Trial of Thiamine Supplementation in Cambodia
Primary Purpose
Thiamine Deficiency
Status
Completed
Phase
Not Applicable
Locations
Cambodia
Study Type
Interventional
Intervention
thiamine (as thiamine hydrochloride)
Sponsored by
About this trial
This is an interventional prevention trial for Thiamine Deficiency
Eligibility Criteria
Inclusion Criteria:
Mothers of a newborn who:
- are aged 18 - 45 years
- had a recent normal pregnancy (i.e. no known chronic conditions, no preeclampsia, gestational diabetes etc), and the singleton infant was born without complications (e.g. low birth weight (<2.5 kg), tongue tie, cleft palate)
- are intending to exclusively breastfeed for six months
- reside in Kampong Thom province, Cambodia, and are not planning to move in the next six months
- are willing to consume one capsule daily from 2 weeks through to 24 weeks postpartum
- are willing for her entire household consume only salt provided by the study team
- are willing for the following biological samples to be collected: a maternal venous blood sample and human milk sample at 2 weeks postpartum, a human milk sample at 4 and 12 weeks postpartum, and maternal and infant blood samples and a human milk sample at 24 weeks postpartum.
Exclusion Criteria:
Mothers of a newborn who:
- are currently taking or has taken thiamine-containing supplements over the past 4 months
- are currently participating in nutrition programs beyond normal care
Sites / Locations
- Helen Keller International
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Placebo Comparator
Experimental
Experimental
Experimental
Arm Label
Negative Control
EAR Group
Double EAR Group
Positive Control
Arm Description
placebo; 0 mg thiamine
1.2 mg thiamine as thiamine hydrochloride
2.4 mg thiamine as thiamine hydrochloride
10 mg thiamine as thiamine hydrochloride
Outcomes
Primary Outcome Measures
Human milk total thiamine concentration
To estimate the dose on the dose response curve where additional maternal intake of thiamine (oral dose) no longer meaningfully increases human milk total thiamine concentration at 24 weeks postpartum.
Secondary Outcome Measures
Full Information
NCT ID
NCT03616288
First Posted
July 31, 2018
Last Updated
February 22, 2021
Sponsor
Mount Saint Vincent University
Collaborators
Sackler Institute for Nutrition Science, Bill and Melinda Gates Foundation, Helen Keller International, NCHADS - Ministry of Health of Cambodia, Ministry of Planning, Cambodia, South Australian Health and Medical Research Institute, Institut de Recherche pour le Developpement, University of Oregon
1. Study Identification
Unique Protocol Identification Number
NCT03616288
Brief Title
Trial of Thiamine Supplementation in Cambodia
Official Title
Improving Estimates of the Global Burden of Thiamine Deficiency Disorders and Approaches to Their Control: Trial of Thiamine Supplementation in Cambodia
Study Type
Interventional
2. Study Status
Record Verification Date
February 2021
Overall Recruitment Status
Completed
Study Start Date
August 28, 2018 (Actual)
Primary Completion Date
May 5, 2020 (Actual)
Study Completion Date
January 28, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Mount Saint Vincent University
Collaborators
Sackler Institute for Nutrition Science, Bill and Melinda Gates Foundation, Helen Keller International, NCHADS - Ministry of Health of Cambodia, Ministry of Planning, Cambodia, South Australian Health and Medical Research Institute, Institut de Recherche pour le Developpement, University of Oregon
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
Beriberi is a potentially fatal disease caused by vitamin B1 (thiamine) deficiency that still occurs in Southeast Asia despite near eradication elsewhere. Mothers with a diet low in thiamine produce thiamine-poor milk, putting their infants at a high risk of developing thiamine deficiency and beriberi. There is also a growing body of evidence suggesting thiamine deficiency not severe enough to cause clinical symptoms may negatively effect cognitive development and functioning of the infant. Since human milk should be the sole source of nutrition for babies during the first six months, maternal thiamine intake must be improved to combat this disease.
The investigators' recent study of thiamine-fortified fish sauce in Cambodia showed that fortification could increase maternal and infant thiamine status'. However, centrally produced fish sauce may not reach the poorest communities who make their own fish sauce, and fish sauce is not consumed in all regions where we find thiamine deficiency. Salt, by contrast, is a common condiment in most regions of the world and has proven to be a successful global fortification vehicle for iodine.
Suboptimal maternal thiamine intake puts exclusively breastfed infants at risk of low thiamine status, impaired cognitive development, and infantile beriberi, which can be fatal. Thiamine fortification of salt is a potentially low-cost and sustainable means of combating suboptimal thiamine status; however knowledge gaps must be filled before thiamine fortification can proceed. In this study, mothers will consume thiamine supplements in order to model the thiamine dose required to optimize human milk thiamine concentrations for the prevention of beriberi. Other thiamine biomarkers will be assessed, and usual salt intake will be measured. Finally, the investigators will assess the effects of early-life thiamine exposure on infant neuro-cognitive development.
