Rituximab (RTX) Therapy in Steroid Resistant Patients or Patients Relapsing After Intravenous Steroids With Active TAO
Phase: PHASE4
Conditions: Ophthalmopathy, Thyroid-Associated
Sponsor: Göteborg University

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).