Clinical Trial Details (PDF Generation Date :- Thu, 30 Sep 2021 00:31:36 GMT)

PDF of Trial CTRI Website URL - http://ctri.nic.in

CTRI Number CTRI/2013/12/004264 [Registered on: 31/12/2013] - Trial Registered Retrospectively Last Modified On 10/12/2013 Post Graduate Thesis Yes Type of Trial Interventional Type of Study Drug Study Design Randomized, Parallel Group Trial Public Title of Study Oral glucocorticoids vs. intravenous glucocorticoids in managing thyroid associated orbitopathy Scientific Title of Monthly pulse methylprednisolone vs. oral prednisolone in treatment of thyroid ophthalmopathy: An Study open label randomized controlled trial Secondary IDs if Any Secondary ID Identifier NIL NIL Details of Principal Details of Principal Investigator Investigator or overall Name Dr Subhankar Chowdhury Trial Coordinator (multi-center study) Designation Professor and Head of the Department Affiliation IPGMER and SSKM Hospital Address Department of Endocrinology and Metabolism Room 8, 4th floor, Ronald Ross Building IPGMER and SSKM Hospital 244 AJC Bose Road Calcutta Kolkata WEST BENGAL 700020 India Phone 9831076501 Fax Email [email protected] Details Contact Details Contact Person (Scientific Query) Person (Scientific Name Dr Ajitesh Roy Query) Designation Post-doctoral trainee Affiliation IPGMER and SSKM Hospital Address Room 8, 4th floor, Ronald Ross Building Department of Endocrinology Institute of Post-Graduate Medical Education & Research (IPGMER) Kolkata-700020 Kolkata WEST BENGAL 700020 India Phone 9433135863 Fax Email [email protected] Details Contact Details Contact Person (Public Query) Person (Public Query) Name Dr Deep Dutta Designation MD (Medicine), DM (Endocrinology) Affiliation IPGMER and SSKM Hospital Address Room 9A, 4th floor, Ronald Ross Building Department of Endocrinology & Metabolism IPGMER and SSKM Hospital 244 AJC Bose Road Calcutta

WEST BENGAL 700020

page 1 / 8 PDF of Trial CTRI Website URL - http://ctri.nic.in

India Phone 9477406630 Fax Email [email protected] Source of Monetary or Source of Monetary or Material Support Material Support > Department of Endocrinology and Metabolism, IPGMER and SSKM Hospital, 244 AJC Bose Road, Kolkata-700020 Primary Sponsor Primary Sponsor Details Name Department of Endocrinology and Metabolism Address Room 6, 4th Floor Ronald Ross Building IPGMER and SSKM Hospital 244 AJC Bose Road, Kolkata-700020 Type of Sponsor Government medical college Details of Secondary Name Address Sponsor NIL NIL Countries of List of Countries Recruitment India Sites of Study Name of Principal Name of Site Site Address Phone/Fax/Email Investigator Dr Deep Dutta Endocrinology Clinic Room-8, 4th Floor 9477406630 Ronald Ross Building Department of deepdutta2000@yahoo. Endocrinology and com Metabolism IPGMER and SSKM Hospital 244 AJC Bose Road, Kolkata-700020 Kolkata WEST BENGAL Details of Ethics Name of Committee Approval Status Date of Approval Is Independent Ethics Committee Committee? Institutional Ethics Approved 11/04/2011 No Committee IPGMER and SSKM Hospital Regulatory Clearance Status Date Status from DCGI Not Applicable No Date Specified Health Condition / Health Type Condition Problems Studied Patients Patients of Graves’ disease with eye symptoms suggestive of Thyroid associated orbitopathy Intervention / Type Name Details Comparator Agent Comparator Agent Group-B Patients receiving oral Patients receiving oral prednisolone prednisolone (starting with 1mg/kg/day for 6 weeks then tapered gradually and stopped over 34-40 weeks, to reach a cumulative dose of prednisolone of 7.5 grams, e.g. in a 60 kg patient, 60mg/day for 6 weeks followed by tapering of 10mg 4 weekly till 20mg/day, then tapering by 5mg 4 weekly till 10 mg/day, then 7.5mg/day for 4 weeks, then 5mg/d till post

