Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

Transcription

1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Marcocci C, Kahaly GJ, Krassas GE, et al. Selenium and the course of mild Graves orbitopathy. N Engl J Med 2011;364:

2 EUGOGO STUDY B A randomized placebo-controlled double-blind clinical trial comparing selenium and pentoxiphyilline in patients with mild Graves' ophthalmopathy Definitive version April 1, 2003 Mark F. Prummel Gerry Krassas 1

3 INTRODUCTION Severe forms of Graves ophthalmopathy (GO) can be treated effectively with corticosteroids and/or orbital irradiation. These treatments are usually recommended only to patients with active and incapacitating forms of GO. Patients with milder forms of GO are usually not offered any specific treatment and physicians will adopt a "wait-and-see policy", because the natural history of GO shows a tendency towards spontaneous improvement,(1) and available effective treatments are associated with significant side-effects. However, this wait-and-see policy can be challenged for two reasons. First, it was recently shown that even patients with mild ophthalmopathy suffer a significant decrease in quality of life when measured using either a general health related quality-of-life (QoL) questionnaire,(2) or a disease specific QoL (GO-QoL) questionnaire.(3) Secondly, in a study of the natural history in 59 GO patients with a follow-up of one year, only 22% showed a substantial improvement of the eye disease, whereas 62% had no clinically significant improvement, and 14% actually deteriorated.(4) Thus, only one-fifth of the patients may actually benefit from a "wait-and-see policy". Because of these considerations an intervention in patients with mild GO may be beneficial. However, in view of the mildness of the eye disease, interventions with side effects (e.g. corticosteroids), or with high costs and hypothetical long-term risks (e.g. radiotherapy) are undesirable. An intervention in patients with mild GO should consist of a cheap, well tolerated, safe and widely available drugs. Two such drugs have recently emerged. Pentoxifylline Pentoxifylline (PTX, Trental, oxpentifylline) is a xanthine derivative and a nonspecific phosphodiesterase inhibitor. It is licensed in Europe and the USA for the treatment of intermittent claudication, because it decreases blood viscosity. However, it also has antiinflammatory effects by suppressing TNFα production. PTX seems to inhibit the activation of NF-κB, thereby decreasing the secretion of various cytokines by T-lymphocytes like TNFα, 2

4 and IL-2.(5) It also suppresses the secretion of other pro-inflammatory cytokines, reduces ICAM-1 expression and increases a Th2 response.(6) All these factors are relevant for the pathogenesis of GO,(7;8) and PTX was indeed found to reduce cytokine-induced GAG production and HLA-DR expression in vitro by retrobulbar fibroblasts.(9) The same group then performed a small, uncontrolled pilot study using PTX in 10 patients with moderately severe GO, and found promising improvements in 8/10 patients.(10) These investigators used a regimen of 10 days i.v. infusion of 200 mg/day, followed by oral administration of 1800 mg/d for 4 weeks, followed by 1200 mg/d for the remaining 7 weeks. The drug is safe and well tolerated. Side effects are mild and include nausea, gastrointestinal disturbances, bloating, dizziness and headache. 10 In most studies intolerance to the drug rarely led to discontinuation.(11) Because of its rheologic effects, PTX may cause bleeding-disorders, a side effect reported rarely, usually in association with bleeding risk factors.(12) PTX is readily absorbed and metabolized in the liver. The usual dose in intermittent claudicatio is 400 mg three times daily, taken with meals, or if side effects are encountered 400 mg twice daily. Selenium Selenium (Se) is a trace mineral and an essential nutrient for selenocysteine synthesis (also called the "21st aminoacid"), which is incorporated into 35 selenoproteins, mostly enzymes.(13)these seleno-enzymes are Se dependent, with a selenocysteine at the active site and Se acts as a redox center and to function as antioxidant.(13) Se also has a marked influence on the immune system and Se supplementation has a significant immunostimulant effect. Selenium deficiency on the other hand is associated with the susceptibility to viral infections. One explanation for this effect on the immune system, is that T-lymphocytes may have an important functional need for Se.(13) 3

