Zambia Chlorhexidine Application Trial (ZamCAT)

• ClinicalTrials.gov Identifier: NCT01241318
• Recruitment Status: Completed
• First Posted: November 16, 2010
• Results First Posted: May 3, 2019
• Last Update Posted: August 31, 2020
• Sponsor: Boston University
• Collaborators: Bill and Melinda Gates Foundation; Ministry of Health, Zambia; Zambia Center for Applied Health Research and Development
• Information provided by (Responsible Party): Boston University

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Prevention
• Condition: Sepsis
• Interventions: Drug: Chlorhexidine gluconate (4%); Procedure: Dry cord care
• Enrollment: 77535

Participant Flow

Recruitment Details	In the 90 clusters (i.e. government-run health facilities), pregnant women who met eligibility criteria attending antenatal care were offered enrollment. Recruitment started February 15, 2011 and ended January 30, 2013.
Pre-assignment Details	Mothers were enrolled in the study while pregnant and infants were enrolled after delivery; thus the total protocol enrollment is women + infants. Study reporting is completed at the woman level and thus the total enrolled is listed at the woman level in the outcomes tables.

Arm/Group Title	Chlorhexidine Cord Care	Dry Cord Care
Arm/Group Description	Mothers located in health facility catchment areas assigned to this arm will apply chlorhexidine to their infants daily until three days after the cord completely separates. Chlorhexidine gluconate (4%): Chlorhexidine is a topical antiseptic that has long been tested for safety and widely used in developed country hospitals, pre-surgical antiseptic technique, wound cleaning and disinfection. Mothers will be instructed to apply 10 ml of 4% chlorhexidine once a day following the infants bath every day from birth until three days after the cord completely separates from the infant's body.	Mothers in health facility catchment areas assigned to this arm will use dry cord care - keeping their babies' umbilical stumps clean and dry - as per normal routine standard of care and in accordance with Zambia Ministry of Health policy. Dry cord care: Mothers will be instructed to keep their infants' umbilical cord stumps clean and dry and to not apply any foreign substances to the cord stump.
Period Title: Overall Study
Started	19629 [1]	20050 [1]
Liveborn Infant	18510 [2]	19346 [2]
Completed	18450 [2]	19308 [2]
Not Completed	1179	742
Reason Not Completed
Woman: false pregnancies	27	15
Woman: miscarriage/abortion	46	38
Withdrawal by Subject	175	46
Lost to Follow-up	740	455
Death	2	4
Withdrew/Lost to Follow after delivery	60	38
Woman: Stillborn infant	129	146
[1] Women enrolled; [2] Infants

