Clean Trial - Chlorination to Reduce Enteric and Antibiotic Resistant Infections in Neonates (CLEAN)

Multi-component Chlorination Intervention to Reduce Neonatal Infections in Rural Health Facilities

The CLEAN (ChLorine to reduce Enteric and Antibiotic resistant infections in Neonates) cluster randomized controlled trial in western Kenya will evaluate the impact of a multi-component chlorination intervention in health care facilities on maternal and neonatal health. Intervention facilities will receive a passive chlorination technology for water supply treatment and a reliable supply of sodium hypochlorite disinfectant. Both intervention and treatment facilities will receive infection prevention and control messaging. The goal of the study is to evaluate the impact of the intervention on bacterial contamination of water supply, on staff hands, and on high-touch surfaces in maternity wards, and the following outcomes among facility-born neonates and their mothers: (1) gut carriage of bacterial pathogens associated with sepsis one week post-birth, (2) gut carriage of antibiotic resistant bacteria one week post-birth, and (3) symptoms of possible serious bacterial infection one week following birth.

Study Overview

• Status: Recruiting
• Conditions: Sepsis; Antibiotic Resistant Infection; Serious Bacterial Infection; Neonatal Mortality; Enteric Infections
• Intervention / Treatment: Behavioral: infection prevention and control messaging; Device: chlorination for water disinfection and surface disinfection

Detailed Description

The proportion of births occurring at healthcare facilities is rising globally, yet healthcare facilities in low-income settings have been found to be highly contaminated with bacterial pathogens, including antibiotic resistant pathogens. There is a need for effective strategies to reduce contamination in healthcare facilities in order to reduce infection risks among facility-born neonates. In this trial, medium-sized public health facilities will be randomized to control or to receive an intervention consisting of passive chlorination for water supply treatment and a reliable supply of chlorine disinfectant. Reliable supply is randomized as either (a) an electrochlorinator for on-site production or (b) bulk chlorine delivery.

This cluster randomized controlled trial will enroll 36 health facilities to generate rigorous evidence on the maternal and neonatal health benefits of chlorinated water supply paired with reliable supplies of chlorine disinfectant. This study has the following aims: 1) determine the impact of the intervention on pathogenic and antibiotic resistant bacterial contamination in water supplies, on high-touch surfaces, and on healthcare worker hands, 2) quantify intervention effects on gut colonization of mothers and neonates by a panel of pathogenic and antibiotic resistant bacteria species linked to serious infection, using molecular and culture-based methods, and 3) follow up with mother-neonate dyads to measure intervention effects on symptoms of possible serious bacterial infection in the week following birth. Data collection will be for a duration of 24 months.

Infection prevention through effective water, sanitation, and hygiene (WASH) has been cited by national action plans as a key tool in the fight against antimicrobial resistance and, while global data show dire WASH conditions in low- and middle-income (LMIC) health facilities, there exists very little guidance for implementing effective interventions. The overarching goal is to generate actionable evidence to inform investments in chlorination at health facilities to improve maternal and neonatal health and reduce the threat of antibiotic resistant infections.

• Study Type: Interventional
• Enrollment (Estimated): 45450
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Amy J Pickering, PhD; Phone Number: 1-510-410-2666; Email: amyjanel@gmail.com
• Study Contact Backup: Name: Yoshika Crider, PhD; Phone Number: 1-785-550-5227; Email: ycrider@berkeley.edu

Study Locations

• Kenya
  • Nairobi, Kenya
    • Recruiting
    • Kenya Medical Research Institute
    • Contact: Phelgona Otieno, PhD; Phone Number: +254-721973971; Email: phelgona@gmail.com
    • Principal Investigator: Phelgona Otieno, PhD
• United States
  • California
    • Berkeley, California, United States, 94720
      • Active, not recruiting
      • University of California, Berkeley

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Facility Inclusion Criteria:

• Public health care facility
• 25 live births or more per month
• Infrastructure compatible with inline chlorination device

Participant Inclusion Criteria:

• Pregnant adults/mature minors arriving at enrolled facilities to give birth and their neonates

Facility Exclusion Criteria:

• Existing facility-level chlorination

Participant Exclusion Criteria:

• Miscarriage (<28 weeks gestation)
• Stillbirth (for neonatal analysis only)
• Unable to give informed consent/do not consent
• Reside >2 hours away from facility for enrollment into swab sampling cohort

