Delivery of Iron and Zinc Supplements: Evaluation of Interaction Effect on Biochemical and Clinical Outcomes

• Sponsor: Johns Hopkins Bloomberg School of Public Health (Other)
• Overall Status: Completed
• CT.gov ID: NCT00470158
• Collaborator: International Centre for Diarrhoeal Disease Research, Bangladesh (Other), United States Agency for International Development (USAID) (U.S. Fed), Agency for Healthcare Research and Quality (AHRQ) (U.S. Fed)
• Enrollment: 1,000
• Location: 1
• Arms: 5
• Duration (Months): 9.1
• Patients Per Site Per Month: 110.3

Study Details

Study Description

Brief Summary

With the long-term public health goal of developing an effective micronutrient supplementation program to improve child health by improving iron and zinc status and decreasing morbidity due to diarrhea in areas with high rates of childhood malnutrition, we seek to determine the most efficacious method of decreasing childhood morbidity and mortality due to diarrhea in toddlers by re-examining the issue of iron and zinc interaction and determining if this interaction can be minimized by separate administration of iron and zinc supplementation.

Condition or Disease	Intervention/Treatment	Phase
Anemia; Diarrhea; Iron	Dietary Supplement: iron and zinc combined; Dietary Supplement: iron and zinc on separate days; Dietary Supplement: iron; Dietary Supplement: Zinc; Dietary Supplement: placebo	Phase 4

Detailed Description

Iron supplementation is used in reducing anemia and improving hemoglobin status. Zinc supplementation is emerging as possibly an efficacious preventive measure in decreasing incidence of severe diarrhea. Previous studies have suggested interactions of zinc and iron when given together, reducing the effects of supplementation with both minerals. One study in Peru has shown a decrease in interaction effect with separate supplementation of iron and zinc in time when compared to iron administration alone or placebo; however, an evaluation of clinical outcomes and zinc or iron status when iron and zinc are administered separately compared to supplementation of zinc and iron together or each alone has not previously been done. This trial will assess the effect of iron and zinc supplementation given on alternate days compared with giving them together in a combined supplement.

We propose a randomized, double blind, placebo-controlled community trial of children 6-23 months in Mirzapur, Bangladesh. We will recruit and enroll 1000 children 6-23 months old who are permanent residents of the selected villages. Each child will be randomly assigned to 1) daily alternating zinc and placebo 2) daily alternating iron/folic acid and placebo 3) daily alternating zinc/iron/folic acid and placebo 4) daily alternating zinc and iron/folic acid 5) daily placebo. Primary outcomes will include incidence of severe diarrhea, evaluated weekly for 6 months, hemoglobin, prevalence of anemia, and serum zinc.