Detailed Description
(see full protocol)
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Thiamine Deficiency
7. Study Design
Primary Purpose
Prevention
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
Randomized placebo controlled, double-blinded, four-parallel arm, multicentre trial
Masking
ParticipantInvestigator
Masking Description
double-blinded
Allocation
Randomized
Enrollment
335 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Negative Control
Arm Type
Placebo Comparator
Arm Description
placebo; 0 mg thiamine
Arm Title
EAR Group
Arm Type
Experimental
Arm Description
1.2 mg thiamine as thiamine hydrochloride
Arm Title
Double EAR Group
Arm Type
Experimental
Arm Description
2.4 mg thiamine as thiamine hydrochloride
Arm Title
Positive Control
Arm Type
Experimental
Arm Description
10 mg thiamine as thiamine hydrochloride
Intervention Type
Dietary Supplement
Intervention Name(s)
thiamine (as thiamine hydrochloride)
Intervention Description
Opaque capsules containing varying amounts of thiamine hydrochloride and cellulose filler. All thiamine is delivered as thiamine hydrochloride, calculated using a 1.271 correction factor (ratio of molecular weights of thiamine hydrochloride and thiamine).
Primary Outcome Measure Information:
Title
Human milk total thiamine concentration
Description
To estimate the dose on the dose response curve where additional maternal intake of thiamine (oral dose) no longer meaningfully increases human milk total thiamine concentration at 24 weeks postpartum.
Time Frame
24 weeks postpartum
Other Pre-specified Outcome Measures:
Title
Infant thiamine diphosphate concentrations (ThDP)
Description
To estimate the dose on the dose response curve where additional maternal intake of thiamine (oral dose) no longer meaningfully increases infant thiamine diphosphate concentrations (ThDP) 24 weeks postnatally, and assess whether this depends on the presence/absence of a genetic hemoglobin disorder.
Time Frame
24 weeks postnatal
Title
Human milk total thiamine concentrations
Description
To estimate the dose on the dose response curve where additional maternal intake of thiamine (oral dose) no longer meaningfully increases human milk total thiamine concentration at 4 and 12 weeks postpartum.
Time Frame
4 and 12 weeks postpartum
Title
Infant transketolase activity
Description
To estimate the dose on the dose response curve where additional maternal intake of thiamine (oral dose) no longer meaningfully increases infant transketolase activity at 24 weeks postnatally, and assess whether this depends on the presence/absence of a genetic hemoglobin disorder.
Time Frame
24 weeks postnatal
Title
Maternal ThDP (dose response)
Description
To estimate the dose on the dose response curve where additional maternal intake of thiamine (oral dose) no longer meaningfully increases maternal ThDP at 24 weeks postpartum, and assess whether this depends on the presence/absence of a genetic hemoglobin disorder.
Time Frame
24 weeks postpartum
Title
Maternal transketolase activity (dose response)
Description
To estimate the dose on the dose response curve where additional maternal intake of thiamine (oral dose) no longer meaningfully increases maternal ETKac at 24 weeks postpartum, and assess whether this depends on the presence/absence of a genetic hemoglobin disorder.
Time Frame
24 weeks postpartum
Title
Human milk total thiamine concentrations
Description
To test for differences between the 4 randomized groups on human milk total thiamine at 4, 12, and 24 weeks postpartum.
Time Frame
4, 12, and 24 weeks postpartum
Title
Maternal ThDP (by arm)
Description
To test for differences between the 4 randomized groups on maternal ThDP at 24 weeks postpartum, and assess whether this depends on the presence/absence of genetic hemoglobin disorder.
Time Frame
24 weeks postpartum
Title
Maternal transketolase activity (by arm)
Description
To test for differences between the 4 randomized groups on maternal ETKac at 24 weeks postpartum and assess whether this depends on the presence/absence of a genetic hemoglobin disorder.
Time Frame
24 weeks postpartum
Title
Household salt intake
Description
To estimate usual household salt intake from mean fortnightly salt disappearance (weight lost, in g).
Time Frame
within 2 and 24 weeks postpartum
Title
Salt intake of household members
Description
To estimate salt intake among a subset of 100 lactating women, their male partners (if applicable), and their children 24-59 months (if applicable) using observed weighed salt intake records.
Time Frame
within 2 and 24 weeks postpartum
Title
Sodium intake of women
Description
To estimate sodium intake using 24 hr urinary sodium concentrations among a subset of 100 lactating women.
Time Frame
within 2 and 24 weeks postpartum
Title
Mullen scores
Description
To test for differences between the 0 & 10 mg randomized groups on Composite Mullen and the 5 subscales of the Mullen at 24 and 52 weeks postnatally.
Score notes for Mullen Scales of Early Learning
Gross Motor Scale: Raw score range: 0-36 (higher scores reflect better performance) Visual Reception Scale: Raw score range: 0-50 (higher scores reflect better performance) Fine Motor Scale: Raw score range: 0-49 (higher scores reflect better performance) Receptive Language Scale: Raw score range: 0-48 (higher scores reflect better performance) Expressive Language Scale: Raw score range: 0-50 (higher scores reflect better performance)
All raw scores are converted to age-adjusted T-scores (provided by manual).