5 Furthermore, Se acts as antioxidant and anti-inflammatory agent by reducing free radical formation and thereby dampening the production of inflammatory prostaglandins and leukotrienes. Se plays an essential role in thyroid hormone synthesis, which is dependent on two selenoproteins: the deiodinases and glutathione peroxidase.(14) Deficiency of Se and iodine leads to myxedematous cretinism, and when iodine is substituted without Se supplementation in rats, necrosis and inflammation of the thyroid gland is observed.(14) It has also been observed that autoimmune thyroiditis is more prevalent in Se deficient countries. In a recent double-blind randomized clinical trial, a significant 36% decrease in anti-tpo autoantibodies was found in a group treated with 200 ug Se daily compared to a 12% decrease in the placebo group.(15) In addition, Se supplementation led to a significant improvement in subjective well-being. In a small study, Se supplementation in patients with lymphocytic autoimmune thyroiditis also led to a decrease in TSH-R autoantibodies (cited by 13), an observation of particular interest as TSH-R autoantibodies are likely to play a role in the pathogenesis of GO.(16) We conclude that Se may be of benefit in GO patients, because a leading hypothesis on the pathogenesis of the eye disease implicates antibodies cross-reacting with shared orbitalthyroidal antigen. Se supplementation may therefore reduce the level of such a crossreacting antibody. Selenium is readily absorbed and is not associated with any side-effects. In this regard it should be noted that the daily Se intake in Europe is mostly well below the UK Reference Nutrient Intake of 75 ug daily for males, and 60 ug per day for females.(13) This intake results in a plasma Se concentration of around 95 ug/l, the level necessary to maximize the activity of the antioxidant glutathione peroxidases. According to the Standing Committee on the Scientific Evaluation of Dietary Reference, the upper safe level of intake is 400 ug per day.(17) 4

6 In view of these promising promising preliminary reports and the lack of side-effects, we propose to embark on a large prospective, placebo-controlled, randomized, multicenter, double-blind trial to investigate the efficacy, tolerability, and safety of pentoxifylline or selenium versus placebo, using the EUGOGO Case Record Forms, on which consensus was reached. AIM OF THE STUDY To investigate whether pentoxifylline or selenium in comparison with placebo given to patients with mild GO can 1) diminish the signs of GO, 2) improve the health related quality of life, or 3) prevent worsening of mild GO. STUDY DESIGN Prospective, double-blind, randomized clinical trial with three study arms. Patients will receive placebo, or 200 ug selenium selenite, or 1200 mg pentoxifylline. The intervention will last for 6 months, followed by a follow-up period of another 6 months; total duration of the trial will thus be 12 months. PATIENT SELECTION Patients will be recruited from the 9 centers participating in the EUGOGO consortium (see appendix). All consecutive patients seen at the nine centres with signs and/or symptoms of Graves' ophthalmopathy of less than 18 months duration according to the patient's recollection will be asked to participate. Inclusion criteria. 1. Patients with a history of Graves hyperthyroidism, who have been rendered euthyroid for at least 2 months by antithyroid drugs, or surgery. If 131-Iodine is used, at least 6 months should lapse before recruitment. Euthyroidism is defined as normal serum free T4, and normal free T3 or total T3 levels, in the absence of an elevated serum TSH concentration. All patients should remain euthyroid during the duration of the 5

7 study, and no thyroid surgery or treatment with 131I should be given. Patients should not be treated with systemic steroids, orbital radiotherapy or any other specific medical or surgical treatment for their eye disease during the study, unless the deteriorates. 2. Patients should at least have one sign of Graves ophthalmopathy, with a disease duration of less than 18 months (as recorded by the patient). 3. The ophthalmopathy has not been treated in the past by any means, except for local measures (e.g. eye drops). 4. Age years. Exclusion criteria. Only patients with very mild to moderate GO will be included, thus patients will be excluded if they have one or more of the following exclusion criteria: 1. Soft tissue swelling NO SPECS class 2.c (e.g. severe chemosis, severe eye lid swelling) according to the Color Atlas. 2. Proptosis of >22 mm 3. Diplopia in primary or reading position, and/or ocular torticollis. 4. Mono-ocular duction in any direction of less than 20 degrees. 5. Signs or symptoms of optic nerve involvement Other exclusion criteria are: 1. Pregnancy, 2. Drug and/or alcohol abuse, 3. Severe concomitant illness, 4. Inability to comply with the study protocol, 5. No informed consent, 6. Use of selenium or pentoxifyllin containing preparations. INTERVENTION The drugs or placebo will be administered orally for six months. Assessments will be performed at baseline, after 2-3 months of initiation of treatment (or placebo), 6, and 12 months. Pentoxifylline (Trental, Aventis) will be given in two divided doses of 600 mg (total dose 1200 mg) daily, which is the lowest dose used in the Balazs regimen.(10) Selenium will be given 6

