Therapeutic Zinc in Infant Bacterial Illness

NCT00347386 | Completed Phase 2 DMC

• 1 other identifier: INCO-CT-2004-003740-3
• Study Type: interventional
• Target: 700
• Locations: 1 country
• Sites: 3

Brief Summary

Infections are the important cause of high mortality in young infants in developing countries. Zinc is a crucial micronutrient as it influences various immune mechanisms and modulates host resistance to several pathogens. It has shown benefits as an adjunct therapy in infections like diarrhea and pneumonia in older children Given the predisposition of young infants in developing countries to zinc deficiency and infections, addition of zinc to standard treatment of serious bacterial infections may lead to significant improvements in the outcomes. Several hypotheses will be examined in this clinical trial. The primary objective is to measure, in a double blind randomized controlled trial, the efficacy of giving 2 RDA (Required Daily Allowance 10 mg) of zinc orally in addition to routine antibiotics, for treatment of possible serious bacterial infection in infants \>= 7 days and up to 4 months of age in reducing the proportion of treatment failures and time to discharge from the hospital. This will evaluate the clinical consequences of the possible immunomodulation by zinc supplementation. This is critical to demonstrate because nearly 80% of infant mortality occurs in first months of life. Young infants with possible serious bacterial infections fulfilling the inclusion criteria will be enrolled in the study and stratified into 4 groups on basis of weight for age 'z' scores \< -2 z and \>=- 2 z and whether he/she has diarrhea or not. Within each stratum the subjects will be randomized to receive zinc or placebo. Treatment failures will be defined by the need for a change of initial antibiotic therapy. The minimum duration of monitoring will be till clinical recovery (using predetermined criteria). Serum copper, serum ferritin and serum transferrin receptors will be determined at enrollment, 72 hours after enrollment and at discharge from the hospital. Concentrations of CRP and procalcitonin will be measured at baseline, 72 hours after enrolment and at clinical recovery. Documentation of efficacy of addition of zinc to standard therapy may provide a simple and low-cost strategy to improve survival in serious infections in young infants. This is likely to have a significant impact on infant morbidity and mortality. It will be good example of using a simple immunomodulator beneficially in improving child health.

Conditions

Sepsis; Bacterial Infections; Pneumonia

Keywords

Infants; India; Zinc; Bacterial illness; Treatment

Outcome Measures

Primary Outcomes (1)

• proportion with treatment failures

  Within 3 weeks after enrollment

Secondary Outcomes (3)

• the effect of zinc administration on plasma zinc and copper

  up to three weeks

• The efficacy of zinc on the duration of severe bacterial illness

  3 weeks

• The efficacy of zinc given during severe bacterial illness on markers of inflammation

  3 weeks

Study Arms (2)

Zinc

EXPERIMENTAL

Administration of zinc sulphate every day during illness

Drug: Drug: Zinc (zinc sulphate)

Placebo

PLACEBO COMPARATOR

Placebo tablet

Drug: Placebo

Interventions

Drug: Zinc (zinc sulphate) DRUG

Dissolvable tablet 10 mg. Once daily during the illness

Also known as: Produced by Nutriset, Malaunay, France

Zinc

Placebo DRUG

Placebo tablet, once daily

Also known as: Produced by Nutriset, Malaunay, France

Placebo

Eligibility Criteria

• Age: 1 Week - 4 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Evidence of possible serious bacterial infection, defined as a CRP \>= 12 mg/L and any one of the following clinical features:
• Fever (axillary temperature \>= 37.5 degrees C) or hypothermia (axillary temperature \<35.5 degrees C).
• Lethargic or unconscious. No attachment to the breast in breast fed infants. No suckling in breast fed infants. Convulsions in the present episode. Bulging fontanel.
• History of acute refusal of feed in the present episode.
• Acute history of excessive cry or irritability in the present episode.
• Fast breathing defined as \>= 60 breaths/minute (on second count) for infants \< 2 months and \>= 50 breaths/min in infants 2 months up to 4 months.
• Grunting in the absence of any non infective cause.
• Cyanosis in the absence of any non infective cause.
• Severe chest in drawing.
• Unexplained shock.
• Diarrhea in present episode.

