A Multi-center, Open Label, Randomised Parallel- Group Study to Compare the Efficacy of Cholestyramine Plus Standard Treatment Versus Prednisolone Plus Standard Treatment Versus Standard Treatment Alone in Treatment of Overt Hyperthyroidism
Phase: PHASE3
Conditions: Hyperthyroidism, Graves Disease
Sponsor: Clinical Research Centre, Malaysia

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Study Title: "A multi-center, open label, randomised, parallel-group study to 
compare the efficacy of cholestyramine plus standard treatment versus 
prednisolone plus standard treatment versus standard treatment alone in the 
treatment of overt hyperthyroidism”  
 
 
Clinical study protocol number/version: 3.0 
Development phase: Phase III 
Study initiation date: May 2017 or upon approval from MREC 
Study completion date: 31st December 2017 
Date of protocol : 5th June 2017 Version 3.0 
Amendment number(s) and date : Ammendment No. 1 (3rd May 2017) 
 
 
 
 
 
       Ammendment No. 2 (5th June 2017) 
 
Author(s):  
Principal Investigator(s): 
1. Dr. Serena Khoo Sert Kim, Physician, Hospital Putrajaya 
2. Dr. Zanariah Hussein, Consultant Endocrinologst, Hospital Putrajaya 
3. Dr. Fung Yin Khet, Consultant Endocrinologist, Hospital Queen 
Elizabeth II, Kota Kinabalu, Sabah 
4. Dr. Vijiya Mala Valayatham, Consultant Endocrinologist, Hospital 
Ampang 
 
Sub Investigator (s): 
1. Dr. Gayathri Devi Krishnan, Physician, Hospital Queen Elizabeth II, 
Kota Kinabalu, Sabah 
2. Dr. Chan Pei Lin, Physician, Hospital Queen Elizabeth II 
3. Dr. Lisa Mohamed Nor, Medical Officer, Hospital Putrajaya 
4. Dr. Rashidah Binti Bahari, Medical Officer, Hospital Putrajaya 
5. Dr. Siti Aribah Binti Alias, Medical Officer, Hospital Putrajaya 
6. Nurul Zaidah Badarudin, Pharmacist, Hospital Putrajaya 
 
 

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Author’s and Reviewer’s signature and date: 
Protocol Author 
Reviewed and approved by 
Signature:  
                       
Signature: 
Date: 7th March 2017 
Date: 
 
This protocol incorporates the following amendment(s): 
 
Amendment No. 
Date of Amendment 
Initials of CRC 
coordinator 
     1 
3rd May 2017 
2 
5th June 2017 
 
Confidentiality Statement 
May not be used, divulged, published or otherwise disclosed without the 
written consent of the primary investigator. 

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1 
SYNOPSIS 
 
Title of study: "A multi-center, open label, randomised, parallel-group study to 
compare the efficacy of cholestyramine plus standard treatment versus prednisolone 
plus standard treatment versus standard treatment alone in the treatment of overt 
hyperthyroidism”  
 
Sponsor: Ministry of Health, Malaysia 
 
Clinical Phase: III 
 
Investigators: 
Primary investigators:   
1. Dr. Serena Khoo Sert Kim, Physician, Hospital Putrajaya 
2. Dr. Zanariah Hussein, Consultant Endocrinologist, Hospital Putrajaya 
3. Dr. Fung Yin Khet, Consultant Endocrinologist, Hospital Queen Elizabeth II, 
Kota Kinabalu, Sabah 
4. Dr. Vijiya Mala Valayatham, Consultant Endocrinologist, Hospital Ampang 
 
Sub Investigators:  
 
1. Dr. Gayathri Devi Krishnan, Physician, Hospital Queen Elizabeth II, Kota 
Kinabalu, Sabah 
2. Dr. Chan Pei Lin, Physician, Hospital Queen Elizabeth II, Kota Kinabalu 
3. Nurul Zaidah Badarudin, Pharmacist, Hospital Putrajaya 
4. Dr. Lisa Mohamed Nor, Medical Officer, Hospital Putrajaya  
5. Dr. Rashidah Binti Bahari, Medical Officer, Hospital Putrajaya 
6. Dr. Siti Aribah Binti Alias, Medical Officer, Hospital Putrajaya 
 
Study period: One year 
Planned date of first subject enrolment: May 2017 or upon obtaining approval from 
MREC 

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Planned date of last subject completed: 31st December 2017 
 
Objectives: 
 
Primary objective:  
1. To assess the efficacy between Cholestyramine plus Standard treatment 
(Carbimazole plus Propanolol), Prednisolone plus Standard treatment and 
Standard treatment alone in subjects with overt hyperthyroidism  
 
Secondary objective:  
1. To assess the safety profile of Cholestyramine plus standard treatment, 
Prednisolone plus standard treatment and standard treatment alone. 
 
Methodology: 
This is a randomised, open label, controlled, parallel group with allocation ratio 1:1:1 
design 
 
Number of patients: 
It is planned to randomise an estimated total of 135 adult patients with overt 
hyperthyroidism into this study, with 45 patients randomised into each treatment 
group. 
 
Number of centres: 3  
 
Inclusion criteria: 
1. Subject is > 18 years of age at initial screening visit  
2. Subject has signed and dated Informed Consent form 
3. Subject with moderate to severe overt hyperthyroidism (defined as FT4 > 1.5 times 
upper limit of normal) caused by Graves’ disease 
4. Women of childbearing potential can be included if surgically sterile or using double 
contraception with at least one method being barrier contraception  
 
 
 

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Exclusion criteria: 
1. Inability or unwillingness to provide written consent 
2. Inability or unwillingness to comply with the requirements of the protocol as 
determined by the investigator 
3. Pregnancy, breastfeeding or use of non-reliable method of contraception 
4. Subjects with history of chronic liver disease, chronic renal failure, heart failure, 
diabetes mellitus 
5. Previous history of hypersensitivity to cholestyramine 
6. Subjects with complete biliary obstruction, intestinal obstruction 
7. Previous history of hypersensitivity to prednisolone or other steroid compound 
8. Subjects with underlying infection (systemic fungal, tuberculosis, bacterial, malaria, 
viral hepatitis, ocular herpes simplex, HIV) 
9. Subjects with psychiatric disorder 
10. Subjects with gastrointestinal diseases (diverticulitis, fresh intestinal anastomoses, 
active or latent peptic ulcer, ulcerative colitis, abscess or other pyogenic infection) 
11. Subjects with ocular disease (cataract, glaucoma) 
12. Subjects with osteoporosis or osteoporotic fracture 
13. Participation in another clinical trial/ receipt of investigational drug within 4 weeks 
prior to screening visit 
14. Current use of cholestyramine or other bile acid resins (colestipol, colesevelam) 
15. Current use of prednisolone or other steroid compound (hydrocortisone, 
dexamethasone) 
16. Subjects with history of bronchial asthma, bronchospasm, peripheral vascular 
disease or adverse reactions to propanolol 
17. Subjects with adverse reactions to carbimazole such as agranulocytosis, severe 
skin rash 
18. Hypokalemia (Serum K+< 3.5mmol/L) 
19. Thyroid storm defined as Burch Wartofsky score of >45 
 
 
 
 
 

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Test treatment, dose and mode of administration: 
 
There are 3 treatment groups: 
Group 1: Cholestyramine plus standard treatment 
Group 2: Prednisolone plus standard treatment 
Group 3: Standard Treatment only 
 
Standard treatment consists of Tablet Carbimazole 30 mg daily and Tablet 
Propanolol 40 mg twice daily. The duration of treatment for each group will be 4 
weeks. 
 
Group 1: Cholestyramine plus standard treatment 
Cholestyramine powder 4g twice daily, Tablet Carbimazole 30 mg 
daily, Tablet Propanolol 40 mg twice daily. 
Group 2: Prednisolone plus standard treatment 
 
Tablet Prednisolone 30 mg daily for week 1, 20 mg daily for week 2, 10 
mg daily for week 3 and 5 mg daily for week 4, Tablet Carbimazole 30 
mg daily, Tablet Propanolol 40 mg twice daily 
Group 3: Standard Treatment only 
 
Tablet Carbimazole 30 mg daily, Tablet Propanolol 40 mg twice daily 
 
 
Duration of treatment with study medication: 
4 weeks 
 
Criteria for evaluation: 
1. Efficacy endpoint(s) 
 Primary endpoint 
1. Proportion of subjects with normal thyroid hormone levels (Defined 

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as serum free T4 or serum free T3 levels) measured at 2 and 4 weeks 
after initiation of study treatment. 
 
 
2. Safety endpoints  
• Number of subjects with adverse effects during the intervention and 
follow up period (total duration 6 weeks) 
 
• 
Number of subjects with serious adverse events during intervention 
and follow up period (total duration 6 weeks) 
 
 
 
 
Statistical methods: 
1. For primary objectives, all comparisons of means between treatment will be 
analysed using one-way ANOVA and all pairwise comparisons of proportions 
between treatments will be analysed using two-sided Z test. Analyses will be 
based on intention-to-treat and per protocol analysis. 
 
2. For secondary objectives, all comparisons of means between treatment will be 
analysed using one-way ANOVA and all comparisons of proportions will be 
analysed using chi-square test of independence. Analyses will be based on 
safety set analysis. 

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2. TABLE OF CONTENTS 
1 SYNOPSIS ............................................................................................................ 3 
2 TABLE OF CONTENTS ....................................................................................... 8 
3 LIST OF ABBREVIATIONS ................................................................................ 12 
4 GLOSSARY OF TERMS .................................................................................... 13 
5 ETHICS & REGULATORY CONSIDERATIONS ................................................ 14 
5.1 INDEPENDENT ETHICS COMMITTEE ............................................................ 14 
5.2 ETHICAL CONDUCT OF THE STUDY ............................................................ 14 
5.3 INFORMED CONSENT AND SUBJECT INFORMATION ............................... 14 
5.4 PATIENT PROTECTION PROCEDURES ........................................................ 16 
5.4.1 PROCEDURES IN THE EVENT OF EMERGENCY ...................................... 16 
5.4.2 PROCEDURES IN THE EVENT OF PREGNANCY ....................................... 16 
5.4.3 PATIENT DATA PROTECTION ..................................................................... 16 
5.4.4 INSURANCE .................................................................................................. 17 
6 INTRODUCTION AND BACKGROUND ............................................................. 18 
6.1 POTENTIAL RISK………………………………………………………………………………22 
6.2 POTENTIAL BENEFITS………………………………………………………………………..23 
7 OBJECTIVES ..................................................................................................... 24 
7.1 PRIMARY OBJECTIVE .................................................................................... 24 
7.2 SECONDARY OBJECTIVE(S): ....................................................................... 24 
8 STUDY DESIGN ................................................................................................. 25 
8.1 OVERALL STUDY DESIGN ............................................................................. 25 
8.2 SCHEMATIC DIAGRAM OF STUDY DESIGN ................................................ 26 