Analysis of the data will be done to compare the effect of separate iron and zinc supplementation as compared to combined iron and zinc supplementation as well as compared to iron, zinc, or placebo single supplementation. We will evaluate the difference in incidence rate of severe diarrhea, serum hemoglobin, percent anemia, and serum zinc. Since this will be a randomized, double-blind, placebo controlled trial, differences in effect will be most likely explained by the timing of supplement doses. If there is an improvement in clinical and biochemical outcomes, this would be consistent with a decreased interaction of absorption. If no difference is found, there may be another mechanism for the seeming interaction of iron and zinc besides that of mutually inhibitory absorption in the intestine.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1000 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Delivery of Iron and Zinc Supplements: Evaluation of Interaction Effect on Biochemical and Clinical Outcomes
• Study Start Date: May 1, 2007
• Actual Primary Completion Date: Feb 1, 2008
• Actual Study Completion Date: Feb 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: combined iron and zinc Iron and zinc together	Dietary Supplement: iron and zinc combined; Children >= 12 months received an average of 5mg zinc/day, 6.25 Iron/day, and 25IU folic acid/day. children<12 received half that dose. This dose was alternated daily with placebo. Dissolvable doses were distributed in blister packs and reconstituted with a teaspoon of water. Doses were administered in the morning. For missed doses, the mother gave the child the next morning dose, and a second dose in the evening.; Other Names: Tablets were manufactured by Nutriset S.A.S. (Malaunay, France).
Experimental: Separate iron and zinc Iron and zinc on separate days	Dietary Supplement: iron and zinc on separate days; Children >= 12 months received an average of 5mg zinc/day, alternating daily with 6.25 Iron/day, and 25IU folic acid/day. Children<12 received half that dose. Dissolvable doses were distributed in blister packs and reconstituted with a teaspoon of water. Doses were administered in the morning. For missed doses, the mother gave the child the next morning dose, and a second dose in the evening.; Other Names: Tablets were manufactured by Nutriset S.A.S. (Malaunay, France).
Experimental: iron alone Iron	Dietary Supplement: iron; Children >= 12 months received an average 6.25 Iron/day, and 25IU folic acid/day. Children<12 received half that dose. This dose was alternated daily with placebo. Dissolvable doses were distributed in blister packs and reconstituted with a teaspoon of water. Doses were administered in the morning. For missed doses, the mother gave the child the next morning dose, and a second dose in the evening.
Experimental: zinc alone Zinc	Dietary Supplement: Zinc; Children >= 12 months received an average of 5mg zinc/day. Children<12 received half that dose. This dose was alternated daily with placebo. Dissolvable doses were distributed in blister packs and reconstituted with a teaspoon of water. Doses were administered in the morning. For missed doses, the mother gave the child the next morning dose, and a second dose in the evening.
Placebo Comparator: placebo	Dietary Supplement: placebo; Children received daily placebo. Dissolvable doses were distributed in blister packs and reconstituted with a teaspoon of water. Doses were administered in the morning. For missed doses, the mother gave the child the next morning dose, and a second dose in the evening.

Outcome Measures

Primary Outcome Measures

1. Incidence of Diarrhea [6 months]

   A diarrhea episode was defined as three or more loose, liquid, or watery stools for 2 consecutive days, separated in time from an earlier or subsequent episode by at least 2 consecutive diarrhea-free days.

Secondary Outcome Measures

1. Change in Hemoglobin [6 months]

2. Change in Zinc Status [6 months]

3. Percent Anemic [6 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Months to 18 Months
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Children 6-18 months old

• Permanent residents of the selected villages

Exclusion Criteria:

• Severe malnutrition requiring hospitalization (defined as weight for height <-3 SD Z-score)

• Severe anemia requiring treatment (hemoglobin < 70 g/L)

• Chronic illness that would impair feeding ability

• Likely to move in next 6 months.

• Fever greater than 38.5

• Regular iron supplementation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	ICDDR,B	Dhaka	Mohakhali	Bangladesh	1212

Sponsors and Collaborators

• Johns Hopkins Bloomberg School of Public Health
• International Centre for Diarrhoeal Disease Research, Bangladesh
• United States Agency for International Development (USAID)
• Agency for Healthcare Research and Quality (AHRQ)

Investigators

• Principal Investigator: Robert E Black, MD, MPH, Johns Hopkins Bloomberg School of Public Health

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Johns Hopkins Bloomberg School of Public Health
• ClinicalTrials.gov Identifier: NCT00470158
• Other Study ID Numbers: H.22.05.03.11.C2; GHS-A-00-03-00019-00-90027844
• First Posted: May 7, 2007
• Last Update Posted: Apr 20, 2018
• Last Verified: Dec 1, 2009

• Keywords provided by Johns Hopkins Bloomberg School of Public Health: zinc; iron; interaction; diarrhea; delivery
• Additional relevant MeSH terms: Diarrhea; Iron; Zinc

Study Results

Participant Flow

Recruitment Details	All 6-18 month old permanent residents of selected villages near Kumudini Hospital were enrolled from May 8, 2007-August 31, 2007.
Pre-assignment Detail	If one family had two eligible children, one was randomly selected for enrollment. Children with severe malnutrition (weight for height z-score -3 s.d.), severe anemia (hemoglobin <70 g/l), chronic illnesses that would impair feeding ability, planned move during the study period, or active fever (>38.5 C) were excluded from the study.

