Ignite Creation Date:
2024-05-05 @ 5:36 PM
Last Modification Date:
2024-10-26 @ 9:34 AM
Study NCT ID:
NCT00495690
Status:
COMPLETED
Last Update Posted:
2011-09-15
First Post:
2007-06-30
Brief Title:
Impact of Daily Zinc Supplementation to Infants Born With Low Birth Weight on Death and Severe Disease
Sponsor:
Society for Applied Studies
Organization:
Society for Applied Studies
Study Overview
Official Title:
Impact of Daily Zinc Supplementation to Infants Born With Low Birth Weight on Mortality and Severe Disease Requiring Hospitalization
Status:
COMPLETED
Status Verified Date:
2011-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Title Impact of daily zinc supplementation to infants born with low birth weight on mortality and severe disease requiring hospitalization Background Zinc supplementation was shown to prevent diarrhea and pneumonia in 6 month to 3 year old children Little is known about the impact of zinc supplementation of low birth weight LBW babies during first 6 months of life
Objective The objectives were to determine the impact of daily zinc administration at 1RDA 5 mg of elemental zinc to LBW infants on severe morbidity requiring hospitalization and on all cause mortality
Design In a double blind randomized placebo controlled trial 2012 hospital-born infants with a birth weight 2500 g were randomly assigned to receive zinc or placebo for 6 months Zinc group received 5 mg elemental zinc as acetate daily from 4 weeks age Cause specific hospitalization deaths episodes of diarrhea acute respiratory infections other illness visits to health care providers and hospital OPDs were ascertained by in-depth interview and from documents like prescriptions hospital tickets medicine cartons at 3 and 6 months of age
Results Number of infants with one or more diarrhea episodes was less by 17 95 CI 1 to 35 in the zinc group but the numbers for ARI were similar in the two groups The hospitalization rates due to all causes or diarrhea or ARI were similar in the two groups Twelve in the zinc group and 9 in the placebo group died during 4 weeks to 6 months p036 We observed no significant difference for gain in weight and length at 3 months and 6 months between the groups In a subgroup of infants the mean serum zinc concentration in the zinc group was 27 higher p0004 than the placebo group
Conclusion Hospital born low birth weight infants do not seem to derive worthwhile benefit from daily zinc supplementation of recommended dietary allowance for zinc in terms of morbidity and growth during first six months of life
Objective The objectives were to determine the impact of daily zinc administration at 1RDA 5 mg of elemental zinc to LBW infants on severe morbidity requiring hospitalization and on all cause mortality
Design In a double blind randomized placebo controlled trial 2012 hospital-born infants with a birth weight 2500 g were randomly assigned to receive zinc or placebo for 6 months Zinc group received 5 mg elemental zinc as acetate daily from 4 weeks age Cause specific hospitalization deaths episodes of diarrhea acute respiratory infections other illness visits to health care providers and hospital OPDs were ascertained by in-depth interview and from documents like prescriptions hospital tickets medicine cartons at 3 and 6 months of age
Results Number of infants with one or more diarrhea episodes was less by 17 95 CI 1 to 35 in the zinc group but the numbers for ARI were similar in the two groups The hospitalization rates due to all causes or diarrhea or ARI were similar in the two groups Twelve in the zinc group and 9 in the placebo group died during 4 weeks to 6 months p036 We observed no significant difference for gain in weight and length at 3 months and 6 months between the groups In a subgroup of infants the mean serum zinc concentration in the zinc group was 27 higher p0004 than the placebo group
Conclusion Hospital born low birth weight infants do not seem to derive worthwhile benefit from daily zinc supplementation of recommended dietary allowance for zinc in terms of morbidity and growth during first six months of life
Detailed Description:
Objectives
iTo determine the impact of daily administration of 1 RDA 5 mg of elemental zinc to LBW infants from 4 weeks to 6 months of life on all-cause mortality
iiTo determine the impact of zinc supplementation on severe morbidity requiring hospitalization
Rationale
iThe prevalence of LBW is high in Asia particularly in South Asian countries like India Pakistan and Bangladesh LBW infants have a high neonatal and infant mortality and morbidity rates
iiA recent preliminary study showed that zinc supplementation of LBW infants reduced mortality Sazawal et al 2001
iiiA targeted intervention in LBW infants starting at about 4 weeks of age is programmatically highly attractive It can be combined with immunization program and with recent recommendation to give iron and folate to infants
ivThe fact that mortality rate is very high in LBW infants means a relatively smaller study will give us results suitable for a policy decision
Study population and location
The infants were recruited at birth at the maternity ward of MR Bangur General Hospital where more than 6000 deliveries take place in a year Located in Kolkata this hospital serves a district of West Bengal Preliminary data collected by us from four hospitals in West Bengal showed that little over 37 of the babies born there have a birth weight of less than 2500 g Taking conservative estimate of 35 of babies born to be of LBW 2500 g more than 2000 LBW babies are expected to be born at this hospital in a year LBW infants born at this hospital was recruited in this study and followed up at home Mainly the urban and peri-urban poor use these Government hospitals The hospital services are rendered free of charge by the Government
