Impact of Vitamin D Therapy on Thyroid Function and Antibody Levels in Pediatric Graves' Disease: A Pilot Feasibility Trial
Phase: PHASE2
Conditions: Graves Disease, Graves' Disease, Hyperthyroidism
Sponsor: Northwell Health

 
Template version: xx,xx, 202 
PROTOCOL: INTERVENTION STUDY (CLINICAL TRIALS) 
Title: Impact of Vitamin D Therapy on Thyroid Function and Antibody Levels in Pediatric 
Graves’ Disease: A Pilot Feasibility Trial 
 
 
Protocol Number: 25-0285 
 
Principal Investigator:  
Name Sharon Hyman, MD 
Title Pediatric Endocrinologist 
Address 1991 Marcus Ave, Suite M100, New Hyde Park NY 11042 
Phone number 516 472 3750 
Email address 
 
 
Investigational Product Name(s): ergocalciferol 
 
 
IND or IDE Number (if applicable): NA 
 
 
Regulatory Sponsor (Sponsor-Investigator or IND/IDE holder, if applicable): NA 
Name 
Address 
Phone number 
Email address 
 
 
Protocol Version and Date: version 1. 6.26.2025 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
ii 
 
Protocol History 
 
Protocol Version
Date 
Version 1
6/26/25
 
 
Protocol Amendment Summary of Changes 
 
Section
Summary of Revisions 
Rationale
 
 
 
 

 
 
 
 
 
iii 
 
Study Team 
DSMB Members
Sanjeev Kothare
Medical Monitor
Biostatistician
Suhail Rubab; Jane Cerise
Project Coordinator
Jillian Charyn, Nafeesa Saadi
Data Coordinator
Clinical Laboratory
Investigational Product Supplier
CCMC Pediatric Research Pharmacy
Clinical Research Monitor
 
Participating Site Teams 
Northwell Health
CCMC Pediatric Endocrinology 
1991 Marcus Ave, Suite M100 
New Hyde Park, NY 11042 
PI: Sharon Hyman
Co-Investigator: Sofya Ilmer 
Study Coordinators: Jillian Charyn, Nafeesa 
Saadi 
Research Nurses: Joanne Twaits 
Research Pharmacists: Uzma Afzal 
 
 
 
 
 

 
 
 
 
 
 
 
iv 
 
CONTENTS 
STATEMENT OF COMPLIANCE .......................................................................................................................... VII 
ABBREVIATIONS OF TERMS ............................................................................................................................ VIII 
PROTOCOL SYNOPSIS .......................................................................................................................................... X 
EXAMPLE: TABLE 1: SCHEDULE OF STUDY PROCEDURES ................................................................................ XII 
EXAMPLE: FIGURE 1: STUDY DIAGRAM ......................................................................................................... XIII 
1 
INTRODUCTION .......................................................................................................................................... 14 
1.1      BACKGROUND INFORMATION AND RATIONALE ..................................................................................... 14 
1.2     INVESTIGATIONAL PRODUCT .................................................................................................................. 14 
1.3 
FINDINGS FROM PREVIOUS STUDIES .................................................................................................... 15 
1.3.1 
Data from Non-Clinical Studies ...................................................... Error! Bookmark not defined. 
1.3.2 
Data from Clinical Studies .............................................................. Error! Bookmark not defined. 
1.4 
BENEFIT AND RISK ASSESSMENT ......................................................................................................... 16 
1.4.1 
Known Potential Risks .................................................................................................................. 16 
1.4.2 
Known Potential Benefits .............................................................................................................. 17 
1.4.3 
Assessment of Potential Risks and Benefits ................................................................................... 18 
1.5 
IND OR IDE APPLICABILITY ................................................................................................................ 18 
2 
STUDY OBJECTIVES AND ENDPOINTS ........................................................................................................ 18 
3 
INVESTIGATIONAL PLAN ............................................................................................................................ 19 
3.1       OVERALL STUDY DESIGN AND PLAN .................................................................................................... 19 
3.2       PARTICIPATING SITES AND ENROLLMENT ............................................................................................. 20 
3.3 
STUDY POPULATION ............................................................................................................................ 20 
3.4 
SUBJECT ELIGIBILITY ............................................................................................................................ 1 
3.4.1 
Inclusion Criteria ............................................................................................................................ 1 
3.4.2 
Exclusion Criteria ........................................................................................................................... 1 
3.4.3 
Screen Failures ............................................................................................................................... 2 
4 
EVALUATIONS BY VISIT ................................................................................................................................ 2 
4.1       SCREENING VISIT .................................................................................................................................... 2 
4.2 
VISIT 1 (DAY/WEEK/MONTH #) ............................................................................................................. 3 
4.3        VISIT 2  (DAY/WEEK/MONTH # INCLUDE VISIT WINDOW) .................................................................... 4 
4.4        VISIT 3  (FOLLOW UP OR DAY/WEEK/MONTH # INCLUDE VISIT WINDOW) ........................................... 6 
4.5        VISIT 4: END OF STUDY ................................................................. ERROR! BOOKMARK NOT DEFINED. 
4.6        UNSCHEDULED VISITS ........................................................................................................................... 6 
4.7 
EARLY TERMINATION STUDY VISIT ....................................................................................................... 7 
4.8 
SUBJECT DISCONTINUATION AND WITHDRAWAL .................................................................................. 8 
4.9 
LOST TO FOLLOW UP ........................................................................................................................... 10 
5 
STUDY PROCEDURES AND EVALUATIONS ................................................................................................. 10 
5.1 
ELIGIBILITY ASSESSMENTS .................................................................................................................. 10 
5.2 
EFFICACY AND SAFETY ASSESSMENTS ................................................................................................ 11 
5.3 
ASSESSMENT OF ADVERSE EVENTS. .................................................................................................... 12 
5.4 
OTHER ASSESSMENTS .......................................................................................................................... 12 
6   STUDY INTERVENTION ................................................................................................................................... 12 
6.1 
TREATMENT REGIMEN (OR DESCRIPTION OF DEVICE USE) .................................................................. 12 
6.2 
RANDOMIZATION AND BLINDING (IF APPLICABLE) .............................................................................. 13 
6.2.1 
Unblinding Procedures ................................................................................................................. 14 
6.3 
PROCEDURES FOR STUDY PRODUCT .................................................................................................... 14 

 
 
 
 
 
 
 
v 
 
6.3.1 
Intervention Description ............................................................................................................... 14 
6.3.2 
Procurement .................................................................................................................................. 15 
6.3.3 
Storage .......................................................................................................................................... 15 
6.3.4 
Preparation and Administration of IP ........................................................................................... 16 
6.3.5 
Subject Compliance Monitoring .................................................................................................... 17 
6.3.6 
Accountability ............................................................................................................................... 18 
6.3.7 
Return or Destruction of IP ........................................................................................................... 19 
6.4 
PRIOR AND CONCOMITANT THERAPY .................................................................................................. 20 
6.5 
RESCUE MEDICATION ADMINISTRATION ............................................................................................. 22 
7 
STATISTICAL CONSIDERATIONS ................................................................................................................. 22 
7.1    BRIEF DESCRIPTION OF STUDY DESIGN ................................................................................................... 22 
7.2     PRIMARY ENDPOINT(S) ........................................................................................................................... 23 
7.3 
SECONDARY ENDPOINT(S) ................................................................................................................... 23 
7.4 
SAFETY ENPOINTS (IF APPLICABLE) ..................................................................................................... 24 
7.5 
INTENTION – TO-TREAT (ITT) AND PER PROTOCOL (PP) ANALYSIS SETS ............................................ 24 
7.6 
STATISTICAL METHODS ....................................................................................................................... 25 
7.7.1      Analysis of the Primary Endpoint ................................................................................................... 25 
7.7.2     Analysis of Secondary Endpoint(s) .................................................................................................. 25 
7.7.3      Analysis of Safety Endpoints (if applicable) ................................................................................... 26 
7.7.4      Pre-specified Subgroup Analyses ................................................................................................... 26 
7.7.5     INTERIM ANALYSIS AND EARLY STOPPING RULES (IF APPLICABLE) ........................................................................ 26 
7.7.6       SAMPLE SIZE JUSTIFICATION ...................................................................................................................... 26 
8   ADVERSE EVENT, SERIOUS ADVERSE EVENT AND UNANTICIPATED PROBLEM ........................................... 27 
8.1     ADVERSE EVENT (AE) ........................................................................................................................... 27 
8.2 
SERIOUS ADVERSE EVENTS (SAE) ...................................................................................................... 27 
8.3 
UNANTICIPATED PROBLEMS (UP)/ UNANTICIPATED DEVICE EFFECT (UADE) ................................... 27 
8.4 
RECORDING ......................................................................................................................................... 27 
8.5 
ASSESSMENT ....................................................................................................................................... 28 
8.5.1 
Severity of Event ............................................................................................................................ 28 
8.5.2 
Relationship to Study Intervention ................................................................................................ 28 
8.5.3 
Expectedness ................................................................................................................................. 29 
8.5.4 
Time Period and Frequency for Event Assessment and Follow-Up .............................................. 29 
8.6 
REPORTING .......................................................................................................................................... 29 
8.6.1 
Adverse Event (AE) Reporting ...................................................................................................... 29 
8.6.2 
Serious Adverse Event (SAE) Reporting ........................................................................................ 29 
8.6.3 
Unanticipated Problem/ Unanticipated Device Effect Reporting ................................................. 30 
8.6.4 
Reporting to Participants (If Applicable) ...................................................................................... 30 
9 
REGULATORY, ETHICAL AND STUDY OVERSIGHT CONSIDERATIONS ....................................................... 31 
9.1 
INFORMED CONSENT/ASSENT AND HIPAA AUTHORIZATION .............................................................. 31 
9.2 
SAFETY OVERSIGHT ............................................................................................................................ 31 
9.2.1 
Data Safety Monitoring Plan ........................................................................................................ 31 
9.2.2 
Medical Monitoring ...................................................................................................................... 32 
9.2.3 
Independent Data and Safety Monitoring Board .......................................................................... 32 
9.2.4 
Stopping Rules ............................................................................................................................... 32 
9.3 
DATA HANDLING AND RECORD KEEPING ............................................................................................ 32 
9.3.1 
Data Collection and Management ................................................................................................ 33 
9.3.2 
Confidentiality and Privacy .......................................................................................................... 34 
9.3.3 
Source Documents ......................................................................................................................... 34 
9.3.4 
Case Report Forms ....................................................................................................................... 34 
9.3.5 
Availability and Retention of Records ........................................................................................... 34 
9.3.6 
Future Use of Stored Specimens and Data .................................................................................... 34 
9.4 
STUDY OVERSIGHT .............................................................................................................................. 34 

 
 
 
 
 
 
 
vi 
 
9.4.1      Protocol Deviations ...................................................................................................................... 34 
9.4.2 
Study Status ................................................................................................................................... 35 
9.4.3 
Conflict of Interest ......................................................................................................................... 35 
9.4.4 
Institutional Review Board/Independent Ethics Committee Review and Approval ....................... 35 
9.4.5     Publication .................................................................................................................................... 35 
9.5 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................................................. 35 
9.5.1 
Clinical Monitoring ....................................................................................................................... 35 
9.5.2 
Auditing and Inspecting ................................................................................................................ 35 
10 
REFERENCES ............................................................................................................................................... 35 
APPENDIX ............................................................................................ ERROR! BOOKMARK NOT DEFINED. 
 
 
 
 

 
 
 
 
 
 
 
vii 
 
STATEMENT OF COMPLIANCE 
1. The trial will be conducted in accordance with International Conference on Harmonisation 
Good Clinical Practice (ICH GCP) and the following:  
 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, 21 CFR Part 812 and/or other 
applicable CFRs).  
 
2. Investigators and clinical trial site staff who are responsible for the conduct, management, or 
oversight of clinical trials have completed the appropriate Human Subjects Protection and ICH 
GCP Training. 
 
3. The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study, except for changes necessary to eliminate an immediate hazard to 
study participants.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made if participants will need to be re-consented with the most recent 
version of the IRB approved consent form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
viii 
 
ABBREVIATIONS OF TERMS 
The list below includes abbreviations utilized in this template.  Therefore, this list should be 
customized for each protocol by removing unused abbreviations and adding unlisted abbreviations. 
 
ADE
Adverse Device Effect
AE
Adverse Event
ANCOVA
Analysis of Covariance
CBC
Complete Blood Count
CFR
Code of Federal Regulations
CLIA
Clinical Laboratory Improvement Amendments
CMP
Clinical Monitoring Plan
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form
DHHS
Department of Health and Human Services
DSMB
Data Safety Monitoring Board
DRE
Disease-Related Event
EC
Ethics Committee
eCRF
Electronic Case Report Forms
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act of 2007
FFR
Federal Financial Report
GD
Graves’ Disease
GCP
Good Clinical Practice
GLP
Good Laboratory Practices
GMP
Good Manufacturing Practices
GWAS
Genome-Wide Association Studies
HIPAA
Health Insurance Portability and Accountability Act 
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IDE
Investigational Device Exemption
IND
Investigational New Drug Application
IRB
Institutional Review Board
ISM
Independent Safety Monitor
ISO
International Organization for Standardization
ITT
Intention-To-Treat
LSMEANS
Least-squares Means
MedDRA
Medical Dictionary for Regulatory Activities
MOP
Manual of Operating Procedures
MSDS
Material Safety Data Sheet
NCT
National Clinical Trial
NIH 
National Institutes of Health
OHRP
Office for Human Research Protections
PI
Principal Investigator
QA
Quality Assurance
QC
Quality Control

 
 
 
 
 
 
 
ix 
 
RCT
Randomized Controlled Trial
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SMC
Safety Monitoring Committee
SOA
Schedule of Activities
SOP
Standard Operating Procedure
TFT
Thyroid Function Test
UADE
Unanticipated Adverse Device Effect
UP
Unanticipated Problem
US
United States
 

 
 
 
 
 
 
 
x 
 
PROTOCOL SYNOPSIS 
Protocol Title 
Impact of Vitamin D Therapy on Thyroid Function and Antibody Levels in 
Pediatric Graves’ Disease: A Pilot Feasibility Trial 
Study Description 
Our long-term goal is to investigate whether achieving optimal vitamin D 
levels should be standard of care in pediatric patients diagnosed with 
Graves’ Disease (GD). Our objective is to investigate the feasibility of 
protocol implementation for a larger clinical trial to help determine 
whether high dose vitamin D supplementation can promote earlier 
normalization of thyroid function and earlier reduction in Graves’ 
antibody levels in newly diagnosed pediatric patients with GD compared 
to monotherapy with methimazole alone. 
Funder 
CCMC Pediatric Endocrinology – Departmental Funding 
Clinical Phase 
Pilot Feasibility Study 
Study Objective(s) 
 
Primary: To evaluate the feasibility and refine procedures for a 
future, adequately powered randomized controlled trial of high-dose 
vitamin D supplementation in pediatric GD  
 
Secondary (exploratory): To explore the trends in thyroid function 
(TSH, T3, FT4, and T4) in pediatric GD patients receiving either 
methimazole alone or methimazole plus high-dose vitamin D 
supplementation. 
 
Tertiary (exploratory): To evaluate the impact of high-dose vitamin D 
supplementation on TSH receptor antibody (TRAb) and Thyroid 
Stimulating immunoglobulin (TSI) levels in children with newly 
diagnosed GD. 
Interventions or Test 
Article(s) 
 
The investigational product is vitamin D ergocalciferol 50,000 IU, 
administered orally. In this study, participants will be randomized to 
either the experimental (vitamin D + methimazole) or control 
(methimazole only) group at the time of the initial visit. The starting dose 
of methimazole and dose adjustments will be made by the treating 
endocrinologist based on established clinical practice guidelines. The 
control arm will receive no additional intervention other than 
methimazole (standard of care). While the control group will not receive 
the high-dose vitamin D intervention, they will be allowed to take up to 
1000 IU of vitamin D daily. This approach balances the need for a 
comparison group against the ethical responsibility of not withholding a 
potentially beneficial supplement for those with low levels. 
Study Design 
 
This is an open label randomized clinical pilot feasibility trial 
Subject Population  
Specify the sample size, gender, age, demographic group, general health 
status, and geographic location. 
Criteria for Inclusion and 
Exclusion:   
Inclusion Criteria:  
o All new pediatric 
Exclusion Criteria: 
o Initial hydroxy vitamin D levels 

 
 
 
 
 
 
 
xi 
 
participants aged 9-17 
years with a new diagnosis 
of GD who will be started 
on methimazole, will be 
offered to participate at 
the time of diagnosis.  
o Biochemical features 
include: 
o Suppressed TSH <0.1. 
o Elevated T3  
o Elevated Free T4 
o Elevated T4 
o Positive TSI or TRAb. The 
presence of antibodies is 
diagnostic. 
o Our study will offer 
enrollment to non-English 
speaking participants 
>80 ng/mL
o Hypocalcemia, corrected calcium 
based on albumin <8.4 mg/dL 
o Hypercalcemia, corrected 
calcium based on albumin >10.5 
mg/dL 
o Conditions that affect vitamin D 
metabolism such as: 
malabsorption, chronic kidney or 
liver disease, nephrocalcinosis, 
hyperparathyroidism 
o Current use of medications which 
are known to affect thyroid 
function or vitamin D metabolism 
such as thyroid hormone 
replacement, corticosteroids, 
anticonvulsants 
o Allergy to vitamin D or 
methimazole  
o Diagnosis of Hashitoxicosis or 
thyrotoxicosis (both TSH receptor 
antibody (TRAb) and thyroid-
stimulating immunoglobulin (TSI) 
levels are negative) 
o Participants under the age of 9 
years at the time of diagnosis 
o Pregnant participants 
o Active or uncontrolled infections, 
other significant medical 
conditions deemed by the 
investigator to interfere with 
study participation or pose undue 
risk to the participant. 
Target Enrollment 
 
30 participants are to be enrolled at CCMC Pediatric Endocrinology 
clinical practice. 
Study Duration: 
August 1, 2025 – August 31, 2026. 
Participant Duration: 
24 weeks from initial enrollment in the study 
Data and Safety Monitoring 
Plan 
DSMP officer and PI 

 
 
 
 
 
 
xii 
 
TABLE 1: SCHEDULE OF STUDY PROCEDURES  
 
Study Phase
Screening/
Baseline 
Treatment/Intervention
Study Procedure
D-0 (±1 d)
VISIT 1
(6-week 
Phone call  
(±1 d) 
VISIT 2
(12 week/3-
month visit 
(±1 d) 
VISIT 3 - FINAL
(24 week/6-
month visit) 
 (±1 d) 
Informed Consent/Assent
x
Inclusion/Exclusion Criteria
x
Demographics
x
Medical 
History-
Past 
and 
current medical conditions   
x
x
x
Physical Examination
x
x
x
Vital Signs: BP, HR, RR
x
x
x
Height and Weight
x
x
x
Pregnancy Test (PRN)
Prior/Concomitant Medications
x
x
x
x
Clinical Laboratory Evaluation 
x
x
x
x
Randomization 
x
Dispense Investigational Product
x
IP Accountability/Return
x
Drug Compliance
x
x
x
Adverse Event Assessment
x
x
x
 
.

