Clinical trial NCT01950260
Conditions: Graves' Disease
Keywords: Graves' disease Radioactive iodine Hypothyroidism
Sponsor: Mayo Clinic
Start date: 2013-09-01; Completion date: 2017-04-01
Enrollment: 61 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study will try to answer the question of whether early treatment with levothyroxine at 4 weeks after radioactive iodine for Graves'disease will prevent overt hypothyroidism (low thyroid hormone levels).

Detailed description:

Arms: arm 1: In the intervention arm patients will start levothyroxine therapy at 4 weeks after RAI therapy. The initial dose of levothyroxine will be 25 mcg/day. It will be increased to 50 mcg/day 2 weeks later and then adjusted at 8 weeks post RAI based on a full face-to-face clinical and biochemical evaluation. arm 2: In the control arm patients will receive placebo capsules and be evaluated for levothyroxine therapy during a full face-to-face evaluation at 8 weeks.
Interventions: intervention 1: Levothyroxine intervention 2: Placebo
Intervention descriptions: intervention 1: Early initiation of levothyroxine after radioactive iodine (to start at 4 weeks). intervention 2: Placebo to start at 4 weeks after RAI

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Prevention of overt 
hypothyroidism following 
radioactive iodine therapy for 
Graves’ disease; a novel 
protocol with implications for 
future studies 
 
NCT# 01950260 
 
February 12, 2015 


 Prevention of overt hypothyroidism following radioactive iodine therapy for Graves’ 
disease; a novel protocol with implications for future studies  
Principal Investigator: Marius N. Stan, MD 
I. Specific Aims 
We aim to test the hypothesis that early treatment with levothyroxine after radioactive therapy for Graves’ 
disease will prevent overt hypothyroidism (primary outcome).  
II. Background and Significance 
The most common method of treating Graves’ disease (GD) in the US relies on rendering the patient 
hypothyroid with the use of radioactive iodine (RAI) ablation of the thyroid gland followed by lifelong 
replacement with thyroid hormone (levothyroxine). Our current practice is to reevaluate GD patients 2-4 
months after their therapy with RAI. At that time their hyperthyroidism is expected to have been resolved, 
however the majority are clearly hypothyroid at that point. While many are asymptomatic or minimally 
symptomatic, some are frankly hypothyroid with related troublesome symptoms (cold intolerance, 
sleepiness, fatigue, weight gain, hoarse voice etc.).  
We and others have identified hypothyroidism following treatment of GD as a risk factor for the 
development of future Graves’ ophthalmopathy (GO), a potentially vision-threatening complication of 
GD1-3. These studies show that development of hypothyroidism increases the risk of developing GO by an 
average factor of 3.3. Cohort data from centers where early levothyroxine replacement is routinely 
administered following RAI therapy 1,4 suggests that this approach  can decrease the risk of GO 
development. In addition, these data show a very low occurrence of  hyperthyroidism symptoms that may 
present when levothyroxine is given prior to documentation of hypothyroidism. Based on these data, the 
recent publication of guidelines for the treatment of patients with hyperthyroidism5 (with Drs. Bahn and 
Stan as task-force chair and member) recommended that hypothyroidism be avoided following RAI 
therapy for GD. However, no randomized trial has yet been performed to test the impact of preventing 
hypothyroidism through a precise protocol of early T4 administration on both GO development and QOL, 
a lapse that our trial intends to correct.  
Completion of our current study to test the hypothesis that early initiation of levothyroxine following a 
precise protocol using small doses of the medication can prevent development of overt hypothyroidism 
without an increase in rate of symptomatic hyperthyroidism is necessary before we can design our 
subsequent study. That study will be a larger multi-center investigation testing the hypothesis that 
prevention of overt hypothyroidism after RAI using this (or a refined) protocol can prevent development 
or worsening of GO and at the same time improve the quality of life of these individuals.  
III.  Progress Report and Preliminary Studies 
This project involves performing a therapeutic trial in patients with GD. I have to date participated in 3 
such trials. The first trial 6 was a placebo-controlled trial that involved administration of octreotide or 
placebo for therapy of active GO. My participation in that trial included data collection, data analysis and 
drafting of the final manuscript. The second trial (Clinicaltrials.gov Identifier NCT00595335;PI:RS Bahn) 
is an ongoing placebo-controlled study that tests the benefit of rituximab in patients with active and 
moderate-to-severe GO. I was involved in designing the trial and I’m currently enrolling and following 
patients throughout the trial. The third trial (Clinicaltrials.gov Identifier NCT01171690 ) is another 
ongoing study testing the impact of teriparatide on the duration of hospitalization post thyroidectomy, in 
patients that develop postsurgical hypoparathyroidism. I am the PI in this single arm study with historical 
controls. We expect to complete patient enrollment by the end of 2014. In addition to these trials we have 


