Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624001258549
Ethics application status
Approved
Date submitted
18/09/2024
Date registered
16/10/2024
Date last updated
1/12/2024
Date data sharing statement initially provided
16/10/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
STAR-MOG: A phase III randomised, double-blind, placebo-controlled, multicentre study to evaluate the efficacy and safety of treatment with corticoSTeroids at onset, And Rituximab during a relapse, of Myelin Oligodendrocyte Glycoprotein antibody-associated disease.
Scientific title
A phase III randomised, double-blind, placebo-controlled, multicentre study to evaluate the efficacy and safety of treatment with corticoSTeroids at onset, And Rituximab during a relapse, of Myelin Oligodendrocyte Glycoprotein antibody-associated disease in children and adults
Secondary ID [1] 312995 0
Nil
Universal Trial Number (UTN)
U1111-1310-7631
Trial acronym
STAR-MOG
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Myelin Oligodendrocyte Glycoprotein antibody-associated disease 335184 0
optic neuritis 335251 0
transverse myelitis 335252 0
Condition category
Condition code
Neurological 331672 331672 0 0
Other neurological disorders
Inflammatory and Immune System 331673 331673 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Onset arm: To evaluate the efficacy of an optimised corticosteroid tapering regime at the onset of Myelin Oligodendrocyte Glycoprotein antibody-associated disease (MOGAD) in delaying time to first centrally adjudicated relapse compared to placebo. Dose: 4 months of tapered oral prednisone or placebo administered.

Adults and paediatric patients >40kg: All patients – Week -2 and -1 up till randomisation – 3 to 5 days of IV methylprednisolone or high dose oral prednisone, followed by oral prednisone >20 mg/day till randomisation (Week 0). Active treatment arm: Active oral prednisone Weeks 1 and 2: 20mg per day, Weeks 3 and 4: 15mg per day, Weeks 5-10 12.5mg per day, Week 11: 10mg per day, Week 12: 7.5mg per day, Week 13: 5mg per day, Week 14: 2.5mg per day, then cease. Placebo arm: Week 1: 10mg active oral prednisone per day, Week 2: 5 mg active oral prednisone per day, Weeks 3-14 matched oral placebo, then cease.

Paediatric patients 20-39 kg: All patients – Week -2 and -1 up till randomisation – 3 to 5 days of IV methylprednisolone or high dose oral prednisone, followed by oral prednisone >15 mg/day till randomisation (Week 0). Active treatment arm: Weeks 1 to 4: active oral prednisone 12.5mg per day, Weeks 5 to 10: 10mg per day, Week 11: 7.5mg per day, Week 12: 5mg per day, Week 13: 5mg per day, Week 14: 2.5mg per day. Placebo arm: Weeks 1 and 2: 2.5mg active oral prednisone per day, Weeks 3-14 matched oral placebo, then cease.

Paediatric patients <20kg: All patients – Week -2 and -1 up till randomisation – 3 to 5 days of IV methylprednisolone or high dose oral prednisone, followed by oral prednisone >10 mg/day till randomisation (Week 0). Active treatment arm: Weeks 1 to 4: 10mg per day, Weeks 5 to 10: 7.5mg per day, Weeks 11 and 12: 5mg per day, Weeks 13 and 14: 2.5mg per day, then cease. Placebo arm: Weeks 1 and 2: 2.5mg active oral prednisone per day, Weeks 3-14 matched oral placebo, then cease.

Adherence will be monitored by tablet returns and a participant diary.

Relapsing arm: To evaluate the efficacy of 12 months of B cell depletion with rituximab infusion following a relapse of MOGAD in delaying time to first centrally adjudicated relapse compared to placebo.

Adults and paediatric patients >40kgs; 1000mg rituximab infusions at Week 0, Week 2 and at 6 months.
Paediatric patients 25-40kgs, 750mg rituximab infusions at Week 0 and Week 2, and two x 750mg infusions over a 2 week interval at month 6.
Paediatric patients <25kgs, 500mg rituximab infusions at Week 0 and Week 2, and two x 500mg infusions over a 2 week interval at month 6.