An optional Early Learning Composite Score can be calculated by summing the T-scores of all but the Gross Motor Scale.
Time Frame
24 and 52 weeks postnatal
Title
Visual paired comparison
Description
To test for differences between the 0 & 10 mg randomized groups on Visual Paired Comparison Novelty Score and the attention and processing speed subscales at 24 and 52 weeks postnatally.
Score notes for Visual Paired Comparison task
Scale ranges: An overall novelty score is calculated that averages across all face and pattern trials, and is a percentage reflecting the percent of time infants' looked at the novel item during the test phase, calculated as the duration looking to the novel item divided by the sum of the duration of looking to the novel item plus the duration looking to the familiar item.
Sub-scales: Two sub-scales are calculated: the novelty score averaged across face trials, and the novelty score averaged across pattern trials. The total scale composite averages the novelty score across the two sub-scales.
For all scales, he range is 0-100%, and higher novelty scores indicate better outcomes.
Time Frame
24 and 52 weeks postnatal
Title
Language Preference Task
Description
To test for differences between the 0 & 10 mg randomized groups on the Language Preference Task Score at 24 weeks postnatally.
Time Frame
24 weeks postnatal
Title
Oculomotor scores
Description
To test for differences between 0 & 10 mg randomized groups on oculomotor scores at 24 weeks postnatally.
Score notes for the Oculomotor Test:
The proposed oculomotor test is not a single, published instrument, but instead, combines several standard screening items.
Strabismus: absent or present; score: 0-1 Nystagmus: absent or present; score: 0-1 Amblyopia: absent or present; score 0-1
Saccade:
guided saccade: absent or present; score 0-1
scanning: absent or present; score 0-1
predicted saccade: absent or present; score 0-1
Smooth pursuit:
overall pursuit: absent or present; score 0-1
horizontal pursuit: score 0-1
vertical pursuit: score 0-1
Total oculomotor score (optional): sum of all scored exam items: range 0-9
Time Frame
24 weeks postnatal
Title
Inflammation
Description
To determine the effect of inflammation, as measured by C-reactive protein (CRP) and α-1-acid-glycoprotein (AGP) on maternal ThDP at 2 and 24 weeks postpartum, and infant ThDP at 24 weeks postnatal.
Time Frame
24 weeks postnatal
10. Eligibility
Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Mothers of a newborn who:
are aged 18 - 45 years
had a recent normal pregnancy (i.e. no known chronic conditions, no preeclampsia, gestational diabetes etc), and the singleton infant was born without complications (e.g. low birth weight (<2.5 kg), tongue tie, cleft palate)
are intending to exclusively breastfeed for six months
reside in Kampong Thom province, Cambodia, and are not planning to move in the next six months
are willing to consume one capsule daily from 2 weeks through to 24 weeks postpartum
are willing for her entire household consume only salt provided by the study team
are willing for the following biological samples to be collected: a maternal venous blood sample and human milk sample at 2 weeks postpartum, a human milk sample at 4 and 12 weeks postpartum, and maternal and infant blood samples and a human milk sample at 24 weeks postpartum.
Exclusion Criteria:
Mothers of a newborn who:
are currently taking or has taken thiamine-containing supplements over the past 4 months
are currently participating in nutrition programs beyond normal care
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kyly C Whitfield, PhD
Organizational Affiliation
Mount Saint Vincent University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Helen Keller International
City
Kampong Thom
State/Province
Kapmong Thom Province
Country
Cambodia
12. IPD Sharing Statement
Citations:
PubMed Identifier
33829271
Citation
Gallant J, Chan K, Green TJ, Wieringa FT, Leemaqz S, Ngik R, Measelle JR, Baldwin DA, Borath M, Sophonneary P, Yelland LN, Hampel D, Shahab-Ferdows S, Allen LH, Jones KS, Koulman A, Parkington DA, Meadows SR, Kroeun H, Whitfield KC. Low-dose thiamine supplementation of lactating Cambodian mothers improves human milk thiamine concentrations: a randomized controlled trial. Am J Clin Nutr. 2021 Jul 1;114(1):90-100. doi: 10.1093/ajcn/nqab052.
Results Reference
derived
PubMed Identifier
31292183
Citation
Whitfield KC, Kroeun H, Green T, Wieringa FT, Borath M, Sophonneary P, Measelle JR, Baldwin D, Yelland LN, Leemaqz S, Chan K, Gallant J. Thiamine dose response in human milk with supplementation among lactating women in Cambodia: study protocol for a double-blind, four-parallel arm randomised controlled trial. BMJ Open. 2019 Jul 9;9(7):e029255. doi: 10.1136/bmjopen-2019-029255.
Results Reference
derived
Learn more about this trial
Trial of Thiamine Supplementation in Cambodia
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