 
 
  
xiii 
 
FIGURE 1: STUDY DIAGRAM 
 
 
Consent, Screening Visit 
And Randomization 
Visit #0 
Screen Failures 
 
Screening Visit & 
Consent 
Visit # 1 (6-week phone call) 
Intervention 
Methimazole + 50,000 IU 
ergocalciferol 
Visit # 1 (6-week phone call) 
Control  
Methimazole (+/- 1000 IU 
vitamin D – optional) 
Visits # 3 (24 week/6 months) 
Follow-up & End of Study 
Visit # 2 (12 week/3 months) 
Control  
Methimazole (+/- 1000 IU 
vitamin D – optional) 
Visit # 2 (12 week/3 months) 
Intervention 
Methimazole + 50,000 IU 
ergocalciferol 

 
 
  
14 
 
 
1. INTRODUCTION 
1.1      Background Information and Rationale 
 
Graves' disease (GD) is an autoimmune disorder causing hyperthyroidism, with remission (sustained euthyroidism 
off medication) being the ultimate treatment goal. Clinical features of GD include thyroid enlargement or goiter; 
palpitations, diarrhea, weight loss, polyphagia, ophthalmopathy, poor sleep, hyperactivity, mood swings, anxiety, 
increased risk of osteoporosis and fractures from higher bone turnover, proximal muscle weakness, hyperhidrosis, 
heat intolerance, fatigue, growth acceleration and advanced bone maturation.[1] Most pediatric endocrinologists 
start treatment with methimazole and titrate the dose to maintain normal thyroid hormone levels. The goal of 
treatment in GD is to ultimately achieve remission. Remission is defined as remaining euthyroid for at least 12 
months after discontinuation of anti-thyroid therapy. In children, the predictive factors for earlier remission are: 
lower baseline severity of disease at diagnosis as measured by free thyroxine (FT4), total thyroxine (T4), total 
triiodothyronine (T3) levels, Thyroid stimulating immunoglobulin (TSI), TSH Receptor Antibody (TRAb) levels; older 
age, smaller thyroid size at diagnosis, higher Body Mass Index (BMI), lower heart rate at diagnosis, rapid 
normalization of thyroid hormone levels after starting treatment, rate of decline of TRAb after 6 months of 
treatment.[2-4] 
 
While predictive factors for remission in both adults and children include lower baseline disease severity (as 
measured by FT4, T3, TSI, and TRAb levels) and smaller thyroid size, TRAb and TSI levels are key factors influencing 
treatment decisions. Persistently positive antibody levels often necessitate continued anti-thyroid drug (ATD) 
therapy, as they indicate a high likelihood of relapse. Monitoring the rate of TRAb decline, particularly at 6 months 
and upon ATD withdrawal, has been shown to predict remission in adults[5]. Furthermore, emerging evidence 
suggests a strong association between vitamin D and autoimmune regulation. Studies have linked low vitamin D 
levels to an increased risk of GD in both adults and children, with some research indicating a dose-response 
relationship between vitamin D levels and GD risk[6-8]. While one small pediatric trial (n=25) found that vitamin D 
supplementation alongside standard GD therapy improved TSH levels faster[9], data on the impact of vitamin D 
supplementation on treatment outcomes in children with GD remains extremely limited. 
 
This study addresses the critical gap in research regarding the effect of vitamin D supplementation on antibody and 
thyroid hormone trends in children with GD. Current literature demonstrates a correlation between vitamin D 
deficiency and GD, but the impact of supplementation on disease course, particularly antibody levels which are 
crucial for treatment decisions, remains unexplored in pediatric populations. This study will investigate the feasibility 
of protocol implementation for a larger clinical trial. The secondary goals will be to investigate whether high-dose 
vitamin D supplementation, in conjunction with standard methimazole therapy, influences the trajectory of TRAb 
and TSI levels, as well as thyroid hormone levels, in children newly diagnosed with GD. By examining these trends, 
the study will contribute valuable scientific knowledge regarding the potential role of vitamin D in modulating the 
autoimmune response in pediatric GD. Positive findings could significantly impact clinical practice by providing 
evidence to support the use of vitamin D supplementation as an adjunctive therapy, potentially improving 
remission rates and reducing the duration of ATD treatment in children with this condition. 
 
1.2     Investigational Product 
Study Intervention: High-dose Vitamin D (Ergocalciferol) Supplementation 
Description of Investigational Agent: The intervention in this study is ergocalciferol (vitamin D2), a fat-soluble 
vitamin crucial for calcium absorption, bone health, and immune system regulation. Ergocalciferol is a white to 
yellowish-white crystalline powder practically insoluble in water but soluble in organic solvents like ethanol and 
ether. It is commercially available as oral capsules and is not an investigational drug. 
Market Status: FDA-approved (Over the counter and prescription) 

 
 
  
15 
 
Dosage Form: Oral capsules containing 50,000 International Units (IU) of ergocalciferol will be used. 
Justification for Route, Dosage, Regimen, and Duration: 
Oral administration is the standard and most convenient route for vitamin D supplementation. Participants in the 
intervention arm will receive 50,000 IU of ergocalciferol weekly for the first 8 weeks, followed by 50,000 IU every 
two weeks for another 4 months of the 6-month study period. This high-dose regimen is designed to rapidly replete 
vitamin D stores and achieve optimal serum levels. This regimen is supported by a previous study by Nwosu et al. 
[10] which used the same high-dose vitamin D supplementation protocol in patients with new-onset type 1 diabetes 
without significant adverse effects. The 6-month intervention period is chosen to align with the typical timeframe 
for initial treatment response assessment in pediatric Graves' disease. This duration allows sufficient time to 
evaluate the effects of vitamin D supplementation on thyroid hormone and antibody levels. Furthermore, it is a 
reasonable timeframe for a pilot study to assess feasibility before embarking on a larger, longer-term trial. 
Justification for Off-Label Use: While high-dose vitamin D is sometimes used clinically, the specific regimen in this 
study (50,000 IU weekly followed by every two weeks) might be considered off-label in some contexts. This is 
justified by: 
 
Safety: The chosen dosage is well below the tolerable upper intake level for vitamin D in children older than 
9 years, minimizing the risk of toxicity [10]. Careful monitoring of 25-hydroxyvitamin D levels and calcium 
will be implemented throughout the study to ensure participant safety. Any participant with a vitamin D 
level > 80 ng/mL will have their dosage reduced to 1000 IU daily to mitigate potential toxicity. 
 
Rationale: The dosing regimen is modeled after a successful and safe protocol used in a prior study in a 
similar patient population (type 1 diabetes)[10]. This provides evidence to support the safety and potential 
efficacy of this approach. 
Pilot Study Design: This is a pilot feasibility study. The primary objective is to determine the feasibility of the 
intervention and its impact on antibodies and thyroid hormones, rather than claiming any therapeutic benefit. The 
data generated by this study can inform optimal dosing regimens in subsequent trials. 
Safety Monitoring: Close monitoring of 25-hydroxyvitamin D levels at regular intervals will help mitigate any risks 
associated with high-dose vitamin D. Participants will be contacted regularly to reinforce adherence and ensure they 
are undergoing the required monitoring. 
 
1.3 Findings from Previous Studies  
Graves’ disease (GD) is an autoimmune process which is caused by autoantibodies that bind to the thyrotropin 
receptor, stimulating growth of the thyroid and overproduction of thyroid hormone. GD in children presents 
significant treatment challenges. The only available antithyroid drug (ATD) therapy for children, methimazole, 
has low remission rates (<25%), often necessitating more aggressive interventions like radioactive iodine or 
surgery, each with inherent risks. The risk of severe adverse reactions to ATDs, such as hepatic failure and bone 
marrow suppression, further complicates management and contributes to the overall morbidity thus 
necessitating need for alternative treatments. 
Historically, vitamin D has been associated with the regulation of bone metabolism. Recent evidence suggests a 
strong association between vitamin D and autoimmune regulation in diseases such as Systemic Lupus 
Erythematosus (SLE), Multiple Sclerosis (MS) and Type 1 Diabetes. Due to its unique capability to bind to vitamin 
D receptor and serve as a transcriptional factor, vitamin D can regulate gene expression and further exert its 
immunomodulatory effects on immune cells. It has been shown to inhibit Th17 cytokine production, enhance 
Treg activity, induce NKT cell functions, suppress Th1, and promote Th2 cytokine production.[11] Because of the 
high prevalence of vitamin D insufficiency and deficiency in patients with MS, T1DM, and SLE, vitamin D 
supplementation has been considered a potential candidate for the treatment of autoimmune diseases with 
some studies showing promising results in these autoimmune diseases. The relationship between vitamin D and 
GD has not been studied as extensively. Monitoring and replacing low vitamin D levels is not a standard of care 
in patients with GD. While some adult studies suggest that vitamin D supplementation improves GD treatment 
outcomes, there is extremely limited data in children. 
 

 
 
  
16 
 
1.4 Benefit and Risk Assessment 
1.4.1 Known Potential Risks  
This study involves the use of high-dose vitamin D (ergocalciferol) supplementation in conjunction with standard 
methimazole therapy for pediatric Graves' disease. The following potential risks have been identified: 
 
Risks Associated with High-Dose Vitamin D Supplementation: 
 
Hypercalcemia: The primary risk of high-dose vitamin D is hypercalcemia (elevated blood calcium levels). 
Symptoms can include nausea, vomiting, constipation, abdominal pain, muscle weakness, confusion, and in 
severe cases, cardiac arrhythmias. Regular monitoring of calcium levels will be performed to mitigate this 
risk. If hypercalcemia occurs, the vitamin D dose will be reduced to 1000 IU daily or discontinued, and 
appropriate medical management will be implemented. 
 
Hypercalciuria: Increased urinary calcium excretion can occur with high-dose vitamin D, potentially leading 
to kidney stones in susceptible individuals. Adequate hydration will be encouraged, and urine calcium levels 
may be monitored if clinically indicated. 
 
Other potential side effects: Less common side effects of vitamin D supplementation can include nausea, 
vomiting, constipation, loss of appetite, weakness, and weight loss. These are usually mild and transient. 
 
Risks Associated with Methimazole Therapy: 
 
Minor side effects: Common side effects of methimazole include rash, itching, nausea, vomiting, joint pains 
and altered taste sensation. These are usually mild and self-limiting. 
 
Serious adverse events: Rare but serious adverse events associated with methimazole include 
agranulocytosis (severe decrease in white blood cells), hepatotoxicity (liver damage), and vasculitis 
(inflammation of blood vessels). Regular monitoring of blood counts and liver function tests will be 
conducted to detect these potential complications early. Participants will be educated about the signs and 
symptoms of these adverse events and instructed to report them immediately. 
 
Allergic reactions: Allergic reactions to methimazole, ranging from mild skin rashes to severe anaphylaxis, 
can occur. Participants will be closely monitored for signs of allergy. 
 
Risks Related to Study Procedures: 
 
Phlebotomy: The study involves multiple blood draws for laboratory testing. Risks associated with 
phlebotomy include bruising, pain, infection, and rarely, nerve damage or fainting. Standard phlebotomy 
procedures will be followed by trained personnel to minimize these risks. 
 
Discomfort or anxiety: Some participants may experience discomfort or anxiety related to study 
procedures, such as blood draws or clinic visits. The study team will strive to create a supportive and 
comfortable environment for all participants. 
Immediate, Short-Term, and Long-Term Risks: 
 
Immediate risks: The most immediate risks are related to phlebotomy (bruising, pain, infection) and 
potential allergic reactions to methimazole. 
 
Short-term risks: Short-term risks include the potential side effects of vitamin D and methimazole, primarily 
hypercalcemia, hypercalciuria, gastrointestinal symptoms, rash, joint pains and minor allergic reactions. 
 
Long-term risks: The long-term risks of this study are minimal. The duration of exposure to high-dose 
vitamin D is limited to 24 weeks. Long-term monitoring of thyroid function and antibody levels will be 
performed as part of standard clinical care for Graves' disease. 
 
Alternative Procedures Considered: 
 
Lower dose vitamin D: A lower dose of vitamin D supplementation was considered. However, the chosen 
high-dose regimen is supported by prior research[10] and is more likely to achieve optimal serum vitamin D 
levels within the study timeframe. 

 
 
  
17 
 
 
Placebo control: A placebo control group was considered. However, due to the ethical implications of 
potentially withholding vitamin D in participants with low levels, a standard of care control group 
(methimazole alone with the option of taking up to 1000 IU of vitamin D daily) was chosen. This allows all 
participants to receive appropriate management of their vitamin D levels while still permitting comparison 
between the intervention and control groups. Should the patients in the control group have vitamin D 
levels <20 ng/mL, patients will be strongly advised to take the 1000 IU of vitamin D daily for repletion. 
 
Other Risks: 
 
Social, legal, and economic risks: There are no anticipated social, legal, or economic risks associated with 
study participation. Participation is voluntary, and participants can withdraw at any time without penalty. 
Confidentiality will be maintained according to HIPAA regulations. 
 
Psychological risks: Participation in the study is not expected to pose significant psychological risks. 
However, the study team will be sensitive to any emotional distress that may arise and will provide 
appropriate support and referrals as needed. 
 
1.4.2 Known Potential Benefits  
Direct Benefits to Study Participants: 
Potential Improvement in Graves' Disease Symptoms: While not a guaranteed outcome of this pilot study, some 
participants may experience improvements in their GD symptoms (e.g., reduced fatigue, palpitations, anxiety, 
improved sleep) due to either the vitamin D supplementation or the optimized management of their GD as part of 
the study protocol. It is crucial to emphasize that this is not the primary aim of the study and cannot be guaranteed. 
Close Monitoring and Medical Care: Participants will receive close monitoring of their thyroid function, antibody 
levels, vitamin D levels, and overall health throughout the study. This enhanced medical attention could lead to 
earlier detection and management of any potential complications related to GD or vitamin D supplementation. 
Increased Knowledge and Understanding: Participants will gain a better understanding of GD, its management, and 
the potential role of vitamin D in autoimmune diseases. They will also learn about the importance of research and 
contribute to scientific knowledge. 
Potential Earlier Identification of Vitamin D Deficiency: Participants will have their vitamin D levels measured, 
which may identify a deficiency that could be addressed, even in the control group (who can take up to 1000 
IU/day). Correcting vitamin D deficiency can have general health benefits beyond GD, such as improved bone health 
and immune function. 
Indirect Benefits (to Individuals or Society): 
Contribution to Scientific Knowledge: The study will generate valuable data on the feasibility of conducting larger 
trials on vitamin D supplementation in pediatric GD. This will pave the way for future research that could ultimately 
lead to improved treatments and better outcomes for children with GD. 
Potential for Improved Treatment Strategies: If the pilot study findings are positive and a subsequent larger trial 
demonstrates the efficacy of vitamin D supplementation, it could lead to changes in standard clinical practice, 
potentially offering a safe and effective adjunctive therapy for pediatric GD. This could improve remission rates, 
reduce the need for more aggressive treatments, and minimize long-term complications. 
Enhanced Understanding of Vitamin D's Role in Autoimmune Diseases: The study may contribute to a broader 
understanding of vitamin D's role in autoimmune diseases, potentially informing research and treatment strategies 
for other conditions beyond GD. 
Immediate, Short-Term, and Long-Term Potential Benefits: 
 
Immediate Benefits: Primarily include the close monitoring and enhanced medical care received throughout the 
study, as well as the increased knowledge about GD and vitamin D. Some participants might also experience an early 
improvement in symptoms, though this is not guaranteed. 
Short-Term Benefits: Similar to immediate benefits but may also include improved control of GD symptoms and 
earlier identification and management of potential complications. 

