Diarrhea Infectious, Growth & Development, Shigella
Conditions
Keywords
shigella, children, randomized clinical trial, weight for age, growth outcomes, Azithromycin, Diarrhea
Brief summary
The purpose of this study is to evaluate whether antibiotic treatment of non-dysentery Shigella associated watery diarrhea (NDSD) cases improves clinical outcomes and growth in children. Children with NDSD seeking care for diarrhea at the study hospitals in Bangladesh and Zambia will be enrolled and randomized to receive Azithromycin or placebo (a look-alike substance that contains no drug). Enrolled children will be followed for three months with household visits. The investigators will determine whether antibiotic treatment of NDSD reduces the duration of diarrhea and time to microbiological cure (shedding of Shigella in stool), and whether it improves growth in children compared with the placebo group.
Detailed description
The current World Health Organization (WHO) guidelines for the treatment of diarrhea recommend antibiotics when visible blood is present in the stool and in cases suspected of cholera. Currently, \>50% of Shigella-associated diarrhea cases are non-dysentery or watery diarrhea in nature; thus, would not be treated with antibiotics according to guidelines. Absence of dysentery does not exclude Shigella as a cause of diarrhea and may not indicate a lower risk of death. For particularly vulnerable younger or malnourished children, identification and treatment of Shigella infection might be lifesaving. Consequently, a critical question remains to be answered. Should cases of non-dysentery Shigella associated watery diarrhea (NDSD) be treated with antibiotics? The goal of this study is to determine whether antibiotic treatment of NDSD cases improves clinical outcomes and growth in children. This is a phase 2B, randomized, double-blind, placebo-controlled study. Children aged \>6-59 months with NDSD who are seeking care for diarrhea at the study hospitals in Bangladesh and Zambia will be enrolled and randomized to receive either Azithromycin or a placebo (a look-alike substance that contains no drug). All children will be rehydrated with either oral rehydration solution or intravenous fluids, depending on the degree of dehydration, and will receive zinc in accordance with standard of care. Enrolled children will be followed for three months through household visits to collect morbidity and anthropometry data. Primary Outcomes * Time to Cessation of Diarrhea (TCD) between intervention and placebo * Change of Weight-for-age z-score (∆WAZ) in the 90 days following enrolment between intervention and placebo arms. Secondary Outcomes * Change in linear growth measured as change in length-for-age z score (∆LAZ) in the 90 days following enrolment between the placebo and treatment arms * Time to microbiological cure between the intervention and placebo groups.
Interventions
DRUGAzithromycin
Azithromycin will be given as 10 mg/kg body weight once daily for 5 days
DRUGPlacebo
Placebo will be similar in appearance to the intervention but will contain inactive ingredients.
Sponsors
Johns Hopkins Bloomberg School of Public Health
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
All participating parties with the exception of the study statistician will be masked.
Eligibility
Sex/Gender
ALL
Age
6 Months to 59 Months
Healthy volunteers
No
Inclusion criteria
* Patients \>6 and ≤59 months of age seeking care in the study hospitals * Patients residing within the study catchment area * Present with watery diarrhea and positive for Shigella by RLDT * Willing to be available for sample and data collection during the follow up visits
Exclusion criteria
* Inability or unwillingness of a participant's parent/guardian to give written informed consent or comply with study protocol * Diarrhea started more than 96 hours before enrollment * Antibiotics related to shigellosis treatment (including the investigational drug azithromycin) taken in the past 5 days * More than 2 doses of antidiarrheal drugs taken in the past 24 hours * History of allergy to Azithromycin * Presence of visible blood in stool * Children with severe acute malnutrition (below -3z scores of the median WHO growth standards). * History of congenital heart diseases, known gastrointestinal abnormalities, including short bowel syndrome, chronic (inflammatory or irritable) bowel disease, inherited or acquired immune system deficiency rendering the patient immunocompromised, including chronic/long-term steroid treatment or other immunosuppressive treatment * Fever over 39°C (102°F) with other complications that require antibiotic treatment * Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to cessation of diarrhea (TCD) | From the time of the administration of Azithromycin or placebo until cessation of the diarrhea episode (approximately up to a month) | Diarrhea will be defined as 3 or more liquid or loose stool during a 24 hours period (not calendar day). Two diarrhea episodes will be separated by three diarrhea free days in between. Time to cessation of diarrhea (TCD) will be expressed in hours. |
| Change in weight for age Z score (WAZ) | From enrollment to the 90-day follow up | The change in weight for age Z scores from enrollment to the 90-day follow-up |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to microbiological cure | Enrollment to microbiological cure (up to 3 months) | The interval between the administration of the intervention or placebo and two consecutive Shigella-negative stools by culture or Rapid LAMP-based Diagnostic test (RLDT) - a validated point-of-care diagnostic test. |
| Change in length for age Z score (LAZ) | From enrollment to 90-day follow-up. | Percentage change and mean difference in LAZ from enrollment to 90-day follow-up between the two arms. |
Countries
Bangladesh, Zambia
Contacts
CONTACTSubhra Chakraborty, PhD, MPH, MSc
CONTACTMelissa Higdon, MPH
PRINCIPAL_INVESTIGATORSubhra Chakraborty, PhD, MPH, MSc
Johns Hopkins Bloomberg School of Public Health
Outcome results
None listed