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8.3 DISCUSSION OF STUDY DESIGN ................................................................. 27 
8.4 STUDY POPULATION ..................................................................................... 28 
8.4.1 INCLUSION CRITERIA .................................................................................. 29 
8.4.2 EXCLUSION CRITERIA ................................................................................. 29 
8.4.3 SUBJECT WITHDRAWAL & DROP-OUT ...................................................... 30 
8.4.4 PROCEDURES FOR HANDLING WITHDRAWAL ........................................ 31 
8.4.5 SUBJECT REPLACEMENT POLICY ............................................................. 31 
8.4.6 SCREENING FAILURES ............................................................................... 31 
9 
TREATMENT AND STUDY PROCEDURES .................................................... 32 
9.1 
DESCRIPTION OF STUDY DRUG/INTERVENTION ..................................... 32 
9.2 
INVESTIGATIONAL PRODUCT SUPPLY AND HANDLING ......................... 34 
9.2.1 
SUPPLY, PACKAGING AND LABELLING ................................................... 34 
9.2.2 
STORAGE .................................................................................................... 34 
9.2.3 
DISPENSING ............................................................................................... 34 
9.2.4 
ACCOUNTABILITY ...................................................................................... 35 
9.3 
CONCOMITANT MEDICATION/TREATMENT .............................................. 36 
9.4 
TREATMENT ALLOCATION AND RANDOMIZATION ................................. 36 
9.5 
BASELINE ASSESSMENT AND LABORATORY TESTS ............................. 37 
9.6 
ASSESSMENT OF COMPLIANCE ................................................................ 37 
9.7 
DISCONTINUATION AND INTERRUPTION OF TREATMENT ................... 38 
9.8 
ASSESSMENT OF EFFICACY ..................................................................... 38 
9.9 
ASSESSMENT OF SAFETY......................................................................... 38 
10 ADVERSE EVENTS .......................................................................................... 39 
10.1 DEFINITIONS ................................................................................................... 39 
10.1.1 ADVERSE EVENT………………………………………………………………...39 
10.1.2 UNEXPECTED ADVERSE EVENT……………………………………………...40 
10.1.3 SERIOUS ADVERSE EVENT……………………………………………………40 
10.2  DETECTING AND DOCUMENTING AE………………………………………   41 
10.3  REPORTING SAE………………………………………………………………… 43 
10.4 TREATMENT AND FOLLOW UP OF AE………………………………………..44 
10.5 SAFETY UPDATE…………………………………………………………………..45 

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11 STUDY CONDUCT ........................................................................................... 46 
11.1 STUDY VISITS AND PROCEDURES ............................................................ 46 
11.1.1 SCREENING VISIT ...................................................................................... 46 
11.1.2 BASELINE VISIT .......................................................................................... 47 
11.1.3 RANDOMISATION ....................................................................................... 48 
11.1.4 STUDY TREATMENT AND VISITS .............................................................. 48 
11.1.5 STUDY ACTIVITIES TABLE ……………………………………………………...50 
11.2 CRITERIA FOR STOPPING SUBJECT TREATMENT .................................. 51 
11.3 SAMPLE HANDLING AND ANALYSIS ......................................................... 51 
11.3.1 COLLECTION ............................................................................................... 51 
11.3.2 LABELLING .................................................................................................. 52 
11.4 LABORATORY ANALYSIS ............................................................................ 53 
12 DATA MANAGEMENT ..................................................................................... 55 
13 STATISTICAL METHODS ............................................................................. 55 
13.1 SAMPLE SIZE AND POWER CONSIDERATIONS ....................................... 55 
13.2 ANALYSIS ...................................................................................................... 56 
13.2.1 BASELINE COMPARABILITY ...................................................................... 56 
13.2.2 EFFICACY ANALYSIS ................................................................................. 56 
14 ADMINISTRATIVE MATTERS .......................................................................... 58 
14.1 NOTIFICATION OF REGULATORY AUTHORITY(IES)................................. 58 
14.2 NOTIFICATION OF PRIMARY CARE PHYSICIAN ....................................... 58 
14.3 STUDY INITIATION ........................................................................................ 58 
14.4 PROTOCOL DEVIATION ............................................................................... 58 
14.5 STUDY DOCUMENTATION ........................................................................... 58 
14.5.1 ESSENTIAL DOCUMENTS .......................................................................... 59 
14.5.2 SOURCE DOCUMENTS .............................................................................. 59 
14.6 PATIENT IDENTIFICATION LIST/ENROLLMENT LOG ................................ 60 
14.7 CURRICULUM VITAE .................................................................................... 60 
14.8 RETENTION OF DOCUMENTS ..................................................................... 60 

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14.9 FINANCE ........................................................................................................ 61 
14.10 STUDY TERMINATION AND SITE CLOSURE .............................................. 61 
14.11 CONFIDENTIALLY ......................................................................................... 61 
14.12 PUBLICATION POLICY ................................................................................. 61 
14.13 ANTICIPATED SUBJECT ACCRUAL AND DURATION OF THE STUDY .... 61 
15 REFERENCES .................................................................................................. 62 
16 APPENDICES ................................................................................................... 64 

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3 
LIST OF ABBREVIATIONS 
0C 
Degree Centigrade 
AE 
Adverse event 
ATD 
Anti thyroid drug 
BD 
Twice daily dose 
BP 
Blood pressure 
CRF 
Case report form 
CV 
Curriculum vitae 
FPG 
Fasting plasma glucose 
FT4 
Free T4 
FT3 
Free T3 
GCP 
Good clinical practice 
HR 
Heart rate 
ID 
Identification 
mmHg 
Millimetre mercury 
MREC 
Medical Research and Ethics Committee 
OD 
Daily dose 
RPG 
Random plasma glucose 
RAI 
Radioactive iodine 
SAE 
Serious adverse event 
TDS 
Three times a day dose 
TSH 
Thyroid stimulating hormone 
TRAb 
Thyroid stimulating receptor antibody 
LFT 
Liver function test 
RFT 
Renal function test 
 
 
 
 

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4 
GLOSSARY OF TERMS 
 
Eligible 
Qualified for enrolment into the study based on strict 
adherence to inclusion and exclusion criteria 
Investigator 
Treating physician 
Subject(s) 
Individuals enrolled in the clinical study 
Diabetes 
Fasting plasma glucose more ≥7 mmol/L or Random plasma 
glucose ≥ 11.1 mmol/L 
Hypokalemia 
Serum potassium (K+) <3.5mmol/L 
New onset sepsis Defined as new onset life-threatening organ dysfunction 
caused by a dysregulated host response to infection. 
Hypothyroid 
Symptoms of hypothyroidism coupled with biochemical Free 
T4 normal or below lower limit of reference range and TSH 
above upper limit of reference range 
Drug 
hypersensitivity 
Reaction 
An immune mediated reaction to a drug and manifests as 
mild to severe skin rash, anaphylaxis or serum sickness 
Hospitalisation 
An event that results in an admission to the hospital for 
any length of time or prolongs the subject’s hospital stay. 
This does not include an emergency room visit or 
admission to an outpatient facility 
All-cause 
mortality 
An event that results in death of a subject 
Constipation 
Fewer than 3 bowel movements a week 
Diarrhea 
Abrupt onset of 3 or more loose stools per day 
 
 
 
 
 
 
 
 
 

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5 
ETHICS & REGULATORY CONSIDERATIONS 
5.1    Independent Ethics Committee   
The study protocol and any other documents including the Patient 
Information Sheet, Consent Form, subject requirement procedures and 
advertisements to be used, and information on payments and compensation 
available to subjects, will be submitted to MREC. The study will be started 
only after receiving MREC approval. MREC approval will be requested if 
there is any amendment to the protocol, other than administrative ones.  
 
The following will be informed to the MREC: 
 Any amendment to the protocol, informed consent changes or 
revisions of other documents originally submitted for review. 
 Any serious and/or unexpected events occurring during the study, 
where required. 
 Any new information that may adversely affect the safety of the 
subjects or the conduct of the study. 
 An annual update on the progress of the study and/or request for re- 
approval, where required. 
 Final study report when the study has been completed, where required. 
 
All correspondence with the MREC will be filed in the Investigator's Study 
File. 
 
5.2 
Ethical conduct of the study 
The study will be conducted in compliance with the protocol. These are 
designed to ensure adherence to the ethical principles that have their origin 
in the "World Medical Association Declaration of Helsinki" (see Appendix), 
"Malaysian Guidelines for Good Clinical Practice" and applicable regulatory 
Requirements. 
 
5.3 
Informed consent and subject information 
The written, informed consent will be obtained from every subject prior to 
participation in this study by the research investigator. This is following the 

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subject’s complete understanding of the study. The investigator will inform 
every subject in detail about the nature of the study, its purpose, the 
treatments and the probability of random assignment to treatment groups, 
those aspects of the study that are experimental, the procedures involved 
including all invasive procedures and the discomfort they may entail, the 
possible risks including to an embryo, foetus or nursing infant where 
applicable, the reasonably expected benefits the expected duration and the 
approximate number of subjects involved and the subject's responsibilities. 
 
Study subjects will also be informed that: 
 Participation in this study is voluntary and that he/she may withdraw 
from this study at any time for any reason and that withdrawal of 
consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
 Alternative procedures or treatments that may be available and the 
important potential benefits and risks of these available alternative 
procedures or treatments. 
 Any compensation for additional costs and/or injury caused to a 
subject attributable to participation in the study. 
 Any foreseeable circumstances and/or reasons under which the 
subject's participation in the study may be terminated. 
 Subject will be provided the Investigator’s contact details for further 
information regarding the study and who to contact in the event of 
study related injury. 
 
Written consent will be obtained from each subject involved in the study. If written 
consent is not possible, oral consent can be obtained if witnessed by a signed 
statement from one or more persons not involved in the study, stating why the 
patient was unable to sign the consent form. The informed consent form used to 
document written or oral consent in the study must be received prior to approval 
from the MREC. If the subject and his/her parent/guardian are unable to read, the 
investigator or designee will explain to the subject the content of the Patient 
Information Sheet and Consent Form point by point in the presence of an impartial 
witness. The witness will personally sign and date the consent form. The potential 

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study subject and/or his/her parent/guardian should be given the opportunity to ask 
questions and time for consideration. 
 
A copy of the Patient Information Sheet and signed Consent Form should be given 
to the subject. The original document must be filed by the principal investigator in 
the Investigator's Study File. A sample of the Patient Information Sheet and 
Consent Form can be found in the Appendix of this protocol 
 
Study subjects may have the right to access, and make a copy of their medical 
and/or clinical study records as allowed by applicable privacy laws. Subjects may 
ask to see their records by requesting such records from the study doctor or the 
facilities where the study is being conducted. However, to ensure the valid results of 
the study, subjects may not be able to review or make a copy of some of the 
records related to the study until after the study has been completed. 
 
5.4 
Patient protection procedures 
5.4.1  
Procedures in the event of Emergency 
All appropriate measures will be taken to ensure the safety of the patients, 
including referral to a specialist if needed. There will be follow up of the outcome 
of any adverse events (clinical signs, laboratory values or other, etc.) until the 
return to normal or stabilization of the patient’s condition. In the case of any 
serious adverse event, the patient will be followed up until clinical recovery is 
complete and laboratory results have returned to normal, or until progression In 
the event of emergency, subjects will be instructed to proceed to the nearest 
emergency department and notify the investigator immediately. An emergency 
may constitute an SAE. 
 