page 2 / 8 PDF of Trial CTRI Website URL - http://ctri.nic.in

synacthen 250mcg 1-hour cortisol18mcg/dl Intervention GROUP-A Patients receiving Patients receiving monthly iv. intravenous pulse methylprednisolone (0.5gm for 3 methylprednisolone consecutive days in a month for 4 months; total dose 6gm Inclusion Criteria Inclusion Criteria Age From 18.00 Year(s) Age To 80.00 Year(s) Gender Both Details Patients of moderately severe Thyroid associated orbitopathy (TAO) with moderate activity (Clinical activity score>2)were included.
Moderate to severe TAO was defined as marked soft tissue swelling (2c by NOSPECS), and/or proptosis (?18mm in females; ?20mm in males; 3a or more by NOSPECS), and/or inconstant/constant diplopia in primary or reading position (4b by NOSPECS), and/or punctuate staining of cornea, without any optic nerve involvement, as suggested by European Group on Graves’ Orbitopathy Exclusion Criteria Exclusion Criteria Details Patients with mild TAO, dysthyroid optic neuropathy (DON) and severe sight-threatening TAO were excluded.Patients were excluded who had received steroids, radiotherapy, immunosuppressive therapy or surgery for TAO. Patients with comorbidities making glucocorticoid administration difficult (uncontrolled hypertension, uncontrolled diabetes, tuberculosis, immune-compromised state, chronic liver disease, viral hepatitis, tuberculosis) were excluded. Method of Generating Computer generated randomization Random Sequence Method of Case Record Numbers Concealment Blinding/Masking Open Label Primary Outcome Outcome Timepoints Treatment outcomes will be assessed in terms of Patients will be followed up 3 monthly for the major response criteria (MRC) and Minor duration of study Response Criteria (MiRC. MRC include decrease in CAS score by ?3 points or improvement in diplopia. MiRC include decrease in lid retraction by ?2mm, decrease in proptosis by 2mm, decrease in CAS score by ?2 points or improvement in grade of soft tissue swelling. Responders (R) were defined as improvement in ?1 major criteria or ?2 minor criteria. Secondary Outcome Outcome Timepoints NIL NIL Target Sample Size Total Sample Size=50 Sample Size from India=50 Final Enrollment numbers achieved (Total)=Applicable only for Completed/Terminated trials Final Enrollment numbers achieved (India)=Applicable only for Completed/Terminated trials Phase of Trial N/A Date of First 02/05/2011 Enrollment (India) Date of First No Date Specified Enrollment (Global) Estimated Duration of Years=3

page 3 / 8 PDF of Trial CTRI Website URL - http://ctri.nic.in

Trial Months=0 Days=0 Recruitment Status of Not Applicable Trial (Global) Recruitment Status of Open to Recruitment Trial (India) Publication Details NIL Brief Summary Introduction:

Thyroid associated opthalmopathy (TAO) is the most common extrathyroidal manifestation of Graves’ disease is a disfiguring disorder physically mentally, emotionally and significantly impairing the quality of life.. Steroids, immunosuppressive therapy, radiation all have been tried in the treatment of TAO. However steroids form the mainstay of therapy in patients with moderately severe TAO. (1) Glucocorticoids are believed to act by inhibition of leucocyte chemotaxis and cytokine release, reduction in glycosaminoglycan synthesis by orbital fibroblasts, and down regulation of adhesion molecules (2) Glucocorticoids have been found to be most effective in patients with active opthalmopathy, with significant inflammatory features, with significant dysmotility especially diplopia in primary gaze and in whom vision is threatened. (3) Among the various available routes for administration of steroids, topical steroid drops have no role in managing TAO. Subconjunctival and retro-orbital steroid administration is not justified as neither they are more efficacious than oral or intravenous steroids nor do they protect from systemic side effects of steroids.

