Thyroid-Associated OphthalmopathyPhase 2NCT04936854
Sirolimus vs Corticosteroids in Treatment of Thyroid Eye Disease
A Phase 2 study testing Sirolimus 1 mg Oral Tablet and Methylprednisolone in people with Thyroid-Associated Ophthalmopathy, run by Haukeland University Hospital at 1 site in Norway.
Trial summary
The purpose of this study is to determine whether Sirolimus is more effective and burdened with less side effects than conventional treatment with corticosteroids in patients with active thyroid eye disease. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Thyroid-Associated Ophthalmopathy
- What is being tested?
- Sirolimus 1 mg Oral Tablet and Methylprednisolone
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 60 participants
- Where
- 1 siteNorway
- Study dates
- 1 Jan 2023to Dec 2028
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- The participant want treatment for active thyroid eye disease and is willing to be included in the study
- Clinical diagnosis of Graves' disease associated with active TED with a Clinical Activity Score (CAS) ≥ 4 (on the 7-item scale)
- Moderate-to-severe active TED (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
- Onset of active TED symptoms (as determined by participant records) within 9 months prior to inculsion
- Participants must be euthyroid with the Graves disease under control or have mild hypo- or hyperthyroidism (defined as free thyroxine and free triiodothyronine levels < 50% above or below the normal limits).
- Does not require immediate surgical ophthalmological intervention and is not planning corrective surgery/irradiation during the course of the study
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- Diabetic participants must have well-controlled stable disease (defined as HbA1C < 9.0% with no new diabetic medication [oral or insulin] or more than a 10% change in the dose of a currently prescribed diabetic medication within 60 days prior to Screening)
- 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 2 reliable forms of contraception during the trial, one of which is recommended to be hormonal, 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
- 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
- Active Influenza and Pneumococcal vaccines
Who cannot join
- The participant dont want treatment for active thyroid eye disease or dont want to participate in the study
- Decreased vision due to optic neuropathy as defined by a significant decrease in best corrected visual acuity, new visual field defect, or color defect secondary to optic nerve involvement within the last 6 months
- Corneal decompensation unresponsive to medical management
- Previous orbital irradiation or surgery for TED 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 4 weeks prior to inclusion
- Corticosteroid use for conditions other than TED within 4 weeks prior to inclusion (topical steroids for dermatological conditions and inhaled steroids are allowed)
- Selenium and biotin must be discontinued 3 weeks prior to Screening and must not be restarted during the clinical trial; however, taking a multivitamin that includes selenium and/or biotin is allowed
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- Use of any other non-steroid immunosuppressive including agent, new biologic drugs within 3 months prior to Screening
- Use of an investigational agent for any condition within 60 days prior to inclusion or anticipated use during the course of the trial
- Identified pre-existing ophthalmic disease that, in the judgment of the Investigator, would preclude study participation or complicate interpretation of study results
- Bleeding diathesis that in the judgment of the Investigator would preclude inclusion in the clinical trial
- Malignant condition in the past 12 months (except successfully treated basal/squamous cell carcinoma of the skin)
- Pregnant or lactating women
- 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
- Biopsy-proven or clinically suspected inflammatory bowel disease
- Known hypersensitivity to any of the components Sirolimus.
- Any other condition that, in the opinion of the Investigator, would preclude inclusion in the study
- Previous enrollment in this study
- Human immunodeficiency virus (HIV), tuberculosis, hepatitis C or hepatitis B infections
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Norway1 site, 1 recruiting
- Recruiting
Department of Ophthalmology Haukeland University Hospital
Bergen, Hordaland, 5021
Hans O Ueland, MD, +47 55 97 57 19, uela@helse-bergen.no
Eyvind Rødahl, MD PhD, + 47 55 97 41 10, Eyvind.Rodahl@uib.no
About this study
Official title: Prospective Comparison of Sirolimus Against Corticosteroids in Treatment of Patients With Active Thyroid Eye Disease
The purpose of this study is to determine whether Sirolimus is more effective and burdened with less side effects than conventional treatment with corticosteroids in patients with active thyroid eye disease.