5.4.2 
Procedures in the event of Pregnancy 
The subject will be instructed to inform the investigator if she becomes pregnant 
during the study and seek advice regarding continuation of the study treatment. 
The investigator will follow up the pregnancy until the outcome is known. 
 
5.4.3 
Patient data protection 

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The investigator will assure that the subjects' anonymity will be 
maintained and that the confidentiality of records and documents that 
could identify subjects will be protected, respecting the privacy and 
confidentiality 
rules 
in 
accordance 
with 
applicable 
regulatory 
requirements. 
 Subjects will be identified only by their assigned identification 
number and initial on all CRFs and other records and documents 
submitted  
 The investigator will keep a Patient Identification List with complete 
identification information (name, address, contact number, IC#) on 
each subject. 
 Documents that are not for submission such as subject's written 
informed consent form, should be maintained by the investigator in 
strict confidence. 
 
Representatives of MREC or other regulatory agencies will be granted 
direct access to subject medical records and other study documents for 
verification of study procedures and data without violating the 
confidentiality of the subject. The subject should be informed that by 
signing a written informed consent form, the subject or his/parent or 
guardian is authorizing such access. 
All electronic data processed will be identified by patient numbers only, 
thereby ensuring that patients' identity remains unknown.  
 
5.4.4 Insurance 
With respect to any liability directly or indirectly caused by the 
investigational products in connection with this study, the sponsor 
assumes liability by law on behalf of the investigator and his/her staff for 
possible injury to the subject, provided the investigator and his/her staff 
have followed the instructions of the sponsor in accordance with this 
protocol and any amendments thereto, that the investigational products 
administered to the subject in this study have been supplied by the 
sponsor and that the investigator and his/her staff have in general 
performed this study in accordance with scientific practice and currently 
acceptable techniques and know how. 

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6 
INTRODUCTION AND BACKGROUND 
 
Hyperthyroidism is the second most common endocrine disorder in the world 
with an estimate prevalence rate of 0.5-1.3%2,3. Its incidence is 0.4 per 1000 
women and 0.1 per 1000 men. Graves’ disease is the commonest cause of 
hyperthyroidism followed by toxic multinodular goiter, toxic adenoma and 
thyroiditis.  
 
Hyperthyroidism is diagnosed clinically and biochemically with typical signs and 
symptoms of hyperactivity, irritability, heat intolerance, sweating, palpitations, 
fatigue, weakness and weight loss with normal or increased appetite. The 2016 
American Thyroid Association (ATA) Guidelines for Diagnosis and Management 
of Hyperthyroidism and other causes of Thyrotoxicosis have defined overt 
hyperthyroidism as elevated serum free T4 (FT4) and/or total T3 (TT3) and low 
serum TSH (usually <0.01mU/L). The ATA taskforce has recommended a rough 
guide to methimazole dosing based on the biochemical severity of 
hyperthyroidism, classified as mild (FT4 levels 1-1.5 times upper limit of normal), 
moderate (FT4 1.5-2 times the upper limit of normal and severe (FT4 
approximately 2 to 3 times upper limit of normal) 4.  
 
Elevated thyroid hormones have profound effects on almost every tissue and 
organ system. Uncontrolled hyperthyroidism results in increase cardiovascular 
morbidity and mortality primarily due to heart failure and thromboembolism. 
About 6% of thyrotoxic patients develop symptoms of heart failure secondary to 
tachycardia-mediated mechanism and isolated right sided heart failure as a 
result of pulmonary artery hypertension. Therefore treatment is essential to 
restore a euthyroid state that will lead to resolution of signs and symptoms of 
heart failure. Early recognition and prompt treatment can reverse the 
cardiovascular manifestations thus reducing the risk of developing permanent 
dilated cardiomyopathy with impaired left ventricular function5. Atrial fibrillation 
occurs in 10-20% of patients with hyperthyroidism, more commonly in older 
patients. In several studies 10 to 40% of patients with hyperthyroidism and atrial 
fibrillation had an arterial embolus resulting in a higher risk of thromboembolic 
stroke6. Studies have also shown that 60% of hyperthyroid patients with atrial 
fibrillation will revert to sinus rhythm spontaneously when hyperthyroidism is 

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treated to a euthyroid state7.  
 
Three treatment modalities are currently available for the management of 
hyperthyroidism: antithyroid drugs (ATDs), surgery, and radioactive iodine (RAI) 
therapy. Treatment for hyperthyroidism is aimed at restoring euthyroidism with 
ATDs while awaiting disease remission and resolution of autoimmunity or 
inducing permanent hypothyroidism with subsequent thyroxine replacement by 
total thyroidectomy or RAI therapy. Beta-blockers (for example propanolol and 
atenolol) are added to block beta-adrenergic tone for symptomatic relief of 
palpitations, tachycardia, tremulousness, anxiety, heat intolerance, fatigability 
and shortness of breath. There is currently no consensus on the “best” treatment 
option with various practices in different centers and countries. The choice of 
treatment depends on the cause of hyperthyroidism, patient’s age and 
preference, severity of disease, glandular size, activity and severity of Graves’ 
opthalmopathy, local practices and resources.  
ATDs including methimazole, carbimazole, and propylthiouracil are effective 
treatments that inhibit thyroid hormone synthesis, and have clinically important 
immunosuppresive effects including reducing serum antithyrotropin receptor 
antibody concentration with time. Antithyroid drugs are an effective treatment 
option but these drugs take in most cases between 6 to 8 weeks to achieve 
euthyroidism. It has also shown to have the highest relapse rate at 52.7% 
compared to RAI (15%) and surgery (10%) in a recent meta analysis8. In 
addition 13% of patients on ATDs experienced adverse events with rash most 
common with methimazole and hepatic involvement with propylthiouracil8.  
Therefore there may be a role for adjunctive treatment added on to ATDs. It may 
be situations where adjunctive treatment is required to alleviate symptoms and 
restore euthyroidism rapidly. It may be useful for preoperative preparation or pre 
radioactive iodine treatment where rapid control is necessary to achieve 
euthyroidism to prevent the risk of thyrotoxic crisis. It may be helpful to alleviate 
symptoms of patients with severe hyperthyroidism and especially those who are 
more vulnerable such as the elderly or patients with heart failure from thyrotoxic 
cardiomyopathy, and atrial fibrillation. It has been proven useful in thyroid 
storms. It is also effective in situations where ATDs have failed to control 

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disease because of ATD resistance, intolerance or poor compliance. There are 
several adjunctive agents studied previously in literature, namely iodine and 
iodide 
containing 
compounds, 
lithium, 
potassium 
perchlorate, 
and 
cholestyramine. We are interested to study the effects of cholestyramine and 
prednisolone as adjunctive treatment to ATDs in patients with overt 
hyperthyroidism. 
Thyroid hormone is metabolized in the liver where it is conjugated to 
glucuronides and sulfates and excreted in the bile. Usually only 20% of 
circulating T4 is excreted in the bile and released into the intestine and 
reabsorbed completing the enterohepatic circulation. However in the thyrotoxic 
states there is an increased enterohepatic circulation of thyroid hormones with 
an increased urinary and fecal excretion of both conjugated and FT4
9. 
Cholestyramine is an anion exchange resin that binds T4 in the intestine 
resulting in fecal excretion of T4 thus reducing the enterohepatic circulation and 
absorption in hyperthyroidism. Cholestyramine has been used in cases of 
thyroid storm10. Cholestyramine has been studied as an adjunctive therapy to 
thionamides and found to be effective in reducing thyroid hormones rapidly. 
Solomon et al first studied the effects of cholestyramine powder (4g QID) on 15 
thyrotoxic patients and shown a more rapid decline in all thyroid hormone levels 
in the cholestyramine group in the first 2 weeks (P<0.01)11. Mercado et al 
similarly reported rapid decline in total and free T4 and T3 when cholestyramine 
4g tds was added to methimazole and propanolol12. Kaykhaei et al. 
demonstrated a similar efficacy with a lower dose of cholestyramine (2g BD vs 
1g BD) with all patients in the cholestyramine group achieving euthyroidism in 4 
weeks9. The main adverse effects are flatulence and constipation in 10% of 
cases and vomiting, diarrhea, indigestion, abdominal pain, abnormal stools, 
bloating, headache, and raised triglyceride levels in 1-10%, whereas muscle 
pain, raised liver enzymes and difficulty in swallowing are rare13. Patients in the 
trials above tolerated the drug well with only 2 reported hyperdefecation and 
complained of bad taste11.  
Steroids have been shown to be effective in controlling hyperthyroidism. It 
demonstrates immediate effects by inhibiting the conversion of thyroxine to 
triiodothyronine peripherally and also blocks the release of thyroxine from the 
thyroid gland. It may also have the potential to suppress the immune response 

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and hence decrease stimulation of the thyroid gland in Graves’ disease14. Few 
case reports have documented its efficacy in situation where rapid control of 
hyperthyroidism is required. Ozawa in his case series documented that following 
oral administration of 30 mg daily dose of prednisolone with or without ATDs, 
both serum T4 and T3 concentrations decreased rapidly and reached 
euthyroidism within 2 weeks and subtotal thyroidectomies were performed 
uneventfully in all 4 cases17. Another study reported the addition of 
betamethasone 0.5mg 6 hourly, iopanoic acid 500 mg 6 hourly and propanolol 
40 mg 8 hourly to 14 patients with hyperthyroidism submitted to subtotal 
thyroidectomy because ATDs have failed to control thyrotoxicosis and found that 
patients had normal T3 levels by day 5 and T4 reduction noted but has not 
reached normal levels by 5 days of treatment15. One study reported rapid 
normalization of thyroid function with prednisolone 20 mg daily as an adjunct 
when patients develop resistance to maximum treatment of carbimazole14.  
There were no reported serious side effects in the case series mentioned above. 
Evidence in literature shows that adjunctive therapy such as cholestyramine and 
prednisolone may have a role to play in the management of hyperthyroidism. So 
far, studies on cholestyramine have proven its efficacy but they are small in size 
and have not been recommended in clinical guidelines. There are no clinical 
trials conducted in the asian population. A Cochrane systematic and current 
review is currently ongoing by Salazar et al. to asesss the efficacy of bile acid 
sequestrants as a standard adjunctive treatment therapy in hyperthyroidism and 
whether to recommend it in clinical practice guidelines18. This study would add 
weight to the ongoing systematic review.  On the other hand, no clinical trials 
have been conducted to assess prednisolone as an adjunctive therapy to date 
and the safety profile unknown. We aim to compare the efficacy and safety 
profile of cholestyramine or prednisolone as adjunctive therapy to no adjunct. 
We also aim to compare the efficacy of cholestyramine and prednisolone as 
adjunctive therapy. We hypothesize that with the addition of cholestyramine or 
prednisolone to ATDs, we are able to achieve euthyroidism more effectively and 
rapidly compared to ATDs alone which may be useful in many crucial clinical 
situations described above. 
 

