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    Clinical Trial Results:
    Phase III: UbLiTuximab In Multiple Sclerosis Treatment Effects (ULTIMATE I STUDY)

    Summary
    EudraCT number
    		 2017-000638-75
    Trial protocol
    		 GB   PL   ES  
    Global end of trial date
    06 Nov 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Nov 2021
    First version publication date
    19 Nov 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    TG1101-RMS301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03277261
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    TG Therapeutics, Inc.
    Sponsor organisation address
    2 Gansevoort St; 9th Floor, New York, United States, 10014
    Public contact
    Clinical Support Team, TG Therapeutics, 1 877-575-8489, Clinicalsupport@tgtxinc.com
    Scientific contact
    Clinical Support Team, TG Therapeutics, 1 877-575-8489, Clinicalsupport@tgtxinc.com
    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
    23 Jul 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Nov 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study determines the Annualized Relapse Rate (ARR) in subjects with Relapsing Forms of Multiple Sclerosis (RMS) after 96 weeks (approximately 2 years) treatment with intravenous (IV) infusion of ublituximab/oral placebo compared to 14 mg oral teriflunomide/IV placebo.
    Protection of trial subjects
    This study was conducted in accordance with the protocol and consensus ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all ICH GCP Guidelines. The Investigator or his/her representative explained the nature of the study to the subject or his/her legally authorized representative and answered all questions regarding the study. Subjects and/or their legally authorized representative were informed that their participation was voluntary. Subjects or their legally authorized representative were required to sign a statement of informed consent that met the requirements of 21 CFR 50, local regulations, ICH guidelines, HIPAA requirements, where applicable, and the IRB/IEC or study center. Investigative sites were instructed to obtain written informed consent before the subject was enrolled in the study and document the date the written consent was obtained. The authorized person obtaining the informed consent was also instructed to sign the ICF. Subjects were re-consented to the most current version of the ICF(s) during their participation and/or upon either IRAP-confirmed relapse or Treating Neurologist medically confirmed relapse. The DSMB was an independent group of individuals not involved in the study or study sites or had other conflicts of interest with the study and were charged with reviewing safety data and conduct of the trial. The committee met periodically, but at least annually to fulfill the duties and obligations outlined in the DSMB Charter. The committee received unblinded safety data to allow review and assessment by treatment group. In addition, the committee received unblinded efficacy data to perform a benefit/risk assessment. Based on their reviews and analyses of safety and efficacy data, the committee had the right to advise the Sponsor to stop the study after any meeting for efficacy or detrimental effects or futility.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Sep 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 5 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Russian Federation: 133
    Country: Number of subjects enrolled
    Serbia: 64
    Country: Number of subjects enrolled
    Ukraine: 107
    Country: Number of subjects enrolled
    Belarus: 64
    Country: Number of subjects enrolled
    Georgia: 83
    Country: Number of subjects enrolled
    United States: 48
    Country: Number of subjects enrolled
    Poland: 41
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    United Kingdom: 4
    Worldwide total number of subjects
    549
    EEA total number of subjects
    46
    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)
    549
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 549 subjects were enrolled across investigative sites in Belarus, Spain, the United Kingdom, Georgia, Poland, Russia, Serbia, Ukraine, and the United States from 19 September 2017 to 6 November 2020.

    Pre-assignment
    Screening details
    		 A total of 646 subjects were screened and of those, 549 were enrolled and randomized to receive either ublituximab/oral placebo or teriflunomide/IV placebo.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Carer, Assessor, Subject
    Blinding implementation details
    All oral study drugs were prepared in identical tablets and containers and all IV study drugs were prepared in identical vials to ensure adequate blinding. All personnel involved with the conduct and interpretation of the study, including the Investigators, study site personnel, and Sponsor were blinded to treatment until after the database was locked and the study was officially unblinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ublituximab + Oral Placebo
    Arm description
    		 Subjects were administered ublituximab 150 milligrams (mg), intravenous (IV) infusion over 4 hours (h) on Day 1 followed by 450 mg over 1 h on Days 15, 168, 336 and 504 (Week 72) along with the oral placebo once daily (QD) from Day 1 up to the last day of Week 95.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ublituximab
    Investigational medicinal product code
    Other name
    TG-1101
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ublituximab 150 mg, 450 mg administered IV.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo administered orally.