You may not qualify if:

• Congenital malformations e.g. hydrocephalus, structural CNS malformation.
• Severe birth asphyxia defined as:
• One minute APGAR (if available) of \< 4/10.
• CT scan or MRI or EEG abnormalities if available suggestive of hypoxic ischemic encephalopathy.
• Known structural defects, which interfere with feeding, e.g.cleft palate esophageal abnormalities, intestinal atresia and stenosis, malrotation of the gut,anorectal malformation.
• Subjects requiring ventilation or ionotropic support.
• History of diarrhea in the present episode.
• Known inborn error of metabolism.
• Chronic disorders of other organs e.g. neonatal cholestasis, chronic renal failure, pre-existing seizure disorder.
• Infants born of known HIV mothers.
• Clinical suspicion of necrotising enterocolitis.
• Congenital heart disease.
• Any CVS malformation:
• Congenital heart disease.
• Cyanosis before present episode.

Sponsors & Collaborators

• Centre For International Health: lead
• All India Institute of Medical Sciences: collaborator

Study Sites (3)

Deen Dayal Upadhyay Hospital,

New Delhi, New Delhi, 110064, India

Location

All India Institute Of Medical Sciences

New Delhi, New Delhi, India

Location

Kalawati Saran Children Hospital

New Delhi, New Delhi, India

Location

Related Publications (24)

• Mahalanabis D, Bhan MK. Micronutrients as adjunct therapy of acute illness in children: impact on the episode outcome and policy implications of current findings. Br J Nutr. 2001 May;85 Suppl 2:S151-8. doi: 10.1079/bjn2000308.

  PMID: 11509104 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.

  PMID: 9701160 BACKGROUND

• Bhutta ZA, Bird SM, Black RE, Brown KH, Gardner JM, Hidayat A, Khatun F, Martorell R, Ninh NX, Penny ME, Rosado JL, Roy SK, Ruel M, Sazawal S, Shankar A. Therapeutic effects of oral zinc in acute and persistent diarrhea in children in developing countries: pooled analysis of randomized controlled trials. Am J Clin Nutr. 2000 Dec;72(6):1516-22. doi: 10.1093/ajcn/72.6.1516.

  PMID: 11101480 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.

  PMID: 10586170 BACKGROUND

• Murray CJ, Lopez AD. Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet. 1997 May 17;349(9063):1436-42. doi: 10.1016/S0140-6736(96)07495-8.

  PMID: 9164317 BACKGROUND

• UNICEF. The State of the Worlds Children. New York, NY: Oxford University Press; 1999.

  BACKGROUND

• Singh PP, Khushlani K, Veerwal PC, Gupta RC. Maternal hypozincemia and low-birth-weight infants. Clin Chem. 1987 Oct;33(10):1950. No abstract available.

  PMID: 3665076 BACKGROUND

• Goel R, Misra PK. Study of plasma zinc in neonates and their mothers. Indian Pediatr. 1982 Jul;19(7):611-4. No abstract available.

  PMID: 7174090 BACKGROUND

• Jeswani RM, Vani SN. A study of serum zinc levels in cord blood of neonates and their mothers. Indian J Pediatr. 1991 Sep-Oct;58(5):683-6. doi: 10.1007/BF02820191.

  PMID: 1813415 BACKGROUND

• Prasad AS. Effects of zinc deficiency on Th1 and Th2 cytokine shifts. J Infect Dis. 2000 Sep;182 Suppl 1:S62-8. doi: 10.1086/315916.

  PMID: 10944485 BACKGROUND

• Brown KH, Peerson JM, Rivera J, Allen LH. Effect of supplemental zinc on the growth and serum zinc concentrations of prepubertal children: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2002 Jun;75(6):1062-71. doi: 10.1093/ajcn/75.6.1062.

  PMID: 12036814 BACKGROUND

• Cousins RJ, Leinart AS. Tissue-specific regulation of zinc metabolism and metallothionein genes by interleukin 1. FASEB J. 1988 Oct;2(13):2884-90. doi: 10.1096/fasebj.2.13.2458983.

  PMID: 2458983 BACKGROUND

• Zlotkin S, Arthur P, Schauer C, Antwi KY, Yeung G, Piekarz A. Home-fortification with iron and zinc sprinkles or iron sprinkles alone successfully treats anemia in infants and young children. J Nutr. 2003 Apr;133(4):1075-80. doi: 10.1093/jn/133.4.1075.

