results of a Prospective and Hybrid Retrospective Multicenter Diagnostic Accuracy Study in Kenya and Pakistan. J Clin Microbiol. 2022 Dec 21;60(12):e0100022. doi: 10.1128/jcm.01000-22. Epub 2022 Nov 30.

Reference Type: DERIVED

PMID: 36448816 (View on PubMed)

Other Identifiers

FE006

Identifier Type: -

Identifier Source: org_study_id