Ciprofloxacin Versus Azithromycin for Children Hospitalised With Dysentery (CIPAZ)

An Open Label Randomised Controlled Trial of Azithromycin Versus Ciprofloxacin for the Treatment of Children Hospitalised With Dysentery in Ho Chi Minh City, Vietnam

The purpose of this study is to assess the efficacy of 3 days of azithromycin (AZI) compared to 3 days of ciprofloxacin (CIP) (standard-of-care) for the treatment of children hospitalised with dysentery in Ho Chi Minh City.

Study Overview

• Status: Completed
• Conditions: Diarrhea; Shigellosis; Dysentery, Shigella
• Intervention / Treatment: Drug: Ciprofloxacin; Drug: Azithromycin

Detailed Description

Antimicrobial resistance is a well-established international healthcare crisis and children with diarrhoeal infections represent a significant proportion of the global infectious disease burden. With the increasing rates of antimicrobial resistance observed in the organisms associated with children presenting with dysentery in Vietnam and the investigator's capacity to demonstrate international transmission events, new data regarding alternative treatment options such as azithromycin, in particular for the new highly-antimicrobial resistant S. sonnei, are urgently needed.

The study team will perform a phase IV open label randomised controlled trial to compare the efficacy of AZI to CIP (standard-of-care) for the treatment of children hospitalised with dysentery in Ho Chi Minh City, Vietnam. Children aged 6 to 60 months presenting to the participating hospital with symptoms/signs of dysentery (diarrhoea with blood and/or mucus accompanied by 1 or more of: fever ≥37.8°C, abdominal pain and /or tenesmus) within the previous 72 hours will be enrolled to the study.

After enrolment, participants will be managed according to WHO and local algorithms for children with bloody diarrhoea. In addition, after providing a stool sample, children will be randomly allocated to receive CIP 15mg/kg body weight/ twice daily or AZI 10mg/kg body weight/ daily for 3 days. After enrolment, children will be reviewed for clinical and microbiological response to treatment.

• Study Type: Interventional
• Enrollment (Actual): 364
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Stephen Baker, Professor; Phone Number: +84 903 021175; Email: sbaker@oucru.org
• Study Contact Backup: Name: Clinical Trials Unit Oxford University Clinical Research Unit; Phone Number: +84 28 3924 1983; Email: CTU-Admin@oucru.org

Study Locations

• Vietnam
  • Ho Chi Minh City, Vietnam, 70000
    • Children's Hospital 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 5 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female aged 6 months to 60 months at time of hospital presentation.
2. Have symptoms and/or signs of dysentery, specifically passing stools containing mucus and/or blood with/without abdominal pain, tenesmus or fever (≥37.8˚C).
3. Be eligible for treatment with oral medication in the opinion of the admitting physician (i.e. no clinical requirement for parenteral treatment on admission).
4. Be within 72 hours of the onset of signs/symptoms.
5. Have a parent/guardian present at admission who can provide written informed consent.

Exclusion Criteria:

1. Those known to have specific medical (patients with known prolongation of the QT interval, congenital long QT syndrome)/surgical conditions which may affect disease severity/presentation or response to treatment (e.g. affecting antimicrobial absorption), including:

