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

Graves Disease Clinical Trial

— ChoPS  

Official 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 Treatment of Overt Hyperthyroidism

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03303053
• Other study ID #: ChoPS Study Version 3.0
• Status: Recruiting
• Phase: Phase 3
• First received: September 13, 2017
• Last updated: October 1, 2017
• Start date: May 11, 2017
• Est. completion date: March 1, 2018

Study information

• Verified date: October 2017
• Source: Clinical Research Centre, Malaysia
• Contact: Serena SK Khoo, Dr.
• Phone: +603 83124200
• Email: sk_liv[@]rocketmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 135
• Est. completion date: March 1, 2018
• Est. primary completion date: March 1, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Graves Disease
• Hyperthyroidism

Intervention

Drug:
• Cholestyramine Powder 4g
Cholestyramine powder 4g twice daily, Tablet Carbimazole 30 mg daily, Tablet propanolol 40 mg twice daily for 4 weeks
• 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
• Standard treatment
Carbimazole 30 mg daily and propanolol 40 mg twice daily for 4 weeks

Locations

Country	Name	City	State
Malaysia	Hospital Ampang	Ampang	Selangor
Malaysia	Hospital Queen Elizabeth 2	Kota Kinabalu	Sabah
Malaysia	Hospital Putrajaya	Putrajaya	Wilayah Persekutuan

Sponsors (2)

Lead Sponsor	Collaborator
Clinical Research Centre, Malaysia	Ministry of Health, Malaysia

Country where clinical trial is conducted

Malaysia, 

References & Publications (16)

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Kaykhaei MA, Shams M, Sadegholvad A, Dabbaghmanesh MH, Omrani GR. Low doses of cholestyramine in the treatment of hyperthyroidism. Endocrine. 2008 Aug-Dec;34(1-3):52-5. doi: 10.1007/s12020-008-9107-5. Epub 2008 Oct 23. — View Citation

Mercado M, Mendoza-Zubieta V, Bautista-Osorio R, Espinoza-de los Monteros AL. Treatment of hyperthyroidism with a combination of methimazole and cholestyramine. J Clin Endocrinol Metab. 1996 Sep;81(9):3191-3. — View Citation

Migneco A, Ojetti V, Testa A, De Lorenzo A, Gentiloni Silveri N. Management of thyrotoxic crisis. Eur Rev Med Pharmacol Sci. 2005 Jan-Feb;9(1):69-74. Review. — View Citation

Nakamura H, Noh JY, Itoh K, Fukata S, Miyauchi A, Hamada N. Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves' disease. J Clin Endocrinol Metab. 2007 Jun;92(6):2157-62. Epub 2007 Mar 27. — View Citation

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Page SR, Sheard CE, Herbert M, Hopton M, Jeffcoate WJ. A comparison of 20 or 40 mg per day of carbimazole in the initial treatment of hyperthyroidism. Clin Endocrinol (Oxf). 1996 Nov;45(5):511-6. Erratum in: Clin Endocrinol (Oxf) 1997 Feb;46(2):240. — View Citation

Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, Rivkees SA, Samuels M, Sosa JA, Stan MN, Walter MA. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016 Oct;26(10):1343-1421. — View Citation

Solomon BL, Wartofsky L, Burman KD. Adjunctive cholestyramine therapy for thyrotoxicosis. Clin Endocrinol (Oxf). 1993 Jan;38(1):39-43. — View Citation

Sundaresh V, Brito JP, Wang Z, Prokop LJ, Stan MN, Murad MH, Bahn RS. Comparative effectiveness of therapies for Graves' hyperthyroidism: a systematic review and network meta-analysis. J Clin Endocrinol Metab. 2013 Sep;98(9):3671-7. doi: 10.1210/jc.2013-1954. Epub 2013 Jul 3. Review. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of patients whose Free T4 normalize between the groups	Normal Free T4 is defined as Free T4 level between 9-25 pmol/L	4 weeks
Primary	Percentage of patients whose Free T3 normalize between the groups	Normal free T3 is defined as Free T3 level between 3.5-6.5 pmol/L	4 weeks
Secondary	Adverse events between the groups	Number of adverse events between the groups	6 weeks
Secondary	Reduction in Free T4 levels	Reduction in Free T4 levels ( Change from baseline within 4 weeks)	4 weeks
Secondary	Reduction in Free T3 levels	Reduction in Free T3 levels (Change from baseline within 4 weeks)	4 weeks