Clinical trial NCT02378298
Conditions: Ophthalmopathy, Thyroid-Associated
Sponsor: Göteborg University
Start date: 2011-12-01; Completion date: 2020-02-01
Enrollment: 38 participants; Allocation: NON_RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
Thyroid Associated Ophthalmopathy is condition affecting the eyes of about 10% of patients with Graves disease. Its combination of protrusion affecting the looks of the patient and pain is often severely affecting the quality of life among these patients.

The standard treatment for this illness today is intravenous glucocorticoids together with methotrexate. The purpose of this study is to evaluate the effect of rituximab on patients that do not respond to or relapse after conventional therapy.

Detailed description:
Diffuse autoimmune hyperthyroidism or Graves' disease (GD) is a common condition mainly affecting women with 2-3% prevalence The increased production of thyroid hormones in GD is driven by autoantibodies directed against the thyroid stimulating hormone (TSH) receptor (TRab). In most cases, this autoimmunity will also affect other tissues, above all the orbital tissue by mechanisms not fully understood -Thyroid Associate Ophthalmopathy (TAO). Symptoms and signs can be mild (grittiness, dry eyes, periorbital swollen, chemosis, redness)-moderate (double eye vision, exophthalmia or severe (optic nerve compression, corneal ulcers). Serious-moderate ocular engagement in TAO is seen in approximately 10% of patients with GD.

Not only has the hyperthyroidism a marked impact on mental health, but the presence of TAO has an additional negative impact on the well-being of these patients, even many years after successful treatment of the hyperthyroidism. It has been suggested that smoking and stress are negative prognostic factors for the course of TAO indicating that a vicious circle. MRI may detect earlier changes than CT that can be used to predict the course of TAO.

The aims of treatment are to retain euthyroidism which can be achieved by anti thyrostatic drugs (ATD), radioiodine treatment or surgery (where patients are pre-treated with ATD) and to avoid TAO as long as possible. If moderate-severe TAO occurs, high dose if intravenous glucocorticoids (GC) are the gold standard considering the side effects. However, many patients are non-steroid responders and for them no treatment except for acute orbital decompression, retro bulbar irradiation and later reconstructive surgery can be offered. When patients relapse immediately after steroids often per oral steroids are given although not recommended from the literature.

Rituximab (RTX) is a mouse-human chimeric antibody designed towards pre B and mature B lymphocytes and that blocks B-cells activation without affecting the regenerating of B cells from stem cells or the plasma cells immunoglobulin production. TAO is a B- lymphocyte mediated disease and in two studies RTX inhibits the active phase of TAO. In a study by Khanna et al a positive effect from RTX is observed in six steroid resistant patients with TAO with a decrease of the inflammation in the orbit, even though no effect on strabismus or proptosis was observed. In another study by Salvi et al , RTX treatment is compared with steroids as a first line treatment for TAO and after 30 weeks of follow up in an unrandomised study design. RTX decreased the activity and severity significantly compared to the steroid group. No relapse was observed in the RTX group but in the steroid group (10%). In the RTX all patients improved, but in the steroid group only 65%. There were more side-effects in the steroid group.

Selection criteria All patients with indication for i.v GC will be evaluate for the study. The patients are recruited consecutively from the region as we are a tertial referral center and iv steroids for TAO is not given on local hospitals..

Patients and study design All patients aged 18-70 years in the western region in Sweden with TAO and indication for iv GC (CAS ≥4) will be evaluated for this prospective open study with RTX+MTX to GC non-responders. If GC respondent but relapsing after 12 weeks of iv GC treatment, patients will be randomized to RTX+MTX or per oral GC+MTX. If non respondent after 4 weeks of intravenous steroid infusion the patient will be eligible for RTX treatment Patients are seen for ophthalmological and endocrine investigations at baseline, 4, 12, 18, 32, 44, 56 and 68 weeks. At similar occasions anthropometric measurements, immunological markers and measures of GC effects (ACTH test, body composition (not all occasions)) will be performed. At baseline and after 30 weeks high quality MRI and Gallium (GA)-PET is performed. Patients undergoing Ga-PET in another study focusing on pituitary imaging (principle investigator HFN) will serve as controls for orbital muscles. The aim of the RTX study is to recruit at least 10 patients in the RTX arm and probably 40-50 patients will be included.

