Double-Blind, Placebo-Controlled Trial of Octreotide Long-Acting Repeatable (LAR) in Thyroid-Associated Ophthalmopathy

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1 X/04/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 89(12): Printed in U.S.A. Copyright 2004 by The Endocrine Society doi: /jc Double-Blind, Placebo-Controlled Trial of Octreotide Long-Acting Repeatable (LAR) in Thyroid-Associated Ophthalmopathy A. JANE DICKINSON, BIJAY VAIDYA, MARGARET MILLER, ALAN COULTHARD, PETROS PERROS, ELIZABETH BAISTER, CHRISTOPHER D. ANDREWS, LUTZ HESSE, JOHANNES T. HEVERHAGEN, ARMIN E. HEUFELDER, AND PAT KENDALL-TAYLOR Royal Victoria Infirmary (A.J.D., M.M., A.C.), Newcastle upon Tyne NE1 4LP, United Kingdom; University of Newcastle upon Tyne (B.V., P.P., P.K.-T.), Newcastle upon Tyne NE2 4HH, United Kingdom; Novartis Pharmaceuticals, Frimley GU16 7SR, United Kingdom (E.B., C.D.A.); and Phillips University Marburg (L.H., J.T.H., A.E.H.), Marburg 35033, Germany Several uncontrolled studies suggest octreotide is beneficial in thyroid-associated ophthalmopathy (TAO); however, the natural tendency of TAO to improve mandates randomized, controlled trials. We report results of a double-blind, placebo-controlled trial of octreotide long-acting repeatable (LAR). Fifty euthyroid patients (11 males, 39 females; age yr, median 50 yr) with active TAO [clinical activity score (CAS) >3, NOSPECS (no signs or symptoms; only signs, no symptoms; signs only; proptosis; eye muscle involvement; corneal involvement; sight visual acuity reduction) 2a-5a] of median duration 0.9 yr received either 30 mg LAR or placebo every 4 wk for 16 wk; both groups then received 30 mg LAR for wk and were followed up without treatment for a further 24 wk. Objective assessments included all individual parameters of TAO, CAS, and derived scores for soft tissue inflammation Abbreviations: ANCOVA, Analysis of covariance; CAS, clinical activity score; diop, rise in intraocular pressure on upgaze; LAR, longacting repeatable; NOSPECS, No signs or symptoms; Only signs, no symptoms; Signs only; Proptosis; Eye muscle involvement; Corneal involvement; Sight visual acuity reduction; OI, ophthalmopathy index; STI, soft tissue inflammation; TAO, thyroid-associated ophthalmopathy. JCEM is published monthly by The Endocrine Society ( endo-society.org), the foremost professional society serving the endocrine community. (STI) and ophthalmopathy index (OI). During wk 0 16 there was significant reduction in STI, subjective diplopia, and CAS in LAR-treated patients; STI and CAS were also reduced with placebo. The OI reduced by 1.12 in LAR (P ) vs in placebo (P 0.33), giving a barely significant treatment effect by Wilcoxon (P 0.043), but analysis of covariance failed to confirm this (P 0.16). During wk there was no significant change in OI in either group. The overall results (wk 0 32) showed reduction in STI and CAS in both groups. In this double-blind, placebo-controlled trial, no significant therapeutic effect of octreotide LAR was seen in patients with moderately severe TAO. The improvements in both treated and placebo groups emphasize that the results of open studies must be viewed with caution. (J Clin Endocrinol Metab 89: , 2004) THYROID-ASSOCIATED OPHTHALMOPATHY (TAO) is an autoimmune disorder, closely associated with Graves hyperthyroidism (1 4), which causes orbital tissue swelling. This results in disfigurement, diplopia, and occasionally visual loss. Whereas severe, sight-threatening disease warrants treatment options such as systemic steroids, orbital irradiation, or surgical decompression of the orbit with their associated risks, these options are unacceptable to most patients with TAO, who nevertheless suffer significant morbidity. A new effective medical treatment is therefore much needed. Several recent observations have suggested a therapeutic role for somatostatin analogs in TAO. Functional somatostatin receptors are expressed on activated lymphocytes and orbital fibroblasts and are thought to be involved in its pathogenesis (5, 6). Orbital scintigraphy has demonstrated specific uptake of radiolabeled somatostatin analogs, which correlates with disease activity (7, 8). Furthermore, several clinical studies using somatostatin analogs, octreotide, or lanreotide have yielded encouraging results (9 15). However, these studies