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Treatment Trial of Subclinical Hypothyroidism in Down Syndrome

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01832753
Recruitment Status : Completed
First Posted : April 16, 2013
Results First Posted : June 13, 2019
Last Update Posted : September 6, 2019
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Children's Hospital of Philadelphia

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Down Syndrome Subclinical Hypothyroidism Drug: Levothyroxine Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary Purpose: Treatment
Official Title: Levothyroxine Treatment and Cardiometabolic Outcomes in Adolescents With Down Syndrome
Actual Study Start Date : January 2013
Actual Primary Completion Date : October 18, 2017
Actual Study Completion Date : October 18, 2017

Resource links provided by the National Library of Medicine

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:
  • Synthroid
  • Levothroid
  • Levoxyl
  • Tirosint
  • Unithroid

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.

Primary Outcome Measures :
  1. Change in Lipid Panel From Baseline at 6, 12 and 18 Months. [ Time Frame: baseline, 6 months, 12 months & 18 months ]
    Lipid panel will be measured via fasting blood draw.

Secondary Outcome Measures :
  1. Change in Quality of Life From Baseline at 6, 12 and 18 Months. [ Time Frame: baseline, 6 months, 12 months, & 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.

Information from the National Library of Medicine

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Ages Eligible for Study:   8 Years to 20 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01832753

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United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010
United States, Pennsylvania
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
Children's Hospital of Philadelphia
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
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Principal Investigator: Andrea Kelly, MD, MSCE Children's Hospital of Philadelphia
  Study Documents (Full-Text)

Documents provided by Children's Hospital of Philadelphia:
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Responsible Party: Children's Hospital of Philadelphia Identifier: NCT01832753    
Other Study ID Numbers: 12-009578
1R01HD071981-01A1 ( U.S. NIH Grant/Contract )
First Posted: April 16, 2013    Key Record Dates
Results First Posted: June 13, 2019
Last Update Posted: September 6, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Children's Hospital of Philadelphia:
Down syndrome
subclinical hypothyroidism
Additional relevant MeSH terms:
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Down Syndrome
Pathologic Processes
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Abnormalities, Multiple
Congenital Abnormalities
Chromosome Disorders
Genetic Diseases, Inborn
Thyroid Diseases
Endocrine System Diseases