Baseline Characteristics

Arm/Group Title		Chlorhexidine Cord Care	Dry Cord Care	Total
Arm/Group Description		Mothers located in health facility catchment areas assigned to this arm will apply chlorhexidine to their infants daily until three days after the cord completely separates. Chlorhexidine gluconate (4%): Chlorhexidine is a topical antiseptic that has long been tested for safety and widely used in developed country hospitals, pre-surgical antiseptic technique, wound cleaning and disinfection. Mothers will be instructed to apply 10 ml of 4% chlorhexidine once a day following the infants bath every day from birth until three days after the cord completely separates from the infant's body.	Mothers in health facility catchment areas assigned to this arm will use dry cord care - keeping their babies' umbilical stumps clean and dry - as per normal routine standard of care and in accordance with Zambia Ministry of Health policy. Dry cord care: Mothers will be instructed to keep their infants' umbilical cord stumps clean and dry and to not apply any foreign substances to the cord stump.	Total of all reporting groups
Overall Number of Baseline Participants		19629	20050	39679
Baseline Analysis Population Description		Pregnant women attending health facilities for antenatal care
Age, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	19629 participants	20050 participants	39679 participants
<20 years		4671	4580	9251
20-35 years		12772	13122	25894
>35 years		2012	2194	4206
Missing (not recorded)		174	154	328
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	19629 participants	20050 participants	39679 participants
	Female	19629 100.0%	20050 100.0%	39679 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	19629 participants	20050 participants	39679 participants
Tonga		17003	17650	34653
Ila		105	121	226
Lozi		786	795	1581
Nyanja		525	432	957
Bemba		413	433	846
Other		629	481	1110
Missing (not recorded)		168	138	306
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
Zambia	Number Analyzed	19629 participants	20050 participants	39679 participants
		19629	20050	39679
Maternal Education; Measure Type: Number; Unit of measure: Participants	Number Analyzed	19629 participants	20050 participants	39679 participants
No eduction		1936	1958	3894
Lower Primary		2293	2563	4856
Upper Primary		7731	7874	15605
Junior Secondary		5422	5499	10921
Upper Secondary		1895	1840	3735
>Upper Secondary		180	160	340
Do not know		3	10	13
Missing (not recorded)		169	146	315
Marital Status; Measure Type: Number; Unit of measure: Participants	Number Analyzed	19629 participants	20050 participants	39679 participants
Single		3021	3133	6154
Married		16107	16499	32606
Separated, divorced or widowed		224	187	411
Cohabiting		109	89	198
Missing (not recorded)		168	142	310
Maternal literacy; Measure Type: Number; Unit of measure: Participants	Number Analyzed	19629 participants	20050 participants	39679 participants
Not at all		5037	5491	10528
A bit		8835	9516	18351
Very well		5492	4835	10327
No response from mother		77	61	138
Missing (not recorded)		188	147	335
Household water source; Measure Type: Number; Unit of measure: Participants	Number Analyzed	19629 participants	20050 participants	39679 participants
Household tap		1861	1715	3576
Community tap		1919	1761	3680
Other water source on own property		2295	2403	4698
Community well or river		13241	13768	27009
No answer from Mother		56	62	118
Other		67	166	233
Missing (Not recorded)		190	175	365
Parity; Mean (Standard Deviation); Unit of measure: Pregnancies
	Number Analyzed	19629 participants	20050 participants	39679 participants
		2.4 (2.3)	2.5 (2.4)	2.5 (2.4)
Gravida; Mean (Standard Deviation); Unit of measure: Deliveries
	Number Analyzed	19629 participants	20050 participants	39679 participants
		3.5 (2.3)	3.6 (2.4)	3.6 (2.4)
Gestational Age at enrollment; Mean (Standard Deviation); Unit of measure: Weeks
	Number Analyzed	19629 participants	20050 participants	39679 participants
		28.0 (7.2)	28.4 (7.2)	28.3 (7.2)
Slept under mosquito bednet the previous night; Measure Type: Number; Unit of measure: Participants	Number Analyzed	19629 participants	20050 participants	39679 participants
Yes		11092	11783	22875
No		8310	8075	16385
Missing (not recorded)		227	192	419

Outcome Measures

1. Primary Outcome

Title	All-cause Neonatal Mortality
Description	All-cause neonatal mortality based on vital status at 28 days post-partum
Time Frame	28 days post-partum

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Chlorhexidine Cord Care	Dry Cord Care
Arm/Group Description:	Mothers located in health facility catchment areas assigned to this arm will apply chlorhexidine to their infants daily until three days after the cord completely separates. Chlorhexidine gluconate (4%): Chlorhexidine is a topical antiseptic that has long been tested for safety and widely used in developed country hospitals, pre-surgical antiseptic technique, wound cleaning and disinfection. Mothers will be instructed to apply 10 ml of 4% chlorhexidine once a day following the infants bath every day from birth until three days after the cord completely separates from the infant's body.	Mothers in health facility catchment areas assigned to this arm will use dry cord care - keeping their babies' umbilical stumps clean and dry - as per normal routine standard of care and in accordance with Zambia Ministry of Health policy. Dry cord care: Mothers will be instructed to keep their infants' umbilical cord stumps clean and dry and to not apply any foreign substances to the cord stump.
Overall Number of Participants Analyzed	18450	19308
Measure Type: Number; Unit of Measure: participants
Neonatal mortality	282	263
Survived to day 28	18168	19045

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chlorhexidine Cord Care, Dry Cord Care
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.12
	Confidence Interval	(2-Sided) 95%; 0.88 to 1.44
	Estimation Comments	The chlorhexidine arm is the numerator and dry cord care arm is the denominator in the relative risk calculation. Generalised estimating equation models were used to adjust for cluster randomized design.

