CHIZAP: Community- and Health Facility-Based Intervention With Zinc as Adjuvant Therapy for Childhood Pneumonia

• Sponsor: Centre For International Health (Other)
• Overall Status: Completed
• CT.gov ID: NCT00148733
• Collaborator: Tribhuvan University, Nepal (Other), Statens Serum Institut (Other), All India Institute of Medical Sciences, New Delhi (Other), IRD, Epidemiologie et Prevention, Montpelier, France (Other), Society for Applied Studies (Other)
• Enrollment: 2,628
• Location: 1
• Arms: 2
• Duration (Months): 48
• Patients Per Site Per Month: 54.8

Study Details

Study Description

Brief Summary

The aim of the study described is to measure the degree with which zinc given as adjunct therapy to standard antibiotic treatment during childhood pneumonia reduces the risk of treatment failure and the duration of the illness.

Condition or Disease	Intervention/Treatment	Phase
Pneumonia	Drug: Zinc	Phase 2/Phase 3

Detailed Description

Hypothesis: Zinc deficiency is a major public health problem in developing counties. Poor zinc status is associated with stunted growth and reduced resistance to infections. Several in vitro experiments and in vivo studies in animals and humans have demonstrated detrimental effects of zinc depletion on almost all facets of the immune system. The epithelial linings in the gut and in the respiratory tract are important for the resistance to infections and continuous cell division is required for proper function of these barriers. Zinc is crucial for cellular division and for the maintenance of organs with cells with a rapid turnover, including epithelial cells. Clinical trials in children in developing countries have demonstrated improved growth and reduced prevalence of diarrhea and respiratory tract infections following zinc supplementation. Furthermore, zinc has a well-documented therapeutic effect when given during acute or persistent diarrhea. The effect of zinc may be explained by correction of a deficiency state and/or by a pharmacological, as yet poorly described, action.

Due to the promising results from previous studies, WHO are now supporting large clinical trials in Nepal, India and Tanzania to assess whether routine zinc supplementation reduces mortality in early childhood. If the results of these trials show a mortality reduction, routine zinc supplementation or zinc dense foods may be promoted. However, while the first approach is logistically difficult and expensive, the second approach is difficult because zinc dense foods and foods with low phytic acid content are expensive and not readily available. Moreover, both approaches may be perceived to be incompatible with the current breast-feeding recommendations for the youngest children in most developing countries.

There is limited information on zinc as adjunct therapy for pneumonia. A recent hospital-based study in young children with severe pneumonia, showed that the zinc group had a faster recovery, resulting in a shortening of stay in hospital of one day. However, this study was small and no community based study has been conducted so far. Whether zinc has an effect during respiratory infections has to be assessed in studies with larger sample sizes in children with less severe disease and should be repeated in children with more severe disease. Short-term zinc administration during infections may become an alternative or an addition to long-term supplementation or promotion of zinc dense foods. Furthermore, therapeutic administration of zinc will not interfere with the current breast-feeding recommendations.

Hypothesis: Zinc as adjunct therapy for pneumonia may lead to faster recovery. Furthermore, long-term beneficial effects may include improved immuno-nutritional status measured by thymus size, less morbidity and improved growth.

Comparison: Duration of illness, risk of treatment failure, for those with severe pneumonia:

length of hospital stay. Number of non-injury clinic visits and hospitalizations during the intervention with Zinc and an in a 6 month period after enrolment. Growth assessed by anthropometry and thymus size assessed by ultrasonography. Explore the efficacy of zinc in etiology-sub groups including those defined by nutritional status, inflammation, fever, gender, breastfeeding status and viral etiology.