generally involved small patient numbers, failed to take note of the natural history of TAO (16), and lack appropriate controls so cannot be regarded as conclusive. Only appropriately controlled studies will assess the efficacy of such agents. We report results of a randomized, doubleblind, placebo-controlled trial, using a long-acting release preparation of octreotide, octreotide LAR (long-acting release), in patients with moderately severe active TAO. Objectives Patients and Methods A double-blind, placebo-controlled trial was designed to investigate the efficacy of octreotide LAR in the treatment of TAO. The primary objective was to document changes in the clinical features of TAO as assessed by ophthalmopathy index (OI) score, clinical activity score (CAS), and measure of the individual disease parameters. Additional objectives included documenting changes in quality of life and also changes in orbital muscle volumes using magnetic resonance imaging. Patients Patients recruited from each of two centers showed active TAO as defined by CAS 3 or more (17) with obvious inflammatory signs. Their disease severity ranged from a minimum of NOSPECS (No signs or 5910

2 Dickinson et al. RCT of Octreotide in Thyroid Orbitopathy J Clin Endocrinol Metab, December 2004, 89(12): symptoms; Only signs, no symptoms; Signs only; Proptosis; Eye muscle involvement; Corneal involvement; Sight visual acuity reduction) class 2a, 3a to 3c, 4b, or 5a (18), but patients with sight-threatening disease (NOSPECS 5b, 5c, or 6) were excluded. Consecutive patients were enrolled provided they satisfied the inclusion and exclusion criteria. Only patients euthyroid (normal serum free T 4 and T 3 with normal or suppressed serum TSH) for at least 2 months who had not been treated with 131 I, immunosuppressive therapy, orbital surgery, or orbital radiotherapy within the previous year, or with corticosteroids in the previous 6 months, were eligible for recruitment. Forty-six patients had been previously treated for hyperthyroidism and one for hypothyroidism. Euthyroidism was rigorously maintained throughout the study, with T 4 replacement or antithyroid drugs when necessary. Study design A 2-month screening period before baseline assessment ensured that thyroid status was stable and that TAO was not spontaneously improving: thyroid tests and medication check were done and ophthalmic assessment as detailed below, with estimation of CAS and OI. 111 Inpentetreotide orbital uptake was measured. Patients were randomly allocated to either LAR or placebo group for the first 16 wk (phase I). For the second 16-wk period (wk 16 32, phase II), all patients received LAR. After wk 32, treatment was discontinued and patients were monitored for the following 24 wk (6 months, phase III). The two groups are referred to as LAR-LAR and placebo-lar. This design was selected on ethical grounds to avoid denying some patients potentially beneficial therapy. LAR (30 mg) was given by deep im injection at 4-wk intervals. Placebo was in the form of vehicle prepared in ampoules of same volume and appearance as LAR. Injections were prepared by the research nurse in a separate room, inaccessible to patients and medical staff, all of whom were blinded to the treatment group. Assessments were carried out at the screening visit, the baseline visit (time 0) and 16, 32, 44, and 56 wk. The trial was approved by the ethics committees of the institutions at Newcastle on Tyne, United Kingdom, and Marburg, Germany, and patients gave written informed consent. 111 In-pentetreotide scan 111 In-pentetreotide uptake was measured 4 h after iv injection of approximately 3 mci (c.111 MBq; range MBq) 111 Indium-diethylenetriamine-pentacetic acid octreotide with a neuro-single-photon emission-computed tomography camera, as described by Gerding et al. (8). Regions of interest (orbital and occipital) were created using three single-pixel-thick axial slices centered about the slice with the best orbital definition. Counts in the three regions of interest were obtained and the orbit to occiput ratio calculated. Ophthalmic assessment All ophthalmic assessments in the two centers were performed by one of three ophthalmologists at each visit. Objectively measurable features of TAO [palpebral aperture, proptosis, and rise in intraocular pressure on upgaze (diop) plus ocular