Oral and intravenous steroids both have been commonly used in the treatment of TAO and have their advantages and disadvantages. (4-9) Two recent randomized controlled trials (RCT) have shown that pulse intravenous steroids have a higher rate of favorable response (88% vs. 63% and 77% vs. 51% respectively) with fewer side effects than oral steroids. (14,15) It has been suggested that clinical response can be seen as early as 1-2 weeks following initiation of intravenous steroids. (14,15) However hepatic failure is a rare complication of high dose intravenous steroids (seen at cumulative doses of methylprednisolone > 8gm and should be avoided). In another randomized trial, intravenous methylprednisolone (four cycles at 500 mg for 3 consecutive days at 4-week intervals) was found to be effective in treating inflammatory changes and ocular movements in 83% of patients as compared to 11% in those who received placebo. (11) Another regimen that has been tried consists of 12 weekly infusions of methylprednisolone with a cumulative dose of 4.5 g (500 mg weekly for 6 weeks, then 250 mg weekly for 6 weeks). (12) Optimal regimen for intravenous steroid therapy in TAO has not yet been established. Also on closely analyzing the data, it can be seen that monthly intravenous pulse methylprednisolone was found to be only marginally better than oral prednisolone (88% vs. 63%; P~0.02) (14) In fact in the same study, on patient self assessment, there was no significant difference in the response between intravenous vs. oral steroids (p=0.27) (14)

It must be noted that the dose of oral steroid used while comparing intravenous vs. oral steroid regimens in TAO, was quite high, starting with 100mg/day (14,15). It is a well known fact that higher the dose, more the side effects. The standard immunosuppressive

page 4 / 8 PDF of Trial CTRI Website URL - http://ctri.nic.in

dose of prednisolone is 1mg/kg/day. The average body weight of an Indian is usually around 50-60 kg. So we intend to evaluate the effects of intravenous vs. oral steroids in the treatment of TAO using lower doses of oral steroids, starting with prednisolone 60mg/day, which we plan to taper over 40 weeks with a cumulative dose of oral prednisolone at 7.5 grams which would be comparable to 6 grams of methyl prednisolone we have planned to administer to those in the intravenous group. We have decided to start with a relatively lower dose of oral prednisolone, taper gradually and plan to continue over a long period of 40 weeks. The lower dose is expected to minimize the side effects, and prolonged therapy with low doses is expected to minimize the risk of relapse.

The aim of this study is to compare pulse iv methylprednisolone vs. low dose prolonged oral prednisolone in the treatment of TAO and to assess the clinical biochemical and radiological outcomes keeping a note of the occurrence of any adverse effects or complications during the course of therapy.

Material and Methods:

All patients of Graves’ disease with eye symptoms attending endocrine out patient department (OPD) of SSKM Hospital and IPGMER will be initially considered. Approval from the institutional ethics committee will be obtained before initiation of the study. Only patients between 18 to 80 years of age were considered. All patients had to be euthyroid for at least 3 months before the date of inclusion. Only patients with untreated moderate-severe thyroid associated opthalmopathy (TAO) with moderate activity would be considered for the study. Disease severity was estimated using NOSPECS as suggested by European Group on Graves’ Orbitopathy (EUGOGO) (12,14)

Ocular examination was done by an ophthalmologist who did severity assessment (NOSPECS), did activity assessment (CAS), evaluated the range of movement of extraocular muscles, did diplopia charting. The eyelid aperture was measured with a ruler as the distance in the midline between the eyelids. Visual acuity was tested with a Snellen chart and expressed as a decimal (e.g. 20/20=1.0). Field of vision was checked using automated perimetry. Fundoscopy was done to evaluate the disc and macula. Subjective eye score was done by asking the patient to rate their eye condition in in the range of 1 (worst) to 10 (best).

Moderate severe TAO was defined as patients having marked soft tissue swelling (2d by NOSPECS), and/or proptosis (3b or more by NOSPECS), and/or intermittent or inconstant diplopia (4a or more by NOSPECS), and/or punctuate staining of cornea, without any optic nerve involvement. (13) Disease activity was estimated using clinical activity score (CAS). (15) Only patients with moderate activity (CAS>2) were included in the study. Patients with mild TAO or severe TAO were excluded (13). Also patients with CAS?2 were excluded. Patients were excluded who had received steroids, radiotherapy, immunosuppressive therapy or surgery for TAO. Also patients with concomitant medical conditions which make administering glucocorticoids difficult were excluded like patients with uncontrolled hypetension, uncontrolled diabetes, tuberculosis, immunocompromised state, chronic liver disease, viral hepatitis or any previous use of steroids for any other

page 5 / 8 PDF of Trial CTRI Website URL - http://ctri.nic.in

condition in the last 3 years. All patients would undergo detailed clinical examination before inclusion. Patients eye symptoms and signs would be noted, height, weight and waist circumference would be recorded. Blood investigations will be done in all patients after a 12 hour overnight fast on an OPD basis. Blood sample would be collected for fasting blood sugar (FBS), 2hour postprandial sugar (2hPG) after a standard meal, hemogram, electrolytes, renal function, liver function, lipid profile, anti-TPO titre, anti-TSH receptor antibody titre, calcium, phosphorous, 25(OH)vitamin-D and iPTH. Baseline Dual energy X-ray Absorptiometry (DEXA) scan would be done in all patients for obtaining bone mineral density (BMD). The patients would be divided into 2 groups based on a computer generated randomization table. GROUP-A: Patients receiving monthly iv. Pulse methylprednisolone (0.5gm for 3 consecutive days in a month for 4 months; total dose=6gm) or GROUP-B: Patients receiving oral prednisolone (starting with 60mg/day for 6 weeks, tapering by 10mg 4 weekly till 20mg/day, then tapering by 5mg 2 weekly till 10 mg/day, then 7.5mg/day for 2 weeks; total dose 6.895gm over 40 weeks. The equivalent dose of prednisolone for 6 grams of methylprednisolone is 7.5 grams. Hence the total dose of oral prednisolone approximates the total iv methylprednisolone dose. After 40 weeks patients would be checked for adrenal sufficiency by synacthen (250?g) stimulation test, and dose with relative insufficiency, steroids would be continued at replacement dose till hypothalamic-pituitary-adrenal axis recovers. The type of therapy give will not be known to the ophthalmologist or the radiologist.

Treatment outcomes were assessed in terms of major response criteria (MRC) and Minor Response Criteria (MiRC) adapted from previous studies. (11,16) The 3 major response criteria (MRC) are improvement in diplopia according to NOSPECS class 4, an improvement in eye movement in any direction of ?8º and a decrease in CAS score of ? 3 points. The minor response criteria (MiRC) are decrease in eye lid retraction of ? 2mm, decrease in proptosis of ?2mm, improvement in grade of soft tissue swelling as per NOSPECS class 2 and a decrease in CAS score of 2 points. The eye with the worse features will be used for assessment of response to therapy by comparing baseline and post treatment scores. Successful therapy (response to therapy; R) is defined as improvement in ?1 major criteria or ?2 minor criteria. Response to treatment was assessed at 8 weeks, 16 weeks, 24 weeks, 32 weeks and 48 weeks. Treatment failure (TF) was defined as presence of any one of the following even if the patient fulfills the criteria for successful therapy: worsening of one grade or more soft tissue involvement and/or diplopia, and/or an increase of lid aperture of ?2 mm, and/or ?2 mm increase of proptosis, and/or decrease of duction of 8º or more. (10) Patients who did not fulfill the response to therapy criteria, but without any features suggestive of treatment failure were classified as non-responders (NR)

One investigator will be given the responsibility of keeping a record of methylprednisolone injections and the packs of prednisolone tablets. He will not be involved in other components of the study. The investigator who collects the blood samples, the ophthalmologist who examines the eyes of the patient, the radiologist who does ultrasonography (USG) of the eyes and computerized tomography (CT) of the orbits and the statistician would be blinded to the nature of treatment given.

page 6 / 8 PDF of Trial CTRI Website URL - http://ctri.nic.in

Statistical Analysis:

Student’s t test was used for analysis of continuous variables, Fisher’s exact test for binary variables, and the ?2 test was used for categorical variables. All results of continuous variables are expressed as mean ± SD. SPSS version-17 software would be used for statistical analysis.

References:

1) Hart RH, Perros P. Glucocorticoids in the medical management of Graves’ ophthalmopathy. Minerva Endocrinol 2003;28(3):223–31.