 
 
  
18 
 
Long-Term Benefits: Primarily relate to the potential for improved treatment strategies and a better understanding 
of vitamin D's role in autoimmune diseases, benefiting future generations of children with GD and potentially other 
autoimmune conditions. 
1.4.3 Assessment of Potential Risks and Benefits  
The risks associated with this pilot study are generally low and manageable with the implemented mitigation 
strategies. The potential benefits, while not guaranteed for individual participants, are substantial in terms of the 
potential for future advancements in pediatric GD treatment. The knowledge gained from this feasibility study, 
including data on recruitment, adherence, and data collection, is crucial for designing a future, adequately powered 
RCT that could ultimately lead to improved outcomes for children with this condition. Therefore, the potential benefits 
of conducting this pilot study, in terms of informing future research and potentially improving patient care, outweigh 
the relatively low and manageable risks. 
1.5       IND or IDE Applicability 
This research study does not involve an investigational new drug (IND) or an investigational device (IDE). The 
intervention, vitamin D (ergocalciferol), is an FDA-approved product available both over the counter and by 
prescription. While the specific high-dose regimen used in this study may be considered off-label use, it does not 
meet the criteria for an IND application as defined in 21 CFR 312. Therefore, no IND is required for this study. 
Similarly, no devices are being investigated, so an IDE application under 21 CFR 812 is not applicable. 
2 STUDY OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS 
Primary
To evaluate the feasibility and 
refine procedures for a future, 
adequately powered randomized 
controlled trial of high-dose 
vitamin D supplementation in 
pediatric GD.  
 
This pilot will assess: (a) 
recruitment rates and strategies; 
(b) adherence to the high-dose 
vitamin D protocols, including 
evaluating different adherence 
monitoring strategies (e.g., pill 
counts, medication logs, phone 
calls); and (c) the completeness 
and variability of collected data for 
primary and secondary outcome 
measures; (d) identify barriers to 
large-scale implementation. 
These data will direct the 
design and sample size 
calculation of a subsequent 
definitive large-scale trial. 
Secondary/Exploratory
To explore the trends in thyroid 
function (TSH, T3, FT4, and T4) in 
pediatric GD patients receiving 
either methimazole alone or 
methimazole plus high-dose 
vitamin D supplementation.  
These preliminary data will be 
used to estimate effect sizes and 
inform sample size calculations for 
a future, fully powered trial 
investigating the impact of vitamin 
D on thyroid hormone 
normalization. We hypothesize 
that patients receiving high-dose 
vitamin D will achieve normal TSH, 
T3, Free T4 and T4 levels 
significantly faster than those 
receiving methimazole alone. 
Thyroid function tests will be 
measured at baseline, 6, 12 and 24 
Faster normalization can 
improve patient well-being, 
reduce methimazole 
dosage requirements and 
potentially reduce long-
term complications. 

 
 
  
19 
 
OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS 
weeks, and time to normalization 
will be compared between groups.
Tertiary/Exploratory 
To evaluate the impact of high-
dose vitamin D supplementation 
on TSH receptor antibody (TRAb) 
and Thyroid Stimulating 
immunoglobulin (TSI) levels in 
children with newly diagnosed GD
We hypothesize that patients 
receiving high-dose vitamin D will 
experience a significantly greater 
percentage reduction in TSH R-Ab 
and TSI levels at 24 weeks 
compared to those receiving 
methimazole alone. Antibody 
levels will be measured at baseline 
and 24 weeks, and the percentage 
change from baseline will be 
compared between groups.
A greater reduction in 
antibody levels may 
indicate a more effective 
treatment response and 
potentially predict a higher 
likelihood of remission. 
 
 
3 INVESTIGATIONAL PLAN 
3.1       Overall Study Design and Plan 
A. Rationale: This pilot study represents a critical first step towards evaluating the therapeutic potential of high-dose 
vitamin D supplementation in pediatric GD. By focusing on feasibility aspects such as recruitment, adherence, and 
data collection, this pilot will lay the foundation for a future definitive trial designed to assess the efficacy and safety 
of this promising adjunctive therapy. 
B. Study Overview: This study aims to determine the feasibility of protocol implementation for investigating the 
potential benefits of adding high dose vitamin D to standard therapy for pediatric Graves’ Disease. To efficiently 
accomplish the goals of this study, we will recruit pediatric patients aged 9-17 years that are newly diagnosed with 
Graves’ disease in our division of pediatric endocrinology at Cohen Children’s Medical Center.  
C. Study Design and Methods: 
This is an open label randomized clinical pilot feasibility trial. In this study, participants will be randomized to either 
the experimental (vitamin D + methimazole) or control (methimazole only) group at the time of the initial visit. The 
starting dose of methimazole and dose adjustments will be made by the treating endocrinologist based on 
established clinical practice guidelines. The control arm will receive no additional intervention other than 
methimazole (standard of care). While the control group will not receive the high-dose vitamin D intervention, they 
will be allowed to take up to 1000 IU of vitamin D daily. This approach balances the need for a comparison group 
against the ethical responsibility of not withholding a potentially beneficial supplement for those with low levels. 
The experimental arm will be given vitamin D 50000 IU weekly for 8 weeks followed by 50000 IU every 2 weeks for 
another 16 weeks in addition to standard of care (methimazole). This dose is below the standard tolerable upper 
intake level for ergocalciferol for people older than 9 years and thus unlikely to lead to ergocalciferol toxicity. This 
dosing regimen was modeled after a randomized controlled trial for vitamin D supplementation in type 1 diabetes 
mellitus by Nwosu et al and there were no toxicity issues during the course of that study.[10] 
Participants enrolled in the study will obtain bloodwork for 25-hydroxy vitamin D levels at baseline, 12 and 24 weeks 
in addition to thyroid function tests to monitor for toxicity. They will also obtain thyroid function levels at 6 weeks 
which is standard of care. CMP for calcium levels will be drawn at baseline, 6, 12 and 24 weeks to minimize risk of 
hypercalcemia from vitamin D supplementation and for monitoring of the liver function tests while on methimazole 
which is standard of care. 

 
 
  
20 
 
 
D. Key Variables: Demographic data (Date of diagnosis, Age, Sex, BMI z-scores, Race, Ethnicity, Weight), 
Hyperthyroidism Disease severity (based on Free thyroxine levels). We will document whether the thyroid hormone 
levels have normalized at each specific time point. We will also document whether there was at least a 50% decrease 
in the TSH Receptor Antibody level or Thyroid stimulating immunoglobin at 24 weeks. Thyroid levels at diagnosis, 6, 
12 and 24 weeks will be recorded as well as 25 hydroxy vitamin D levels at diagnosis, 12 and 24 weeks. 
E. Exposure & Outcome Measures: We will compare changes and trends in thyroid (T4, FT4, T3, TSH) in the 
treatment group (vitamin D + methimazole) compared to controls (methimazole only) at 6, 12 and 24 weeks. We will 
compare changes in Graves’ antibody levels (TRAb, TSI) at baseline and 24 weeks compared to levels at diagnosis to 
see if there was a >50% decrease in the antibodies in the treatment group compared to controls at 24 weeks. We will 
also evaluate the trends in thyroid function and vitamin D at 12 weeks and 24 weeks and changes or trends in 
Graves’ antibodies at 24 weeks compared to levels at diagnosis in both groups. 
G. Statistical Plan: Data will be analyzed based on intention to treat. Descriptive statistics will be computed for all 
aims (frequencies and proportions for categorical data, means ± standard deviation (SD) or medians and Q1-Q3 for 
continuous data), as appropriate. For each thyroid hormone level and for TSH, logistic regression will be performed 
using a generalized linear mixed model (GLMM) to simultaneously assess the odds of normalization at 6, 12 and 24 
weeks. GLMMs can account for correlations of measurements at different timepoints that are from the same patient. 
Logistic regression will be utilized to assess the odds of >50% decrease in antibody levels at 24 weeks from diagnosis. 
If the sample size is sufficient, we will adjust for disease severity at diagnosis in each model. If GLMMs are not 
feasible, analysis will be performed separately at each timepoint. A linear mixed model (appropriate data 
transformations may be applied) with an interaction term of group by time will be utilized to compare absolute and 
percentage changes in thyroid function (T4, FT4, T3) at 6, 12 and 24 weeks, vitamin D levels at 12 & 24 weeks, and 
Graves’ antibody levels (TRAb, TSI) at 0 & 24 weeks within participants in each group (treatment and control) from 
time of diagnosis and between groups at each time point. Separate models will be built for each thyroid function 
hormone (T4, FT4, T3), for vitamin D, and for each Graves’ antibody (TRAb, TSI) for absolute and for percentage 
change. As with GLMMs, linear mixed models can account for correlations of measurements at different timepoints 
that are from the same patient. For all analyses, results yielding p-values <0.05 will be considered statistically 
significant.  All analyses will be conducted using SAS version 9.4 (SAS Institute Inc., Cary, NC). 
3.2       Participating Sites and Enrollment  
This pilot study will be conducted at a single site: Cohen Children's Medical Center (CCMC), within the 
Division of Pediatric Endocrinology, Northwell Health. We aim to enroll a total of 30 participants. 
Recruitment will cease once 30 participants have consented and been enrolled in the study. We anticipate 
that all enrolled participants will be evaluable, assuming adherence to study procedures and complete data 
collection. Therefore, the target number of evaluable participants is also 30. While unforeseen 
circumstances may lead to some participants becoming ineligible for analysis, our recruitment target 
accounts for a reasonable level of attrition. 
 
3.3   Study Population 
Our target population consists of pediatric patients aged 9-17 with newly diagnosed GD. We will recruit 
participants from Northwell Pediatric Endocrinology practice, where approximately 20-30 patients meeting 
the inclusion criteria are seen annually, indicating a sufficient pool of potential participants. Recruitment 
will occur over 11 months (Dec 2024 - Oct 2025), with a target enrollment of up to 30 participants. 
Physicians at our practice will be trained to identify and refer eligible patients using provided study criteria. 
Potential participants will be informed about the study during their initial clinic visit. If enrollment is slower 

 
 
  
21 
 
than anticipated, we will explore expanding recruitment efforts to another site and/or extending the 
recruitment period.

 
 
 
1 
 
 
 
This study focuses on a pediatric population under the care of our pediatric endocrinology practice aged 
9-17 years old. Graves' disease can significantly impact growth and development in children, and there is 
a lack of data on the efficacy of adjunctive vitamin D therapy in this age group. This research has the 
potential to improve treatment outcomes and quality of life for children with Graves' disease. The study 
is designed to minimize risks through rigorous safety monitoring, including regular blood tests and dose 
adjustments as needed. Informed consent will be obtained from parents/guardians, and assent will be 
obtained from children. Participation is voluntary, and withdrawal is permitted at any time. The potential 
benefits of this research outweigh the minimal risks, and the study will be overseen by the IRB to ensure 
participant safety and ethical conduct If applicable and available, describe high-level strategies and 
methods for recruiting participants.   
No ads will be used.  
 
3.4 
   Subject Eligibility 
3.4.1 
Inclusion Criteria 
To be eligible for participation in this study, individuals must meet all the following inclusion 
criteria: 
1. Provision of signed and dated informed consent form by the participant or by the 
participant's parent/legal guardian (if the participant is aged 9-17 years). Assent will be 
obtained from participants aged 9-17 years. 
2. A new diagnosis of Graves' disease (GD), defined as: 
o 
Suppressed TSH level 
o 
Elevated free T4 (FT4) and/or total T4 (T4) and/or total T3 (T3) level 
o 
Positive TSH receptor antibody (TRAb) or thyroid-stimulating immunoglobulin (TSI) 
level – note patient may sign the consent form prior to these results coming back. If 
both are negative the patient will be excluded from the study and considered a 
screen failure. 
3. Age 9-17 years, inclusive. 
4. Initiation of methimazole therapy as part of standard GD treatment. 
5. Willingness and ability to comply with all study procedures, including attending scheduled 
study visits, taking study medications as prescribed, and undergoing required laboratory 
testing. 
6. Ability to take oral medications. 
7. For females of reproductive potential: 
o 
Not currently pregnant or breastfeeding 
8. Willingness to have their 25-hydroxyvitamin D levels measured and ability to take vitamin D 
supplementation if initial vitamin D level is <80ng/mL. 
9. Our study will offer enrollment to non-English speaking participants 
 
3.4.2 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
 
Initial hydroxy vitamin D levels >80 ng/mL (which may not be available at the time 
of initial screening) 
 
Hypocalcemia, corrected calcium based on albumin <8.4 mg/dL 
 
Hypercalcemia, corrected calcium based on albumin >10.5 mg/dL 

 
 
 
2 
 
 
Conditions that affect vitamin D metabolism such as: malabsorption, chronic 
kidney or liver disease, nephrocalcinosis, hyperparathyroidism 
 
Current use of medications which are known to affect thyroid function or vitamin 
D metabolism such as thyroid hormone replacement, corticosteroids, 
anticonvulsants 
 
Allergy to vitamin D or methimazole  
 
Diagnosis of Hashitoxicosis or thyrotoxicosis (both TSH receptor antibody (TRAb) 
and thyroid-stimulating immunoglobulin (TSI) levels are negative) 
 
Participants under the age of 9 years at the time of diagnosis 
 
Pregnant participants 
 
Active or uncontrolled infections, other significant medical conditions (e.g., 
uncontrolled diabetes mellitus, active malignancy, severe liver or kidney disease), 
or any condition deemed by the investigator to interfere with study participation 
or pose undue risk to the participant. 
 
 
3.4.3 
Screen Failures 
Screen failures will be notified of their ineligibility and thanked for their interest in the study. 
Appropriate medical care and referrals will be provided as needed, regardless of eligibility status. 
Data collected during screening for screen failures will be documented (e.g., screening log) and 
retained per study protocol and institutional requirements but will not be included in the final study 
analysis. 
 
Vitamin D Level: Participants with a 25-hydroxyvitamin D level > 80 ng/mL at screening 
will not be eligible for re-screening. This is because high vitamin D levels at baseline could 
confound the study results and potentially increase the risk of hypercalcemia with 
supplementation. These participants will be counseled on the importance of appropriate 
vitamin D intake and may be referred for additional clinical care as needed. 
 
Negative TRAb and TSI: Participants who are screen failures due to negative TRAb and TSI 
antibodies, confirming the absence of Graves' disease, will not be eligible for re-screening. 
This is because the study is specifically designed to evaluate the effect of vitamin D 
supplementation in newly diagnosed pediatric Graves' disease. 
 
4 EVALUATIONS BY VISIT  
:   
4.1       Screening Visit  
Baseline/Screening Visit (Day 0): 
 
Combined Visit Rationale: To minimize participant burden and streamline the study 
process, the screening and baseline visits will be conducted on the same day. This approach 
allows for immediate enrollment of eligible participants without requiring a separate 
screening visit. 
 
Procedures: 
1. Eligibility Assessment and Informed Consent/Assent: The visit will begin with a 
comprehensive eligibility assessment, including: 
 
Review of inclusion/exclusion criteria based on medical history, current 
medications, and any relevant pre-existing conditions. 
 
Physical examination, including height, weight, and vital signs. 

 
 
 
3 
 
 
If eligible, the informed consent process will begin. This includes explaining 
the study's purpose, procedures, risks, benefits, and the participant's rights, 
as well as obtaining written informed consent from the parent/legal 
guardian. Assent will also be obtained from the participants aged 9-17 
years. 
2. Laboratory Testing (Contingent on Consent): Following informed consent/assent, 
initial laboratory tests will be performed, including: 
 
Thyroid function tests (TSH, free T4, total T4, total T3) 
 
TSH receptor antibodies (TRAb) and Thyroid Stimulating Immunoglobulin 
(TSI) 
 
25-hydroxyvitamin D level 
 
Complete blood count (CBC) 
 
Comprehensive metabolic panel (CMP) to assess calcium, renal and liver 
function 
 
Except for vitamin D level all the above would be considered standard of 
care. 
3. Enrollment Confirmation (Contingent on Eligibility): If the patient qualifies for the 
study based on initial laboratory testing from the referral (suppressed TSH and 
elevated T4 or Free T4), they would be offered to participate. If any eligibility criteria 
are not met based on the laboratory results, the participant will be classified as a 
screen failure and appropriate procedures for screen failures will be followed. 
4. Study Randomization (For Enrolled Participants): Enrolled participants will be 
randomized to either the intervention arm (methimazole + high-dose vitamin D) or 
the control arm (methimazole alone, with the option of taking up to 1000 IU of 
vitamin D2 daily) at the time of the initial visit following the consent. 
5. Medication Dispensing and Instructions (For Enrolled Participants): 
 
Intervention Arm: Dispense the initial dose of vitamin D2 (50,000 IU 
ergocalciferol) and provide detailed instructions on the dosing schedule 
(weekly for 8 weeks, then every two weeks). Provide a study medication 
diary/log for participants to track their doses. 
 
Control Arm: Reinforce standard methimazole dosing instructions and 
provide education on the optional use of up to 1000 IU/day of vitamin D2 if 
levels are below recommendations. 
6. Review of Potential Adverse Events (For Enrolled Participants): Educate 
participants/families on how to recognize and report any potential adverse events 
related to study medications or any changes from baseline. 
 
4.2 
Visit 1 (Phone call follow-up, 6 weeks from initiation) 
Purpose: This phone call serves as a mid-point check-in to assess medication adherence, 
reinforce study procedures, and remind participants about their upcoming Week 6 
laboratory testing. 
Procedures: 
1. Contact the Participant/Parent/Guardian: Attempt to contact the participant or 
their parent/guardian by phone. Document the date and time of the call, as well 
as the outcome (successful contact, left voicemail, no answer). If unable to reach 
the participant after multiple attempts (at least 3 attempts should be made on 
different dates during different times), document this and consider alternative 
contact methods. 