No study with this design has previously been published. The present situation does not offer the patients not responding to GC or with relapses after iv GC infusions any effective treatment. If the RTX proves safe and effective future non-respondent patients will be able to get this treatment. In small studies RTX have had a good effect in TAO, sometimes even better than GC and with less side-effects. It will also lay the ground for future studies that compare RTX and GC in a randomised study design as first line treatment. If GA-PET shows useful in the management of patients with TAO it may become a routine investigation.

Arms: arm 1: Patients with moderate-severe TAO with an inflammatory CAS of ≥ 4 that do not respond to iv GC (deltaCAS \<2 compared to baseline after 4 weeks of iv GC ) or do relapse (deltaCAS ≥2 and total CAS ≥4) after steroid treatment compared to previous CAS measurement at 12 weeks. Rituximab (1000 mg iv with 2 weeks in between) is combined with methotrexate (15-20 mg once a week) to minimize the risk of antibody developement. MTX is always combined with RTX and is never given as a monotherapy in this study.

rituximab and methotrexate arm 2: Patients that respond to iv GC (Methylprednisolone iv) but relapse after 6 weeks will be randomised to either RTX+MTX or per oral GC (po GC+MTX) rituximab and methotrexate arm 3: Patients that respond to iv GC but relapse after 6 weeks will be randomised to either RTX+MTX or per oral GC (po GC+MTX) This is the conventional therapy arm.

methotrexate and methylprednisolone arm 4: Patients that respond to iv GC and have no relapse at 18 weeks of study. arm 5: All patients in the study have a 4 weeks period of 500 mg methylprednisolone iv/week. Depending of the response patients are classified as non- responders (and are given RTX and MTX) or responders. The responders continue with intravenous infusion of Methylprednisolone 500 mg /week in 2 weeks and thereafter 250 mg iv/week in 6 weeks.
Interventions: intervention 1: Rituximab intervention 2: Iv Methylprednisolone intervention 3: peroral methylprednisolone and Methotrexate
Intervention descriptions: intervention 1: Rituximab (RTX) is a mouse-human chimeric antibody designed towards (CD20) pre B and mature B lymphocytes and that blocks B-cells activation without affecting the regenerating of B cells from stem cells or the plasma cells immunoglobulin production. Rituximab is used in the treatment of hematologic malignancies (B cells lymphoma, chronic lymphatic leukaemia, Waldenströms macroglobulinemia) and autoimmune diseases with B-cell involvement such as rheumatoid arthritis, thrombocytopenic purpura, SLE). intervention 2: Solumedrol is an intravenous glucocorticoid that are the gold standard in TAO. All patients start with 500 mg/weeks for 4 weeks. The response is evaluated and patients are randomised to non-responders or responders. The responders continues with the gold standard treatment that is another 500 mg solumedrol/ week in 2 weeks and then 250 mg/ week in 6 weeks. intervention 3: Peroral GC (starting with 30 mg and tapering down) is combined with 15-20 mg MTX /week to reduce the needed dose of steroids

Protocol documents:
Prot_000.pdf: 
PROTOCOL 
 
TITLE. Rituximab (RTX) Therapy in Patients With Active TAO 
 
 
 
 
 
NCT 02378298 
Date 2011-08-24 
 
 


Background 
Every year, 2000 patients in Sweden get the diagnosis of a diffuse autoimmune 
hyperthyroidism (Grave’s disease (GD)). About 40% of the patients with GD have some 
complaints from their eyes indicating thyroid associated ophthalmopathy (TAO) in its mild 
form. Moderate-severe forms are seen in approximately 5-10% of GD patients. TAO is an 
autoimmune complication of GD and the inflammation causes swelling of the periorbital fat, 
muscles and connective tissue. The patient obtains symptoms such as red eyes, pain, 
epiphora, diplopia and sometimes exophthalmos. This affects the patient’s quality of life 
(QoL) negatively.  
Today, the primary treatment of moderate-severe TAO is high doses of intravenous (iv) 
steroids, with the purpose to suppress the inflammation. High doses of iv steroids cause side 
effects, therefore, it is motivated only in moderate-severe cases. Even when the treatment is 
given early in the course of the disease, only 70-80% of the patients respond to the treatment 
(responders). The treatment effect on the inflammation is most commonly measured with 
Clinical Activity Score (CAS) – a score recommended by the European Group of Graves 
orbitopathy (EUGOGO). 
Ten years ago, small observational studies reported promising result on Rituximab (RTX) 
treatment in TAO, given less side-effects. RTX is an immunomodulating drug where 
antibodies affect B-cells.  
 
