Antibacterial Treatment Against Diarrhea in Oral Rehydration Solution

Randomized, Double Blind Placebo-controlled Studies to Evaluate the Effect of an Orally-fed Escherichia Coli (E. Coli) Phage in the Management of ETEC and EPEC Induced Diarrhea in Children

This study hopes to demonstrate the potentials of a new form of therapy for childhood diarrhea, a major cause of morbidity and deaths in Bangladesh and other developing countries, and thus a priority for improving child health.

Study Overview

• Status: Terminated
• Conditions: Diarrhea
• Intervention / Treatment: Other: T4 phage cocktail test; Other: Commercial T4 phage cocktail; Other: standard oral rehydration solution (ORS)

Detailed Description

This randomized double-blind, placebo controlled trial (RCT) aims to evaluate the effect of oral administered E. coli phage in children aged 4-60 months of age with proven ETEC and EPEC diarrhea. Children will be screened to exclude V. cholerae infections by dark field microscopy, rotavirus by stool ELISA, and invasive diarrhoea clinically as well as by stool microscopy, to identify children with possible ETEC and EPEC diarrhoea. Enrolled children will be randomly assigned, in equal numbers, to receive either: (i) a new T4 phage cocktail or (ii) Russian anti-E. coli phage cocktail (Microgen) at the dose recommended by the manufacturer or (iii) only oral rehydration solution (placebo) for 5 days in addition to management of dehydration and continued feeding in accordance with WHO guidelines. Duration of diarrhea, daily and cumulative stool output, volume of oral rehydration solution intake, stool frequency, time to recovery and weight gain will be the main outcome measures. As the dose of phage we intend to use in this therapeutic trial is higher than the dose administered to young children in earlier safety trial, we plan to initially conduct a safety study with these three study products in 45 children with non cholera, non rotavirus and non invasive diarrhea, to randomize equally in the three intervention groups, as for the final study mentioned above. The outcome measures in this safety part will include assessment of laboratory parameters including renal and liver function tests, haematological indices, and microbiological efficacy of phage by measuring phage and E. coli titre in daily stool samples. If the higher dose is found safe, tolerable, and not associated with any significant adverse event, we will proceed to the clinical efficacy trial.

We believe if T4 coli phage is assessed to be effective in the overall diarrhea management, this might lead to development of an affordable and sustainable adjunct to the currently available case management of E. coli diarrhea, benefiting millions of children worldwide.

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Bangladesh
  • Dhaka, Bangladesh, 1212
    • Clinical Sciences Division, ICDDR,B, Mohakhali,

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 2 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. Sex: male
2. Age: 6 - 24 months
3. Better nourished (weight for age > 60 NCHS median)
4. H/o. diarrhea of less than 48 hours
5. Written informed consent from either parents/guardian (thumb impression for those who are not literate) for children
6. Negative test results for dark field microscopy of Vibrio cholerae and ELISA test for rotavirus in initial stool samples

Exclusion Criteria:

1. Systemic infection requiring antibiotic treatment
2. Severe malnutrition (W/A < 60%)
3. Unwilling to comply with study procedures
4. Currently participating or have participated in another clinical trial within the last 4 weeks at screening
5. Clinically significant abnormalities from medical history, physical examination, vital signs, haematology, clinical chemistry results, or other laboratory abnormalities
6. Clinically suggestive of invasive diarrhea

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Test product	Other: T4 phage cocktail test; T4 phages 106 PFU/ ml up to 5 days
Placebo Comparator: Standard care	Other: standard oral rehydration solution (ORS); Standard hospital treatment with ORS
Active Comparator: Commercial product	Other: Commercial T4 phage cocktail; Treatment as recommended by the manufacturer (Microgen phages)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Assessment of safety, tolerability and efficacy (reduce severity of diarrhea assessed by reduced stool volume and stool frequency) of oral administration of T4 phages in young children with diarrhea due to ETEC and/or EPEC infections	5 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Clinical assessment, blood tests, morbidity, duration of hospitalization	5 days

Collaborators and Investigators

• Sponsor: Nestlé
• Investigators: Principal Investigator: Shafiqul A Sarker, MD, PhD, Clinical Sciences Division, ICDDR,B, Mohakhali, Dhaka 1212, Bangladesh

Publications and helpful links

General Publications

• Sarker SA, Sultana S, Reuteler G, Moine D, Descombes P, Charton F, Bourdin G, McCallin S, Ngom-Bru C, Neville T, Akter M, Huq S, Qadri F, Talukdar K, Kassam M, Delley M, Loiseau C, Deng Y, El Aidy S, Berger B, Brussow H. Oral Phage Therapy of Acute Bacterial Diarrhea With Two Coliphage Preparations: A Randomized Trial in Children From Bangladesh. EBioMedicine. 2016 Jan 5;4:124-37. doi: 10.1016/j.ebiom.2015.12.023. eCollection 2016 Feb.

Study record dates

Study Major Dates

• Study Start: August 1, 2009
• Primary Completion (Actual): January 1, 2013
• Study Completion (Actual): January 1, 2013

Study Registration Dates

• First Submitted: July 8, 2009
• First Submitted That Met QC Criteria: July 9, 2009
• First Posted (Estimate): July 10, 2009

Study Record Updates

• Last Update Posted (Estimate): November 13, 2013
• Last Update Submitted That Met QC Criteria: November 12, 2013
• Last Verified: November 1, 2013

More Information

Terms related to this study

• Keywords: ORS; ETEC EPEC diarrhoea; phage therapy
• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Diarrhea
• Other Study ID Numbers: 08.11.INF