Adherence will be monitored by attendance to infusion visits.
Intervention code [1] 329535 0
Treatment: Drugs
Comparator / control treatment
Onset arm: Oral vegetable-based microcellulose placebo tablet

Relapsing arm: Sterile intravenous saline solution 0.9%
Control group
Placebo

Outcomes
Primary outcome [1] 339399 0
Time to first centrally adjudicated relapse
Timepoint [1] 339399 0
This will be measured if participants present to their treating clinician with any symptoms of a relapse for a follow-up period of 12 months following randomisation.
Secondary outcome [1] 442413 0
Safety and tolerability of recommended therapeutic interventions
Timepoint [1] 442413 0
Secondary outcome [2] 442414 0
Safety and tolerability of recommended therapeutic interventions
Timepoint [2] 442414 0
6 months and 12 months post following randomisation, and at time of any relapse
Secondary outcome [3] 442415 0
Safety and tolerability of recommended therapeutic interventions
Timepoint [3] 442415 0
6 months and 12 months post following randomisation, and at time of any relapse
Secondary outcome [4] 442416 0
Safety and tolerability of recommended therapeutic interventions
Timepoint [4] 442416 0
0 and 12 months following randomisation for onset and relapsing arms, plus an additional assessment at 2 months for onset group only
Secondary outcome [5] 442417 0
Disease activity
Timepoint [5] 442417 0
0 and 12 months following randomisation for onset and relapsing arms, plus an additional assessment at 2 months for onset group only
Secondary outcome [6] 442418 0
Disease activity
Timepoint [6] 442418 0
Baseline, 6 months, 12 months post following randomisation, and at time of any relapse
Secondary outcome [7] 442419 0
Disease activity
Timepoint [7] 442419 0
Baseline, 6 months, 12 months post following randomisation, and at time of any relapse
Secondary outcome [8] 442420 0
Disease activity
Timepoint [8] 442420 0
Baseline, 6 months, 12 months post following randomisation, and at time of any relapse
Secondary outcome [9] 442421 0
Disease activity
Timepoint [9] 442421 0
Baseline, 6 months, 12 months post following randomisation, and at time of any relapse
Secondary outcome [10] 442422 0
Disease activity
Timepoint [10] 442422 0
Baseline, 6 months, 12 months post following randomisation, and at time of any relapse
Secondary outcome [11] 442423 0
Neurological function
Timepoint [11] 442423 0
Baseline, 6 months, 12 months post following randomisation, and at time of any relapse
Secondary outcome [12] 442424 0
Neurological function
Timepoint [12] 442424 0
Baseline, 6 months, 12 months post following randomisation, and at time of any relapse
Secondary outcome [13] 442425 0
Neurological function
Timepoint [13] 442425 0
Baseline, 6 months, 12 months post following randomisation, and at time of any relapse
Secondary outcome [14] 442426 0
Neurological function
Timepoint [14] 442426 0
Baseline, 6 months, 12 months post following randomisation, and at time of any relapse
Secondary outcome [15] 442427 0
Neurological function
Timepoint [15] 442427 0
Baseline, 6 months, 12 months post following randomisation, and at time of any relapse
Secondary outcome [16] 442428 0
Neurological function
Timepoint [16] 442428 0
Baseline, 6 months, 12 months from randomisation, and at time of any relapse
Secondary outcome [17] 442429 0
Neurological function
Timepoint [17] 442429 0
Baseline, 6 months, 12 months from randomisation, and at time of any relapse
Secondary outcome [18] 442430 0
Neurological function
Timepoint [18] 442430 0
Baseline, 6 months, 12 months from randomisation, and at time of any relapse
Secondary outcome [19] 442431 0
Visual function
Timepoint [19] 442431 0
Baseline, 6 months, 12 months from randomisation, and at time of any relapse
Secondary outcome [20] 442432 0
Visual function
Timepoint [20] 442432 0
Baseline, 6 months, 12 months from randomisation
Secondary outcome [21] 442433 0
Visual function
Timepoint [21] 442433 0
Baseline, 6 months, 12 months from randomisation
Secondary outcome [22] 442434 0
Visual function
Timepoint [22] 442434 0
Baseline, 6 months, 12 months from randomisation
Secondary outcome [23] 442435 0
Visual function
Timepoint [23] 442435 0
Baseline, 6 months, 12 months from randomisation
Secondary outcome [24] 442436 0
Visual function
Timepoint [24] 442436 0
Baseline, 6 months, 12 months from randomisation
Secondary outcome [25] 442437 0
Patient Reported outcome measures (PROMS) - Anxiety and Depression. This will be assessed as a composite outcome as the combined scoring on the Hospital Anxiety and Depression Scale
