Ignite Creation Date:
2024-05-06 @ 2:12 PM
Last Modification Date:
2024-10-26 @ 1:26 PM
Study NCT ID:
NCT04244474
Status:
UNKNOWN
Last Update Posted:
2020-01-28
First Post:
2020-01-24
Brief Title:
Effect of Vitamin D Supplementation on Improvement of Pneumonic Children
Sponsor:
Cairo University
Organization:
Cairo University
Study Overview
Official Title:
Randomized Controlled Trial of Vitamin D Supplementation on Improvement of Pneumonic Children at Tertiary Pediatric Hospital in Egypt
Status:
UNKNOWN
Status Verified Date:
2020-01
Last Known Status:
ACTIVE_NOT_RECRUITING
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:
In Egypt according to UNICEF 2018 Acute Respiratory Tract Infection ARTIswas estimated to account for 11 and 19 of the under-five and post-neonatal mortalities respectively
Despite the well-recognized role of vitamin D in metabolism and homeostasis in the general population there is now growing interest in its probable association with pneumonia
Globally about 30 to 90 of Under-5 children experience vitamin D deficiency This could vary among children according to the socioeconomic environmental and behavioral circumstances
Studies evaluating the association of 125 OH2D deficiency and the severity of respiratory tract infection are rare and showed controversial findings
However an Indian systematic review polled the results of 12 studies with 2279 participants highlighted the significant correlation between vitamin D deficiency and incidence and severity of ALRIs
A prospective cohort study conducted in Yemen examined the ability of deficient levels of vitD to predict the outcomes of severe pneumonia The study documented the significant association between vitamin D deficiency with neutropenia and hypoxia in patients with severe pneumonia thus predicting the poor prognosis
In Egypt 2010 a case-control study conducted on children aged 2 to 5 years to examine the impact of vitamin D deficiency on the susceptibility of pneumonia The study illustrated that Vitamin D deficiency is associated with a higher incidence and more severe pneumonia
Recent studies advocated providing childrenparticularly suffering from pneumonia with adequate amounts of vitamin D supplements
Nevertheless few studies have been conducted to evaluate the impact of vitamin D supplementation on the outcome of pneumonic infants
Thus we urge to conduct a randomized controlled trial RCT in Abou ElReesh tertiary Pediatric hospital to evaluate the effects of vitamin D3 supplementation to children with pneumonia We postulated that supplementation of 100 000 IU of vitamin D3 Cholecalciferol will reduce the duration of illness in those children and improve their outcome
Despite the well-recognized role of vitamin D in metabolism and homeostasis in the general population there is now growing interest in its probable association with pneumonia
Globally about 30 to 90 of Under-5 children experience vitamin D deficiency This could vary among children according to the socioeconomic environmental and behavioral circumstances
Studies evaluating the association of 125 OH2D deficiency and the severity of respiratory tract infection are rare and showed controversial findings
However an Indian systematic review polled the results of 12 studies with 2279 participants highlighted the significant correlation between vitamin D deficiency and incidence and severity of ALRIs
A prospective cohort study conducted in Yemen examined the ability of deficient levels of vitD to predict the outcomes of severe pneumonia The study documented the significant association between vitamin D deficiency with neutropenia and hypoxia in patients with severe pneumonia thus predicting the poor prognosis
In Egypt 2010 a case-control study conducted on children aged 2 to 5 years to examine the impact of vitamin D deficiency on the susceptibility of pneumonia The study illustrated that Vitamin D deficiency is associated with a higher incidence and more severe pneumonia
Recent studies advocated providing childrenparticularly suffering from pneumonia with adequate amounts of vitamin D supplements
Nevertheless few studies have been conducted to evaluate the impact of vitamin D supplementation on the outcome of pneumonic infants
Thus we urge to conduct a randomized controlled trial RCT in Abou ElReesh tertiary Pediatric hospital to evaluate the effects of vitamin D3 supplementation to children with pneumonia We postulated that supplementation of 100 000 IU of vitamin D3 Cholecalciferol will reduce the duration of illness in those children and improve their outcome
Detailed Description:
Subjects and Methods
