Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT01276782 |
| Other study ID # |
NA_00042993 |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
Phase 4
|
| First received |
January 12, 2011 |
| Last updated |
September 9, 2015 |
| Start date |
January 2011 |
| Est. completion date |
June 2011 |
Study information
| Verified date |
September 2015 |
| Source |
Johns Hopkins University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
United States: Food and Drug Administration |
| Study type |
Interventional
|
Clinical Trial Summary
The last two decades have witnessed an explosion of new research documenting the deleterious
impact that thyroid disease has on pregnancy and the postpartum period, in relation to
miscarriage preterm delivery intelligence quotient of the unborn child and health of the
mother postpartum. Both subclinical hypothyroidism and thyroid antibody positivity in
euthyroid women have been associated with miscarriage and preterm delivery. Approximately 5%
of all pregnant women have a thyroid disorder. both spontaneous miscarriage and preterm
delivery.
Systemic lupus erythematosus (SLE), an autoimmune disorder of unknown etiology, has also
been documented to negatively impact pregnancy. Women with Systemic lupus erythematosus
(SLE)have increased rates of miscarriage and preterm delivery. Women with Systemic lupus
erythematosus (SLE) also have increased rates of hypothyroidism and autoimmune thyroid
disease (AITD, defined as the presence of thyroid antibodies with or without thyroid
dysfunction). Preterm delivery (PTD), defined as birth prior to 37 weeks gestation, is the
leading cause of neonatal mortality and morbidity in the United States. Although risk
factors for preterm delivery exist, the majority of women have no known risk factors.
Recently, both hypothyroidism and autoimmune thyroid disease have also been linked to
preterm delivery. Given the increased prevalence of negative outcomes documented in pregnant
women with thyroid disease, and the increased rates of hypothyroidism and Autoimmune thyroid
disease in women with Systemic lupus erythematosus (SLE), the investigators determined that
Autoimmune thyroid disease was associated with both preterm delivery and miscarriage. This
has led to this application to begin a pilot randomized clinical trial of thyroxine in
autoimmune thyroid disease in systemic lupus erythematosus pregnancy.
Description:
Objectives: The investigators hypothesize that levothyroxine decreases miscarriages and
preterm birth.
The investigators will compare levothyroxine versus placebo to determine the effects on
pregnant women with Autoimmune thyroid disease.
Background:The last two decades have witnessed an explosion of new research documenting the
deleterious impact that thyroid disease has on pregnancy and the postpartum period, in
relation to miscarriage, preterm delivery , Intelligence quotient (IQ) of the unborn child
and health of the mother postpartum . Both subclinical hypothyroidism and thyroid antibody
positivity in euthyroid women have been associated with miscarriage and preterm delivery.
.Even minor perturbations of thyroid function have been linked to decreased Intelligence
Quotients and impaired neurological development of the unborn child. Approximately 5% of all
pregnant women have a thyroid disorder (either subclinical or overt hypothyroidism or
hyperthyroidism). Intervention in pregnancy with levothyroxine in euthyroid thyroid antibody
positive women has been shown in a prospective study, performed in an area of mild iodine
deficiency, to significantly decrease the rate of both spontaneous miscarriage and preterm
delivery .
SLE has also been documented to negatively impact pregnancy. Women with systemic lupus
erythematosus (SLE) have increased rates of miscarriage and preterm delivery, especially in
the setting of active Systemic lupus erythematosus and antiphospholipid antibodies . The
offspring of women with Systemic lupus erythematosus are at increased risk for heart block
and require neonatal intensive care unit care more frequently . Furthermore, pregnant women
with Systemic lupus erythematosus (SLE) have increased mortality rates. Women with Systemic
lupus erythematosus (SLE) also have increased rates of hypothyroidism and autoimmune thyroid
disease (AITD, defined as the presence of thyroid antibodies with or without thyroid
dysfunction). In a recent case-control study performed by questionnaire, Yuen et al
documented a 21% prevalence of thyroid disease in Systemic lupus erythematosus (SLE) women
versus 10% in controls (p=0.02).
Preterm delivery (PTD), defined as birth prior to 37 weeks gestation, is the leading cause
of neonatal mortality and morbidity in the United States. Despite a public health effort to
decrease the prevalence of Preterm Delivery (PTD) , the prevalence has increased from 11% in
1996 to 12.7% in 2007, with an annual societal cost of over 26 billion dollars. In an
attempt to affect the societal impact of preterm delivery, the Surgeon General made
decreasing the prevalence of Preterm Delivery to 7.6% a goal of Healthy People 2010.
