Efficacy and Safety of Cholestyramine and Prednisolone as Adjunctive Therapy in Treatment of Overt Hyperthyroidism

Phase 3

• Conditions: Hyperthyroidism; Graves Disease
• Interventions: Drug: Standard treatment; Drug: Cholestyramine Powder 4g; Drug: Prednisolone

• Registration Number: NCT03303053
• Lead Sponsor: Clinical Research Centre, Malaysia

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Study Start: 2017-05-11
• Study First Submitted: 2017-09-13
• Status Verified: 2017-10
• Study First Submitted QC: 2017-10-01
• Last Update Submitted: 2017-10-01
• Study First Posted: 2017-10-05
• Last Update Posted: 2017-10-05
• Primary Completion: 2018-03-01
• Study Completion: 2018-03-01

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 135

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group 3: Standard treatment alone	Standard treatment	Carbimazole 30 mg daily and propanolol 40 mg twice daily for 4 weeks
Group1:Cholestyramine+standard treatment	Cholestyramine Powder 4g	Cholestyramine powder 4g twice daily, Tablet Carbimazole 30 mg daily, Tablet propanolol 40 mg twice daily for 4 weeks
Group2:Prednisolone+standard treatment	Prednisolone	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 for 4 weeks

Primary Outcome Measures

Name	Time	Method
Percentage of patients whose Free T4 normalize between the groups	4 weeks	Normal Free T4 is defined as Free T4 level between 9-25 pmol/L
Percentage of patients whose Free T3 normalize between the groups	4 weeks	Normal free T3 is defined as Free T3 level between 3.5-6.5 pmol/L

Secondary Outcome Measures

Name	Time	Method
Reduction in Free T4 levels	4 weeks	Reduction in Free T4 levels ( Change from baseline within 4 weeks)
Adverse events between the groups	6 weeks	Number of adverse events between the groups
Reduction in Free T3 levels	4 weeks	Reduction in Free T3 levels (Change from baseline within 4 weeks)

Trial Locations

Locations (3)

Hospital Queen Elizabeth 2; 🇲🇾 Kota Kinabalu, Sabah, Malaysia

Hospital Ampang; 🇲🇾 Ampang, Selangor, Malaysia

Hospital Putrajaya; 🇲🇾 Putrajaya, Wilayah Persekutuan, Malaysia