   1. gastrointestinal abnormalities, including short bowel syndrome, chronic (inflammatory or irritable) bowel disease.
   2. inherited or acquired immune system deficiency rendering the patient immunocompromised, including chronic/long-term steroid treatment or other immunosuppressive treatment
2. Presentation with severe infection requiring parenteral antimicrobial treatment, including shock jaundice, extensive gastrointestinal bleeding, convulsion , drowsiness or coma, reduced or less movement when stimulated, tachypnea > 60 times per minute, grunting, chest retraction, refuse to suck.
3. Known hypersensitivity to any of the trial drugs (CIP or AZI).
4. Coexisting infection requiring other or additional antimicrobials to be prescribed/ administered.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ciprofloxacin; Each sachet CIPROFLOXACIN of 3g powder contains: 250mg Ciprofloxacin HCl, dissolved in water, dosed to 15mg/kg body weight /twice daily (apart 12 hours)/ 3 days.	Drug: Ciprofloxacin; Fluoroquinolone, ATC code: J01MA02 DNA-gyrase and topoisomerase IV inhibitor
Experimental: Azithromycin; Each sachet AZICINE of 1.5 g powder contains: 250mg of Azithromycin dihydrate, dissolved in warm water, dosed to 10mg/kg body weight /daily/ 3 days	Drug: Azithromycin; Macrolide, ATC code: J01FA10 Binds to ribosomal 50S sub-unit inhibiting translocation of peptides thereby suppressing bacterial protein synthesis.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess the Clinical treatment failure between treatment groups.	Clinical treatment failure including: fever ≥38.0°C or the persistence of signs or symptoms of the infection (vomiting, abdominal pain, passing loose stools more than 3 times per 24 hours ( with blood and mucus, blood or mucus, without both))	after 120 hours of start of either treatment.
Assess the microbiological treatment failure between treatment groups.	The microbiological treatment failure is assessed by positive PCR stool with original pathogen after day 3 of treatment.	after 72 hours of start of either treatment.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measure differences in symptom duration between treatment groups by stratifying stool PCR.	Compare the duration of symptom ( from the onset to disappear) between the two groups. The duration of symptom will be stratified by stool PCR.	120 hours of start of either treatment.
Measure differences in symptom duration between treatment groups by stratifying stool culture.	Compare the duration of symptom ( from the onset to disappear) between the two groups. The duration of symptom will be stratified by stool culture.	120 hours of start of either treatment.
Assess the time to resolution of objective markers of infection and inflammation, including cessation of culture- and PCR-confirmed Shigella shedding, normalization of blood total white cell count, C-reactive protein and stool lipocalin	Time to cessation of Shigella shedding in stool (PCR).	at enrolment, day 7th (+3 days) and day 28th (+3 days)
Assess the rates of adverse events associated with exposure to the antimicrobial agents used.	Adverse effects of antimicrobial treatment, including (i) life-threatening events, (ii) events requiring drug discontinuation, (iii) mild adverse events that require additional medication to be used but not resulting in drug discontinuation.	at enrolment, during 31 days after enrolment
Assess the effects of antimicrobial exposure on the host microbiome, including diversity and abundance of specific bacterial species in stool.	The extend of intestinal microbial colonisation will be assessed by analyses of stool sample collected at enrolment, day 7th (+3 days) and day 28th (+3 days)	at enrolment, day 7th (+3 days) and day 28th (+3 days).

Collaborators and Investigators

• Sponsor: Oxford University Clinical Research Unit, Vietnam
• Collaborators: University of Liverpool; Number 2 Children's Hospital, Ho Chi Minh City
• Investigators: Principal Investigator: Stephen Stephen, Professor, Oxford University Clinical Research Unit

Study record dates

Study Major Dates

• Study Start (Actual): December 11, 2019
• Primary Completion (Actual): February 6, 2021
• Study Completion (Actual): July 12, 2022

Study Registration Dates

• First Submitted: February 21, 2019
• First Submitted That Met QC Criteria: February 25, 2019
• First Posted (Actual): February 26, 2019

Study Record Updates

• Last Update Posted (Actual): June 7, 2023
• Last Update Submitted That Met QC Criteria: June 5, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Children; Azithromycin; Vietnam; Ciprofloxacin; Dysentery
• Additional Relevant MeSH Terms: Digestive System Diseases; Infections; Signs and Symptoms, Digestive; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Enterobacteriaceae Infections; Diarrhea; Dysentery, Bacillary; Dysentery; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Ciprofloxacin; Azithromycin
• Other Study ID Numbers: 26EN

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No