    Arm title
    		 Teriflunomide + IV Placebo
    Arm description
    		 Subjects were administered teriflunomide 14 mg tablet, orally, QD from Day 1 up to the last day of Week 95 along with the placebo IV infusion on Days 1, 15, 168, 336 and 504 (Week 72).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Teriflunomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Teriflunomide 14 mg tablets administered orally.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo administered IV.

    Number of subjects in period 1
    		Ublituximab + Oral Placebo Teriflunomide + IV Placebo
    Started
    274
    275
    Completed
    240
    252
    Not completed
    34
    23
         Consent withdrawn by subject
    6
    15
         Investigator / Sponsor decision
    4
    2
         Pregnancy
    2
    -
         Adverse event
    17
    1
         Other-Alternative Treatment/Unspecified Reasons
    1
    1
         Lost to follow-up
    2
    2
         Lack of efficacy
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ublituximab + Oral Placebo
    Reporting group description
    		 Subjects were administered ublituximab 150 milligrams (mg), intravenous (IV) infusion over 4 hours (h) on Day 1 followed by 450 mg over 1 h on Days 15, 168, 336 and 504 (Week 72) along with the oral placebo once daily (QD) from Day 1 up to the last day of Week 95.

    Reporting group title
    Teriflunomide + IV Placebo
    Reporting group description
    		 Subjects were administered teriflunomide 14 mg tablet, orally, QD from Day 1 up to the last day of Week 95 along with the placebo IV infusion on Days 1, 15, 168, 336 and 504 (Week 72).

    Reporting group values
    		 Ublituximab + Oral Placebo Teriflunomide + IV Placebo Total
    Number of subjects
    		 274 275 549
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 36.3 ( 8.48 ) 37.0 ( 9.62 ) -
    Gender categorical
    Units: Subjects
        Female
    		 167 180 347
        Male
    		 107 95 202
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 7 2 9
        Not Hispanic or Latino
    		 263 267 530
        Unknown or Not Reported
    		 4 6 10
    Race/Ethnicity
    Units: Subjects
        Black or African American
    		 6 6 12
        White
    		 267 267 534
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Other
    		 0 2 2

    End points

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    End points reporting groups
    Reporting group title
    Ublituximab + Oral Placebo
    Reporting group description
    		 Subjects were administered ublituximab 150 milligrams (mg), intravenous (IV) infusion over 4 hours (h) on Day 1 followed by 450 mg over 1 h on Days 15, 168, 336 and 504 (Week 72) along with the oral placebo once daily (QD) from Day 1 up to the last day of Week 95.

    Reporting group title
    Teriflunomide + IV Placebo
    Reporting group description
    		 Subjects were administered teriflunomide 14 mg tablet, orally, QD from Day 1 up to the last day of Week 95 along with the placebo IV infusion on Days 1, 15, 168, 336 and 504 (Week 72).

    Subject analysis set title
    Ublituximab + Oral Placebo
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Subjects were administered ublituximab 150 mg, IV infusion over 4 h on Day 1 followed by 450 mg over 1 h on Days 15, 168, 336 and 504 (Week 72) along with the oral placebo QD from Day 1 up to the last day of Week 95. As per protocol, data was summarized for the mITT Population using pooled data from subjects in this study and TG1101-RMS302 [NCT03277248].

    Subject analysis set title
    Teriflunomide + IV Placebo
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Subjects were administered teriflunomide 14 mg tablet, orally, QD from Day 1 up to the last day of Week 95 along with the placebo IV infusion on Days 1, 15, 168, 336 and 504 (Week 72). As per protocol, data was summarized for the mITT Population using pooled data from subjects in this study and TG1101-RMS302 [NCT03277248].