Sample size
One preliminary zinc supplementation trial in small-for-date infants reported as high as 67 reduction in the mortality rate with zinc supplementation between 2 and 9 months of age We consider this effect as highly optimistic Therefore we calculated the required sample size based on more conservative estimates at various levels of expected reduction in mortality rate associated with zinc supplementation of LBW infants
Taking a figure of infant mortality rate of 40100 in LBW infants and assuming that at least 50 of these deaths occurred between 4 weeks and 6 months of age We expect 20 deaths per 100 infants during the observation period for this study Assuming a reduction in the mortality rate by 35 with 95 confidence and 80 power we need a total sample size of 970 infants which includes 10 excess to account for deviated course eg Loss to follow-up withdrawal of consent Assuming a mortality rate reduction of 30 with similar assumption the total plus 10 for deviated courses sample size should be 1360 in LBW infants If we expect a reduction in mortality rate by 25 the total sample size would be 1900 infants which include 10 for deviated course
Inclusion criteria
1 Weight at birth less than 2500 g
2 Infant is likely to stay in the city for the next 6 months
3 Absence of gross congenital malformation
Exclusion criteria
1 Perinatal illness requiring hospital stay after birth for more than 7 days
2 Written informed consent was not provided by parents
3 Presence of gross congenital anomaly
4 Resides at a distance that makes it difficult to reach for home visit estimated time to reach in more than 3 hours
Randomization and blinding
The inclusion criteria were ascertained and those eligible were considered for inclusion into the study The child visited the clinic or a home visit was made at 3-4 weeks by a team of health workers and if still alive the infant was randomly assigned to the zinc or to the placebo group A master randomization code was prepared by using permuted blocks of random numbers using block lengths of 4 6 and 8 This code was held by a person not involved with the study who numbered the bottles containing the formulation or placebo for each child according to the randomization chart and the bottles were labeled only with the serial numbers of the child in the study The final code was kept with a person not involved with the study The zinc syrup and the placebo were similar in appearance consistency and taste
Intervention
Each infant in the study received placebo or 5 mg of elemental zinc 1 RDA as zinc acetate syrup daily from 4 weeks of age For routine immunization and other care parents were advised to attend the baby clinic of the same hospital or another hospital in the locality In case of any reported or detected illness by the field workers free drugs were provided and hospitalization facilitated when required
Enrollment of subjects
We estimate that 80 of the LBW babies can be realistically included in the study We have earlier estimated that approximately a little over 2000 LBW babies were born in a year in each hospital We recruited a total of 2012 infants 1005 in the zinc group and 1007 in the placebo group
After obtaining an informed verbal consent the infant eligible for enrollment at the maternity ward was escorted home by a health worker to note the exact location of their stay The mother was advised to bring the infant to the hospital at 4 weeks where baseline information on the infant were recorded and 8 weeks supply of the zincplacebo formulation was provided to the parents with instruction for use The mother under supervision gave the first dose at the clinic If the mother did not return at 4 weeks after birth field workers were visited home and the medicine was provided as above The field workers visited the home 8 weeks later recorded the events about the infant and provided another 8 weeks to medicine After 16 weeks of medication the infant visited the clinic or a field visit was made to ascertain the state of the infant and was provided with 8 weeks of medication and evaluation was recorded after 8 weeks
Measurement of study outcome
Death if any was recorded at each contact The cause of death was ascertained by a verbal autopsy Available hospital records were examined and a team of pediatricians independently reviewed verbal autopsy questionnaires The diagnosis was made by consensus or through discussion Similarly illness events requiring hospitalization were documented at each contact A questionnaire was used and hospital records examined including all prescriptions At each contact either at the clinic or at home the details of illness events and treatment received were recorded in a standardized data forms and documentations such as prescriptions medicine bottles or cartons were physically checked and recorded Anthropometric measurements were recorded at 3 and 6 months of receiving the medicines All documentations on morbidity were evaluated at fortnightly meetings of the health workers with the two pediatricians involved the study DM AS and the causes of hospital admissions deaths and morbidities were reviewed and a diagnosis was made recorded
Ethical considerations
Written informed consent was obtained from the parents Ethics Review Committee of the Society for Applied Studies Kolkata approved the protocol
Data management and statistical analysis
