Overview
Sponsor-declared trial summary
Phase
Therapeutic confirmatory (Phase III)
Status
Authorised, recruiting
Participants planned
600
Countries
1
Sites
21
Hypothyroidism Triiodothyronine Quality of Life Persistant complaints
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 treatm…
Key facts
- Sponsor
- Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC), ZonMW
- Participant type
- Patients
- Age range
- 18-64 years, 65+ years
- Gender
- Male and Female
- Therapeutic area
- Diseases [C] - Hormonal diseases [C19]
- Trial duration
- 2 Nov 2025 → ongoing
- Decision date (initial)
- 2024-11-27
- Transition trial
- Yes
- Low-intervention
- Yes
- Rare-disease indication
- No
- Vulnerable population
- No
- Funding sources
- ACE Pharmaceuticals BV · ZonMw
External identifiers
- EU CT number
- 2024-513883-24-00
- EudraCT number
- 2020-003214-12
Trial design
CTIS Part I — objectives, methods, condition coding
Main objective
Scope: Others, Efficacy, Therapy
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).
Secondary objectives 1
- 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 (see section 9.2)
Conditions and MedDRA coding
Hypothyroidism Triiodothyronine Quality of Life Persistant complaints
Study design 1 period
| # | Title | Allocation | Blinding | Roles blinded | Arms |
|---|---|---|---|---|---|
| 1 | Multicenter RCT of LT4/LT3 combination therapy in hypothyroid patients At the baseline RCT visit, a computer randomisation algorithm in Castor will be run, stratified by gender. Castor uses a validated variable block randomization model. This randomization algorithm is constructed in such a way that randomized inclusions are divided across groups in variable block sizes. This is done to ensure true randomness during the allocation. The allocation is available in Castor for the trial pharmacy (Pharmacy Ace Pharmaceuticals), so that the trial pharmacy can prepare and deliver the study medication. Medication is blinded for both the patient and treating physician.
|
Randomised Controlled | Double | [{"id":133419,"code":2,"name":"Investigator"},{"id":133420,"code":3,"name":"Monitor"},{"id":133421,"code":1,"name":"Subject"}] | Multicenter RCT of LT4/LT3 combination therapy in hypothyroid patients: In the run-in stage, all patients switch to blinded generic LT4. In the RCT, they are randomized to either blinded LT3 or placebo addition. |
Eligibility criteria
Principal inclusion / exclusion criteria as submitted by sponsor
Inclusion criteria 1
- Patients with overt or subclinical 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 1.2microg/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 6months, 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.
Exclusion criteria 1
- Thyroid surgery Radioactive iodine treatment 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 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) Frequentventricular 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)
Endpoints
Primary and secondary outcome measures (English text)
Primary endpoints 1
- Mean change from baseline to 52 weeks in the ThyPRO tiredness subscale scores.
Secondary endpoints 4
- 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
Investigational products
Investigational medicinal products (IMPs), comparators, placebo, auxiliary
Test 2
—
SCP108721542 · ATC
- Route of administration
- ORAL
- Max daily dose
- 100
- Max total dose
- 200
- Max treatment duration
- 52 Week(s)
- Authorisation status
- Authorised
- ATC code
- H03AA01 — LEVOTHYROXINE SODIUM
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- Yes
- Modification description
- - Levothyroxine 62.5 - 237.5 µg tablets formulation, composition and manufacturing are based upon the authorized product Cytomel®. The amount of excipients and active ingredient are adapted to obtain the desired weight and strength of 62.5 - 237.5 µg levothyroxine per tablet.
—
SCP10298029 · ATC
- Route of administration
- ORAL
- Max daily dose
- 100 AµCi/Aµg microcurie(s)/microgram
- Max total dose
- 200 AµCi/Aµg microcurie(s)/microgram
- Max treatment duration
- 52 Week(s)
- Authorisation status
- Authorised
- ATC code
- H03AA02 — LIOTHYRONINE SODIUM
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- Yes
- Modification description
- iothyronine 2, 2.5, 3.75, and 5 µg tablets formulation is based upon the authorized products Cytomel® 5 µg, 12.5 µg and 25 µg tablets. The composition and excipients are essentially similar; however, the tablet weight is about half of the weight of the Cytomel® tablets. The amount of excipients and active ingredient are adapted to obtain the desired weight and strength of 2, 2.5, 3.75, and 5 µg liothyronine per tablet.
Placebo 1
N/A · Product
- Other product name
- N/A
- Pharmaceutical form
- N/A
- ATC code
- N/A — N/A
- Marketing authorisation
- N/A
- MA holder
- N/A
- MA country
- Iceland
- Paediatric formulation
- No
Sponsors and contacts
Sponsor organisations, regulatory contacts, third parties
Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)
- Sponsor organisation
- Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)
- Address
- Dr. Molewaterplein 40
- City
- Rotterdam
- Postcode
- 3015 GD
- Country
- Netherlands
Scientific contact point
- Organisation
- Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)
- Contact name
- Dr M. Medici
Public contact point
- Organisation
- Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)
- Contact name
- Dr M. Medici
ZonMW
- Sponsor organisation
- ZonMW
- Address
- Laan Van Nieuw-Oost-Indie 334
- City
- S-Gravenhage
- Postcode
- 2593 CE
- Country
- Netherlands
Scientific contact point
- Organisation
- Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)
- Contact name
- Marco Medici
Public contact point
- Organisation
- Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)
- Contact name
- Marco Medici
Sponsor responsibilities
- Article 77 compliance
- Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)
- Contact point sponsor
- Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)
- Article 77 implementation
- Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)
Locations
1 EU/EEA country · 21 investigational sites
By country
| Country | MS status | Planned subjects | Sites |
|---|---|---|---|
| Netherlands | Authorised, recruiting | 600 | 21 |
| Rest of world | — | 0 | — |
Investigational sites
Admiraal De Ruyter Ziekenhuis B.V.
