Thiamine Responsive Disorders (TRD) Among Infants in Lao PDR

Thiamine Deficiency Clinical Trial

Official title:

A Study to Establish a Case Definition of Thiamine Responsive Disorders (TRD) Among Infants in Lao PDR

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03626337
• Other study ID #: 1329444
• Status: Completed
• Start date: June 17, 2019
• Est. completion date: February 25, 2021

Study information

• Verified date: August 2022
• Source: University of California, Davis
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

A hospital- and community-based study in Luang Prabang, Lao PDR, which will include a group of hospitalized children 21 days to <18 months of age who are diagnosed with symptoms compatible with thiamine deficiency disorder (TDD). Based on the infants' response to thiamine administration, children will be defined as either thiamine responsive disorder (TRD) cases or non-responders. A community-based comparison group of infants in the same age range will be included in the study to serve as a control group for identification of potential risk factors.

Description:

The study's primary objective is the development of a case definition for TRD among infants and young children with symptoms consistent with TDD, with the case definition being based on those clinical symptoms and other predictors that we find are better able to distinguish those who respond positively to thiamine administration from those who do not respond. As diagnostic tools available to treating physicians may differ by setting, we will repeat analyses after excluding from the set of candidate predictors those that are derived from assessments only available in higher-resource settings, such as laboratory biomarkers and ultrasonography. A secondary objective is to fill the knowledge gap surrounding biomarkers of thiamine status in at-risk populations. Biomarker cut-offs for TRD will be developed in the hospital cohort and distributions will be characterised in both the hospital and community cohorts. The performance of our proposed cut-off will be compared to the performance of existing literature cut-offs. Additionally, all identified predictors and biomarker cut-offs will be compared across the community cohort, non-TRD hospital cohort, and TRD hospital cohort to assess the prevalence of risk factors among apparently healthy infants and young children and assess the usefulness of the TRD case definition in various settings. Infants and children in the target age range, who are seeking care at the collaborating hospital, will be screened by study staff to determine the presence of any of the inclusion criteria. The list of inclusion criteria has been developed based on a broad range of TDD-compatible symptoms to reduce the risk of potentially missing children who would respond clinically to thiamine administration to correct the deficiency. If a child is in the target age range (21 days to <18 months) meets any one of the inclusion criteria, parental consent will be obtained and children will be referred to a study physician for a detailed physical exam. An echocardiogram and cranial ultrasound will be performed to explore the complete range of TDD complications. A venous blood sample will be obtained by venipuncture for assessment of indicators of thiamine status. The data collection will follow a structured timeline after the first thiamine dose has been administered. In particular, the thiamine administration will be defined as hour zero, and the above described physical exam will be repeated 4, 8, 12, 24, 36, 48, and 72 hours after the initial thiamine administration Blood samples will be analyzed for whole blood thiamine diphosphate (ThDP) and erythrocyte transketolase activity coefficient (ETKac), inflammation and cardiac biomarkers and for a complete blood count (CBC). The purpose of determining these indicators is to better describe the TRD cases and explore differences between TRD cases, non-TRD children and children in the community, with the ultimate goal that these indicators may be useful for screening in the future. Moreover, to determine the association between TRD and maternal thiamine status as a potential risk factor, investigators will collect a blood sample from infants's mothers to assess maternal thiamine status, and among breast feeding mothers a breastmilk sample for assessment of thiamine concentration.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1394
• Est. completion date: February 25, 2021
• Est. primary completion date: February 25, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 21 Days to 17 Months

Eligibility

Inclusion criteria of hospital-based children:

• 21 days to <18 months and seeking care at the collaborating hospital and meeting at

least one of the following inclusion criteria:

• Liver enlargement (>2 cm below right costal margin on calm, supine exam)
• Edema
• Tachypnea (> 60/min for 3-8 wks; >50/min for 2-11 mo; >40/min for 12 - 18 mo)
• Tachycardia (heart rate >160/min for <12 mo; >120/min for 12 mo - 18 mo)
• Oxygen saturation (<92%)
• Difficulty breathing (i.e. chest in-drawing, nasal flaring)
• Refusal to breastfeed or refusal of infant formula or food for greater than 24 hours
• Repetitive or recurring vomiting with no obvious other cause(i.e. vomiting >3 times in past 24 hours)
• Persistent crying not relieved by soothing and feeding with no obvious other cause
• Hoarse voice/cry or loss of voice
• Nystagmus or other unusual eye movement
• Muscle twitching
• Loss of consciousness
• Convulsion
• Opisthotonus / abnormal posturing
• Acute paralysis / flaccid paralysis

Exclusion criteria of hospital-based children:

• None Inclusion criteria of community-based children, who will be frequency-matched based on sex,

age and residence to hospital-based participants :

• Children aged 21 days to <18 months
• Residing in selected communities

Exclusion criteria of community-based children:

• Severe acute illness warranting immediate hospital referral

Inclusion criteria of participants' mothers:

• Mother of hospital-based study participant or community-based study participant

Exclusion criteria of participants' mothers:

• Severe acute illness warranting immediate hospital referral
• Unable to provide informed consent due to reduced decision making ability

Related Conditions & MeSH terms

• Beriberi
• Thiamine Deficiency

Intervention

Drug:
• Thiamine 100 MG/ML
100 mg thiamine provided as intramuscular injection

Locations

Country	Name	City	State
Lao People's Democratic Republic	Lao Friends Hospital for Children	Luang Prabang

Sponsors (2)

Lead Sponsor	Collaborator
University of California, Davis	Lao Tropical and Public Health Institute

Country where clinical trial is conducted

Lao People's Democratic Republic, 

References & Publications (2)

Hess SY, Smith TJ, Fischer PR, Trehan I, Hiffler L, Arnold CD, Sitthideth D, Tancredi DJ, Schick MA, Yeh J, Stein-Wexler R, McBeth CN, Tan X, Nhiacha K, Kounnavong S. Establishing a case definition of thiamine responsive disorders among infants and young children in Lao PDR: protocol for a prospective cohort study. BMJ Open. 2020 Feb 13;10(2):e036539. doi: 10.1136/bmjopen-2019-036539. — View Citation

Smith TJ, Tan X, Arnold CD, Sitthideth D, Kounnavong S, Hess SY. Traditional prenatal and postpartum food restrictions among women in northern Lao PDR. Matern Child Nutr. 2022 Jan;18(1):e13273. doi: 10.1111/mcn.13273. Epub 2021 Sep 30. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Thiamine Responsive Disorder (TRD)	Diagnosis of TRD will be determined based on improvements of initially abnormal physical findings such as hepatomegaly, heart rate, and respiratory rate, and resolution of echocardiographic findings of enlarged and poorly functioning ventricles	48-72 hours
Secondary	Biomarkers of whole blood thiamine diphosphate (ThDP) and erythrocyte transketolase activity coefficient (ETKac)	Associations between ThDP and ETKac with TRD will be determined and appropriate cut-offs of these biomarkers suggesting TRD will be proposed	Baseline
Secondary	Hemoglobin and biomarkers of other micronutrients (ferritin, transferrin receptor, retinol binding protein, erythrocyte glutathione reductase activation coefficient (EGRAC)), and inflammation (CRP, AGP)	Nutrition and health status will be assessed to explore potential risk factors for TRD	Baseline