Enterics for Global Health (EFGH)

Diarrhea Clinical Trial

— EFGH  

Official title:

The Incidence and Burden of Shigella Diarrhea in Children Aged 6-35 Months: the Enterics for Global Health (EFGH) - Shigella Burden Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06047821
• Other study ID #: INV-01665
• Status: Recruiting
• Start date: August 25, 2022
• Est. completion date: May 31, 2025

Study information

• Verified date: November 2023
• Source: University of Washington
• Contact: Patricia B Pavlinac, PhD
• Phone: 206-616-8326
• Email: ppav[@]uw.edu
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Diarrhea remains a leading cause of death among young children, with the majority of diarrhea deaths occurring in low- and middle-income countries. Childhood diarrhea caused by a type of bacteria called "Shigella" is responsible for an estimated 60,000 deaths each year and may cause particularly severe illness among children. Currently, there are several promising vaccines to prevent Shigella diarrhea in development, but key information is still needed to inform future vaccine studies. The purpose of this study, titled Enterics for Global Health (or the "EFGH"), is to determine the number and rate of new cases of Shigella diarrhea among children 6 to 35 months of age presenting to health facilities with diarrhea or dysentery. Over a two-year period, the EFGH study will enroll 1,400 children from each of the seven countries: Peru, Pakistan, Bangladesh, Mali, Malawi, Kenya, and The Gambia (9,800 children total).

Description:

In low- and middle-income countries, nearly one third of children experience at least one episode of Shigella-attributable diarrhea during their first 2 years of life. In addition to it being a leading cause of diarrhea, this enteric bacterium is also associated with linear growth faltering, a precursor to stunting. Stunting is a marker of vulnerability to childhood infection, decreased vaccine efficacy and lifelong morbidity. Currently, several promising Shigella vaccines are in development. Eventual Phase 2b/3 Shigella vaccine trials will require a consortium of potential vaccine trial sites in settings with a high incidence of Shigella-attributed medically-attended diarrhea, high participant retention, and the laboratory capacity to confirm Shigella infection. The Enterics for Global Health (EFGH) Shigella burden study will employ cross-sectional and longitudinal study designs to establish updated incidence rates and document consequences of Shigella diarrhea within 7 country sites in Africa, Asia, and Latin America. Over a two-year period, the EFGH study will enroll 9,800 children (1,400 per country site) between 6-35 months with medically-attended diarrhea. Through this multi-country surveillance network, selected EFGH sites will be ready to quickly implement rigorous and efficient vaccine trials and provide critical data to policy makers about the relative importance of this vaccine-preventable disease, accelerating the time to vaccine availability and uptake among children in high Shigella burden settings.

Primary Aims

1. Determine the incidence of Shigella-attributed medically-attended diarrhea in children 6 to 35 months of age in each of the EFGH country sites.

Secondary Aims

1. Determine the incidence of Shigella medically-attended diarrhea by serotype, severity definition, laboratory method (culture vs. qPCR), age, and by season.

2. Describe the prevalence of resistance to commonly used antibiotics in Shigella isolates in each EFGH country site.

3. Determine the risk of death, hospitalization, persistent diarrhea, diarrhea recurrence, and linear growth faltering in the 3 months following an episode of Shigella medically-attended diarrhea.

4. Compare various severity definitions in their ability to distinguish Shigella from non-Shigella attributable diarrhea and ability to predict risk of death or hospitalization in the subsequent 3 months.

5. Quantify the cost incurred by families and health care systems due to Shigella morbidity and mortality.

6. Identify optimal laboratory methods for Shigella culture by:

1. comparing the isolation rate of Shigella between two transport media for rectal swabs (Cary-Blair and modified Buffered Glycerol Saline [BGS])

2. comparing the isolation rate of Shigella between two fecal sample types (rectal swabs and whole stool) among the subset of children who produced whole stool in The Gambia and Bangladesh country sites.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 9800
• Est. completion date: May 31, 2025
• Est. primary completion date: December 25, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months to 35 Months

Eligibility

Inclusion Criteria:

1. Child is 6-35 months of age

2. Primary caregiver and child plan to remain at their current residence for at least the next 4 months

3. Primary caregiver is able to provide informed consent (legal age or emancipated minor) and provides consent within a common language for which translations are available

4. Child presents to health facility with diarrhea (=3 abnormally loose or watery stools in the previous 24 hours) with or without the presence of blood

5. Child resides within the pre-defined study area

6. Fewer than 4 hours have passed since the child presented to a health facility

7. Diarrhea episode is:

• Acute (onset within 7 days of study enrollment) and

• Represents a new episode (onset after at least 2 diarrhea-free days)

8. Caregiver is willing to have child participate in follow-up visits at week 4 and month 3

9. Willingness to have samples collected from the child (rectal swabs at enrollment)

10. Site enrollment cap has not been met

11. Child is not being referred to a non-EFGH facility at the time of screening

Exclusion Criteria:

• Child is < 6-35 months of age

• Child is > 6-35 months of age

• Primary caregiver and child do not plan to remain at their current residence for at least the next 4 months