2) Bartalena L, Pinchera A, Marcocci C Management of Graves’ ophthalmopathy: reality and perspectives. Endocr Rev. 2000 Apr;21(2):168-99

3) Perros P, Dickenson AJ. Opthalmopathy. In: Werner and Ingbar’s The thyroid: A fundamental and clinical text. 9th ed 2005; 474-487

4) Nagayama Y, Izumi M, Kiriyama T, Yokoyama N, Morita S, Kakezono F, Ohtakara S, Morimoto I, Okamoto S, Nagataki S 1987 Treatment of Graves’ ophthalmopathy with high-dose intravenous methylprednisolone pulse therapy. Acta Endocrinol (Copenh) 116:513–518

5) Kendall-Taylor P, Crombie AL, Stephenson AM, Hardiwick M, Hall K 1988 Intravenous methylprednisolone in the treatment of Graves’ ophthalmopathy. Br Med J 297:1574–1578

6) Koshiyama H, Koh T, Fujiwara K, Hayakawa K, Shimbo SI, Misaki T 1994 Therapy of Graves’ ophthalmopathy with intravenous high-dose steroid followed by orbital irradiation. Thyroid 4:409–413

7) Ohtsuka K, Sato A, Kawaguchi S, Hashimoto M, Suzuki Y 2002 effect of high-dose intravenous steroid pulse therapy followed by 3-month oral steroid therapy for Graves’ ophthalmopathy. Jpn J Ophthalmol 46:563–567

8) Ohtsuka K, Sato A, Kawaguchi S, Hashimoto M, Suzuki Y 2003 Effect of steroid pulse therapy with orbital radiotherapy on Graves’ ophthalmopathy. Am J Ophthalmol 135:285–290 18.

9) Marcocci C, Bartalena L, Tanda ML, et al. Comparison of the effectiveness and tolerability of intravenous or oral glucocorticoids associated with orbital radiotherapy in the management of severe Graves’ ophthalmopathy: results of a prospective, single-blind, randomized study. J Clin Endocrinol Metab 2001;86(8):3562–7.

10) Kahaly GJ, Pitz S, Hommel G, et al. Randomized, single-blind trial of intravenous versus oral steroid monotherapy in Graves’ orbitopathy. J Clin Endocrinol Metab 2005;90(90):5234–40.

page 7 / 8 PDF of Trial CTRI Website URL - http://ctri.nic.in

11) van Geest RJ, Sasim IV, Koppeschaar HPF, et al. Methylprednisolone pulse therapy for patients with moderately severe Graves’ orbitopathy: a prospective, randomized,placebo-controlled study. Eur J Endocrinol 2008;158:229-37.

12) Kahaly GJ, Pitz 35. S, Hommel G, Dittmar M. Randomized, single blind trial of intravenous versus oral steroid monotherapy in Graves’ orbitopathy. J Clin Endocrinol Metab 2005;90:5234-40.

13) Prummel MF, Bakker A, Wiersinga, WM, Baldeschi L, Mourits MP, Kendall- Taylor P, Perros P, Neoh C, Dickinson AJ, Lazarus JH, Lane CM, Heufelder AE, Kahaly GJ, Pitz S, Orgiazzi J, Hullo A, Pinchera A, Marcocci C, Sartini MS, Rocchi R, Nardi M, Krassas GE, Halkias A 2003 Multi-center study on the characteristics and treatment strategies of patients with Graves’ orbitopathy: the first European group on Graves’ orbitopathy experience. Eur J Endocrinol 148:491–495

14) Prummel MF, Mourits MP, Berghout A, Krenning EP, van der Gaag R, Koornneef L, Wiersinga WM. Prednisone and cyclosporine in the treatment of severe Graves’ ophthalmopathy N Engl J Med. 1989 Nov 16;321(20):1353-9.

15) Mourits MP, Prummel MF, Wiersinga WM & Koorneef L. Clinical activity score as a guide in the management of patients with Graves’ ophthalmopathy. Clinical Endocrinology 1997 47 9–14

16) Bartalena L, Marcocci C, Bogazzi F, Manetti L, Tanda ML, Dell’Unto E, Bruno-Bossio G, Nardi M, Bartolomei MP, Lepri A, Rossi G, Martino E & Pinchera A. Relation between therapy for hyperthyroidism and the course of Graves’ ophthalmopathy. New England Journal of Medicine 1998 338 73–78

page 8 / 8