 
 
 
4 
 
2. Medication Adherence Assessment: If contact is made, inquire about the 
participant's adherence to both methimazole and (if applicable) vitamin D 
supplementation. Utilize open-ended questions to assess adherence (e.g., "Can 
you tell me how you've been taking your medications over the past few weeks?"). 
Review the medication logs/diaries and reconcile pill counts (if feasible). Address 
any reported adherence issues and provide appropriate guidance and support. 
Refer to study clinicians if clinically significant deviations from the protocol are 
found. For patients in the control arm, ask the parent or participant whether they 
are taking any supplemental vitamin D and how often. 
3. Laboratory Test Reminder: Remind the participant/parent/guardian about the 
importance of completing the required Week 6 laboratory tests: 
 
Thyroid function tests (TSH, free T4, total T4, total T3) 
 
Complete blood count (CBC) 
 
Comprehensive metabolic panel (CMP) with calcium 
Provide clear instructions on how to schedule the blood draw and where to 
submit the samples (Northwell labs). Answer any questions the 
participant/parent/guardian may have about the laboratory procedures. 
4. Adverse Event Inquiry: Inquire about any potential adverse events experienced 
since the Baseline Visit. Document any reported adverse events using 
standardized terminology and follow appropriate reporting procedures as 
outlined in the study protocol. If there are clinically significant reports, contact the 
study physician. 
5. Answer Questions and Provide Support: Address any questions or concerns the 
participant/parent/guardian may have about the study. Provide ongoing support 
and encouragement. 
6. Confirm Next Contact: Confirm the date and time of the next scheduled in person 
follow-up visit (Week 12). 
 
4.3        Visit 2 (Week 12/3month study visit) 
Purpose: This visit allows for a comprehensive assessment of the participant's progress, 
including medication adherence, thyroid function, vitamin D levels, safety labs, and any 
potential adverse events. The visit will be combined with a formal outpatient visit that is 
normally scheduled at this timeframe. 
Window: The Week 12 visit should ideally occur within a +/- 1-week window (i.e., between 
Week 11 and Week 13) to allow for flexibility in scheduling. Document the actual visit date. 
Procedures: 
1. Medication Review and Adherence Assessment: 
1. Review the participant's medication adherence using pill counts, 
medication logs, and participant/parent reports. 
2. Address any reported adherence issues and provide appropriate 
guidance and support. 
3. Refer to study clinicians for clinically significant deviations from the 
protocol or any other issues/concerns requiring physician input. 
2. Physical Examination: 
Documented height, weight, and vital signs (blood pressure, heart 
rate). 
Document any relevant physical findings. 
3. Laboratory Testing: Obtain the following laboratory tests: 

 
 
 
5 
 
 
Thyroid function tests (TSH, free T4, total T4, and total T3) 
 
25-hydroxyvitamin D level 
 
Complete blood count (CBC) 
 
Comprehensive metabolic panel (CMP) including calcium 
4. Adverse Event Assessment: 
 
Systematically inquire about any adverse events experienced since 
the last visit (Week 6 phone call). 
 
Document the onset, duration, severity, and relationship to study 
medications for each reported adverse event. 
 
Follow appropriate reporting procedures as outlined in the study 
protocol for all adverse events and contact study clinicians as 
needed. 
5. Concomitant Medication Review: Inquire about any new medications or 
changes to existing medications since the last visit. Document all current 
medications. 
6. Answer Questions and Provide Support: Address any questions or concerns the 
participant/parent/guardian may have about the study. Provide ongoing 
support and encouragement. 
7. Schedule Next Visit/Contact: Schedule the next follow-up visit (24 weeks / 6 
months) and remind participants about the procedures to be conducted at that 
visit. Provide contact information for the study team in case of any questions or 
concerns. 
 

 
 
 
6 
 
4.4   Visit 3 (24 weeks/ 6 months: Final study visit)      
1. Purpose: This visit marks the conclusion of the 6-month study period. The purpose is to 
collect final data on thyroid function, antibody levels, vitamin D status, safety labs, and any 
potential adverse events. 
1.3 Visit Window: The 24 weeks / 6-month visit should ideally occur within a +/- 2-week 
window (between Week 22 and Week 26) to allow for flexibility in scheduling. Document 
the actual visit date. 
2. Procedures: 
1. Medication Review and Adherence Assessment: 
 
Conduct a final review of medication adherence for both methimazole and 
vitamin D (if applicable): Utilize pill counts, medication logs, and 
participant/parent reports. 
 
Collect any remaining unused study medication (vitamin D) 
2. Physical Examination: 
 
Measure height, weight, and vital signs (blood pressure, heart rate, 
respiratory rate). 
 
Document any relevant physical findings. 
3. Laboratory Testing: Obtain the following laboratory tests: 
 
Thyroid function tests (TSH, free T4, total T4, and total T3) 
 
TSH receptor antibodies (TRAb) and Thyroid Stimulating Immunoglobulin 
(TSI) 
 
25-hydroxyvitamin D level 
 
Complete blood count (CBC) 
 
Comprehensive metabolic panel (CMP)  
4. Adverse Event Assessment: 
 
Conduct a thorough assessment of any adverse events experienced since 
the last visit (Week 12 visit). 
 
Document all adverse events, including their onset, duration, severity, and 
relationship to study medications using standardized terminology. 
 
Follow the study's adverse event reporting procedures. 
5. Concomitant Medication Review: Inquire about any changes to concomitant 
medications since the last visit. Document all current medications. 
6. Study Completion Procedures: 
 
Thank the participant and their family for their participation in the study. 
 
Provide contact information for the study team in case of any future 
questions or concerns. 
4.5 Visit 4  
N/A 
4.6        Unscheduled Visits 
Handling of Unscheduled Visits: 
1. Contacting the Study Team: Participants will be instructed to contact the study team or 
their primary endocrinologist immediately if they experience any significant adverse events, 
worsening of their Graves' disease symptoms, or have any other concerns that necessitate 
an unscheduled visit. Clear contact information (phone number, email address) for the study 
team will be provided to all participants at the Baseline/Screening visit. 
2. Triage and Assessment: Upon contact, the study team will triage the situation to determine 
the urgency and nature of the visit. This may involve phone consultation with the study 
physician to determine the appropriate course of action. Depending on the reason for the 

 
 
 
7 
 
unscheduled visit, the study team will guide the participant and may recommend seeking 
immediate medical attention if the situation warrants it. 
3. Documentation: All unscheduled visits will be documented in the participant's study record, 
including the date and time of the visit, the reason for the visit, any assessments performed, 
and any actions taken. 
Assessments During Unscheduled Visits: 
The specific assessments performed during an unscheduled visit will depend on the reason for the 
visit. Possible assessments include: 
 
Physical Examination: If the participant presents for an in-person unscheduled visit, a 
physical examination may be conducted, focusing on relevant systems based on the 
participant's reported symptoms or concerns. 
 
Laboratory Testing: Laboratory tests (e.g., thyroid function tests, vitamin D levels, CBC, CMP 
including calcium) may be ordered as needed to evaluate the participant's condition and 
assess for potential adverse events. 
 
Adverse Event Assessment: A thorough assessment of any reported adverse events will be 
conducted, including their onset, duration, severity, and relationship to study medications. 
Appropriate reporting procedures will be followed for all adverse events. 
 
Medication Review: The participant's current medications, including study medications and 
any concomitant medications, will be reviewed. 
 
Other Assessments: Other assessments may be performed as deemed clinically necessary 
by the study physician. 
 
Study Discontinuation Due to Unscheduled Visits: 
In some cases, an unscheduled visit may result in study discontinuation. This could occur if: 
 
The participant experiences a serious adverse event that necessitates discontinuation of 
study medication. 
 
The participant's condition worsens significantly, requiring alternative treatment strategies. 
 
The participant is non-compliant with study procedures. 
 
The participant withdraws consent. 
 
4.7 
      Early Termination Study Visit 
 Participants may withdraw from the study at any time, for any reason, without penalty. Every 
effort will be made to understand the reason for withdrawal, but the participant is not 
obligated to provide a reason. 
Procedures for Early Termination: 
Ideally, participants who withdraw from the study will complete an Early Termination Visit. 
The procedures conducted during this visit will be adapted based on the timing of withdrawal 
and the participant's willingness to undergo further assessments. The following procedures 
will be attempted, whenever feasible: 
1. Contact Information and Reason for Withdrawal: Document the date of withdrawal and 
attempt to contact the participant/parent/guardian to confirm the withdrawal and, if 
possible, ascertain the reason for withdrawal (e.g., adverse events, lack of efficacy, personal 
reasons). Respect the participant's decision if they decline to provide a reason. 
2. Medication Reconciliation: Inquire about any remaining study medication (vitamin D) and 
advise on appropriate disposal. This can be evaluated via phone. 
3. Final Laboratory Testing (Ideal, but not required): If the participant is willing, the study 
team will request that they undergo final laboratory testing, mirroring the tests performed 
at the 24 weeks / 6-month visit (thyroid function tests, TRAb/TSI, 25-hydroxyvitamin D, CBC, 

 
 
 
8 
 
CMP including calcium. This is to capture the participant's status at the time of withdrawal. 
Explain that their primary endocrinologist would be drawing these labs at that time frame 
except for vitamin D. While the vitamin D level will not be required, it will be encouraged. 
4. Adverse Event Assessment: Inquire about any adverse events experienced since the last 
study visit, even if these events are not believed to be related to the study. Document all 
reported adverse events using standardized terminology. It is especially important to 
capture AEs in early withdrawal visits in case they provide insights as to why the patient 
withdrew. 
5. Final Interview (Optional): A brief interview may be conducted (with appropriate consent) 
to gather feedback on the participant's experience in the study. This information can be 
valuable for improving future research protocols. This could be done via phone. 
6. Referral and Follow-up Care: Ensure that the participant has appropriate follow-up care for 
their Graves' disease with their primary endocrinologist. Remind the participant of the 
importance of continued monitoring and treatment. Document these referrals and 
recommendations in the participant's study file. 
If a participant withdraws and declines an Early Termination Visit: 
If a participant withdraws from the study and declines any further contact or assessments, 
document the date of withdrawal and the reason provided (if any). No further study-related 
procedures will be conducted. 
4.8 
      Subject Discontinuation and Withdrawal 
 
Discontinuation of Study Intervention: 
Participants may be discontinued from the study intervention (vitamin D supplementation) for the 
following reasons: 
 
Hypervitaminosis D: 
o 
Monitoring Test: Vitamin D levels measured at study visits (baseline, 12 and 24 
week) and at any unscheduled visits. 
o 
Clinical Decision Point: If a participant's serum 25-OH vitamin D level >80 ng/mL at 
any study visit, Vitamin D (ergocalciferol) will be reduced to 1000 IU daily or 
temporarily discontinued and 25 hydroxy vitamin D level rechecked in 1 month. If 
unchanged or higher at that time, subject will be taken off therapy and followed 
until end of study period.  
o 
Restarting Study Intervention: After normalization of serum vitamin D to <60 
ng/mL, vitamin D supplementation may be restarted per original protocol. The 
decision to restart and the adjusted dose will be made in consultation with the 
study physician. 
 
Hypercalcemia: 
o 
Monitoring Test: Serum calcium levels measured at each study visit (baseline, weeks 
6, 12, 24 weeks) and at any unscheduled visits. 
o 
Clinical Decision Point: If a participant's serum calcium level exceeds the upper limit 
of normal (>10.5 mg/dL corrected for albumin levels), additional screening will be 
done for symptoms of hypercalcemia.  If the participant complains of symptoms 
concerning for hypercalcemia: hypotonia, poor feeding, vomiting, constipation, 
severe abdominal pain, lethargy, polyuria, dehydration, failure to thrive; Vitamin D 
will be held until the serum calcium level returns to within the normal range. If no 
additional symptoms are experienced and the calcium levels are <11.0 mg/dL, 
therapy may be continued with repeat calcium levels repeated every 1-2 weeks until 
normalization under 10.6 mg/dL 

 
 
 
9 
 
o 
Restarting Study Intervention: After normalization of serum calcium, vitamin D 
supplementation may be restarted. The decision to restart and the adjusted dose 
will be made in consultation with the study physician. If hypercalcemia recurs, the 
vitamin D supplementation will be permanently discontinued.  
 
Other Adverse Events: Vitamin D supplementation may be temporarily or permanently 
discontinued if the participant experiences other adverse events deemed related to the 
study medication and clinically significant by the study physician. Please see appendix for list 
of adverse events.  
 
Non-compliance: If a participant consistently fails to adhere to the prescribed vitamin D 
regimen, they may be discontinued from the study intervention. For details see section 
6.3.5. 
 
Participant Request: Participants may choose to discontinue the vitamin D supplementation 
at any time for any reason. 
Data Collected at the Time of Discontinuation: 
At the time of discontinuation of the study intervention, the following data will be collected: 
 
Date of discontinuation 
 
Reason for discontinuation 
 
Current medications 
 
Recent laboratory results (including serum calcium, 25-hydroxyvitamin D, CBC, and CMP) 
 
Assessment of any adverse events 
 
Concomitant medications and medical conditions 
 
Participant-reported outcome measures (as applicable) 
Withdrawal of Subjects: 
Participants may withdraw from the study entirely at any time, for any reason, without penalty or 
prejudice to their future medical care. The procedures for early termination (described in Section 
4.7) will be followed. 
Provision of Care After Withdrawal: 
Following withdrawal from the study or discontinuation of the study intervention, participants will 
be continuing care with their primary endocrinologist for their Graves' disease. The study team will 
provide any necessary information or documentation for the participant's medical records. 
Participants will continue to receive standard medical care for their condition, regardless of their 
study participation status. 
 

 
 
 
10 
 
4.9 
      Lost to Follow Up 
A participant will be considered lost to follow-up if they meet all the following criteria: 
1. Missed Visit: The participant fails to attend a scheduled study visit (Week 12 or week 24) or 
complete a required phone call (Week 6) and does not contact the study team to reschedule 
within a defined timeframe. Rescheduling and completing the required visit within a week will 
be appropriate for study purposes. 
2. Unreachable After Multiple Attempts: The study team has made multiple documented 
attempts to contact the participant using various methods. These attempts should include: 
o 
Phone calls: At least three phone calls at different times of the day and on different 
days of the week to the participant's primary contact number and any alternative 
contact numbers provided. Document the date, time, and outcome of each call (e.g., 
no answer, left voicemail, spoke with participant). 
o 
Other contact methods: Consider other contact methods such as sending a certified 
letter to the participant's last known mailing address. Document any such attempts.  
3. No Response: The participant does not respond to any of the study team's contact attempts 
within a reasonable timeframe (within 1 week of the initial missed visit/call). 
Actions to be Taken for Missed Visits/Calls: 
 
Prompt Contact: The study team will attempt to contact the participant as soon as possible 
after a missed visit/call to reschedule and determine the reason for the missed appointment. 
 
Counseling: The study team will counsel the participant/parent/guardian on the importance 
of adhering to the study visit schedule and the potential impact of missed visits on the study 
results. 
 
Assessment of Continued Participation: The study team will assess whether the participant 
still wishes to and/or should continue in the study. If the participant expresses a desire to 
withdraw, the procedures for early termination (Section 4.7) will be followed. 
 
Documentation: All contact attempts and their outcomes will be carefully documented in the 
participant's study record. Also, any actions taken (e.g. rescheduling a visit) should be clearly 
documented. 
Consequences of Being Lost to Follow-Up: 
Once a participant is deemed lost to follow-up, they will be considered withdrawn from the 
study. Their data will be handled according to the study's data analysis plan. Every effort will be 
made to prevent participants from becoming lost to follow-up. 
 
 
5 STUDY PROCEDURES AND EVALUATIONS 
5.1 
      Eligibility Assessments 
The screening process will follow these steps: 
1. Initial Contact and Information Provision: Potential participants will be identified through 
clinic referrals. Study staff will provide information about the study and answer any initial 
questions at the time of their initial visit in the clinic. 
2. Screening Consent: If the participant is interested, they will be asked to sign a screening 
consent form. 
3. Medical History Review: The investigator or co-investigator will review the participant's 
medical history to assess for any pre-existing conditions or medications that may meet 
exclusion criteria. 

 
 
 
11 
 
4. Physical Examination: A brief physical exam will be conducted by a qualified medical 
professional (physician, nurse practitioner, or physician assistant) to assess overall health and 
measure height, weight, and vital signs. 
5. Laboratory Screening: If the participant meets initial eligibility criteria based on medical 
history and physical exam, laboratory tests will be ordered (thyroid function tests, TRAb/TSI 
antibodies, 25-hydroxyvitamin D, CBC, CMP including calcium). 
6. Eligibility Determination: The study physician will review all screening data (medical history, 
physical exam, and laboratory results) to make a final determination of eligibility. Participants 
meeting all inclusion criteria and none of the exclusion criteria will be deemed eligible. 
7. Informed Consent/Assent: Eligible participants will be asked to provide written informed 
assent (if 9-17 years old), along with parental/guardian consent. The study coordinator will 
review the consent form in detail with the participant/parent/guardian, answer questions, 
and ensure understanding of the study procedures, risks, and benefits 
  
5.2 
      Efficacy and Safety Assessments 
 
 Study Intervention Administration: Vitamin D supplementation (50,000 IU ergocalciferol 
weekly for 8 weeks, then bi-weekly for another 16 weeks), and Methimazole as prescribed 
per current standard of care. 
 