• Primary caregiver is not able to provide informed consent (legal age or emancipated minor)

• Primary caregiver does not provide consent within a common language for which translations are available

• Child does not present to health facility with diarrhea (=3 abnormally loose or watery stools in the previous 24 hours) with or without the presence of blood

• Child does not reside within the pre-defined study area

• 4 or more hours have passed since the child presented to a health facility

• Diarrhea episode is not Acute (onset within 7 days of study enrollment)

• Diarrhea episode does not represent a new episode (onset after at least 2 diarrhea-free days)

• Caregiver is unwilling to have child participate in follow-up visits at week 4 and month 3

• Unwillingness to have samples collected from the child (rectal swabs at enrollment)

• Site enrollment cap has been met

• Child is being referred to a non-EFGH facility at the time of screening

Related Conditions & MeSH terms

• Child
• Diarrhea
• Dysentery, Bacillary
• Shigella

Locations

Country	Name	City	State
Bangladesh	Dhaka Medical College Hospital	Dhaka
Bangladesh	EFGH Field Clinic	Dhaka
Bangladesh	icddr,b Dhaka Hospital	Dhaka
Bangladesh	Mugda Medical College Hospital	Dhaka
Bangladesh	Sir Salimullah Medical College Hospital	Dhaka
Gambia	Basse Hospital	Basse Santa Su	Upper River Region
Gambia	Gambisara Health Centre (HC)	Basse Santa Su	Upper River Region
Kenya	Abidha Health Center	Siaya
Kenya	Akala Health Center	Siaya
Kenya	Bar Agulu Health Center	Siaya
Kenya	Dienya Health Centre	Siaya
Kenya	Lwak Mission Hospital	Siaya
Kenya	Ongielo Health Centre	Siaya
Kenya	Siaya County Referral Hospital	Siaya
Kenya	Ting Wangi Health Center	Siaya
Kenya	Wagai Health Center	Siaya
Malawi	Ndirande Health Centre	Blantyre
Mali	Asacodjeneka Cscom	Bamako
Mali	Asacodjip Cscom	Bamako
Mali	Banconi CSCOM (ASACOBA)	Bamako
Mali	CSREF Commune 1	Bamako
Pakistan	Abbasi Shaheed Hospital	Karachi
Pakistan	Ali Akbar Shah Center	Karachi
Pakistan	Bhains colony AKU site	Karachi
Pakistan	Khidmat e Alam Medical Centre	Karachi
Pakistan	Sindh Government Hospital, Ibrahim Hyderi	Karachi
Pakistan	Sindh Government Hospital, Korangi	Karachi
Peru	America Health Post	Iquitos	Maynas
Peru	Hospital de Apoloyo	Iquitos	Maynas
Peru	Modelo Health Post	Iquitos	Maynas
Peru	Progreso Health Post	Iquitos	Maynas
Peru	San Juan Health Post	Iquitos	Maynas
Peru	Santo Tomas Health Post	Iquitos	Maynas

Sponsors (11)

Lead Sponsor	Collaborator
University of Washington	Aga Khan University, Asociacion Benefica Prisma, Bill and Melinda Gates Foundation, Center for Vaccine Development - Mali, International Centre for Diarrhoeal Disease Research, Bangladesh, Kenya Medical Research Institute, Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Medical Research Council Unit, The Gambia, University of Maryland, Baltimore, University of Virginia

Countries where clinical trial is conducted

Bangladesh,  Gambia,  Kenya,  Malawi,  Mali,  Pakistan,  Peru, 

References & Publications (6)

Kasumba IN, Badji H, Powell H, Hossain MJ, Omore R, Sow SO, Verani JR, Platts-Mills JA, Widdowson MA, Zaman SMA, Jones J, Sen S, Permala-Booth J, Nasrin S, Roose A, Nasrin D, Ochieng JB, Juma J, Doh S, Jones JCM, Antonio M, Awuor AO, Sugerman CE, Watson N, Focht C, Liu J, Houpt E, Kotloff KL, Tennant SM. Shigella in Africa: New Insights From the Vaccine Impact on Diarrhea in Africa (VIDA) Study. Clin Infect Dis. 2023 Apr 19;76(76 Suppl1):S66-S76. doi: 10.1093/cid/ciac969. — View Citation

Kotloff KL, Nataro JP, Blackwelder WC, Nasrin D, Farag TH, Panchalingam S, Wu Y, Sow SO, Sur D, Breiman RF, Faruque AS, Zaidi AK, Saha D, Alonso PL, Tamboura B, Sanogo D, Onwuchekwa U, Manna B, Ramamurthy T, Kanungo S, Ochieng JB, Omore R, Oundo JO, Hossain A, Das SK, Ahmed S, Qureshi S, Quadri F, Adegbola RA, Antonio M, Hossain MJ, Akinsola A, Mandomando I, Nhampossa T, Acacio S, Biswas K, O'Reilly CE, Mintz ED, Berkeley LY, Muhsen K, Sommerfelt H, Robins-Browne RM, Levine MM. Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study. Lancet. 2013 Jul 20;382(9888):209-22. doi: 10.1016/S0140-6736(13)60844-2. Epub 2013 May 14. — View Citation