2. Primary Outcome

Title	All-cause Neonatal Mortality Among Newborns Who Survived at Least First Day of Life
Description	All-cause mortality by day 28 of life among newborns who survive at least the first day of life
Time Frame	28 days post-partum

Outcome Measure Data

Analysis Population Description

All liveborn neonates who survived the first 24 hours after delivery

Arm/Group Title	Chlorhexidine Cord Care	Dry Cord Care
Arm/Group Description:	Mothers located in health facility catchment areas assigned to this arm will apply chlorhexidine to their infants daily until three days after the cord completely separates. Chlorhexidine gluconate (4%): Chlorhexidine is a topical antiseptic that has long been tested for safety and widely used in developed country hospitals, pre-surgical antiseptic technique, wound cleaning and disinfection. Mothers will be instructed to apply 10 ml of 4% chlorhexidine once a day following the infants bath every day from birth until three days after the cord completely separates from the infant's body.	Mothers in health facility catchment areas assigned to this arm will use dry cord care - keeping their babies' umbilical stumps clean and dry - as per normal routine standard of care and in accordance with Zambia Ministry of Health policy. Dry cord care: Mothers will be instructed to keep their infants' umbilical cord stumps clean and dry and to not apply any foreign substances to the cord stump.
Overall Number of Participants Analyzed	18424	19266
Measure Type: Number; Unit of Measure: neonates who survived first 24 hours
Neonatal mortality	200	186
Survived to day 28	18224	19080

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chlorhexidine Cord Care, Dry Cord Care
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.12
	Confidence Interval	(2-Sided) 95%; 0.86 to 1.47
	Estimation Comments	Generalized estimating equation models adjusting for cluster-randomized design were used.

3. Secondary Outcome

Title	Incidence of Omphalitis
Description	Omphalitis, or umbilical cord infection, defined as: presence of umbilical cord pus and mild, moderate or severe redness; moderate or severe redness without the presence of umbilical cord pus
Time Frame	28 days postpartum

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Chlorhexidine Cord Care	Dry Cord Care
Arm/Group Description:	Mothers located in health facility catchment areas assigned to this arm will apply chlorhexidine to their infants daily until three days after the cord completely separates. Chlorhexidine gluconate (4%): Chlorhexidine is a topical antiseptic that has long been tested for safety and widely used in developed country hospitals, pre-surgical antiseptic technique, wound cleaning and disinfection. Mothers will be instructed to apply 10 ml of 4% chlorhexidine once a day following the infants bath every day from birth until three days after the cord completely separates from the infant's body.	Mothers in health facility catchment areas assigned to this arm will use dry cord care - keeping their babies' umbilical stumps clean and dry - as per normal routine standard of care and in accordance with Zambia Ministry of Health policy. Dry cord care: Mothers will be instructed to keep their infants' umbilical cord stumps clean and dry and to not apply any foreign substances to the cord stump.
Overall Number of Participants Analyzed	18510	19346
Measure Type: Number; Unit of Measure: neonates
Omphalitis	82	118
No omphalitis	18428	19228

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chlorhexidine Cord Care, Dry Cord Care
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.47 to 1.13
	Estimation Comments	Generalized estimating equation models adjusting for cluster-randomized design were used.

4. Secondary Outcome

Title	Place of Delivery
Description	The location where mothers gave birth (home versus a health facility) will be compared to their planned delivery location.
Time Frame	28 days postpartum

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Chlorhexidine Cord Care	Dry Cord Care
Arm/Group Description:	Mothers located in health facility catchment areas assigned to this arm will apply chlorhexidine to their infants daily until three days after the cord completely separates. Chlorhexidine gluconate (4%): Chlorhexidine is a topical antiseptic that has long been tested for safety and widely used in developed country hospitals, pre-surgical antiseptic technique, wound cleaning and disinfection. Mothers will be instructed to apply 10 ml of 4% chlorhexidine once a day following the infants bath every day from birth until three days after the cord completely separates from the infant's body.	Mothers in health facility catchment areas assigned to this arm will use dry cord care - keeping their babies' umbilical stumps clean and dry - as per normal routine standard of care and in accordance with Zambia Ministry of Health policy. Dry cord care: Mothers will be instructed to keep their infants' umbilical cord stumps clean and dry and to not apply any foreign substances to the cord stump.
Overall Number of Participants Analyzed	18510	19346
Measure Type: Count of Participants; Unit of Measure: Participants
Home Delivery	6509 35.2%	6682 34.5%
Facility Delivery	11456 61.9%	12204 63.1%
Other	190 1.0%	128 0.7%
Missing	355 1.9%	332 1.7%

5. Secondary Outcome

Title	Factors Influencing Delivery Location
Description	Health facility characteristics and maternal decision making factors that influence choice of delivery location (health facility vs. home delivery)
Time Frame	28 days postpartum

Outcome Measure Data

Analysis Population Description

Women enrolled in the ZamCAT study and delivery location known. Please note these are different denominators reported as this analysis is not based on intervention randomization, but rather an analysis focused on women's location of childbirth. Therefore, the number of women included in this analysis is based on a subset of all women enrolled.