Follow-Up Procedures: 
o 
Radiographic or other imaging assessments: N/A 
o 
Physical Examinations: Conducted by a qualified medical professional (physician, 
nurse practitioner, or physician assistant) at baseline and all subsequent in-person 
visits (Week 12 and 24 weeks). Physical examinations will include assessment of 
height, weight, vital signs, and overall health. Any new or worsening physical findings 
will be documented and evaluated by the study physician. 
o 
Laboratory Evaluations: Blood will be collected at baseline and at weeks 6, 12, and 
24, and at any unscheduled visits as clinically indicated. All laboratory testing will be 
performed at a CLIA-certified laboratory (Northwell Lab). The study physician will 
review all labs. Except vitamin D levels, all other laboratory testing is considered 
standard of care for treatment and monitoring of Graves’ Disease response to 
methimazole.  
 
Clinical Laboratory Tests: 
 
Hematology: CBC with differential: frequency of monitoring 
determined by the patient’s primary endocrinologist 
 
Complete Metabolic Panel: at baseline, 6, 12 and 24 weeks 
 
Thyroid Function Tests: TSH, free T4, total T4, total T3 at baseline, 6, 
12 and 24 weeks 
 
TSH 
Receptor 
Antibodies 
(TRAb) 
and 
Thyroid 
Stimulating 
Immunoglobulin (TSI) at baseline and 24 weeks. 
 
25-hydroxyvitamin D Level at baseline, 12 and 24 weeks 
 
Research Laboratory Tests: None 
 
Genetic Testing. None 
 
Pregnancy Testing: Only performed if applicable 
 
Specimen Handling:  Specific instructions for specimen collection, handling, 
storage, and shipment will be detailed in the study's Manual of Operating 
Procedures (MOP). 
o 
Medication Adherence: Assessed at each visit (baseline, 6, 12 and 24 weeks) through 
pill counts, medication logs, and participant/parent self-report. 

 
 
 
12 
 
o 
Adverse Event Assessment: Assessed at every study visit and phone calls. 
Participants will also be instructed to report any adverse events to the study team 
between visits. 
o 
Medical Record Review: Relevant medical history, including the history of Graves’ 
disease, concomitant conditions, and medication history, will be abstracted from the 
participant’s electronic medical record. 
o 
Questionnaires/Patient-Reported Outcomes: medication and supplementation 
adherence logs 
o 
Patients will be provided with their test results. 
5.3 
    Assessment of Adverse Events.  
Adverse events will be assessed at every study visit (baseline, 6, 12, and 24 weeks) and 
during any unscheduled visits or phone calls. Details regarding adverse event 
documentation, grading, and reporting will be provided in Section 8.       
5.4 
Other Assessments  
N/A 
 
6   STUDY INTERVENTION 
6.1 
     Treatment Regimen  
(1) Vitamin D Supplementation (Intervention Arm): 
 
 
Drug: Ergocalciferol (Vitamin D2) 
 
Dose: 50,000 IU 
 
Route of Administration: Oral capsules 
 
Treatment Duration: 24 weeks total 
 
Loading Dose: 50,000 IU weekly for the first 8 weeks 
 
Maintenance Dose: 50,000 IU every two weeks for the remaining 16 weeks. 
 
Dose Modification Criteria: See section 4.8 for details on managing 
hypervitaminosis D or hypercalcemia, which may necessitate dose adjustments 
or discontinuation of vitamin D.  
 
(2) Methimazole (Both Arms): 
 
 
Drug: Methimazole 
 
Dose: Standard dosing per established pediatric guidelines for Graves' disease 
(typically weight-based). Initial and follow-up doses are determined by the 
treating physician. 
 
Route of Administration: Oral 
 
Treatment Duration: Ongoing, as determined by the treating physician, as part of 
standard Graves' disease management.  Methimazole use during the 24-week 
study period will be recorded. 
 
Dose Modification Criteria: Dose adjustments are per standard clinical practice 
and not study directed. All adjustments will be recorded in the medical record. 
 
(3) Vitamin D Supplementation (Optional, Control Arm): 
 
 
Drug: Cholecalciferol or Ergocalciferol 
 
Dose: Up to 1000 IU daily 

 
 
 
13 
 
 
Route of Administration: Oral (tablets, capsules, or other commercially available 
forms) 
 
Source: Over the counter (OTC), obtained independently by participants 
 
Study Team Involvement: The study team will monitor vitamin D use via 
participant self-report in the medication adherence log. Data on the type, dose, 
and frequency of OTC vitamin D used will be collected. However, the study team 
will not provide vitamin D or manage any related adverse events.  
 
Multivitamins: If participants take a multivitamin containing vitamin D, the 
combined total daily intake from the multivitamin and any additional vitamin D 
supplements should not exceed 1000 IU. 
 
6.2 
     Randomization and Blinding  
 
Randomization: 
1. Allocation: Participants will be randomized 1:1 to either the intervention arm 
(methimazole + high dose vitamin D) or the control arm (methimazole alone, with 
the option of taking up to 1000 IU/day of vitamin D2). 
2. Method: Randomization will be performed using the RedCap randomization tool.  
3. Stratification: Stratification will not be performed during the randomization 
process for this pilot study. However, data collected on baseline disease severity 
(based on Free thyroxine levels) and vitamin D deficiency status (deficient <20 
ng/mL, insufficient 20-30 ng/mL, sufficient ≥30 ng/mL) will be carefully documented 
and used for stratification purposes in the design of a subsequent, larger clinical 
trial. This pilot study will inform the development of the stratification strategy for 
the larger trial, allowing for better balance between treatment groups and 
potentially increasing the power of the larger study to detect treatment effects. The 
information gathered regarding the distribution and impact of these variables will 
be crucial in optimizing the design of the future trial. While these factors won't be 
used for stratification in the current study, they will be considered during data 
analysis to assess their potential influence on the outcomes and to inform the 
stratification plan for the larger trial. 
4. Implementation: After providing informed consent/assent and completing the 
baseline assessment, the designated study staff member will access the 
randomization system to obtain the participant's assigned treatment group. 
 
Blinding: 
o Due to the nature of the intervention (vitamin D supplementation), complete 
blinding of participants and study staff is not feasible. Participants and clinicians 
will be aware of the treatment assignment due to the difference in 
supplementation regimens.  
o Blinding is deemed unethical in this study, as it would necessitate withholding 
vitamin D supplementation from participants with low levels, a practice 
considered unethical given the established standard of care and potential 
health benefits of vitamin D. Participants in the control group will have the 
option of taking low-dose (up to 1000 IU daily) vitamin D supplementation and 
even encouraged to, if they are severely vitamin D deficient. 
 
 

 
 
 
14 
 
6.2.1 
Unblinding Procedures 
 Due to the nature of the intervention (vitamin D supplementation), complete blinding of 
participants and study staff is not feasible. Participants and clinicians will be aware of the 
treatment assignment due to the difference in supplementation regimens. 
 
6.3 
Procedures for Study Product 
6.3.1 
Intervention Description 
This study involves two medications: vitamin D (ergocalciferol) and methimazole. 
(1) Vitamin D (Ergocalciferol): Intervention Arm 
 
Market Status: Commercially available. 
 
Manufacturer: Avet Pharmaceuticals. Please note the manufacturer may change 
depending on availability of the product. 
 
Formulation: Oral capsules. 50000 IU ergocalciferol 
 
Packaging: The study pharmacist will repackage the capsules into smaller bottles of 
16 capsules each 
 
Labeling: Study-specific labels will be affixed to each dispensed bottle/package and 
will include: 
o 
Study name and number 
o 
Participant ID (to be filled by the study coordinator) 
o 
Drug name (Ergocalciferol) 
o 
Dosage and administration instructions (50,000 IU weekly for 8 weeks, then 
50,000 IU every two weeks for 4 months) 
o 
Storage instructions 
o 
Dispensing date (to be filled by the study coordinator) 
o 
Expiration date 
o 
Study contact information 
 
Manufacturing: The commercially available vitamin D will be purchased from a 
reputable supplier and is manufactured in compliance with Good Manufacturing 
Practices (GMP). 
(2) Methimazole (Both Arms): 
 
Methimazole will be prescribed by the participant’s treating physician and dispensed 
by the participant's usual pharmacy as part of their standard medical care. The study 
will not supply methimazole directly. Methimazole prescribing and management will 
be per standard of care and usual clinical practice and not dictated by the study 
protocol. 
(3) Vitamin D2 (Optional, Control Arm): 
 
Participants in the control arm will be informed that they may take standard, OTC 
vitamin D2 supplements at a dose of up to 1000 IU per day, if desired. This is optional 
and will not be supplied by the study. Participants will be instructed to follow the 
manufacturer’s instructions on the OTC product label. If vitamin D levels are below 
recommendations, vitamin D2 at 1000 IU daily may be recommended, but this is not 
mandated. 
 
Devices: 
 
N/A 
 

 
 
 
15 
 
6.3.2 
Procurement 
1) Vitamin D (Ergocalciferol): Intervention Arm 
 
Provider: The study's CCMC Pediatric Research Pharmacy will procure the 
commercially available vitamin D (ergocalciferol) from a reputable, licensed 
wholesale distributor/supplier. 
 
Requesting Product: The Pediatric Research Pharmacy will maintain an adequate 
supply of vitamin D and will manage inventory. Study staff will submit requests to 
the pharmacy through secure Northwell e-mail and order forms. 
 
Recipient: The Pediatric Research Pharmacy will receive the bulk supply of vitamin 
D. The pharmacy will then dispense the vitamin D to individual participants 
according to study protocol and maintain appropriate records. 
 
(2) Methimazole (Both Arms): 
 
Procurement and Dispensing: Methimazole is standard of care and will not be 
procured or dispensed by the research pharmacy. Participants will obtain 
methimazole through their usual pharmacy, as part of their routine medical care. 
The study team will not be involved in the procurement or dispensing of 
methimazole. This is important to emphasize for the IRB. 
 
Study Responsibilities: The treating physician will document the dose, frequency, 
and any changes to the methimazole regimen during the study period, as this is 
important clinical information. 
 
(3) Vitamin D2 (Optional, Control Arm): 
 
Procurement: Vitamin D2 (up to 1000 IU daily) is optional for the control arm, 
available OTC, and will be obtained by participants independently, if desired and if 
recommended by their physician for low vitamin D levels. The study is not involved 
in the procurement, dispensing, or management of vitamin D2 in the control arm.  
 
6.3.3 
Storage   
1) Vitamin D (Ergocalciferol): Intervention Arm 
 
Storage Location: The Pediatric Research Pharmacy will store the bulk supply of 
vitamin D in a dedicated, secure, and temperature-controlled area within the 
pharmacy.  
 
Temperature Requirements: The vitamin D will be stored according to the 
manufacturer's labeled storage recommendations: 25°C (77° F), excursions 
permitted between 15°-30° C 
 
Security: The vitamin D storage area within the pharmacy will be secure and locked 
to prevent unauthorized access. Access will be limited to authorized pharmacy 
personnel. Once dispensed to the study personnel, the vitamin D will be stored in a 
secured cabinet under key. 
 
(2-3) Methimazole (Both Arms) and Vitamin D2 (Optional, Control Arm): 
 
As previously stated, these are not handled by the study team or research 
pharmacy, and therefore no study-specific storage procedures apply. Participants 
are responsible for storing their own medications according to the manufacturer's 
instructions. 
 

 
 
 
16 
 
 
6.3.4 
Preparation and Administration of IP  
 
(1) Vitamin D (Ergocalciferol): Intervention Arm 
 
Preparation: 
o 
Location: Vitamin D will be dispensed to the study staff by the Pediatric 
Research Pharmacy. No further preparation (e.g., mixing, reconstitution) is 
required for the commercially available oral capsules. 
o 
Documentation: The pharmacy will maintain records of all dispensing 
activities, including date dispensed, lot number, and quantity dispensed. The 
study staff will provide logs to the research pharmacy regarding participant 
ID, date dispensed, lot number, and quantity dispensed. 
o 
Per the Northwell policy and federal regulations, the investigational product 
label must display the below language: 
 
“Caution: investigational use only” 
 
 
Administration: 
o 
Route: Oral 
o 
Schedule: 
 
Initial Phase: 50,000 IU once weekly for 8 weeks. 
 
Maintenance Phase: 50,000 IU every two weeks for the remaining 4 
months. 
o 
Timing: Participants will be instructed to take their vitamin D dose on the 
same day each week, at a time convenient for them. No specific time of day 
is required.  
o 
Instructions to Participants: Participants will receive clear written and verbal 
instructions on how and when to take their vitamin D. They will be 
encouraged to establish a routine to aid adherence. Written instructions will 
be provided as well. 
o 
Safety Precautions: Participants will be instructed to contact the study team 
immediately if they experience any adverse events, particularly symptoms of 
hypercalcemia (nausea, vomiting, constipation, increased thirst, increased 
urination, muscle weakness, confusion). 
o 
Expiration: Participants will be instructed to check the expiration date on the 
vitamin D bottle/package and to notify the study team if the medication is 
expired. The Pediatric Research Pharmacy will ensure that dispensed vitamin 
D has a sufficient remaining shelf life. 
(2) Methimazole (Both Arms): 
 
Preparation and Administration: Methimazole preparation and administration will 
be directed as part of standard medical care by the treating physician and patient. The 
study will not dictate these procedures. The dose, frequency, and any adjustments to 
the methimazole regimen will be documented by the study team, but the study does 
not provide specific instructions regarding methimazole. 
(3) Vitamin D2 (Optional, Control Arm): 
 
The study team will not provide any instructions on taking vitamin D2. Participants 
may choose to take commercially available vitamin D2 and will be instructed to follow 
the manufacturer's instructions. 

 
 
 
17 
 
 
 
6.3.5 
Subject Compliance Monitoring 
(1) Vitamin D (Ergocalciferol): Intervention Arm 
The following methods will be used to assess and track participant compliance with 
the vitamin D supplementation regimen: 
 
Pill Counts: At each study visit (baseline, 12 and 24 week) study staff will count 
the remaining vitamin D capsules to estimate the number of doses taken.  
 
Medication Logs: Participants/parents will be provided with medication and 
adherence logs to record each dose of vitamin D taken. They will be instructed to 
bring the completed log to each study visit.  
 
Self-Report: At each study visit and during the Week 6 phone call, study staff will 
ask participants/parents about their vitamin D intake to confirm adherence. 
Procedures for Non-Compliance: 
 
Definition of Significant Non-Compliance: Significant non-compliance will be 
defined as missing more than two doses of vitamin D during the study period.  
 
Actions for Significant Non-Compliance: 
1. Contact and Counseling: If significant non-compliance is identified, the 
study coordinator will contact the participant/parent to discuss the 
reasons for non-compliance and reinforce the importance of adherence 
to the study protocol. 
2. Problem-Solving: The 
study 
coordinator 
will 
work 
with 
the 
participant/parent to identify and address any barriers to adherence 
(e.g., difficulty remembering to take the medication, side effects, 
concerns about the medication). Strategies may include providing 
medication reminders, adjusting the dosing schedule (if feasible and with 
physician approval), or addressing any misconceptions about the study 
medication. 
3. Documentation: All instances of non-compliance, discussions with the 
participant, and actions taken will be documented in the participant's 
study record. 
4. Discontinuation from Study Intervention (if necessary): If non-
compliance persists despite interventions, the participant may be 
discontinued from the vitamin D supplementation portion of the 
study but should remain in follow-up for the remainder of the study 
duration to allow for data collection for the primary study outcome. The 
rationale for this approach should be clearly explained to the IRB, e.g., to 
preserve the integrity of the primary outcome analysis, to maintain 
monitoring of thyroid function, and to assess potential long-term impacts 
of the study. This is a nuanced point that the IRB is likely to question. 
 
Withdrawal from Study: If the participant chooses to discontinue from the study 
completely due to non-compliance issues, they will be able to do so without 
penalty. The early termination visit procedures outlined in section 4.7 will be 
followed. 
Mandatory Documents and Source Documents for Compliance Calculation: 
 
Mandatory Documents: 
o 
Medication logs completed by participants/parents 

 
 
 
18 
 
 
Source Documents: 
o 
Pill count records 
o 
Medication and Adherence logs 
o 
Notes from discussions with participants/parents regarding 
adherence 
The primary source document for calculating study intervention compliance will be 
the pill count records, supported by medication logs and participant self-report.  
 
 
6.3.6 
Accountability 
 
(1) Vitamin D (Ergocalciferol): Intervention Arm 
 
Responsibilities of Investigators and Designees: The following personnel will have 
designated responsibilities for drug accountability: 
o 
Principal Investigator (PI) or co-investigators: Overall responsibility for 
ensuring compliance with the drug accountability procedures outlined in the 
protocol. Responsible for dispensing vitamin D to participants at the study 
visits. To facilitate participant convenience, given the study site's location 
separate from the hospital, the PI or the co-investigator will dispense study 
medication directly to participants at the clinic. This reduces participant 
burden by eliminating the need for an additional trip to the hospital 
pharmacy. 
o 
Research Pharmacist: Responsible for receiving, storing, dispensing, and 
maintaining inventory records of the vitamin D. 
o 
Study Coordinator: Collecting returned unused medication, documenting 
administration, and maintaining participant-specific drug accountability 
records.  
 