Endocrinologie, 'S-Gravenpolderseweg 114, 4462 RA, Goes
Universitair Medisch Centrum Utrecht
Interne Geneeskunde, Heidelberglaan 100, 3584 CX, Utrecht
Saxenburgh Medisch Centrum
Endocrinologie, Jan Weitkamplaan 4a, 7772 SE, Hardenberg
Gelre Hospitals
Endocrinologie, Albert Schweitzerlaan 31, 7334 DZ, Apeldoorn
Stichting Viecuri Medisch Centrum voor Noord-Limburg
Endocrinologie, Tegelseweg 210, 5912 BL, Venlo
Maasstad Ziekenhuis Stichting
Endocrinologie, Maasstadweg 21, 3079 DZ, Rotterdam
Albert Schweitzer Ziekenhuis
Endocrinologie, Albert Schweitzerplaats 25, 3318 AT, Dordrecht
Radboud universitair medisch centrum / RADBOUDUMC
Afdeling Interne Geneeskunde, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen
Treant Ziekenhuiszorg Stichting
Endocrinologie, Boermarkeweg 60, 7824 AA, Emmen
Flevoziekenhuis Stichting
Endocrinologie, Hospitaalweg 1, 1315 RA, Almere
Sint Franciscus Vlietland Groep Stichting
Endocrinologie, Kleiweg 500, 3045 PM, Rotterdam
Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)
Endocrinologie, Dr. Molewaterplein 60, 3015 GJ, Rotterdam
Tergooiziekenhuizen
Interne Geneeskunde, Van Riebeeckweg 212, 1213 XZ, Hilversum
Zuyderland Medisch Centrum Stichting
Endocrinologie, Dr. H. Van Der Hoffplein 1, 6162 BG, Geleen
Universitair Medisch Centrum Groningen
Interne Geneeskunde, Hanzeplein 1, 9713 GZ, Groningen
Academic Medical Center at the University of Amsterdam
Endocrinologie, Meibergdreef 9, 1105 AZ, Amsterdam
Het Van Weel-Bethesda Ziekenhuis
Endocrinologie, Stationsweg 22, 3247 BW, Dirksland
Amphia Hospital
Endocrinologie, Molengracht 21, 4818 CK, Breda
Maxima Medisch Centrum
Endocrinologie, Ds Theodor Fliednerstraat 1, 5631 BM, Eindhoven
Rijnstate Ziekenhuis Stichting
Interne Geneeskunde, Wagnerlaan 55, 6815 AD, Arnhem
Noordwest Ziekenhuisgroep Stichting
Endocrinologie, Wilhelminalaan 12, 1815 JD, Alkmaar
Country notifications
Trial-start, recruitment-start, end and early-termination notifications submitted per Member State
| Country | Trial start | Trial end | Recruitment start | Recruitment end | Early termination |
|---|---|---|---|---|---|
| Netherlands | 2025-11-02 |
Results and documents
Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial
Documents 14 files
Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.
| Type | Title | Version |
|---|---|---|
| Protocol (for publication) | D1_Protocol 2024-513883-24-00_redacted | 9 |
| Protocol (for publication) | D4_NL-NL_patient facing document_questionnaires form | 1 |
| Protocol (for publication) | D4_NL-NL_patient facing document_questionnaires form_part C | 1 |
| Protocol (for publication) | D4_NL-NL_patient facing document_questionnaires form_part C_ TC | 1 |
| Recruitment arrangements (for publication) | K1_Recruitment arangements | 1 |
| Recruitment arrangements (for publication) | K2_NL-NL_Recruitment material_Flyer | 1 |
| Recruitment arrangements (for publication) | K2_NL-NL_Recruitment material_Informatiefolder voor potentiele deelnemers | 1.2 |
| Recruitment arrangements (for publication) | K2_NL-NL_Recruitment material_Poster | 2.1 |
| Recruitment arrangements (for publication) | K2_NL-NL_Recuitment material_wervingsbrief | 1.3 |
| Subject information and informed consent form (for publication) | L1_SIS and ICF adults | 7.1 |
| Summary of Product Characteristics (SmPC) (for publication) | G2_SmPC Levothyroxinenatrium | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | G2_SmPC_Annex_I_IMPD_Liothyronine_en_Placebo_SmPC_Cytomel | 4 |
| Synopsis of the protocol (for publication) | D1_EN-EN_Protocol synopsis_2024-513883-24-00 | 9 |
| Synopsis of the protocol (for publication) | D1_NL-NL_Protocol synopsis_2024-513883-24-00 | 9 |
Application history
2 submissions — initial application plus substantial / non-substantial modifications
| # | Type | Code | Submitted | Reference MS | Conclusion | Decision date |
|---|---|---|---|---|---|---|
| 1 | INITIAL | IN | 2024-10-16 | Netherlands | Acceptable 2024-11-27
|
2024-11-27 |
| 2 | SUBSTANTIAL MODIFICATION | SM-3 | 2025-04-10 | Netherlands | Acceptable 2025-07-11
|
2025-07-11 |