Study design and study setting The current study is a randomized double-blinded placebo-controlled trial RCT that was conducted in Cairo University Abou ElReesh Children hospital which is a university-affiliated teaching hospital in Egypt to evaluate the effect of vitamin D3 supplementation on the outcome of treatment of children with pneumonia Pneumonia cases were recruited from two of the hospital general pediatric departments and the four pediatric intensive care units PICUs of the hospital
Sample Size and study population To detect a 20 difference in the mean duration of pneumonia between the vitamin D arm and control arm 5 days vs 6 days SD 2 allowing Type I error of 5 and Type II error of 10 86 per group 172 total is the minimum number to be recruited After allowing for 10 for nonresponse or loss for follow-up and 25 for the exclusion of children diagnosed with sufficient or toxic level of vitamin D after vitamin D testing Box 1 according to the prevalence of vitamin deficiency in a pediatric hospital of eastern India 233 was the minimum number to start with
Mild and moderate pneumonia cases were recruited from two of the hospital general pediatric departments chosen by a simple random sample from a total of six hospital departments while severe pneumonia cases were recruited from the four PICUs of the hospital
All children 259 children between 1 month and 12 years of age admitted to the selected departments during the period from 9th September 2019 to 15th December 2019 and diagnosed clinically with pneumonia according to the World Health Organization criteria of severity Box 2 were screened for the inclusion criteria Children who had clinical signs of rickets 2 children severe illnesses meningitis heart or renal disorders measles severe malnutrition endocrine dysfunction hypercalcemia hyperthyroidism and suspected tuberculosis 4 children or were known to have received high-dose vitamin D treatment in the past 3 months 3 children were excluded from the study Children with sufficient 52 children or toxic 7 children levels of vitamin D were also excluded
Thus 191 child 93 in the intervention arm and 98 in the control arm who had pneumonia with insufficient or deficient level of vitamin D and their parents consented to participate were enrolled in the study completed the baseline and the outcome assessments and continued the daily clinical follow up till their discharge improvement or death from the hospital
Box 1 Level of vitamin D Sufficient vitamin D 25OHD 30 ngmL Insufficient vitamin D 25OHD or at risk of deficiency 10-29 ngmL and Deficient vitamin D 25OHD 10 ng mL
Box 2 Diagnosis of Pneumonia Pneumonia i Age-specific tachypnoea 60 min if 2 months 50 min if 2-11 months 40 if 12-24 months and ii absence of wheeze with or without fever
Fever Axillary temperature 3750 _C age 1 week- 3 months or 380 _C 2-23 months
axillary temperature was measured using a standard mercury thermometers Respiratory rate was measured twice for one full minute while the child is quiet using stopwatches taking the average count
Mild pneumonia Minimally increased work of breathing no hypoxemia able to tolerate PO Moderate pneumonia Hypoxemia inability to tolerate PO moderately increased work of breathing grunting retracting tachypnea
Severe Pneumonia Significantly increased work of breathing altered mental state concern for respiratory failure sepsis failure to maintain oxygen saturation with Fi02 of 50 need for positive pressure ventilation Oxygen saturation was measured using a pulse oximeter with a probe on a finger or toe in-room air
Improvement discharge criteria Meets all tolerating PO not hypoxemic more than 90 mildly increase or normal work of breathing
Vitamin D testing Two milliliters of venous blood was collected on plain tubes left for 10 min to clot and then centrifuged at 3000 rpm for 5 min the separated serum samples were stored at -20 C till the time of assay and used for detection of concentrations of serum 25OH Vitamin D Total 25OH Vitamin D2 and D3 by ELISA using DIAsource 25OH Vitamin D Total ELISA Kit Catalogue No KAP 1971 supplied by DIA source Immunoassays SA Rue Du Bosquet 2 B-1348 Louvain-la Neuve Belgium according to the manufacturers instructions and based on the principle of solid-phase Enzyme-Linked Immunosorbent Assay performed on microtiter plates The amount of substrate turnover is determined colorimetrically by measuring the absorbance which is inversely proportional to the total 25OH Vitamin D D2 and D3 concentration A calibration curve is plotted and the total 25OH Vitamin D D2 and D3 concentrations of the samples are determined by dose interpolation from the calibration curve
