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    Clinical Trial Results:
    Rituximab (RTX) therapy in steroid resistant patients or patients relapsing after intravenous steroids with active TAO Rescue RTX

    Summary
    EudraCT number
    		 2011-000899-33
    Trial protocol
    		 SE  
    Global end of trial date
    09 Feb 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 May 2024
    First version publication date
    26 May 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    rescue RTX
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02378298
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Department of Endocrinology, Sahlgrenska University Hospital
    Sponsor organisation address
    Medicinmottagningen, Sahlgrenska Universitetssjukhus, Blå stråket 5, vån 1 , Gothenburg, Sweden, 413 45
    Public contact
    Helena Filipsson Nyström, Department of Endocrinology, Sahlgrenska University Hospital, 0046 31-7863398,
    Scientific contact
    Helena Filipsson Nyström, Department of Endocrinology, Sahlgrenska University Hospital, 0046 31-7863398,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Feb 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Feb 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Feb 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary scientific question 1. To evaluate the effect of RTX+MTX in patients with active TAO unresponsive to steroids or active TAO relapsing after steroid treatment.
    Protection of trial subjects
    This study was approved by the Ethics committee in Göteborg and by the Swedish Medical Product Agency, Uppsala, Sweden, and was registered at www.clinicaltrials.gov (NCT02378298). Informed consent was received from all study participants. The retrospective data collection did not require individual informed consent. We adhered to the Declaration of Helsinki and the study conduct was closely followed by a monitor.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 37
    Worldwide total number of subjects
    37
    EEA total number of subjects
    37
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    32
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study took place at the Departments of Ophthalmology, Endocrinology, and Rheumatology at Sahlgrenska University Hospital (SU) in Mölndal and Göteborg, Sweden. Eligible patients were consecutively asked by the ophthalmologist for participation.

    Pre-assignment period milestones
    Number of subjects started
    		 37
    Number of subjects completed
    		 37

    Period 1
    Period 1 title
    Run-In (0-4 WEEKS)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Non-responders RTX+MTX (NR-RTX)
    Arm description
    		 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 type
    		 Experimental

    Investigational medicinal product name
    methylprednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    methylprednisolone 500 mg once weekly

    Arm title
    		 Responders (R-CG)
    Arm description
    		 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.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    methylprednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    methylprednisolone 500 mg once weekly

    Arm title
    		 Non-responders Control Group (R-C)
    Arm description
    		 A retrospective group of non-responsive patients after 4 weeks with iv glucocorticoids, who received regular care, i.e. full 12-week treatment with glucocorticoids according to clinical praxis. This group was used as control and received the same therapy as Responders (R-CG).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    methylprednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    methylprednisolone 500 mg once weekly

    Number of subjects in period 1
    		Non-responders RTX+MTX (NR-RTX) Responders (R-CG) Non-responders Control Group (R-C)
    Started
    12
    13
    12
    Completed
    10
    13
    12
    Not completed
    2
    0
    0
         Physician decision
    2
    -
    -
    Period 2
    Period 2 title
    Intervention (5-12 Weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Non-responders RTX+MTX (NR-RTX)
    Arm description
    		 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 type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    Rituximab (1000 mg) was administered at 5 and 7 weeks after the baseline visit

    Investigational medicinal product name
    methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravesical use
    Dosage and administration details
    15–20 mg/week

    Arm title
    		 Responders (R-CG)
    Arm description
    		 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.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    methylprednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    methylprednisolone 500 mg once weekly for 6 weeks followed by 250 mg once weekly for 2 weeks

    Arm title
    		 Non-responders Control Group (R-C)
    Arm description
    		 A retrospective group of non-responsive patients after 4 weeks with iv glucocorticoids, who received regular care, i.e. full 12-week treatment with glucocorticoids according to clinical praxis. This group was used as control and received the same therapy as Responders (R-CG).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    methylprednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    methylprednisolone 500 mg once weekly for 6 weeks followed by 250 mg once weekly for 2 weeks