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6.1  Potential Risks 
Cholestyramine is a bile acid sequestrant that works by increasing the 
removal of bile acids from the body. The most common adverse reaction is 
constipation but most instances are mild, transient and controlled with 
conventional therapy. Other less frequent adverse reactions are abdominal 
discomfort, flatulence, nausea, vomiting and bleeding tendencies due to 
hypoprothrombinemia if use long term. Detailed information can be found on 
the drug leaflet attached at the appendix. Solomon et al. reported all patients 
tolerated cholestyramine without inordinate difficulty with 2 patients 
experienced hyperdefecation for a couple of days and all patients complained 
of the taste of the powders11.  
 
Prednisolone is a corticosteroid and work by modifying the body’s immune 
response 
to 
various 
conditions 
and 
decreasing 
inflammation. 
In 
hyperthyroidism it reduces the conversion of T4 to T3. The common adverse 
reactions include fluid retention, alteration in glucose tolerance, elevation in 
blood pressure, behavioural and mood changes, increased appetite and 
weight gain. There is a risk of hypothalamic-pituitary-adrenal axis suppresion 
and Cushing’s syndrome if given long term. It may increase the risks related 
to infection but rate of occurrence increases with the dose of steroids. There 
may be an increase risk of peptic ulcer disease. If used long term may 
decrease bone density. In a meta analysis, the use of prednisone 35 mg daily 
for a mean 64 days increased the risk for diabetes (OR 1.7 (1.1-2.6) P= 
0.02), hypertension (OR 2.2 (1.4-3.8) P =0.01), dermatologic effects (OR 4.5 
(3.5-5.7) P= 0.001) but was not statistically significant association for peptic 
ulcer, bacterial sepsis, osteoporosis, psychosis and tuberculosis19. Steroids 
may cause muscle weakness from renal potassium loss and myopathy if 
taken long term but there are case reports of thyrotoxic periodic paralysis 
soon after glucocorticoid administration22. The detailed information regarding 
risks and adverse reactions to prednisolone can be found in the drug leaflet 
attached in the appendix. 
 
The immediate risks foreseeable in this study would be the risk of iatrogenic 
hypothyroidism. However this risk is closely monitored and the event of 

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iatrogenic hypothyroidism action will be taken. The long-range risks would be 
the possibility of suppresion of the adrenal axis from the prolonged steroid 
use. However, this risk would be minimised as the prednisolone dose would 
be tapered over time. 
 
6.2  Potential Benefits 
Cholestyramine is a bile acid sequestrant that decreases the enterohepatic 
circulation of thyroid hormones in subjects with overt hyperthyroidism. 
Solomon, Kaykhaei, Mercado and Tsai et al. have all demonstrated that 
Cholestyramine is effective in reducing thyroid hormones with minimal side 
effects when added to standard therapy for up to 4 weeks of treatment. 
Although the common side effect is constipation, it may prove useful in 
hyperthyroid patients with hyperdefecation. 
Prednisolone reduces the conversion of T4 to T3 in the circulation. 
Prednisolone 30 mg daily used short term effectively normalised thyroid 
hormone levels in 2 weeks in a series of 4 cases prior to subtotal 
thyroidectomy. No adverse reactions reported in this case series. In a similar 
study using betamethasone 0.5 mg 6 hourly coupled with iopanoic acid (500 
mg 6 hourly) and propanolol for 5 days as preparation for hyperthyroid patients 
for surgery, drug tolerance was excellent with no serious side effects noted 
even in pregnant patients and no anesthetic incidents or post operative 
complications. 
This study conducted with Cholestyramine or Prednisolone as adjunctive 
therapy is short term (4 weeks) and therefore minimise long term side effects 
of both drugs and minimise the risk of iatrogenic hypothyroidism. It has the 
potential to rapidly reduce thyroid hormones in a short span of time thus 
achieving euthyroidism promptly, improving thyrotoxic symptoms especially 
those with severe hyperthyroidism, the elderly and those complicated with fast 
atrial fibrillation and thyrotoxic cardiomyopathy. It may be useful in 
preoperative or pre radioactive iodine treatment where there is a need to 
achieve euthyroidism to prevent risks of thyrotoxic crisis. Prednisolone is 
readily available in most hospitals in Malaysia and fairly cheap.  
This study will provide definitive efficacy and safety information of both 

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Cholestyramine and Prednisolone as adjunctive treatment in patients with 
overt hyperthyroidism. The overall benefits of this study outweigh the potential 
risks. 
 
7 
OBJECTIVES 
7.1 
Primary objectives: 
1. To assess the efficacy between Cholestyramine plus standard 
treatment (Carbimazole plus Propanolol), Prednisolone plus standard 
treatment and standard treatment alone in subjects with overt 
hyperthyroidism  
 
7.2 
Secondary objective(s): 
1. To assess the safety profile of Cholestyramine plus standard 
treatment, Prednisolone plus standard treatment and standard 
treatment alone. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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8 STUDY DESIGN 
8.1 
Overall study design 
This a multi-center, open-label, randomised, parallel-group study to 
compare the efficacy of cholestyramine plus standard treatment versus 
prednisolone plus standard treatment versus standard treatment alone in 
the treatment of overt hyperthyroidism. The allocation ratio is 1:1:1.  
 
                      Group 1: Cholestyramine plus standard treatment 
Cholestyramine powder 4g BD, Tablet Carbimazole 30 mg OD, Tablet 
Propanolol 40 mg BD for 4 weeks 
Group 2: Prednisolone plus standard treatment 
Tablet Prednisolone 30 mg OD for week 1, 20 mg OD for week 2, 10 mg 
OD for week 3 and 5 mg OD for week 4, Tablet Carbimazole 30 mg OD, 
Tablet Propanolol 40 mg bd for 4 weeks 
                      Group 3: Standard Treatment alone 
Tablet Carbimazole 30 mg OD, Tablet Propanolol 40 mg BD for 4 weeks 
 

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8.2 
Schematic diagram of study design: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Obtain Written inform consent 
Include patients who do meet the 
Inclusion Criteria (Eligible) 
Exclude patient 
who meets the 
exclusion criteria 
Screening  
Randomisation 
Group 1 
Cholestyramine 
+ 
Standard 
Treatment 
Group 2 
Prednisolone 
+ 
Standard 
Treatment 
Group 3 
 
Standard 
Treatment 
 
Follow up visit 
Final Analysis 
Enrollment 
Intervention 
Follow up 
Analysis 
4 weeks 
Lost to follow-up  
(n=x, give reasons) 
Discontinued intervention  
(n=x, give reasons) 
 
1 week 

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8.3 
Discussion of study design 
All hyperthyroid subjects secondary to Graves disease identified at endocrine, 
endocrine surgery, general medical clinics and medical wards in Hospital 
Putrajaya, Hospital Queen Elizabeth II and Hospital Ampang will be screened 
from May 2017/ Upon approval from MREC to 31st December 2017. Potential 
participants will be invited to a screening visit.  
 
 
Screening visit  
 
The screening visit consists of providing information about the study, obtaining 
informed consent and screening assessment. The investigator will further explain 
the study, answer any questions and seek informed consent. All subjects will 
provide written informed consent to their participation in the study. The subject will 
then have a complete history taking, clinical examination and anthropometric 
measures. They will have their blood sampled, approximately 10 ml for screening 
tests. Subjects are eligible for the trial, if they comply with the following inclusion 
and exclusion criteria.  
 
Group 1: Cholestyramine+ Standard Treatment 
Group 2: Prednisolone+ Standard Treatment 
Group 3: Standard Treatment 
Baseline 
Assessment & 
Randomisation 
Screening 
Follow up Study 
Ends 
Trial Treatment 
Visit No.  1                           2                              3                             4                   5     
Timeline  -1                          0                              2                             4                    6               
(week) 

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        Baseline visit and Randomisation 
 
Subjects eligible for the trial will return for baseline assessment and 
randomisation. They will be assigned a unique sequentially numbered study 
identifier according to the order in which he or she is enrolled in the trial. 
 
The subject will then complete the baseline assessment including history taking, 
clinical examination, anthropometric measures, blood sampling (6 ml) and 
imaging (if not done previously). Following baseline assessment, subjects will be 
randomised into either of the 3 treatment groups. A subject will be randomly 
allocated to one of the three treatments per random allocation sequence that will 
be generated by a member of the study team.  
 
Duration 
The total trial duration is expected to be 7 weeks (1 weeks screening period, 4 
weeks intervention period and 2 weeks follow up period). The intervention period 
for each subject will be 4 weeks. The subject will return at week 2 and week 4 of 
intervention for safety and compliance assessment and blood sampling (6 ml 
each visit) for biochemical monitoring. There will be a follow up visit 2 weeks from 
the end of intervention period to monitor for any adverse effects and 
complications and a repeat blood sampling  (6ml) for biochemical monitoring.  
 
 
8.4  
Study population 
All subjects with current overt hyperthyroidism secondary to Graves’ disease who 
are being referred to or being followed up at Hospital Putrajaya, Hospital Queen 
Elizabeth II and Hospital Ampang are considered for participation. Patients are 
eligible for the trial if they comply with the following inclusion and exclusion 
criteria. 
 
 
 
 
 
 

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8.4.1  
Inclusion criteria 
1. 
Provision of written consent by subject or guardian. 
2. 
Subject of either sex, more than 18 years of age  
3. 
Subjects with moderate to severe overt hyperthyroidism (caused 
by Graves’ disease). 
 Moderate to severe overt hyperthyroidism is defined as Free T4> 
1.5 times upper limit of normal reference range and TSH below 
lower limit of reference range, who are either newly diagnosed or 
previously diagnosed and receiving ATDs currently.   
 Graves disease is defined as hyperthyroidism coupled with clinical 
signs of symmetrical diffuse goiter, thyroid orbitopathy, or diffuse 
and vascular thyroid on ultrasound or positive TRAb antibody. 
 
4. 
Female patients will either be 
 post-menopausal for > 2 years 
 Women of childbearing potential can be included if surgically 
sterile or using double contraception with at least one method 
being barrier contraception. Women of childbearing potential 
must have a negative pregnancy test at screening and at 
randomisation. Pregnancy tests will be repeated during each 
visit. 
 
 
 
 
8.4.2  
Exclusion criteria 
1. Inability or unwillingness to provide written consent. 
2. Inability or unwillingness to comply with the requirements of the 
protocol as determined by the investigator. 
3. Pregnancy, breastfeeding or use of non-reliable method of 
contraception. 
4. Subjects with history of chronic liver disease, chronic renal failure, 
heart failure, diabetes mellitus 
5. Subjects with history of peptic ulcer disease, upper gastrointestinal 
bleeding, diverticulitis or ulcerative colitis. 