Study Design

• Study Type: Interventional
• Actual Enrollment: 2628 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Community- and Health Facility-based Intervention With Zinc as Adjuvant Therapy for Pneumonia to Enhance Child Health and Nutrition
• Study Start Date: Jan 1, 2004
• Actual Primary Completion Date: Jan 1, 2008
• Actual Study Completion Date: Jan 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Zinc Zinc sulphate 10 or 20 mg (elemental zinc) per day. Intervention and placebo given perorally mixed with approximately 5 mL of breastmilk or clean water	Drug: Zinc; Dissolvable zinc tablet 10 mg elemental zinc per day for infants 20 mg elemental zinc per day for children 12 to 35 months; Other Names: Produced by Nutriset, Malaunay, France
Placebo Comparator: Placebo Placebo	Drug: Zinc; Dissolvable zinc tablet 10 mg elemental zinc per day for infants 20 mg elemental zinc per day for children 12 to 35 months; Other Names: Produced by Nutriset, Malaunay, France

Outcome Measures

Primary Outcome Measures

1. Risk of Treatment Failure. [Within 2 weeks after enrollment]

   Enrolled children will be followed and given zinc or placebo for 14 days. We will compare the proportion with treatment failure (i.e. lack of improvement within 3 days) between the two groups

2. Non-injury Clinic Visits and Hospital Admissions After Treatment Has Been Initiated [Within 2 weeks after enrollment]

   We will measure to what extent the intervention can reduce the number of severe events.

3. Active and Passive Morbidity Surveillance for Six Months After the 14-day Supplementation Period is Completed [six months]

   We will measure to what extent short term zinc administration has an impact on growth and morbidity for up to 6 months after end of supplementation

4. Difference in Growth and Thymic Size Between the Treatment Groups Measured at Three and Six Months After the Zinc Supplementation [six months]

   Thymus size will be measured using ultrasonography and compared between the two groups. at two occasions 2.5 and 6 months after end of supplementation

5. Adverse Effects [14 days]

   Vomiting, regurgitation, pain in abdomen for 15 minutes after zinc or placebo administration.

Secondary Outcome Measures

1. Effect Modifiers for the Effect of Zinc Given During Pneumonia [Within 2 weeks after enrollment]

   We will also measure of there are factors at baseline that modifies the effect of zinc. Whether the following are modifiers for the above-mentioned effect of zinc given during pneumonia: i.severe inflammation, reflected in: high fever and/or elevated plasma C-reactive protein (CRP) concentration

2. The Efficacy of Zinc According to Breast Feeding Status and in Different Age Categories [Within 2 weeks after enrollment]

   We will measure to what extent breastfeeding status modifies the effect of zinc on pneumonia

3. The Efficacy of Zinc in Malnourished and Non-malnourished Children [Within 2 weeks after enrollment]

   We will compare the efficacy of zinc in those that are stunted, wasted or underweight with those who are not.

4. Will Presence of a RNA Virus Modify the Effect of Zinc [14 days]

   We will compare the efficacy of zinc according to virus detected in nasopharyngeal secretions

5. Folate, Cobalamin and Vitamin D Status of the Enrolled Children [14 days]

   And whether or not these vitamins predict treatment failure and duration of illness.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Months to 3 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Pneumonia: Child presenting with cough or difficult breathing and elevated respiratory rate.

• Severe pneumonia: Child presenting with cough or difficult breathing and chest indrawing , but without any of the following danger signs:

• not able to drink/breastfeed,

• vomit everything,

• has had convulsions,

• is lethargic or unconscious.

• Must be able to take Zinc

Exclusion Criteria:

• The child requires special care for severe illness other than pneumonia

• Severe malnutrition defined as being < 70% National Center for Health Statistics (NCHS) median weight for height

• Presence of congenital heart disease

• Documented tuberculosis

• Any antibiotic treatment during the last 48 hours

• The child was enrolled less than 6 months ago

• Presence of dysentery

• Cough for more than 14 days

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Siddhi Memorial Hospital (SMH),Bhelukhel, Bhimsensthan	Bhaktapur		Nepal	P.O.Box 40

Sponsors and Collaborators

• Centre For International Health
• Tribhuvan University, Nepal
• Statens Serum Institut
• All India Institute of Medical Sciences, New Delhi
• IRD, Epidemiologie et Prevention, Montpelier, France
• Society for Applied Studies