alignment, uniocular excursions, and binocular visual field] were scored for each eye by a predetermined protocol with strict methodology. NOSPECS is a time-honored method of classifying and grading TAO severity (19); patients with sight-threatening features (NOSPECS class 5b, 5c, or 6) mandated study withdrawal; hence, these were also assessed. The CAS (17, 19) is an established method for assessing activity of the disease by scoring pain and soft tissue inflammatory features at any single time point to give a maximum of 7 points; a worsening of objective features of severity over time is also indicative of activity and has been used to calculate the full 10-point score on which the validity of the CAS was based (20). A comparative atlas (21) enabled these soft tissue inflammatory features to be assessed consistently, and a summary score for soft tissue inflammation (STI) was also derived. This comprised periorbital edema, conjunctival redness, chemosis, redness of lateral rectus insertion, and caruncle inflammation scored with equal weighting to give a maximum of 5. The OI provides a summary score for all features of the disease (excluding in this study visual acuity and corneal lesions), weighted according to their severity, as described by Perros et al. (22). For the summary scores OI and STI, measurements reflected the mean of the two eyes. In patients with unilateral or asymmetrical disease (difference between eyes in OI of 2 or greater at baseline), this averaging has the potential to mask significant change; however, individual measurements from each eye were also analyzed separately to ensure such changes were not missed. Patient self-assessment and quality of life Patients completed a self-assessment questionnaire at each visit, grading their appearance, vision, discomfort, and double vision on a 10-point visual analog scale (maximum score 40). Quality of life relating to perceived visual function and appearance was assessed by a validated disease-specific Graves ophthalmopathy quality of life questionnaire (23). Magnetic resonance imaging All patients were scanned at baseline and wk 16 and 32 at 1 Tesla using a T1-weighted three-dimensional gradient echo sequence to generate contiguous 1-mm-thick coronal plane images through the orbits. A semiautomated technique (24) was used to calculate volumes for inferior rectus, medial rectus, lateral rectus, and superior rectus/levator (superior group). Total fat volume was also calculated for each orbit. IGF-I assay IGF-I was measured in a single lab by RIA at baseline and 16 and 32 wk to document response to LAR. The IGF-I RIA (Diasorin, Rome, Italy) is a double-antibody disequilibrium assay that includes ODS silica extraction processing of acidified samples. Within-batch coefficient of variation ranged from 4.5 to 7.3% and between batch 15.8 to 17.7%. Safety parameters Adverse events were recorded at each visit; routine lab tests including hemoglobin A1c were monitored. Gall bladder ultrasound was performed at baseline and wk 32. Statistical analysis Sample size. Perros et al. (22) quoted a mean OI of 6.49 (sd 3.3) in a sample of 101 subjects with TAO. From these data and the anticipated clinical response, a sample size of 25 in each group was chosen. This would have 80% power to detect a difference between the treatment groups of 2.7 mean OI score using a two-group t test with a 0.05 two-sided significance level. Randomization. Randomization was performed centrally using an automated validated system. Patients were stratified by both age ( 45 and 45 yr) and gender. Randomization data were kept strictly confidential, and only when the study had been completed, the data validated, and the database locked were the drug codes made available for data analysis. Data analysis. The data from all randomized patients were analyzed on an intention-to-treat basis. Statistical analysis was carried out (by C.D.A.) using SAS (version 8.2; SAS Institute Inc, Cary, NC) on data pooled from both centers. The primary efficacy variable was the change in OI score from baseline at the end of the blinded treatment period (wk 16). Because OI scores are dependent on gender and age (22), these were therefore included as covariates when analyzing covariance models comparing treatments. Covariance models also included terms for baseline OI and to assess the presence of a treatment by center interaction. Other efficacy variables were tested for between-treatment effects using the Wilcoxon two-sample test and within-treatment effects using the Wilcoxon signed ranks test. All reported P values are two-sided. Results After screening, 50 of 56 patients fulfilled the entry criteria and were recruited, 25 from each center. All patients com-