just published our retrospective cohort results describing the development of hypothyroidism in patients 
with GD treated with RAI, and its impact on GO development3. This cohort is very similar to the group of 
patients that we intend to enroll in the current study. Lastly, I have completed a Masters in Clinical 
Research and Translational Sciences through the Mayo Clinic CTSA. This training has given me 
important background in clinical study protocol design to data analysis.   
In our review of Mayo Clinic 
records, 
the 
majority 
(102/195;52%) of patients were 
overtly hypothyroid by the time 
of their first evaluation after RAI 
(Fig.1) and 36% had a TSH value 
> 20 mIU/L.3 Furthermore, we 
found that 21% of patients are in 
reality seen for their first return 
visit after > 3 months post RAI 
due to practicalities of scheduling 
and the lack of a standardized 
protocol for this process. We 
found that the prevalence of 
hyperthyroidism 
decreased 
as 
expected between the 2 groups 
and dropped below 25% in groups 
with first follow-up after 6 weeks. We calculated the ratio between euthyroidism and hypothyroidism at 
each follow-up and found the ration to drop below 1.0, favoring hypothyroidism, starting from follow-up 
period 8-10 weeks and then to decrease linearly thereafter. It is very likely that the development of 
hypothyroidism in the latter groups is associated with a significant symptomatic hypothyroidism and 
decrease in patients’ quality of life (QOL).  
 
 
 
 
 
Fig.1 
Table 1. Distribution of thyroid status at first biochemical follow-up 


We found that hypothyroidism present at 
the first follow-up visit was strongly 
associated with GO development or 
deterioration with OR of 3.3, 95% CI:1.3-
8.7,p=0.011 (Fig. 2). A multi-variate 
analysis was performed and included 
hypothyroidism status at the first follow-
up, the administration of corticosteroids 
concurrently with RAI, smoking status, 
fT4 level at baseline, gender, age, 24 hr 
RAI uptake test results, thyroid size and 
dose of RAI. The factors that remained 
independently 
significant 
were 
development of hypothyroidism by the 
first follow-up visit after RAI therapy 
(OR=3.6) and preexisting GO (OR=2.8; 
Table 2). 
 
 
IV.  Research Design and Methods 
 
a. Study Design/Overview –The design for this study was developed based upon the findings of our 
retrospective cohort study described above. We propose a randomized trial with 2 arms, intervention and 
control, as depicted in Figure 3. The randomization will be done in blocks of 6 patients. In the 
intervention arm patients will start levothyroxine therapy 4 weeks prior to return evaluation with Mayo 
Endocrinologist, approximately 4 weeks after RAI therapy. The initial dose of levothyroxine will be 25 
mcg/day. It will be increased to 50 mcg/day 2 weeks later and then adjusted at 8 weeks post RAI based on 
a full face-to-face clinical and biochemical evaluation. At the 8 weeks visit the treating physician can be 
informed about the randomization status (actual levothyroxine dose received by the patient). This will be 
done only if requested by the treating physician for optimal clinical care and the information will be 
delivered through the secretarial staff or the study coordinator, after communication with the research 
pharmacy. Both the active capsules and the placebo will be provided by Mayo Research Pharmacy, who 
will also coordinate the randomization process. In the control arm patients will receive placebo capsules 
and be evaluated for levothyroxine therapy during a full face-to-face evaluation at 8 weeks, following 
currently accepted clinical practice. Patients in both groups will have blood drawn at 4 and 6 weeks (in 
Rochester if agreed by the patient or by mail-in kit to maximize the percent of data collection), stored and 
analyzed at a later time (batch processing for limiting costs) for free thyroxine and TSH.  The study 
Table 2. GO changes correlated with thyroid status at first biochemical 
Fig.2 


