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

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ClinicalTrials.gov Identifier: NCT03303053
Recruitment Status : Unknown
Verified October 2017 by Clinical Research Centre, Malaysia.
Recruitment status was:  Recruiting
First Posted : October 5, 2017
Last Update Posted : October 5, 2017
Sponsor:
Collaborator:
Ministry of Health, Malaysia
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Hyperthyroidism Graves Disease Drug: Cholestyramine Powder 4g Drug: Prednisolone Drug: Standard treatment Phase 3

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 135 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Multi-center, open label, randomised, parallel-group
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 11, 2017
Estimated Primary Completion Date : March 1, 2018
Estimated Study Completion Date : March 1, 2018


Arm Intervention/treatment
Experimental: Group1:Cholestyramine+standard treatment
Cholestyramine powder 4g twice daily, Tablet Carbimazole 30 mg daily, Tablet propanolol 40 mg twice daily for 4 weeks
Drug: Cholestyramine Powder 4g
Cholestyramine powder 4g twice daily, Tablet Carbimazole 30 mg daily, Tablet propanolol 40 mg twice daily for 4 weeks
Other Name: Questran

Experimental: Group2:Prednisolone+standard treatment
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
Drug: 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

Active Comparator: Group 3: Standard treatment alone
Carbimazole 30 mg daily and propanolol 40 mg twice daily for 4 weeks
Drug: Standard treatment
Carbimazole 30 mg daily and propanolol 40 mg twice daily for 4 weeks
Other Name: Carbimazole + Propanolol




Primary Outcome Measures :
  1. Percentage of patients whose Free T4 normalize between the groups [ Time Frame: 4 weeks ]
    Normal Free T4 is defined as Free T4 level between 9-25 pmol/L

  2. Percentage of patients whose Free T3 normalize between the groups [ Time Frame: 4 weeks ]
    Normal free T3 is defined as Free T3 level between 3.5-6.5 pmol/L


Secondary Outcome Measures :
  1. Adverse events between the groups [ Time Frame: 6 weeks ]
    Number of adverse events between the groups

  2. Reduction in Free T4 levels [ Time Frame: 4 weeks ]
    Reduction in Free T4 levels ( Change from baseline within 4 weeks)

  3. Reduction in Free T3 levels [ Time Frame: 4 weeks ]
    Reduction in Free T3 levels (Change from baseline within 4 weeks)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03303053


Contacts
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Contact: Serena SK Khoo, Dr. +603 83124200 sk_liv@rocketmail.com
Contact: Zanariah Hussein, Dr. +03 83124200 zanariahh@hotmail.com

Locations
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Malaysia
Hospital Queen Elizabeth 2 Recruiting
Kota Kinabalu, Sabah, Malaysia, 88300
Contact: Yin Khet Fung, Dr.    +6 088324600    fung@doctors.org.uk   
Contact: Gayathri D Krishnan, Dr.    +6 088324600    kgaya3@yahoo.com   
Sub-Investigator: Pei Lin Chan, Dr.         
Hospital Ampang Recruiting
Ampang, Selangor, Malaysia, 68000
Contact: Vijiya M Valayatham, Dr    +60342896000    ammu_vj@yahoo.com   
Hospital Putrajaya Recruiting
Putrajaya, Wilayah Persekutuan, Malaysia, 62250
Contact: Serena SK Khoo, Dr.    +6 03 83124200    sk_liv@rocketmail.com   
Contact: Zanariah Hussein, Dr.    +6 03 83124200    zanariahh@hotmail.com   
Sub-Investigator: Siti A Alias, Dr         
Sub-Investigator: Lisa Mohamed Nor, Dr         
Sub-Investigator: Rashidah Bahari, Dr         
Sub-Investigator: Nurul Z Badarudin, Dr         
Sponsors and Collaborators
Clinical Research Centre, Malaysia
Ministry of Health, Malaysia
Investigators
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Principal Investigator: Serena SK Khoo, Dr. HospitalPutrajaya
  Study Documents (Full-Text)

Documents provided by Clinical Research Centre, Malaysia:
Informed Consent Form  [PDF] June 5, 2017


Publications:

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Responsible Party: Clinical Research Centre, Malaysia
ClinicalTrials.gov Identifier: NCT03303053     History of Changes
Other Study ID Numbers: ChoPS Study Version 3.0
First Posted: October 5, 2017    Key Record Dates
Last Update Posted: October 5, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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
Keywords provided by Clinical Research Centre, Malaysia:
Hyperthyroidism,Graves disease,Cholestyramine,Prednisolone
Additional relevant MeSH terms:
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Hyperthyroidism
Anti-Inflammatory Agents
Graves Disease
Exophthalmos
Orbital Diseases
Eye Diseases
Goiter
Thyroid Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Prednisolone
Methylprednisolone Acetate
Methylprednisolone
Methylprednisolone Hemisuccinate
Prednisolone acetate
Propranolol
Cholestyramine Resin
Prednisolone hemisuccinate
Prednisolone phosphate
Carbimazole
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents