- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03131726
Treatment of Graves´Ophthalmopathy With Simvastatin (GO-S)
Study Overview
Status
Intervention / Treatment
Detailed Description
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:
- Patients may withdraw from the trial at any time without any consequences for their future treatment.
- Patients may be withdrawn from the trial at the discretion of the investigator if judged to be non-compliant with trial procedures or due to safety concerns.
- Patients must be withdrawn from the trial if they become pregnant or develop congestive heart failure, renal insufficiency, coagulopathy, gastric ulcer, inflammatory bowel disease,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:
- Side effects of treatment
- 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
Study Type
Enrollment (Anticipated)
Phase
- Phase 3
Contacts and Locations
Study Contact
- Name: Tereza Planck, MD, PhD
- Phone Number: +46-733873399
- Email: tereza.planck@med.lu.se
Study Contact Backup
- Name: Mikael Lantz, MD, PhD
- Phone Number: +46-708202315
- Email: mikael.lantz@med.lu.se
Study Locations
-
-
-
Malmö, Sweden
- Recruiting
- Dpt. of Endocrinology, SUS Malmö
-
Contact:
- Tereza Planck, MD, PhD
- Email: tereza.planck@med.lu.se
-
Contact:
- Mikael Lantz, MD, PhD
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Age 18-70 years
- 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)
- 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:
- Pregnancy or breast-feeding
- Previous treatment of Graves´ ophthalmopathy
- Severe Graves ophthalmopathy requiring corticosteroid treatment, retrobulbar irradiation, orbital decompression surgery
- Current or previous treatment with simvastatin or other statins (within 3 months)
- Allergy (skin rash or systemic reactions) to statins
- Congestive heart failure
- Renal insufficiency (glomerular filtration rate <60 ml/min)
- ASAT or ALAT > 2.5 times the upper limit of the local laboratory
- Alcoholism as judged by local criteria
- Coagulopathy including treatment with warfarin or new oral anti-coagulation drugs
- Previous or current gastric ulcer
- Inflammatory bowel disease diabetic retinopathy or nephropathy
- Trauma within 10 days
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
No Intervention: No treatment
|
|
Experimental: Simvastatin
simvastatin 40 mg daily for 6 months
|
see arm description
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Clinical activity score (CAS) after 6 months
Time Frame: 6 months
|
Change in 7-point clinical activity score (CAS) after 6 months treatment with simvastatin or no treatment
|
6 months
|
Number of patients with progression to severe GO during 6 months
Time Frame: 6 months
|
Number of patients with progression to severe GO in each group (simvastatin, no treatment) during 6 months treatment
|
6 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Modified Clinical activity score
Time Frame: 3 and 6 months
|
Change in Modified clinical activity score after 3 and 6 months treatment with simvastatin or no treatment
|
3 and 6 months
|
Optical coherence tomography
Time Frame: 3 and 6 months
|
Evaluation of conjunctival thickness with optical coherence tomography after 3 and 6 months treatment with simvastatin or no treatment
|
3 and 6 months
|
Quality of life with SF36
Time Frame: 6 months
|
Quality of life after 6 months treatment with simvastatin or no treatment assessed with the SF36 questionnaire
|
6 months
|
Quality of life with ThyrPro
Time Frame: 6 months
|
Quality of life after 6 months treatment with simvastatin or no treatment assessed with the ThyPro questionnaire
|
6 months
|
Quality of life with GO-QoL
Time Frame: 6 months
|
Quality of life after 6 months treatment with simvastatin or no treatment assessed with the GO-QoL questionnaire
|
6 months
|
TRAb
Time Frame: 3 and 6 months
|
TRAb after 3 and 6 months treatment with simvastatin or no treatment
|
3 and 6 months
|
TPO-Ab
Time Frame: 3 and 6 months
|
TPOAb after 3 and 6 months treatment with simvastatin or no treatment
|
3 and 6 months
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Tereza Planck, MD, PhD, Lund University and Skåne University Hospital
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Immune System Diseases
- Autoimmune Diseases
- Endocrine System Diseases
- Genetic Diseases, Inborn
- Eye Diseases, Hereditary
- Graves Disease
- Exophthalmos
- Orbital Diseases
- Goiter
- Hyperthyroidism
- Eye Diseases
- Graves Ophthalmopathy
- Thyroid Diseases
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antimetabolites
- Anticholesteremic Agents
- Hypolipidemic Agents
- Lipid Regulating Agents
- Hydroxymethylglutaryl-CoA Reductase Inhibitors
- Simvastatin
Other Study ID Numbers
- Tereza Planck
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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