search
Back to results

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

Primary Purpose

Hyperthyroidism, Graves Disease

Status
Unknown status
Phase
Phase 3
Locations
Malaysia
Study Type
Interventional
Intervention
Cholestyramine Powder 4g
Prednisolone
Standard treatment
Sponsored by
Clinical Research Centre, Malaysia
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hyperthyroidism focused on measuring Hyperthyroidism,Graves disease,Cholestyramine,Prednisolone

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Hospital Queen Elizabeth 2Recruiting
  • Hospital AmpangRecruiting
  • Hospital PutrajayaRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Active Comparator

Arm Label

Group1:Cholestyramine+standard treatment

Group2:Prednisolone+standard treatment

Group 3: Standard treatment alone

Arm Description

Cholestyramine powder 4g twice daily, Tablet Carbimazole 30 mg daily, Tablet propanolol 40 mg twice daily for 4 weeks

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

Carbimazole 30 mg daily and propanolol 40 mg twice daily for 4 weeks

Outcomes

Primary Outcome Measures

Percentage of patients whose Free T4 normalize between the groups
Normal Free T4 is defined as Free T4 level between 9-25 pmol/L
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

Secondary Outcome Measures

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

Full Information

First Posted
September 13, 2017
Last Updated
October 1, 2017
Sponsor
Clinical Research Centre, Malaysia
Collaborators
Ministry of Health, Malaysia
search

1. Study Identification

Unique Protocol Identification Number
NCT03303053
Brief Title
Efficacy and Safety of Cholestyramine and Prednisolone as Adjunctive Therapy in Treatment of Overt Hyperthyroidism
Acronym
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2017
Overall Recruitment Status
Unknown status
Study Start Date
May 11, 2017 (Actual)
Primary Completion Date
March 1, 2018 (Anticipated)
Study Completion Date
March 1, 2018 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Clinical Research Centre, Malaysia
Collaborators
Ministry of Health, Malaysia

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hyperthyroidism, Graves Disease
Keywords
Hyperthyroidism,Graves disease,Cholestyramine,Prednisolone

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
Multi-center, open label, randomised, parallel-group
Masking
None (Open Label)
Allocation
Randomized
Enrollment
135 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Group1:Cholestyramine+standard treatment
Arm Type
Experimental
Arm Description
Cholestyramine powder 4g twice daily, Tablet Carbimazole 30 mg daily, Tablet propanolol 40 mg twice daily for 4 weeks
Arm Title
Group2:Prednisolone+standard treatment
Arm Type
Experimental
Arm Description
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
Arm Title
Group 3: Standard treatment alone
Arm Type
Active Comparator
Arm Description
Carbimazole 30 mg daily and propanolol 40 mg twice daily for 4 weeks
Intervention Type
Drug
Intervention Name(s)
Cholestyramine Powder 4g
Other Intervention Name(s)
Questran
Intervention Description
Cholestyramine powder 4g twice daily, Tablet Carbimazole 30 mg daily, Tablet propanolol 40 mg twice daily for 4 weeks
Intervention Type
Drug
Intervention Name(s)
Prednisolone
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Standard treatment
Other Intervention Name(s)
Carbimazole + Propanolol
Intervention Description
Carbimazole 30 mg daily and propanolol 40 mg twice daily for 4 weeks
Primary Outcome Measure Information:
Title
Percentage of patients whose Free T4 normalize between the groups
Description
Normal Free T4 is defined as Free T4 level between 9-25 pmol/L
Time Frame
4 weeks
Title
Percentage of patients whose Free T3 normalize between the groups
Description
Normal free T3 is defined as Free T3 level between 3.5-6.5 pmol/L
Time Frame
4 weeks
Secondary Outcome Measure Information:
Title
Adverse events between the groups
Description
Number of adverse events between the groups
Time Frame
6 weeks
Title
Reduction in Free T4 levels
Description
Reduction in Free T4 levels ( Change from baseline within 4 weeks)
Time Frame
4 weeks
Title
Reduction in Free T3 levels
Description
Reduction in Free T3 levels (Change from baseline within 4 weeks)
Time Frame
4 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Provision of written consent by subject or guardian. Subject of either sex, more than 18 years of age 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 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: Inability or unwillingness to provide written consent. Inability or unwillingness to comply with the requirements of the protocol as determined by the investigator. Pregnancy, breastfeeding or use of non-reliable method of contraception. Subjects with history of chronic liver disease, chronic renal failure, heart failure, diabetes mellitus Subjects with history of peptic ulcer disease, upper gastrointestinal bleeding, diverticulitis or ulcerative colitis. Subjects who have recently had live or attenuated virus vaccines Subjects with current infection (systemic fungal, active tuberculosis, cerebral malaria, viral hepatitis, HIV) Subjects with cataracts and glaucoma Subjects with osteoporosis Subjects with psychiatric disorders Subjects with complete biliary obstruction, bleeding disorders, hypertriglyceridemia (fasting triglyceride levels > 300mg/dL) Previous history of adverse reactions to cholestyramine or other bile acid sequestrants Previous history of adverse reactions to prednisolone or other steroid compound Current use of cholestyramine or prednisolone or other steroid compound Participation in another clinical trial and/or receipt of cholestyramine or prednisolone within 4 weeks prior to screening visit. Subjects with history of bronchial asthma, bronchospasm, peripheral vascular disease or adverse reactions to propanolol Subjects with adverse reactions to carbimazole Hypokalemia (serum K+ <3.5 mmol/L) Thyroid storm defined as Burch Wartofsky Score >45
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Serena SK Khoo, Dr.
Phone
+603 83124200
Email
sk_liv@rocketmail.com
First Name & Middle Initial & Last Name or Official Title & Degree
Zanariah Hussein, Dr.
Phone
+03 83124200
Email
zanariahh@hotmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Serena SK Khoo, Dr.
Organizational Affiliation
HospitalPutrajaya
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hospital Queen Elizabeth 2
City
Kota Kinabalu
State/Province
Sabah
ZIP/Postal Code
88300
Country
Malaysia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yin Khet Fung, Dr.
Phone
+6 088324600
Email
fung@doctors.org.uk
First Name & Middle Initial & Last Name & Degree
Gayathri D Krishnan, Dr.
Phone
+6 088324600
Email
kgaya3@yahoo.com
First Name & Middle Initial & Last Name & Degree
Pei Lin Chan, Dr.
Facility Name
Hospital Ampang
City
Ampang
State/Province
Selangor
ZIP/Postal Code
68000
Country
Malaysia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Vijiya M Valayatham, Dr
Phone
+60342896000
Email
ammu_vj@yahoo.com
Facility Name
Hospital Putrajaya
City
Putrajaya
State/Province
Wilayah Persekutuan
ZIP/Postal Code
62250
Country
Malaysia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Serena SK Khoo, Dr.
Phone
+6 03 83124200
Email
sk_liv@rocketmail.com
First Name & Middle Initial & Last Name & Degree
Zanariah Hussein, Dr.
Phone
+6 03 83124200
Email
zanariahh@hotmail.com
First Name & Middle Initial & Last Name & Degree
Siti A Alias, Dr
First Name & Middle Initial & Last Name & Degree
Lisa Mohamed Nor, Dr
First Name & Middle Initial & Last Name & Degree
Rashidah Bahari, Dr
First Name & Middle Initial & Last Name & Degree
Nurul Z Badarudin, Dr

