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SepsisPhase 2/3NCT00347386

Therapeutic Zinc in Infant Bacterial Illness

A Phase 2/3 study testing Drug: Zinc (zinc sulphate) in people with Sepsis and Bacterial Infections, run by Centre For International Health at 3 sites in India.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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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. Read more about this study

Who is it for?
Ages 1 week to 4 months
Conditions the study is for
Sepsis, Bacterial Infections, Pneumonia
What is being tested?
Drug: Zinc (zinc sulphate)
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
700 participants
Where
3 sitesIndia
Study dates
Jul 2005to Dec 2008
Phase
Phase 2/3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 1 week to 4 months
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • 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.
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  • 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.

Who cannot join

  • 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.
Show all 19Show fewer
  • 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.

Trial locations and contacts

3 sites in 1 country.

India3 sites
  • Deen Dayal Upadhyay Hospital,

    New Delhi, New Delhi, 110064

  • All India Institute Of Medical Sciences

    New Delhi, New Delhi

  • Kalawati Saran Children Hospital

    New Delhi, New Delhi

Other trials in India

About this study

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

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.

Read more

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.

Read the 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.

Being tested
Drug: Zinc (zinc sulphate), Placebo
Keywords
Infants, India, Zinc, Bacterial illness, Treatment
Medical subject headings
Sepsis, Bacterial Infections, Pneumonia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Drug: Zinc (zinc sulphate)Drug

    Also called Produced by Nutriset, Malaunay, France

    Dissolvable tablet 10 mg. Once daily during the illness

  • PlaceboDrug

    Also called Produced by Nutriset, Malaunay, France

    Placebo tablet, once daily

Study groups in NCT00347386
Study groupRoleWhat they receive
ZincExperimentalAdministration of zinc sulphate every day during illness
Receives: Drug: Drug: Zinc (zinc sulphate)
PlaceboPlacebo comparatorPlacebo tablet
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. proportion with treatment failures

    Measured: Within 3 weeks after enrollment

Secondary outcomes (3)
  1. the effect of zinc administration on plasma zinc and copper

    Measured: up to three weeks

  2. The efficacy of zinc on the duration of severe bacterial illness

    Measured: 3 weeks

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

    Measured: 3 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted4 Jul 2006 (estimated)
  2. Study startJul 2005
  3. Primary completionDec 2008
  4. Study completionDec 2008

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
700 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00347386
Sponsor's protocol ID
INCO-CT-2004-003740-3
Status last verified
Dec 2010
First submitted
30 Jun 2006
Last updated
7 Dec 2010
Results posted
No
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 11509104
  • 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.

    PubMed 9701160
  • 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.

    PubMed 11101480
  • 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.

    PubMed 10586170
  • 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.

    PubMed 9164317
  • UNICEF. The State of the Worlds Children. New York, NY: Oxford University Press; 1999.

  • 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.

    PubMed 3665076
  • Goel R, Misra PK. Study of plasma zinc in neonates and their mothers. Indian Pediatr. 1982 Jul;19(7):611-4. No abstract available.

    PubMed 7174090
  • 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.

    PubMed 1813415
  • 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.

    PubMed 10944485
  • 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.

    PubMed 12036814
  • 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.

    PubMed 2458983
  • 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.

    PubMed 12672922
  • 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.

    PubMed 11694609
  • 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.

    PubMed 12324295

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Drug: Zinc (zinc sulphate) in people with Sepsis and Bacterial Infections, run by Centre For International Health at 3 sites in India.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 7 Dec 2010. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in India. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

proportion with treatment failures (time frame: Within 3 weeks after enrollment). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00347386, which also lists 24 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Dec 2010.

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