Clinical Trials Register

Summary
EudraCT Number:	2011-004554-26
Sponsor's Protocol Code Number:	GN11GE272
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-10-04
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2011-004554-26

A.3

Full title of the trial

Multimodal effects of Thyroid hormone Replacement
for Untreated older adults with Subclinical hypothyroidism;
a randomised placebo controlled Trial (TRUST)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A.3.2

Name or abbreviated title of the trial where available

Thyroid hormone replacement for subclinical hypothyroidism

A.4.1

Sponsor's protocol code number

GN11GE272

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01660126

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Leiden University Medical Center, division 3
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	European Commission
B.4.2	Country	European Union
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Leiden University Medical Center
B.5.2	Functional name of contact point	Jacobijn Gussekloo
B.5.3	Address:
B.5.3.1	Street Address	Hippocratespad 21
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333 ZD
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	31715268444
B.5.6	E-mail	j.gussekloo@lumc.nl

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Euthyrox
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck KGAa
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Levothyroxine
D.3.2	Product code	Not applicable
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	LEVOTHYROXINE SODIUM
D.3.9.1	CAS number	55-03-8
D.3.9.4	EV Substance Code	SUB08495MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	LEVOTHYROXINE SODIUM
D.3.9.1	CAS number	55-03-8
D.3.9.4	EV Substance Code	SUB08495MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Subclinical hypothyroidism

Subklinische hypothyreoidie

E.1.1.1

Medical condition in easily understood language

Thyroid hormone has multiple actions. In subclinical hypothyroidism the thyroid gland is mildly underactive. This does not cause major symptoms but may contribute to poor health in old age.

E.1.1.2

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

1. Does Levothyroxine treatment for SCH give multi-modal benefits for older people with SCH?

2. Are benefits seen across a wide range of outcomes, including improving health-related quality of life, muscle function, cognition and prevention of cardiovascular disease?

3. Are benefits seen in specific subgroups of older people with SCH, including women, very elderly and those with mild degrees of SCH (TSH 4.6-10 mU/L)?

4. Are any benefits offset by adverse effects, such as atrial fibrillation or heart failure?

E.2.2

Secondary objectives of the trial

i. To establish a strong European network of complementary research expertise on SCH in older people, including geriatric medicine, endocrinology and metabolic medicine, primary care, cardiovascular disease and biostatistics.
ii. To link this research expertise with strong focus on patient perspective and needs.
iii. To provide the necessary evidence to properly inform best practice for treatment of SCH in older people.
iv. To disseminate this evidence to health care practitioners and patients.
v. To improve clinical practice in management of SCH in older people.
vi. To improve health and wellbeing of older people with SCH.
vii. To establish a blood biobank, to be used in future research into causes and mechanisms of health, disease and disability later in life.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Community-dwelling patients aged >=65 years with SCH.

SCH is defined as persistently elevated TSH levels (>=4.6 and ≤19.9 mU/L) and free thyroxine (fT4) in reference range measured on a minimum of two occasions at least 3 months apart.

E.4

Principal exclusion criteria

•Subjects currently on Levothyroxine, antithyroid drugs , amiodarone or lithium.
•Recent thyroid surgery or radio-iodine therapy (within 12 months).
•Grade IV NYHA heart failure.
•Prior clinical diagnosis of dementia.
•Recent hospitalisation for major illness or elective surgery (within 4 weeks).
•Recent acute coronary syndrome, including myocardial infarction or unstable angina (within 4 weeks).
• Acute myocarditis or acute pancarditis
• Untreated adrenal insufficiency
•Terminal illness.
•Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
•Subjects who are participating in ongoing RCTs of therapeutic interventions (including clinical trials of investigational medicinal products [CTIMPs])
•Plan to move out of the region in which the trial is being conducted within the next 2 years (proposed minimum follow-up period).

Atrial fibrillation (sustained or paroxysmal) will not be an exclusion, as in itself this cardiac arrhythmia is not a contra-indication to Levothyroxine treatment. In addition, AF is a common finding in the studied age groups and exclusion of subjects with it would potentially compromise the generalisability of our results.

Adherence to treatment allocation: drop-ins (where subjects allocated to placebo are prescribed Levothyroxine) and drop outs (where subjects allocated to Levothyroxine stop this treatment) are each estimated at less than 5% at 1 year and less than 10% at the end of the study (mean 3 years follow-up).

E.5 End points

E.5.1

Primary end point(s)

Change in disease specific QOL (measured using symptom and fatigue domains from the Thyroid-specific Quality of Life patient-reported outcome measure (ThyPRO) published by Watt22) – measured at baseline; 6-8 weeks; 12 months and close-out.

E.5.1.1

Timepoint(s) of evaluation of this end point

The ThyPRO will be measured at baseline; 6-8 weeks; 12 months and close-out.

E.5.2

Secondary end point(s)

• General QOL (measured using EuroQOL) at baseline; 6-8 weeks; 12 months and final follow up.
•Handgrip strength (measured using the Jamar hand dynamometer) at baseline; 12 months and final follow up.
•Cognitive function, particularly executive function (measured using Letter Digit Coding Test [LDCT] at baseline and final follow-up.
•Total mortality
• Functional ability (basic Activities of Daily Living (ADL) measured using Barthel Index [BI]; extended activities of daily living measured using the older American resources and services [OARS]) at baseline and final follow-up.
• Haemoglobin, measured on a full blood count at baseline and 12 months
• Fatal and non-fatal cardiovascular events (this will include acute myocardial infarction; stroke; amputations for peripheral vascular disease; revascularisations for atherosclerotic vascular disease, including for acute coronary syndrome and heart failure hospitalisations).

E.5.2.1

Timepoint(s) of evaluation of this end point

Timepoints listed above with each secondary endpoint.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Switzerland

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Last visit of last subject

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

750

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

188

F.4.2

For a multinational trial

F.4.2.1

In the EEA

562

F.4.2.2

In the whole clinical trial

750

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Participants who either complete or withdraw from the study treatment will be referred back to their general practitioner for their ongoing care. Any future treatment would be at the discretion of the patient’s general practitioner or treating physician in the hospital. When the research is finished and the database is locked, participants will be informed of whether they were allocated to levothyroxine or placebo and will be advised to discuss this with their GP or treating physician.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2012-10-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-11-20

P. End of Trial
P.	End of Trial Status	Completed

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