Timepoint [25] 442437 0
Baseline, 6 months, 12 months from randomisation
Secondary outcome [26] 442438 0
Patient Reported outcome measures (PROMS) - Anxiety and Depression. This will be assessed as a composite outcome as the combined scoring on the Hospital Anxiety and Depression Scale
Timepoint [26] 442438 0
Baseline, 6 months, 12 months from randomisation, and at time of any relapse
Secondary outcome [27] 442439 0
Patient Reported outcome measures (PROMS) - Fatigue
Timepoint [27] 442439 0
Baseline, 6 months, 12 months from randomisation, and at time of any relapse
Secondary outcome [28] 442440 0
Patient Reported outcome measures (PROMS) - Fatigue
Timepoint [28] 442440 0
Baseline, 6 months, 12 months from randomisation, and at time of any relapse
Secondary outcome [29] 442441 0
Patient Reported outcome measures (PROMS) - Fatigue
Timepoint [29] 442441 0
Baseline, 6 months, 12 months from randomisation, and at time of any relapse
Secondary outcome [30] 442442 0
Patient Reported outcome measures (PROMS) - Fatigue
Timepoint [30] 442442 0
Baseline, 6 months, 12 months from randomisation, and at time of any relapse
Secondary outcome [31] 442443 0
Patient Reported outcome measures (PROMS) - Quality of Life
Timepoint [31] 442443 0
Baseline, 6 months, 12 months from randomisation, and at time of any relapse
Secondary outcome [32] 442444 0
Patient Reported outcome measures (PROMS) - Quality of Life
Timepoint [32] 442444 0
Baseline, 6 months, 12 months from randomisation, and at time of any relapse
Secondary outcome [33] 442445 0
Patient Reported outcome measures (PROMS)- Fatigue
Timepoint [33] 442445 0
Baseline, 6 months, 12 months from randomisation, and at time of any relapse
Secondary outcome [34] 442446 0
Patient Reported outcome measures (PROMS)- Fatigue
Timepoint [34] 442446 0
Baseline, 6 months, 12 months from randomisation, and at time of any relapse
Secondary outcome [35] 442447 0
Patient Reported outcome measures (PROMS) - Pain
Timepoint [35] 442447 0
Baseline, 6 months, 12 months from randomisation, and at time of any relapse
Secondary outcome [36] 442448 0
Patient Reported outcome measures (PROMS) - Pain
Timepoint [36] 442448 0
Baseline, 6 months, 12 months from randomisation, and at time of any relapse
Secondary outcome [37] 442449 0
Patient Reported outcome measures (PROMS)- Visual function
Timepoint [37] 442449 0
Baseline, 6 months, 12 months from randomisation, and at time of any relapse
Secondary outcome [38] 442450 0
Patient Reported outcome measures (PROMS)- Visual function
Timepoint [38] 442450 0
Baseline, 6 months, 12 months from randomisation, and at time of any relapse
Secondary outcome [39] 442451 0
Patient Reported outcome measures (PROMS) - Bladder function
Timepoint [39] 442451 0
Baseline, 6 months, 12 months from randomisation, and at time of any relapse
Secondary outcome [40] 442452 0
Patient Reported outcome measures (PROMS) - Bladder function
Timepoint [40] 442452 0
Baseline, 6 months, 12 months post following randomisation, and at time of any relapse
Secondary outcome [41] 442453 0
Patient Reported outcome measures (PROMS)- bowel function
Timepoint [41] 442453 0
Baseline, 6 months, 12 months post following randomisation, and at time of any relapse
Secondary outcome [42] 442454 0
Patient Reported outcome measures (PROMS)- bowel function
Timepoint [42] 442454 0
Baseline, 6 months, 12 months post following randomisation, and at time of any relapse
Secondary outcome [43] 442455 0
Patient Reported outcome measures (PROMS) - Sexual function (adults only)
Timepoint [43] 442455 0
Baseline, 6 months, 12 months post following randomisation, and at time of any relapse
Secondary outcome [44] 442456 0
Patient Reported outcome measures (PROMS) - Sexual function (adults only)
Timepoint [44] 442456 0
Baseline, 6 months, 12 months post following randomisation, and at time of any relapse
Secondary outcome [45] 442457 0
Patient Reported outcome measures (PROMS) - Strengths and Difficulties (Paediatric only). This will be assessed as a composite outcome as a score resulting from the participant reported score.
Timepoint [45] 442457 0
Baseline, 6 months, 12 months post following randomisation, and at time of any relapse
Secondary outcome [46] 442458 0
Patient Reported outcome measures (PROMS) - Strengths and Difficulties (Paediatric only). This will be assessed as a composite outcome as a score resulting from the participant reported score.
Timepoint [46] 442458 0
Baseline, 6 months, 12 months post following randomisation, and at time of any relapse