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control; Control group. At the conclusion of the trial, facilities will receive a chlorine doser.	Behavioral: infection prevention and control messaging; Infection prevention and control guidance and messaging
Experimental: Multi-component chlorine intervention; Health care facilities will receive one or more inline chlorine dosers that will automatically chlorinate all water accessed by the maternity wards. Intervention facilities will also be randomized to either receive an electrochlorinator for on-site production of liquid chlorine solution or to receive bulk chlorine deliveries. Chlorine will be use to refill the chlorine dosers and for surface disinfection. Facilities will also receive hardware to facilitate surface disinfection.	Behavioral: infection prevention and control messaging; Infection prevention and control guidance and messaging; Device: chlorination for water disinfection and surface disinfection; Installation of inline chlorine doser(s) for automated water disinfection.; Provision of chlorine solution for water and surface disinfection (half of treatment facilities randomized to receive electrochlorinator, half receive bulk chlorine solution deliveries).; Provision of mop(s), bucket(s), and spray bottles for surface cleaning.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Possible serious bacterial infection in neonate	Incidence of one or more of the following severe infection symptoms of neonates based on WHO criteria for possible serious bacterial infection: Not able to feed at all or not feeding well; Convulsions; Severe chest indrawing; Fever - High body temperature (38°C* or above); Low body temperature (less than 35.5°C*); Movement only when stimulated or no movement at all; Fast breathing (60 breaths per minute or more)	From birth to 7 days post birth
Possible maternal sepsis	Any of the following listed with fever or hypothermia: fast heartbeat; low blood pressure; respiratory distress; jaundice; decreased urination/dysuria; altered mental status	From birth to 7 days post birth
Neonatal infection with at least one bacterial pathogen	Detection of any pre-specified bacterial pathogen detected by qPCR in infant rectal swabs (among swab subset of participants) Includes: ETEC, STEC, EPEC, EAEC, EIEC, EHEC O157:H7, Escherichia coli/Shigella, Shigella spp, Shigella flexneri, Salmonella spp., Salmonella enteritidis, Salmonella typhi, Campylobacter jejuni/coli, Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Streptococcus agalactiae (Group B strep), Serratia marcescens, Pseudomonas aeruginosa, Acinetobacter baumannii, Clostridium difficile, Vibrio cholerae	7 days after birth

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Any symptom or sign of infection in neonate	One or more of the following symptoms: Difficulty feeding, Hyperthermia/fever, Hypothermia, Tachypnea, Severe chest indrawing, Convulsions, Movement only when stimulated/no movement, Bulging fontanel, Labored breathing, Skin infection, Umbilical redness, Oozing ears, Diarrhea, Three or more loose or watery stools in a 24 hour period, Vomiting, Cyanosis, Cough, Runny nose or congestion, Tachycardia (>160 bpm at rest)	From birth until 7 days post birth
Any symptom or sign of infection in mother	One or more of the following symptoms: Hypothermia, Fever, Foul smelling vaginal discharge, Fits/convulsions, Tachycardia (>100 bpm at rest), Low blood pressure, Diarrhea (self-defined), Difficulty breathing, Jaundice, Decreased urination or difficult or painful urination, Confusion or altered mental state, Mastitis, Chills, Body aches, Low appetite, Lower abdominal pain, Three or more loose or watery stools in a 24 hour period, Vomiting, Cough, Runny nose or congestion, Chest pain, Bloody stool, Skin infection	From birth to 7 days post birth
Clinical diagnosis of sepsis in neonate	Abstracted diagnosis from medical charts OR self-reported diagnosis confirmed by clinician	From birth to 7 days post birth
Clinical diagnosis of sepsis in mother	Abstracted diagnosis from medical charts OR self-reported diagnosis confirmed by clinician	From birth to 7 days post birth
Neonatal mortality	Report of neonatal death up to 28 days	From birth to 28 days after birth
Maternal mortality	Report of maternal death	From birth to 28 days after birth
Neonatal rectal colonization with at least one bacterial pathogen by culture	Detection of any pre-specified bacterial pathogen detected by culture in neonate rectal swabs (among swab subset of participants) Includes: Acinetobacter spp., Pseudomonas spp., Salmonella spp., Shigella, Staphylococcus aureus, Group B streptococcus	7 days after birth
Maternal rectal colonization with at least one bacterial pathogen by culture-based method	Detection of any pre-specified bacterial pathogen detected by culture in maternal rectal swabs (among swab subset of participants) Acinetobacter spp., Pseudomonas spp., Salmonella spp., Shigella spp., Staphylococcus aureus, Group B streptococcus	7 days postpartum
Number of clinically relevant antibiotic resistance genes (ARGs) detected in neonatal rectal swabs	Measured by qPCR. Includes: resistance to quinolone, macrolide, sulfonamide, tetracycline, vancomycin, aminoglycoside, beta-lactams (cephalosporin, penicillin, ampicillin) , carbapenem, colistin	7 days post birth
Rectal colonization with one or more antibiotic resistant bacteria (neonates)	Detection of ESBL enterobacteriaceae by culture in rectal swabs Includes: Klebsiella spp./Enterobacter/Citrobacter spp. (KEC), Acinetobacter spp., Pseudomonas spp., E. coli	7 days post birth
Rectal colonization with one or more antibiotic resistant bacteria (mothers)	Detection of ESBL enterobacteriaceae by culture in rectal swabs Includes: Klebsiella spp./Enterobacter/Citrobacter spp. (KEC), Acinetobacter spp., Pseudomonas spp., E. coli	7 days postpartum
Number of bacterial pathogens in rectal swabs (neonates)	Number of unique bacterial pathogens (see pre-specified list above) detected by qPCR	7 days post birth
Number of bacterial pathogens in rectal swabs (mothers)	Number of unique bacterial pathogens (see pre-specified list above) by culture	7 days postpartum

