Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04039828 |
| Other study ID # |
PR-19033 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
September 9, 2019 |
| Est. completion date |
September 30, 2020 |
Study information
| Verified date |
July 2019 |
| Source |
International Centre for Diarrhoeal Disease Research, Bangladesh |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Introduction:
Zinc (Zn) is an essential mineral widely distributed within the human body with
metalloproteins, Zinc-binding proteins, etc. It is necessary for signal transduction and also
cell growth and proliferation via respective metallo- and zinc-dependent enzymes. Zinc
supplementation can significantly reduce diarrheal severity and duration as well as prevents
future incidences and reduces use of other medications in diarrhoea. For this reason WHO,
UNICEF, USAID and experts worldwide jointly recommended zinc supplementation (10 mg for
infants less than 6 months old and 20 mg in 6 - 59 months old) combined with reduced
osmolarity ORS for clinical management of acute diarrhoea. But due to strong metallic taste
zinc products are less palatable to children even after using masking flavours as recommended
by WHO. Several companies have formulated the product since WHO recommendations came but
still transient side effects like vomiting and regurgitation remain evident. Despite careful
counselling to the caregivers expected adherence rate to 10 days regimen of zinc supplement
is yet to be reached.
With the aim to increase zinc supplement coverage during acute diarrheal illness, it is
necessary to conduct a study to introduce new formulation Zinc tablet which is more
palatable, more dispersible and more acceptable.
Intervention:
Zinc sulfate [Zinc Dispersible Tablet, 20 mg; (Elemental Zinc 20 mg as Zinc Sulfate
Monohydrate / Tablet)]
Methods: Prospective, open label, interventional study
Hypothesis:
Improved formulation of Zinc Sulfate will have good acceptability.
Study population:
Stratum 1: 3 months - <18 months = 175 children Stratum 2: 18 months - 59 months = 175
children
Objectives:
1. Primary Objective:
Acceptability of the zinc product in the management of childhood diarrhea will be
assessed by observing:
i) Incidence of vomiting or regurgitation among enrolled children receiving the
improvised zinc formulation.
ii) The adherence: The number of days (out of the total 10 days) the child took the
protocol-prescribed dose of the medicine. The treatment will be considered to have good
acceptability if at least 80% of the prescribed treatment is taken by at least 70% of
the children over the duration of 10 days, as per WHO guidelines.
2. Secondary objective :
To assess palatability Secondary end point evaluation (Palatability): The statistical
analysis will comprise the calculation of the percentage of patients out of 350 who found the
investigational product to have "very well-tolerated, well-tolerated or tolerated" scores
(i.e. any of the upper 3 possible scores). A 95% confidence interval, using the normal
approximation of the binomial distribution, will be calculated for the percentage.
Description:
Background:
Zinc is a metalloprotein. The two important function of zinc are- first, unlike other metals
zinc is virtually non-toxic (1). The homeostatic mechanisms that regulate its entrance,
allocation, and excretion from cells and tissues are so well-organized that no disorders are
known to be associated with its excessive accumulation, in contrast to iron, copper, mercury,
and other metals. Second, its physical and chemical properties, including its generally
stable relationship with macromolecules and its co-ordination flexibility, make it extremely
adaptable in meeting the needs of proteins and enzymes that take diverse biological functions
(2-4). Zinc is one of the most common metal ion distributed widely in cytoplasm as well as
building blocks for keratin like structures and intracellular organelles like chromosomes(5).
Importance of zinc as an essential trace element is well established for its role on growth
and development, protection against free radical damage, endocrine, reproductive and
cognitive functions(6). Globally, zinc deficiency is associated with 16% of lower respiratory
tract infections and 10% of diarrheal diseases respectively with higher attributable
fractions in sub-regions(7). Severe zinc deficiency is a rare entity whereas mild to moderate
zinc deficiency is quite evident mostly in children living in poverty and associated with
approximately 453,000 deaths each year(8, 9). Simultaneously, diarrhoea as the second most
prevalent cause of under five deaths and is responsible for 800,000 deaths each year (10). A
meta-analysis of 12 studies observed the impact of zinc supplements on the management of
acute diarrhea, 11 studies showed a reduction in the duration of the diarrheal episode. In
eight of these reported that the reduction of diarrheal episode was statistically
significant. Five of these studies also found that zinc supplements reduced stool output and
frequency. The data revealed that zinc supplementation had a significant effect on the
clinical course of acute diarrhea, reducing its duration as well as severity (11). Another
meta-analysis of 18 trials with 6165 enrolled participants observed that in acute diarrhea,
zinc reduced duration of diarrhea (MD -- 12.27 hours, 95% CI -23.02 to -1.52 hours; 2741
children, nine trials), and a reduced amount of diarrhea by day three (RR 0.69, 95% CI 0.59
to 0.81; 1073 children, two trials), day five (RR 0.55, 95% CI 0.32 to 0.95; 346 children,
two trials), and day seven (RR 0.71, 95% CI 0.52 to 0.98; 4087 children, seven trials). Zinc
also reduced the period of persistent diarrhea (MD -15.84 hours, 95% CI -25.43 to - 6.24
hours; 529 children, five trials). In few trials there was report on the severity, but the
results were not consistent (12).
