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

Pneumonia Clinical Trial

Official title:

Community- and Health Facility-based Intervention With Zinc as Adjuvant Therapy for Pneumonia to Enhance Child Health and Nutrition

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00148733
• Other study ID #: 003740
• Secondary ID: 003740(Eur. Comm
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: January 2004
• Est. completion date: January 2008

Study information

• Verified date: March 2022
• Source: Centre For International Health
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2628
• Est. completion date: January 2008
• Est. primary completion date: January 2008
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Months to 3 Years

Eligibility

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

Related Conditions & MeSH terms

• Pneumonia

Intervention

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

Locations

Country	Name	City	State
Nepal	Siddhi Memorial Hospital (SMH),Bhelukhel, Bhimsensthan	Bhaktapur

Sponsors (6)

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

Country where clinical trial is conducted

Nepal, 

References & Publications (19)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Integrated management of the sick child. Bull World Health Organ. 1995;73(6):735-40. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Risk of Treatment Failure.	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	Within 2 weeks after enrollment
Primary	Non-injury Clinic Visits and Hospital Admissions After Treatment Has Been Initiated	We will measure to what extent the intervention can reduce the number of severe events.	Within 2 weeks after enrollment
Primary	Active and Passive Morbidity Surveillance for Six Months After the 14-day Supplementation Period is Completed	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	six months
Primary	Difference in Growth and Thymic Size Between the Treatment Groups Measured at Three and Six Months After the Zinc Supplementation	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	six months
Primary	Adverse Effects	Vomiting, regurgitation, pain in abdomen for 15 minutes after zinc or placebo administration.	14 days
Secondary	Effect Modifiers for the Effect of Zinc Given During Pneumonia	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	Within 2 weeks after enrollment
Secondary	The Efficacy of Zinc According to Breast Feeding Status and in Different Age Categories	We will measure to what extent breastfeeding status modifies the effect of zinc on pneumonia	Within 2 weeks after enrollment
Secondary	The Efficacy of Zinc in Malnourished and Non-malnourished Children	We will compare the efficacy of zinc in those that are stunted, wasted or underweight with those who are not.	Within 2 weeks after enrollment
Secondary	Will Presence of a RNA Virus Modify the Effect of Zinc	We will compare the efficacy of zinc according to virus detected in nasopharyngeal secretions	14 days
Secondary	Folate, Cobalamin and Vitamin D Status of the Enrolled Children	And whether or not these vitamins predict treatment failure and duration of illness.	14 days