Investigators

• Principal Investigator: Tor A Strand, MD PhD, Centre for International Health, University of Bergen, 5021 Bergen, Norway
• Study Director: Halvor Sommerfelt, MD PhD, Centre for International Health, University of Bergen, 5021 Bergen, Norway
• Study Director: Prakash S Shrestha, MD Professor, Child Health Research Project, Department of Child Health, Institute of Medicine, Maharajganj
• Study Chair: Ramesh K Adhikari, MD Dean, Child Health Research Project, Department of Child Health, Institute of Medicine, Maharajganj
• Principal Investigator: Palle Valentiner-Branth, MD PhD, Department of Epidemiology Research, Statens Serum Institut, 2300 Copenhagen S, Denmark

Study Documents (Full-Text)

None provided.

More Information

Publications

• Bates CJ, Evans PH, Dardenne M, Prentice A, Lunn PG, Northrop-Clewes CA, Hoare S, Cole TJ, Horan SJ, Longman SC, et al. A trial of zinc supplementation in young rural Gambian children. Br J Nutr. 1993 Jan;69(1):243-55.
• Bates CJ, Prentice A. Breast milk as a source of vitamins, essential minerals and trace elements. Pharmacol Ther. 1994 Apr-May;62(1-2):193-220. Review.
• Bhandari N, Bahl R, Hambidge KM, Bhan MK. Increased diarrhoeal and respiratory morbidity in association with zinc deficiency--a preliminary report. Acta Paediatr. 1996 Feb;85(2):148-50.
• Bhandari N, Bahl R, Taneja S, Strand T, Mølbak K, Ulvik RJ, Sommerfelt H, Bhan MK. Effect of routine zinc supplementation on pneumonia in children aged 6 months to 3 years: randomised controlled trial in an urban slum. BMJ. 2002 Jun 8;324(7350):1358.
• Bhandari N, Bahl R, Taneja S, Strand T, Mølbak K, Ulvik RJ, Sommerfelt H, Bhan MK. Substantial reduction in severe diarrheal morbidity by daily zinc supplementation in young north Indian children. Pediatrics. 2002 Jun;109(6):e86.
• Bhutta ZA, Black RE, Brown KH, Gardner JM, Gore S, Hidayat A, Khatun F, Martorell R, Ninh NX, Penny ME, Rosado JL, Roy SK, Ruel M, Sazawal S, Shankar A. Prevention of diarrhea and pneumonia by zinc supplementation in children in developing countries: pooled analysis of randomized controlled trials. Zinc Investigators' Collaborative Group. J Pediatr. 1999 Dec;135(6):689-97.
• Black RE. Therapeutic and preventive effects of zinc on serious childhood infectious diseases in developing countries. Am J Clin Nutr. 1998 Aug;68(2 Suppl):476S-479S. doi: 10.1093/ajcn/68.2.476S. Review.
• Brooks WA, Yunus M, Santosham M, Wahed MA, Nahar K, Yeasmin S, Black RE. Zinc for severe pneumonia in very young children: double-blind placebo-controlled trial. Lancet. 2004 May 22;363(9422):1683-8.
• Chai F, Truong-Tran AQ, Ho LH, Zalewski PD. Regulation of caspase activation and apoptosis by cellular zinc fluxes and zinc deprivation: A review. Immunol Cell Biol. 1999 Jun;77(3):272-8. Review.
• Hambidge KM, Krebs NF, Miller L. Evaluation of zinc metabolism with use of stable-isotope techniques: implications for the assessment of zinc status. Am J Clin Nutr. 1998 Aug;68(2 Suppl):410S-413S. doi: 10.1093/ajcn/68.2.410S. Review.
• Integrated management of the sick child. Bull World Health Organ. 1995;73(6):735-40.
• Lira PI, Ashworth A, Morris SS. Effect of zinc supplementation on the morbidity, immune function, and growth of low-birth-weight, full-term infants in northeast Brazil. Am J Clin Nutr. 1998 Aug;68(2 Suppl):418S-424S. doi: 10.1093/ajcn/68.2.418S.
• Sazawal S, Black RE, Bhan MK, Bhandari N, Sinha A, Jalla S. Zinc supplementation in young children with acute diarrhea in India. N Engl J Med. 1995 Sep 28;333(13):839-44.
• Sazawal S, Black RE, Bhan MK, Jalla S, Sinha A, Bhandari N. Efficacy of zinc supplementation in reducing the incidence and prevalence of acute diarrhea--a community-based, double-blind, controlled trial. Am J Clin Nutr. 1997 Aug;66(2):413-8.
• Sazawal S, Black RE, Jalla S, Mazumdar S, Sinha A, Bhan MK. Zinc supplementation reduces the incidence of acute lower respiratory infections in infants and preschool children: a double-blind, controlled trial. Pediatrics. 1998 Jul;102(1 Pt 1):1-5.
• Shankar AH, Prasad AS. Zinc and immune function: the biological basis of altered resistance to infection. Am J Clin Nutr. 1998 Aug;68(2 Suppl):447S-463S. doi: 10.1093/ajcn/68.2.447S. Review.
• Strand TA, Chandyo RK, Bahl R, Sharma PR, Adhikari RK, Bhandari N, Ulvik RJ, Mølbak K, Bhan MK, Sommerfelt H. Effectiveness and efficacy of zinc for the treatment of acute diarrhea in young children. Pediatrics. 2002 May;109(5):898-903.
• Truong-Tran AQ, Carter J, Ruffin R, Zalewski PD. New insights into the role of zinc in the respiratory epithelium. Immunol Cell Biol. 2001 Apr;79(2):170-7. Review.
• Walsh CT, Sandstead HH, Prasad AS, Newberne PM, Fraker PJ. Zinc: health effects and research priorities for the 1990s. Environ Health Perspect. 1994 Jun;102 Suppl 2:5-46. Review.

