Clinical Trials Register

Summary
EudraCT Number:	2020-003214-12
Sponsor's Protocol Code Number:	NL74281.078.21
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-04-29
Trial 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

2020-003214-12

A.3

Full title of the trial

A national randomized placebo-controlled double-blind multicenter trial of
LT4/LT3 combination therapy in patients with autoimmune
hypothyroidism.

Een nationaal gerandomiseerde dubbel-blind placebo-gecontroleerde
multicenter trial van LT4/LT3 combinatietherapie in patiënten met
autoimmuun hypothyreoïdie.

A.3.1

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

Study to investigate the effectiveness of LT4/LT3 combination therapy in
patients with autoimmune hypothyroidism with persistent tiredness on LT4
monotherapy.

Onderzoek naar de effectiviteit van LT4/LT3 combinatietherapie in
hypothyreoïdie patiënten met blijvende vermoeidheid bij behandeling met
LT4 monotherapie

A.3.2

Name or abbreviated title of the trial where available

T3-4-Hypo trial

A.4.1

Sponsor's protocol code number

NL74281.078.21

A.5.4

Other Identifiers

Name:

Nederlands Trial Register

Number:

NL9314

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	Erasmus Medical Center
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	NWO- The Netherlands Organization for Healt Research & Development
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Erasmus Medical Center
B.5.2	Functional name of contact point	Project Leader
B.5.3	Address:
B.5.3.1	Street Address	Dr. Molewaterplein 40
B.5.3.2	Town/ city	Rotterdam
B.5.3.3	Post code	3015 GC
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31107040570
B.5.6	E-mail	m.medici@erasmusmc.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	Cytomel®
D.2.1.1.2	Name of the Marketing Authorisation holder	Ace Pharmaceuticals BV
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Cytomel®
D.3.2	Product code	RVG 1211883
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.3.11 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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	No
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 sodium
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	range
D.3.10.3	Concentration number	62.5 to 237.5
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

Hypothyroidism

E.1.1.1

Medical condition in easily understood language

slow-acting thyroid gland

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

To investigate the effects of LT4/LT3 combination therapy compared to LT4 monotherapy on tiredness in those patients with autoimmune hypothyroidism and persisting tiredness on LT4 monotherapy, after 1 year of treatment.

In case it is confirmed that LT4/LT3 combination therapy reduces tiredness compared to LT4 treatment alone, the primary objective includes investigating simultaneously whether effect sizes are higher in patients with genetic variation in the type 2 deiodinase (DIO2-rs225014) and effect sizes are higher in patients with genetic variation in the monocarboxylate transporter 10 (MCT10-rs17606253).

E.2.2

Secondary objectives of the trial

1.To investigate other determinants of effects of LT4/LT3 combination therapy compared to LT4 therapy alone on tiredness.
2.To investigate the (determinants of the) effects of LT4/LT3 combination therapy compared to LT4 therapy alone on other thyroid related complaints and quality of life.
3.To explore the (determinants of the) effects of LT4/LT3 combination therapy compared to LT4 therapy alone on cardiovascular, metabolic, and bone outcomes.
4.To explore the (determinants of the) effects of LT4/LT3 combination therapy compared to LT4 therapy alone on neurocognitive function.
5.To perform an economic evaluation including cost-effectiveness analysis comparing LT4/LT3 combination therapy and LT4 monotherapy.
6.To compare the number of adverse events during LT4/LT3 combination therapy vs LT4 therapy alone.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients with overt or subclinical primary hypothyroidism 18 years or older.
LT4 monotherapy for at least 6 months.
LT4 monotherapy dose of 75-225 microg, with at least a dose of 1.2
microg/kg.
TSH levels within the assay-specific reference ranges for at least 3 months.
Severe tiredness with a large negative impact on daily life for at least 6
months, with or without other persisting complaints. This is based on the
patient's own experience, without judgment of the treating physician.
Sufficiently fluent in Dutch and able to read Dutch.