Read the detailed description
Grave's disease is one of the most common autoimmune diseases. Thyroid eye disease is affecting nearly 50% of patients with Grave's disease. European guidelines recommend treating patients with serious TED in the acute face with intravenous steroids for 12 weeks. This treatment is burdened with metabolic complications, like raised blood pressure, high blood glucose, worsening of diabetes, osteoporosis, and weight gain. In addition, peptic ulcer and psychological disturbances are frequently seen. Long-term treatment with high doses of steroids could also suppress the corticotropic axis for a variable time period, giving temporary iatrogenic adrenal insufficiency. It is paramount to develop a treatment with equal or better effect and fewer complications for this group of patients. Recently, Teprotumumab, which act by inhibiting Insulin-Like Growth Factor-1 (IGF-1), has been introduced in treatment of TED. This represents a new area in the anti-inflammatory treatment of the disease. The anti-inflammatory effect of Sirolimus has not been examined in patients with TED, but there are two promising case-reports describing excellent response. Sirolimus have multiple immunosuppressive actions that may be favourable in the inflammatory response in TED. These are: inhibiting T-cell activation, anti-fibroblast effect and blocking the IGF-1 pathway. In contrast to other immunosuppressive drugs, Sirolimus is associated few side effects at low doses.
The investigators are planning a comparative study of conventional treatment (corticosteroids) compared with Sirolimus, regarding clinical outcomes and adverse effects. The investigators plan to include a total of 60 patients (30 in each group) with moderate to severe TED over a period of approximately 3 years.
- Conditions
- Thyroid-Associated Ophthalmopathy
- Being tested
- Sirolimus 1 mg Oral Tablet, Methylprednisolone
- Keywords
- Thyroid eye disease, Graves' Orbitopathy, Immunosuppressive Agents, Exophthalmos, Sirolimus
- Medical subject headings
- Graves Ophthalmopathy, Exophthalmos
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Sirolimus 1 mg Oral TabletDrug
Also called Rapamycin, Rapamune
2 mg Sirolimus (two 1 mg tablets) on the first day, followed by 0,5 mg Sirolimus (half 1 mg tablet) per day for 12 weeks.
Also called Solu-Medrol
500 mg Methylprednisolone intravenously once a week for 6 weeks, followed by 250 mg once a week for 6 weeks. Total period of treatment 12 weeks.
| Study group | Role | What they receive |
|---|---|---|
| Sirolimus | Active comparator | Patients with active thyroid eye disease will receive 2 mg Sirolimus (two 1 mg tablets) on the first day, followed by 0,5 mg Sirolimus (half 1 mg tablet) per day for 12 weeks. Receives: Drug: Sirolimus 1 mg Oral Tablet |
| Corticosteroids | Active comparator | Patients with active thyroid eye disease will receive 500 mg Methylprednisolone intravenously once a week for 6 weeks, followed by 250 mg once a week for 6 weeks. Receives: Drug: Methylprednisolone |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage of participants who were CAS categorical responders at week 12
CAS categorical responders were defined as participants with a reduction of ≥ 2 CAS points.
The CAS is a 7-item description of clinical activity, including: 1. Spontaneous orbital pain; 2. Gaze evoked orbital pain; 3. Eyelid swelling that is considered to be due to active (inflammatory phase) thyroid eye disease/ Graves' Ophthalmopathy or Orbitopathy (TED/GO); 4. Eyelid erythema; 5. Conjunctival redness that is considered to be due to active (inflammatory phase) TED/GO (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 inflammatory symptoms) to 7 (most inflammatory symptoms).
Measured: Week 12
Secondary outcomes (3)
Percentage of participants who were proptosis responders at week 12
Proptosis responders were defined as percentage of participants with ≥ 2 mm reduction from baseline in proptosis in one eye at week 12.
Measured: Week 12
Percentage of participants who were eyelid retraction responders at week 12
Eyelid retraction responders were defined as percentage of participants with ≥ 3 mm reduction from baseline in vertical lid aperture in one eye at week 12
Measured: Week 12
Percentage of participants who were diplopia responders at week 12
Diplopia responders were defined as percentage of participants with ≥ 1 class improvement of eye motility from baseline assessed by Gorman score.
Gorman score: 1 = no diplopia, 2 =intermittent diplopia, 3 = inconstant (gaze-evoked) diplopia, 4 = constant diplopia in primary or reading position.