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6. Subjects who have recently had live or attenuated virus vaccines 
7. Subjects 
with 
current 
infection 
(systemic 
fungal, 
active 
tuberculosis, cerebral malaria, viral hepatitis, HIV) 
8. Subjects with cataracts and glaucoma 
9. Subjects with osteoporosis  
10. Subjects with psychiatric disorders 
11. Subjects with complete biliary obstruction, bleeding disorders, 
hypertriglyceridemia (fasting triglyceride levels > 300mg/dL) 
12. Previous history of adverse reactions to cholestyramine or other 
bile acid sequestrants 
13. Previous history of adverse reactions to prednisolone or other 
steroid compound 
14. Current use of cholestyramine or prednisolone or other steroid 
compound 
15. Participation 
in 
another 
clinical 
trial 
and/or 
receipt 
of 
cholestyramine or prednisolone within 4 weeks prior to screening 
visit. 
16. Subjects with history of bronchial asthma, bronchospasm, 
peripheral vascular disease or adverse reactions to propanolol 
17. Subjects with adverse reactions to carbimazole 
18. Hypokalemia (serum K+ <3.5 mmol/L) 
19. Thyroid storm defined as Burch Wartofsky Score >45 
 
8.4.3  
Subject withdrawal & drop-out 
Subjects are free to withdraw from the study at any time for any reason. 
Subjects may also be withdrawn from the study at any time at the discretion 
of the investigator. The following are anticipated conditions/events that would 
require a subject to be withdrawn from the study: 
 
 Adverse reactions or intolerance to study drug 
 Protocol violation  
 Subject requires use of unacceptable concomitant medication 

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 Subject not compliant with protocol procedures 
 Subject develops a condition during the study that violates the 
inclusion/exclusion criteria 
 
 Lost to follow-up 
 Administrative problems 
 Death 
 
8.4.4  
Procedures for handling withdrawal 
Subjects who withdraw or are withdrawn from the study should: 
 Have the reason(s) for their withdrawal recorded 
 Be asked about the presence of any AEs and if so should be followed up 
by regular scheduled visits, telephone contact, correspondence or home 
visits until satisfactory clinical resolution of AEs is achieved. 
 Be seen by an investigator and all final assessments will be performed and 
recorded in the OFF STUDY form.  
 Be encouraged to continue coming for regular visits and assessments 
 Have at least one follow-up contact (scheduled visit, telephone contact, 
correspondence or home visit) for safety evaluation during the 30 days 
following the last dose of study treatment. 
 In the event of pregnancy, the subject should be monitored until  
conclusion of the pregnancy and the outcome of pregnancy reported. 
 Have study treatment returned. 
 
 
8.4.5  
Subject replacement policy 
Withdrawn subjects would not be replaced.  
 
 
 
8.4.6  
Screening failures 
Patients who fail to meet the inclusion and exclusion criteria are defined as 
screening failures. A screening log will be maintained which includes screen 
failures. The log will document the subject number, subject initials, 
demographics and the reason(s) for excluding the patient from the study. This 
log will be kept in the Investigator's Study File.

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9 
TREATMENT AND STUDY PROCEDURES 
9.1 
Description of study drug 
 
9.1.1  Treatment for Group 1: Cholestyramine group 
 
Cholestyramine 4g twice daily + Carbimazole 30 mg daily+ Propanolol 40 
mg twice daily for 4 weeks 
 
Study treatment consists of cholestyramine powder 4g (1 sachet) twice a day 
and standard treatment which includes tablet carbimazole 30 mg daily and 
tablet propanolol 40 mg twice a day to be taken orally for 4 weeks.  
The trial dosage of cholestyramine is based on available clinical data and is not 
considered to cause adverse reactions9,12. The trial dosage for carbimazole is 
based on available clinical data16 and in line with the current ATA 2016 
hyperthyroid guidelines4 and our current local standard practice in treating 
patients with moderate to severe hyperthyroidism. The trial dosage of 
propanolol is as per ATA 2016 recommendations to provide symptom relief4.  
Subjects are instructed to mix cholestyramine powder with 60-180 mls of fluid, 
to be taken before breakfast and dinner and advised to drink plenty of fluids to 
prevent constipation. It is recommended to take other drugs one hour before or 
4-6 hours after cholestyramine to prevent interference from the powders with 
absorption. Please refer to drug leaflet attached for full description of 
cholestyramine. Tablet carbimazole is to be taken whole before, during or after 
meal at the same time of the day. Propanolol should be taken at the same time 
daily either before or with meals. Please refer to drug leaflet for more 
information. 
 
 
 
 
 
 
 

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9.1.2 Treatment for Group 2: Prednisolone group 
 
Prednisolone 30 mg daily for week 1, 20 mg daily for week 2, 10 mg daily 
for week 3 and 5 mg daily for week 4+ Carbimazole 30 mg 
daily+Propanolol twice daily for 4 weeks 
 
The study treatment for Group 2 consists of tablet prednisolone 30 mg daily for 
week 1, tapered down to 20 mg daily for week 2, 10 mg daily for week 3 and 5 
mg daily for week 4 (total 4 weeks) and standard treatment which includes 
tablet carbimazole 30 mg daily and tablet propanolol 40 mg twice a day for 4 
weeks. 
 
There are no previous clinical trials conducted on adding prednisolone as 
adjunctive treatment for hyperthyroidism. The trial dosage for tablet 
prednisolone was selected based on a case series by Ozawa et al. as there 
were no clinical trials, who added 30 mg of prednisolone to patients who were 
thyrotoxic and intolerant to thionamides. The dose of prednisolone in his case 
series of 4 patients were either tapered down within a month or maintained at 
30 mg daily less than a month. All patients achieved normal thyroid function in 
2-4 weeks and underwent subtotal thyroidectomy successfully17. We have also 
used similar doses in clinical practice and found it to be effective. Therefore the 
starting dose for prednisolone in this trial was chosen at 30 mg daily with a 
tapering down dose over 4 weeks to to minimize potential side effects of 
prolonged steroid use. Trial dosage for carbimazole and propanolol is as 
mentioned above 
 
Subjects are instructed to take the tablets in the morning with or after meals to 
decrease gastrointestinal upset. Subjects are encouraged not to miss any 
doses and if they do miss a dose, to take it as soon as possible and if it is 
almost time for the next dose, skip the missed dose and go back to regular 
dosing schedule and not to take 2 doses at once. They are advised to avoid 
alcohol while on prednisolone. Please refer to drug leaflet for more information. 
 

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9.1.3 Group 3 Standard treatment group 
Carbimazole 30 mg daily + Propanolol 40 mg twice daily 
 
Standard treatment group consists of tablet carbimazole 30 mg daily and tablet 
propanolol 40 mg twice a day for 4 weeks. Please refer to drug leaflet for more 
information. 
 
 
9.2 
Investigational product supply and handling 
9.2.1 Supply, packaging and labeling 
Each study drug box will be labeled with the following information: 
1. Participant’s ID 
2. Drug’s name 
3. Dose 
4. Instruction on how to use 
5. Storage condition 
6. Expiry date 
7. PI’s name 
 
 9.2.2  
Storage 
The study drug will be stored between 20-250C, protected from moisture and 
be stored in accordance with the manufacturers' instructions. 
The study drug will be kept under adequate security by the investigator and 
only accessible to authorised study personnel. 
 
 9.2.3  
Dispensing 
Each patient will be dispensed sufficient medication for two weeks of therapy. 
Upon dispensation, the research pharmacist will write the following in the 
Investigational Product Dispensing Log: subject ID and initials and date 
dispensed, the total dose given weekly/monthly and frequency of dosage, total 
bottles dispensed, batch number and expiry date of product. 

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9.2.4 
 Accountability 
The investigator will maintain current and accurate record of the receipt, 
inventory and dispensing, including shipping invoices, of all study supplies. The 
Investigational Product Accountability Log will include: 
 Date received 
 Delivery order (D.O.#) reference number and amount received         
and placed in storage 
 Name of study medication and dosage 
 Amount currently in storage area 
 Label ID number or batch number/Lot number  
 Amount dispensed to and returned by each subject, including 
unique subject identifiers 
 
Accountability logs must be available at any time. Upon completion/termination 
of the study, unused study drug must be returned to the sponsor for 
reconciliation and destruction. 
 

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9.3  
Concomitant medication/treatment 
 
A concomitant medication is any medicatiom, other than the trial product, which 
is taken during the trial. Details of any concomitant medication must be recorded 
at visit 1. Changes in concomitant medication must be recorded at each 
subsequent visit as they occur. 
 
Concomitant medications that are not permitted during the study period 
           Plasma levels and efficacy of prednisolone may be affected by the 
concomitant use amphotericin B, anticholinesterase agents, CYP 3A4 
 
inducers (e.g. barbiturates, phenytoin, carbamazepine, and rifampin), CYP 3A4 
inhibitors (e.g., ketoconazole, macrolide antibiotics), cyclosporine and digitalis. 
 
Lithium, Propylthiouracil, Lugols iodine, Contrast medium are not permited as 
 it will affect the results of the study.  
 
Cautious use of phenylbutazone, warfarin, thiazide diuretics (acidic) as well as 
tetracycline penicillin G, phenobarbital, thyroid and thyroxine preparations, 
estrogens and progestins and digitalis as cholestyramine resin may delay or 
reduce the absorption of these drugs. 
.  
9.4 
 Treatment allocation and randomization 
A participant will be randomly allocated to one of the three treatments per 
random allocation sequence that will be generated by a member of the study 
team. The allocation ratio is 1:1:1.The random allocation sequence will 
be generated 
by 
using 
the 
Web 
site 
Randomization.com 
⟨http://www.randomization.com⟩. Blocked randomisation will be used. The 
random allocation sequence will be generated by a member of the study team 
who will not be involved in the enrolment of subjects and assessment of 
outcomes. The block size of 6 will be used. The allocation sequence generated 
will be will be concealed in an opaque sealed envelope with the following 
information written: 
Front page 
1. Study title 
2. Site name and code 

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3. Study PI name 
4. Protocol number 
5. Sequential randomization number 
 
Inside the randomization envelope 
1. Study title 
2. Site name and code 
3. Study PI name 
4. Protocol number 
5. Sequential randomization number 
6. Subject ID 
7. Date and time the envelope open 
8 Signature and name of the person opening the envelope 
9. Study treatment the patient is allocated to 
 
 
The identity of the treatment that will be assigned to each subject will only 
be revealed on the first day of treatment. Principal Investigator and/or Sub 
Investigator will screen and enrol the subjects. Principal Investigator and/or Sub 
Investigator will assign the treatment to each subject, according to the allocation 
sequence. 
 
9.5 Baseline assessment and laboratory tests 
Information on subject’s demographics, anthropometric measures and vital 
signs will be obtained. A detailed history taking of subject’s current medical and 
past medical history along with full clinical examination. Blood sampling will be 
conducted. Ultrasound thyroid and ECG scheduled and ECHO if needed. UPT 
will be done prior to randomisation. Please refer to section 12 for more details. 
 
9.6 Assessment of compliance 
Adherence will be assessed at each visit during therapy by checking the 
subject diary card, 2 weekly count of sachets/ tablets from returned bottles. 
And this will be documented by a member of the study team. 
 
