Selenium Supplementation Versus Placebo in Patients with Graves' Hyperthyroidism (GRASS)

GRAves Selenium Supplementation Trial (GRASS) - an Investigator-initiated Randomised, Blinded, Multicentre Clinical Trial of Selenium Supplementation Versus Placebo in Patients with Graves' Hyperthyroidism

The purpose of this study is to investigate if selenium supplementation to the standard treatment with anti-thyroid drugs in patients with Graves' hyperthyroidism, will lead to a fewer people with anti-thyroid treatment failure and faster remission, in terms of better quality of life during the first year of treatment and more patients staying in remission.

Study Overview

• Status: Completed
• Conditions: Graves' Hyperthyroidism
• Intervention / Treatment: Dietary supplement: Selenium; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 431
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark
    • Department of Endocrinology and Gastroenterology, Bispebjerg Hospital
  • Copenhagen, Denmark
    • Department of Medical Endocrinology, Rigshospitalet
  • Esbjerg, Denmark
    • Department of Endocrinology, Hospital of Southwest Denmark
  • Gentofte, Denmark
    • Department of Medicine, Gentofte Hospital
  • Herlev, Denmark
    • Department of Internal Medicine O 106, Endocrine Unit, Herlev Hospital
  • Hillerød, Denmark
    • Department of Cardiology and Endocrinology, Endocrine Unit, Hillerød Hospital
  • Hvidovre, Denmark
    • Department of Endocrinology, Section 541, Hvidovre Hospital
  • Odense, Denmark
    • Department of Endocrinology and Metabolism, Odense University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18 years or older.
• Active Graves' hyperthyroidism (suppressed TSH (< 0.1) and positive TRAb) measured within the last two months prior to the inclusion date.
• Written informed consent

Exclusion Criteria:

• Major co-morbidity, making the participants unlikely to continuously receive trial intervention in the intervention period.
• Previous treatment with radioactive iodine.
• Current ATD treatment having been received for more than two months.
• Treatment with immunomodulatory drugs, such as cyclosporine A, methotrexate, cyclophosphamide.
• Allergy towards the components in the selenium and placebo pills.
• Pregnant or breast-feeding women.
• Intake of selenium supplementation above 70 µg per day (70 µg corresponds to the amount in a multivitamin tablet).
• Unable to read and understand Danish.
• Lack of informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Other: Placebo; Placebo tablets, identical in regards to size, appearance, taste, smell, and solubility to the experimental intervention tablet will be produced by Jemo-Pharm A/S, http://www.jemo-pharm.dk/frame.cfm/cms/id=977/sprog=2/grp=6/menu=1/ (content as in section: Auxiliary agents). The placebo regimen will be identical to the selenium regimen, but consist of two non-active tablets per day for 24-30 months.
Active Comparator: Selenium	Dietary supplement: Selenium; 100 µg tablets. The dose of daily supplement of selenium is set at 200 µg (two tablets). The duration of the intervention period is between 24-30 months. This is defined by the time of ATD treatment withdrawal, which is scheduled between approximately 12-18 months after randomisation. Selenium supplementation will continue 12 months after withdrawal of ATD treatment.; Other Names: 'Selen, organisk selen', produced by Jemo-Pharm A/S

