Adjuvant Treatment of Graves´ Ophthalmopathy With NSAID (aGO Study)
Condition: Graves´ Disease
MeSH terms: Graves Disease; Eye Diseases; Graves Ophthalmopathy
Study type: Interventional
Phase: Phase 4

Summary: 
      AGO study - adjuvant treatment, with NSAID, of endocrine ophthalmopathy in Graves´ disease

      Background - Already at diagnosis of Graves disease approximately 98% of the patients have
      morphological changes of the retrobulbar tissue concordant with ophthalmopathy. Factors known
      to induce clinical symptoms of ophthalmopathy are mainly unknown. An interesting observation
      is that a patient with stable and inactive Graves´ disease developed ophthalmopathy when
      treated with a glitazone due to diabetes type 2. Glitazones have been shown to increase
      differentiation of orbital preadipocytes to mature adipocytes. Glitazones are PPAR-gamma
      agonists and recently diclofenac have been shown to interact with PPAR-gamma in physiological
      concentrations. Other non-steroidal antiinflammatory drugs, NSAID, like indomethacin lack
      this effect. In addition, diclofenac inhibit synthesis of prostaglandins which also may be of
      importance because the natural ligand to PPAR-gamma is prostaglandin J. Inflammation and
      adipogenesis are hallmarks of the pathological process in Graves ophthalmopathy and NSAID
      like diclofenac may affect both. There is only one earlier study demonstrating effects of
      NSAID (indomethacin) in 7 patients with effects on soft tissue symptoms, eye muscle symptoms
      and eye protrusion.

      Aim - to investigate if diclofenac can prevent ophthalmopathy and/or progress of
      ophthalmopathy.

      Specific aims:

        1. To study the frequency of clinical ophthalmopathy in Graves´ disease after 12 months
           treatment with or without diclofenac.

        2. To study the frequency of progress of clinical signs and symptoms in ophthalmopathy
           after 12 months treatment with or without diclofenac.

        3. To study the frequency of optic neuropathy in clinical ophthalmopathy after 12 months
           treatment with or without diclofenac.

      Study plan and randomisation -

      150 patients with newly diagnosed Graves´disease without ophthalmopathy will be treated with
      anti-thyroid drugs and L-thyroxin (block and replace) according to clinical routine for 18
      months. These patients will be randomized to diclofenac 50 mg twice daily or not for 12
      months.
    

Detailed description: 
      Adjuvant treatment of Graves´ ophthalmopathy with NSAID (aGO study)

        1. Background.

           When performing MRI / CT / ultrasound of the orbital room 98 % of the patients with
           Graves´ thyrotoxicosis exhibit changes of ophthalmopathy without clinical symptoms of
           endocrine ophthalmopathy (Burch 1993). Thus, almost all patients with Graves´ disease
           are at risk to develop clinical ophthalmopathy. Tobacco exposition and treatment with
           radioiodine ar known factors that trigger ophthalmopathy but other factors are poorly
           defined. However it is well known that both environmental and genetic factors is of
           importance because monozygotic twins show a concordance of 20 - 50 %. One interesting
           observation is a patient with inactive and stable Graves´ ophthalmopathy who developed
           clinical ophthalmopathy when treated with pioglitazone due to type 2 diabetes (Starkey
           2003). One pathogenic mechanism in Graves´ ophthalmopathy is increased orbital
           adipogenesis and glitazones are known to increase the volume of subcutaneous adipose
           tissue. Orbital fibroblasts from patients with ophthalmopathy have been shown to
           differentiate to adipocytes in response to rosiglitazone (Valyasevi 2002). Glitazones
           are PPAR-gamma agonists and it could be of interest to study effects of PPARgamma
           antagonists in endocrine ophthalmopathy. Diclofenac has been shown to interact with
           PPAR-gamma in physiological concentrations and to antagonise PPAR-gamma mediated effects
           like adipogenesis of the preadipocyte cell line 3T3-L1(Adamsson 2002, Vondrichova 2007).
           In addition diclofenac is a well-known inhibitor of cyclooxygenases with effects on the
           synthesis of prostaglandins in for example fibroblasts, lymphocytes and monocytes. The
           natural ligand for PPAR-gamma is prostaglandin J (Forman 1995). To conclude, NSAID like
           diclofenac may affect both synthesis of prostaglandins and concomittantly antagonise the
           effects of the natural ligand to PPAR-gamma, prostaglandin J2. We have recently
           demonstrated upregulation of immediate early genes, including COX-2, with important
           functions in adipogenesis in patients with severe ophthalmopathy (Lantz 2005).
           Previously there is only one study published on treatment of ophthalmopathy with NSAID
           ,indometacin (Amemia 1982). Although only 7 patients were studied there were effects on
           soft tissue symptoms, eye protrusion and eye muscle symptoms. Due to the knowledge of
           retrobulbar morphological changes in patients with Graves´ thyrotoxicosis without
           clinical ophthalmopathy it may be of importance to interact as early as possible. We
           therefore plan to start a randomised single-blind study where patients will receive
           diclofenac for 12 months in parallel with the standard treatment for thyrotoxicosis.