Drug Life-Cycle Accountability: 
o 
Delivery to Site: Upon delivery to the Pediatric Research Pharmacy, the 
pharmacist will verify the shipment, document the receipt (date, quantity, lot 
number, expiration date), and store the vitamin D according to the 
designated storage procedures. 
o 
Dispensing to Participants: While the main supply of vitamin D will be stored 
and managed by the Pediatric Research Pharmacy, a limited supply of study 
drug will be kept on hand at the study site for dispensing to participants to 
facilitate study visits. The study site will maintain a detailed inventory log of 
all vitamin D received from the pharmacy and dispensed to participants. This 
log will include the participant ID, date dispensed, quantity dispensed, lot 
number, and the initials of the study staff member dispensing the medication. 
The study site's inventory will be reconciled with the pharmacy’s inventory 
monthly to ensure accountability. The study coordinator will be responsible 
for requesting additional vitamin D from the pharmacy when needed. 
o 
Participant Use and Documentation: 
 
Participants will be instructed to record each dose of vitamin D taken 
in a participant drug log/diary (Medication Adherence log). The log 
should include date and time of dose, quantity taken, and any missed 
doses or other relevant information (e.g., adverse events). 

 
 
 
19 
 
 
Study coordinators will review participant drug logs at each study 
visit to monitor compliance and address any questions or concerns. 
 
At each visit, pill counts will be performed to verify adherence and 
reconcile with the participant’s drug log. 
o 
Return of Unused Product: Participants will be instructed to return any 
unused vitamin D to the study team at the end of their participation or at any 
time they discontinue the study intervention. Study staff will count and 
document the returned medication and its disposition. 
o 
Final Disposition: All unused or expired vitamin D will be returned to the 
Pediatric Research Pharmacy for disposal according to institutional policies 
and applicable regulations. The pharmacy will maintain records of drug 
destruction. 
 
Documentation: 
o 
Pharmacy Inventory Logs: The pharmacy will maintain detailed logs of all 
vitamin D received, dispensed, returned, and destroyed.  
o 
Participant Drug Logs/Diaries: Participants will document each dose taken in 
a provided Medication Adherence and Supplementation logs 
o 
Dispensing Records: The pharmacy will maintain dispensing records for each 
participant, including the date, quantity, and lot number dispensed. 
(2) Methimazole (Both Arms) and Vitamin D2 (Optional, Control Arm): 
 
As previously stated, these medications are not part of the study’s drug 
accountability procedures. Participants will obtain methimazole through their usual 
prescriptions, and vitamin D2 is an optional OTC supplement. The study team will 
document the methimazole dose and any adjustments during the study, but no 
formal accountability procedures apply. This is important to state clearly for the IRB. 
 
6.3.7 
Return or Destruction of IP 
 
 
1) Vitamin D (Ergocalciferol): Intervention Arm 
 
Final Reconciliation: At the conclusion of the study (after the final participant's 
last visit/follow-up), a final reconciliation of vitamin D will be performed. This will 
involve: 
1. Study Site Reconciliation: The study team will account for all vitamin D 
dispensed to participants. This includes vitamin D dispensed directly at 
the study site and any remaining study drug returned by participants. 
2. Pharmacy Reconciliation: The Pediatric Research Pharmacy will perform 
a final inventory reconciliation, accounting for all vitamin D received from 
the supplier, dispensed to the study site or directly to participants, and 
returned from the study site or participants. 
3. Comparison and Discrepancy Resolution: The study site's and 
pharmacy's records will be compared to ensure agreement. Any 
discrepancies will be thoroughly investigated and documented. The PI or 
co-investigator, research pharmacist, and study coordinator will 
collaborate to resolve any discrepancies before the final disposition of 
the study drug. A written report of the discrepancy and resolution should 
be filed with the study documentation. 
 
Return or Destruction: 

 
 
 
20 
 
o 
Expired/Damaged Vitamin D: Any expired or damaged vitamin D will be 
returned to the Pediatric Research Pharmacy for destruction.  
o 
Unused Vitamin D: At the study's conclusion, all unused vitamin D at both 
the study site and the research pharmacy will be destroyed according to 
the research pharmacy's procedures.  
 
Documentation: 
o 
Drug Accountability Logs: All transactions (receipt, dispensing, return, 
destruction) will be documented in the designated drug accountability 
logs maintained by both the study site and the research pharmacy. These 
logs must include dates, quantities, lot numbers, participant IDs (for 
dispensed medication), and the initials of the personnel involved in each 
transaction. 
o 
Destruction Records: If vitamin D is destroyed, the research pharmacy 
will maintain detailed destruction records, including the date of 
destruction, method of destruction, quantity destroyed, lot numbers, 
and the witness signature(s) of authorized personnel. Provide the 
template or specify the location where this record can be found in study 
materials for IRB review. 
o 
Final Reconciliation Report: A final reconciliation report will be 
generated, summarizing the overall drug accountability for the study. 
This report should document the initial quantity of vitamin D received, 
the quantity dispensed, the quantity returned, the quantity destroyed, 
and the final disposition of the study drug. The report must be signed and 
dated by the PI and research pharmacist.  
(2) Methimazole (Both Arms) and Vitamin D2 (Optional, Control Arm): 
These medications are not subject to the study-specific return/destruction 
procedures. Methimazole is handled as part of routine patient care, and 
optional vitamin D2 is an OTC product obtained independently by 
participants. The study team has no responsibility for the disposition of these 
medications. It's important to clearly reiterate this distinction for the IRB. 
 
 
 
6.4 
Prior and Concomitant Therapy 
 
This section outlines permitted and prohibited concomitant medications/therapies 
during the study. It aligns with the medication restrictions specified in the 
inclusion/exclusion criteria. 
 
 
Data Collection Time Points: Information on prior and concomitant medications will 
be collected at the following time points: 
o 
Screening Visit: A comprehensive medication history, including all current 
and past medications (prescription, over the counter, and supplements), will 
be obtained. 
o 
All Subsequent Study Visits (baseline, 6, 12, and 24 week) and at any 
unscheduled visits: Participants/parents will be asked about any changes to 
their medication regimen, including new medications, discontinued 

 
 
 
21 
 
medications, and changes in doses. This includes recording standard of care 
methimazole regimens and noting any dose adjustments/changes. 
 
Prior and Concomitant Medical Therapy to be Collected: As this study focuses on 
Graves’ disease in the pediatric population and vitamin D, all prior and concomitant 
therapies 
will 
be 
recorded, 
but 
the 
study 
team 
will 
focus 
on 
medications/supplements that might affect vitamin D or calcium levels, interact with 
vitamin D or methimazole, or affect thyroid function. The study team will pay 
particular attention to calcium, vitamin D (including OTC supplements), medications 
that affect bone metabolism, and other thyroid-related medications. 
 
Permitted Concomitant Medications/Therapies: 
o 
Medications for Co-existing Conditions: Participants are permitted to take 
medications for pre-existing medical conditions (e.g., asthma, allergies) if 
these medications are deemed safe by the study physician and do not meet 
the exclusion criteria. For any permitted medication, the rationale will be 
clearly documented. 
o 
Over-the-Counter Medications (OTC): Occasional use of OTC medications 
(e.g. analgesics, antipyretics, antihistamines, antacids) is permitted, provided 
they are used according to standard dosing guidelines and do not meet the 
exclusion criteria. Participants should report their use of OTC medications to 
the study team at each visit. The control group may take OTC vitamin D2 
o 
 1000 IU/day if desired. Total amount of OTC vitamin D that can be taken is 
not to exceed 1000 IU/day which may include multivitamin supplements. 
 
Prohibited Concomitant Medications/Therapies. 
o 
Vitamin D Supplementation (Intervention Arm): Participants in the 
intervention arm are prohibited from taking any other vitamin D 
supplements, including OTC vitamin D, other than the study-provided 
ergocalciferol.  
o 
Medications Affecting Calcium or Bone Metabolism: Medications known to 
significantly affect calcium or bone metabolism (e.g., high-dose calcium 
supplements, bisphosphonates, thiazide diuretics) are prohibited unless 
deemed medically necessary by the study physician.  
o 
Other Thyroid Medications: Any medications, other than methimazole, used 
to treat thyroid disorders (e.g., levothyroxine, propylthiouracil) are 
prohibited, as they could confound the study results.  
o 
Other Excluded Medications: Current use of medications known to 
significantly affect thyroid function will be prohibited (e.g. corticosteroids, 
amiodarone) or vitamin D metabolism (e.g., anticonvulsants, rifampin). These 
medications will also be prohibited during the study period. 
 
 
Potential Effects of Permitted Concomitant Therapy and Assessment of 
Independent Effects: Drug-Drug Interactions: The study physician will review all 
concomitant medications for potential drug-drug interactions with vitamin D or 
methimazole. If any potentially significant interactions are identified, the study 
physician will assess the risk/benefit of continued study participation and may 
recommend alternative therapies or dose adjustments.  
 
While detailed concomitant medication data will not be systematically collected in 
REDCap for this pilot study, information on key medications/supplements known to 
potentially affect vitamin D, calcium levels, or thyroid function (e.g., calcium 

 
 
 
22 
 
supplements, vitamin D supplements, medications affecting bone metabolism, other 
thyroid medications) will be documented in the medical record and summarized in 
the study record. This limited information will be used to describe potential 
confounding medications and to inform the development of a more comprehensive 
medication assessment strategy for the subsequent, larger clinical trial. Given the 
limitations of the medication data in this pilot, a full disentanglement of the 
independent effects of vitamin D from other medications may not be feasible. 
However, descriptive analyses of the use of these key medications/supplements will 
be performed and considered when interpreting the study results and planning the 
larger trial. The statistical analysis plan for the larger trial will include robust methods 
to address potential confounding from concomitant medications, based on the 
learnings from this pilot study. 
 
 
6.5 
     Rescue Medication Administration 
 
1) Vitamin D (Ergocalciferol): Intervention Arm 
 
Hypervitaminosis D or hypercalcemia: Please see section 4.8 for dose adjustments 
in those clinical scenarios. 
 Other Adverse Events: If a participant experiences other adverse events deemed 
related to vitamin D and requiring intervention, the study physician will determine 
the appropriate course of action, which may include symptomatic treatment or 
discontinuation of vitamin D supplementation.  
(2) Methimazole (Both Arms) 
 Management of adverse events or inadequate response to methimazole is part of 
standard medical practice for Graves' disease and will be handled by the participant's 
treating physician, not the study. The study team will document any changes in 
methimazole regimen (dose, frequency), but these decisions will be made by the 
treating physician based on the participant's clinical condition and standard of care 
guidelines.  
(3) Vitamin D2 (Optional - Control Arm) 
 Participants in the control arm may choose to take OTC vitamin D2 supplements. The 
study team will not provide any specific recommendations or guidance for the 
management of adverse events potentially related to OTC vitamin D2 use. It is 
recommended that they follow the manufacturer's instructions or consult with their 
physician or pharmacist. 
 
7 STATISTICAL CONSIDERATIONS 
7.1    Brief Description of Study Design 
This is an open label randomized clinical pilot feasibility trial. In this study, participants will be 
randomized to either the experimental (vitamin D + methimazole) or control (methimazole only) 
group at the time of the initial visit. The starting dose of methimazole and dose adjustments will 
be made by the treating endocrinologist based on established clinical practice guidelines. The 
control arm will receive no additional intervention other than methimazole (standard of care). 
While the control group will not receive the high-dose vitamin D intervention, they will be 
allowed to take up to 1000 IU of vitamin D daily. This approach balances the need for a 

 
 
 
23 
 
comparison group against the ethical responsibility of not withholding a potentially beneficial 
supplement for those with low levels.  
7.2     Primary Endpoint(s) 
This pilot study's primary objective is to assess the feasibility of conducting a larger randomized 
controlled trial (RCT) of high-dose vitamin D in pediatric Graves' disease (GD). Therefore, the 
primary "endpoints" of this pilot are feasibility metrics, not clinical outcomes. These metrics will 
inform the design and sample size calculation of the future, larger RCT. Specifically, the primary 
feasibility endpoints are: 
 
(a) Recruitment Rate: The proportion of eligible participants who consent/assent to 
participate in the study within the designated recruitment period March 2025-October 2025. 
This will be calculated as the number of enrolled participants divided by the number of eligible 
participants approached. 
 
(b) Adherence Rate: The proportion of prescribed vitamin D doses taken by participants in 
the intervention arm, as measured by pill counts at each visit, corroborated by medication 
logs and patient/parent self-report. This will help to determine the feasibility of achieving 
adequate adherence in a larger trial and help in evaluating the various adherence monitoring 
strategies employed. 
 
(c) Data Completeness: The proportion of completed data fields for pre-specified primary and 
secondary outcome measures in the final dataset. This will be assessed for all enrolled 
participants and will help identify potential challenges in data collection for a larger RCT. Data 
variability will also be evaluated as descriptive statistics to understand potential dispersion of 
these values. 
 
(d) Barriers to Implementation: A qualitative assessment of any challenges or obstacles 
encountered during the pilot study that could hinder the successful implementation of a 
larger-scale RCT. This assessment will be based on the experiences of the study team, 
feedback from participants/families, and any unforeseen logistical or operational issues 
encountered. 
Sample Size Justification: 
The sample size of 30 participants is considered adequate for this pilot study based on feasibility 
considerations and recommendations for pilot studies. This sample size is likely not powered to 
detect statistically significant differences in clinical outcomes, as the primary aim is to assess 
feasibility for a larger RCT. It is expected that this sample size will provide sufficient data to 
evaluate recruitment rates, adherence to the intervention, data completeness, and potential 
barriers to implementation, thus informing the design and sample size calculation of a 
subsequent, adequately powered RCT. 
 
7.3 
   Secondary Endpoint(s) 
Exploratory Outcomes 
This pilot study will explore the following outcomes to generate preliminary data and inform the 
design of a future, larger randomized controlled trial. These are not formal secondary endpoints, 
as this pilot is likely not powered to detect statistically significant differences in these outcomes. 
The purpose of collecting this data is to observe trends, estimate effect sizes and their 
variability, and assess the feasibility of collecting these data in a larger trial. 
 
Thyroid Function Normalization: Time to normalization of thyroid function tests (T3, FT4, 
and T4) will be explored. Normalization will be defined as achieving age-appropriate normal 
ranges for T3, FT4 and T4 tests simultaneously.  Time to normalization of TSH will be 
explored separately. Time to normalization will be calculated as the time from baseline to 
the first visit at which T3, FT4 and T4 tests are within normal limits and a separate TSH time 

 
 
 
24 
 
to normalization will be documented. The proportion of participants achieving 
normalization in each arm (methimazole alone vs. methimazole + vitamin D) will also be 
described. These exploratory analyses will inform the sample size calculation for a future, 
adequately powered trial investigating the impact of vitamin D on thyroid hormone 
normalization. 
 
TSH Receptor Antibody (TRAb) and Thyroid Stimulating Immunoglobulin (TSI) Levels: The 
percentage change from baseline in TRAb and TSI levels at 24 weeks will be explored. The 
percentage change will be calculated as [(24-week value - Baseline value) / Baseline value] * 
100. The difference in percentage change between the two treatment arms (methimazole 
alone vs. methimazole + vitamin D) will be described. This information will inform the design 
of a future trial examining the impact of vitamin D on these antibody levels. 
 
7.4 
   Safety Endpoints 
 
Safety and tolerability of high-dose vitamin D are important considerations in this pilot study. All 
participants receiving at least one dose of vitamin D or methimazole will be included in the safety 
analysis. Adverse events (AEs) will be collected, coded, and analyzed as follows: 
 
AE Definition: An AE is any untoward medical occurrence temporally associated with the 
use of a medicinal product, whether or not related to that product. This includes abnormal 
laboratory findings, symptoms, and disease. AEs related to both vitamin D (study 
intervention) and methimazole (standard of care) will be documented. Methimazole AEs, 
while not study-related, will be monitored for participant safety and to distinguish them 
from potential vitamin D effects in this open-label study. 
 
AE Coding: AEs will be coded using MedDRA terminology (System Organ Class and PT). 
 
AE Calculation and Presentation: Each distinct AE will be counted once per participant. AE 
data will be presented by SOC and PT, including start/stop dates, severity (using CTCAE v 
[5.0]), relationship to vitamin D or methimazole (causality for methimazole AEs assessed per 
routine clinical practice), expectedness, outcome, duration, and any action taken regarding 
vitamin D dosing (with rationale). 
 
AEs Leading to Discontinuation: All AEs leading to vitamin D discontinuation will be 
reported. Discontinuation of vitamin D only, with continued study follow-up, will be 
distinguished from complete study withdrawal. Details, rationale, and outcome of AEs 
leading to vitamin D discontinuation will be documented. 
 
Serious Adverse Events (SAEs): All SAEs will be reported. An SAE is any untoward medical 
occurrence that: results in death; is life-threatening; requires or prolongs hospitalization; 
results in persistent disability/incapacity; is a congenital anomaly/birth defect; or is deemed 
serious by the study physician. 
 
Treatment-Emergent AEs: AEs occurring or worsening after the first dose of vitamin D will 
be analyzed. 
 
Safety and Tolerability Assessment: The safety and tolerability of high-dose vitamin D will 
be evaluated by monitoring all reported AEs, with particular attention to those potentially 
related to vitamin D or hypercalcemia (e.g., nausea, vomiting, constipation, polyuria, 
polydipsia). 
 
