A Randomized Controlled Clinical Trial on the Effectiveness of Lithium in Comparison to Carbimazole as a Bridging Therapy Prior to Radioactive Iodine for Hyperthyroidism
Phase: PHASE4
Conditions: Hyperthyroidism/Thyrotoxicosis
Sponsor: Universiti Kebangsaan Malaysia Medical Centre

 
A Randomized Controlled Clinical Trial on the Effectiveness of Lithium in 
comparison to Carbimazole as a Bridging Therapy prior to Radioactive 
Iodine for Hyperthyroidism 
 
 
Protocol version: 
Version 3.0, Date 1/7/2021 
 
 
Principal Investigator: 
Prof Dr. Norlela Sukor 
Endocrine unit, Department of Medicine,  
Pusat Perubatan Universiti Kebangsaan Malaysia 
 
 
Co Investigators: 
Prof Dr. Nor Azmi Kamaruddin 
Endocrine unit, Department of Medicine,  
Pusat Perubatan Universiti Kebangsaan Malaysia 
 
Dr. Thanuja Mahaletchumy  
Department of Molecular Imaging and Nuclear Medicine,  
Pusat Perubatan Univeristi Kebangsaan Malaysia  
 
Dr. Deviga A/P Lachumanan 
Endocrine Fellow,  
Ministry of Health  
 
 
 
Study site: 
Endocrine Unit, Department of Medicine, PPUKM 
 
 
 

 
2 
CONTENT  
 
1.  
List of Abbreviation  
3 
2.  
Research Synopsis 
4 
3.  
Background and Significance  
5-6 
4.  
Hypotheses and Objectives  
6 
5.  
Methodology 
Study Design 
Study Population 
Inclusion Criteria 
Exclusion Criteria 
Refusals, Withdrawals, Lost to Follow-up 
Adverse Events  
Sample Size 
Study Duration and Timeline 
Study Visits and Procedures  
Statistical Analysis Plan  
Risk and Benefit to Participants  
Risk Benefit Assessment 
Ethics of Study  
Informed Consent 
Privacy and Confidentiality 
Conflict of Interest  
Publication Policy  
Termination of Study  
 
7-8 
8 
9 
9 
9 
9-12 
13 
13 
14 
14 
14 
15 
15 
15 
15 
15 
15 
15 
6.  
Reference  
16-17 
7.  
Appendix  
1 List of Medications Not Permitted during Trial 
2 Gantt Chart 
3 Study Flow Chart 
4 Estimated Budget Proposal 
 
18 
19 
20 
21 
 
 
 

 
3 
LIST OF ABBREVIATIONS 
<List commonly used abbreviations/acronyms> 
<RAI> 
<Radioactive Iodine> 
<RP> 
<Renal Profile> 
<LFT> 
<Liver Function Test> 
<TFT> 
<Thyroid Function Test> 
<ATD> 
<Antithyroid Drug> 
<CMZ> 
<Carbimazole> 
<TED> 
<Thyroid Eye Disease> 
<SAE> 
<Serious Adverse Events> 
<AE> 
<Adverse Events> 
 
 

 
4 
RESEARCH SYNOPSIS 
 
Study Title 
 
A randomized controlled trial on the effectiveness of lithium in comparison to 
carbimazole as a bridging therapy prior to radioactive iodine for hyperthyroidism. 
 
Objective  
 
Primary  
To assess the proportion of cure at 6months of radioactive iodine between those 
who were pre-treated with lithium versus carbimazole. 
 
Secondary  
To assess change in serum thyroid hormone levels following two months of lithium 
versus carbimazole therapy prior to the administration of radioactive iodine.  
 
Study Designs  
 
A prospective randomized controlled, open label, single centre study. Subjects will 
be randomized into lithium or carbimazole arms in a 1:1 ratio. Lithium arm will 
receive tab Lithium Carbonate 300mg OD while Carbimazole arm will receive tab 
Carbimazole 10mg OD for a duration of two months prior to radioactive iodine 
treatment.  
 
Study Endpoints 
/ Outcomes 
 
Changes in the thyroid hormone levels at 2 months of treatment and at months 1,3 
and 6 following radioactive iodine. 
Study Population 
 
All adult patients who are 18 years and above with hyperthyroidism either newly 
diagnosed or relapse disease secondary to Graves’ Disease, toxic multinodular 
goitre and toxic adenoma who are planned for radioactive iodine therapy as a 
definitive treatment from 18/12/2020 till 31/12/2021 at Pusat Perubatan Universiti 
Kebangsaan Malaysia. 
 
Inclusion / 
Exclusion 
Criteria 
 
Inclusion Criteria  
• 
Adult patients aged 18 years old and above with thyrotoxicosis who have 
been planned for definitive RAI:  
o 
consented for radioactive therapy as a definitive treatment. 
o 
able to comply with requirement of radioiodine therapy. 
o 
FT4 level below 40pmol/L. 
 
Exclusion Criteria 
• 
Pregnancy or Lactating mother  
• 
Moderate to severe and active thyroid eye disease based on EUGOGO 
criteria, requires steroid cover  
• 
Renal impairment, egfr <45ml/min (stage 3b) 
• 
Underlying active malignancy  
• 
Underlying active schizophrenia or bipolar disorder 
• 
Patients on medications that may interact with lithium (refer to 
APPENDIX 1) 
• 
Patients on medications that may interfere with RAI effectiveness: 
o 
Amiodarone 
o 
Less than a month of intravenous contrast medium 
• 
Previous RAI < 6months 
• 
Previous history of adverse effect following exposure to lithium or 
carbimazole. 
• 
Thyroid carcinoma 
 
Sample Size 
 
86 subjects  
Study Duration  
 
18/12/2020 – 31/12/2021 

 
5 
BACKGROUND AND SIGNIFICANCE  
 
Hyperthyroidism is a state of overactive thyroid gland due to autoimmune Graves’ Disease, 
toxic multinodular goitre or toxic adenoma. Radioactive iodine (RAI) therapy is a common 
treatment modality for hyperthyroidism either as primary treatment or after failure of medical 
treatment. The aim of radioactive iodine therapy is a stable restoration to euthyroid state, 
however, a substantial proportion of patients become hypothyroid.  
 
Although generally safe, radioiodine therapy has some potential side effects include 
gastrointestinal symptoms, radiation thyroiditis, sialadenitis/xerostomia, bone marrow 
suppression, gonadal damage and pulmonary fibrosis. Therefore it is pivotal to render cure in 
patients who are undergoing radioactive iodine at the first attempt to minimize the unwanted 
adverse effects.  
 
Cure rate within a year post RAI is around 72%, however cure rates seems to differ from 
centre to centre. Several factors have been found to affect the success of RAI therapy and 
some of the known ones are prior use of thionamide, hyperthyroid state, gender, dose of RAI, 
RAI uptake and retention of RAI in the thyroid gland.  
 
Simultaneous use of antithyroid drug (ATD) with RAI has consistently been shown to result 
in lower efficacy and higher failure rate than treatment with RAI alone.(1-5) Antithyroid drug 
have a radioprotective effect and pre-treatment with ATD has been shown to increase the risk 
of treatment failure with subsequent RAI. The result is consistent even if the drugs are 
discontinued 4-7 days before RAI therapy. Carbimazole (CMZ) is the current standard 
therapy in the management of hyperthyroidism prior to radioactive iodine therapy. Connell et 
al., reported that CMZ stopped 5 days before RAI reduced the rate of hypothyroidism at 1-
year compared to non-pretreated patients.(6) There are two other studies that have reported 
CMZ pre-treatment reduced the efficacy of RAI therapy.(7,8) In a meta-analysis of 14 
randomized controlled trials, adjunctive ATD, including CMZ, was associated with an 
increased risk of treatment failure with RAI.(9) Despite these evidences, ATD are still being 
given in clinical practice prior to RAI in an attempt to avoid thyroid storm associated with 
high levels of thyroid hormones prior to RAI administration. 
 
It is important to note that since Malaysia do not produce its own RAI and has to imported 
from overseas there will always be a significant waiting period. The waiting period may 
range between 2-3months in most of the centres including in Pusat Perubatan Universiti 
Kebangsaan Malaysia. In the past, patients would be continued on the usual ATD until 3days 
before the administration of RAI. Unfortunately, the ongoing use of ATD continued until 
prior to RAI may result in lowering of the RAI uptake and thus reduce the efficacy of RAI 
therapy. This is where an alternative bridging therapy with lithium may offer a better 
alternative especially in terms of RAI uptake.  
 