Measured: Baseline, up to Week 12
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Jun 2021
- Study start1 Jan 2023
- Primary completionJan 2028 (estimated)
- Study completionDec 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Thyroid-Associated OphthalmopathyStudies of the same condition, open and under way.
- More trials run by Haukeland University HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 60 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Haukeland University Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Hans O Ueland, MD Phd, Principal investigator, Haukeland University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04936854
- Sponsor's protocol ID
- 234527
- Status last verified
- Mar 2025
- First submitted
- 15 Jun 2021
- Last updated
- 22 Sep 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Roos JCP, Murthy R. Sirolimus (rapamycin) for the targeted treatment of the fibrotic sequelae of Graves' orbitopathy. Eye (Lond). 2019 Apr;33(4):679-682. doi: 10.1038/s41433-019-0340-3. Epub 2019 Feb 12.
PubMed 30755726Chang S, Perry JD, Kosmorsky GS, Braun WE. Rapamycin for treatment of refractory dysthyroid compressive optic neuropathy. Ophthalmic Plast Reconstr Surg. 2007 May-Jun;23(3):225-6. doi: 10.1097/IOP.0b013e3180500d57.
PubMed 17519662Roos JCP, Eglitis V, Murthy R. Inhibition of Fibrotic Contraction by Sirolimus (Rapamycin) in an Ex Vivo Model of Thyroid Eye Disease. Ophthalmic Plast Reconstr Surg. 2021 Jul-Aug 01;37(4):366-371. doi: 10.1097/IOP.0000000000001876.
PubMed 33237667
Study at a glance
From the registry record, last updated by the sponsor on 22 Sep 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prospective Comparison of Sirolimus Against Corticosteroids in Treatment of Patients With Active Thyroid Eye Disease
- ClinicalTrials.gov ID
- NCT04936854
- Acronym / sponsor ID
- 234527
- Conditions
- Thyroid-Associated Ophthalmopathy
- Keywords
- Thyroid eye disease, Graves' Orbitopathy, Immunosuppressive Agents, Exophthalmos, Sirolimus
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 60 participants (estimated)
- Lead sponsor
- Haukeland University HospitalUniversity, hospital or other
- Study start
- 1 Jan 2023 (actual)
- Primary completion
- Jan 2028 (estimated)
- Study completion
- Dec 2028 (estimated)
- First posted
- 23 Jun 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to determine whether Sirolimus is more effective and burdened with less side effects than conventional treatment with corticosteroids in patients with active thyroid eye disease.
Detailed description
Grave's disease is one of the most common autoimmune diseases. Thyroid eye disease is affecting nearly 50% of patients with Grave's disease. European guidelines recommend treating patients with serious TED in the acute face with intravenous steroids for 12 weeks. This treatment is burdened with metabolic complications, like raised blood pressure, high blood glucose, worsening of diabetes, osteoporosis, and weight gain. In addition, peptic ulcer and psychological disturbances are frequently seen. Long-term treatment with high doses of steroids could also suppress the corticotropic axis for a variable time period, giving temporary iatrogenic adrenal insufficiency. It is paramount to develop a treatment with equal or better effect and fewer complications for this group of patients. Recently, Teprotumumab, which act by inhibiting Insulin-Like Growth Factor-1 (IGF-1), has been introduced in treatment of TED. This represents a new area in the anti-inflammatory treatment of the disease. The anti-inflammatory effect of Sirolimus has not been examined in patients with TED, but there are two promising case-reports describing excellent response. Sirolimus have multiple immunosuppressive actions that may be favourable in the inflammatory response in TED. These are: inhibiting T-cell activation, anti-fibroblast effect and blocking the IGF-1 pathway. In contrast to other immunosuppressive drugs, Sirolimus is associated few side effects at low doses.