• Responsible Party: Tor A. Strand, Professor, Centre For International Health
• ClinicalTrials.gov Identifier: NCT00148733
• Other Study ID Numbers: 003740; 003740(Eur. Comm. INCO); NUFU PRO 36/2002
• First Posted: Sep 8, 2005
• Last Update Posted: Mar 16, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Tor A. Strand, Professor, Centre For International Health: Child; pneumonia; Zinc; clinical trial; Nepal; nutrition; therapeutic
• Additional relevant MeSH terms: Pneumonia

Study Results

Participant Flow

Arm/Group Title	Zinc	Placebo
Arm/Group Description	Zinc sulphate 10 or 20 mg (elemental zinc) per day. Intervention and placebo given perorally mixed with approximately 5 mL of breastmilk or clean water Zinc: Dissolvable zinc tablet 10 mg elemental zinc per day for infants 20 mg elemental zinc per day for children 12 to 35 months	Placebo Zinc: Dissolvable zinc tablet 10 mg elemental zinc per day for infants 20 mg elemental zinc per day for children 12 to 35 months
Period Title: Overall Study
STARTED	1314	1314
COMPLETED	1300	1299
NOT COMPLETED	14	15

Baseline Characteristics

Arm/Group Title	Zinc	Placebo	Total
Arm/Group Description	Zinc sulphate 10 or 20 mg (elemental zinc) per day. Intervention and placebo given perorally mixed with approximately 5 mL of breastmilk or clean water Zinc: Dissolvable zinc tablet 10 mg elemental zinc per day for infants 20 mg elemental zinc per day for children 12 to 35 months	Placebo Zinc: Dissolvable zinc tablet 10 mg elemental zinc per day for infants 20 mg elemental zinc per day for children 12 to 35 months	Total of all reporting groups
Overall Participants	1314	1314	2628
Age (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	7.3 (7.4)	7.2 (7.2)	7.2 (7.3)
Sex: Female, Male (Count of Participants)
Female	575 43.8%	576 43.8%	1151 43.8%
Male	739 56.2%	738 56.2%	1477 56.2%