   

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9.7 Discontinuation and interruption of treatment 
Participants will be advised to be compliant to study drug at all times and 
advised to take the missed dose as soon as they can remember and not to take 
a double dose to make up for missed doses.  
 
9.8 Assessment of efficacy 
 Primary efficacy endpoints are: 
1. Proportion of subjects with normal thyroid hormone levels: defined as 
serum free T4 or serum Free T3 levels measured at 2 and 4 weeks after 
initiation of study treatment. 
 
9.9  Assessment of safety 
 
Safety data will be analysed for the data collected throughout 
intervention period and up to follow up period. The following endpoints 
will be collected: 
 Number of subjects with adverse effects during the intervention period 
and follow up period (total duration 6 weeks) 
 Subjects will be asked to report about adverse reactions (specified 
in the protocol) at 2 weeks, 4 weeks of intervention period and 2 
weeks after end of study treatment period. 
 
• 
Number of subjects with serious adverse events during intervention 
period and follow up period (total duration 6 weeks) 
 Subjects will be asked to report about SAE immediately during the 
intervention period and follow up period 
Safety and tolerability assessments will consist of: 
 Regular performance of physical examinations 
1. BP, PR, Temperature, Weight (kg) 
 Regular monitoring of laboratory tests 
2. FPG/ RPG, Electrolytes (Na+, K+, Urea, Creatinine), FT4, FT3, 
TSH 
 Monitoring and recording all adverse reactions and serious adverse 
events 
 

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10 
ADVERSE EVENTS 
 
10.1   Definitions 
10.1.1 
Adverse event (AE) 
Any untoward medical occurrence in a subject administered an investigational 
product and which does not necessarily have a causal relationship with 
treatment.  
An AE includes: 
1. A clinically significant worsening of a concomitant illness 
2. A clinical laboratory adverse event: a clinical laboratory 
abnormality which is clinically significant, i.e an abnormality 
that suggests a disease and/or organ toxicity and is of a 
severity 
that 
requires 
active 
management, 
Active 
management 
includes 
active 
treatment 
or 
further 
investigations, for example change of medicine dose or more 
freqeunt follow-up due to the abnormality. 
 
The following should be reported as AE: 
 
Treatment of emergent symptoms which include: 
 Medical conditions or signs or symptoms that was absent before 
starting study treatment. 
 In this trial the following events must be collected and reported:  
1. SAEs 
2. AEs leading to discontinuation of study drug 
3. Gastrointestinal symptoms 
a. Constipation 
b. Bloating 
c. Diarrhea 
d. Abdominal pain 
e. Vomiting 
4. Diabetes 
5. Hypokalemia 
6. Hypothyroid 

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 The following abnormal laboratory values particularly to this study will 
be observed 
o Fasting plasma glucose more ≥7 mmol/L or Random plasma 
glucose ≥ 11.1 mmol/L 
o Serum K+ <3.5mmol/L 
o TSH above upper limit of reference range and FT4 normal or 
below lower limit of reference range 
 
 Any doubtful event should be treated as an AE. 
 
10.1.2 
Unexpected adverse event 
Any adverse event not reported in the safety section of the Investigator's 
Brochure or if the event is of greater frequency, specificity or severity. 
 
10.1.3 
Serious adverse event (SAE) 
Any adverse event occurring that: 
 Results in death 
 Is a life threatening adverse experience defined as any adverse event 
that places the subject, in the view of the investigator, at immediate risk 
of death from the reaction as it occurred. Note that this does not include 
a reaction that had it occurred in a more severe form, it would have 
caused death. 
 Results 
in 
subject 
hospitalisation 
or 
prolongation 
of 
existing 
hospitalisation. 
 Subject becomes pregnant while on study drug 
 
The following hospitalisations are not considered to be SAEs: 
 Those planned before entry into the study 
 Elective treatment for a condition unrelated to study indication or study 
treatment 
 Occur on an emergency outpatient basis and do not result in admission 
(unless fulfilling other criteria in SAE definition) 
 Part of normal treatment or monitoring of the study indication and are 

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not associated with any deterioration in condition. 
 Results in a significant or persistent disability or incapacity defined as 
any event that results in a substantial and/or permanent disruption of 
the subject's ability to carry out normal life functions. 
 Is any instance of overdose, either accidental or intentional (suspected 
or confirmed) 
 Is any other important medical event, based upon appropriate medical 
judgement, that may jeopardise the subject or may require medical or 
surgical intervention to prevent or avert one of the outcomes listed 
above. 
 
10.2 
Detecting and documenting AE 
Information about all AEs, whether volunteered by the patient, discovered by 
investigator questioning or detected through physical examination, laboratory 
test or other means, would be documented on the Adverse Event Form and 
followed up as appropriate. The AE form should be faxed to the coordinating 
investigator Dr. Serena Khoo Sert Kim at fax number 03-88889169 and email 
sk_liv@rocketmail.com.  
 
When eliciting experiences of AE from a subject, ask a standard non-leading 
question like "Do you feel different in any way since starting the new 
treatment/the last visit?" This question will be put to the subject in his/her own 
language at each study visit. 
Each AE should be described by: 
1. Nature of AE 
This should be documented in terms of a medical diagnosis(es). When  
this is not possible, the AE should be documented in terms of signs and/or 
symptoms observed by the investigator or reported by the subject. 
 
 2. Duration 
Start and end dates 
 
 
3. Assessment of causality 
The investigator should attempt to explain each AE and assess its 

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relationship, if any, to the study treatment. Causality should be assessed 
using the following definitions: 
 Very likely 
- 
The AE follows a reasonable temporal sequence from study 
treatment administration 
- 
Abates upon discontinuation of study treatment 
- 
Reappears on repeated exposure (re-challenge) 
 Probable 
- 
The AE follows a reasonable temporal sequence from study 
treatment administration 
- 
Abates upon discontinuation of study  treatment 
- 
Cannot reasonably be explained by known characteristics of the 
subject's clinical state 
 Possible 
- 
The AE follows a reasonable temporal sequence from study 
treatment administration 
- 
But could have been produced by the subject's clinical state or  
other mode of therapy administered to the subject 
 Doubtful 
- 
The temporal association between study treatment and AE is such 
that the study treatment is not likely to have any reasonable 
association with the observed event 
 Very unlikely 
- 
The AE is definitely produced by the subject's clinical state or other 
mode of therapy administered to the subject 
The degree of certainty with which an AE is attributed to study treatment or 
alternative cause like natural history of disease or concomitant treatment 
should be guided by the following considerations: 
- 
Time relationship between treatment and occurrence of AE 
- 
De-challenge and re-challenge information, if  applicable 
- 
Known pharmacology of the drug 
- 
Dose response relationships 
- 
Lack of alternative explanations i.e. no concomitant drug used and 
no other inter-current disease 

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- 
Reaction of similar nature being previously observed with this drug 
or class of drug 
- 
Reaction having often been reported in literature for similar drug 
 
4. Severity of AE 
 Mild: awareness of signs or symptoms, but they are easily tolerated 
 Moderate: enough discomfort to cause interference with usual activity 
 Severe: incapacitating, with inability to work or do usual activity. 
Note that a severe AE is not necessarily serious. The term severe is a 
measure of the intensity while a serious AE is determined based on 
regulatory criteria.  A life threatening AE is an SAE. 
 
5. Final outcome 
 Recovered/ resolved- The subject has fully recovered, or by medical 
or surgical treatment the condition has returned to the level 
observed at the first trial-related activity after the subject signed the 
informed consent 
 Recovering/resolving- The condition is improving and the subject is 
expected to recover from the event. This term is only applicable if 
the subject has completed the trial or has died from another AE. 
 Recovered/ resolved with sequelae- The subject has recovered 
from the condition, but with lasting effect due to a disease, injury, 
treatment or procedure. If a sequela meets an SAE criterion, the AE 
must be reported as SAE. 
 Not recovered/not resolved- The condition of the subject has not 
improved and the symptoms are unchanged, or the outcome is not 
known. 
 Fatal- This term is only applicable if the subject died from a 
condition related to the reported AE. 
 Unknown- This term is only applicable if the subject is lost to follow-
up 
            10.3 
Reporting SAE 
Information about all SAE will be documented in the AE form and reported to 
Coordinating Investigator of the study – Dr. Serena Khoo Sert KIm (Fax 

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number: 03-88889169, email: sk_liv@rocketmail.com) and MREC directly 
within 24 hours. 
10.4 Treatment and follow up of AE 
Treatment of any AE is at the sole discretion of the investigator who should 
follow up subjects with AE until the event has resolved or until the condition 
has stabilised. Otherwise appropriate medical care should be arranged for the 
patient. Abnormal tests should be repeated until they return to baseline levels 
or an adequate explanation of the abnormality has been found.  
1. Treatment of over-dosage significant enough to cause adverse effects 
 Study medication must be stopped immediately and subject be 
monitored closely for all adverse reactions. Immediate thyroid function 
test to be sent and reviewed.  
 
2. Pregnancy 
 A female subject must be instructed to stop taking study medication 
and immediately inform the investigator if she becomes pregnant 
during the study. The investigator should counsel the subject and 
discuss the risks of continuing with the pregnancy and the possible 
effects on the foetus. Monitoring of the subject should continue until 
conclusion of the pregnancy. The investigator should report all 
pregnancies to the coordinating investigator and MREC within 24 hours 
of being notified of the pregnancy. 
 Pregnancy occurring in the partner of a subject participating in the 
study should also be reported to the investigator and sponsor. The 
partner should be counseled and followed as described above. 
Pregnancies will be formally reported as SAEs. 
 
3. 
Hypokalemia 
 If mild hypokalemia (3-3.5 mmol/L), to replace with Mist Potassium 
Chloride and reassess K+ levels after 3 days. If moderate to severe 
hypokalemia (<3 mmol/L), to assess for symptoms and consider 
admission for close monitoring, ECG and oral/IV potassium 
replacement. 
To 
consider 
withdrawing 
treatment 
(especially 
prednisolone) if refractory to active intervention. 

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4. 
Diabetes 
 To reconfirm by sending a repeat FPG and 2 hour post prandial 
glucose. Upon confirming diagnosis of diabetes, consider starting 
oral hypoglycemic drugs. Consider discontinuing study treatment if 
severe 
uncontrolled 
hyperglycemia 
or 
hospitalisation 
for 
hyperglycemic emergencies. 
 
5. 
Hypothyroid 
 Hypothyroid is defined as symptoms of hypothyroidism coupled with 
elevated TSH more 4.7mU/L and normal or low levels of Free T4 <9 
pmol/L measured during intervention with study drug 
 If hypothyroidism occurs during study treatment, stop study treatment 
and repeat thyroid function test one week later. Thyroid function tests 
will be reviewed and medication adjusted. All adjustment to 
medications will be documented in CRF. No thyroxine will be given 
as hypothyroid will recover upon discontinuing study treatment. 
Subject will discontinue study treatment if develop persistent and 
severe profound symptoms of hypothyroidism  
 
6.  
Hyperthyroid and thyroid storm 
 If subjects are still hyperthyroid (no reduction in Free T4 and Free T4 
from baseline) at the end of week 4, Carbimazole will be increased in 
accordance to the standard practice. In the event if subjects are 
symptomatic of thyrotoxicosis throughout trial period, propanolol doses 
may be increased as per clinician judgement and documented in CRF. In 
the event that subject develops thyroid storm during trial period, SAE will 
be reported, study treatment discontinued and treatment of thyroid storm 
with lugol’s iodine, beta blockers, hydrocortisone and high doses of 
propylthiouracil will be initiated as per standard practice.  
 
