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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Pneumonia

Intervention / Treatment
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* Drug: Zinc


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 2 Months
Maximum Age: 3 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zinc<br>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<br>* Dissolvable zinc tablet 10 mg elemental zinc per day for infants 20 mg elemental zinc per day for children 12 to 35 months<br>* Other names: Produced by Nutriset, Malaunay, France;|
| Placebo Comparator: Placebo<br>Placebo | Drug: Zinc<br>* Dissolvable zinc tablet 10 mg elemental zinc per day for infants 20 mg elemental zinc per day for children 12 to 35 months<br>* Other names: Produced by Nutriset, Malaunay, France;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Child, pneumonia, Zinc, clinical trial, Nepal, nutrition, therapeutic