Arm/Group Title	Facility Delivery	Home Delivery
Arm/Group Description:	Women who enrolled in ZamCAT study and delivered at a facility	Women who enrolled in ZamCAT study and delivered at home
Overall Number of Participants Analyzed	23815	13255
Measure Type: Count of Participants; Unit of Measure: Participants
Same Location as Prior Delivery	3198 13.4%	2082 15.7%
Need for Skilled Attendance12991	12991 54.5%	5693 42.9%
Financial Constraints	1823 7.7%	1249 9.4%
Physical Distance	6345 26.6%	3930 29.6%
Relationship with Provider	572 2.4%	429 3.2%
Family/Social Expectations	1255 5.3%	990 7.5%
Safety for Mother/Baby	14129 59.3%	5911 44.6%
Other	1480 6.2%	803 6.1%
Missing	1364 5.7%	770 5.8%

6. Secondary Outcome

Title	Health Facility Characteristics
Description	Characterization of the health services available to pregnant women, postpartum women and their offspring as assessed by comprehensive health facility and health worker surveys. This data was assessed and reported on 100 facilities (10 district hospitals and 90 health facilities).
Time Frame	12 months after study initiation

Outcome Measure Data

Analysis Population Description

Health facilities

Arm/Group Title	Study Health Facilities & Hospitals
Arm/Group Description:	90 health facilities and 10 district hospitals were included in the main chlorhexidine trial. A survey was completed to assess availability of emergency obstetric care.
Overall Number of Participants Analyzed	39679
Overall Number of Units Analyzed; Type of Units Analyzed: Health facilities	100
Measure Type: Number; Unit of Measure: Health facilities
Basic emergency obstetrical and newborn care	6
No basic emergency obstetrical and newborn care	94

Adverse Events

Time Frame	Adverse event data were collected during the 1 month follow up period past delivery.
Adverse Event Reporting Description	Umbilical cord was observed by the field data collector at every visit (day 1, 4, 10, 28 post-partum). Adverse events were defined as ocular exposure to chlorhexidine, local skin irritation, accidental ingestion, contact dermatitis, or anaphylaxis.
Arm/Group Title	Chlorhexidine Cord Care		Dry Cord Care
Arm/Group Description	Mothers located in health facility catchment areas assigned to this arm will apply chlorhexidine to their infants daily until three days after the cord completely separates. Chlorhexidine gluconate (4%): Chlorhexidine is a topical antiseptic that has long been tested for safety and widely used in developed country hospitals, pre-surgical antiseptic technique, wound cleaning and disinfection. Mothers will be instructed to apply 10 ml of 4% chlorhexidine once a day following the infants bath every day from birth until three days after the cord completely separates from the infant's body.		Mothers in health facility catchment areas assigned to this arm will use dry cord care - keeping their babies' umbilical stumps clean and dry - as per normal routine standard of care and in accordance with Zambia Ministry of Health policy. Dry cord care: Mothers will be instructed to keep their infants' umbilical cord stumps clean and dry and to not apply any foreign substances to the cord stump.
All-Cause Mortality
	Chlorhexidine Cord Care		Dry Cord Care
	Affected / at Risk (%)		Affected / at Risk (%)
Total	282/18510 (1.52%)		263/19346 (1.36%)
Serious Adverse Events
	Chlorhexidine Cord Care		Dry Cord Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18510 (0.00%)		0/19346 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Chlorhexidine Cord Care		Dry Cord Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/18510 (0.05%)		0/19346 (0.00%)
Eye disorders
Chlorhexidine ocular exposure *	1/18510 (0.01%)	1	0/19346 (0.00%)	0
Skin and subcutaneous tissue disorders
Chlorhexidine-related adverse events †	8/18510 (0.04%)	8	0/19346 (0.00%)	0
* Indicates events were collected by non-systematic assessment; † Indicates events were collected by systematic assessment

Limitations and Caveats

Only 89% (37 856 of 42 570) of the target sample size was attained. When we completed a post-hoc power calculation with the obtained sample size and observed Neonatal Mortality Rate (NMR), we had 80% power to detect a 28% reduction in NMR.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Katherine Semrau (Epidemiologist, co-PI)
• Organization: Ariadne Labs|BWH & HSPH
• Phone: 6177805311
• EMail: ksemrau@ariadnelabs.org

Publications:

Mullany LC, El Arifeen S, Winch PJ, Shah R, Mannan I, Rahman SM, Rahman MR, Darmstadt GL, Ahmed S, Santosham M, Black RE, Baqui AH. Impact of 4.0% chlorhexidine cleansing of the umbilical cord on mortality and omphalitis among newborns of Sylhet, Bangladesh: design of a community-based cluster randomized trial. BMC Pediatr. 2009 Oct 21;9:67. doi: 10.1186/1471-2431-9-67.

