Treatment Trial of Subclinical Hypothyroidism in Down Syndrome

Levothyroxine Treatment and Cardiometabolic Outcomes in Adolescents With Down Syndrome

The purpose of this research study is to learn about the effects of treating subclinical hypothyroidism (SCH) with thyroid hormone replacement in children and adolescents with Down syndrome (DS). We hypothesize that treatment of SCH with thyroid hormone replacement will improve cardiometabolic health and quality of life.

Study Overview

• Status: Completed
• Conditions: Down Syndrome; Subclinical Hypothyroidism
• Intervention / Treatment: Drug: Levothyroxine

Detailed Description

The American Academy of Pediatrics (AAP) recommends yearly screening of thyroid studies in DS. Clinical experience suggests that thyroid stimulating hormone (TSH) concentrations in the subclinical hypothyroid range (5-10 milli international units(mIU/L)) are not uncommon in DS, but the benefits and risks of treating SCH in the DS population are not known. In adults, SCH has been associated with increased cardiometabolic risk (CMR) and individuals with DS may be at increased cardiometabolic risk as well.

Data in children with SCH are limited. Despite the recommendations to screen for thyroid dysfunction, evidence to guide management of elevated TSH in children with DS is equally sparse. In non-DS children, TSH>4.65 mIU/L was associated with lower HDL. One year of levothyroxine treatment in short children with subclinical hypothyroidism and short stature improved growth velocity. Left ventricular (LV) function and LV mass (by echocardiography) was not different in 16 children with DS and subclinical hypothyroidism (TSH>6.5 mIU/L; mean TSH = 7.8 mIU/L) vs. 25 children with DS and normal TSH. However, these findings may be limited by the small sample size. An intervention study of 7 subjects age 2-42 years with DS and hypothyroidism, defined as low T4 and normal or elevated TSH (0.2-18.9 mIU/L) on 8 weeks of levothyroxine treatment did not improve developmental or functional outcomes. Anthropometrics and CMR factors were not examined. In contrast, increased TSH in the absence of overt congenital hypothyroidism is common in neonates with DS and prompted a randomized controlled trial (RCT) in 181 neonates with DS. TSH-directed levothyroxine treatment was associated with better growth, weight gain, and motor development after 24 months compared to placebo. These findings highlight that the "asymptomatic" component of subclinical hypothyroidism may have medically-relevant effects. This study will provide potentially clinically relevant preliminary evidence for the treatment of subclinical hypothyroidism in DS.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 20 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Males and females, ages 8 - 20 years
• Diagnosis of Down syndrome
• Subclinical hypothyroidism: TSH level between 5 - 10 mIU/L, normal T4
• Parental/guardian permission (informed consent) and if appropriate, child assent
• Females who are at least 11 years of age or who are menarchal must have a negative urine/serum pregnancy test
• Committed to adherence to levothyroxine treatment and study completion

Exclusion Criteria:

• Pregnancy
• Type 1/Type 2 diabetes
• Chronic medical conditions or medication use that can affect growth, nutrition, blood glucose, insulin secretion, or thyroid function (such as lithium or certain seizure medications)
• Current use of levothyroxine or anti-thyroid hormone
• Cyanotic congenital heart disease, or pulmonary hypertension (as described by last echo report in subjects with CHD), or congenital heart disease considered medically unstable by the study cardiologists

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Treatment Phase: Months 6-18; Subject who are found to have SCH at the 6-month visit will be randomized to receive either levothyroxine or placebo during months 6-12. Levothyroxine dose will be between 0.5 - 1 mcg/kg/day. There will be 1 blood draw visit at month 7.5 (6 weeks after randomization) and 1 study visit at month 12 that will provide the opportunity for dose adjustments if needed. From months 12-18, all subjects will receive levothyroxine. Levothyroxine dose will be between 0.5 - 1 mcg/kg/day. There will be one blood draw visit at month 13.5 that will provide the opportunity for dose adjustments if needed.	Drug: Levothyroxine; Other Names: Tirosint; Synthroid; Levoxyl; Unithroid; Levothroid
No Intervention: Observation Phase: Months 0-6; Subjects will be observed for the first 6 months of the study to ensure that the subclinical hypothyroidism is persistent. Subjects who do not have SCH at 6 months will not proceed to the treatment phase. Subjects that have TSH >10 mIU/L during the 6 month Observational Phase will not be considered subclinical and will not qualify to continue the study. They will be referred to an endocrinologist for treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Lipid Panel From Baseline at 6, 12 and 18 Months.	Lipid panel will be measured via fasting blood draw.	baseline, 6 months, 12 months & 18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Quality of Life From Baseline at 6, 12 and 18 Months.	Questionnaires will be done with participants and parents on the day of each study visit to determine body image and quality of life. The Pediatric Quality of Life (PedsQL) scale is a 5-item scale (values 1-5). 1 - "Always True", to 5 - "Never True". Items are reverse-scored and linearly transformed to a 0-100 scale (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0), so that greater scores indicate better QOL.	baseline, 6 months, 12 months, & 18 months

Collaborators and Investigators

• Sponsor: Children's Hospital of Philadelphia
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Andrea Kelly, MD, MSCE, Children's Hospital of Philadelphia

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2013
• Primary Completion (Actual): October 18, 2017
• Study Completion (Actual): October 18, 2017

Study Registration Dates

• First Submitted: April 9, 2013
• First Submitted That Met QC Criteria: April 12, 2013
• First Posted (Estimate): April 16, 2013

Study Record Updates

• Last Update Posted (Actual): September 6, 2019
• Last Update Submitted That Met QC Criteria: September 4, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: thyroid; Down syndrome; levothyroxine; subclinical hypothyroidism
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Endocrine System Diseases; Disease; Congenital Abnormalities; Genetic Diseases, Inborn; Thyroid Diseases; Intellectual Disability; Abnormalities, Multiple; Chromosome Disorders; Syndrome; Hypothyroidism; Down Syndrome
• Other Study ID Numbers: 12-009578; 1R01HD071981-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO