Treatment of Graves´Ophthalmopathy With Simvastatin (GO-DS)
Treatment of Graves´Ophthalmopathy With Simvastatin (GO-DS)
In an investigator initiated multicenter trial (Malmö, Odense, Århus) the investigators aim
 at evaluating activity of Graves´ophthalmopathy (GO) and progress to severe GO in patients
 with mild to moderate Graves´ ophthalmopathy treated with simvastatin or no treatment.
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 Patients may be withdrawn from the trial at the discretion of the investigator if judged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 Patients must be withdrawn from the trial if they become pregnant or develop congestive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
Inclusion Criteria:

 1. Age 18-70 years

 2. Active mild to moderate with at least one sign of mild GO (NO SPECS class 2a and b)
 with reference to Colour Atlas at EUGOGO website (www.eugogo.eu). Exophthalmos up to
 24 mm with a disease duration of <18 months (as recorded by the patient)

 3. Graves´ disease with clinical and laboratory euthyroidism after stopping treatment
 with anti thyroid drugs (ATD), or 2 months treatment with ATD, or euthyroid 6 months
 after treatment with radioiodine, or euthyroid after total thyroidectomy. Clinical and
 laboratory euthyroidism is defined as normal fT4, fT3 and TSH below the upper limit of
 the local reference interval and no clinical symptoms or signs of hyperthyroidism.
 L-thyroxine is used to achieve euthyroidism during the study period.

 Exclusion Criteria:

 1. Pregnancy or breast-feeding

 2. Previous treatment of Graves´ ophthalmopathy

 3. Severe Graves ophthalmopathy requiring corticosteroid treatment, retrobulbar
 irradiation, orbital decompression surgery

 4. Current or previous treatment with simvastatin or other statins (within 3 months)

 5. Allergy (skin rash or systemic reactions) to statins

 6. Congestive heart failure

 7. Renal insufficiency (glomerular filtration rate <60 ml/min)

 8. ASAT or ALAT > 2.5 times the upper limit of the local laboratory

 9. Alcoholism as judged by local criteria

 10. Coagulopathy including treatment with warfarin or new oral anti-coagulation drugs

 11. Previous or current gastric ulcer

 12. Inflammatory bowel disease diabetic retinopathy or nephropathy

 13. Trauma within 10 days