coordinator will follow on this process to ensure that the patients perform these interim studies. 
Development of hypothyroidism will be assessed using these tests at 4, 6 and 8 weeks using the cutoffs 
for free thyroxine and TSH values as described previously3. For the 8 weeks visit all patients will be 
asked to bring their medication bottles and the study coordinator will perform a pill count to assess 
compliance with the protocol. Final evaluation for both groups will be at 6 months after RAI at which 
time patients will undergo a phone questionnaire which will assess the rate of recurrence of 
hyperthyroidism and test the feasibility of screening for changes in GO status over the phone. In both 
groups a quality of life instrument will be used at baseline, 4, 6 and 8 weeks and at 6 months. We will use 
the hypothyroid-Health Related Quality of Life (hypothyroid-HRQL)7 and also the Thyroid Specific 
Questionnaire (TSQ)8. These questionnaires are disease-specific for hypothyroidism. A major advantage 
to our study is also their ability to be self-administered. These last 2 interventions will be used to assess 
the feasibility of using them in the larger, multi-center trial where GO prevention and QOL benefit will be 
the primary outcomes. 
 
Figure 3 – Trial flow chart 
 
b. Study Subjects - Inclusion criteria target all adult patients (ages 18-70 years) with GD who will receive 
RAI for treatment of GD. We plan to have 60 individuals complete the study. For that up to 90individuals 
may need to be screened. Exclusion criteria - Patient with clinically manifest GO will be excluded from 
the study. We will also exclude patients with recent (<1 yr.) history of arrhythmias or any history of 
ventricular arrhythmias, those with preexistent cardiomyopathy, those with malnutrition and those with 
psychiatric history that could get worse if patient remains persistently hyperthyroid. Patients unlikely to 
return for the planned follow-up visits, to comply with the blood drawing schedule and with the 
completion of the hypothyroid-HDQL and TQS questionnaires will also be excluded. If a medical 
examination was performed within the last 4 weeks by an endocrinologist we can discuss the study over 
the phone. The consent material can be exchanged by mail or fax. 
 
d. Data Collection - The data will be collected prospectively and stored in an electronic database. 
Baseline assessment will include demographic data, thyroid size, thyroid functional parameters (TSH, T4 
and T3 levels), RAI uptake and dose, smoking status and history of therapy with corticosteroids or 
methimazole (pre and post RAI) . The development of hypothyroidism is defined as TSH > 3.0 mIU/L or 
free thyroxine (fT4) < 0.8 ng/dL. The methodology for thyroid functional parameters will be the currently 
used clinical assays. We will offer blood collection for all the required samples here in Rochester. For 
Intervention group - 6 months - Control group 
Telephone interview and QOL; face-to-face evaluation for 
GO per MD 
Telephone interview and QOL; face-to-face evaluation for 
GO per MD 
Intervention group  
- 8 weeks -  
Control group 
Face-to-face evaluation; bloods and QOL; LT4 dose 
adjustment  per MD 
Face-to-face evaluation; bloods and QOL; LT4 initiation  per 
MD 
Intervention group 
- 6 weeks -  
Control group 
Blood drawing and QOL; double up LT4 to 50 mcg daily 
Blood drawing and QOL; double up placebo to 2 tabs daily 
Intervention group 
- 4 weeks -  
Control group 
Blood drawing and QOL; start 25 mcg LT4 
Blood drawing and QOL; start placebo 
Intervention group  
- Baseline -  
Control group 
RAI therapy 
RAI therapy 