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
17389704
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. doi: 10.1210/jc.2006-2135. Epub 2007 Mar 27.
Results Reference
background
PubMed Identifier
11836274
Citation
Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, Braverman LE. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002 Feb;87(2):489-99. doi: 10.1210/jcem.87.2.8182.
Results Reference
background
PubMed Identifier
24423323
Citation
Garmendia Madariaga A, Santos Palacios S, Guillen-Grima F, Galofre JC. The incidence and prevalence of thyroid dysfunction in Europe: a meta-analysis. J Clin Endocrinol Metab. 2014 Mar;99(3):923-31. doi: 10.1210/jc.2013-2409. Epub 2014 Jan 1.
Results Reference
background
PubMed Identifier
27521067
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. doi: 10.1089/thy.2016.0229. Erratum In: Thyroid. 2017 Nov;27(11):1462.
Results Reference
background
PubMed Identifier
18752767
Citation
Dahl P, Danzi S, Klein I. Thyrotoxic cardiac disease. Curr Heart Fail Rep. 2008 Sep;5(3):170-6. doi: 10.1007/s11897-008-0026-9.
Results Reference
background
PubMed Identifier
15302638
Citation
Frost L, Vestergaard P, Mosekilde L. Hyperthyroidism and risk of atrial fibrillation or flutter: a population-based study. Arch Intern Med. 2004 Aug 9-23;164(15):1675-8. doi: 10.1001/archinte.164.15.1675. Erratum In: Arch Intern Med. 2005 Feb 14;165(3):307.
Results Reference
background
PubMed Identifier
23824415
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.
Results Reference
background
PubMed Identifier
18946743
Citation
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.
Results Reference
background
PubMed Identifier
15850146
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.
Results Reference
background
PubMed Identifier
8435884
Citation
Solomon BL, Wartofsky L, Burman KD. Adjunctive cholestyramine therapy for thyrotoxicosis. Clin Endocrinol (Oxf). 1993 Jan;38(1):39-43. doi: 10.1111/j.1365-2265.1993.tb00970.x.
Results Reference
background
PubMed Identifier
8784067
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. doi: 10.1210/jcem.81.9.8784067.
Results Reference
background
PubMed Identifier
8796215
Citation
Jude EB, Dale J, Kumar S, Dodson PM. Treatment of thyrotoxicosis resistant to carbimazole with corticosteroids. Postgrad Med J. 1996 Aug;72(850):489-91. doi: 10.1136/pgmj.72.850.489.
Results Reference
background
PubMed Identifier
1814659
Citation
Baeza A, Aguayo J, Barria M, Pineda G. Rapid preoperative preparation in hyperthyroidism. Clin Endocrinol (Oxf). 1991 Nov;35(5):439-42. doi: 10.1111/j.1365-2265.1991.tb03562.x.
Results Reference
background
PubMed Identifier
8977745
Citation
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. doi: 10.1046/j.1365-2265.1996.00800.x. Erratum In: Clin Endocrinol (Oxf) 1997 Feb;46(2):240.
Results Reference
background
PubMed Identifier
6688394
Citation
Ozawa Y, Daida H, Shimizu T, Shishiba Y. Rapid improvement of thyroid function by using glucocorticoid indicated for the preoperative preparation of subtotal thyroidectomy in Graves' disease. Endocrinol Jpn. 1983 Feb;30(1):93-100. doi: 10.1507/endocrj1954.30.93.
Results Reference
background
PubMed Identifier
7989897
Citation
Conn HO, Poynard T. Corticosteroids and peptic ulcer: meta-analysis of adverse events during steroid therapy. J Intern Med. 1994 Dec;236(6):619-32. doi: 10.1111/j.1365-2796.1994.tb00855.x.
Results Reference
background

Learn more about this trial

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

We'll reach out to this number within 24 hrs