Lithium has been shown not to interfere with the RAI uptake. In fact, some studies 
demonstrated lithium improves the success rate of RAI.(10,11) Lithium plays multiple roles in 
thyroid hormone synthesis process. Lithium inhibits the coupling of iodotyrosine residues to 
form iodothyronines thyroxine (T4) and triiodothyronine (T3), and inhibits release of T4 and 
T3.(12) Lithium blocks the release of organic iodine from the thyroid gland, therefore it is able 
to increase RAI retention in the thyroid and does not interfere with thyroidal RAI uptake.(13) 
 

 
6 
Lithium use in treating hyperthyroidism has not been used widely due to its potential adverse 
effects including a spectrum of central nervous system, cardiovascular, and renal side effects 
namely confusion, coma, seizures, ventricular irritability, sinus node dysfunction, sinoatrial 
block, nephrogenic diabetes insipidus and electrolyte imbalance. However these adverse 
effects associated with higher doses of lithium. In this particular study a very low dose of 
lithium (300mg daily) will be used. Previous studies showed that the occurrence of 
significant side effects of lithium was low with lower doses. The study by Bal et al used a 
dose of 300mg three times daily for 21 days did not demonstrate any severe adverse effects 
and only a small group of patients experienced mild gastrointestinal symptoms. 
 
Currently hyperthyroidism is mainly being treated with medical therapy using carbimazole 
for a duration of 12 to 18 months duration. However, the relapse rate can be as high as 80% 
following cessation of ATD due to the nature of the disease. Hence, some patients will need 
RAI as a definitive treatment because it is a well-known fact that another course of ATD in 
this kind of patients will not render cure. In certain patients, eg those with thyrotoxic 
cardiomyopathy or hypokalaemic periodic paralysis RAI would be a primary treatment 
because it is important to render cure in these subset of patients to avoid cardiovascular 
sequeale.  
 
In view of the waiting period to receive RAI, most patients will be pre-treated with ATD 
prior to RAI. However, some patients may develop side effects towards carbimazole such as 
liver impairment, allergic reaction or agranulocytosis. In this respect, lithium is being used as 
an alternative treatment. To the best of our knowledge there are no head to head study 
comparing lithium versus carbimazole as the pre-treatment medications prior to RAI. This 
would be the first study to explore the effects of the two medications prior to RAI and the 
novelty of this study would shed some insights into their roles and clinical applicability as 
well as filling up the gaps of the current literature.  
 
 
HYPOTHESES 
 
In relation to the overall objective, the following are the hypotheses: 
 
• Lithium resulted in higher proportion of cure compared to carbimazole at 6 months of 
radioactive iodine. 
• Lithium resulted in comparable thyroid hormone levels as carbimazole at two months 
following treatment prior to RAI administration. 
 
 
OBJECTIVES 
 
Primary  
 
To assess the proportion of cure at 6 months of radioactive iodine between those who were 
pre-treated with lithium versus carbimazole. 
 
Secondary  
 
To assess change in serum thyroid hormone levels following two months of lithium versus 
carbimazole therapy prior to the administration of radioactive iodine.  

 
7 
METHODOLOGY 
Study Design  
This is a prospective randomized, open label, single center interventional study comparing 
the effectiveness of lithium versus carbimazole in lowering the thyroid hormone levels in 
patients undergoing radioactive iodine. 
Patients will be randomized into lithium or carbimazole arms in a 1:1 ratio. Patients will 
receive either lithium carbonate 300mg once daily or carbimazole 10mg once daily, which is 
the current standard therapy. The necessary precautions will be given with regards to the 
study drugs. Patients will be on the above treatment for a duration of 2 months and 
carbimazole will be stopped 3 days prior to radioactive iodine treatment whereas lithium will 
be discontinued on day 3 post RAI as per usual practice. RAI will be administered at a fixed 
dose of 15mCi in both groups.  
Antithyroid drug (ie. Methimazole or carbimazole) is restarted if needed (in symptomatic 
patients with FT4 of more than 40 pmol/L) at least a week after radioactive iodine and 
titrated as per standard treatment protocol. 
Patients are declared to be cured at the end of 6 months based on thyroid function test and 
requirement of treatment either with thyroxine or antithyroid drug. 
Randomization  
 
Block randomization method will be utilised to randomize subjects into the two groups by 
selecting treatment arm from a box consisting of 8 options (4 lithium and 4 carbimazole). 
Once the box is empty, it will replenished by the same 8 options. 
 