7.5 
   Intention – To-Treat (ITT) and Per Protocol (PP) Analysis Sets 
 
Data from this pilot study will be analyzed using an intention-to-treat (ITT) approach. The ITT 
analysis set will include all participants who are randomized to either the intervention arm 

 
 
 
25 
 
(vitamin D + methimazole) or the control arm (methimazole alone), regardless of whether 
they receive any study intervention (vitamin D) or complete all follow-up visits. This approach 
is consistent with the intention-to-treat principle, which aims to minimize bias by analyzing 
participants based on their assigned treatment group, rather than their actual treatment 
received. For this pilot, descriptive statistics for key feasibility and exploratory outcomes will 
be calculated for the entire ITT population. While a modified intention-to-treat (mITT) analysis 
set may also be used for certain exploratory outcomes requiring a minimum amount of follow-
up data for meaningful interpretation (e.g. thyroid function or antibody levels), the primary 
analysis set for this pilot feasibility study is the ITT population. Any deviations from the ITT 
principle for individual exploratory analyses (e.g. use of mITT), will be pre-specified prior to 
data analysis and the rationale clearly documented in the statistical analysis plan 
accompanying study publication. 
 
7.6 
    Statistical Methods 
 
The primary objective of this pilot study is to assess the feasibility of conducting a larger 
RCT, not to test hypotheses about treatment efficacy. Therefore, the statistical analyses will 
primarily be descriptive. Inferential statistics will be used for exploratory analyses of clinical 
outcomes, but these analyses will focus on estimating effect sizes and variability to inform 
the design of the future RCT, rather than on drawing definitive conclusions about treatment 
effects. 
 
7.7.1      Analysis of the Primary Endpoint 
The primary “endpoints” of this pilot study are feasibility metrics. These will be analyzed 
as follows: 
 
Recruitment Rate: Calculated as the number of enrolled participants divided by 
the number of eligible participants approached. Presented as a percentage with 
95% confidence intervals. 
 
Adherence Rate: Calculated as the percentage of prescribed vitamin D doses 
taken, based on pill counts corroborated by medication logs and self-report. 
Presented as a percentage with 95% confidence intervals. Different adherence 
monitoring strategies (pill counts, logs, phone calls) will be compared 
descriptively. 
 
Data Completeness: Calculated as the proportion of completed data fields for 
pre-specified outcome measures. Presented as a percentage. Variability in 
collected data will be described using descriptive statistics (means, standard 
deviations, interquartile ranges). 
 
Barriers to Implementation: Qualitative data on barriers will be summarized 
thematically. 
Missing data for feasibility outcomes will be minimal as they are primarily process 
related. Any missing data will be documented and described. 
 
7.7.2     Analysis of Secondary Endpoint(s) 
Exploratory outcomes will be analyzed descriptively to understand trends and estimate 
effect sizes for the future RCT. 
 
Thyroid Function Normalization: For each thyroid hormone level and for TSH, 
logistic regression will be performed using a generalized linear mixed model 

 
 
 
26 
 
(GLMM) to simultaneously assess the odds of normalization at 6 weeks, 12 
week, 24 weeks. GLMMs can account for correlations of measurements at 
different timepoints that are from the same patient. Logistic regression will be 
utilized to assess the odds of >50% decrease in antibody levels at 24 weeks from 
diagnosis. If the sample size is sufficient, we will adjust for disease severity at 
diagnosis in each model. If GLMMs are not feasible, analysis will be performed 
separately at each timepoint. 
 
TRAb and TSI Levels: A linear mixed model (appropriate data transformations 
may be applied) with an interaction term of group by time will be utilized to 
compare absolute and percentage changes in thyroid function (T4, FT4, T3) at 6, 
12 and 24 weeks, vitamin D levels at 12 and 24 weeks months, and Graves’ 
antibody levels (TSH-R Ab, TSI) at baseline and 24 weeks within participants in 
each group (treatment and control) from time of diagnosis and between groups 
at each time point. Separate models will be built for each thyroid function 
hormone (T4, FT4, T3), for vitamin D, and for each Graves’ antibody (TSH-R Ab, 
TSI) for absolute and for percentage change. As with GLMMs, linear mixed 
models can account for correlations of measurements at different timepoints 
that are from the same patient. 
 
Missing Data: Missing data for exploratory outcomes will be addressed using 
simple imputation methods (e.g., last observation carried forward, mean 
imputation) for exploratory purposes only. The limitations of these methods and 
the potential impact of missing data will be discussed. 
 
 
7.7.3      Analysis of Safety Endpoints (if applicable) 
Safety endpoints will be analyzed descriptively. The incidence and severity of adverse 
events (AEs) will be summarized by treatment arm, system organ class, and preferred 
term. The relationship of AEs to study interventions will be assessed and described. 
Serious adverse events (SAEs) will be reported individually. 
 
7.7.4      Pre-specified Subgroup Analyses 
Subgroup analyses are not planned for this pilot study due to the small sample size and 
feasibility focus. The feasibility of conducting subgroup analyses in the larger RCT will 
be assessed based on the variability observed in this pilot. 
 
7.7.5     Interim Analysis and Early Stopping Rules (if applicable) 
No interim analyses or early stopping rules are planned for this pilot feasibility study. 
 
7.7.6       Sample Size Justification 
The sample size of 30 is based on feasibility considerations, anticipated recruitment 
rates, and recommendations for pilot studies. It is not based on a formal power 
calculation for clinical outcomes. This sample size is expected to be sufficient to assess 
feasibility, explore trends in the exploratory outcomes, and inform the design of a 
future, adequately powered RCT. The sample size is justified by the available patient 
volume and ensures adequate data can be collected to estimate effect sizes and their 
variability for the future RCT sample size calculation. 

 
 
 
27 
 
8   ADVERSE EVENT, SERIOUS ADVERSE EVENT AND 
UNANTICIPATED PROBLEM 
8.1     Adverse Event (AE)  
 
An AE is any untoward medical occurrence in a participant temporally associated with the 
use of a medicinal product, whether or not related to that product. This includes abnormal 
laboratory findings, symptoms, intercurrent illnesses, and injuries. Abnormal diagnostic 
results are AEs if they result in study withdrawal, are associated with an SAE or clinical 
signs/symptoms, lead to additional treatment/tests, or are considered clinically significant 
by the investigator. 
 
Specific Considerations: In this pediatric study, special attention will be paid to age-
appropriate AE manifestations and potential long-term effects. Parents/guardians will 
be actively involved in AE reporting. AEs associated with vitamin D (hypervitaminosis D, 
hypercalcemia) and methimazole (rash, itching, nausea, vomiting, joint pains, altered 
LFTs; see package inserts for expected AEs) will be monitored. AEs related to study 
procedures will also be documented. 
 
8.2 Serious Adverse Events (SAE)  
An SAE is any untoward medical occurrence that: results in death; is life-threatening (at the 
time of the event); requires or prolongs hospitalization; results in persistent 
disability/incapacity; or is deemed a serious important medical event. 
 
Specific Considerations: SAEs will be evaluated with attention to developmental 
stage and potential long-term impacts. Methimazole-related SAEs (e.g., 
agranulocytosis, hepatotoxicity, vasculitis), though related to standard of care, will 
be documented and reported. 
 
 
8.3 Unanticipated Problems (UP)/ Unanticipated Device Effect (UADE) 
A UP is any incident, experience, or outcome that is unexpected (given the research 
procedures and participant characteristics), related or possibly related to research 
participation, and suggests increased risk of harm. UADE is not applicable (no device). 
 
Specific Considerations: The threshold for reporting UPs may be lower in children. 
Unexpected AEs related to vitamin D or methimazole, breaches of confidentiality, and 
significant protocol deviations (e.g., delayed or missed doses of vitamin D, incorrect doses 
such as doses significantly over or under recommended, deviations from dose 
modification schedule listed in 4.8) will be evaluated as potential UPs. Serious non-
compliance leading to increased risk (e.g., disallowed concomitant medications) may be 
reported as a UP. 
 
8.4 Recording 
AEs will be elicited at each visit/contact using open-ended and targeted questions, physical 
exams, and lab tests (including serum calcium). Documentation in source documents (medical 
record) will include date of onset, description, severity, relationship to interventions/procedures 
(methimazole causality assessed by treating physician), expectedness, outcome, and action 
taken/rationale. AE data will be entered into REDCap. All AEs will be assessed using CTCAE v5.0. 
The relationship of AEs to vitamin D will be categorized as Definitely, Probably, Possibly, 
Unlikely, or Not Related (see 8.5.2 for details). 

 
 
 
28 
 
 
8.5 Assessment 
All AEs must be assessed by the study clinician using a protocol-defined grading system. 
8.5.1 Severity of Event 
The CTCAE grading scale defines the following severity grades for AEs: 
 
Grade 1 (Mild): Mild adverse event; intervention not indicated. 
 
Grade 2 (Moderate): Moderate adverse event; limiting age-appropriate instrumental 
activities of daily living (IADL); intervention indicated. 
 
Grade 3 (Severe): Severe adverse event; limiting self-care ADL; hospitalization indicated. 
 
Grade 4 (Life-Threatening): Life-threatening consequences; urgent intervention 
indicated. 
 
Grade 5 (Death related to AE): Death related to adverse event. 
 
 
8.5.2 Relationship to Study Intervention 
The relationship of an AE to a study intervention (vitamin D) will be assessed by the clinician 
who examines and evaluates the participant. This assessment will consider the following 
factors: 
 
Temporal Relationship: The time between the start of the study intervention (vitamin 
D administration) and the onset of the AE. 
 
Known Pharmacology/Toxicology: The known pharmacology and toxicology of 
vitamin D, including expected adverse effects and the biological plausibility of a causal 
relationship. The package insert will serve as a reference. 
 
Underlying Medical Conditions: The participant's underlying medical conditions and 
their potential contribution to the AE. 
 
Concomitant Medications: Concomitant medications, both prescription and over the 
counter, and their potential for interaction with vitamin D or for causing the AE 
independently. 
 
Dechallenge/Rechallenge (if applicable): The response of the AE to discontinuation 
(dechallenge) and reintroduction (rechallenge) of vitamin D, if ethically and clinically 
appropriate. This may not always be feasible or ethical. 
 
Other Potential Causes: Other potential causes of the AE, including intercurrent 
illnesses, environmental factors, or other study procedures. 
The relationship of the AE to the study intervention (vitamin D) will be 
categorized using the following terms: 
 
Definitely Related: Clear evidence suggests a causal relationship between vitamin D 
and the AE, and other contributing factors can be ruled out with reasonable certainty. 
The event occurs in a plausible time relationship to vitamin D administration and 
cannot be readily explained by other factors. 
 
Probably Related: Evidence suggests a causal relationship, and the influence of other 
factors is unlikely. The event occurs within a reasonable time after vitamin D 
administration and is unlikely to be attributed to other causes. 
 
Possibly Related: There is some evidence to suggest a causal relationship (e.g., a 
known association, a plausible temporal relationship). However, other factors may 
have also contributed. 

 
 
 
29 
 
 
Unlikely Related: The temporal relationship and/or other factors make a causal 
relationship between vitamin D and the AE improbable. Other explanations are more 
likely. 
 
Not Related: The AE is clearly independent of vitamin D administration, and evidence 
supports an alternative etiology. 
Relationship to Methimazole (Standard of Care): 
For AEs potentially related to methimazole, the treating physician (not the 
study team) will determine the relationship to methimazole based on their 
clinical judgment and standard of care practice. This assessment will be 
documented in the participant's medical record and transcribed into the 
study database. 
If there is any doubt as to whether a clinical observation is an AE, the event 
should be reported. 
 
8.5.3 Expectedness   
Expectedness will be determined by the study physician based on package inserts and 
literature. Unexpected AEs are those not listed, more severe/frequent than listed, or different 
in nature than listed. 
 
8.5.4   Time Period and Frequency for Event Assessment and Follow-Up 
AEs/SAEs will be followed until resolution, stabilization, or non-related determination. Mild 
AEs: follow-up until resolution or next visit. Moderate AEs: weekly assessments until 
resolution/stabilization. Severe AEs/SAEs: frequent assessments, continued follow-up after 
study intervention discontinuation. Documentation in source documents and REDCap. Long-
term follow-up ensured for unresolved events. 
 
8.6 Reporting 
 
8.6.1 Adverse Event (AE) Reporting  
All AEs, regardless of causality or severity, will be documented as described in Section 8.5. 
While all AEs will be recorded, routine, expected AEs associated with Graves' disease 
itself, such as those related to fluctuating thyroid hormone levels (e.g., palpitations, 
anxiety, fatigue, heat intolerance) or the known effects of methimazole (e.g., mild rash, 
nausea) will be managed as part of routine clinical care by the study physicians 
and not reported to the sponsor or IRB as protocol deviations or UPs, unless they meet 
the criteria for an SAE or UP (unexpected, related or possibly related to research 
participation, and suggesting increased risk of harm). All such events will be carefully 
documented in the source documents and the study database (REDCap) for 
comprehensive safety monitoring. The distinction between routine disease management 
and reportable AEs/UPs will be clearly explained to study staff during training. For 
methimazole AEs, causality will be assessed by the treating physician per routine clinical 
practice.  
 
8.6.2 Serious Adverse Event (SAE) Reporting  
All SAEs, regardless of causality or expectedness, will be reported to the Principal 
Investigator (PI) within 24 hours of the study team becoming aware of the event. The PI 

 
 
 
30 
 
will then report the SAE to the IRB within [Specify timeframe, e.g., 7 calendar days] of 
becoming aware of the event, and other regulatory authorities, including the FDA (if 
applicable), using the appropriate reporting forms and procedures, following 
institutional and federal guidelines. For the purposes of SAE reporting in this open-label 
pilot study, where methimazole and vitamin D are used concomitantly, an SAE occurring 
after the first dose of either methimazole or vitamin D will be considered a treatment-
emergent SAE and should be reported to the PI. 
 
8.6.3 Unanticipated Problem/ Unanticipated Device Effect Reporting  
The investigator will report unanticipated problems (UPs) to the reviewing Institutional 
Review Board (IRB) according to the institution's policies and procedures. This study 
does not involve a device; therefore, Unanticipated Adverse Device Effects (UADEs) are not 
applicable. This should be explicitly stated in the protocol for the IRB. 
The UP report will include the following information: 
 
Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number 
 
A detailed description of the event, incident, experience, or outcome 
 
An explanation of the basis for determining that the event represents a UP, 
specifically addressing the three criteria of unexpectedness, relatedness, and 
increased risk of harm. 
 
An assessment of the event's impact on the risks and benefits of study 
participation 
 
A description of any changes to the protocol or other corrective actions that have 
been taken or are proposed in response to the UP 
Timeframe for Reporting UPs: 
 
UPs that are also SAEs will be reported to the IRB within 7 calendar days of the 
investigator becoming aware of the event. 
 
All other UPs will be reported to the IRB within 14 calendar days of the investigator 
becoming aware of the problem. 
 
The PI will ensure that all UPs are reported to appropriate institutional officials (as 
required by the institution’s written reporting procedures), the appropriate 
regulatory authorities, and the Office for Human Research Protections (OHRP), if 
applicable, within the required timeframes per institutional policy. 
 
8.6.4 Reporting to Participants (If Applicable) 
 
Individual AE/SAE Reporting: Participants (or their parents/guardians) will be informed 
of any AEs or SAEs considered related or possibly related to the study intervention 
(vitamin D) or study procedures. This will be done in a timely manner, using age-
appropriate language, during study visits or via phone or other secure communication 
methods. The information shared will include the nature of the event, its severity, the 
suspected relationship to the study, and any actions taken or recommended (e.g., dose 
modification, additional monitoring). Participants will be encouraged to report any new 
or worsening symptoms to the study team promptly. 
 
UP Reporting to Participants: If a UP occurs that might affect the safety or well-being of 
participants, those affected (or their parents/guardians) will be informed promptly. The 
information provided will include the nature of the UP, its potential impact, and any 
actions taken to mitigate risks. 

 
 
 
31 
 
 
Study Results related to Vitamin D Levels: As Vitamin D levels are collected for study 
purposes, clinically relevant results (e.g., significant deficiency, toxicity) will be 
communicated to participants (and their parents/guardians) and their primary care 
physician for appropriate management and referral if necessary. This will occur regardless 
of randomization arm. 
 
Incidental Findings: Thyroid function tests (TFTs) and other tests such as CMP and CBC 
obtained as part of standard care will be reviewed by the participant's primary 
endocrinologist. Any abnormal TFT, CBC and CMP results will be managed according to 
usual clinical practice, including communication of results and any necessary follow-up 
with the participant and their parent/guardian. 
 
9 REGULATORY, ETHICAL AND STUDY OVERSIGHT CONSIDERATIONS 
This section details the ethical, regulatory, and oversight procedures for this pilot study, guided by the 
principles outlined in the Statement of Compliance. 
 