    Primary: Annualized Relapse Rate (ARR)

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    End point title
    		 Annualized Relapse Rate (ARR)
    End point description
    ARR is defined as the number of Independent Relapse Adjudication Panel (IRAP)-confirmed relapses per subject year. The estimate of ARR for a treatment group is the total number of relapses for subject in the respective treatment group divided by the sum of treatment duration for subject in that specific treatment group. Modified Intention-to-Treat (mITT) population consisted of all subjects in the ITT population who received at least one dose of study medication and have at least one baseline and post baseline efficacy assessment.
    End point type
    Primary
    End point timeframe
    Up to 96 weeks
    End point values
    		 Ublituximab + Oral Placebo Teriflunomide + IV Placebo
    Number of subjects analysed
    271
    274
    Units: relapses per subject-years
        least squares mean (confidence interval 95%)
    0.076 (0.042 to 0.138)
    0.188 (0.124 to 0.283)
    Statistical analysis title
    		 Annualized Relapse Rate (ARR)
    Comparison groups
    Teriflunomide + IV Placebo v Ublituximab + Oral Placebo
    Number of subjects included in analysis
    545
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Negative Binomial Model
    Parameter type
    		 Rate Ratio (Ublituximab/Teriflunomide)
    Point estimate
    0.406
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.268
         upper limit
    		 0.615
    Notes
    [1] - GEE (Generalized Estimating Equation) model for the relapse count per subject with logarithmic link function, treatment, region, and baseline Expanded Disability Status Scale (EDSS) strata as covariates and log (years of treatment) as offset.

    Secondary: Total Number of Gadolinium (Gd)-Enhancing T1-Lesions Per Magnetic Resonance Imaging (MRI) Scan Per Subject

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    End point title
    		 Total Number of Gadolinium (Gd)-Enhancing T1-Lesions Per Magnetic Resonance Imaging (MRI) Scan Per Subject
    End point description
    The total number of Gd-enhancing T1-lesions were calculated as the sum of the individual number of lesions at Weeks 12, 24, 48, and 96, divided by the total number of MRI scans of the brain. mITT- MRI population included subjects in mITT population who have baseline and post-baseline MRI efficacy assessments. Overall number of subjects analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Weeks 12, 24, 48, and 96
    End point values
    		 Ublituximab + Oral Placebo Teriflunomide + IV Placebo
    Number of subjects analysed
    264
    269
    Units: lesions per scan per subject
        least squares mean (confidence interval 95%)
    0.016 (0.008 to 0.032)
    0.491 (0.355 to 0.679)
    Statistical analysis title
    		 Total Number of Gd-Enhancing T1-Lesions
    Comparison groups
    Ublituximab + Oral Placebo v Teriflunomide + IV Placebo
    Number of subjects included in analysis
    533
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 Negative Binomial Model
    Parameter type
    		 Rate Ratio (Ublituximab/Teriflunomide)
    Point estimate
    0.033
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.019
         upper limit
    		 0.058
    Notes
    [2] - GEE model for the relapse count per subject with logarithmic link function, treatment, region, and baseline EDSS strata as covariates and log (years of treatment) as offset.

    Secondary: Total Number of New and Enlarging T2 Hyperintense Lesions (NELs) Per MRI Scan Per Subject

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    End point title
    		 Total Number of New and Enlarging T2 Hyperintense Lesions (NELs) Per MRI Scan Per Subject
    End point description
    The total number of NELs were calculated as the sum of the individual number of lesions at Weeks 24, 48, and 96, divided by the total number of MRI scans of the brain. mITT- MRI population included subjects in mITT population who have baseline and post-baseline MRI efficacy assessments. Overall number of subjects analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Weeks 24, 48, and 96
    End point values
    		 Ublituximab + Oral Placebo Teriflunomide + IV Placebo
    Number of subjects analysed
    260
    267
    Units: lesions per scan per subject
        least squares mean (confidence interval 95%)
    0.213 (0.144 to 0.316)
    2.789 (2.136 to 3.643)
    Statistical analysis title
    		 Total Number of T2 NELs
    Comparison groups
    Ublituximab + Oral Placebo v Teriflunomide + IV Placebo
    Number of subjects included in analysis
    527
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 Negative Binomial Model
    Parameter type
    		 Rate Ratio (Ublituximab/Teriflunomide)
    Point estimate
    0.076
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.056
         upper limit
    		 0.104
    Notes
    [3] - GEE model for the relapse count per subject with logarithmic link function, treatment, region, and baseline EDSS strata as covariates and log (years of treatment) as offset.