Assays and values  
 
Thyroid Function Test  
Thyroid Stimulating Hormone (TSH) and Free T4 (FT4) are measured using 
Chemiluminescent Microparticle Immunoassay (CMIA) method.  
The normal range for TSH is 0.35-4.94 uIU/ml and for FT4 is 9-19.05 pmol/L.  
 
Renal Profile 
Renal profile is measured by Indirect Ion selective electrode (ISE) method, and urea and 
creatinine are measured using urease and Jaffe’s method respectively.  
The normal range for creatinine is 50.4-98.1 umol/L. 
 
eGFR  
eGFR is calculated using MDRD formula: 186 x (creatinine/88.4)-1.154 x (age)-0.203 x (0.742 if 
female) x (1.210 if black) 
 
Lithium Therapeutic Drug monitoring  
Lithium level measured using Colorimetric method. Target serum concentration ranges from 
0.6-1.2mM. Serum level >1.5mM is associated with sharp increase in severe adverse effects. 
 
 

 
8 
Definition of cure  
Cure is defined as achievement of euthyroidism or hypothyroidism at 6 months after 
radioactive iodine therapy. Euthyroidism is defined as having serum TSH and Free T4 level 
within normal range without anti thyroid drug. Hypothyroidism is defined as having elevated 
TSH with low or normal free T4 level or requiring thyroxine replacement. 
 
 
Setting  
Patients who are able to comply with the requirement of radioiodine therapy and consented to 
participate in this trial will be given appropriate counselling. These patients will be screened 
for inclusion and exclusion criteria. A written informed consent will be obtained and patients 
will then be recruited into this study.  
Once recruited, history, physical examination including baseline eye examination for possible 
Thyroid Eye Disease (TED) will be carried out. TED as defined according to the presence of 
eye signs in categories 2–6 of the NOSPECS classification and determined clinical activity 
score of thyroid eye disease according to EUGOGO criteria.  
Patients will be then assessed for baseline thyroid function test (TFT), renal profile (RP) and 
liver function test (LFT) during screening. Patients will receive either lithium carbonate 
300mg once daily or carbimazole 10mg once daily, which is the current standard therapy. 
The necessary precautions will be given with regards to the study drugs.  
 
Patients will be enquired of any possible side effects during the clinic visits. Lithium levels 
will be checked at week 1 and at the end of 2 months of initiation (refer study flow chart). If 
patient develops intolerable side effects or the lithium level exceeded therapeutic range, the 
confounding drug will be stopped and patient will be managed accordingly. The patient will 
subsequently be withdrawn from the study. It is important to note that the lithium dose used 
in this study is of low dose, hence the side effects risks anticipated would be low. 
 
Current waiting period in PPUKM is about 2months. Patients will be on the above treatment 
for a duration of 2 months and carbimazole will be stopped 3 days prior to radioactive iodine 
treatment. RAI will be administered at a fixed dose of 15mCi in both groups. Bloods will be 
drawn for TFT, RP, LFT and lithium level on the RAI day. Lithium will be discontinued on 
day 3 post RAI. The timeline for stopping both the carbimazole and lithium are as per clinical 
practice guidelines. Patients will be followed up at months 1, 3 and 6 post RAI with TFT 
during each visit.  
 
Study Population  
All adult patients who are 18 years and above with hyperthyroidism either newly diagnosed 
or relapse disease secondary to Graves’ Disease, toxic multinodular goitre and toxic adenoma 
who are planned for radioactive iodine therapy as a definitive treatment will be included in 
this study.  
The study period is from 18/12/2020 till 31/12/2021 at Pusat Perubatan Universiti 
Kebangsaan Malaysia. 

 
9 
Inclusion Criteria  
 
• Adult patients aged 18 years old and above with thyrotoxicosis who have been 
planned for definitive RAI:  
o consented for radioactive therapy as a definitive treatment. 
o able to comply with requirement of radioiodine therapy. 
o FT4 level below 40pmol/L 
 
Exclusion Criteria 
 
• Pregnancy or Lactating mother  
• Moderate to severe and active thyroid eye disease based on EUGOGO criteria, 
requires steroid cover  
• Renal impairment, egfr <45ml/min (stage 3b) 
• Underlying active malignancy  
• Patients on medications that may interact with lithium (refer to APPENDIX 1) 
• Patients on medications that may interfere with RAI effectiveness: 
o Amiodarone 
o Less than a month intravenous contrast  
• Previous RAI < 6months 
• Previous history of adverse effect following exposure to lithium or carbimazole. 
• Thyroid carcinoma  
 