The investigators are planning a comparative study of conventional treatment (corticosteroids) compared with Sirolimus, regarding clinical outcomes and adverse effects. The investigators plan to include a total of 60 patients (30 in each group) with moderate to severe TED over a period of approximately 3 years.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (participant)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Sirolimus | Active comparator | Drug: Sirolimus 1 mg Oral TabletPatients with active thyroid eye disease will receive 2 mg Sirolimus (two 1 mg tablets) on the first day, followed by 0,5 mg Sirolimus (half 1 mg tablet) per day for 12 weeks. |
| Corticosteroids | Active comparator | Drug: MethylprednisolonePatients with active thyroid eye disease will receive 500 mg Methylprednisolone intravenously once a week for 6 weeks, followed by 250 mg once a week for 6 weeks. |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- The participant want treatment for active thyroid eye disease and is willing to be included in the study
- Clinical diagnosis of Graves' disease associated with active TED with a Clinical Activity Score (CAS) ≥ 4 (on the 7-item scale)
- Moderate-to-severe active TED (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
- Onset of active TED symptoms (as determined by participant records) within 9 months prior to inculsion
- Participants must be euthyroid with the Graves disease under control or have mild hypo- or hyperthyroidism (defined as free thyroxine and free triiodothyronine levels < 50% above or below the normal limits).
Key exclusion criteria (18 listed)
- The participant dont want treatment for active thyroid eye disease or dont want to participate in the study
- Decreased vision due to optic neuropathy as defined by a significant decrease in best corrected visual acuity, new visual field defect, or color defect secondary to optic nerve involvement within the last 6 months
- Corneal decompensation unresponsive to medical management
- Previous orbital irradiation or surgery for TED 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 4 weeks prior to inclusion
- Corticosteroid use for conditions other than TED within 4 weeks prior to inclusion (topical steroids for dermatological conditions and inhaled steroids are allowed)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Sirolimus 1 mg Oral TabletAlso: Rapamycin, Rapamune2 mg Sirolimus (two 1 mg tablets) on the first day, followed by 0,5 mg Sirolimus (half 1 mg tablet) per day for 12 weeks. | Drug | Sirolimus |
| MethylprednisoloneAlso: Solu-Medrol500 mg Methylprednisolone intravenously once a week for 6 weeks, followed by 250 mg once a week for 6 weeks. Total period of treatment 12 weeks. | Drug | Corticosteroids |
Primary outcome
Percentage of participants who were CAS categorical responders at week 12
Time frame: Week 12
CAS categorical responders were defined as participants with a reduction of ≥ 2 CAS points. The CAS is a 7-item description of clinical activity, including: 1. Spontaneous orbital pain; 2. Gaze evoked orbital pain; 3. Eyelid swelling that is considered to be due to active (inflammatory phase) thyroid eye disease/ Graves' Ophthalmopathy or Orbitopathy (TED/GO); 4. Eyelid erythema; 5. Conjunctival redness that is considered to be due to active (inflammatory phase) TED/GO (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 inflammatory symptoms) to 7 (most inflammatory symptoms).
3 secondary outcomes
Percentage of participants who were proptosis responders at week 12
Time frame: Week 12
Percentage of participants who were eyelid retraction responders at week 12
Time frame: Week 12
Percentage of participants who were diplopia responders at week 12
Time frame: Baseline, up to Week 12
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Sep 2025.
- Background: PubMed 30755726Roos JCP, Murthy R. Sirolimus (rapamycin) for the targeted treatment of the fibrotic sequelae of Graves' orbitopathy. Eye (Lond). 2019 Apr;33(4):679-682. doi: 10.1038/s41433-019-0340-3. Epub 2019 Feb 12.
- Background: PubMed 17519662Chang S, Perry JD, Kosmorsky GS, Braun WE. Rapamycin for treatment of refractory dysthyroid compressive optic neuropathy. Ophthalmic Plast Reconstr Surg. 2007 May-Jun;23(3):225-6. doi: 10.1097/IOP.0b013e3180500d57.
- Background: PubMed 33237667Roos JCP, Eglitis V, Murthy R. Inhibition of Fibrotic Contraction by Sirolimus (Rapamycin) in an Ex Vivo Model of Thyroid Eye Disease. Ophthalmic Plast Reconstr Surg. 2021 Jul-Aug 01;37(4):366-371. doi: 10.1097/IOP.0000000000001876.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Hans O Ueland, MD Phd principal investigator
Haukeland University Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Sirolimus 1 mg Oral Tablet and Methylprednisolone in people with Thyroid-Associated Ophthalmopathy, run by Haukeland University Hospital at 1 site in Norway.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 22 Sep 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Norway. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Hans O ueland, MD PhD (+47 55 97 57 19, uela@helse-bergen.no), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of participants who were CAS categorical responders at week 12 (time frame: Week 12). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04936854, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Sep 2025.