The data were entered into a desktop computer and edited using a software EPI Info CDC Atlanta USA and WHO Geneva and analyzed by EPI Info and another software named Stata Stata Corporation Texas USA The main comparison was between those who received zinc and those who received placebo Baseline information was compared to evaluate the comparability of the two groups These include socio-economic variables type of delivery gestation birth weight breast-feeding status etc The two groups were compared for all-cause mortality The proportion of infants having illness requiring hospitalization in the two groups was compared For this comparison only the first episode requiring hospitalization in a particular infant was considered Although the follow-up period would be very similar some degree of variable follow-up was expected which was addressed by using person-time calculation between 4 weeks and end of the study The analysis was based on intention-to-treat
Results
About 20248 neonates were evaluated for eligibility at the maternity ward of MR Bangur Hospital of whom 5942 had 2500g weight A total of 2012 infants were admitted into the study 1005 being in the zinc group and 1007 in the placebo group A total of 909 infants in the zinc group and 913 in the placebo group completed 6 months of follow-up The birth weight type of delivery birth order and mothers education were comparable in the two groups Weight length head and midarm circumference at 3 and 6 months were similar in the two groups In a subgroup of infants blood hemoglobin levels were determined on completion of the study and the mean values in the two groups were similar In a subgroup of infants zinc supplemented group should a substantially higher mean zinc concentration compared to placebo The numbers of deaths in the two groups were not significantly different Hospitalization rates with diarrhea ARI and all causes are similar in the two groups The number of infants with one or more episodes of diarrhea was significantly less among zinc supplemented group by 17 95 CI1 to 35 The number of infants with one or more episodes of acute respiratory infection was similar in two groups p076
iTo determine the impact of daily administration of 1 RDA 5 mg of elemental zinc to LBW infants from 4 weeks to 6 months of life on all-cause mortality
iiTo determine the impact of zinc supplementation on severe morbidity requiring hospitalization
Rationale
iThe prevalence of LBW is high in Asia particularly in South Asian countries like India Pakistan and Bangladesh LBW infants have a high neonatal and infant mortality and morbidity rates
iiA recent preliminary study showed that zinc supplementation of LBW infants reduced mortality Sazawal et al 2001
iiiA targeted intervention in LBW infants starting at about 4 weeks of age is programmatically highly attractive It can be combined with immunization program and with recent recommendation to give iron and folate to infants
ivThe fact that mortality rate is very high in LBW infants means a relatively smaller study will give us results suitable for a policy decision
Study population and location
The infants were recruited at birth at the maternity ward of MR Bangur General Hospital where more than 6000 deliveries take place in a year Located in Kolkata this hospital serves a district of West Bengal Preliminary data collected by us from four hospitals in West Bengal showed that little over 37 of the babies born there have a birth weight of less than 2500 g Taking conservative estimate of 35 of babies born to be of LBW 2500 g more than 2000 LBW babies are expected to be born at this hospital in a year LBW infants born at this hospital was recruited in this study and followed up at home Mainly the urban and peri-urban poor use these Government hospitals The hospital services are rendered free of charge by the Government
Sample size
One preliminary zinc supplementation trial in small-for-date infants reported as high as 67 reduction in the mortality rate with zinc supplementation between 2 and 9 months of age We consider this effect as highly optimistic Therefore we calculated the required sample size based on more conservative estimates at various levels of expected reduction in mortality rate associated with zinc supplementation of LBW infants
Taking a figure of infant mortality rate of 40100 in LBW infants and assuming that at least 50 of these deaths occurred between 4 weeks and 6 months of age We expect 20 deaths per 100 infants during the observation period for this study Assuming a reduction in the mortality rate by 35 with 95 confidence and 80 power we need a total sample size of 970 infants which includes 10 excess to account for deviated course eg Loss to follow-up withdrawal of consent Assuming a mortality rate reduction of 30 with similar assumption the total plus 10 for deviated courses sample size should be 1360 in LBW infants If we expect a reduction in mortality rate by 25 the total sample size would be 1900 infants which include 10 for deviated course
Inclusion criteria
1 Weight at birth less than 2500 g
2 Infant is likely to stay in the city for the next 6 months
3 Absence of gross congenital malformation
Exclusion criteria
1 Perinatal illness requiring hospital stay after birth for more than 7 days
2 Written informed consent was not provided by parents
3 Presence of gross congenital anomaly
4 Resides at a distance that makes it difficult to reach for home visit estimated time to reach in more than 3 hours
Randomization and blinding
