Prospective comparison of sirolimus against corticosteroids in treatment of patients with active thyroid eye disease
- Conditions
- Thyroid eye disease
- Registration Number
- 2023-510166-27-01
- Lead Sponsor
- Helse Bergen HF
- Brief 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.
- 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.
Recruitment & Eligibility
- Status
- Authorised, recruitment pending
- Sex
- Not specified
- Target Recruitment
- 70
Clinical diagnosis of Graves` disease associated with active TED with a CAS ≥ 4 for the most severely affected eye
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 average value for race and gender, and/or inconstant or constant diplopia
Participants must be euthyroid with the thyroid 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.
Onset of active TED symptoms within 6 months prior to baseline
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 each follow up (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
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
Must be at least 18 years of age and below 80 years old.
Vaccinated according to the national guidelines.
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.
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
Use of an investigational agent for any condition within 60 days prior to inclusion or anticipated use during 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 diagnosis of inflammatory bowel disease according to ECCO-ESGAR guidelines
Known hypersensitivity to any of the components in Sirolimus and Solu-Medrol, including soya beans and peanuts
Previous enrolment in this study
Ongoing infection with human immunodeficiency virus (HIV), tuberculosis, COVID-19, hepatitis C or hepatitis B
Require immediate surgical ophthalmological intervention OR is planning corrective surgery/orbital irradiation during the study
Previous infection with tuberculosis, hepatitt B or C virus.
Any laboratory values outside the reference range that is of clinical relevance, including but not limited to hematological parameters, electrolytes, liver and kidney function parameters, serum lipid levels.
Need to use medications contraindicated according to SmPC of the IMP(s)
Any other contraindication listed on the SmPC of the IMP(s)
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.
Any reason why, in the opinion of the investigator, the patient should not participate (e.g. not able to comply with study procedures)
Uncontrolled diabetes defined as HbA1C > 9.0% and more than a 10% change in the dose of a currently prescribed anti-diabetic medication, or no new anti-diabetic medication within 60 days prior to screening
Corneal decompensation unresponsive to medical managemen
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 before screening
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 at screening and must not be restarted during the clinical trial..
Use of any other non-steroid immunosuppressive agent, including biologic drugs within 3 months prior to screening (6 months prior to screening after treatment with rituximab).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Primary Outcome Measures
Name Time Method ≥2 point reduction in Clinical Activity Score (CAS) from baseline at week 12. ≥2 point reduction in Clinical Activity Score (CAS) from baseline at week 12.
- Secondary Outcome Measures
Name Time Method ≥ 2 mm reduction from baseline in proptosis in one eye at week 12. ≥ 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. ≥ 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. ≥ 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 Gorman score: 1 = no diplopia, 2 intermittent diplopia, 3 = inconstant (gaze-evoked) diplopia, 4 = constant diplopia in primary or reading position
≥ 6 points improvement in GO-QOL score ≥ 6 points improvement in GO-QOL score
Trial Locations
- Locations (4)
St. Olavs Hospital HF
🇳🇴Trondheim, Norway
Sorlandet Sykehus HF
🇳🇴Arendal, Norway
Helse Bergen HF
🇳🇴Bergen, Norway
Universitetssykehuset Nord-Norge HF
🇳🇴Tromsoe, Norway
St. Olavs Hospital HF🇳🇴Trondheim, NorwayAndreas HelvigSite contact+4948180517andreas.helvig@stolav.no