3 5912 J Clin Endocrinol Metab, December 2004, 89(12): Dickinson et al. RCT of Octreotide in Thyroid Orbitopathy pleted the study. Baseline demographic data and previous treatments are shown in Table 1. The two treatment groups were well matched for age, gender, and cigarette smoking. Ophthalmopathy data Baseline. Ophthalmopathy measurements at baseline are shown in Table 2. There were no important differences in severity between the two groups: 95% confidence intervals encompassed zero for all parameters except proptosis, which was slightly higher in the LAR-LAR group. There was a very close balance in duration of active disease between the two groups (Table 1). Analysis of covariance (ANCOVA) showed that duration of active disease was not a significant covariate with respect to outcome. Phase I (placebo-controlled phase). The OI reduced significantly from baseline in LAR-treated patients (Fig. 1A) (P 0.002) but not in the placebo group, giving a modest treatment effect in favor of LAR, which was significant on two-sample Wilcoxon analysis (P 0.043) but not confirmed to be significant TABLE 1. Baseline data LAR-LAR Placebo-LAR Total Female Male 4 7 Age (yr; median, range) 50 (22 67) 50.0 (29 74) Duration of active TAO 1.0 ( ) 1.1 ( ) (yr; median, range) Cigarette smoker 12 (52%) 13 (48%) Ex-smoker 4 (17%) 6 (22%) No previous treatment 14 (61%) 19 (70%) for TAO Previous steroids 9 (39%) 7 (26%) Previous orbital irradiation 5 (22%) 4 (15%) using ANCOVA (P 0.16). The CAS fell markedly in both groups with P at each time point (Fig. 2). STI also reduced markedly in both groups (Fig. 1B), consistent with the fall in CAS. The changes from baseline of the individual components of the OI are shown in Fig. 3; subjective diplopia score reduced in the LAR group but with no significant treatment effect. Proptosis and diop also tended to decrease with LAR, compared with baseline, but not significantly and with no treatment effect. Ten patients had asymmetrical disease at baseline, eight of whom received placebo. Further analysis ascertained that no unilateral treatment effect was missed in any of these patients by adopting mean scores between eyes. Phase II. There was remarkably little change during phase II, when all patients received LAR (Figs. 1 3). Certain features that had decreased in the LAR-LAR group during phase I now showed a tendency to increase, albeit not significant. Phase III. After 6 months of follow-up after treatment cessation (wk 56), OI and CAS had decreased significantly in both groups. Proptosis fell significantly from baseline in the LAR- LAR group (P 0.025) with a significant difference between the two groups at wk 56 (P 0.031). 111 In-Pentetreotide uptake The orbital uptake was increased bilaterally in 21 of 48 patients (43.7%) and unilaterally in 10 of 48 patients (20.8%). There was a positive correlation of uptake with baseline CAS (r 0.387, P ) but not with baseline OI. It did not correlate with OI after either treatment phase (wk 16 or 32), thus failing to predict a response to treatment. Response to treatment did not correlate with orbital/occipital 111 Inpentetriotide uptake ratios or OctreoScan status (positive or negative scan) (P tests). In addition, correlation TABLE 2. Comparison of the ophthalmopathy data at baseline, with 95% confidence intervals (95% CI) LAR-LAR Placebo-LAR Mean Mean (SD) Range Mean (SD) Range difference a CAS 5.39 (1.56) (1.51) ,0.44 OI 7.23 (2.04) (1.94) ,2.04 STI 1.57 (0.77) (0.72) ,0.32 Proptosis (mm) (2.85) (3.39) ,3.73 Palpebral aperture (mm) (1.87) (1.78) ,1.88 diop (mm Hg) 4.70 (3.29) (4.16) ,1.90 Diplopia (subjective score) 1.13 (1.10) (1.14) ,0.49 Visual acuity 1.09 (0.30) 1.10 (0.31) ,0.17 a The mean difference between the two groups. 95% CI FIG. 1. Change from baseline of OI score (A) and soft-tissue inflammation score (B). Values are for the mean of two eyes and show mean and SD., LAR-LAR; placebo-lar. *, P 0.05, **, P 0.005, compared with baseline.