Although risk factors for Preterm Delivery exist, the majority of women have no known risk
factors. Recently, both hypothyroidism and autoimmune thyroid disease have also been linked
to preterm delivery.
Given the increased prevalence of negative outcomes documented in pregnant women with
thyroid disease, and the increased rates of hypothyroidism and Autoimmune thyroid disease in
women with systemic lupus erythematosus, the investigators previously evaluated the
prevalence of thyroid disease during pregnancy and postpartum in women with systemic lupus
erythematosus, as well as pregnancy outcome. The investigators determined that autoimmune
thyroid disease was associated with both preterm delivery and miscarriage in the Hopkins
Lupus Cohort . This has led to this application to begin a pilot randomized clinical trial
of levothyroxine in autoimmune thyroid disease in Systemic Lupus Erythematosus pregnancy.
Preliminary Data:
The prevalence of thyroid antibody positivity was 31.5%. Preterm birth was strongly
associated with Autoimmune Thyroid Disease in systemic lupus erythematosus (p=0.002). The
investigators found: 1) a high percentage of women (13%) were on thyroid hormone replacement
prior to becoming pregnant, 2) a high percentage of women (10.9%) presented with previously
undiagnosed subclinical hypothyroidism during pregnancy, 3) 14% of women developed
postpartum thyroiditis, 4) antibody positivity during pregnancy was not predictive of the
occurrence of postpartum thyroiditis, and 5) women with thyroid disease had a dramatic
increase in the prevalence of preterm delivery as compared to women who had no thyroid
disease. Overall, the percentage of women with systemic lupus erythematosus who either had
levothyroxine treated thyroid disease prior to pregnancy, who were diagnosed with thyroid
disease during pregnancy, or who developed postpartum thyroiditis, was 37.9%. None of the
demographic, laboratory, medication usage, or disease activity index data affected the
association of autoimmune thyroid disease with adverse pregnancy outcome.
Significance:
Preterm delivery was markedly increased in the group of Systemic Lupus Erythematosus women
who had thyroid disease diagnosed either prior to, during, or in the postpartum period, as
compared to the group of women who were thyroid disease free, in our previous study. Our
results were not affected by the dosage of prednisone administered or the cardiolipin
antibody titer. Furthermore, the increased rate of preterm delivery in the Systemic Lupus
Erythematosus women with thyroid disease was not secondary to Systemic Lupus Erythematosus
activity, as the Physician Global Assessment score and Systemic Lupus Erythematosus Disease
Activity Index were similar in Systemic Lupus Erythematosus women with or without thyroid
disease. These results are consistent with a growing body of evidence linking thyroid
disorders, both hypothyroidism and autoimmune thyroid antibodies in euthyroid women, to
Preterm delivery .
In conclusion, women with Systemic Lupus Erythematosus have a high prevalence of primary
hypothyroidism,undiagnosed subclinical hypothyroidism, and postpartum thyroiditis. In sum, a
minimum of one in every three pregnant women with systemic lupus erythematosus falls into
one of these categories. Autoimmune thyroid disease is highly associated with adverse
pregnancy outcomes.
Our current application will begin a pilot trial of levothyroxine versus placebo at the
United States sites with a long track record of interest in Systemic Lupus Erythematosus and
pregnancy.
Study Procedures Systemic lupus erythematosus (SLE) will be defined by the American College
of Rheumatology (ACR) classification criteria or by the Systemic Lupus International
Collaborative Clinics revised American College of Rheumatology criteria. Systemic lupus
erythematosus (SLE) patients already on levothyroxine and those discovered to be hypothyroid
needing levothyroxine, will be excluded.
Pregnant Systemic lupus erythematosus patients with autoimmune thyroid antibodies who give
informed consent will be randomized to levothyroxine (50mcg) versus placebo.
Outcome measures will follow those used in the Predictors of Pregnancy Outcome: Biomarkers
in Anti-Phospholipid Antibody Syndrome (APS) and Systemic Lupus Erythematosus (SLE)
(PROMISSE) study. The outcome will be adverse pregnancy outcome (preterm birth, miscarriage,
or stillbirth).
