Therapeutic Zinc in Infant Bacterial Illness

Sepsis Clinical Trial

Official title:

Zinc as an Immunomodulator in the Treatment of Possible Serious Bacterial Infections in Infants 7 Days and up to 4 Months of Age

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00347386
• Other study ID #: INCO-CT-2004-003740-3
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: June 30, 2006
• Last updated: December 6, 2010
• Start date: July 2005
• Est. completion date: December 2008

Study information

• Verified date: December 2010
• Source: Centre For International Health
• Contact: n/a
• Is FDA regulated: No
• Health authority: India: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

Description:

Infant mortality rate continues to be high in most developing countries despite advances in child health care. Infections are the most important cause of deaths in infants. There is increasing recognition that nutritional deficiencies including micronutrients are important determinants of infection and their outcomes. Zinc is a crucial micronutrient as it influences various immune mechanisms and modulates host resistance to several pathogens. Supplementation with zinc has been documented to provide protection against common childhood infections. It has also 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. This is critical to demonstrate because nearly 80% of infant mortality occurs in first 2 months of life.

The infant mortality rates in India continue to be in excess of 60 per 1000 live births. Neonatal mortality contributes to over 64% of the infant deaths particularly in those who are born low birth weight. Most of the other deaths occur in the second and third months. Serious systemic infections like sepsis and pneumonia constitute 30-40% of the causes of mortality. Any health programme that aims at reducing infant mortality rate needs to address mortality in the first two months of life.

Almost 90% of all low birth weight (LBW) babies are born in developing countries, particularly in the Indian subcontinent. Nearly 70% of these are small for gestational age unlike in the developed world where the bulk of low birth weight babies are preterms. Zinc deficiency during fetal development is documented to cause intra-uterine growth retardation and also impaired postnatal immune functions making these babies more susceptible to severe infections. Studies have shown good correlation between cord blood zinc, maternal zinc concentration and birth weights.

The zinc content of the breast milk decreases rapidly after birth. In addition, the requirements are likely to be high as young infants in developing countries live in high microbial load environment and are exposed to recurrent infections. Further, malnourished infants need more zinc for catch up growth. All these predispose them to develop zinc deficiency and infections. In a population based study by our group last year, nearly 40% of young infants had low plasma zinc despite being breast-fed, probably a reflection of inadequate tissue stores (unpublished data).

Zinc influences many aspects of the immune system starting with its effects on the barrier and various components of innate and acquired immunity. There is sufficient data from animal and human studies of increased host susceptibility to infections with zinc deficiency. A vicious cycle of infection and zinc deficiency exists. Infection reduces the plasma zinc concentration, which reflects the severity of the infection and inflammation. This may be observed early during the illness. Organs such as the skin, thymus, bones and the epithelium also become depleted during this process. Severe bacterial illnesses also lead to zinc redistribution. It is plausible that this redistribution increases the infection severity.

There is limited data on therapeutic effect of zinc supplementation on severe infections in young infants less than 4 months of age. A short inexpensive course of zinc for patients with serious bacterial infections can become a simple but potent intervention to reduce young infant mortality and morbidity. While the effects of zinc deficiency and of supplementation are reasonably well documented eventually the benefits on clinical outcome alone can result in its application.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 700
• Est. completion date: December 2008
• Est. primary completion date: December 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 4 Months

Eligibility

Inclusion Criteria:

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.

Exclusion Criteria:

• 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.

• Presence of murmur > grade 3/6.

• Ambiguous genitalia.

• Known chromosomal abnormality.

• Infants requiring exchange transfusion.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Bacterial Infections
• Pneumonia
• Sepsis

Intervention

Drug:
• Drug: Zinc (zinc sulphate)
Dissolvable tablet 10 mg. Once daily during the illness
• Placebo
Placebo tablet, once daily

Locations

Country	Name	City	State
India	All India Institute Of Medical Sciences	New Delhi
India	Deen Dayal Upadhyay Hospital,	New Delhi
India	Kalawati Saran Children Hospital	New Delhi

Sponsors (2)

Lead Sponsor	Collaborator
Centre For International Health	All India Institute of Medical Sciences, New Delhi

Country where clinical trial is conducted

India, 

References & Publications (22)

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. — 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, 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. — 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

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. — 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

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. — View Citation

Cousins RJ, Leinart AS. Tissue-specific regulation of zinc metabolism and metallothionein genes by interleukin 1. FASEB J. 1988 Oct;2(13):2884-90. — View Citation

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. — View Citation

Goel R, Misra PK. Study of plasma zinc in neonates and their mothers. Indian Pediatr. 1982 Jul;19(7):611-4. — View Citation

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. — View Citation

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. — View Citation

Lind T, Lönnerdal B, Stenlund H, Ismail D, Seswandhana R, Ekström 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. — View Citation

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. — View Citation

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. — View Citation

Prasad AS. Effects of zinc deficiency on Th1 and Th2 cytokine shifts. J Infect Dis. 2000 Sep;182 Suppl 1:S62-8. — View Citation

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

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. Review. — View Citation

Singh PP, Khushlani K, Veerwal PC, Gupta RC. Maternal hypozincemia and low-birth-weight infants. Clin Chem. 1987 Oct;33(10):1950. — 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

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

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. — View Citation

* Note: There are 22 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	proportion with treatment failures		Within 3 weeks after enrollment	No
Secondary	the effect of zinc administration on plasma zinc and copper		up to three weeks	No
Secondary	The efficacy of zinc on the duration of severe bacterial illness		3 weeks	No
Secondary	The efficacy of zinc given during severe bacterial illness on markers of inflammation		3 weeks	No