4 Dickinson et al. RCT of Octreotide in Thyroid Orbitopathy J Clin Endocrinol Metab, December 2004, 89(12): analysis between change in OI from baseline and orbital to occipital uptake ratios failed to reveal any significant relationship between OctreoScan result and response to treatment. For example, the correlation coefficient for OctreoScan mean orbital uptake vs. baseline OI was , P and vs. OI change from baseline to 16 wk, r , P FIG. 2. CAS, mean SD., LAR-LAR;, placebo-lar. At each time point, the change from baseline was highly significant in both groups (P 0.001). Prediction of individual response to octreotide A high baseline CAS (more active disease) did not predict response; of those with a baseline CAS greater than 5, 73% of LAR-treated patients had a reduction in CAS greater than 2, compared with 81% on placebo, during phase 1 (P 0.66). The following baseline clinical and laboratory parameters were examined to determine whether they would predict response to octreotide therapy: age, sex, duration of active TAO, orbital uptake of 111 In-pentetreotide, and CAS. Responders were arbitrarily defined as patients whose OI decreased by 2 or more points at any time during either treatment phase. No parameter was related to the responder status, using Fisher s exact test. During phase I (0 16 wk), eight patients in the LAR group and four placebo-treated patients showed a decrease in OI of 2 or more points. However, during the subsequent 16 wk when all patients received octreotide, only one patient in each group improved; also in three LAR and one placebo patient, the earlier apparent improvement was reversed by 2 points or more. Smoking history Smoking history was not a significant covariate for change from baseline in either CAS or OI. There were no statistically significant differences between non- or ex-smokers and smokers in baseline CAS or OI, nor in changes in these parameters from baseline. Orbital volumes Total pooled volume of the extraocular muscles at baseline was similar between the two groups. The total eye muscle volumes, mean of two eyes, showed small reductions in both groups at 32 wk (LAR-LAR: 4.4%, P 006; placebo-lar: 2.6% P 0.082), but the difference between treatments was not significant (P 0.61). Total orbital fat increased slightly in the LAR-LAR group at 32 wk (P 0.008). Patient self-assessment scores and quality of life Analysis of summed visual analog scores for the four questions showed a highly significant reduction between baseline and wk 16 and between wk 16 and 32 in both groups, indicating improvement, but two-sample analysis showed no treatment-effect. Analysis of Graves ophthalmopathy quality of life questionnaire (GO-QOL) showed significant improvement, compared with baseline, in perceived visual FIG. 3. Change from baseline of proptosis (A), palpebral aperture (PA) (B), subjective diplopia score (C), and diop (D). Values are for the mean of two eyes and show mean and SD., LAR-LAR;, placebo- LAR. *, P 0.05, **, P 0.005, compared with baseline., P 0.05 between-treatment effect.