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of participants with the composite outcome of 'ATD treatment failure'	'ATD treatment failure' is defined as: The participant receives ATD treatment (at any level) during the last 12 months (± 1 month) of the intervention period; or; The participant has thyroid hyperfunction (TSH <0.1) during the last 12 months (± 1 month) of the intervention period; or; The participant has been referred to ablative therapy (radioactive iodine or thyroid surgery) at some point during the entire intervention period.	Last 12 months (± 1 month) of the intervention period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of participants who receives ATD treatment (at any level) during the last 12 months (± 1 month) of the intervention period		Last 12 months (± 1 month) of the intervention period
Proportion of participants who has thyroid hyperfunction (TSH <0.1) during the last 12 months (± 1 month) of the intervention period		Last 12 months (± 1 month) of the intervention period
Proportion of participants who has been referred to ablative therapy (radioactive iodine or thyroid surgery) at some point during the entire intervention period		Intervention period (24-30 months)
Thyroid-specific QoL during the first year after randomisation, and at the end of the intervention period (24-30 months), as measured by the global score in the ThyPRO questionnaire		First year after randomisation, and at the end of the intervention period (24-30 months)
Level of TRAb at 18 months, and at the end of the intervention period (24-30 months)		18 months, and at the end of the intervention period (24-30 months)
Hyperthyroid symptoms (ThyPRO subscale) during first year after randomisation		First year after randomisation
Eye symptoms (ThyPRO subscale) during first year after randomisation, and at end of the intervention period (24-30 months)		First year after randomisation, and at end of the intervention period (24-30 months)
Number of participants with adverse reactions during the intervention period	Participants will be asked to report about known adverse reactions (specified in the protocol) at 6 weeks, 12 weeks, 6 months, 12 months, 18 months, 24 months, and 12 months after ATD treatment withdrawal. In addition, participants are instructed to contact their trial contact person in case they experience adverse reactions.	Intervention period (24-30 months)
Number of participants with serious adverse events during the intervention period	To make sure we get information on serious adverse events, data on hospital admissions and mortality will be obtained through the national databases (the National Patient Registry and the Danish Civil Registration System) at the end of the trial. Also, participants are informed and instructed to contact their trial contact person in case they: are admitted to a hospital for selenium intoxication;; experience a clinical picture indicative of selenium intoxication; or; experience a clinical picture unexpected, but suspected to be related to selenium intoxication.	Intervention period (24-30 months)

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Collaborators: Odense University Hospital; Hvidovre University Hospital; Bispebjerg Hospital; Herlev Hospital; Hillerod Hospital, Denmark; Danish Council for Independent Research; Copenhagen Trial Unit, Center for Clinical Intervention Research; The Danish Council for Strategic Research; Esbjerg Hospital - University Hospital of Southern Denmark
• Investigators: Study Chair: Aase K Rasmussen, DMSc, Department of Medical Endocrinology, Rigshospitalet; Study Chair: Torquil Watt, Ph.D., Department of Medical Endocrinology, Rigshospitalet; Study Chair: Laszlo Hegedüs, DMSc, Department of Endocrinology and Metabolism, Odense University Hospital; Study Chair: Steen J Bonnema, Ph.D., Department of Endocrinology and Metabolism, Odense University Hospital; Study Chair: Jeppe Gram, Ph.D., Department of Endocrinology, Hospital of Southwest Denmark; Study Chair: Christian Gluud, DMSc, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet; Study Chair: Jakob B Bjorner, Ph.D., National Research Centre for the Working Environment, and Institue of Public Health Science, University of Copenhagen; Principal Investigator: Per Cramon, MD, Department of Medical Endocrinology, Rigshospitalet

Publications and helpful links

General Publications

• Cramon P, Rasmussen AK, Bonnema SJ, Bjorner JB, Feldt-Rasmussen U, Groenvold M, Hegedus L, Watt T. Development and implementation of PROgmatic: A clinical trial management system for pragmatic multi-centre trials, optimised for electronic data capture and patient-reported outcomes. Clin Trials. 2014 Jun;11(3):344-354. doi: 10.1177/1740774513517778.
• Watt T, Cramon P, Bjorner JB, Bonnema SJ, Feldt-Rasmussen U, Gluud C, Gram J, Hansen JL, Hegedus L, Knudsen N, Bach-Mortensen P, Nolsoe R, Nygaard B, Pociot F, Skoog M, Winkel P, Rasmussen AK. Selenium supplementation for patients with Graves' hyperthyroidism (the GRASS trial): study protocol for a randomized controlled trial. Trials. 2013 Apr 30;14:119. doi: 10.1186/1745-6215-14-119.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2012
• Primary Completion (Actual): June 1, 2021
• Study Completion (Actual): August 1, 2024

Study Registration Dates

• First Submitted: May 29, 2012
• First Submitted That Met QC Criteria: May 31, 2012
• First Posted (Estimated): June 5, 2012

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 11, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Quality of Life; Autoimmunity; Selenium; Graves' disease; Graves' hyperthyroidism; ThyPRO
• Additional Relevant MeSH Terms: Endocrine System Diseases; Thyroid Diseases; Hyperthyroidism; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Trace Elements; Micronutrients; Antioxidants; Protective Agents; Selenium
• Other Study ID Numbers: H-4-2012-026 (Other Identifier: Regional Research Ethical Committee for the Capital Region); GRASS-DP-240 (Other Identifier: Copenhagen Trial Unit); 2007-58-0015, 30-0770 (Other Identifier: Danish Data Protection Agency)