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rectal colonization with individual bacterial pathogens (neonates)	Detection of individual bacterial pathogen by qPCR or by culture (see list in secondary outcomes)	7 days post birth
Rectal colonization with individual bacterial pathogens (mothers)	Detection of individual bacterial pathogen (see pre-specified list in secondary outcomes) by culture or qPCR	7 days postpartum
Presence of individual ARGs in neonatal rectal swabs	Presence/absence of pre-specified clinically relevant ARGs by qPCR	7 days post birth
Presence and concentration of bacterial pathogens on high touch surfaces	Measured by culture-based assays Includes: Acinetobacter spp., Pseudomonas spp., Salmonella spp., Shigella, Staphylococcus aureus, Group B streptococci	Measured quarterly over 24 months post intervention delivery (every 3 months)
Presence and concentration of antibiotic resistant bacterial pathogens on high touch surfaces	Detection of ESBL enterobacteriaceae by culture in surface swabs Includes: Klebsiella spp./Enterobacter/Citrobacter spp. (KEC), Acinetobacter spp., Pseudomonas spp., E. coli	Measured quarterly over 24 months post intervention delivery (every 3 months)
Proportion of water samples meeting WHO "safe" criteria	Measured as <1 CFU E. coli per 100ml water tested by culture	Measured quarterly over 24 months post intervention delivery (every 3 months)
Concentration of E. coli / 100 ml water	Measured by culture-based membrane filtration assay	Measured quarterly over 24 months post intervention delivery (every 3 months)
Presence and concentration of E. coli and total coliform on healthcare staff hands	Measured by membrane filtration culture assay	Measured quarterly over 24 months post intervention delivery (every 3 months)
Presence and concentration of antibiotic resistant bacterial pathogens on healthcare staff hands	Detection of ESBL enterobacteriaceae by culture in hand rinses and swabs Includes: Klebsiella spp./Enterobacter/Citrobacter spp. (KEC), Acinetobacter spp., Pseudomonas spp., E. coli	Measured quarterly over 24 months post intervention delivery (every 3 months)
Proportion of water supply samples with detectable free chlorine residual in water	Measured as >0.1 ppm by DPD method	Measured quarterly over 24 months post intervention delivery (every 3 months)

Collaborators and Investigators

• Sponsor: University of California, Berkeley
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); Walter Reed Army Institute of Research (WRAIR); Kenya Medical Research Institute
• Investigators: Principal Investigator: Amy J Pickering, PhD, University of California, Berkeley; Principal Investigator: Phelgona Otieno, PhD, Kenya Medical Research Institute; Principal Investigator: Lillian Musila, PhD, Walter Reed Army Institute of Research-Africa

Publications and helpful links

General Publications

• Lindmark M, Cherukumilli K, Crider YS, Marcenac P, Lozier M, Voth-Gaeddert L, Lantagne DS, Mihelcic JR, Zhang QM, Just C, Pickering AJ. Passive In-Line Chlorination for Drinking Water Disinfection: A Critical Review. Environ Sci Technol. 2022 Jul 5;56(13):9164-9181. doi: 10.1021/acs.est.1c08580. Epub 2022 Jun 14.
• Pickering AJ, Crider Y, Sultana S, Swarthout J, Goddard FG, Anjerul Islam S, Sen S, Ayyagari R, Luby SP. Effect of in-line drinking water chlorination at the point of collection on child diarrhoea in urban Bangladesh: a double-blind, cluster-randomised controlled trial. Lancet Glob Health. 2019 Sep;7(9):e1247-e1256. doi: 10.1016/S2214-109X(19)30315-8.

Study record dates

Study Major Dates

• Study Start (Actual): January 21, 2025
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): July 1, 2027

Study Registration Dates

• First Submitted: February 7, 2025
• First Submitted That Met QC Criteria: February 7, 2025
• First Posted (Actual): February 13, 2025

Study Record Updates

• Last Update Posted (Actual): May 25, 2025
• Last Update Submitted That Met QC Criteria: May 20, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: sepsis; antibiotic resistance; neonatal mortality; sodium hypochlorite; chlorine; infection prevention and control; bacterial enteric infection; water disinfection; hospital acquired infections
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Bacterial Infections and Mycoses; Infections; Communicable Diseases; Bacterial Infections
• Other Study ID Numbers: 2024-01-17100; R01AI184756 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Any data shared will be de-identified. Participants will not be contacted or re-consented for future sharing or accessing data through repositories. Privacy and confidentiality protections will be consistent with applicable local laws in Kenya. Data will be de-identified prior to sharing. All data sharing plans will be reviewed and approved by the respective institutional review boards at all participating institutions and will be reviewed during the informed consent process with caregivers.

Drug and device information, study documents

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