E.4

Principal exclusion criteria

Congenital hypothyroidism
hypothyroidism after (sub)acute thyroiditis
secondary (central) hypothyroidism.
Thyroid surgery
Radioactive iodine treatment
Head and/or neck radiotherapy
Use of thyroid interfering drugs (current/past use of amiodarone,
immunotherapy, tyrosin kinase inhibitors, interferon or lithium and
current use of oral or iv corticosteroids or dopamine)
Current psychiatric disease treated at a "gespecialiseerde GGZ instelling"
Clinical diagnosis of dementia
Pregnancy, breastfeeding or wish to become pregnant within 2 years
Women of reproductive age not using adequate contraception, who are not sterilized and do not have a sterilized partner. Adequate contraceptives include the contraceptive pill, patch, injection, implant, intrauterine device or system, vaginal ring, diaphragm or cap, and condom.
Current/past atrial fibrillation
Functional or structural abnormal heart
(e.g. cardiomyopathy or valve disease)
Current conduction disorder on ECG (i.e. Prolonged QRS > 100 ms;
or prolonged QTc; QTc women > 460 msec / men > 450 msec)
Frequent ventricular extrasystole (=doublet, trigeminy, bigeminy or
(non-sustained) ventricular tachycardia) in the past or on current ECG
Recent acute coronary syndrome or unstable angina pectoris (< 4
weeks)
Other obvious medical explanation for tiredness (e.g. end-stage renal
disease, anemia, COPD stage IV, cancer, etc.)
Other obvious major life event explanation for tiredness (e.g.
mourning, loss of job)

E.5 End points

E.5.1

Primary end point(s)

Mean change from baseline to 52 weeks in the ThyPRO tiredness subscale scores.

In case it is confirmed that LT4/LT3 combination therapy reduces tiredness compared to LT4 treatment alone, we will simultaneously investigate whether effect sizes are higher in patients with genetic variation in the type 2 deiodinase (DIO2-rs225014) and effect sizes are higher in patients with genetic variation in the monocarboxylate transporter 10 (MCT10-rs17606253), ensuring control of the study-wise type 1 error (of 5% two-sided) across these three main questions.

E.5.1.1

Timepoint(s) of evaluation of this end point

After 12 months of LT3/LT4 combination therapy or LT4/Placebo therapy or at premature discontinuation

E.5.2

Secondary end point(s)

1. Mean change from baseline to 52 weeks in the ThyPRO-39 composite scale scores.
2. Improvement from baseline to 52 weeks in the ThyPRO tiredness subscale scores ≥ minimal important difference (=14.3).
3. Mean change from baseline to 52 weeks in the ThyPRO tiredness subscale scores in participants with a baseline score > 57 (= population mean, unpublished results; personal communication with Dr T Watt, developer of the ThyPRO questionnaire).
4. Mean change from baseline to 52 weeks in the ThyPRO tiredness subscale scores in participants with a normal-range TSH level at 52 weeks.
5. Determinants of the effects of LT4/LT3 combination therapy on tiredness.
6. The (determinants of the) effects of LT4/LT3 combination therapy compared to LT4 therapy alone on other thyroid related complaints and quality of life.
7. The (determinants of the) effects of LT4/LT3 combination therapy compared to LT4 therapy alone on cardiovascular, metabolic, and bone outcomes.
8. The (determinants of the) effects of LT4/LT3 combination therapy compared to LT4 therapy alone on neurocognitive function.
9. Economic evaluation including cost-effectiveness analysis comparing LT4/LT3 combination therapy and LT4 monotherapy.
10. Number of adverse events in the LT4/LT3 combination therapy compared to the LT4 monotherapy groups.

E.5.2.1

Timepoint(s) of evaluation of this end point

After 12 months of LT3/LT4 combination therapy or LT4/Placebo therapy or at premature discontinuation

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

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)

Yes

E.7.4

Therapeutic use (Phase IV)

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

Yes

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

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

LVLS

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

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)

Yes

F.1.2.1

Number of subjects for this age range:

500

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

100

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

Yes

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2021-04-29.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

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

600

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)

None

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

2021-04-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-10-11

P. End of Trial
P.	End of Trial Status	Ongoing

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