Arm/Group Title	Combined Iron and Zinc	Separate Iron and Zinc	Iron Alone	Zinc Alone	Placebo
Arm/Group Description	combined iron and zinc, alternating daily with placebo	iron, alternating daily with zinc	iron, alternating daily with placebo	zinc, alternating daily with placebo	placebo daily
Period Title: Overall Study
STARTED	201	199	201	198	201
COMPLETED	193	191	193	193	195
NOT COMPLETED	8	8	8	5	6

Baseline Characteristics

Arm/Group Title	Combined Iron and Zinc	Separate Iron and Zinc	Iron Alone	Zinc Alone	Placebo	Total
Arm/Group Description	combined iron and zinc, alternating daily with placebo	iron, alternating daily with zinc	iron, alternating daily with placebo	zinc, alternating daily with placebo	placebo daily	Total of all reporting groups
Overall Participants	201	199	201	198	201	1000
Age (Count of Participants)
<=18 years	201 100%	199 100%	201 100%	198 100%	201 100%	1000 100%
Between 18 and 65 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	0.93 (0.31)	0.925 (0.32)	0.9 (0.33)	0.925 (0.33)	0.9 (0.32)	0.92 (0.32)
Sex: Female, Male (Count of Participants)
Female	87 43.3%	107 53.8%	93 46.3%	109 55.1%	88 43.8%	484 48.4%
Male	114 56.7%	92 46.2%	108 53.7%	89 44.9%	113 56.2%	516 51.6%
Region of Enrollment (participants) [Number]
Bangladesh	201 100%	199 100%	201 100%	198 100%	201 100%	1000 100%

Outcome Measures

1. Primary Outcome

Title	Incidence of Diarrhea
Description	A diarrhea episode was defined as three or more loose, liquid, or watery stools for 2 consecutive days, separated in time from an earlier or subsequent episode by at least 2 consecutive diarrhea-free days.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combined Iron and Zinc	Separate Iron and Zinc	Iron Alone	Zinc Alone	Placebo
Arm/Group Description	combined iron and zinc, alternating daily with placebo	iron, alternating daily with zinc	iron, alternating daily with placebo	zinc, alternating daily with placebo	placebo daily
Measure Participants	201	199	201	198	201
Number [episodes]	201	204	260	224	235

2. Secondary Outcome

Title	Change in Hemoglobin
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Change in Zinc Status
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Percent Anemic
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	Combined Iron and Zinc		Separate Iron and Zinc		Iron Alone		Zinc Alone		Placebo
Arm/Group Description	combined iron and zinc, alternating daily with placebo		iron, alternating daily with zinc		iron, alternating daily with placebo		zinc, alternating daily with placebo		placebo daily
All Cause Mortality
	Combined Iron and Zinc		Separate Iron and Zinc		Iron Alone		Zinc Alone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Combined Iron and Zinc		Separate Iron and Zinc		Iron Alone		Zinc Alone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/201 (5.5%)		8/199 (4%)		17/201 (8.5%)		10/198 (5.1%)		22/201 (10.9%)
Infections and infestations
infectious hospitalizations	11/201 (5.5%)		8/199 (4%)		17/201 (8.5%)		10/198 (5.1%)		22/201 (10.9%)
Other (Not Including Serious) Adverse Events
	Combined Iron and Zinc		Separate Iron and Zinc		Iron Alone		Zinc Alone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/201 (1%)		2/199 (1%)		0/201 (0%)		4/198 (2%)		4/201 (2%)
Pregnancy, puerperium and perinatal conditions
noninfectious hospitalizations	2/201 (1%)		2/199 (1%)		0/201 (0%)		4/198 (2%)		4/201 (2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.