Objectives  
The primary aim of this study is to evaluate the effect of Rituximab (RTX) in Thyroid 
Associated Ofthalmopathy (TAO) patients who are non-responsive to treatment with iv GC 
(NR-RTX), with patients controls that continued with iv GC even though they did not 
respond (NR-C). A second aim is to compare the NR-RTX patients with the steroid 
responsive ones (R-GC) and NR-C, regarding background variables (gender, age, smoking 
status, duration of GD, duration of eye symptoms, thyroid treatment and lab) and efficacy 
variables (CAS, CAS SU/M, severity, proptosis and subjective diplopia). Lastly, a third aim is 
to evaluate and compare the QoL between the R-GC and the NR-RTX in the study at given 
time points. 


Research questions 
Does RTX lower the CAS of the non-steroid responsive TAO-patients (NR-RTX), in 
comparison to NR-C, that continued with iv GC, and R-GC? Do the background variables 
differ between NR-RTX and NR-GC or R-GC? And lastly, does the QoL differ between the 
R-GC and the NR-RTX at given measuring points?  
 
Material and Methods  
Study design  
The RTX-study is a non-randomized prospective study that covers patients with moderate-
severe TAO with indication for treatment with iv GC. For this study, a control group (NR-C) 
will be created.   
Patients with TAO are evaluated at Department of Ophthalmology at Sahlgrenska University 
Hospital/ Mölndal’s and are asked for participation if eligible. Variables collected at each visit 
Clinical Activity Score (CAS), Quality of Life (QoL) through ThyPRO self-assessment 
questionnaire, biochemical tests (fT4, fT3, TSH, TRAb, liver function tests, fasting blood 
glucose), blood pressure and waist. An oral glucose tolerance test (OGTT) is performed at 12, 
18, and 46 weeks, and a short adrenocorticotropic hormone (ACTH) test at 12 and 46 weeks. 
Dual-energy x-ray absorptiometry (DXA) of the spine is conducted at 0 and 18 weeks. 
All patients in the RTX-study start the 12-week scheme of iv GC at baseline. After four 
weeks of treatment, an evaluation of the treatment outcome is made. If the patients have 
improved their CAS score by ≥ 2 points, they are classified as responders to iv GC (R-GC) 
and continue their 12-week iv GC scheme. The remainder of the patients are classified as 
non-responders to the treatment with iv GC and are switched to 1000 mg iv RTX in week 5 
and 7, combined with a weekly oral dose of 12.5 – 15 mg MTX (NR-RTX). The RTX is 
administered at the department of Rheumatology at Sahlgrenska University Hospital. All 
included patients have thereafter follow-up visits at week 12, 18, 32, 46 and 68 weeks after 
baseline.   
At week 18 and at all follow-up timepoints thereafter, patients in R-GC group are evaluated 
for possible relapse. If a patient in R-GC has a CAS ≥ 4 points and CAS has worsened by ≥ 2 
points compared to the value measured in the prior evaluation time-point, the patient is 


considered having a relapse. Patients with relapse are randomized to either treatment with 
RTX and MTX or with per oral GC and MTX.  
All patients included in the study are assessed according to study protocol, but if DON is 
developed, the affected patient is treated outside the study protocol in order to follow DON 
treatment regimen. The patients with DON still have the same evaluation time points as the 
other patients in the study, but they are excluded from the comparisons between groups after 
the occurrence of DON.  
From the group of patients with moderate – severe TAO with indication for treatment with iv 
GC that do not meet inclusion/exclusion criteria for the RTX-study or declined participation, 
a control group (NR-C) of non-responders will be created. As they are not included in the 
RTX study, they continue with their 12 weeks scheme of iv GC treatment. 
Data collected at the follow-up timepoints: QoL, safety data and information on adverse 
events. 
Study population 
Inclusion criteria for the RTX study: man or woman between 18-70 years old, TAO with 7-
point score system of CAS ≥ 4 (less than 3 months old), euthyroid for at least 6 weeks.  
Exclusion criteria for the RTX study were: DON, ulcerative corneal involvement, previous 
treatment with steroids for TAO (except for prophylaxis for TAO in connection with RAI), 
previous treatment with RTX, positive Hepatitis B or C serology, obtained a living vaccine 
within 4 weeks prior RTX+MTX to evaluation, history of recurrent significant infection or 
history of recurrent bacterial infections, assessment by the investigator that the patient may 
not attend to the protocol, current pregnancy or lactation, significant cardiac disease, 
including significant or uncontrolled arrhythmia, previous active tuberculosis, bone marrow 
depression with leukopenia, thrombocytopenia or significant anaemia, allergy to the active 
substance or any other substance in the medications or murine proteins, active, severe 
infections (such as tuberculosis, sepsis or opportunistic infections), patients with severe 
immunosuppression, severe cardiac failure  or severe uncontrolled heart disease.  
The TAO patients not included in the RTX-study will be identified using the diagnosis-related 
group (DRG) registry according to the 10th revision (ICD-10) in VGR. In DRG, a 
combination of different codes was used (TAO [H06.2], Graves’ disease [E05.0] and iv 
infusion [DT016]).    