8 as Selenium selenite in two divided doses of 100 ug each. Placebo capsules will be administered two times daily as a capsule. OUTCOME MEASUREMENTS There will be two primary outcome measurements: a) the objective assessment of the eye changes by a blinded ophthalmologist, and b) the subjective disease-specific Quality of Life (GO-QoL) questionnaire filled in by the masked patient. Secondary outcome measurements will consist of the diplopia score and the Clinical Activity Score. Outcomes will be determined at 6 and 12 months. The primary objective outcome will be classified as a beneficial response in case of improvement in at least one eye in one of the following outcome measures, without deterioration in any of these measures in both eyes. 1. Improvement in lid aperture of at least 2 mm 2. Improvement in any of the Class 2 signs by at least one grade 3. Improvement in proptosis by at least 2 mm using the same Hertel exophthalmometer 4. Improvement in extra-ocular muscle involvement, defined as improvement of any duction by at least 8 degrees. Deterioration is defined as: 1. Worsening by at least one grade in NO SPECS classification 2. If a new NO SPECS class occurs 3. If visual acuity worsens due to optic nerve involvement by at least one line on the Snellen chart, or other evidence (eg impaired colour vision) or suspicion of optic nerve compression The subjective primary outcome will be classified as a response if there is an improvement of 6 or more points on either one (or both) the GO-QoL scales. Deterioration is defined when there is a decrease of 6 points on any one of the two scales. 7

9 The secondary outcome measurements are more subjective in nature, but are thought to be important. In order to have a meaningful assessment of these items, the patients will be masked to the kind of treatment they are receiving. The secondary outcome measures are: 1. The Gorman Diplopia Score 2. The 7 first items of the Clinical Activity Score Assessment of eye changes All patients will be investigated at baseline, after 2-3 months, 6 months, and 12 months. This will be done by a blinded ophthalmologist unaware of the kind of treatment received by the patient, using the EUGOGO Case Record Form, including at least the following items: 1. Lid aperture in mm 2. Soft tissue involvement according to the Color Atlas(18) 3. Proptosis in mm, using the same kind of exophthalmometer 4. Eye muscle involvement assessed in monocular ductions in degrees 5. Visual acuity using the Snellen chart in decimals The GO-QoL has been well validated,(19) and has now been translated into the six languages used in the EUGOGO consortium. The Clinical Activity Score(20) consists of 7 items and the final score is the sum of all items present: 1. Spontaneous retrobulbar pain, 2. Pain on attempted up- or down gaze, 3. Redness of the conjunctiva, 4. Redness of the eye lids, 5. Chemosis, 6. Swelling of the caruncle, 7. Swelling of the eye lids. The Diplopia Score has 4 possible categories: 1. No diplopia, 2. Diplopia when tired or when first awakening, 3. Diplopia at extremes of gaze, 4. Continuous diplopia in primary or reading position. Assessment of tolerability and safety Side effects will be noted at all follow-up visits (baseline, 2-3, 6, 12 months after entry in the study). Blood will be drawn at all visits for assessment of thyroid function (free T4, total or free T3, TSH) and of thyroid autoantibodies (against TPO and the TSH-Receptor). Selenium levels will be determined at base-line and at 6 months. In addition 20 ml of blood will be 8

10 drawn and stored as serum for the future assessment of immunological parameters, and as blood cells for DNA analysis. Randomization Will be done centrally at the Amsterdam office, using envelopes. For each Center, separate sets of six randomization envelopes will be prepared, ensuring balanced randomization per center to correct for regional differences. The result of the randomization willbe kept secret to the patient (till the end of the study at 12 months) and the assessing ophthalmologists. Analysis, premature stops, and withdrawals. Analysis will be done using the intention to treat method. E.g., patients withdrawing from the study because of side effects, incompliance, or worsening of their eye disease requiring specific eye treatment will be kept in the primary analysis. The results at the last visit will be carried on and evaluated as the last visit. Only patients lost to follow-up before the second visit at 2-3 months, and those who were not kept euthyroid, will be excluded from the analysis and will be replaced. The response rate in the three arms will be assessed using Chi-square analysis. Changes in the several assessment methods and the secondary outcome measures will be analyzed using appropriate parametric and non-parametric tests. Sample size The natural history in mild GO over a one year period shows improvement in 25%, no change in 61% and worsening in 15% of 103 patients pooled from two studies. 4,17 To find an increase of 25% in the proportion of patients showing improvement at 6 months of treatment, 52 patients per study arm are needed with a power of 80% at the significance level of