Zinc supplementation can significantly reduce diarrheal severity and duration as well as
prevents future incidences and reduces use of other medications in diarrhea (13-16). Several
studies evaluated the effect of zinc supplementation on diarrhea and found a preventive and
long-lasting impact. These showed that 10 mg to 20 mg of zinc per day, for 10 - 14 days,
reduced the number of diarrheal episodes in 2 - 3 months after the supplementation (12). For
this reason WHO, UNICEF, USAID and experts worldwide jointly recommended zinc supplementation
(10 mg for infants less than 6 months old and 20 mg in 6 - 59 months old) combined with
reduced osmolarity ORS for clinical management of acute diarrhoea (17).
The physiological effect of zinc on intestinal ion transport has not yet been established
thoroughly. In in-vitro studies with rat ileum recently established that zinc inhibits
cAMP-induced, chloride-dependent fluid secretion by inhibiting basolateral potassium (K)
channels. This study has also observed the specificity of Zn to cAMP-activated K channels,
because zinc did not block the calcium (Ca)-mediated pottasium channels. As this study was
not done in Zn-deficient animals, it provides support that Zn is probably effective in the
absence of Zn deficiency (18, 19). Zinc also improves the absorption of water and
electrolytes, improves regeneration of the intestinal epithelium, increases the levels of
brush border enzymes, and enhances the immune response, allowing for a better clearance of
the pathogens. Another report has recently shown evidence that zinc inhibits toxin-induced
cholera, but not Escherichia coli heat-stable, enterotoxin-induced, ion secretion in cultured
Caco-2 cells (20). In this way, Zinc plays an important role in modulating the host
resistance to infectious agents and decreases the risk, severity, and duration of diarrheal
diseases. It also plays an important role in metallo-enzymes, polyribosomes, and the cell
membrane and cellular function, giving belief that it plays a central role in cellular growth
and in the function of the immune system (21).
The primary site of absorption of exogenous zinc in the human is in the proximal small bowel,
either the distal duodenum or proximal jejunum ((22). Factors known to control absorption
include the amount of zinc present in the intestinal lumen, the presence of dietary promoters
(e.g., human milk, animal proteins) or inhibitors (e.g., phytate, other minerals), zinc
"status" especially in relation to chronic zinc intake, and physiologic states (23).
After absorption zinc is bound to protein metallothionein in the intestines. Zinc is widely
distributed throughout the body. It is primarily stored in RBCs, WBCs, muscles, bones, Skin,
Kidneys, Liver, Pancreas, retina, and prostate. The extent of Zinc binding is 60 - 70% to
plasma albumin, 30 - 40% to alpha 2 macroglobulins or transferring, and 1% to amino acids
like histidine and cysteine. Peak plasma concentration of Zinc occurs in approximately two
hours. The processes of secretion and reabsorption or excretion of intestinal endogenous zinc
have not been well characterized in humans. There are several potential sources of the
endogenous zinc: pancreatic and biliary secretions, gastroduodenal secretions,
transepithelial flux from the enterocytes or other intestinal cell types and sloughing of
mucosal cells.(23) Zinc sulfate, acetate, and gluconate are all acceptable zinc salt
formulations, of which zinc sulfate is low-cost, efficacious, safe, and therefore, optimal
for the national program. Zinc sulfate tablets may be dispersed in breast milk, in oral
rehydration solutions, or in water on a small spoon. Zinc sulfate dispersible tablet is also
available in the market, containing 20 mg of elemental zinc. Pediatric zinc sulfate tablets
are also available(24) It has been anticipated that the successful scaling up of zinc
supplementation for childhood diarrhea could potentially save 400,000 under-five deaths per
year (25). The Scaling Up of Zinc for Young Children (SUZY) Project was established in 2003
with the aim of setting Bangladesh on the path to covering all under-five children with zinc
supplementation in any diarrheal illness episode. In December, 2006 a national mass media
campaign to promote a dispersible tablet zinc formulation, "Baby Zinc," for management of
childhood diarrhea was launched. All media messages linked zinc treatment to the continued
use of oral rehydration salts (ORS)(26). However, by 2012, zinc coverage was below 5%
globally though in some countries such as Bangladesh, coverage was as high as 41% (27).
