Rituximab (RTX) Therapy in Patients With Active TAO

Study Overview
=================
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.

Official Title
-----------------
Rituximab (RTX) Therapy in Steroid Resistant Patients or Patients Relapsing After Intravenous Steroids With Active TAO

Conditions
-----------------
Ophthalmopathy, Thyroid-Associated

Intervention / Treatment
-----------------
* Drug: Rituximab
* Drug: Iv Methylprednisolone
* Drug: peroral methylprednisolone and Methotrexate


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: ◦Man or woman between 18-70 years TAO with CAS of ≥ 4 (less than 3 months). Euthyroid for at least 6 weeks Exclusion Criteria: Dysthyroid optic neuropathy (DON) Ulcerative Keratitis Previous treatment with steroids for TAO (do not include prophylaxis for TAO in connection with radio iodine treatment) Previous Treatment with Rituximab (MabThera®) Positive Hepatitis B or C serology. Receipt of a live vaccine within 4 weeks prior RTX+MTX to randomization History of recurrent significant infection or history of recurrent bacterial infections Patient who may not attend to the protocol according to the investigators opinion. Pregnancy or lactation Significant cardiac, including significant or uncontrolled arrhythmia, or pulmonary disease (including obstructive pulmonary disease). Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications Concomitant malignancies or previous malignancies. Previous active tuberculosis Alcoholism Alcoholic related liver disease or other chronical liver disease Bone marrow depression with leukopenia, thrombocytopenia or significant anemia Rheumatoid or other significant pulmonary disease 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Non-responder RTX+MTX<br>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 | Drug: Rituximab<br>* 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).<br>* Other names: L01XC02;|
| Active Comparator: Relapse RTX+MTX<br>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 | Drug: Rituximab<br>* 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).<br>* Other names: L01XC02;|
| Active Comparator: Relapse po GC+MTX<br>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 | Drug: peroral methylprednisolone and Methotrexate<br>* Peroral GC (starting with 30 mg and tapering down) is combined with 15-20 mg MTX /week to reduce the needed dose of steroids<br>* Other names: Prednisolone;|
| No Intervention: Responders without relapse<br>Patients that respond to iv GC and have no relapse at 18 weeks of study. | |
| Active Comparator: Methylprednisolone iv<br>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. | Drug: Iv Methylprednisolone<br>* 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.<br>* Other names: Solumedrol;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Clinical Activity Score (a composite measure of ophthalmological signs and symptoms) between arms | The primary outcome measurement is the responder analysis in Clinical activity score (CAS) according to Mouritz et al and the consensus statement from European Group of Graves orbitopathy (EUGOGO) in the responder analysis. A responder is defined as an improvement in CAS ≥2 compared with before treatment. This can be analyzed at four occasions At 4 weeks iv Steroid treatment compared to baseline In the responder group 12 weeks compared to baseline In the non-responder group 18 weeks compared to 4 weeks In the relapse group at 32 and 46 weeks compared to 18 weeks | At 4, 12, 18, 32 and 46 weeks | 
| Comparison of Clinical Activity Score (a composite measure of ophthalmological signs and symptoms) between arms | The primary outcome measurement is the responder analysis in Clinical activity score (CAS) according to Mouritz et al and the consensus statement from European Group of Graves orbitopathy (EUGOGO) in the responder analysis. A responder is defined as an improvement in CAS ≥2 compared with before treatment. This can be analyzed at four occasions At 4 weeks iv Steroid treatment compared to baseline In the responder group 12 weeks compared to baseline In the non-responder group 18 weeks compared to 4 weeks In the relapse group at 32 and 46 weeks compared to 18 weeks | At 4, 12, 18, 32 and 46 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean/Median change in CAS (a composite measure of of ophthalmological signs and symptoms according to Mouritz et al and the EUGOGO | Mean/Median change in CAS is a secondary measurement outcome and can be evaluated at: 12 weeks in the responder group compared to baseline 18 weeks in the non-responder group compared to 4 weeks In the relapse group at 32 and 46 weeks compared to 18 weeks in relapse RTX+MTX and po GC+MTX, respectively | 12, 18, 32 and 46 weeks | 
| Comparison of Adverse (a composite measure) events between arms | Adverse events are recorded regarding symptoms and effects on glucose metabolism and body composition | At 4, 12, 18, 32 and 46 and 68 weeks | 
| Comparison of MRI attenuation of inflammation and CAS | MRI is performed at baseline and after 30 weeks to detect degree of inflammation. This will be compared to the CAS score | At baseline and 30 weeks | 
| Comparison of the change in the dynamic measure of standardized uptake values in PET of the orbital muscles to detect inflammation to that on MRI and CAS | PET of orbital muscles is performed at baseline and after 30 weeks | At baseline and 30 weeks |