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| ID | Type | Description | Link |
|---|---|---|---|
| 003740(Eur. Comm. INCO) | Other Grant/Funding Number | European Union | |
| NUFU PRO 36/2002 | Other Grant/Funding Number | NUFU |
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| Name | Class |
|---|---|
| Tribhuvan University, Nepal | OTHER |
| Statens Serum Institut | OTHER |
| All India Institute of Medical Sciences | OTHER |
| IRD, Epidemiologie et Prevention, Montpelier, France |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Zinc | Experimental | 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 |
|
| Placebo | Placebo Comparator | Placebo |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Zinc | Drug | Dissolvable zinc tablet 10 mg elemental zinc per day for infants 20 mg elemental zinc per day for children 12 to 35 months |
|
| 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 |
| 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 |
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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:
Must be able to take Zinc
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Tor A Strand, MD PhD | Centre for International Health, University of Bergen, 5021 Bergen, Norway | Principal Investigator |
| 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 Director |
| Ramesh K Adhikari, MD Dean | Child Health Research Project, Department of Child Health, Institute of Medicine, Maharajganj | Study Chair |
| Palle Valentiner-Branth, MD PhD | Department of Epidemiology Research, Statens Serum Institut, 2300 Copenhagen S, Denmark | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Siddhi Memorial Hospital (SMH),Bhelukhel, Bhimsensthan | Bhaktapur | P.O.Box 40 | Nepal |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 10586170 | Background | 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. doi: 10.1016/s0022-3476(99)70086-7. | |
| 7991643 |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 Zinc: Dissolvable zinc tablet 10 mg elemental zinc per day for infants 20 mg elemental zinc per day for children 12 to 35 months |
| FG001 | Placebo | 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 |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 Zinc: Dissolvable zinc tablet 10 mg elemental zinc per day for infants 20 mg elemental zinc per day for children 12 to 35 months |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 | Posted | Number | participants | Within 2 weeks after enrollment |
|
14 days, while zinc or placebo were given
Vomiting following zinc or placebo supplementation
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 Zinc: Dissolvable zinc tablet 10 mg elemental zinc per day for infants 20 mg elemental zinc per day for children 12 to 35 months |
Not provided
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Regurgitation | Gastrointestinal disorders | Vomiting | Systematic Assessment | Study staff were observing the participants for 30 minutes after each dose of zinc or placebo. |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Tor A Strand | University of Bergen | 90971086 | tor.strand@cih.uib.no |
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| ID | Term |
|---|---|
| D011014 | Pneumonia |
| ID | Term |
|---|---|
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
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| ID | Term |
|---|---|
| D015032 | Zinc |
| ID | Term |
|---|---|
| D019216 | Metals, Heavy |
| D004602 | Elements |
| D007287 | Inorganic Chemicals |
| D028561 | Transition Elements |
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| UNKNOWN |
| Society for Applied Studies | OTHER |
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| 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 |
| Background |
| 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. doi: 10.1016/0163-7258(94)90011-6. |
| 7925188 | Background | 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(Suppl 2):5-46. doi: 10.1289/ehp.941025. |
| 11986453 | Background | Strand TA, Chandyo RK, Bahl R, Sharma PR, Adhikari RK, Bhandari N, Ulvik RJ, Molbak 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. doi: 10.1542/peds.109.5.898. |
| 8457531 | Background | 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. doi: 10.1079/bjn19930026. |
| 9701163 | Background | 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. |
| 9651405 | Background | 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. doi: 10.1542/peds.102.1.1. |
| 12052800 | Background | Bhandari N, Bahl R, Taneja S, Strand T, Molbak 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. doi: 10.1136/bmj.324.7350.1358. |
| 9701153 | Background | 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. |
| 10361260 | Background | 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. doi: 10.1046/j.1440-1711.1999.00825.x. |
| 11264713 | Background | 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. doi: 10.1046/j.1440-1711.2001.00986.x. |
| 9701160 | Background | 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. |
| 9701155 | Background | 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. |
| 12042580 | Background | Bhandari N, Bahl R, Taneja S, Strand T, Molbak 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. doi: 10.1542/peds.109.6.e86. |
| 15158629 | Background | 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. doi: 10.1016/S0140-6736(04)16252-1. |
| 8640039 | Background | 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. doi: 10.1111/j.1651-2227.1996.tb13981.x. |
| 9250122 | Background | 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. doi: 10.1093/ajcn/66.2.413. |
| 7651474 | Background | 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. doi: 10.1056/NEJM199509283331304. |
| 8907767 | Background | Integrated management of the sick child. Bull World Health Organ. 1995;73(6):735-40. |
| 26407163 | Derived | Haugen J, Chandyo RK, Brokstad KA, Mathisen M, Ulak M, Basnet S, Valentiner-Branth P, Strand TA. Cytokine Concentrations in Plasma from Children with Severe and Non-Severe Community Acquired Pneumonia. PLoS One. 2015 Sep 25;10(9):e0138978. doi: 10.1371/journal.pone.0138978. eCollection 2015. |
| 20375190 | Derived | Valentiner-Branth P, Shrestha PS, Chandyo RK, Mathisen M, Basnet S, Bhandari N, Adhikari RK, Sommerfelt H, Strand TA. A randomized controlled trial of the effect of zinc as adjuvant therapy in children 2-35 mo of age with severe or nonsevere pneumonia in Bhaktapur, Nepal. Am J Clin Nutr. 2010 Jun;91(6):1667-74. doi: 10.3945/ajcn.2009.28907. Epub 2010 Apr 7. |
| Placebo |
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 |
| BG002 | Total | Total of all reporting groups |
| months |
|
| Sex: Female, Male | Count of Participants | Participants |
|
|
|
| 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. | Not Posted | Dec 2024 | Within 2 weeks after enrollment | Participants |
| 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 | Not Posted | Dec 2024 | six months | Participants |
| 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 | Not Posted | Dec 2024 | six months | Participants |
| Primary | Adverse Effects | Vomiting, regurgitation, pain in abdomen for 15 minutes after zinc or placebo administration. | Not Posted | Dec 2024 | 14 days | Participants |
| 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 | Not Posted | Dec 2024 | Within 2 weeks after enrollment | Participants |
| 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 | Not Posted | Dec 2024 | Within 2 weeks after enrollment | Participants |
| 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. | Not Posted | Dec 2024 | Within 2 weeks after enrollment | Participants |
| 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 | Not Posted | Dec 2024 | 14 days | Participants |
| Secondary | Folate, Cobalamin and Vitamin D Status of the Enrolled Children | And whether or not these vitamins predict treatment failure and duration of illness. | Not Posted | Dec 2024 | 14 days | Participants |
| 0 |
| 1,314 |
| 181 |
| 1,314 |
| EG001 | Placebo | 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 | 0 | 1,314 | 53 | 1,314 |
|
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| D008670 |
| Metals |