According to WHO, Bangladesh was the only country to achieve high treatment rates nationally:
as of 2014 nearly 80% of children with diarrhea received ORS, and 34% received both ORS and
zinc (28). This was achieved through decades of investment by the government, icddr,b, the
international development organizations, BRAC, and other key stakeholders (29, 30). This
endeavor included the large-scale Scaling Up Zinc for Young Children (SUZY) Project which was
initiated in 2003 and included partnerships with the government, non-governmental
organizations (NGOs), the private sector to improve provider dispensing, caregiver demand and
availability of optimal, affordable products (26, 31).
But combined data collected from five RCTs (n = 3156) observed that zinc significantly
increased the chance of vomiting compared to the control agent (RR1.2, 95% CI 1.05-1.4)(32).
Due to strong metallic taste zinc products are less palatable to children even after using
masking flavours as recommended by WHO. Several companies have formulated the product since
WHO recommendations came but still transient side effects like vomiting and regurgitation
remain evident (33-36). Despite careful counselling to the caregivers expected adherence rate
to 10 days regimen of zinc supplement is yet to be reached (33, 35, 37, 38).
A clinical trial with new formulation Zinc Sulfate for use in acute diarrheal illness will be
conducted to achieve good adherence rate. New improvised Zinc preparation will be palatable,
more dispersible and thereby acceptable to young children with diarrhea.
Study design: Prospective, open label, interventional study
Study Site: The study will be conducted at the Dhaka Hospital of the International Centre for
Diarrhoeal Disease Research, Bangladesh (icddr,b).
Study population:
Stratum- I : 3 months - <18 months Stratum- II : 18 months - 59 months
Sample size:
Sample size is estimated considering the primary outcome variables:
For one component of the primary objective we have considered the study-report done by Khan
et al (34), where they found incidence of vomiting or regurgitation in 22% of enrolled
children. We assume that the incidence of vomiting or regurgitation on receiving the
improvised zinc formula would not be greater than 10 % cases in this study, thus a total 300
children will be needed that would accommodate up to 19% attrition. Sample size is calculated
using the formula [ 2(Zα + Zβ)2 * p * q] / d2
Where:
P = (p1+p2)/2 p1 = 22% incidence of vomiting or regurgitation according to study report done
by Khan et al p2 = 10% incidence of vomiting or regurgitation with the improvised zinc
formula that we are assuming Zα = 5% significance level Zβ = (1 -β) = 80% power p = [p1 (22%)
+ p2 (10% )]/2 = 16%; q = 100% -16% = 84%; Zα = 1.96 and Zβ = 1.64 Sample size is further
estimated for the other component of the primary objective, i.e. adherence. A total of 350
children will be enrolled (175 patients from 3 months to below 18 months age group, and 175
children from 18 months to 59 months age group). To identify a ± 7.5% minimal difference in
acceptability between children aged over and below 18 months with an anticipated 70%
acceptability (p), setting the level of confidence at 95% (z = 1.96) using the formula: pqz2/
d2 the estimated sample size is 175 children per group allowing 18% dropout.
Intervention:
Investigational product: Zinc Sulfate [Zinc Dispersible Tablet, 20 mg; (Elemental Zinc 20 mg
as Zinc Sulfate Monohydrate / Tablet)]
Dosage:
Half the tablet (10 mg) for 3 to 6 months old children and 20 mg daily for > 6 to 59 months
old children. The tablet will be dissolved in a teaspoon of safe water or breast milk and
administered once daily for 10 days.
Packaging and labeling: Investigational product will be dispensed in a blister pack
containing 10 tablets.
The caregivers will bring the blister packs (even if all tablets are used) on day 11 (after
enrollment) for a follow up visit to the outpatient department (OPD) of the Dhaka Hospital of
icddr,b, and they will be evaluated about the adherence with the supplied drug intake during
the follow up visit. Study investigator will update accountability records of the
investigational product according to ICH E6, GCP guideline. If caregiver failed to have the
follow up visit at hospital, the study staff will visit children's house after 12 days of
enrollment. Investigational product will not be provided to any third party.
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