Random allocation of study groups The children were individually randomized into intervention or control groups using a random number sequence elicited in an Excel spreadsheet with no limitations The allocation was further hidden by using closed dark envelopes A biostatistician and an office secretary who were not members of the investigating team did independently the randomization repackaging sequencing and allocation concealment None of the study staff and participants parents were aware of the drug or placebo being dispensed The codes were revealed only at the time of final data analysis
The children were followed clinically on a daily base by the three study pediatricians to assess the resolution or deterioration of signs and symptoms of pneumonia till being discharged from the hospital whether due to recovery or death The routine treatment of inpatient children is free of charge in Abou ElReesh Childrens hospital while vitamin D was paid by the researchers to be given free of charge to the children in the intervention arm during the study period
Baseline assessment Data was collected for each participant regarding socio-demographic variables age sex feeding practices skin color nature and duration of presenting symptoms All children were examined for vital signs temperature heart rate respiratory rate blood pressure oxygen saturation pallor cyanosis nasal flaring grunt and mental status Pa O2FIO2 was measured and serum creatinine C reactive protein platelet count and serum bilirubin laboratory tests were done SOFA score was assessed for severe pneumonia cases
Intervention All children were treated with antibiotics according to WHO classification and treatment of childhood pneumonia at health facilities 2012 at enrollment after obtaining consent from parents and completing the baseline assessment children were given a single injection of one ml of 100000 IU of vitamin D3 Cholecalciferol vitamin D3 obtained from 2 ml vials containing 200000 IU each Devarol- S- 200000 IU produced by Memphis for Pharmaceutical and Chemical Industries and stored in manufacturers recommended conditions in a dry cool environment for 1-16 weeks depending on the date of recruitment or placebo which is 1 ml saline injection Syringes were labeled with a unique ID number and given by the blinded doctors choosing the next syringe with a randomization code only office secretary aware of randomization codes
Hospital follow-up Children were monitored with recording data every eight hours for respiratory rate chest indrawing oxygen saturation auscultation findings fever feeding cyanosis and mental status The child was discharged when fever and fast breathing were absent for 2 consecutive days
Outcomes assessment Outcomes were assessed 7 days after vitamin D injection the first day whereas vitamin D reaches its maximum level in the blood to guarantee the assessment of all participants before their discharge The primary outcome variables were changed in serum level of 25OHD PaO2FIO2 serum creatinine C reactive protein and serum bilirubin levels and platelets count Also the SOFA score for severe cases The secondary outcomes included the fate of the cases improvement or death and the duration between enrolment and hospital discharge for improved cases
Statistical analysis
Patients percent change of Vitamin D 25 OH2D was calculated to quantify the change levels before and after vitamin D3 Cholecalciferol administration through the equation
Pediatric Blood Vitamin D level BVD change BVD after - BVD before BVD before 100 Collected data were entered and analyzed using the Statistical Package for Social Science Software SPSS program version 210 IBM Tests of normality of data like Shapero-Wilk test revealed that data isnt normally distributed Thats why non-parametric tests like Mann-Whitney and Kruskal-Wallis tests were used in univariable comparisons to quantify the associations of continuous variables Data were summarized using the median and interquartile range for quantitative variables Spearman correlation test was used to detect the relationship between continuous variables P values below 005 were considered statistically significant A multivariate Cox regression analysis model was conducted to explore the independent effect of vitamin D3 supplementation on the overall survival of pneumonic children
Given the short period of the study follow-up and single intervention there was no stopping rule or interim analyses
All children randomized were included in the analysis on an intention-to-treat basis unless the outcome measures were missing n 0 or reported to have recovered or lost within 24 h n 0 Meantime to recovery for the episode of pneumonia at recruitment was compared for the vitamin D group and control group Kaplan-Meier plots and log-rank tests were used to compare the time to recover from the index episode of pneumonia between the vitamin D and placebo groups