those patients that are not local the blood drawing will be organized with the help of mail-in kits. This 
will maximize the likelihood of the tests being completed and the study coordinator will follow with the 
patients over the phone to ensure that this process will happen.  
g. Feasibility and Time Frame - Our own data indicate that every year 150 patients with Graves’ 
hyperthyroidism who are evaluated at Mayo Clinic Rochester by RSB, MNS or one of other members of 
the Endocrinology Division and Thyroid Core Group. This group of physicians collaborates closely on 
clinical studies and would in all likelihood refer their patients with GD for participation in this study. We 
would therefore expect to be able to enroll at least 30% of this patients group and complete enrollment in 
1.5 years’ time. Analysis and drafting of the manuscript will likely take an additional 6 months. 
Compliance with the study planned follow-up time frame should be acceptable for the vast majority of 
patients as the protocol remains close to the current standard of care while the early thyroid testing will be 
done utilizing mail-in kits for patients’ convenience.  
h. Statistical Considerations 
Outcomes:  
Primary endpoint: 
Incidence of overt hypothyroidism at 8 weeks post RAI (TSH > 3.0 mIU/L or fT4 < 0.8 ng/dL) 
Exploratory endpoints: 
 
Quality of Life measured by the hypothyroid-HRQL and the TSQ at 8 weeks and 6 months 
 
Development of GO at 6 months 
Safety Endpoints 
 
New development/deterioration of symptoms of hyperthyroidism. 
Sample Size 
The sample size for this study is based on the incidence of hypothyroidism primary endpoint using an 
alpha=0.10 (two-sided), beta=0.10. The proportions of participants that develop hypothyroidism in the 
placebo and experimental groups are assumed to be 60% and 20%, respectively. A sample size of 30  per 
group will provide 90% power to detect a difference between the group proportions of 40% using the 
two-sided Fisher's Exact test.  
 
Primary Endpoint Analysis: 
The difference in the incidence rates of hypothyroidism at 8 weeks will be tested using Fisher’s exact test.  
Exploratory Endpoint Analysis: 
Change in quality of life is measured serial over the course of the study follow-up. Change from baseline 
will be assessed using a hierarchical linear model (“growth curve”). The primary parameter of interest 
from the model will be the treatment by time interaction term. Time, for this study, will be a collection of 
indicator variables representing each assessment point. The incidence of GO will be tested using Fisher’s 
exact test.  
Safety Analysis: 
Frequency tables of adverse events by treatment groups at the patient level will be tabulated. The relative 
risk of developing a serious, and at least potentially related, adverse event will be estimated along with 
the 90% confidence interval for relative risk.  


Additional Statistical Considerations 
The primary analysis will be conducted according to the intention to treat principle. Efforts will be made 
to ascertain the incidence of hypothyroidism even in participants that are lost to follow up. In the event 
the data cannot be obtained, the primary analysis will assume these participants are positive for 
hypothyroidism. Sensitivity analysis will be conducted on the per protocol data set.   
Missing data for the primary endpoint is addressed through the intention to treat analysis. Missing data in 
exploratory endpoints could occur. The analysis plan for the QOL endpoint include maximum likelihood 
estimation that allows for missing data, provided the data are missing at least missing at random.  
A P-value < 0.10 will be considered significant for the primary endpoint and exploratory analyses.  
 
i. Strengths - The design for this study was developed based upon the findings of our retrospective cohort 
study described above. This trial design will compare an active intervention with the current practice 
using the benefit of blinding and randomization for eliminating a placebo effect and differences in known 
and unknown confounders between the groups. It is also minimally disruptive of patients schedule while 
providing potential benefit for both quality of life and decreasing the risk of GO. By having the free 
thyroxine values at 0, 4, 6 and 8 weeks it will provide us with the ability to better predict the development 
of euthyroidism/hypothyroidism, to decide on the best levothyroxine dose and to adjust the therapeutic 
sequence accordingly. We have allowed for a low recruiting percentage to avoid the possibility of 
extending the study beyond the planned funded time frame. 
 
j. Limitations - There may be patients that will report increase/recurrence of hyperthyroidism-like 
symptoms. Those cases are rare and in the literature early T4 therapy (started at 50 mcg daily 2 weeks 
after RAI) required discontinuation due to symptoms of thyrotoxicosis in only 7/314 patients (2.2%)1,4. In 
that case we will decrease the dose of levothyroxine x 2 weeks and if the symptoms persist the medication 
will be discontinued. Beta-blockers will be used liberally at the discretion of the treating physician.  
 
