Efficacy and Safety of Cholestyramine and Prednisolone as Adjunctive Therapy in Treatment of Overt Hyperthyroidism
Efficacy and Safety of Cholestyramine and Prednisolone as Adjunctive Therapy in Treatment of Overt Hyperthyroidism
Hyperthyroidism is the second most common endocrine disorder in the world with Graves'
 disease being the commonest. Anti thyroid drugs including methimazole, carbimazole, and
 propylthiouracil are effective treatments but take in most cases between 6 to 8 weeks to
 achieve euthyroidism. This study aim to assess the efficacy of cholestyramine and
 prednisolone as adjunctive treatment to standard treatment in patients with overt
 hyperthyroidism in 4 weeks.
Hyperthyroidism is the second most common endocrine disorder in the world with an estimate
 prevalence rate of 0.5-1.3% with Graves' disease being the commonest cause.

 Uncontrolled hyperthyroidism results in increase cardiovascular morbidity and mortality
 primarily due to heart failure and thromboembolism. Therefore treatment is essential to
 restore a euthyroid state in order to reverse the cardiovascular complications.

 Anti thyroid drugs (ATDs) including methimazole, carbimazole, and propylthiouracil are
 effective treatments that inhibit thyroid hormone synthesis, and have clinically important
 immunosuppressive effects including reducing serum antithyrotropin receptor antibody (TRAb)
 concentration with time but take in most cases between 6 to 8 weeks to achieve euthyroidism.
 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
 such as before surgery or radioactive iodine treatment or in vulnerable groups such as the
 elderly or those with serious thyrotoxic complications.

 This study aim to assess the efficacy of cholestyramine and prednisolone as adjunctive
 treatment to standard treatment in patients with overt hyperthyroidism in 4 weeks.
 Cholestyramine is an anion exchange resin that binds thyroxine (T4) in the intestine
 resulting in fecal excretion of T4 thus reducing the enterohepatic circulation and absorption
 in hyperthyroidism. Steroids have been shown to be effective in controlling hyperthyroidism
 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 and hence decrease stimulation of the thyroid gland in Graves.

 135 patients with moderate to severe uncontrolled overt hyperthyroid patients secondary to
 Graves disease will be randomized into 3 groups. Group 1 patients will be treated with
 cholestyramine 4g twice a day plus carbimazole and propanolol for 4 weeks. Group 2 patients
 will be treated with 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 plus carbimazole and propanolol for 4 weeks. Group 3
 patients will be treated with carbimazole 30 mg daily and propanolol 40 mg bd for 4 weeks.
 Patients will have their clinical status (weight, blood pressure, pulse rate) measured at
 baseline along with a TRAb level and Free Triiodotyronine (T3), Free T4 and Thyroid
 stimulating hormone (TSH) levels. They will be evaluated at week 2 and week 4 of intervention
 period and have their clinical status (weight, blood pressure, pulse rate) and laboratory
 (Free T3, Free T4, TSH, Potassium, Fasting/random blood glucose) measured. Adverse events
 will be monitored at week 2, 4, and 6.
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.

 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.

 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