Study design and study setting The current study is a randomized double-blinded placebo-controlled trial RCT that was conducted in Cairo University Abou ElReesh Children hospital which is a university-affiliated teaching hospital in Egypt to evaluate the effect of vitamin D3 supplementation on the outcome of treatment of children with pneumonia Pneumonia cases were recruited from two of the hospital general pediatric departments and the four pediatric intensive care units PICUs of the hospital
Sample Size and study population To detect a 20 difference in the mean duration of pneumonia between the vitamin D arm and control arm 5 days vs 6 days SD 2 allowing Type I error of 5 and Type II error of 10 86 per group 172 total is the minimum number to be recruited After allowing for 10 for nonresponse or loss for follow-up and 25 for the exclusion of children diagnosed with sufficient or toxic level of vitamin D after vitamin D testing Box 1 according to the prevalence of vitamin deficiency in a pediatric hospital of eastern India 233 was the minimum number to start with
Mild and moderate pneumonia cases were recruited from two of the hospital general pediatric departments chosen by a simple random sample from a total of six hospital departments while severe pneumonia cases were recruited from the four PICUs of the hospital
All children 259 children between 1 month and 12 years of age admitted to the selected departments during the period from 9th September 2019 to 15th December 2019 and diagnosed clinically with pneumonia according to the World Health Organization criteria of severity Box 2 were screened for the inclusion criteria Children who had clinical signs of rickets 2 children severe illnesses meningitis heart or renal disorders measles severe malnutrition endocrine dysfunction hypercalcemia hyperthyroidism and suspected tuberculosis 4 children or were known to have received high-dose vitamin D treatment in the past 3 months 3 children were excluded from the study Children with sufficient 52 children or toxic 7 children levels of vitamin D were also excluded
Thus 191 child 93 in the intervention arm and 98 in the control arm who had pneumonia with insufficient or deficient level of vitamin D and their parents consented to participate were enrolled in the study completed the baseline and the outcome assessments and continued the daily clinical follow up till their discharge improvement or death from the hospital
Box 1 Level of vitamin D Sufficient vitamin D 25OHD 30 ngmL Insufficient vitamin D 25OHD or at risk of deficiency 10-29 ngmL and Deficient vitamin D 25OHD 10 ng mL
Box 2 Diagnosis of Pneumonia Pneumonia i Age-specific tachypnoea 60 min if 2 months 50 min if 2-11 months 40 if 12-24 months and ii absence of wheeze with or without fever
Fever Axillary temperature 3750 _C age 1 week- 3 months or 380 _C 2-23 months
axillary temperature was measured using a standard mercury thermometers Respiratory rate was measured twice for one full minute while the child is quiet using stopwatches taking the average count
Mild pneumonia Minimally increased work of breathing no hypoxemia able to tolerate PO Moderate pneumonia Hypoxemia inability to tolerate PO moderately increased work of breathing grunting retracting tachypnea
Severe Pneumonia Significantly increased work of breathing altered mental state concern for respiratory failure sepsis failure to maintain oxygen saturation with Fi02 of 50 need for positive pressure ventilation Oxygen saturation was measured using a pulse oximeter with a probe on a finger or toe in-room air
Improvement discharge criteria Meets all tolerating PO not hypoxemic more than 90 mildly increase or normal work of breathing
Vitamin D testing Two milliliters of venous blood was collected on plain tubes left for 10 min to clot and then centrifuged at 3000 rpm for 5 min the separated serum samples were stored at -20 C till the time of assay and used for detection of concentrations of serum 25OH Vitamin D Total 25OH Vitamin D2 and D3 by ELISA using DIAsource 25OH Vitamin D Total ELISA Kit Catalogue No KAP 1971 supplied by DIA source Immunoassays SA Rue Du Bosquet 2 B-1348 Louvain-la Neuve Belgium according to the manufacturers instructions and based on the principle of solid-phase Enzyme-Linked Immunosorbent Assay performed on microtiter plates The amount of substrate turnover is determined colorimetrically by measuring the absorbance which is inversely proportional to the total 25OH Vitamin D D2 and D3 concentration A calibration curve is plotted and the total 25OH Vitamin D D2 and D3 concentrations of the samples are determined by dose interpolation from the calibration curve