k. Regulatory aspects – We have discussed extensively and consulted with the Office of Research 
Regulatory Support on the issue of applicability for an IND application. The intention of the study is to 
treat with levothyroxine patients that are in the very early stages of developing hypothyroidism. The 
timing of the therapy is based on data that documents onset of hypothyroidism well before the usual 8-12 
weeks follow-up. We have proposed to start at a very conservative dose (25 mcg) which represents 25% 
of the median dose used in the therapy of hypothyroidism. This is quite safe as mentioned above, with 
only 2.2% of patients required discontinuation of therapy in similar studies in Europe. In addition the 
patients will be evaluated 4 weeks later and the dose adjusted as clinically indicated. Given all these 
considerations we have concluded that we are not outside of the scope of the FDA-approved indication 
for levothyroxine in hypothyroidism management and we have decided against submitting an IND 
application. 
 


Table 3 – Schedule of Events  
Schedule of Events 
 
Study Activity 
Wk 0 
Wk 4 
Wk 6 
Wk 8 
Wk 24 
Study Agent(s) 
 
X 
X 
X 
 
Informed consent 
X 
 
 
 
 
History 
X 
 
 
X 
Xc 
Concurrent meds 
X 
X 
 
X 
Xc 
Physical exam (Ht, 
Wt, BSA, VS) 
X 
 
 
X 
 
Goiter size 
X 
 
 
X 
 
RAI uptake/dose 
X 
 
 
 
 
Serum chemistry a 
X 
X 
X 
X 
 
Adverse event 
evaluation 
 
Ongoing 
B-HCG 
Xb 
 
 
 
 
QoL instruments 
 
X 
X 
X 
Xc 
 a: Free thyroxine, TSH; total T3 will be obtained at the discretion of the 
treating physician. 
 b: Serum pregnancy test (women of childbearing potential). 
 c: Phone interview. 
 
V. References 
 
1. 
Tallstedt L, Lundell G, Blomgren H, Bring J. Does early administration of thyroxine reduce the 
development of Graves' ophthalmopathy after radioiodine treatment? Eur J Endocrinol 1994;130:494-7. 
2. 
Kung AW, Yau CC, Cheng A. The incidence of ophthalmopathy after radioiodine therapy for 
Graves' disease: prognostic factors and the role of methimazole. J Clin Endocrinol Metab 1994;79:542-6. 
3. 
Stan M, Durski JM, Brito JP, Bhagra S, Thapa P, Bahn RS. Cohort Study on Radioactive Iodine-
induced Hypothyroidism - Implications for Graves' Ophthalmopathy and Optimal Timing for Thyroid 
Hormone Assessment. Thyroid 2012. 
4. 
Perros P, Kendall-Taylor P, Neoh C, Frewin S, Dickinson J. A prospective study of the effects of 
radioiodine therapy for hyperthyroidism in patients with minimally active graves' ophthalmopathy. 
Journal of Clinical Endocrinology & Metabolism 2005;90:5321-3. 
5. 
Bahn RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes of thyrotoxicosis: 
management guidelines of the American Thyroid Association and American Association of Clinical 
Endocrinologists 
Thyroid 2010;20:593-646. 
6. 
Stan MN, Garrity JA, Bradley EA, et al. Randomized, double-blind, placebo-controlled trial of 
long-acting release octreotide for treatment of Graves' ophthalmopathy. Journal of Clinical Endocrinology 
& Metabolism 2006;91:4817-24. 


7. 
Clyde PW, Harari AE, Getka EJ, Shakir KM. Combined levothyroxine plus liothyronine 
compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial. JAMA : the 
journal of the American Medical Association 2003;290:2952-8. 
8. 
Saravanan P, Chau WF, Roberts N, Vedhara K, Greenwood R, Dayan CM. Psychological well-
being in patients on 'adequate' doses of l-thyroxine: results of a large, controlled community-based 
questionnaire study. Clin Endocrinol (Oxf) 2002;57:577-85.