  PMID: 12672922 BACKGROUND

• Dijkhuizen MA, Wieringa FT, West CE, Martuti S, Muhilal. Effects of iron and zinc supplementation in Indonesian infants on micronutrient status and growth. J Nutr. 2001 Nov;131(11):2860-5. doi: 10.1093/jn/131.11.2860.

  PMID: 11694609 BACKGROUND

• Herman S, Griffin IJ, Suwarti S, Ernawati F, Permaesih D, Pambudi D, Abrams SA. Cofortification of iron-fortified flour with zinc sulfate, but not zinc oxide, decreases iron absorption in Indonesian children. Am J Clin Nutr. 2002 Oct;76(4):813-7. doi: 10.1093/ajcn/76.4.813.

  PMID: 12324295 BACKGROUND

• Lind T, Lonnerdal B, Stenlund H, Ismail D, Seswandhana R, Ekstrom EC, Persson LA. A community-based randomized controlled trial of iron and zinc supplementation in Indonesian infants: interactions between iron and zinc. Am J Clin Nutr. 2003 Apr;77(4):883-90. doi: 10.1093/ajcn/77.4.883.

  PMID: 12663287 BACKGROUND

• Schultink, W., Merzenich, M, Gross, R, Shrimpton, R, Dillon, D(1997). "Effects of iron-zinc supplementation on the iron, zinc, and vitamin A status of anamemic pre-school children. " Food and Nutrition Bulletin 18(4):311-16

  BACKGROUND

• Abdulla M, Suck C. Blood levels of copper, iron, zinc, and lead in adults in India and Pakistan and the effect of oral zinc supplementation for six weeks. Biol Trace Elem Res. 1998 Mar;61(3):323-31. doi: 10.1007/BF02789092.

  PMID: 9533570 BACKGROUND

• Brooks WA, Santosham M, Naheed A, Goswami D, Wahed MA, Diener-West M, Faruque AS, Black RE. Effect of weekly zinc supplements on incidence of pneumonia and diarrhoea in children younger than 2 years in an urban, low-income population in Bangladesh: randomised controlled trial. Lancet. 2005 Sep 17-23;366(9490):999-1004. doi: 10.1016/S0140-6736(05)67109-7.

  PMID: 16168782 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.

  PMID: 15158629 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.

  PMID: 12042580 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.

  PMID: 11986453 BACKGROUND

• Singh P, Wadhwa N, Lodha R, Sommerfelt H, Aneja S, Natchu UC, Chandra J, Rath B, Sharma VK, Kumari M, Saini S, Kabra SK, Bhatnagar S, Strand TA. Predictors of time to recovery in infants with probable serious bacterial infection. PLoS One. 2015 Apr 24;10(4):e0124594. doi: 10.1371/journal.pone.0124594. eCollection 2015.

  PMID: 25909192 DERIVED

• Bhatnagar S, Wadhwa N, Aneja S, Lodha R, Kabra SK, Natchu UC, Sommerfelt H, Dutta AK, Chandra J, Rath B, Sharma M, Sharma VK, Kumari M, Strand TA. Zinc as adjunct treatment in infants aged between 7 and 120 days with probable serious bacterial infection: a randomised, double-blind, placebo-controlled trial. Lancet. 2012 Jun 2;379(9831):2072-8. doi: 10.1016/S0140-6736(12)60477-2.

  PMID: 22656335 DERIVED

MeSH Terms

Conditions

Sepsis; Bacterial Infections; Pneumonia

Interventions

Zinc; Zinc Sulfate

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Bacterial Infections and Mycoses; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Metals, Heavy; Elements; Inorganic Chemicals; Transition Elements; Metals; Sulfates; Sulfuric Acids; Sulfur Acids; Sulfur Compounds; Zinc Compounds

Study Officials

• Shinjini Bhatnagar, DNB, PhD

  All India Institute of Medical Sciences

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: June 30, 2006
• First Posted: July 4, 2006
• Study Start: July 1, 2005
• Primary Completion: December 1, 2008
• Study Completion: December 1, 2008
• Last Updated: December 7, 2010

Record last verified: 2010-12

Locations

IN (3)