Random allocation of study groups The children were individually randomized into intervention or control groups using a random number sequence elicited in an Excel spreadsheet with no limitations The allocation was further hidden by using closed dark envelopes A biostatistician and an office secretary who were not members of the investigating team did independently the randomization repackaging sequencing and allocation concealment None of the study staff and participants parents were aware of the drug or placebo being dispensed The codes were revealed only at the time of final data analysis
The children were followed clinically on a daily base by the three study pediatricians to assess the resolution or deterioration of signs and symptoms of pneumonia till being discharged from the hospital whether due to recovery or death The routine treatment of inpatient children is free of charge in Abou ElReesh Childrens hospital while vitamin D was paid by the researchers to be given free of charge to the children in the intervention arm during the study period
Baseline assessment Data was collected for each participant regarding socio-demographic variables age sex feeding practices skin color nature and duration of presenting symptoms All children were examined for vital signs temperature heart rate respiratory rate blood pressure oxygen saturation pallor cyanosis nasal flaring grunt and mental status Pa O2FIO2 was measured and serum creatinine C reactive protein platelet count and serum bilirubin laboratory tests were done SOFA score was assessed for severe pneumonia cases
Intervention All children were treated with antibiotics according to WHO classification and treatment of childhood pneumonia at health facilities 2012 at enrollment after obtaining consent from parents and completing the baseline assessment children were given a single injection of one ml of 100000 IU of vitamin D3 Cholecalciferol vitamin D3 obtained from 2 ml vials containing 200000 IU each Devarol- S- 200000 IU produced by Memphis for Pharmaceutical and Chemical Industries and stored in manufacturers recommended conditions in a dry cool environment for 1-16 weeks depending on the date of recruitment or placebo which is 1 ml saline injection Syringes were labeled with a unique ID number and given by the blinded doctors choosing the next syringe with a randomization code only office secretary aware of randomization codes
Hospital follow-up Children were monitored with recording data every eight hours for respiratory rate chest indrawing oxygen saturation auscultation findings fever feeding cyanosis and mental status The child was discharged when fever and fast breathing were absent for 2 consecutive days
Outcomes assessment Outcomes were assessed 7 days after vitamin D injection the first day whereas vitamin D reaches its maximum level in the blood to guarantee the assessment of all participants before their discharge The primary outcome variables were changed in serum level of 25OHD PaO2FIO2 serum creatinine C reactive protein and serum bilirubin levels and platelets count Also the SOFA score for severe cases The secondary outcomes included the fate of the cases improvement or death and the duration between enrolment and hospital discharge for improved cases
Statistical analysis
Patients percent change of Vitamin D 25 OH2D was calculated to quantify the change levels before and after vitamin D3 Cholecalciferol administration through the equation
Pediatric Blood Vitamin D level BVD change BVD after - BVD before BVD before 100 Collected data were entered and analyzed using the Statistical Package for Social Science Software SPSS program version 210 IBM Tests of normality of data like Shapero-Wilk test revealed that data isnt normally distributed Thats why non-parametric tests like Mann-Whitney and Kruskal-Wallis tests were used in univariable comparisons to quantify the associations of continuous variables Data were summarized using the median and interquartile range for quantitative variables Spearman correlation test was used to detect the relationship between continuous variables P values below 005 were considered statistically significant A multivariate Cox regression analysis model was conducted to explore the independent effect of vitamin D3 supplementation on the overall survival of pneumonic children
Given the short period of the study follow-up and single intervention there was no stopping rule or interim analyses
All children randomized were included in the analysis on an intention-to-treat basis unless the outcome measures were missing n 0 or reported to have recovered or lost within 24 h n 0 Meantime to recovery for the episode of pneumonia at recruitment was compared for the vitamin D group and control group Kaplan-Meier plots and log-rank tests were used to compare the time to recover from the index episode of pneumonia between the vitamin D and placebo groups
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None