    Number of subjects in period 2
    		Non-responders RTX+MTX (NR-RTX) Responders (R-CG) Non-responders Control Group (R-C)
    Started
    10
    13
    12
    Completed
    10
    13
    11
    Not completed
    0
    0
    1
         Physician decision
    -
    -
    1
    Period 3
    Period 3 title
    Follow-up (13-18 Weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Non-responders RTX+MTX (NR-RTX)
    Arm description
    		 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 type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Responders (R-CG)
    Arm description
    		 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.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Non-responders Control Group (R-C)
    Arm description
    		 A retrospective group of non-responsive patients after 4 weeks with iv glucocorticoids, who received regular care, i.e. full 12-week treatment with glucocorticoids according to clinical praxis. This group was used as control and received the same therapy as Responders (R-CG).
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    		Non-responders RTX+MTX (NR-RTX) Responders (R-CG) Non-responders Control Group (R-C)
    Started
    10
    13
    11
    Completed
    10
    13
    11
    Period 4
    Period 4 title
    Surveillance (19-68 Weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Non-responders RTX+MTX (NR-RTX)
    Arm description
    		 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 type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Responders (R-CG)
    Arm description
    		 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.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Non-responders Control Group (R-C)
    Arm description
    		 A retrospective group of non-responsive patients after 4 weeks with iv glucocorticoids, who received regular care, i.e. full 12-week treatment with glucocorticoids according to clinical praxis. This group was used as control and received the same therapy as Responders (R-CG).
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 4
    		Non-responders RTX+MTX (NR-RTX) Responders (R-CG) Non-responders Control Group (R-C)
    Started
    10
    13
    11
    Completed
    10
    12
    11
    Not completed
    0
    1
    0
         Adverse event, serious fatal
    -
    1
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Non-responders RTX+MTX (NR-RTX)
    Reporting group description
    		 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

    Reporting group title
    Responders (R-CG)
    Reporting group description
    		 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.

    Reporting group title
    Non-responders Control Group (R-C)
    Reporting group description
    		 A retrospective group of non-responsive patients after 4 weeks with iv glucocorticoids, who received regular care, i.e. full 12-week treatment with glucocorticoids according to clinical praxis. This group was used as control and received the same therapy as Responders (R-CG).

    Reporting group values
    		 Non-responders RTX+MTX (NR-RTX) Responders (R-CG) Non-responders Control Group (R-C) Total
    Number of subjects
    		 12 13 12 37
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.8 ( 9.1 ) 54.6 ( 6.9 ) 57.5 ( 12.0 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 12 7 25
        Male
    		 6 1 5 12
    Thyroid-stimulating hormone receptor antibodies (TRAb)
    Units: IE/L
        median (inter-quartile range (Q1-Q3))
    		 -
    Subject analysis sets

    Subject analysis set title
    Non-responders RTX+MTX (NR-RTX)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    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

    Subject analysis set title
    Responders (R-CG)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    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.

    Subject analysis set title
    Non-responders Control Group (R-C)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    A retrospective group of non-responsive patients after 4 weeks with iv glucocorticoids, who received regular care, i.e. full 12-week treatment with glucocorticoids according to clinical praxis. This group was used as control and received the same therapy as Responders (R-CG).

    Subject analysis sets values
    		 Non-responders RTX+MTX (NR-RTX) Responders (R-CG) Non-responders Control Group (R-C)
    Number of subjects
    12
    13
    12
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    52.8 ( 9.1 )
    54.6 ( 6.9 )
    57.5 ( 12.0 )
    Gender categorical
    Units: Subjects
        Female
    6
    12
    7
        Male
    6
    1
    5
    Thyroid-stimulating hormone receptor antibodies (TRAb)
    Units: IE/L
        median (inter-quartile range (Q1-Q3))
    28.6 (7.8 to 41.0)
    11.4 (5.9 to 20.3)
    9.7 (4.7 to 27.0)

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Non-responders RTX+MTX (NR-RTX)
    Reporting group description
    		 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

    Reporting group title
    Responders (R-CG)
    Reporting group description
    		 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.

    Reporting group title
    Non-responders Control Group (R-C)
    Reporting group description
    		 A retrospective group of non-responsive patients after 4 weeks with iv glucocorticoids, who received regular care, i.e. full 12-week treatment with glucocorticoids according to clinical praxis. This group was used as control and received the same therapy as Responders (R-CG).
    Reporting group title
    Non-responders RTX+MTX (NR-RTX)
    Reporting group description
    		 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

    Reporting group title
    Responders (R-CG)
    Reporting group description
    		 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.

    Reporting group title
    Non-responders Control Group (R-C)
    Reporting group description
    		 A retrospective group of non-responsive patients after 4 weeks with iv glucocorticoids, who received regular care, i.e. full 12-week treatment with glucocorticoids according to clinical praxis. This group was used as control and received the same therapy as Responders (R-CG).
    Reporting group title
    Non-responders RTX+MTX (NR-RTX)
    Reporting group description
    		 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

    Reporting group title
    Responders (R-CG)
    Reporting group description
    		 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.