10.5 Safety update 
Any safety updates will be notified to MREC

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11 
STUDY CONDUCT 
11.1  Study visits and procedures 
 
 
11.1.1 
 Screening visit (Week -1, Visit 1) 
1. Screening of all overt hyperthyroid subjects due to Graves disease 
2. Assess subject for eligibility to enter study according to the inclusion and 
exclusion criteria. 
3. Obtain written consent from subject or  parent/guardian. 
4. Obtain medical history 
a. Hyperthyroid history 
b. Past medical history 
c. Cardiovascular complications of hyperthyroidism 
d. Family history of thyroid disease 
e. Smoking history 
f. Medication history 
5. Perform baseline measurements of vital signs (BP, HR, Temperature) and 
anthropometric measurements (Height (cm), Weight (kg) and BMI) 
6. Perform complete examination including 
a. Presence of Graves Opthalmopathy and disease activity 
b. Thyroid examination 
c. Cardiovascular examination including presence of atrial fibrillation 
7. The following screening tests are done (Total of 10 mls of blood will be 
sampled). All screening blood tests will be sent to respective site’s own 
laboratory for analysis.   
a. Free T4, Free T3, TSH 
b. Hep Bs Ag, Anti HCV ab, HIV1/2 ab 
c. FBS/RBS 
d. FLP 
e. Liver function test 
f. Renal function test 

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g. FBC 
h. UPT (For all women of childbearing age) 
8. Record all screened subjects in the Screening Log regardless of whether or 
not the subject has been enrolled in the study. 
9. Refer to the study activities table below. 
 
 
11.1.2 
 Baseline visit (Week 0, Visit 2) 
1. Subjects who are eligible for the study after reviewing both inclusion and 
exclusion criteria will be called up for a baseline visit no longer than 1 
weeks from screening visit. 
2. Perform baseline measurements of vital signs (BP, HR, Temperature) 
and anthropometric measurements (Height (cm), Weight (kg) and BMI 
3. Perform complete medical history and physical examination if not done 
during screening visit 
4. Record any concomitant medications 
5. The following baseline tests will be performed (Total of 6 mls of blood 
will be sampled). Thyroid function test and TRAb levels will be sent 
to central lab (Gribbles laboratory) whereas the other tests will be 
conducted at respective site.  
a. Free T4, Free T3, TSH 
b. TRAb levels 
c. UPT (For all women of childbearing age) 
d. ECG 
e. ECHO if evidence of thyrotoxic cardiomyopathy 
6. Complete relevant section/page of the CRF. 
7. Subject who has fulfilled all inclusion and exclusion criteria and has 
completed baseline assessment will proceed to randomisation into any 
of the 3 treatment groups on the same day. 
8. Refer to the study activities table below 
 
 

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11.1.3 
 Randomisation 
 
A participant will be randomly allocated to one of the three treatments per 
random allocation sequence that will be generated by a member of the study 
team not involved in the subject enrolment and concealed in an envelope. 
 
11.1.4 
 Study treatment and visits 
 
Study treatment (Visit 3 Week 2)  
 
The investigator will perform the following procedures: 
1. Medical history taking 
2. Record any concomitant medication 
3. Record any change of dose administration of study   treatment and 
assess compliance 
4. Record any AE or SAE 
5. Perform physical examination including vital signs (BP, HR, 
Temperature, Weight) 
6. Obtain blood sample (total of 6 mls of blood will be sampled). Thyroid 
function test will be sent to central lab (Gribbles laboratory) whereas 
the others will be sent to respective site’s laboratory. (FT4, FT3, TSH, 
FBS/RBS, Blood urea and serum electrolytes) 
7. UPT for women of childbearing age 
8. Complete relevant section/page of CRF 
9. Dispense study treatment 
10. Refer to the study activities table below 
 
 
    Study treatment (Visit 4 week 4) 
 
    The investigator will perform the following procedures: 
1. Medical history taking 

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2. Record any concomitant medication 
3. Record any change of dose administration of study   treatment and assess 
compliance 
4. Record any AE or SAE 
5. Perform physical examination including vital signs (BP, HR, Temperature, 
Weight) 
6. Obtain blood sample (total of 6mls of blood will be sampled). Thyroid 
function test will be sent to central lab (Gribbles laboratory) whereas the 
others will be sent to respective site’s laboratory. (FT4, FT3, TSH, FBS/ 
RBS, Blood urea and serum electrolytes) 
7. UPT for women of childbearing age 
8. ECG 
9. Complete relevant section/page of CRF 
10. Dispense study treatment 
11. Refer to the study activities table below 
 
 
11.1.5 
Follow up visit (Visit 5, Week 6) 
Safety assessment to monitor for adverse events, monitor for symptoms and signs 
of adrenal insufficiency and monitor for iatrogenic hypothyroidism. 
 
1.  Medical history taking 
2. Perform physical examination including vital signs 
3. Record any AE or SAE 
4. Obtain blood sample (total of 6 ml of blood will be sampled). Thyroid 
function test will be sent to central lab (Gribbles laboratory) whereas the 
others will be sent to respective site’s laboratory. (FT4, FT3, TSH, Blood 
urea and serum electrolytes/ FBS or RBS) 
 
 
 

  
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Study Activities Table 
 
Screening 
Baseline Assessment and Randomisation 
Treatment 
Follow up 
Visit 
1 
2 
3 
4 
5 
Timeline (wks) 
-1 
0 
2 
4 
6 
Procedures 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
Check eligibility 
X 
 
 
 
 
Blood sample for screeninga 
X 
 
 
 
 
Randomisation 
 
X 
 
 
 
Patient demographics 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Complete physical exam  
X 
 
 
 
 
Height (cm), Weight (kg) 
X 
X 
X 
X 
X 
Vital signs (BP, HR, Weight, Temp) 
X 
X 
X 
X 
X 
FT4 & FT3 & TSH 
X 
X (central lab) 
X (central lab) 
X (central lab) 
X (central lab) 
TRAb levels 
 
X (central lab) 
 
 
 
FBS/ RBS 
X 
 
X 
X 
X 
BUSE 
X 
 
X 
X 
X 
UPTb 
X 
X 
X 
X 
 
U/S Thyroid 
 
X 
 
 
 
ECG 
 
X 
 
X 
 
ECHOc 
 
X 
 
 
 
Efficacy assessment 
 
 
X 
X 
 
Concomitant medication 
 
 
X 
X 
 
Report AE and SAE 
 
 
X 
X 
X 
Dispense study treatment 
 
 
X 
X 
 
Assess compliance 
 
 
X 
X 
 
Complete relevant section of CRF 
 
 
X 
X 
X 
 
a HepBsAg, Anti HCV ab, HIV1/2 ab, FBC, BUSE/Creatinine, LFT, FBS/RBS, FLP. Written consent will be taken for HIV test. All blood tests on screening visit including thyroid function test 
will be sent to the respective site’s laboratory. 
 b For women of childbearing age  
c Only if clinically suggestive of thyrotoxic cardiomyopathy or has atrial fibrillation 

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11.2 
Criteria for stopping subject treatment 
 
The investigator will discontinue a subject’s taking of study treatment at 
any time if the subject: 
 
1. Who no longer wishes to participate in the trial and wishes to withdraw 
from the study at any time 
 
2. Experiences intolerable adverse reactions  
 
3. Is diagnosed with any of the exclusion criteria during the intervention 
period 
 
4. Develops hypothyroid during the intervention period (Hypothyroid is 
defined as symptoms of hypothyroidism coupled with elevated TSH > 4.7 
mU/L and normal or low levels of Free T4 <9 pmol/L 
 
 
 
In all these cases, the investigator and/or the treating physicial will if 
possible encourage the subject to continue with the follow up assessment 
and to allow the use of collected data in the analyses. 
 
11.3 
Sample handling and analysis 
11.3.1 Collection 
The only biospecimen involved in this study is blood. Blood draws of 5-
10 mls would be performed as stated in the study activities table and 
before the dose of study drug. Blood specimen will be taken by a 
dedicated nurse or doctor.  
The blood tests for screening visit will be sent to the respective site’s 
own laboratory. The tests are: 
 Free T3, Free T4, TSH 
 HepBsAg, Anti HCV ab, HIV1/2 ab 
 Full Blood Count 
  Renal function test 

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 Liver function test 
 Fasting blood sugar/ Random blood sugar (FBS/RBS) 
 Fasting lipid profile  
 
Subsequent FBS/RBS, renal profile for study treatment visits and follow 
up visits will also be sent to the respective site laboratory. Screening 
thyroid function tests results will not be analysed and therefore would not 
require specimens to be sent to a central laboratory.  
 
Free T4, Free T3, TSH and TRAb levels for baseline and randomisation 
visit, study treatment visits (Visit 3 Week 2 and Visit 4 Week 4) and follow 
up visit (Visit 5 Week 6) will be sent to the centralised laboratory 
(Gribbles Pathology Laboratory Central Headquarters) for processing.  
Request form with the patient’s particulars shall be duly filled at the 
hospital site. Specimen should be individually packed in a specimen 
carrier bag with the request form. A call should be made by Site 
coordinator to Gribbles Pathology Careline number (1300-88-0234) for 
specimen pick up. Gribbles courier will be dispatched for specimen 
collection. Specimen transport will be done using a cooler bag (cool 
transport). Specimens will be collected by courier from the hospital site.  
After checking the specimen from the courier, the laboratory staff will 
proceed to process the sample. Specimens are centifuged prior to sending it 
for analysis. Once centrifugation is done, the blood specimen is sent to the 
central headquarters laboratory for analysis. After test has been done, 
results are reviewed and if needed, validated before release. 
Pre and post counselling test would be offered for HIV test in line with 
general practice and if positive be notified as per Malaysian law. Specimens 
would not be stored for future research. 
 
11.3.2 Labeling 
 The specimens will be labeled the study protocol number, subject number, 
subject initials, study day and name of test. 
 