        2. Trial design

           The trial is a multi-center (Malmö and Stockholm), controlled, single-blind design and
           the subjects are randomised to thyrostatics with and without diclofenac by a body
           independent from the study The total duration of the study is 24 months with 12 months
           treatment with or without diclofenac in addition to regular treatment for
           thyrotoxicosis. The follow up period will be 12 months. Decision of the main treatment
           of thyrotoxicosis is based on clinical terms according to routines in Malmö and
           Stockholm and is given according to the protocol of TT96. Patients are randomised for
           adjuvant therapy with or without diclofenac after choice of main treatment for
           thyrotoxicosis.

           2.1 Monitoring

           The study will be monitored by a science nurse with formal education in monitoring
           clinical trials.

        3. Objectives

      The primary objective

      To find out if diclofenac can prevent development of ophthalmopathy in patients with Graves´
      disease.

      The secondary objectives are:

        1. Determine the activity at diagnosis of ophthalmopathy

        2. Determine the time from thyrotoxicosis to ophthalmopathy

        3. Determine the frequency of patients with corticosteroid requiring ophthalmopathy

           3.1 Endpoints

           The objectives of the trial will be examined by the following endpoints:

           Efficacy

           Primary endpoint:

           The frequency of ophthalmopathy after 24 months as judged by the following clinical
           signs:.

           Optic nerve dysfunction 0. No 1. Yes Eye-lid edema 0. No 1. Yes Chemosis 0. No 1. Yes
           Conjunctival injection 0. No 1. Yes Exophthalmos 0. No 1. Yes Hertel - base right left
           Eye muscle dysfunction 0. No 1. Yes Corneal ulcers 0. No 1. Yes

           Summa:

           Ophthalmopathy is present if the patient has one sign or more.

           Secondary endpoints:

           I. Activity of ophthalmopathy as judged by clinical activity score (CAS)

           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
           Swollenness of caruncula 0. No 1. Yes Eye-lid edema or swollenness 0. No 1. Yes

           Sum:

           II. The time from thyrotoxicosis to ophthalmopathy.

           III. The frequency of corticosteroid requiring ophthalmopathy. Criteria for start of
           steroid treatment are: 1. Risk of corneal ulcers with or without exophthalmos 2. Double
           vision within 30 degrees 3. Optic nerve dysfunction.

           3.2 Treatment of subjects

           All patients that fulfill the inclusion criteria and accept participation in the study
           will after decision of main treatment for thyrotoxicosis be randomised to treatment with
           or without diclofenac. Patients will receive diclofenac 50 mg 1x2 for 12 months in
           addition to standard treatment of thyrotoxicosis according to the following routines.

           Thyrostatics

           Patients will receive p.o. methimazole (Thacapzol) 5 mg 3x2 supplemented with
           L-thyroxine (Euthyrox) after 14 days, initially for the first two weeks 0.5x1, and
           thereafter 1x1. If the patient react with allergic symptoms to methimazole, treatment is
           changed to propylthiouracil (Tiotil) 50 mg 3x3. Adjustment of L-thyroxine is done with
           help of thyroid laboratory parameters (TSH, fT4) and titration after clinical response.
           The dose of thyrostatics is not reduced and if necessary on demand the dose is
           increased. If necessary, a beta-blocker is used, primarily propranolol (Inderal) 40 mg
           1x1-3 or metoprolol (Seloken) 50 mg 1x1-3 which can be increased depending of patients
           response.

           3.3 Measurement of laboratory parameters

           All laboratory analyses will be performed at the department of Clinical Chemistry, Malmö
           University Hospital and at the department of Clinical Chemistry Karolinska University
           Hospital.

        4. Rationale for treatment

           Adjuvant treatment already at diagnosis of thyrotoxicosis has been chosen in the aim to
           prevent clinical ophthalmopathy due to the fact that morphological changes of
           ophthalmopathy in the orbital room exist in Graves´ thyrotoxicosis in up to 98% of the
           patients without clinical symptoms. The long period of time for treatment with
           diclofenac is justified by the knowledge that the majority of patients at risk for
           developing ophthalmopathy exhibit clinical symptoms within 18 months.