The endpoint is adverse pregnancy outcome as defined by the Promisse study
The composite endpoint defined as the occurrence of one or more of the following events:
1. Otherwise unexplained fetal death occurring after 12 weeks gestation
2. Neonatal death prior to hospital discharge and due to complications of prematurity
3. Indicated preterm delivery prior to 36 weeks' gestation because of gestational
hypertension, preeclampsia-eclampsia, or placental insufficiency
4. Intrauterine growth restriction (IUGR) Enrollment will be at Johns Hopkins Hospital,
Hospital for Joint Diseases (Jill Buyon M.D.) Oklahoma Medical Research Foundation
(Joan Merrill M.D.), University of Chicago (Tammy Utset M.D., M.P.H.) Duke University
Medical Center (Megan Clowse M.D., M.P.H) and Stanford University (Eliza F.
Chakravarty, M.D.). Dr D. Ware Branch at the University of Utah will be the gynecologic
consultant to adjudicate the outcomes.
TSH testing will be performed using the Ultrasensitive hTSH II method on an AbbottAxsym.
(Abbott Diagnostics, Abbott Park, Illinois.) This is a Microparticle Enzyme Immunoassay
(MEIA) method. The analytical sensitivity of the Axsym Ultrasensitive hTSH II is 0.03
uIU/mL. The intraassay coefficient of variation (CV) is 4.35% and the interassay coefficient
of variation (CV) is 5.73%. A TSH greater than 2.5 μU/ml in the first trimester, or greater
than 3.0 μU/ml in the second or third trimester was considered abnormal. Glinoer et al has
demonstrated that 18% of women without thyroid disease have a suppressed Thyroid Stimulating
Hormone (TSH) . Therefore, in our previous study TSH values below 0.3 μU/ml were not
considered abnormal during pregnancy unless it occurred after the 20th week of gestation.
Serum thyroglobulin antibody (Tg-Ab) and thyroid peroxidase antibody (TPO-Ab) , also
research test, will be measured by enzyme-linked immunosorbent assay (KRONUS KalibreTM
Thyroglobulin Antibody and Thyroid Peroxidase Antibody ELISA kits will be kindly provided by
KRONUS Corp, Boise, ID). Serum anti-Tg levels above 3 U/mL were considered positive and
anti-TPO levels above 2 U/mL will be considered positive.
Study duration and number of study visits required of research participants:
The study duration is upto 36 weeks of pregnancy after screening. The patient will be seen
monthly using the accepted clinical guidelines devised for the PROMISSE (Predictors of
Pregnancy Outcome: Biomarkers in Anti-Phospholipid Antibody Syndrome (APS) and Systemic
Lupus Erythematosus (SLE)) study, an National Institute of Health funded prospective study
of the role of the antiphospholipid antibodies in pregnancy. At each pregnancy visit, the
Stemic Lupus Erythematosus Pregnancy Disease Activity Index (SLEPDAI), physician global
assessment, blood pressure, urine protein to creatinine ratio,Complement 3 (C3) ,Complement
4 (C4) and anti-double stranded DNA will be recorded. Anticardiolipin and lupus
anticoagulant will be recorded as part of standard of care. All women will be followed by
both their rheumatologist and their obstetrician.
Plan for reporting unanticipated problems or study deviations. The Data Safety Monitoring
Committee will review all adverse events monthly. All serious adverse events will be
reported per Federal and JHM-IRB regulations Definition of treatment failure or participant
removal criteria. Treatment failure does not apply.
1. Systemic lupus erythematosus (SLE) patients who experience an allergic reaction to
Levolevothyroxine.
2. Patients who fail to adhere to study instructions.
3. Patients who develop medium to severe adverse events.
4. Withdrawal of consent.
5. A patient with clinical hypothyroidism, elevated Thyroid Stimulating Hormone or
clinical hyperthyroidism
5. Inclusion/Exclusion Criteria Inclusion Criteria All Systemic lupus erythematosus (SLE)
pregnant women (aged 18 - 45 years) before 14 weeks of gestation, with autoimmune thyroid
antibodies Exclusion Criteria
- Systemic lupus erythematosus (SLE) patients already on levothyroxine.
- Those patients discovered to be hypothyroid who need levothyroxine as part of standard
of care 6. Drugs/ Substances/ Devices In a prospective study Negro et. al has
demonstrated that thyroxin given to women with antithyroid antibodies significantly
decreased the rate of both spontaneous miscarriage and preterm. The investigators plan
to administer the drug/placebo only for the duration of the pregnancy.
The dose will be 50 mcg daily.
