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Trial record 1 of 1 for:    NCT02378298
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Rituximab (RTX) Therapy in Patients With Active TAO

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ClinicalTrials.gov Identifier: NCT02378298
Recruitment Status : Recruiting
First Posted : March 4, 2015
Last Update Posted : August 21, 2018
Sponsor:
Collaborator:
Sahlgrenska University Hospital, Sweden
Information provided by (Responsible Party):
Göteborg University

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.


Condition or disease Intervention/treatment Phase
Ophthalmopathy, Thyroid-Associated Drug: Rituximab Drug: Iv Methylprednisolone Drug: peroral methylprednisolone and Methotrexate Phase 4

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Rituximab (RTX) Therapy in Steroid Resistant Patients or Patients Relapsing After Intravenous Steroids With Active TAO
Study Start Date : December 2011
Estimated Primary Completion Date : May 2019
Estimated Study Completion Date : December 2019


Arm Intervention/treatment
Active Comparator: Non-responder RTX+MTX

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
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).
Other Names:
  • Mabthera
  • Rituxan
  • Zytux
  • L01XC02

Active Comparator: Relapse RTX+MTX
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
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).
Other Names:
  • Mabthera
  • Rituxan
  • Zytux
  • L01XC02

Active Comparator: Relapse po GC+MTX

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

No Intervention: Responders without relapse
Patients that respond to iv GC and have no relapse at 18 weeks of study.
Active Comparator: Methylprednisolone iv
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
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.
Other Name: Solumedrol




Primary Outcome Measures :
  1. Change in Clinical Activity Score (a composite measure of ophthalmological signs and symptoms) between arms [ Time Frame: At 4, 12, 18, 32 and 46 weeks ]

    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

    1. At 4 weeks iv Steroid treatment compared to baseline
    2. In the responder group 12 weeks compared to baseline
    3. In the non-responder group 18 weeks compared to 4 weeks
    4. In the relapse group at 32 and 46 weeks compared to 18 weeks

  2. Comparison of Clinical Activity Score (a composite measure of ophthalmological signs and symptoms) between arms [ Time Frame: At 4, 12, 18, 32 and 46 weeks ]

    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

    1. At 4 weeks iv Steroid treatment compared to baseline
    2. In the responder group 12 weeks compared to baseline
    3. In the non-responder group 18 weeks compared to 4 weeks
    4. In the relapse group at 32 and 46 weeks compared to 18 weeks


Secondary Outcome Measures :
  1. Mean/Median change in CAS (a composite measure of of ophthalmological signs and symptoms according to Mouritz et al and the EUGOGO [ Time Frame: 12, 18, 32 and 46 weeks ]

    Mean/Median change in CAS is a secondary measurement outcome and can be evaluated at:

    1. 12 weeks in the responder group compared to baseline
    2. 18 weeks in the non-responder group compared to 4 weeks
    3. In the relapse group at 32 and 46 weeks compared to 18 weeks in relapse RTX+MTX and po GC+MTX, respectively

  2. Comparison of Adverse (a composite measure) events between arms [ Time Frame: At 4, 12, 18, 32 and 46 and 68 weeks ]
    Adverse events are recorded regarding symptoms and effects on glucose metabolism and body composition

  3. Comparison of MRI attenuation of inflammation and CAS [ Time Frame: At baseline and 30 weeks ]
    MRI is performed at baseline and after 30 weeks to detect degree of inflammation. This will be compared to the CAS score

  4. 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 [ Time Frame: At baseline and 30 weeks ]
    PET of orbital muscles is performed at baseline and after 30 weeks



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02378298


Contacts
Contact: Mats O Holmberg, Phd student +46705266365 mats@xnet.se

Locations
Sweden
Center for Endocrinology and Metabolism, Sahlgrenska University Hospital Recruiting
Gothenburg, Sweden
Contact: Ann-Charlotte Olofsson, Nurse         
MedTech West, Institute of Neuro Science and Physiology, Department for Clinical Neuro Science and Rehabilitation, Sahlgrenska Academy, University of Gothenburg Active, not recruiting
Gothenburg, Sweden
Department of Ophthalmology, Sahlgrenska University Hospital/Mölndal Recruiting
Mölndal, Sweden
Contact: Lena Sjödell, Dr         
Department of Rheumatology, Sahlgrenska University Hospital/Mölndal Active, not recruiting
Mölndal, Sweden
Department of Radiology, Karolinska University Hospital Active, not recruiting
Stockholm, Sweden
Sponsors and Collaborators
Göteborg University
Sahlgrenska University Hospital, Sweden
Investigators
Principal Investigator: Helena Filipsson, Ass Prof Sahlgrenska University Hospital, Sweden

Responsible Party: Göteborg University
ClinicalTrials.gov Identifier: NCT02378298     History of Changes
Other Study ID Numbers: RTX -TAO
First Posted: March 4, 2015    Key Record Dates
Last Update Posted: August 21, 2018
Last Verified: August 2018

Additional relevant MeSH terms:
Eye Diseases
Graves Ophthalmopathy
Eye Diseases, Hereditary
Graves Disease
Exophthalmos
Orbital Diseases
Goiter
Thyroid Diseases
Endocrine System Diseases
Hyperthyroidism
Autoimmune Diseases
Immune System Diseases
Rituximab
Methotrexate
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone acetate
Methylprednisolone acetate
Methylprednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Antimetabolites