Clinical trial NCT00347386: Therapeutic Zinc in Infant Bacterial Illness
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Sepsis
Bacterial Infections
Pneumonia
Keywords: Infants
India
Zinc
Bacterial illness
Treatment
Lead sponsor: Centre For International Health
Sponsor class: OTHER
Collaborators: name: All India Institute of Medical Sciences
First posted: 2006-07-04
Enrollment: 700
Sex: ALL
Minimum age (years): 1
Maximum age (years): 4
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: proportion with treatment failures
timeFrame: Within 3 weeks after enrollment
Secondary outcomes:
measure: the effect of zinc administration on plasma zinc and copper
timeFrame: up to three weeks
measure: The efficacy of zinc on the duration of severe bacterial illness
timeFrame: 3 weeks
measure: The efficacy of zinc given during severe bacterial illness on markers of inflammation
timeFrame: 3 weeks
Other outcomes:
Locations:
city: New Delhi
country: India
facility: Deen Dayal Upadhyay Hospital,
city: New Delhi
country: India
facility: All India Institute Of Medical Sciences
city: New Delhi
country: India
facility: Kalawati Saran Children Hospital
Study officials:
affiliation: All India Institute of Medical Sciences
name: Shinjini Bhatnagar, DNB, PhD
role: PRINCIPAL_INVESTIGATOR
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