9.1 
Informed Consent/Assent and HIPAA Authorization 
Written informed consent will be obtained from parents/guardians, and assent from child 
participants (9-17 years). The process will occur in a private setting, allowing adequate time for 
decision-making (at least 24 hours) and ensuring comprehension through age-appropriate 
language. Participation is voluntary, with no coercion or impact on standard care. Signed 
consent/assent forms and HIPAA Authorization will be documented and securely stored, with copies 
provided to participants. Participants reaching age 18 during the study will be reconsented as adults. 
While we do not anticipate enrolling non-English speaking participants in this study, we will not 
exclude them from participation. In the event that a non-English speaking individual expresses 
interest in enrolling, we will utilize a short form consent and HIPAA Authorization in accordance 
with IRB policy. A qualified interpreter will be provided through Language Line Solutions (either via 
video or phone) to facilitate a line-by-line interpretation of the full English consent form and any 
other study-related documents. This interpretation will be documented on the short form consent, 
noting the interpreter's name, language, and identification number. An impartial witness, who is 
present with the participant and understands the language of the consent, will also sign the short 
form consent, attesting that the information was reviewed with the participant in their preferred 
language with the assistance of the interpreter. 
9.2 
Safety Oversight 
Data and Safety Monitoring Plan (DSMP) and Clinical Monitoring Plan (CMP) 
 
To ensure participant safety and data integrity, this pilot study will implement a 
combined DSMP and CMP, recognizing the smaller scale and minimal risk. 
o 
DSMP: The PI will oversee study safety, including review of all AEs and SAEs, 
recruitment/adherence rates, and data completeness. An independent Safety Officer, 
with expertise in pediatric endocrinology and free from conflicts of interest, will conduct 
formal safety reviews every 6 months and provide ad hoc consultations. DSMB meeting 
will take place every 6 months to review study safety data. The safety report for these 
reviews will include the number of AEs/SAEs, types of AEs/SAEs by system organ class, 
severity of AEs (using CTCAE v5.0), relationship of AEs to the intervention, and any 
actions taken. SAEs will be immediately reported to the PI, co-investigators, Safety 
Officer, Northwell IRB, and other care providers as appropriate. The study will adhere to 
OHRP/FDA/NIH guidelines and reporting requirements. Hypervitaminosis D and 

 
 
 
32 
 
hypercalcemia will be closely monitored through 25-hydroxyvitamin D and CMPs, with 
specific dose modification protocols in Section 4.8. 
o 
CMP: The PI and co-investigator will monitor study conduct, including: 
 
 
100% Source Data Verification (SDV) for primary feasibility outcomes: 
recruitment rate, adherence (verified against pill counts, logs, self-report), and 
data completeness. 
 
Targeted SDV for secondary and safety outcomes: This targeted source data 
verification will include thyroid function tests, antibody levels (TRAb and TSI), 
CMP including calcium, vitamin D levels, and adverse events. 
 
Review of informed consent procedures. 
 
Vitamin D drug accountability and adherence monitoring (procedures in Section 
6.3). 
 
Review of AE/SAE reporting for timeliness and completeness. 
 
Assessment of protocol compliance and data quality (through REDCap range 
checks, validation rules, and data review meetings). 
 
Regular communication/meetings with study staff. 
Monitoring Frequency: Monitoring visits will occur weekly for the first month and 
then monthly thereafter documented in monitoring visit reports. Summaries will be 
provided to the IRB for review. 
 
 
 
 
9.2.1 Medical Monitoring 
The study PI will provide medical monitoring for the study, ensuring appropriate assessment 
and reporting of adverse events, implementation of the data and safety monitoring plan, and 
regular assessment of the number and type of SAEs. 
 
9.2.2  Independent Data and Safety Monitoring Board 
Please see section 9.2 and 9.2.1 
 
9.2.3 
Stopping Rules  
The study may be stopped prematurely for the following reasons: 
 
Evidence of significant or unexpected risks to participants related to vitamin D 
supplementation or study procedures. 
 
Serious or persistent non-compliance with the study protocol. 
 
Inability to recruit an adequate number of participants to assess feasibility. 
 
PI or sponsor decision based on logistical or administrative reasons. 
 
If the study is stopped, the PI or the co-investigator will promptly inform all 
participants, the IRB, and any other relevant stakeholders. The reasons for stopping 
will be documented. 
 
9.3 
 Data Handling and Record Keeping 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with ICH GCP and regulatory and institutional requirements for the protection of 

 
 
 
33 
 
confidentiality of participants.  The following subsections should include a description of the data 
handling and record keeping for the conduct of the trial.  
 
9.3.1 
Data Collection and Management 
Data will be collected electronically using REDCap, a secure, web-based data capture system 
hosted at Northwell Health. Source documents will be stored in the participant’s medical 
records. Data from source documents will be entered into REDCap by trained study staff. Data 
entry will be ongoing throughout the study. CRFs will be submitted electronically within 1 week 
of each study visit. Data quality will be ensured through range checks, data validation rules, and 
regular monitoring by the study team. 
 
Access Control and User Roles: Access to the REDCap database will be strictly 
controlled through a role-based access system. Each study team member will be 
assigned a unique username and password and granted access only to the data 
necessary for their role. The following roles and permissions will be implemented: 
o 
Principal Investigator (PI) and Co-investigators: Full access to all study data. 
o 
Study Coordinator: Access to all de-identified study data. Ability to enter 
and modify data. 
o 
Research Staff: Limited access to data based on their specific 
responsibilities (e.g., data entry personnel will only have data entry 
permissions; those performing data analysis may have read-only access to 
de-identified data). 
o 
Safety Officer: Access to de-identified safety data (AEs, SAEs). 
o 
Clinical Monitor: Access to de-identified data for monitoring purposes. 
o 
Statistician: Access to de-identified data for analysis purposes. Depending 
on the analysis plan, the statistician may have read-only access or 
permission to generate derived variables or perform data transformations 
within REDCap. If interim analyses are planned, access to blinded/unblinded 
data will be managed as per those procedures. 
 
Password Management: Strong password policies will be enforced, requiring a 
minimum length, complexity (combination of uppercase/lowercase letters, 
numbers, and symbols), and regular password changes. Passwords will never be 
shared. Two-factor authentication will be implemented if available. 
 
Data Security Training: All study personnel with REDCap access receive annual 
training on data security procedures and HIPAA compliance per institutional policy. 
 
Confidentiality: All data will be stored securely within the REDCap database. 
Participant identifiers will be replaced with study-specific numeric codes to protect 
confidentiality. The code linking participant identifiers to study codes will be stored 
separately in a secure, locked location accessible only to the PI and authorized study 
coordinator. This key will be destroyed after the study and all required audits are 
complete. 
 
Security: REDCap has robust security measures to prevent unauthorized access, 
including intrusion detection systems and regular security audits. 
 
De-identification: Prior to any publication or sharing of study data, all identifying 
information will be removed and replaced with unique study identifiers. 
 

 
 
 
34 
 
9.3.2 
Confidentiality and Privacy 
All study data will be treated as confidential. Participant privacy will be protected in 
accordance with HIPAA regulations. Access to study data will be restricted to authorized 
study personnel. Identifiers will be removed from any published or shared data. No personal 
identifying information will be released to third parties without explicit consent. Study staff 
will be trained on HIPAA regulations and data security procedures. The PI, co-investigators, 
study coordinator, and designated research staff will have access to study records and data. 
The clinical monitor, IRB representatives, and regulatory agencies may also have access to 
de-identified data for monitoring and audit purposes. 
 
9.3.3 
Source Documents 
Source documents will consist of the participant's medical records, where all clinical 
information, including AEs, will be initially documented.  
 
9.3.4 
Case Report Forms 
Data will be entered in REDCap electronic CRFs. The CRFs will collect data on demographics, 
medical history, vitamin D levels, thyroid function tests, antibody levels, adherence data, and 
AEs. The case report form will not serve as the sole record of study participation. Study 
enrollment will also be documented in the participant's medical record to ensure all 
healthcare providers are aware of the participant's study involvement. 
 
9.3.5 
Availability and Retention of Records 
Study records will be retained for at least 7 years after study completion, consistent with 
institutional policy and any applicable regulations. All essential documents will be accessible 
to the IRB, sponsor, and regulatory authorities upon request. 
 
9.3.6 
Future Use of Stored Specimens and Data 
No biological specimens will be stored for future research in this study. Genetic testing will 
not be performed. 
 
9.4 Study Oversight 
9.4.1      Protocol Deviations 
 
Protocol deviations will be documented and reviewed by the PI. 
 
Major Protocol Deviation: A deviation that affects participant safety, rights, 
welfare, or data integrity (e.g., administering the wrong dose of vitamin D, failing to 
report an SAE, falsification of data). Major deviations will be reported to the IRB 
within 10 working days of discovery. 
 
Minor Protocol Deviation: A deviation that does not significantly impact participant 
safety, rights, or data integrity (e.g., minor scheduling changes, missed phone call 
follow-up if appropriately rescheduled). Minor deviations will be tracked in a log and 
reported to the IRB at the time of continuing review or annual check-in. 
 
All deviations and corrective actions will be documented. 

 
 
 
35 
 
9.4.2 
Study Status 
The study may be terminated or suspended for reasons outlined in section 9.2.4. The PI will 
promptly inform study participants and the IRB of any termination or suspension, providing 
written notification with reasons. 
9.4.3 
Conflict of Interest 
All investigators involved in this study will disclose any potential conflicts of interest to the 
Northwell Health Compliance Department for review and management, as per institutional 
policy. 
 
9.4.4 
Institutional Review Board/Independent Ethics Committee Review and Approval 
This study will be conducted in accordance with all applicable regulations and ethical 
guidelines, including the Declaration of Helsinki, CIOMS guidelines, and ICH GCP. The 
protocol, informed consent/assent documents, and all study materials will be submitted 
to the IRB for review and approval before study initiation. Annual progress reports and 
reports of UPs and SAEs will be submitted to the IRB as required. No other regulatory 
agencies (IBC, RDRC) require review for this study. 
 
9.4.5     Publication 
Aggregate study findings, without any individually identifiable information, will be submitted 
for publication in a peer-reviewed journal. Authorship will be determined per ICMJE 
guidelines. 
 
 
9.5      Quality Control and Quality Assurance 
 
9.5.1 
Clinical Monitoring  
Please see section 9.2 and 9.2.1 for details 
 
9.5.2 
Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, any 
sponsor, regulatory bodies, and institutional compliance offices, providing access to all study 
documents and facilities. 
 
10 REFERENCES 
 
1. 
Quintanilla-Dieck, L., et al., Management of Pediatric Graves Disease: A Review. JAMA 
Otolaryngol Head Neck Surg, 2021. 147(12): p. 1110-1118. 
2. 
Kaguelidou, F., et al., Predictors of autoimmune hyperthyroidism relapse in children 
after discontinuation of antithyroid drug treatment. J Clin Endocrinol Metab, 2008. 
93(10): p. 3817-26. 
3. 
Glaser, N.S. and D.M. Styne, Predicting the likelihood of remission in children with 
Graves' disease: a prospective, multicenter study. Pediatrics, 2008. 121(3): p. e481-8. 

 
 
 
36 
 
4. 
Léger, J., et al., Positive impact of long-term antithyroid drug treatment on the outcome 
of children with Graves' disease: national long-term cohort study. J Clin Endocrinol 
Metab, 2012. 97(1): p. 110-9. 
5. 
Cappelli, C., et al., Prognostic value of thyrotropin receptor antibodies (TRAb) in 
Graves' disease: a 120 months prospective study. Endocr J, 2007. 54(5): p. 713-20. 
6. 
Khozam, S.A., et al., Association Between Vitamin D Deficiency and Autoimmune 
Thyroid Disorder: A Systematic Review. Cureus, 2022. 14(6): p. e25869. 
7. 
Pang, B., et al., Association between serum vitamin D level and Graves' disease: a 
systematic review and meta-analysis. Nutr J, 2024. 23(1): p. 60. 
8. 
Zhang, H., L. Liang, and Z. Xie, Low Vitamin D Status is Associated with Increased 
Thyrotropin-Receptor Antibody Titer in Graves Disease. Endocr Pract, 2015. 21(3): p. 
258-63. 
9. 
Pratita, W., K. Arto, and N. Arto, Efficacy of Vitamin-D Supplement on Thyroid Profile 
in Children with Graves’ Disease. Open Access Macedonian Journal of Medical 
Sciences, 2020. 8: p. 798-801. 
10. 
Nwosu, B.U., et al., Ergocalciferol in New-onset Type 1 Diabetes: A Randomized 
Controlled Trial. J Endocr Soc, 2022. 6(1): p. bvab179. 
11. 
Yang, C.Y., et al., The implication of vitamin D and autoimmunity: a comprehensive 
review. Clin Rev Allergy Immunol, 2013. 45(2): p. 217-26. 
12. 
Marcinowska-Suchowierska E, Kupisz-Urbańska M, Łukaszkiewicz J, Płudowski P, 
Jones G. Vitamin D Toxicity-A Clinical Perspective. Front Endocrinol (Lausanne). 
2018;9:550. Published 2018 Sep 20. doi:10.3389/fendo.2018.00550 
 
 
 
 

 
 
 
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APPENDIX 
 
Anticipated AEs with Severity and Actions 
The CTCAE grading scale (v5.0) defines the following severity grades for AEs: 
 
Grade 1 (Mild): Mild adverse event; intervention not indicated. 
 
Grade 2 (Moderate): Moderate adverse event; limiting age-appropriate instrumental activities of daily living (IADL); intervention indicated. 
 
Grade 3 (Severe): Severe adverse event; limiting self-care ADL; hospitalization indicated. 
 
Grade 4 (Life-Threatening): Life-threatening consequences; urgent intervention indicated. 
 
Grade 5 (Death related to AE): Death related to adverse event. 
 
System Organ 
Class 
Preferred Term 
Severity 
(CTCAE 
v5.0) 
Related to Vitamin 
D 
Related to 
Methimazole 
Actions 
Gastrointestinal 
Nausea 
Grade 1-
2 
Possibly/Probably 
Possibly/Probably 
Evaluate clinically and consider repeating 
thyroid function, calcium and vitamin D 
levels sooner. Adjust vitamin D dose 
accordingly. If calcium and vitamin D are 
normal and nausea persists, consider 
methimazole adjustment based on thyroid 
function levels. 
Gastrointestinal 
Vomiting 
Grade 1-
2 
Possibly/Probably 
Possibly/Probably 
Similar to nausea 
Gastrointestinal 
Constipation 
Grade 1-
2 
Possibly/Probably 
Unlikely 
If persistent or severe (Grade 2), manage 
per standard clinical practice, which may 
include stool softeners or laxatives. 
Consider dose reduction of vitamin D if 
suspected. 

 
 
 
2 
 
System Organ 
Class 
Preferred Term 
Severity 
(CTCAE 
v5.0) 
Related to Vitamin 
D 
Related to 
Methimazole 
Actions 
Gastrointestinal 
Abdominal Pain 
Grade 1-
2 
Possibly 
Unlikely 
Evaluate for other causes. If severe or 
persistent, manage per clinical practice. 
Consider dose reduction or discontinuation 
of either medication if thought to be 
contributing based on clinical judgment. 
Metabolism 
Hypercalcemia 
Grade 2-
4 
Probably/Definitely 
Not Related 
If Grade 2, reduce vitamin D dose to 1000 IU 
daily and monitor calcium levels closely 
(e.g., weekly). If Grade 3 or persistent Grade 
2, discontinue vitamin D and initiate 
appropriate medical management per 
standard of care. Grade 4 is an SAE 
requiring immediate medical intervention. 
Metabolism 
Hypercalciuria 
Grade 1-
2 
Possibly/Probably 
Not Related 
Encourage increased fluid intake. Monitor 
calcium levels closely. If severe or 
persistent, consider vitamin D dose 
reduction or discontinuation. 
Renal and 
Urinary 
Kidney Stones 
(Nephrolithiasis) 
Grade 2-
4 
Possibly (long-
term) 
Not Related 
This is a potential long-term consequence of 
hypercalciuria. Manage as clinically 
indicated. 
Skin 
Rash 
Grade 1-
2 
Possibly/Probably 
Possibly/Probably 
If mild, monitor. If moderate (Grade 2), or if 
concerning to the participant, consider 
antihistamines. If severe or persistent, 
consider discontinuation of vitamin D or 
methimazole and evaluate for other causes. 

 
 
 
3 
 
System Organ 
Class 
Preferred Term 
Severity 
(CTCAE 
v5.0) 
Related to Vitamin 
D 
Related to 
Methimazole 
Actions 
Skin 
Pruritus (Itching) 
Grade 1-
2 
Possibly 
Possibly/Probably 
Similar management to rash 
Hepatobiliary 
Elevated Liver 
Enzymes (ALT/AST) 
Grade 1-
3 
No 
Possibly/Probably 
Monitor liver function tests (LFTs). If the 
AST/ALT are >5 times the upper limit of 
normal, consult with hepatology.  
Hematologic 
Leukopenia 
(Decreased White 
Blood Cell Count) 
Grade 1-
4 
No 
Possibly (rare) 
Monitor CBC. If Grade 3-4 (severe or life-
threatening), or if concerning trends are 
observed, consult with hematology and 
consider discontinuation of methimazole. 
Grades 3 or 4 are SAEs. 
Hematologic 
Agranulocytosis 
Grade 4 
No 
Possibly (rare but 
serious) 
This is an SAE requiring immediate 
discontinuation of methimazole and 
medical intervention. 
Musculoskeletal 
Joint Pains 
Grade 1-
2 
Unlikely 
Possibly/Probably 
Manage per clinical practice (e.g., 
analgesics). Evaluate for other causes. 
Musculoskeletal 
Bone pain 
Grade 1-
2 
Possibly/Probably 
Unlikely 
If Grade 2 and possibly vitamin D-related, 
temporarily hold supplement and re-
evaluate after resolution or reduce to 1000 
IU daily.  
General 
Headache 
Grade 1-
2 
Unlikely 
Possibly 
Manage per clinical practice (e.g., 
analgesics). Evaluate for other causes. 

 
 
 
4 
 
System Organ 
Class 
Preferred Term 
Severity 
(CTCAE 
v5.0) 
Related to Vitamin 
D 
Related to 
Methimazole 
Actions 
General 
Fatigue/Malaise 
Grade 1-
2 
Possibly 
Possibly 
Evaluate clinically and consider repeating
thyroid function, calcium and vitamin D 
levels sooner. Adjust vitamin D dose 
accordingly. If calcium and vitamin D are 
normal and fatigue persists, consider 
methimazole adjustment based on thyroid 
function levels.