Clinical Trials Register

Summary
EudraCT Number:	2021-000641-41
Sponsor's Protocol Code Number:	2021-000641-41
National Competent Authority:	Norway - NOMA
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2021-09-16
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

Norway - NOMA

A.2

EudraCT number

2021-000641-41

A.3

Full title of the trial

PROSPECTIVE COMPARISON OF SIROLIMUS AGAINST CORTICOSTEROIDS IN TREATMENT OF PATIENTS WITH ACTIVE THYROID EYE DISEASE

A.3.1

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

Sirolimus vs Corticosteroids in Treatment of Thyroid Eye Disease

A.4.1

Sponsor's protocol code number

2021-000641-41

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	Helse Bergen HF, Haukeland University Hospital
B.1.3.4	Country	Norway
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	HelseVest
B.4.2	Country	Norway
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Helse Bergen HF, Haukeland University Hospital
B.5.2	Functional name of contact point	Hans Olav Ueland
B.5.3	Address:
B.5.3.1	Street Address	Jonas Liesvei 65
B.5.3.2	Town/ city	Bergen
B.5.3.4	Country	Norway
B.5.6	E-mail	hans.olav.ueland@helse-bergen.no

D. IMP Identification
D.IMP: 1
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	Yes
D.2.1.1.1	Trade name	Solu-Medrol
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer AS, Lysaker, Norge
D.2.1.2	Country which granted the Marketing Authorisation	Norway
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.3.4	Pharmaceutical form	Powder and solvent for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous 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	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	Rapamune
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Europe MA EEIGFmarkedsføringsFF
D.2.1.2	Country which granted the Marketing Authorisation	Belgium
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.3.4	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.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Thyroid Eye Disease (TED) in patients with Graves' Diease.

E.1.1.1

Medical condition in easily understood language

Thyroid Eye Disease (TED) in patients with Graves' Diease.

E.1.1.2

Therapeutic area

Diseases [C] - Eye Diseases [C11]

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 determine whether treatment with Sirolimus in patients with active TED is more effective, and gives less metabolic complications than the established treatment with intravenous corticosteroids

E.2.2

Secondary objectives of the trial

Not applicable.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Clinical diagnosis of Graves` disease associated with active TED with a CAS ≥ 4 for the most severely affected eye

2. Moderate-to-severe active TED according to EUGOGO`s classification (not sight-threatening but has an appreciable impact on daily life), usually associated with one or more of the following: lid retraction ≥ 2 mm, moderate or severe soft tissue involvement, exophthalmos ≥ 3 mm above normal for race and gender, and/or inconstant or constant diplopia

3. Onset of active TED symptoms within 6 months prior to baseline

4. Participants must be euthyroid with the baseline disease under control or have mild hypo- or hyperthyroidism (defined as free thyroxine [FT4] and free triiodothyronine [FT3] levels < 50% above or below the normal limits). Every effort should be made to correct the mild hypo- or hyperthyroidism promptly and to maintain the euthyroid state for the full duration of the clinical trial.

5. Women of childbearing potential (including those with an onset of menopause <2 years prior to screening, non-therapy-induced amenorrhea for <12 months prior to Screening, or not surgically sterile [absence of ovaries and/or uterus]) must have a negative serum pregnancy test at screening and negative urine pregnancy tests at all protocol-specified timepoints (i.e., prior to each dose and through week 48 of the follow-up period); participants who are sexually active with a non-vasectomized male partner must agree to use a reliable contraception during the trial, such as an oral contraceptive. Hormonal contraception must be started at least one full cycle prior to baseline and continue for 180 days after the last dose of study drug. Highly effective contraceptive methods (with a failure rate less than 1% per year) when used consistently and correctly, includes implants, injectables, combined oral contraceptives, intrauterine devices (IUDs), sexual abstinence or vasectomized partner

6. Male participants must be surgically sterile or, if sexually active with a female partner of childbearing potential, must agree to use barrier contraceptive method from screening through 180 days after the last dose of study drug

7. Must be at least 18 years of age and below 80 years old.

8. Vaccinated according to the national guidelines.

9. Signed informed consent and expected cooperation of the patients for the treatment and follow up must be obtained and documented according to ICH GCP, and national/local regulations.