Liu J, Platts-Mills JA, Juma J, Kabir F, Nkeze J, Okoi C, Operario DJ, Uddin J, Ahmed S, Alonso PL, Antonio M, Becker SM, Blackwelder WC, Breiman RF, Faruque AS, Fields B, Gratz J, Haque R, Hossain A, Hossain MJ, Jarju S, Qamar F, Iqbal NT, Kwambana B, Mandomando I, McMurry TL, Ochieng C, Ochieng JB, Ochieng M, Onyango C, Panchalingam S, Kalam A, Aziz F, Qureshi S, Ramamurthy T, Roberts JH, Saha D, Sow SO, Stroup SE, Sur D, Tamboura B, Taniuchi M, Tennant SM, Toema D, Wu Y, Zaidi A, Nataro JP, Kotloff KL, Levine MM, Houpt ER. Use of quantitative molecular diagnostic methods to identify causes of diarrhoea in children: a reanalysis of the GEMS case-control study. Lancet. 2016 Sep 24;388(10051):1291-301. doi: 10.1016/S0140-6736(16)31529-X. — View Citation

Pavlinac PB, Rogawski McQuade ET, Platts-Mills JA, Kotloff KL, Deal C, Giersing BK, Isbrucker RA, Kang G, Ma LF, MacLennan CA, Patriarca P, Steele D, Vannice KS. Pivotal Shigella Vaccine Efficacy Trials-Study Design Considerations from a Shigella Vaccine Trial Design Working Group. Vaccines (Basel). 2022 Mar 22;10(4):489. doi: 10.3390/vaccines10040489. — View Citation

Rogawski McQuade ET, Shaheen F, Kabir F, Rizvi A, Platts-Mills JA, Aziz F, Kalam A, Qureshi S, Elwood S, Liu J, Lima AAM, Kang G, Bessong P, Samie A, Haque R, Mduma ER, Kosek MN, Shrestha S, Leite JP, Bodhidatta L, Page N, Kiwelu I, Shakoor S, Turab A, Soofi SB, Ahmed T, Houpt ER, Bhutta Z, Iqbal NT. Epidemiology of Shigella infections and diarrhea in the first two years of life using culture-independent diagnostics in 8 low-resource settings. PLoS Negl Trop Dis. 2020 Aug 17;14(8):e0008536. doi: 10.1371/journal.pntd.0008536. eCollection 2020 Aug. — View Citation

von Seidlein L, Kim DR, Ali M, Lee H, Wang X, Thiem VD, Canh DG, Chaicumpa W, Agtini MD, Hossain A, Bhutta ZA, Mason C, Sethabutr O, Talukder K, Nair GB, Deen JL, Kotloff K, Clemens J. A multicentre study of Shigella diarrhoea in six Asian countries: disease burden, clinical manifestations, and microbiology. PLoS Med. 2006 Sep;3(9):e353. doi: 10.1371/journal.pmed.0030353. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Shigella incidence	The primary outcome measure is Shigella incidence, defined as incident diarrhea among children enrolled at health clinics attributable to Shigella by microbiological methods (culture or qPCR) divided by the estimated population living in the catchment area. Incidence will be reported as crude incidence as well as adjusted for healthcare seeking and the percentage of children who were enrolled.	At enrollment in the study (cross-sectional)
Secondary	Antimicrobial susceptibility	Antimicrobial susceptibility will be computed separately for Ampicillin, Azithromycin, Ceftriaxone, Ciprofloxacin, Nalidixic Acid, Pivmecillinam, and Trimethoprim-Sulfamethoxazole and defined as intermediate or resistant according to the most recent Clinical and Laboratory Standards Institute (CLSI) interpretive standards at the time of data analysis.	At enrollment in the study (cross-sectional)
Secondary	Cost per episode treated	Cost per episode treated will be calculated using the direct and indirect financial costs and total economic costs of illness per outpatient and inpatient episode of Shigella-associated diarrhea from the household and, separately, payer perspectives.	3 months
Secondary	Death	Death: all cause mortality during follow-up among enrolled children.	3 months
Secondary	Hospitalization	Hospitalization will be defined as an overnight stay (child was on the ward from at least 12am to 6am) that occurs during follow-up among enrolled children	3 months
Secondary	Persistent diarrhea (index episode)	Persistent diarrhea will be defined as 14 or more days of diarrhea (starting from the date at which the diarrhea first started (as opposed to date at presentation to an EFGH facility) and concluding at the last day of diarrhea prior to the two consecutive diarrhea-free days concluding the episode.	3 months
Secondary	Diarrhea/dysentery recurrence	Diarrhea/dysentery recurrence will be defined as new diarrhea/dysentery episodes (>48 hours after a diarrhea-free period).	3 months
Secondary	Change in linear growth	Change in mean length/height-for-age z-score (?LAZ/?HAZ) from enrollment to 3 months. The 2006 World Health Organization (WHO) reference population will be used to calculate HAZ from the average of two repeated length/height (cm) measures per child per time point	3 months