Eligibility
Key inclusion criteria
Onset MOGAD Group:
1. All children and adults who meet 2023 International Diagnostic Criteria for MOGAD, with suspected clinical phenotypes for MOGAD (optic neuritis, transverse myelitis, acute disseminated encephalomyelitis, brainstem/cerebellar demyelination, cortical encephalitis, cerebral monofocal or polyfocal deficits with demyelination) and serum MOG antibody clear positive by cell-based assay and exclusion of alternate diagnosis. If low positive or tested without titre provided or CSF restricted MOG antibody positive, then this patient is required to fulfill additionally required clinical and/or radiological supportive criteria as per International Diagnostic Criteria.
2. Willingness to provide informed consent and participate and comply with study requirements
3. Available to attend clinic visits within one month of each time point on the schedule of assessments.
Relapsing MOGAD Group:
1. All children and adults who meet 2023 International Diagnostic Criteria for MOGAD, with suspected clinical phenotypes for MOGAD (optic neuritis, transverse myelitis, acute disseminated encephalomyelitis, brainstem/cerebellar demyelination, cortical encephalitis, cerebral monofocal or polyfocal deficits with demyelination), and MOG antibody seropositive by cell-based assay in the last 12 months before their relapse, and exclusion of alternate diagnosis.
2. A relapse within 12 months of recruitment into this trial. A relapse is defined by the occurrence of new or worsening, acute neurological symptom(s) with objective changes (clinical findings or signs) on clinical (neurological and ophthalmological) examination that persists for more than 24 hours as confirmed by the investigator, separated by a period of neurological recovery/stability from any prior disease activity by at least one month. The symptoms must be attributable to MOGAD, with other potential causes (such as infection, injury, changes in mood, adverse reactions to medications, or other diagnoses) ruled out.
3. For women of childbearing potential: participants who agree to use adequate contraception during the treatment period and for at least six months after the final dose of IMP or placebo.
4. Willingness to provide informed consent and participate and comply with study requirements
5. Available to attend clinic visits within one month of each time point on the schedule of assessments.
Minimum age
No limit
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Onset MOGAD Group:
1. Presentation clinically and radiologically consistent with multiple sclerosis
2. A clinical presentation considered atypical for MOGAD
3. AQP4-IgG seropositive
4. Significant, active and/or untreated infection (inclusive but not limited to active hepatitis B, hepatitis C, HIV, tuberculosis, syphilis, strongyloides, etc). Patients with active infection will require treatment before they can fulfill inclusion criteria.
5. Patients who will be given additional immunotherapy apart from the Investigational Medicinal Product (IMP) or placebo after four weeks post initiation of high dose corticosteroids.
6. Women of child-bearing potential who are planning pregnancy in the next twelve months or are currently pregnant
7. Any concomitant autoimmune disease other than MOGAD that requires ongoing immunotherapy throughout the trial period
8. A significant comorbidity that in the opinion of the site’s principal investigator, would negatively affect MOGAD outcomes or preclude administration of corticosteroids
9. Circumstances/conditions which may interfere with the participant’s ability to give informed consent
10. Any routine screening test results which the site investigator feels places the patient at risk if they proceed with the trial
11. Known hypersensitivity or allergic reaction to IMP
Relapsing MOGAD Group:
1. Presentation clinically and radiologically consistent with multiple sclerosis
2. A clinical presentation considered atypical for MOGAD
3. AQP4-IgG seropositive
4. Current B cell depletion as determined by B cell subsets at screening visit
5. Significant, active and/or untreated infection (inclusive but not limited to active hepatitis B, hepatitis C, HIV, tuberculosis, syphilis, strongyloides, etc). Patients with active infection will require treatment before they can fulfill inclusion criteria.
6. Women of child-bearing potential who are planning pregnancy in the next twelve months or are currently pregnant
7. Receipt of a live or live attenuated vaccine within six weeks prior to screening visit, or planned live or live attenuated vaccine during the study period
8. Any concomitant autoimmune disease other than MOGAD that requires ongoing immunotherapy throughout the trial period
9. A significant comorbidity that in the opinion of the site’s principal investigator, would negatively affect MOGAD outcomes or preclude administration of rituximab
10. Any routine screening test results which the site investigator feels places the patient at risk if they proceed with the trial
11. Circumstances/conditions which may interfere with the participant’s ability to give informed consent
12. Known hypersensitivity or allergic reaction to the IMP