Outcome Measures

1. Primary Outcome

Title	Risk of Treatment Failure.
Description	Enrolled children will be followed and given zinc or placebo for 14 days. We will compare the proportion with treatment failure (i.e. lack of improvement within 3 days) between the two groups
Time Frame	Within 2 weeks after enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Zinc	Placebo
Arm/Group Description	Zinc sulphate 10 or 20 mg (elemental zinc) per day. Intervention and placebo given perorally mixed with approximately 5 mL of breastmilk or clean water Zinc: Dissolvable zinc tablet 10 mg elemental zinc per day for infants 20 mg elemental zinc per day for children 12 to 35 months	Placebo Zinc: Dissolvable zinc tablet 10 mg elemental zinc per day for infants 20 mg elemental zinc per day for children 12 to 35 months
Measure Participants	1300	1299
Number [participants]	267 20.3%	253 19.3%

2. Primary Outcome

Title	Non-injury Clinic Visits and Hospital Admissions After Treatment Has Been Initiated
Description	We will measure to what extent the intervention can reduce the number of severe events.
Time Frame	Within 2 weeks after enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Primary Outcome

Title	Active and Passive Morbidity Surveillance for Six Months After the 14-day Supplementation Period is Completed
Description	We will measure to what extent short term zinc administration has an impact on growth and morbidity for up to 6 months after end of supplementation
Time Frame	six months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Primary Outcome

Title	Difference in Growth and Thymic Size Between the Treatment Groups Measured at Three and Six Months After the Zinc Supplementation
Description	Thymus size will be measured using ultrasonography and compared between the two groups. at two occasions 2.5 and 6 months after end of supplementation
Time Frame	six months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Primary Outcome

Title	Adverse Effects
Description	Vomiting, regurgitation, pain in abdomen for 15 minutes after zinc or placebo administration.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Effect Modifiers for the Effect of Zinc Given During Pneumonia
Description	We will also measure of there are factors at baseline that modifies the effect of zinc. Whether the following are modifiers for the above-mentioned effect of zinc given during pneumonia: i.severe inflammation, reflected in: high fever and/or elevated plasma C-reactive protein (CRP) concentration
Time Frame	Within 2 weeks after enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	The Efficacy of Zinc According to Breast Feeding Status and in Different Age Categories
Description	We will measure to what extent breastfeeding status modifies the effect of zinc on pneumonia
Time Frame	Within 2 weeks after enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	The Efficacy of Zinc in Malnourished and Non-malnourished Children
Description	We will compare the efficacy of zinc in those that are stunted, wasted or underweight with those who are not.
Time Frame	Within 2 weeks after enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Will Presence of a RNA Virus Modify the Effect of Zinc
Description	We will compare the efficacy of zinc according to virus detected in nasopharyngeal secretions
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	Folate, Cobalamin and Vitamin D Status of the Enrolled Children
Description	And whether or not these vitamins predict treatment failure and duration of illness.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	14 days, while zinc or placebo were given
Adverse Event Reporting Description	Vomiting following zinc or placebo supplementation
Arm/Group Title	Zinc		Placebo
Arm/Group Description	Zinc sulphate 10 or 20 mg (elemental zinc) per day. Intervention and placebo given perorally mixed with approximately 5 mL of breastmilk or clean water Zinc: Dissolvable zinc tablet 10 mg elemental zinc per day for infants 20 mg elemental zinc per day for children 12 to 35 months		Placebo Zinc: Dissolvable zinc tablet 10 mg elemental zinc per day for infants 20 mg elemental zinc per day for children 12 to 35 months
All Cause Mortality
	Zinc		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Zinc		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1314 (0%)		0/1314 (0%)
Other (Not Including Serious) Adverse Events
	Zinc		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	181/1314 (13.8%)		53/1314 (4%)
Gastrointestinal disorders
Regurgitation	181/1314 (13.8%)		53/1314 (4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.