11 References 1. Burch HB, Wartofsky L. Graves' ophthalmopathy: current concepts regarding pathogenesis and management. Endocr.Rev. 1993;14(6): Gerding MN, Terwee CB, Dekker FW, Koornneef L, Prummel MF, Wiersinga WM. Quality of life in patients with Graves' ophthalmopathy is markedly decreased: measurement by the medical outcomes study instrument. Thyroid 1997;7(6): Terwee CB, Dekker FW, Mourits MP, Gerding MN, Baldeschi L, Kalmann R et al. Interpretation and validity of changes in scores on the Graves' ophthalmopathy quality of life questionnaire (GO-QOL) after different treatments. Clin.Endocrinol.(Oxf) 2001;54(3): Perros P, Crombie AL, Kendall-Taylor P. Natural history of thyroid associated ophthalmopathy. Clin.Endocrinol.(Oxf) 1995;42(1): Jimenez JL, Punzon C, Navarro J, Munoz-Fernandez MA, Fresno M. Phosphodiesterase 4 inhibitors prevent cytokine secretion by T lymphocytes by inhibiting nuclear factor-kappab and nuclear factor of activated T cells activation. J.Pharmacol.Exp.Ther. 2001;299(2): Wolf R, Matz H, Orion E, Tuzun B, Tuzun Y. Miscellaneous treatments, I: sulfasalazine and pentoxifylline: unapproved uses, dosages, or indications. Clin.Dermatol. 2002;20(5): Bartalena L, Pinchera A, Marcocci C. Management of Graves' ophthalmopathy: reality and perspectives. Endocr.Rev. 2000;21(2):

12 8. Krassas GE, Pontikides N, Doukidis D, Heufelder G, Heufelder AE. Serum levels of tumor necrosis factor-alpha, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, and soluble interleukin-1 receptor antagonist in patients with thyroid eye disease undergoing treatment with somatostatin analogues. Thyroid 2001;11(12): Balazs C, Kiss H, Farid NR. Inhibitory effect of pentoxifylline on HLA-DR expression and glycosaminoglycan synthesis by retrobulbar fibroblasts. Horm.Metab Res. 1998;30(8): Balazs C, Kiss E, Vamos A, Molnar I, Farid NR. Beneficial effect of pentoxifylline on thyroid associated ophthalmopathy (TAO)*: a pilot study. J.Clin.Endocrinol.Metab 1997;82(6): Jull A, Waters J, Arroll B. Pentoxifylline for treatment of venous leg ulcers: a systematic review. Lancet 2002;359(9317): Martindale. The complete drug reference. 32ed. London, UK: Pharmaceutical Press; Rayman MP. The importance of selenium to human health. Lancet 2000;356(9225): Zimmermann MB, Kohrle J. The impact of iron and selenium deficiencies on iodine and thyroid metabolism: biochemistry and relevance to public health. Thyroid 2002;12(10):

13 15. Gartner R, Gasnier BC, Dietrich JW, Krebs B, Angstwurm MW. Selenium supplementation in patients with autoimmune thyroiditis decreases thyroid peroxidase antibodies concentrations. J.Clin.Endocrinol.Metab 2002;87(4): Stahl W, van den BH, Arthur J, Bast A, Dainty J, Faulks RM et al. Bioavailability and metabolism. Mol.Aspects Med. 2002;23(1-3): Martindale. The complete drug reference. 32ed. London, UK: Pharmaceutical Press; Dickinson AJ, Perros P. Controversies in the clinical evaluation of active thyroidassociated orbitopathy: use of a detailed protocol with comparative photographs for objective assessment. Clin.Endocrinol.(Oxf) 2001;55(3): Terwee CB, Gerding MN, Dekker FW, Prummel MF, Wiersinga WM. Development of a disease specific quality of life questionnaire for patients with Graves' ophthalmopathy: the GO-QOL. Br.J.Ophthalmol. 1998;82(7): Mourits MP, Koornneef L, Wiersinga WM, Prummel MF, Berghout A, Van der GR. Clinical criteria for the assessment of disease activity in Graves' ophthalmopathy: a novel approach. Br.J.Ophthalmol. 1989;73(8):

14 Analysis, premature stops, and withdrawals. Analysis will be done using the intention to treat method. E.g., patients withdrawing from the study because of side effects, incompliance, or worsening of their eye disease requiring specific eye treatment will be kept in the primary analysis. The results at the last visit will be carried on and evaluated as the last visit. Only patients lost to follow-up before the second visit at 2-3 months, and those who were not kept euthyroid, will be excluded from the analysis and will be replaced. The response rate in the three arms will be assessed using Chi-square analysis. Changes in the several assessment methods and the secondary outcome measures will be analyzed using appropriate parametric and non-parametric tests.