Rituximab (RTX) Therapy in Patients With Active TAO

NCT02378298 | Completed Phase 4 Results DMC

• 1 other identifier: RTX -TAO
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 5

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.

Conditions

Ophthalmopathy, Thyroid-Associated

Outcome Measures

Primary Outcomes (1)

• Clinical Activity Score (a Composite Measure of Ophthalmological Signs and Symptoms)

  Clinical activity score (CAS) according to Mouritz et al and the consensus statement from European Group of Graves orbitopathy (EUGOGO). It consists of 10 items (1. Spontaneous retrobulbar pain, 2. Pain on eye movements, 3. Eyelid erythema, 4. Conjunctival injection, 5. Chemosis, 6. Swelling of the caruncle, 7. Eyelid edema or fullness, 8. Change in motility,9. Change in vision acuity,10.Change in proptosis). One point is given to each item, if present. CAS is the sum of single scores, ranging from 0 (no activity) to 10 (maximal activity).

  At 4,12,18 and 68 weeks

Other Outcomes (4)

• Thyroid-stimulating Hormone Receptor Antibodies

  at 4 weeks

• Thyroid-stimulating Hormone Receptor Antibodies

  at12 weeks

• Thyroid-stimulating Hormone Receptor Antibodies

  at18 weeks

Study Arms (5)

Non-responder RTX+MTX

ACTIVE COMPARATOR

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

Relapse RTX+MTX

ACTIVE COMPARATOR

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

Relapse po GC+MTX

ACTIVE COMPARATOR

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

Responders without relapse

NO INTERVENTION

Patients that respond to iv GC and have no relapse at 18 weeks of study.

Methylprednisolone iv

ACTIVE COMPARATOR

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

Interventions

Rituximab DRUG

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).

Also known as: Mabthera, Rituxan, Zytux, L01XC02

Non-responder RTX+MTX; Relapse RTX+MTX

Iv Methylprednisolone DRUG

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.

Also known as: Solumedrol

Methylprednisolone iv

peroral methylprednisolone and Methotrexate DRUG

Peroral GC (starting with 30 mg and tapering down) is combined with 15-20 mg MTX /week to reduce the needed dose of steroids

Also known as: Prednisolone

Relapse po GC+MTX

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ◦Man or woman between 18-70 years TAO with CAS of ≥ 4 (less than 3 months).
• Euthyroid for at least 6 weeks

You may not qualify if:

• 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

Sponsors & Collaborators

• Göteborg University: lead
• Sahlgrenska University Hospital: collaborator

Study Sites (5)

Center for Endocrinology and Metabolism, Sahlgrenska University Hospital

Gothenburg, Sweden

Location

MedTech West, Institute of Neuro Science and Physiology, Department for Clinical Neuro Science and Rehabilitation, Sahlgrenska Academy, University of Gothenburg

Gothenburg, Sweden

Location

Department of Ophthalmology, Sahlgrenska University Hospital/Mölndal

Mölndal, Sweden

Location

Department of Rheumatology, Sahlgrenska University Hospital/Mölndal

Mölndal, Sweden

Location

Department of Radiology, Karolinska University Hospital

Stockholm, Sweden

Location

MeSH Terms

Conditions

Graves Ophthalmopathy

Interventions

Rituximab; Methylprednisolone; Methylprednisolone Hemisuccinate; Methotrexate; Prednisolone

Condition Hierarchy (Ancestors)

Eye Diseases, Hereditary; Eye Diseases; Graves Disease; Exophthalmos; Orbital Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Goiter; Thyroid Diseases; Endocrine System Diseases; Hyperthyroidism; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Helena Filipsson Nyström
• Organization: Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Göteborg

helena.filipsson@medic.gu.se

0046-705833398

Study Officials

• Helena Filipsson, Ass Prof

  Sahlgrenska University Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 20, 2015
• First Posted: March 4, 2015
• Study Start: December 1, 2011
• Primary Completion: September 3, 2019
• Study Completion: February 1, 2020
• Last Updated: March 26, 2025
• Results First Posted: March 26, 2025

Record last verified: 2025-03

Locations

SE (5)