Efficacy variables 
In the study, both patients’ eyes are evaluated regarding CAS and the score of and any 
improvement of the worst eye was used.  
The proptosis is measured in both eyes using the Hertel exophtalmometer.  
The ThyPRO questionnaire is a thyroid specific QoL self-assessment questionnaire. It is one 
questionnaire that measures QoL within 13 different dimensions: goitre symptoms, 
hyperthyroid symptoms (constitutes two dimensions), eye symptoms, tiredness, cognitive 
function, anxiety, depressivity, emotional susceptibility, impairment of social, daily and sex 
life and lastly cosmetic complaints. ThyPRO consists of totally 84 questions. The scores for 
each dimension can be presented as raw or normalised score (raw score/max score x 100) that 
ranges from 0 to 100. A high normalised score indicates decreasing QoL (i.e. more symptoms 
or greater impact of disease).   
 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
Statistical Analysis Plan 
 
 
TITLE. Rituximab (RTX) Therapy in Patients With Active TAO 
 
 
 
 
 
NCT 02378298 
Date 2024-09-30 
 
 
 


 
 
1 
STUDY DETAILS 
1.1 
Study Objectives 
A. Do the background variables differ between NR-RTX and R-GC or 
NR-GC? 
B. Does RTX lower the CAS of the non-steroid responsive TAO-
patients (NR-RTX), in comparison to NR-C, that continued with iv 
GC, and R-GC? 
1.2 
Study Design 
.See Protocol of the study 
 
1.3 
Treatment Groups 
Treatment groups: NR-RTX and R-GC or NR-GC. 
 
1.4 
Power Calculation 
No power calculation was performed due to the lack of data from any similar 
study of RTX in GC non-responders 
 
 
 
2 
STUDY VARIABLES 
2.1 
Baseline Variables 
2.1.1 Demographics and Baseline Characteristics only available at baseline 
• Age (years) 
• Sex (man /woman = m/w) 
• Smoking status (smoker/previous smoker/non-smoker) 
• Previous treatment (operation/RAI/ATD) 
• Current treatment (Levothyrocin/ATD) 
• Time from diagnosis of GD (years) 
• Duration of eye symptoms (months) 
 
2.1.2 Laboratory/evaluation measurements only available at baseline: 
• fT4 (pmol/L) 
• fT3 (pmol/L) 
• TSH (mIE/L) 
• Exophthalmometry left (mm) 
• Exophthalmometry right (mm) 
• Subjective diplopia (non/intermittent/corrected with prism) 
 
 
2.2 
Variables evaluated throughout the study 
• 
TRAb antibodies 
• 
Waist circumference change (%) 


 
• 
High systolic blood pressure (ja/nej) 
• 
High diastolic blood pressure (ja/nej) 
• 
ALT increased (ja/nej) 
• 
AST increased (ja/nej) 
• 
OGTT results (diabetes/glucose intolerance) 
• 
Short ACTH test (normal/inadequate response) 
• 
Collected information on patient-reported adverse events 
 
 
 
 
 
2.3 
Analysis Variables 
2.3.1 Primary Variable 
• Change of CAS (clinical activity score) between the observation 
timepoints and the previous timepoint: comparison between the 
treatment groups 
• CAS: comparison between the treatment groups at the different 
timepoints 
 
 
2.3.2 Secondary Variables 
• Change of CAS between the observation timepoints and the baseline: 
comparison between the treatment groups 
• Comparison of frequency of adverse events between NR-RTX and R-
GC. 
• TRAb antibodies 
 
 
3 
STATISTICAL METHODOLOGY 
Tests between groups will be made for the NR-RTX group and all of the other 
groups one at a time; R-GC and NR-C (where applicable). 
 
For continuous variables Mann-Whitney U-test will be used for analyses 
between two groups. For dichotomous variables Fisher exact test will be used 
for test between two groups. For ordered categorical variables Mantel Haenszel 
Chi Square test will be used for test between two groups.  
 
For all continuous variables Wilcoxon’s Signed-Rank test will be used for 
within group analyses.