Refusals, withdrawals, lost to follow-up  
 
Patients can withdraw themselves from the study at any point of time. If patient had changed 
the decision and opted out of radioactive iodine, endocrinologist should be contacted 
immediately and clinic visits will be arranged to review the patient. If patients were lost to 
follow-up, weekly phone calls will be made on 4 consecutive weeks. Patients may be 
withdrawn if the investigator deems that it is detrimental or risky for the patient to continue. 
Follow up visits at endocrine clinic will be arranged for all withdrawn patients. Withdrawn 
subjects will not be replaced 
 
 
Adverse Events 
 
Definition: 
 
Adverse event (AE)  
Any untoward medical occurrence in a subject administered an investigational intervention 
and which does not necessarily have a causal relationship with treatment. 
 
An AE includes: 
• A clinically significant worsening of a concomitant illness  
• 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 frequent follow-up due to the abnormality.  

 
10 
In this trial, the following should be reported as AE: 
• Treatment emergent symptoms which include: 
o Medical conditions or signs or symptoms that was absent before starting study 
treatment. 
o Medical conditions or signs or symptoms present before starting study 
treatment and worsen (increase severity or frequency) after starting study 
treatment. 
• Abnormal laboratory values or tests that induce clinical signs or symptoms or require 
therapy.  
• Any adverse experience even if no drug has been administered, for example during 
run in or wash out phase of the study.  
• Any doubtful event should be treated as an AE.  
 
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.  
 
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. 
 
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 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.  
 
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 emailed to the coordinating investigator Dr. 
Deviga a/p Lachumanan at devigaonline@gmail.com. 

 
11 
• 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:  
Nature of AE 
o 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. 
Duration:  
o  Start and end dates 
Assessment of causality:  
The investigator should attempt to explain each AE and assess its relationship, if any, 
to the study treatment. Causality should be assessed using the following definitions:  
o 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)  
o 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  
o 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  
o 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  
o 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:  
o Time relationship between treatment and occurrence of AE  
o De-challenge and re-challenge information, if applicable  
o Known pharmacology of the drug  
o Dose response relationships  
o Lack of alternative explanations i.e. no concomitant drug used and no other 
inter-current disease 
o Reaction of similar nature being previously observed with this drug or class of 
drug  
o Reaction having often been reported in literature for similar drug  

 
12 
Severity of AE 
o Mild: awareness of signs or symptoms, but they are easily tolerated  
o Moderate: enough discomfort to cause interference with usual activity  
o 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. 
 
Final outcome  
o 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  
o 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.  
o 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.  
o Not recovered/not resolved - The condition of the subject has not improved 
and the symptoms are unchanged, or the outcome is not known.  
o Fatal - This term is only applicable if the subject died from a condition related 
to the reported AE.  
o Unknown - This term is only applicable if the subject is lost to follow-up  
 
Reporting SAE  
• Information about all SAE will be documented in the AE form and reported to 
Coordinating Investigator of the study, Dr. Deviga a/p Lachumanan at 
devigaonline@gmail.com and UKM ethics directly within 24 hours.  
 
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.  
• Adverse events will be explored and documented at each clinic visit.  
 
Safety update 
• Any safety updates will be notified to UKM ethics committee. 
 
 
 
 

 
13 
Sample size  
 
Sample size calculation was calculated using two population proportion formulae. Prior data 
indicate that the proportion of cure of the patients receiving lithium was 0.91 (Bogazzi et al.)1 
and the proportion of cure of the patients receiving carbimazole was 0.57 (Kartamihardja et 
al.)2 Thus a minimum sample size of 34 samples per group to be able to reject null hypothesis 
with probability power of 0.9. The type 1 error probability associated with this test of the null 
hypothesis is 0.95. Person’s Chi Square test for independence will be used to evaluate this 
null hypothesis. With additional of two 20% dropout rate, the sample size is 43 samples per 
group. 
 
 
 
Reference:  
1. Bogazzi F, Giovannetti C, Fessehatsion R et al. Impact of lithium on efficacy of radioactive iodine 
therapy for Graves' disease: a cohort study on cure rate, time to cure, and frequency of increased serum 
thyroxine after antithyroid drug withdrawal. J Clin Endocrinol Metab. 2010 Jan;95(1):201-8. 
2. Kartamihardja AH, Massora S. The Influence of Antithyroid Drug Discontinuation to the Therapeutic 
Efficacy of (131)I in Hyperthyroidism. World J Nucl Med. 2016 May-Aug;15(2):81-4. 
 