The inclusion criteria were ascertained and those eligible were considered for inclusion into the study The child visited the clinic or a home visit was made at 3-4 weeks by a team of health workers and if still alive the infant was randomly assigned to the zinc or to the placebo group A master randomization code was prepared by using permuted blocks of random numbers using block lengths of 4 6 and 8 This code was held by a person not involved with the study who numbered the bottles containing the formulation or placebo for each child according to the randomization chart and the bottles were labeled only with the serial numbers of the child in the study The final code was kept with a person not involved with the study The zinc syrup and the placebo were similar in appearance consistency and taste
Intervention
Each infant in the study received placebo or 5 mg of elemental zinc 1 RDA as zinc acetate syrup daily from 4 weeks of age For routine immunization and other care parents were advised to attend the baby clinic of the same hospital or another hospital in the locality In case of any reported or detected illness by the field workers free drugs were provided and hospitalization facilitated when required
Enrollment of subjects
We estimate that 80 of the LBW babies can be realistically included in the study We have earlier estimated that approximately a little over 2000 LBW babies were born in a year in each hospital We recruited a total of 2012 infants 1005 in the zinc group and 1007 in the placebo group
After obtaining an informed verbal consent the infant eligible for enrollment at the maternity ward was escorted home by a health worker to note the exact location of their stay The mother was advised to bring the infant to the hospital at 4 weeks where baseline information on the infant were recorded and 8 weeks supply of the zincplacebo formulation was provided to the parents with instruction for use The mother under supervision gave the first dose at the clinic If the mother did not return at 4 weeks after birth field workers were visited home and the medicine was provided as above The field workers visited the home 8 weeks later recorded the events about the infant and provided another 8 weeks to medicine After 16 weeks of medication the infant visited the clinic or a field visit was made to ascertain the state of the infant and was provided with 8 weeks of medication and evaluation was recorded after 8 weeks
Measurement of study outcome
Death if any was recorded at each contact The cause of death was ascertained by a verbal autopsy Available hospital records were examined and a team of pediatricians independently reviewed verbal autopsy questionnaires The diagnosis was made by consensus or through discussion Similarly illness events requiring hospitalization were documented at each contact A questionnaire was used and hospital records examined including all prescriptions At each contact either at the clinic or at home the details of illness events and treatment received were recorded in a standardized data forms and documentations such as prescriptions medicine bottles or cartons were physically checked and recorded Anthropometric measurements were recorded at 3 and 6 months of receiving the medicines All documentations on morbidity were evaluated at fortnightly meetings of the health workers with the two pediatricians involved the study DM AS and the causes of hospital admissions deaths and morbidities were reviewed and a diagnosis was made recorded
Ethical considerations
Written informed consent was obtained from the parents Ethics Review Committee of the Society for Applied Studies Kolkata approved the protocol
Data management and statistical analysis
The data were entered into a desktop computer and edited using a software EPI Info CDC Atlanta USA and WHO Geneva and analyzed by EPI Info and another software named Stata Stata Corporation Texas USA The main comparison was between those who received zinc and those who received placebo Baseline information was compared to evaluate the comparability of the two groups These include socio-economic variables type of delivery gestation birth weight breast-feeding status etc The two groups were compared for all-cause mortality The proportion of infants having illness requiring hospitalization in the two groups was compared For this comparison only the first episode requiring hospitalization in a particular infant was considered Although the follow-up period would be very similar some degree of variable follow-up was expected which was addressed by using person-time calculation between 4 weeks and end of the study The analysis was based on intention-to-treat
Results
About 20248 neonates were evaluated for eligibility at the maternity ward of MR Bangur Hospital of whom 5942 had 2500g weight A total of 2012 infants were admitted into the study 1005 being in the zinc group and 1007 in the placebo group A total of 909 infants in the zinc group and 913 in the placebo group completed 6 months of follow-up The birth weight type of delivery birth order and mothers education were comparable in the two groups Weight length head and midarm circumference at 3 and 6 months were similar in the two groups In a subgroup of infants blood hemoglobin levels were determined on completion of the study and the mean values in the two groups were similar In a subgroup of infants zinc supplemented group should a substantially higher mean zinc concentration compared to placebo The numbers of deaths in the two groups were not significantly different Hospitalization rates with diarrhea ARI and all causes are similar in the two groups The number of infants with one or more episodes of diarrhea was significantly less among zinc supplemented group by 17 95 CI1 to 35 The number of infants with one or more episodes of acute respiratory infection was similar in two groups p076
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None