Mullany LC, Darmstadt GL, Khatry SK, Katz J, LeClerq SC, Shrestha S, Adhikari R, Tielsch JM. Topical applications of chlorhexidine to the umbilical cord for prevention of omphalitis and neonatal mortality in southern Nepal: a community-based, cluster-randomised trial. Lancet. 2006 Mar 18;367(9514):910-8. doi: 10.1016/S0140-6736(06)68381-5.

Arifeen SE, Mullany LC, Shah R, Mannan I, Rahman SM, Talukder MR, Begum N, Al-Kabir A, Darmstadt GL, Santosham M, Black RE, Baqui AH. The effect of cord cleansing with chlorhexidine on neonatal mortality in rural Bangladesh: a community-based, cluster-randomised trial. Lancet. 2012 Mar 17;379(9820):1022-8. doi: 10.1016/S0140-6736(11)61848-5. Epub 2012 Feb 8.

Soofi S, Cousens S, Imdad A, Bhutto N, Ali N, Bhutta ZA. Topical application of chlorhexidine to neonatal umbilical cords for prevention of omphalitis and neonatal mortality in a rural district of Pakistan: a community-based, cluster-randomised trial. Lancet. 2012 Mar 17;379(9820):1029-36. doi: 10.1016/S0140-6736(11)61877-1. Epub 2012 Feb 8.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Solomon H, Henry EG, Herlihy J, Yeboah-Antwi K, Biemba G, Musokotwane K, Bhutta A, Hamer DH, Semrau KEA. Intended versus actual delivery location and factors associated with change in delivery location among pregnant women in Southern Province, Zambia: a prespecified secondary observational analysis of the ZamCAT. BMJ Open. 2022 Mar 7;12(3):e055288. doi: 10.1136/bmjopen-2021-055288.

Park JH, Hamer DH, Mbewe R, Scott NA, Herlihy JM, Yeboah-Antwi K, Semrau KEA. Components of clean delivery kits and newborn mortality in the Zambia Chlorhexidine Application Trial (ZamCAT): An observational study. PLoS Med. 2021 May 5;18(5):e1003610. doi: 10.1371/journal.pmed.1003610. eCollection 2021 May.

Henry EG, Semrau K, Hamer DH, Vian T, Nambao M, Mataka K, Scott NA. The influence of quality maternity waiting homes on utilization of facilities for delivery in rural Zambia. Reprod Health. 2017 May 30;14(1):68. doi: 10.1186/s12978-017-0328-z.

Semrau KEA, Herlihy J, Grogan C, Musokotwane K, Yeboah-Antwi K, Mbewe R, Banda B, Mpamba C, Hamomba F, Pilingana P, Zulu A, Chanda-Kapata P, Biemba G, Thea DM, MacLeod WB, Simon JL, Hamer DH. Effectiveness of 4% chlorhexidine umbilical cord care on neonatal mortality in Southern Province, Zambia (ZamCAT): a cluster-randomised controlled trial. Lancet Glob Health. 2016 Nov;4(11):e827-e836. doi: 10.1016/S2214-109X(16)30215-7. Epub 2016 Sep 29.

Hamer DH, Herlihy JM, Musokotwane K, Banda B, Mpamba C, Mwangelwa B, Pilingana P, Thea DM, Simon JL, Yeboah-Antwi K, Grogan C, Semrau KE. Engagement of the community, traditional leaders, and public health system in the design and implementation of a large community-based, cluster-randomized trial of umbilical cord care in Zambia. Am J Trop Med Hyg. 2015 Mar;92(3):666-72. doi: 10.4269/ajtmh.14-0218. Epub 2015 Feb 2.

• Responsible Party: Boston University
• ClinicalTrials.gov Identifier: NCT01241318
• Other Study ID Numbers: H-29647
• First Submitted: November 12, 2010
• First Posted: November 16, 2010
• Results First Submitted: December 9, 2016
• Results First Posted: May 3, 2019
• Last Update Posted: August 31, 2020