E.4

Principal exclusion criteria

1. Decreased vision due to optic neuropathy as defined by a significant decrease in best corrected visual acuity, new visual field defect, or colour defect secondary to optic nerve involvement within the last 6 months

2. Require immediate surgical ophthalmological intervention OR is planning corrective surgery/irradiation during the course of the study

3. Uncontrolled diabetes defined as HbA1C > 9.0% and more than a 10% change in the dose of a currently prescribed diabetic medication, or no new anti-diabetic medication within 60 days prior to Screening

4. Corneal decompensation unresponsive to medical management

5. Previous orbital irradiation or surgery for TED

6. Any steroid use (intravenous [IV] or oral) with a cumulative dose equivalent to ≥ 1 g of methylprednisolone for the treatment of TED. Previous steroid use (IV or oral) with a cumulative dose of <1 g methylprednisolone or equivalent for the treatment of TED and previous use of steroid eye drops is allowed if the corticosteroid was discontinued at least at screening.

7. Corticosteroid use for conditions other than TED within 4 weeks prior to inclusion (topical steroids for dermatological conditions and inhaled steroids are allowed)

8. Selenium and biotin must be discontinued at screening and must not be restarted during the clinical trial; however, taking a multivitamin that includes selenium and/or biotin is allowed

9. Use of any other non-steroid immunosuppressive including agent, new biologic drugs within 3 months prior to screening

10. Use of an investigational agent for any condition within 60 days prior to inclusion or anticipated use during the course of the trial

11. Identified pre-existing ophthalmic disease that, in the judgment of the investigator, would preclude study participation or complicate interpretation of study results

12. Bleeding diathesis that in the judgment of the investigator would preclude inclusion in the clinical trial

13. Malignant condition in the past 12 months (except successfully treated basal/squamous cell carcinoma of the skin)

14. Pregnant or lactating women

15. Current drug or alcohol abuse, or history of either within the previous 2 years, in the opinion of the investigator or as reported by the participant

16. Biopsy-proven or diagnose of inflammatory bowel disease according to ECCO-ESGAR guidelines

17. Known hypersensitivity to any of the components Sirolimus and Solu-medrol, including soya beans and peanuts.

18. Previous enrolment in this study

19. Ongoing Human immunodeficiency virus (HIV), tuberculosis, COVID-19, hepatitis C or hepatitis B infections

20. Previous tuberculosis, hepatitt C or B.

21. Any laboratory values outside the reference range that is of clinical relevance, including but not limited to hematological parameters, clinical blood chemistry, liver and kidney function parameters, serum lipids levels.

22. Need to use medications contraindicated according to SmPC of the IMP(s).

23. Any other contraindication listed on the SmPC of the IMP(s).

24. Participation in another clinical trial that might affect the current study or that there should be minimum 90 days between participation in another intervention trial.

25. Any reason why, in the opinion of the investigator, the patient should not participate (e.g. not able to comply with study procedures).

E.5 End points

E.5.1

Primary end point(s)

• ≥2 point reduction in Clinical Activity Score (CAS) from baseline at week 12.

The CAS is a 7-item description of clinical symptoms and signs indicating orbital inflammation. These are: 1. Spontaneous orbital pain; 2. Gaze evoked orbital pain; 3. Eyelid swelling that is considered to be due to active inflammatory phase of TED; 4. Eyelid erythema; 5. Conjunctival redness that is considered to be due to active inflammatory phase of TED (ignore "equivocal" redness); 6. Chemosis; 7. Inflammation of caruncle or plica. Each item is scored (1 = present; 0 = absent) and scores for each item are summed for total score of 0 (no clinical activity) to 7 (most clinical activity).

E.5.1.1

Timepoint(s) of evaluation of this end point

Endpoint evaluation after week 12.

E.5.2

Secondary end point(s)

• ≥ 2 mm reduction from baseline in proptosis in one eye at week 12.
• ≥ 2 mm reduction from baseline in vertical lid aperture in one eye at week 12.
• ≥ 1 class improvement of eye motility from baseline assessed by Gorman score at week 12.
Gorman score: 1 = no diplopia, 2 intermittent diplopia, 3 = inconstant (gaze-evoked) diplopia, 4 = constant diplopia in primary or reading position.
• participants with serious adverse effects after 6 months
• participants with minor adverse effects after 6 months
• ≥ 6 points improvement in GO-QOL score

E.5.2.1

Timepoint(s) of evaluation of this end point

Efficacy endpoint evaluation after week 12. Safety endpoint evaluation after 6 months.

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

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Sub-investigator evaluating study endpoints is kept blinded throughout the study.

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

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)

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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 2021-09-16.

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

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)

After end of participation in the trail, the subject will be followed as out-patients at department of Ophthalmology at Haukeland University (or at collaborating cites) every 6 months for 1 year, then as needed dependent on patients' eye disease.
Any sideeffect will be treated and followed up until recovery.

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

2022-01-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-11-24

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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