Down Syndrome, Subclinical Hypothyroidism
Conditions
Keywords
Down syndrome, subclinical hypothyroidism, thyroid, levothyroxine
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.
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.
Interventions
DRUGLevothyroxine
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Children's Hospital of Philadelphia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
8 Years to 20 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | baseline, 6 months, 12 months & 18 months | Lipid panel will be measured via fasting blood draw. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Quality of Life From Baseline at 6, 12 and 18 Months. | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Immediate Treatment Subjects in this group were observed during months 0-6, were randomized to receive levothyroxine during months 6-12, and received levothyroxine as part of the open label phase months 12-18.
All doses were between between 0.5 - 1 mcg/kg/day. | 5 |
| Delayed Treatment Subjects in this group were observed during months 0-6, were randomized to receive placebo during months 6-12, and received levothyroxine as part of the open label phase months 12-18.
All doses were between between 0.5 - 1 mcg/kg/day. | 4 |
| Observation Only Subjects in this group partook in the study during the observational phase months 0-6. Subjects in this group were not randomized to either immediate or delayed treatment groups. | 3 |
| Total | 12 |
Baseline characteristics
| Characteristic | Immediate Treatment | Delayed Treatment | Observation Only | Total |
|---|---|---|---|---|
| Age, Continuous | 12.4 years | 11.6 years | 16.5 years | 14.0 years |
| BMI Percentile | 94 Percentile | 98 Percentile | 98 Percentile | 98 Percentile |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 4 Participants | 3 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 2 Participants | 3 Participants | 8 Participants |
| Region of Enrollment United States | 5 participants | 4 participants | 3 participants | 12 participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 2 Participants | 10 Participants |
| Sex: Female, Male Male | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 4 | 0 / 5 | 0 / 6 |
| other Total, other adverse events | 1 / 12 | 4 / 4 | 4 / 5 | 1 / 6 |
| serious Total, serious adverse events | 0 / 12 | 0 / 4 | 0 / 5 | 0 / 6 |
Outcome results
Primary
Change in Lipid Panel From Baseline at 6, 12 and 18 Months.
Lipid panel will be measured via fasting blood draw.
Time frame: baseline, 6 months, 12 months & 18 months
Population: 3 of the 12 participants (Observation Only) were withdrawn prior to randomization due to normal TSH. 1 of the 4 Delayed Treatment group participants self-withdrew before their 12 month visit. 1 of the 5 Immediate Treatment participants withdrew due to elevated TSH at their 12 month visit, 1 and self-withdrew before their 12 month visit.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Immediate Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | Baseline LDL-C (mg/dL) | 101 mg/dL |
| Immediate Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 18 month Triglycerides (mg/dL) | 108 mg/dL |
| Immediate Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 18 month nonHDL-C (mg/dL) | 112 mg/dL |
| Immediate Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 6 month LDL-C (mg/dL) | 117 mg/dL |
| Immediate Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 18 month Cholesterol (mg/dL) | 150 mg/dL |
| Immediate Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 12 month nonHDL-C (mg/dL) | 137.5 mg/dL |
| Immediate Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 12 month LDL-C (mg/dL) | 111 mg/dL |
| Immediate Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 6 month Cholesterol (mg/dL) | 172 mg/dL |
| Immediate Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 18 month LDL-C (mg/dL) | 90 mg/dL |
| Immediate Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | Baseline HDL-C (mg/dL) | 44 mg/dL |
| Immediate Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | Baseline nonHDL-C (mg/dL) | 116 mg/dL |
| Immediate Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | Baseline Cholesterol (mg/dL) | 160 mg/dL |
| Immediate Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 6 month nonHDL-C (mg/dL) | 134 mg/dL |
| Immediate Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 6 month Triglycerides (mg/dL) | 91 mg/dL |
| Immediate Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 6 month HDL-C (mg/dL) | 35 mg/dL |
| Immediate Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 12 month Triglycerides (mg/dL) | 99 mg/dL |
| Immediate Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 12 month HDL-C (mg/dL) | 42.5 mg/dL |
| Immediate Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 12 month Cholesterol (mg/dL) | 178.5 mg/dL |
| Immediate Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 18 month HDL-C (mg/dL) | 38 mg/dL |
| Immediate Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | Basline Triglycerides (mg/dL) | 73 mg/dL |
| Delayed Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 18 month HDL-C (mg/dL) | 47 mg/dL |
| Delayed Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | Baseline Cholesterol (mg/dL) | 170 mg/dL |