        5. Subjects

           5.1 Number of patients

           A total of 150 statistically analysable patients (the total number of patients included
           will be 10% higher to compensate for loss of subjects) , with 75 in each treatment arm
           will be included in the study.

        6. Visits - summary

      S = Screening tests, TSH, fT4, fT3, Thyroid Receptor antibodies (TRAK), Tissue Peroxidase
      antibodies (TPO-ak), Hb, leukocytes, thrombocytes (trc), diff.-leukocytes, fasting B-glucose,
      HbA1c, Calcium, Albumin, Sodium, Potassium, Creatinine, ASAT, ALAT, ALP, GT, Bil, PK, APTT,
      U-iodine R = Routine tests, TSH, fT4, fT3, Hb, Creatinine R+ = Routine tests + ASAT, ALAT,
      ALP, GT, Bil, TRAK, trc, leukocytes, diff. R++ = Routine tests + + Fasting B-glucose,
      U-iodine B = Biobank samples according to GD2002 (serum, plasma, buffy coat) C = Clinical
      control - vital signs, physical examination, weight, eye status O = Ophthalmologist - eye
      status D = Dietary questionnaire

      Time

      -1 week S, B, C, O, D 0 week C 6 week R, C 3 months R+, B, C 6 months R, B, C 9 months R+, B,
      C 12 months R++, B, C, O, D 15 months R+, B, C 18 months R, B, C 21 months R, B, C 24 months
      R++, B, C, O, D

      6.1 Screening

      Subjects attend to the first screening visit one week before randomisation. Before screening
      the participants have been provided with written information of the trial. The subjects will
      be informed, orally and in writing of their responsibilities / rights during the trial as
      well as possible advantages / disadvantages of the trial. Subjects who wish to participate
      will be asked to sign and date an Informed Consent Form prior to any trial-related activity.

      Subjects will be allocated a subject number and the following will be performed and recorded:

        1. Assessment of inclusion and exclusion criteria

        2. Demographic information

        3. Thyroid history

        4. General physical examination

        5. Measurement of body weight

        6. Vital signs

        7. Blood sampling

        8. Pregnancy test will be performed as per judgement of the investigator

        9. Concomitant illness and medication.

       10. Information and choice of the routine treatments for thyrotoxicosis

       11. Actual eye status, performed by an ophthalmologist within 1 week

       12. An appointment will be made for visit w0

      6.2 Randomization visit, w0

      Laboratory data and other information gathered at screening visit is reviewed and the final
      decision regarding participation in the trial is taken.

      The subject will now be randomised to adjuvant treatment with or without diclofenac. The
      randomization procedure will be designed by an independent body.

      7. Trial material

      The trial is not performed in direct collaboration with the drug manufacturers.

      9. Statistical considerations

      The primary evaluation variable is the proportion of present or new cases of endocrine
      ophthalmopathy. The null-hypothesis is that there is no differences between the two treatment
      alternatives according to this proportion (H0:pi 1 = pi 2). The number of patients in each
      group when performing a two-side significance test on the 5% level for different demands on
      power and different values in the given proportions of the hypothesis is shown in a separate
      diagram. With 72 patients in each group there is 80 % chance (power) to get significant
      results if the real difference is 0.2. The hypothesis is tested with Mantel Haenzels test and
      further analyses performed with logistic regression which take into consideration the effect
      of prognostic factors.
    

Intervention name(s): Diclofenac; Methimazole; L-thyroxin; Propranolol; Metoprolol
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention description(s): T Diclofenac 50 mg twice daily for 12 months; T Methimazole 5 mg 3x2 for 18 months; L-thyroxin approximately 100 to 200 micrograms/day. The dose is adjusted to reach euthyroidism during concomitant treatment with methimazole for 18 months; T Propronalol 40mg 1x1-3 during during 1-3 weeks until the patient has responded to thyrostatics; T Metoprolol 50 mg 1x3 for 1-3 weeks until the patient has responded to thyrostatics
Other intervention name(s): T Diclofenac T 50 mg Ratiopharm; Thacapzol (Recip); Euthyrox (Merck); Inderal (AstraZeneca); Seloken (AstraZeneca)
Intervention MeSH terms: Diclofenac; Propranolol; Metoprolol; Methimazole
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Prevention
Keywords: ophthalmopathy; prevention; diclofenac