Exclusion criteria related to previous or concomitant immunotherapy for MOGAD
B cell depletion in the six months prior to screening
Cycophosphamide in the twelve months prior to screening
IL-6R antagonists such as satralizumab or tocilizumab in the six weeks prior to screening (including participation in the Roche Meteoroid study – satralizumab vs placebo)
Tacrolimus or cyclosporine in the six weeks prior to screening
FcRn mAbs in the six weeks prior to screening (including participation in the UCB CosMOG study – rozanolixizumab vs placebo)
Alemtuzumab in the 12 months prior to screening
Planned ongoing treatment with MS disease modifying therapy (glatiramer acetate, interferon, fumarates, teriflunomide, natalizumab, fingolimod, siponimod, ozanimod, cladribine, alemtuzumab after the documented MOGAD relapse prompting consideration for this trial)
Concurrent immunotherapy apart from IMP/placebo after four weeks post randomisation while in the double blind phase of the trial, until time of first relapse (or to the end of 12 months in patients without a relapse).

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Contacting central unblinded administrator of allocation schedule
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Stratified randomisation based on:
1. Presence/absence of concurrent treatment (IVIg and/or PLEX up to four weeks after treatment initiation for Onset arm; or IVIg and/or PLEX prior to randomisation, and/or oral corticosteroids for first month post randomisation for Relapsing arm) AND
2. Disease phenotype (optic neuritis vs non optic neuritis)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The primary analysis dataset will be based on an intention to treat (ITT analysis) for the primary endpoint. Patient-level follow-up will be censored at the time to first centrally adjudicated relapse, else the date of the last recorded visit or assessment or activity. An ITT analysis will be performed on all primary, secondary and exploratory outcomes as outlined in the Statistical Analysis Plan. The primary outcome, and key secondary and exploratory longitudinal outcomes, will also be analysed using a per protocol (PP) approach as a sensitivity analysis.

Categorical variables will be summarised using frequency and percentage and compared using a chi-square test or Fisher’s exact test as appropriate. Continuous variables will be summarised using mean, standard deviation (SD) and/or standard error (SE) and range; or median, inter-quartile range (IQR) and range compared using a t-test of Wilcoxon rank-sum test as appropriate. Time-to-event data will be visualised using Kaplan-Meier survival and/or failure curves. Cumulative incidence rates for count and event data will be presented as point estimates with associated 95% confidence intervals (95% CI) presuming an underlying Poisson, negative binomial or zero-inflated Poisson distribution as appropriate. All analyses, descriptive and inferential, will be performed for the onset and relapsing cohorts.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
3/02/2025
Actual
Date of last participant enrolment
Anticipated
5/02/2028
Actual
Date of last data collection
Anticipated
3/12/2029
Actual
Sample size
Target
228
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC

Funding & Sponsors
Funding source category [1] 317433 0
Government body
Name [1] 317433 0
Department of Health and Aged Care: MRFF
Country [1] 317433 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
Country
Australia
Secondary sponsor category [1] 319724 0
None
Name [1] 319724 0
Address [1] 319724 0
Country [1] 319724 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 316153 0
Sydney Local Health District Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 316153 0
Ethics committee country [1] 316153 0
Australia
Date submitted for ethics approval [1] 316153 0
20/09/2024
Approval date [1] 316153 0
20/11/2024
Ethics approval number [1] 316153 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 136954 0
A/Prof Sudarshini Ramanathan
Address 136954 0
Kids Neuroscience Centre, Kids Hospital at Westmead, 178A Hawkesbury Rd, Westmead NSW 2145
Country 136954 0
Australia
Phone 136954 0
+61 413314685
Fax 136954 0
Email 136954 0
sudarshini.ramanathan@sydney.edu.au
Contact person for public queries
Name 136955 0
Isabella Cotter
Address 136955 0
Kids Neuroscience Centre, Kids Hospital at Westmead, 178A Hawkesbury Rd, Westmead NSW 2145
Country 136955 0
Australia
Phone 136955 0
+61 405982588
Fax 136955 0
Email 136955 0
isabella.cotter@sydney.edu.au
Contact person for scientific queries
Name 136956 0
Sudarshini Ramanathan
Address 136956 0
Kids Neuroscience Centre, Kids Hospital at Westmead, 178A Hawkesbury Rd, Westmead NSW 2145
Country 136956 0
Australia
Phone 136956 0
+61 413314685
Fax 136956 0
Email 136956 0
sudarshini.ramanathan@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Only analysed data will be publicly available.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
24202Study protocol  tnig.research@sydney.edu.au
24203Statistical analysis plan  tnig.research@sydney.edu.au
24204Informed consent form  tnig.research@sydney.edu.au
24205Ethical approval  tnig.research@sydney.edu.au



Results publications and other study-related documents

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