| Delayed Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 6 month Cholesterol (mg/dL) | 156.5 mg/dL |
| Delayed Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 12 month Cholesterol (mg/dL) | 172 mg/dL |
| Delayed Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 18 month Cholesterol (mg/dL) | 164 mg/dL |
| Delayed Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | Baseline HDL-C (mg/dL) | 45.5 mg/dL |
| Delayed Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 6 month HDL-C (mg/dL) | 46.5 mg/dL |
| Delayed Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 12 month HDL-C (mg/dL) | 44 mg/dL |
| Delayed Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | Baseline LDL-C (mg/dL) | 108 mg/dL |
| Delayed Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 6 month LDL-C (mg/dL) | 96.5 mg/dL |
| Delayed Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 12 month LDL-C (mg/dL) | 101 mg/dL |
| Delayed Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 18 month LDL-C (mg/dL) | 99 mg/dL |
| Delayed Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | Baseline nonHDL-C (mg/dL) | 124.5 mg/dL |
| Delayed Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 6 month nonHDL-C (mg/dL) | 108 mg/dL |
| Delayed Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 12 month nonHDL-C (mg/dL) | 122 mg/dL |
| Delayed Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 18 month nonHDL-C (mg/dL) | 115 mg/dL |
| Delayed Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | Basline Triglycerides (mg/dL) | 88 mg/dL |
| Delayed Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 6 month Triglycerides (mg/dL) | 83 mg/dL |
| Delayed Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 12 month Triglycerides (mg/dL) | 106 mg/dL |
| Delayed Treatment | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 18 month Triglycerides (mg/dL) | 82 mg/dL |
| Observation Only | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 6 month HDL-C (mg/dL) | 48 mg/dL |
| Observation Only | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 6 month Cholesterol (mg/dL) | 226 mg/dL |
| Observation Only | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | Basline Triglycerides (mg/dL) | 117 mg/dL |
| Observation Only | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | Baseline nonHDL-C (mg/dL) | 118 mg/dL |
| Observation Only | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | Baseline HDL-C (mg/dL) | 43 mg/dL |
| Observation Only | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 6 month nonHDL-C (mg/dL) | 178 mg/dL |
| Observation Only | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 6 month LDL-C (mg/dL) | 161 mg/dL |
| Observation Only | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | Baseline Cholesterol (mg/dL) | 163 mg/dL |
| Observation Only | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | Baseline LDL-C (mg/dL) | 95 mg/dL |
| Observation Only | Change in Lipid Panel From Baseline at 6, 12 and 18 Months. | 6 month Triglycerides (mg/dL) | 84 mg/dL |
Secondary
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.
Time frame: baseline, 6 months, 12 months, & 18 months
Population: 3 of the 12 participants (Observation Only) were withdrawn prior to randomization due to normal TSH. 1 of the 4 Delayed Treatment group participants self-withdrew before their 12 month visit. 1 of the 5 Immediate Treatment participants withdrew due to elevated TSH at their 12 month visit, 1 and self-withdrew before their 12 month visit.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Immediate Treatment | Change in Quality of Life From Baseline at 6, 12 and 18 Months. | Baseline Pediatric Quality of Life | 70.65 Unit on a scale, linearly transformed |
| Immediate Treatment | Change in Quality of Life From Baseline at 6, 12 and 18 Months. | 18 month Pediatric Quality of Life | 70.655 Unit on a scale, linearly transformed |
| Immediate Treatment | Change in Quality of Life From Baseline at 6, 12 and 18 Months. | 12 month Pediatric Quality of Life | 75 Unit on a scale, linearly transformed |
| Immediate Treatment | Change in Quality of Life From Baseline at 6, 12 and 18 Months. | 6 month Pediatric Quality of Life | 66.305 Unit on a scale, linearly transformed |
| Delayed Treatment | Change in Quality of Life From Baseline at 6, 12 and 18 Months. | 18 month Pediatric Quality of Life | 90.22 Unit on a scale, linearly transformed |
| Delayed Treatment | Change in Quality of Life From Baseline at 6, 12 and 18 Months. | Baseline Pediatric Quality of Life | 69.02 Unit on a scale, linearly transformed |
| Delayed Treatment | Change in Quality of Life From Baseline at 6, 12 and 18 Months. | 6 month Pediatric Quality of Life | 61.41 Unit on a scale, linearly transformed |
| Delayed Treatment | Change in Quality of Life From Baseline at 6, 12 and 18 Months. | 12 month Pediatric Quality of Life | 76.085 Unit on a scale, linearly transformed |
| Observation Only | Change in Quality of Life From Baseline at 6, 12 and 18 Months. | 6 month Pediatric Quality of Life | 50 Unit on a scale, linearly transformed |
| Observation Only | Change in Quality of Life From Baseline at 6, 12 and 18 Months. | Baseline Pediatric Quality of Life | 52.17 Unit on a scale, linearly transformed |