 
Study Duration and Timeline  
 
Stage 1:  
Recruitment period is 12 months; commencing from the dates of ethics approval. There are 2 
phases of this study:  
• Phase 1: Patients will be followed up for 2months duration from recruitment till date 
of RAI. 
• Phase 2: Patients will be followed up at 1, 3, and 6months post RAI therapy.  
 
Stage 2:  
Data collection and Data Analysis will cover a period of 18months, from January 2021 till 
Jun 2022. 
 
Stage 3:  
Presentation and publication will take about 6months period from March till September 2022. 
 
The participation duration of each subject is 8months in total.  (Refer to Appendix 2) 

 
14 
Study Visits and Procedures  
 
Time line 
Carbimazole arm  
 
Lithium arm  
0 (recruitment) 
History, physical examination including baseline eye examination for 
possible thyroid eye disease will be carried out. 10mls blood will be drawn 
for baseline TFT, RP) and LFT. 
 
1week later 
- 
Patients will be inquired of any possible 
side effects. 4mls blood will be drawn 
for lithium level and RP 
 
2 months later (on 
RAI day) 
 
History and Physical 
Examination and 8mls of blood 
drawn for TFT, RP, LFT 
 
History and Physical Examination and 
10mls of blood drawn for TFT, RP, 
LFT and TDM lithium. Patients will be 
inquired of any possible side effects. 
 
1 months after RAI 
History and Physical Examination and 2mls of blood drawn for TFT 
 
3 months after RAI 
History and Physical Examination and 2mls of blood drawn for TFT 
 
6 months after RAI  
History and Physical Examination and 2mls of blood drawn for TFT 
 
 
 
Statistical Analysis Plan  
 
Data will be entered and analysed using SPSS version 23 with appropriate statistical tools. 
Normally distributed data will be presented as mean±SD. Non-normally distributed data will 
be presented as median and interquartile range. For comparison of baseline characteristics 
between the two groups, (lithium vs carbimazole) the independent sample t-test will be used 
if the numerical data is normally distributed and the Mann-Whitney U-test for non-normally 
distributed data. Pearson’s Chi-square test will be used to compare the categorical data 
between the two groups (lithium vs carbimazole). P <0.05 will be used to determine 
statistical significance; data reported as mean Standard Deviation.  
 
 
Risk and Benefit to Participants  
 
Risks: 
 
Lithium has been used extensively for treatment of various medical conditions. The dose 
used for this study is much lower. The study procedures are all routine procedures for the 
disease/condition studied. There is thus minimal risk for subjects. 
 
Benefits: 
 
This study may benefit you by reducing your high thyroid hormone level in your body prior 
to undergoing radioactive iodine therapy without compromising the outcome of the 
radioactive iodine treatment. 
 
 

 
15 
Risk Benefit Assessment  
 
There is minimal risk for this study as the treatment of these patients are in accordance to 
standards of care. Study findings shall potentially greatly improve treatment outcomes. The 
expected benefit outweighs the risk to the participants and thus this study should be 
supported. This study examines patient-outcomes and results will be beneficial for policy 
makers to plan and structure comprehensive care and tailor it to best suit the patients. If 
patient develops intolerable side effects or lithium level above therapeutic range, the 
confounding drug will be stopped and will be managed accordingly. The patient will be 
excluded from this study. 
 
Ethics of Study   
 
This study will be conducted in compliance with ethical principle in the Declaration of 
Helsinki and Malaysian Good Clinical Practice Guidelines.  
 
Informed Consent  
 
Patients shall be informed of the study during their usual clinic visits. They will be requested 
to contact investigators if they are interested. An appointment will be made where the patient 
information sheet will be provided and explained to them. If they are willing to participate, 
the consent forms will be signed and dated. If they need to, they are allowed to take the 
information sheet home to consult with their family members, and another day for getting 
consent arranged. 
 
Privacy and Confidentiality  
 
Study subjects’ personal details will be remained confidential. Study ID will be assigned to 
each subject and the data that are transcribed into standardized data entry forms will only 
contain the study ID. All data will be entered into computer that is password protected. After 
completion of the study, the data saved into the computer will be erased. The hardcopy and 
pen drive of the data will be stored in a locked cabinet of the principle investigator and 
maintained for a minimum of 7 years after the completion of the study. Both will then be 
destroyed after 7 years of storage. Subjects will not be allowed to view their personal study 
data, as the data will be consolidated into a database. Subjects can write to the investigators 
to request access to study findings. 
 
