Treatment of Graves´ophthalmopathy with Simvastatin (GO-S)

Progression of GO from mild-moderate to severe disease:

Criteria for start of treatment with corticosteroids, retrobulbar irradiation, or orbital decompression are severe soft tissue swelling (NO SPECS class 2c), risk of corneal ulcers with or without exophthalmos, double vision within 30 degrees, and optic nerve dysfunction. Patients who progress will be followed until the end of the study with the ongoing randomized treatment.

Withdrawal criteria:

1. Patients may withdraw from the trial at any time without any consequences for their future treatment. 2. Patients may be withdrawn from the trial at the discretion of the investigator if judged to be non-compliant with trial procedures or due to safety concerns. 3. Patients must be withdrawn from the trial if they become pregnant or develop congestive heart failure, renal insufficiency, coagulopathy, gastric ulcer, inflammatory bowel disease, diabetic retinopathy, diabetic nephropathy, severe myopathy, or rhabdomyolysis.

Laboratory investigations before randomization:

TSH, fT4, fT3, TRAb, TPOAb, p-glucose, HbA1c, creatinine or cystatin C for estimation of GFR according to the routines of the individual study centers. Biobank samples for analysis of potential markers of ophthalmopathy, DNA (buffy coat), RNA (whole blood), serum, and plasma according to separate sampling instructions.

Clinical appointments and treatment of ophthalmopathy:

Endocrinologist and ophthalmologist judge the presence of ophthalmopathy in patients with Graves´ disease and asses inclusion and exclusion criteria before randomization to treatment with or without simvastatin.

The activity of ophthalmopathy is judged according to CAS (clinical activity score) and registered by the ophthalmologist:

Spontaneous retrobulbar pain 0. No 1. Yes Painful eye-movements 0. No 1, Yes Eye lid erythema 0. No 1. Yes Conjunctival injection 0. No 1. Yes Chemosis 0. No 1. Yes Swollen caruncula 0. No 1. Yes Eye lid edema or swelling 0. No 1, Yes Sum (points)

In parallel, evaluation with modified CAS is performed and registered by the ophthalmologist:

Spontaneous retrobulbar pain 0. No 1. Mild 2. Moderate 3. Severe Painful eye-movements 0. No 1. Mild 2. Moderate 3. Severe Eye lid erythema 0. No 1. Mild 2. Moderate 3. Severe Conjunctival injection 0. No 1. Mild 2. Moderate 3. Severe Chemosis 0. No 1. Mild 2. Moderate 3. Severe Swollen caruncula 0. No 1. Mild 2. Moderate 3. Severe Eye lid edema or swelling 0. No 1. Mild 2. Moderate 3. Severe Sum (points)

Severity is judged by the following parameters and registered in the ophthalmologist´s protocol: vision, sense of colour, eye papillae edema, eye protrusion, impaired eye movements, corneal ulcers.

Judgement of thyroid function and ophthalmopathy is performed by an endocrinologist/ophthalmologist at inclusion and after 3 and 6 months. The ophthalmologist who evaluates activity and severity of ophthalmopathy is not aware of which treatment arm (simvastatin or control) the patient has been randomized to (single-blind design).

Patients are photographed at each visit and every fifth photograph of ophthalmopathy status is sent to the other centers for evaluation of selected parameters in CAS to evaluate the inter-observer variation.

All patients who fulfill the inclusion criteria and lack exclusion criteria and have signed informed consent will be randomized to treatment simvastatin 40 mg 1x1 or no additional treatment for 6 months. Drugs for treatment are prescribed for 3 months and repeated at control visits. Information on collection of drugs is checked with lists obtained from the pharmacy.

Thyroid treatment:

Patients with Graves ´ hyperthyroidism are treated with ATD. This can be done with the block and replace approach or by titration of ATD according to the local tradition as long as euthyroidism is achieved during the study period (normal fT4 and fT3 with TSH below the upper limit of the local reference interval).

Patients with clinical ophthalmopathy at diagnosis can be included no earlier than 2 months after treatment with ATD and only if biochemical or clinical euthyroidism has been achieved.

Patients who have stopped medication with ATD can be included at the earliest after 2 months and only if clinically and biochemically euthyroid.

Patients who have been treated with radioiodine can be included 6 months after radioiodine if euthyroid. In case of hypothyroidism, patients must be treated with L-thyroxine and be clinically and biochemically euthyroid before inclusion.

Patients who have had thyroidectomy can be included when euthyroidism has been achieved with L-thyroxine.

Statistical considerations and study design:

The primary evaluation variable is change in CAS after 6 months. If it is assumed that the spontaneous change without treatment is -0.6 and if the treatment groups improvement in CAS is -1.9, 34 patients in each group are needed to achieve 80 % power at significance level of 0.05. The basis of this calculation is a study on the effects of selenium treatment in patients with mild to moderate ophthalmopathy (Marcocci 2011).

The investigators will stratify for smoking at randomization which will be performed in blocks of 6 within each participating center.

The secondary exclusion and lost to follow-up rate of patients is estimated to 10 % during the study period. The investigators therefore plan to include a total of 80 patients. The following reasons are expected to cause secondary exclusion/ loss of patients:

1. Side effects of treatment 2. Lack of compliance or safety routines not being followed

Ethics:

All patients will receive written information on treatment alternatives, possible side-effects of any drugs used, and the aim of the study which has been approved by relevant ethics committees.

Publication and authorship:

The primary results will be reported in an appropriate medical journal after discussion with the participants of the study and authorship can be claimed if the participant has included at least 10 % of the total number of patients.

Visit schedule:

S = Screening tests, TSH, fT4, fT3, TRAb, TPOAb, Hb, fasting- p-glucose, HbA1c, eGFR (creatinine and cystatin C), ASAT, ALAT, ALP, GT, CK, cholesterol, triglycerides R = Routine tests, TSH, fT4, fT3, Hb, eGFR, CK, ASAT, ALAT, ALP, GT, cholesterol, triglycerides, TRAb, anti-TPO B = Biobank samples according to separate instructions C = Clinical control - vital signs, physical examination, eye status O = Ophthalmologist - eye status, OCT of conjunctive Q = Quality of life questionnaire (SF36,ThyrPro and GO-QoL)

Time 0 S, B, C, O, Q 3 months S, B, C, O, Q 6 months S, B, C, O, Q

• Change in Modified Clinical activity score [Time frame: 3 and 6 months]
• Optical coherence tomography [Time frame: 3 and 6 months]
• Quality of life with SF36 [Time frame: 6 months]
• Quality of life with ThyrPro [Time frame: 6 months]
• Quality of life with GO-QoL [Time frame: 6 months]
• TRAb [Time frame: 3 and 6 months]
• TPO-Ab [Time frame: 3 and 6 months]