    Reporting group title
    Non-responders Control Group (R-C)
    Reporting group description
    		 A retrospective group of non-responsive patients after 4 weeks with iv glucocorticoids, who received regular care, i.e. full 12-week treatment with glucocorticoids according to clinical praxis. This group was used as control and received the same therapy as Responders (R-CG).
    Reporting group title
    Non-responders RTX+MTX (NR-RTX)
    Reporting group description
    		 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

    Reporting group title
    Responders (R-CG)
    Reporting group description
    		 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.

    Reporting group title
    Non-responders Control Group (R-C)
    Reporting group description
    		 A retrospective group of non-responsive patients after 4 weeks with iv glucocorticoids, who received regular care, i.e. full 12-week treatment with glucocorticoids according to clinical praxis. This group was used as control and received the same therapy as Responders (R-CG).

    Subject analysis set title
    Non-responders RTX+MTX (NR-RTX)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    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

    Subject analysis set title
    Responders (R-CG)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    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.

    Subject analysis set title
    Non-responders Control Group (R-C)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    A retrospective group of non-responsive patients after 4 weeks with iv glucocorticoids, who received regular care, i.e. full 12-week treatment with glucocorticoids according to clinical praxis. This group was used as control and received the same therapy as Responders (R-CG).

    Primary: Comparison of Clinical Activity Score (a Composite Measure of Ophthalmological Signs and Symptoms) Between Arms

    		 Close Top of page
    End point title
    		 Comparison of Clinical Activity Score (a Composite Measure of Ophthalmological Signs and Symptoms) Between Arms
    End point description
    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). CAS consists of 10 items: the first 7 items are evaluated at the first visit, and the remaining 3 items (change in motility, vision acuity, and change in proptosis) at return visits.
    End point type
    Primary
    End point timeframe
    At 12,18 and 68 weeks
    End point values
    		 Non-responders RTX+MTX (NR-RTX) Responders (R-CG) Non-responders Control Group (R-C) Non-responders RTX+MTX (NR-RTX) Responders (R-CG) Non-responders Control Group (R-C) Non-responders RTX+MTX (NR-RTX) Responders (R-CG) Non-responders Control Group (R-C)
    Number of subjects analysed
    10
    13
    12
    10
    13
    11
    10
    13
    11
    Units: score on a scale
        arithmetic mean (standard deviation)
    4.2 ( 1.03 )
    2.88 ( 1.33 )
    4.0 ( 1.41 )
    4.05 ( 1.23 )
    3.81 ( 1.35 )
    3.63 ( 1.60 )
    3.0 ( 1.39 )
    2.58 ( 1.4 )
    2.14 ( 2.12 )
    Statistical analysis title
    		 multivariable linear mixed models
    Statistical analysis description
    R version 4.3.2 package lme4 and marginal effects
    Comparison groups
    Non-responders RTX+MTX (NR-RTX) v Responders (R-CG) v Non-responders Control Group (R-C) v Non-responders RTX+MTX (NR-RTX) v Responders (R-CG) v Non-responders Control Group (R-C) v Non-responders RTX+MTX (NR-RTX) v Responders (R-CG) v Non-responders Control Group (R-C)
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.047
    Method
    		 Regression, Linear
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Intervention phase = 4-12 weeks Follow-up phase: 13-18 weeks Surveillance phase: 19-68 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Non-responders RTX+MTX (NR-RTX)
    Reporting group description
    		 -

    Reporting group title
    Responders (R-CG)
    Reporting group description
    		 -

    Serious adverse events
    		 Non-responders RTX+MTX (NR-RTX) Responders (R-CG)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 13 (7.69%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    Nervous system disorders
    mental disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral aneurysm
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Non-responders RTX+MTX (NR-RTX) Responders (R-CG)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 10 (80.00%)
    11 / 13 (84.62%)
    Cardiac disorders
    High blood pressure
         subjects affected / exposed
    5 / 10 (50.00%)
    7 / 13 (53.85%)
         occurrences all number
    7
    11
    Hepatobiliary disorders
    Elevated liver blood tests
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Endocrine disorders
    Positive oral glucose tolerance test
         subjects affected / exposed
    3 / 10 (30.00%)
    2 / 13 (15.38%)
         occurrences all number
    4
    4
    Inadequate response to short ACTH
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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