5 5914 J Clin Endocrinol Metab, December 2004, 89(12): Dickinson et al. RCT of Octreotide in Thyroid Orbitopathy function at 16 wk in the LAR-LAR group. At 32 and 56 wk, both groups had improved but with no evidence of a significant treatment effect. Similarly, perceived appearance showed significant improvement in both groups at 32 and 56 wk. IGF-I IGF-I levels changed predictably during phase I when they fell significantly from baseline in the LAR-LAR group, by 3.9 mmol/liter 5.6 (P 0.002) but not in the placebo-lar group (for treatment effect P 0.013). During phase II when all patients received LAR, IGF-I fell in the placebo-lar group ( mmol/liter) but increased by mmol/liter in the LAR-LAR group (difference between groups P 0.038). Adverse events No hypersensitivity reactions occurred. Gastrointestinalrelated adverse events were reported by 65% in the LAR- LAR group and 74% in the placebo-lar group, five of whom rated them as severe; one patient developed cholecystitis during phase III. Biliary sludge on ultrasound increased from baseline to wk 32 in both groups (LAR-LAR, 13 26%, placebo-lar, 7 26%). Between baseline and wk 32, hemoglobin A1c increased slightly but significantly in both groups ( %, placebo-lar; %, LAR-LAR). Discussion The major finding of this randomized, controlled trial is that no clinically significant effects on the ophthalmopathy were noted in response to octreotide LAR treatment. During the placebo-controlled phase of the study, there were significant improvements in CAS and soft tissue features in both groups but no treatment effect. This underlines the natural history of TAO and is the most probable explanation for the discrepancy between the conclusions of this study and the apparently promising results of earlier studies over the past decade. Although several of these did include control subjects, no study was randomized and patient numbers were very small. Although first assessment after treatment was not until 16 wk, it is unlikely that any significant early effect could have been missed because steady-state levels of octreotide are achieved only after 12 wk with LAR depot formulations. As with this study, the main improvements noted in previous studies were in soft tissue features and the related CAS (9, 11 15). Because of the spontaneous improvement noted in the placebo group, it is perhaps surprising that the CAS did not change in the control patients reported by Krassas et al. (14), but this may have been due to the small number of control patients (n 4) and the slightly shorter study duration. The present study found no significant change in proptosis during the first phase of the study; however, by wk 56 there was a significant difference in mean proptosis between those treated with LAR for 8 months and the placebo-lar group who had received it for only 4 months. Although this finding is in keeping with other studies (11, 13 15), the magnitude of a mean change less than 1 mm is of doubtful clinical significance. Several previous studies have reported significant improvement in motility scored by NOSPECS (11, 13, 14). The present results do not support this; however, subjective diplopia is not directly comparable with NOSPECS. Nevertheless, only one previous study (25) noted any reduction in muscle dimensions on imaging. The current study also noted a significant change in total muscle volume during the treatment periods of both groups, but there was no significant treatment effect. Although the differing conclusions of this study and previous reports can be adequately explained by its more robust study design, several other differences might contribute. The first of these relates to the duration of active TAO. It is unclear whether TAO duration differed in the studies reported by Krassas et al. (13, 14); however, Ozata et al. (11) reported patients with 4 6 months TAO duration, compared with mean 10.8 months in this study. The duration of active disease for several subjects in both treatment groups was more than 18 months, but although this could have influenced the response of an individual patient, ANCOVA showed that disease duration was not a significant covariate in its own right when comparing treatment groups. Second, the potential for response to immunosuppressive agents or somatostatin analogs has been thought to be predicted by the findings of orbital scintigraphy, with increased uptake predictive of a response and vice versa (10, 26, 27). Interpretation of scintigraphy data is acknowledged to be difficult (27), and both the accuracy and meaning of such data remain somewhat uncertain. Several previous studies included only patients with increased uptake (13, 14), whereas this was demonstrated in only 65% of our patients. Nevertheless, the data on CAS, which this and other studies have shown to correlate positively with 111 In-pentetreotide uptake (7, 28, 29), do not suggest that our series differed from those reported previously. Also, and in contrast to another study (10), 111 Inpentetreotide uptake failed to predict response to somatostatin analog treatment. Third, whereas smokers represented 50% of this study, they were excluded from two of the apparently positive previous studies (13, 14), and it is thought that smoking could influence response to therapy (30). It is not likely that the discrepant results are due to low bioavailability of octreotide LAR within the orbit: IGF-I levels (31) changed predictably during the first 4 months of treatment, and the duration of treatment was longer than in all previous studies, which, however, used the sc formulations rather than the depot formulations used in this study. In conclusion, this double-blind, placebo-controlled trial showed no clinically significant therapeutic effect of octreotide LAR in patients with moderately severe, active TAO. The improvements in both treated and placebo groups emphasize that the results of open studies must be viewed with caution. It is possible that the newer somatostatin analogs (such as SOM230), which bind specifically to all the somatostatin receptor subtypes expressed on orbital lymphocytes and fibroblasts of TAO patients (5, 6), may be more effective than octreotide or lanreotide and find a place in the treatment of TAO.

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