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11.4   Laboratory analysis 
 
# 
Test 
Method 
1 
Free T4 
1. Type of kit : SIEMENS HEALTHCARE 
DIAGNOSTIC  (SIEMENS HEALTHINEERS) 
2. Name of analyser : CENTAUR Xp 
3. Type of sample:  Serum (recommended) 
4. Methodology:  Direct Chemiluminescence 
competitive immunoassay 
5. Measuring range : 1.3  - 155 pmol/L 
6. Imprecision (CVs) : This assay exhibits total 
imprecision of ≤ 7.3% CV  
7. Reference ranges :  
    Adult : 9-25 pmol/L 
2 
Free T3 
1. Type of kit : SIEMENS HEALTHCARE       
DIAGNOSTIC (SIEMENS HEALTHINEERS) 
2.  Name of analyser : CENTAUR Xp  
3. Type of sample : Serum (recommended) 
4. Methodology : Direct  Chemiluminescence 
competitive immunoassay 
5. Measuring range : FT3 : 0.3  - 30.8   pmol/L 
6. Imprecision (CVs) : 
   This assay exhibits total imprecision of ≤ 3.7%  
7. Reference ranges :  
Adult : 3-6.5 pmol/L 

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3 
TSH 
1. Type of kit : Siemens Healthcare Diagnostic 
(Siemens Healthineers) 
2. Name of analyser : Centaur Xp 
3. Type of sample : Serum (recommended) 
4. Methodology : TSH: 3RD Generation Antibody 
capture. 
5. Measuring range : 0.008  -  150 µIU/L 
6. Imprecision (CVs) : 
This assay exhibits total imprecision of ≤ 3.8%  
7. Reference ranges :  
Adult : 0.4-4.7 mU/L 
4 
TRAb levels 
1. Type of kit : Euroimmun Anti TSH Receptor 
(TRAb) ELISA (IgG) 
2. Name of analyser : EUROANALYSER 
3. Type of sample : Serum only 
4. Methodology : ELISA 
5. Measuring range :  0.16 to 40 IU/ml 
6. Imprecision 
(CVs): 
Interassay 
variation 
(n=20) with mean of 18.57 IU/ml is CV of 
7.6% 
7. Reference ranges :  
Negative: <1.0 IU/ml 
Positive: >1.0 IU/ml 
8. Storing and packaging of sampling instructions 
and methods: Serum sample storage 2-8°C for 
up to 14 days 

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12 
DATA MANAGEMENT 
Data will be written and collected from the CRF. Data collected will be 
transferred to an Excel sheet. Accurate and reliable data collection will be 
assured by verification and cross-check of 100% of the CRFs against the 
investigator's records (source document verification). The investigators will 
have access to the data and will be stored until the study period ends. The 
clinical data (hardcopy) will be archived and stored for 7 years. It will be 
destroyed after 7 years. The softcopy of the medical records of the subjects will 
remain in Electronic Medical Records (EMR) which will depend on the hospital’s 
record office Protocol of Storage. The responsibility of the data handling and 
storage lies with the investigators and the sponsor. 
 
 
13 
STATISTICAL METHODS 
 
13.1 Sample size and power considerations 
 
The sample sizes estimations and analyses plan were made with the caveat 
that the three-treatment groups comparison is as little difference from carrying 
out a series of three independent trials, and to use conventional significance 
tests without adjustment as argued by Saville (1990)20. Sample size and power 
considerations 
 
Sample sizes were estimated by using PASS 11 software21. The estimations 
were based on primary objectives only. 
 
Primary objective: To achieve 80% power to detect a 30% difference in the 
proportions achieving normal FT4 between Group 3 (Carbimazole+Propanolol) 
and each of Group 1 (Cholestyramine + Carbimazole+ Propanolol) and Group 2 
(Prednisolone+ Carbimazole+ Propanolol), 41 patients are needed in each 
group. The proportion achieving normal FT4 in Group 3 was estimated to be 
40%. (1) Allowing for 10% drop out rate, the sample size required is therefore 
45 per arm. The test statistic used is the two-sided Z test with pooled variance. 

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The significance level was targeted at 0.05. 
 
 
Primary objective: To achieve 80% power to detect a 30% difference in the 
proportions achieving normal FT3 between Group 3 (Carbimazole+Propanolol) 
and each of Group 1 (Cholestyramine + Carbimazole+ Propanolol) and Group 2 
(Prednisolone+ Carbimazole+ Propanolol), 41 patients are needed in each 
group. The proportion achieving euthyroid status in Group 3 was estimated to 
be 40%. (1) Allowing for 10% drop out rate, the sample size required is 
therefore 45 per arm. The test statistic used is the two-sided Z test with pooled 
variance. The significance level was targeted at 0.05. 
 
Thus, the final sample size will be 45 per group. 
 
 
13.2 
Analysis 
 
Data entry, cleaning and analyses will be done using SPSS version 21. Categorical 
data will be described by using proportions and numerical data will be described by 
using mean, median, standard deviation, and/or interquartile range, as appropriate. 
The analyses will be based on the intention-to-treat  
 
13.2.1 Baseline Comparability 
 
Baseline characteristics will be compared between the 3 groups using the 
appropriate descriptive statistics. No formal hypothesis test will be made for baseline 
comparison. 
 
13.2.2 Efficacy Analysis 
 
1. For the primary objectives, all comparisons of means between treatment will be 
analysed using one-way ANOVA and all pairwise comparisons of proportions will 
be analysed by using two-sided Z test and 95% confidence interval of the 
estimated difference will be calculated. Alpha level will be set at 0.05 and no  

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adjustment will be made for the multiple pairwise comparisons. Analysis will be 
based on intention to treat and per protocol analysis. 
 
 
2. For secondary objectives, all comparisons of means between treatment will be 
analysed using one-way ANOVA and all comparison of proportions will be analysed 
using chi-square test of independence.  
Alpha level will be set at 0.05. Analyses will be based on safety set analysis.

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14 
 ADMINISTRATIVE MATTERS 
14.1 Notification of regulatory authority(ies) 
All necessary arrangements for the registration and approval of this study with 
the responsible authorities and the disposition of the required data and 
document will be undertaken by the Principal Investigator. 
 
 
14.2 Notification of primary care physician 
The General practioner or primary care physician will be informed of the 
subject’s involvement in this study. This is so that if the patients need to see 
their own physician for any reason, the physician will be aware that they are 
taking a study drug. 
 
 
14.3 Study initiation 
The study will begin only after getting the approval from MREC.  
 
14.4 Protocol deviation 
Any protocol deviation will be documented by the Investigator with rectification 
as soon as possible. The investigator should be notified immediately. With the 
exception of emergency situations, no changes or deviations in the conduct of 
this protocol will be permitted without the prior approval from MREC. In the 
event of any emergency, the investigators will institute any medical 
procedures deemed appropriate. All such procedures must be promptly 
reported to MREC.  
 
14.5 Study documentation 
All documentation will be maintained. These documents are Essential 
Documents and Source Documents. 
 
 
 

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14.5.1 Essential documents 
These are documents that permit evaluation of the study and the quality of the 
data produced.  The Essential Documents are: 
 Signed protocol amendments 
 Sample CRFs 
 MREC approval letter 
 Informed consent form 
 CV of investigator and co-investigator 
 Investigational product accountability and shipping records 
 Other appropriate documents in accordance with GCP guidelines. 
 
The investigator will maintain an Investigators Study File. This file shall be 
used to facilitate and ensure filing of all relevant and Essential Documents 
during and after the study.  The investigator will be responsible for keeping  
the Investigator's Study File updated and ensuring that all required documents 
are filed. The file will be inspected during monitoring visits. 
 
 
14.5.2 Source documents 
These are original hospital records, clinical charts, subject screening checklist, 
original laboratory reports, pharmacy dispensing records, and records kept at 
the pharmacy, at the laboratories and at medico-legal departments involved in 
the study. All source documents would be kept confidential of personal 
information. 
 
The investigator must maintain source documents for each patient in the 
study. All information on CRFs must be traceable to these source documents: 
 Patient identification list 
 Curriculum vitae 
 
 
 
 

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14.6 
Patient identification list/Enrolment log 
An enrolment log will be maintained that contain a list of all enrolled patients 
containing the full name, date of birth, date of enrolment, and the 
randomization number. The list has to show an unequivocal study identification 
number. The list will be filed in the Investigator's Study File on site. 
 
 
14.7 
Curriculum vitae 
The investigator will provide curriculum vitae showing his/her experience in 
the area of the proposed study. These should be filed at CRC as well as in the 
Investigator's Study File on site. 
 
 
14.8 
Retention of documents 
All study documents will be or at least 3 years after completion or 
discontinuation of the study. 
 
If the investigator moves or retires, he/she must nominate someone in writing 
to be responsible for archiving. Archived data may be held in microfiche or 
electronic record, provided a back up exists and a hard copy can be obtained 
from it if required. 
 
If the investigator cannot guarantee this archiving requirement at the study site 
for any or all of the documents, special arrangements must be made with CRC 
to store these in a sealed container(s) outside of the site so that they can be 
returned sealed to the investigator in case of a regulator audit. Where source 
documents are required for the continued care of the subject, appropriate 
copies should be made for storage outside of the site. 
 
 

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14.9 
Finance 
The study will be funded by the Ministry of Health Malaysia to support the 
work of the investigator and supply the required investigational product for the 
study. 
 
 
14.10 
Study Termination and Site Closure 
The study may be terminated early if there is:  
 Deliberate violation of the signed protocol 
 The incidence and/or severity of adverse events in this or other studies 
indicate a potential health hazard caused by the treatments under trial. 
 
 
14.11 
Confidentially 
The investigator agrees that all information will be kept strictly confidential.  
 
 
14.12 
Publication policy 
The investigator shall have the right to publish or permit the publication of any 
information or material relating to or arising out of the work. Publishing will 
protect the confidentialty of subjects’ personal information. 
 
 
14.13  
Anticipated subject accrual and duration of the study 
 
 This study is expected to start in April 2017. The projected study timetable for 
the study is as follows: 
 First patient enrolled is expected in March/ April 2017 
 Last patient enrolled is expected in  December 2017 
 The last patient enrolled is projected to complete the treatment 
period in December 2017 

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15 
REFERENCES 
 
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Sundaresh V, Brito JP, Wang Z, Prokop LJ, Stan MN, Murad MH, et al. 
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Kaykhaei MA, Shams M, Sadegholvad A, Dabbaghmanesh MH, Omrani GR. 
Low doses of cholestyramine in the treatment of hyperthyroidism. Endocrine. 
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10.  Migneco A, Ojetti V, Testa A, De Lorenzo A, Gentiloni Silveri N. Management 
of thyrotoxic crisis. Eur Rev Med Pharmacol Sci. 2005;9(1):69–74.  
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thyrotoxicosis. Clin Endocrinol 1993;38(1):39–43.  
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Treatment of hyperthyroidism with a combination of methimazole and 
cholestyramine. J Clin Endocrinol Metab. 1996;81(9):3191–3.  
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sequestrant therapy for hyperthyroidism in adults. Cochrane Database Syst Rev. 
2016;2016(6).  
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to carbimazole with corticosteroids. Postgrad Med J .1996;72(850):489–91.  
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hyperthyroidism. Clin Endocrinol. 1991;35(5):439–42.  
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20 or 40 mg per day of carbimazole in the initial treatment of hyperthyroidism. 
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134292 
 
16 
APPENDICES 
 
 Declaration of Helsinki 
 Study Procedures 
 Questionnaire and CRF (if applicable) 
 Investigational product labels 
 Elements of informed consent 
 Sample informed consent form (in different languages) 
 Patient information sheet (in different languages) 
 Letter of indemnity 
 Investigators’ curriculum vitae

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