Conflict of Interest  
 
The investigators declare they have no conflict of interest.  
 
Publication Policy  
 
No personal information will be disclosed, and subjects will not be identified when the 
findings of the survey are published.  
 
Termination of Study  
 
If the study needs to be terminated, participants will be informed, and follow-up visits will be 
arranged.  
 

 
16 
REFERENCE  
 
1. Sabri O, Zimny M, Schulz G, Schreckenberger M, Reinartz P, Willmes K, et al. Success rate 
of radioiodine therapy in Graves' disease: The influence of thyrostatic medication. J Clin 
Endocrinol Metab 1999;84:1229-33.  
     
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18 
Appendix 1 
LIST OF MEDICATIONS NOT PERMITTED DURING THIS TRIAL     
During this trial, subjects participating in this research cannot be on these medications 
concomitantly:  
1. Selective serotonin reuptake inhibitors (SSRI) 
2. Monoamine oxidase inhibitors (MAOIs) 
3. Tricyclic antidepressant (TCA) 
4. Anticonvulsants  
5. Methyldopa  
6. Methylxanthine 
7. Muscle relaxants  
8. Non-steroidal anti-inflammatory drugs (NSAIDs) 
9. Phenothiazines 
10. Tramadol  
11. Diuretics   
12. Acetazolamide  
13. Anticonvulsants  
14. Antipsychotic  
 
 

 
19 
Appendix 2 
 
GANTT CHART  
 
 
 
 
 
Year 
2020 
2021 
2022 
    
Oct 
Nov 
Dec 
Jan 
Jun 
Sep 
Dec 
Jan  
Mar  
Jun  
Sep 
Proposal 
Presentation 
 
 
 
 
 
 
 
 
 
 
 
Ethical  
Submission 
and Approval 
 
 
 
 
 
 
 
 
 
 
 
Recruitment  
 
 
 
 
 
 
 
 
 
 
 
Data 
Collection 
 
 
 
 
 
 
 
 
 
 
 
Data Analysis 
 
 
 
 
 
 
 
 
 
 
 
Writing and 
publication 
 
 
 
 
 
 
 
 
 
 
 

 
20 
Appendix 3 
STUDY FLOW CHART  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RECRUITMENT OF PATIENTS  
RANDOMIZATION OF THE PATIENTS 
LITHIUM ARM 
CARBIMAZOLE ARM 
VISIT 1 (0 week) 
History  
Physical Assessment  
Thyroid Eye Disease Evaluation 
Laboratory Sampling - TFT, RP, LFT 
VISIT 1 (0 week) 
History  
Physical Assessment  
Thyroid Eye Disease Evaluation 
Laboratory Sampling - TFT, RP, LFT 
VISIT 2 (1 week later) 
Laboratory Sampling - TDM Lithium, RP 
VISIT 3 (2months later, on RAI day) 
History  
Physical Examination  
Laboratory Sampling - TDM Lithium, TFT, 
RP, LFT 
VISIT  2 (2months later, on RAI day) 
History  
Physical Examination  
Laboratory Sampling – TFT, RP, LFT  
RADIOACTIVE IODINE (15mci) 
Stop Lithium 3 days after 
RAI  
Stop Carbimazole 3 days 
prior to RAI  
VISIT 1 (1 MONTH POST RAI) 
To see the acute effect of RAI  
Laboratory sampling - TFT 
VISIT 2 (3 MONTHS POST RAI) 
History  
Physical examinations  
Laboratory sampling - TFT 
VISIT 3 (6 MONTHS POST RAI) 
History  
Physical examinations  
Laboratory sampling - TFT 

 
21 
Appendix 4 
 
 
ESTIMATED BUDGET PROPOSAL  
 
 
 
 
 
No 
Description 
Price per unit 
(RM) 
Quantity 
 
Total amount 
(RM) 
 
1. 
 
Blood test 
TFT 
TDM Lithium 
Renal profile  
Liver function test 
 
 
 
34 
4 
13 
16 
 
 
430 
86 
258 
172 
 
 
14 620 
344 
3 354 
2 752 
 
 
2.  
 
Radioactive Iodine  
 
405 
 
86 
 
34 830 
 
 
 
 
 
TOTAL 
 
 
55 900