    Secondary: Time to Confirmed Disability Progression (CDP) for at Least 12 Weeks

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    End point title
    		 Time to Confirmed Disability Progression (CDP) for at Least 12 Weeks
    End point description
    12-week CDP is defined as an increase in EDSS at least 1 point higher than baseline EDSS if the baseline EDSS is ≤5.5 or at least 0.5 higher than the baseline EDSS if the baseline EDSS is >5.5. EDSS is based on a standard neurological examination, (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, and cerebral) and ambulation function system assessments. EDSS disability scale ranges in 0.5-point steps from 0 (normal) to 10 (death) where higher scores indicate disability. The time to onset of 12-week CDP is the time to progression to the EDSS change defined above. mITT population = all subjects in the ITT population who received at least one dose of study drug and have at least one baseline and post baseline efficacy assessment. As per protocol, data was summarized for mITT Population using pooled data from subjects in this study and TG1101-RMS302 [2017-000639-15]. Due to EudraCT database constraints data cannot be entered here, please refer the table attachment.
    End point type
    Secondary
    End point timeframe
    Up to Week 96
    End point values
    		 Ublituximab + Oral Placebo Teriflunomide + IV Placebo
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    ( to )
    ( to )
    Attachments
    		 Time to CDP for at Least 12 Weeks
    Notes
    [4] - Data is not presented due to EudraCT database constraints.
    [5] - Data is not presented due to EudraCT database constraints.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With No Evidence of Disease Activity (NEDA)

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    End point title
    		 Percentage of Subjects With No Evidence of Disease Activity (NEDA)
    End point description
    A subject with NEDA is defined as a subject without relapses confirmed by the IRAP, without MRI activities (no T1 Gd+ lesions and no new/enlarging T2 lesions), and no 12-week CDP. Any evidence of disease activity from Week 24 to Week 96 was counted as not reaching NEDA. Any evidence of disease activity before Week 24 was not counted. mITT population consisted of all subjects in the ITT population who received at least one dose of study medication and have at least one baseline and post baseline efficacy assessment.
    End point type
    Secondary
    End point timeframe
    Week 24 up to Week 96
    End point values
    		 Ublituximab + Oral Placebo Teriflunomide + IV Placebo
    Number of subjects analysed
    271
    274
    Units: percentage of subjects
        number (not applicable)
    44.6
    15.0
    Statistical analysis title
    		 Percentage of Subjects with NEDA
    Comparison groups
    Teriflunomide + IV Placebo v Ublituximab + Oral Placebo
    Number of subjects included in analysis
    545
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds Ratio (Ublituximab/Teriflunomide)
    Point estimate
    5.442
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.536
         upper limit
    		 8.375
    Notes
    [6] - Logistic regression model with treatment, region, baseline EDSS strata and log transformed baseline MRI lesion counts (T1 unenhancing, T2, Gd enhancing) as covariates.

    Secondary: Percentage of Subjects With Impaired Symbol Digit Modalities Test (SDMT)

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    End point title
    		 Percentage of Subjects With Impaired Symbol Digit Modalities Test (SDMT)
    End point description
    The SDMT involves a simple substitution task using a reference key, the examinee has 90 seconds to pair specific numbers with given geometric figures. Responses are done verbally. The administration time is approximately 5 minutes. The total SDMT score for each visit ranging from 0-110 is defined as the total number of correct answers reported in the case report form (CRF), where high scores indicate better outcome. Impaired SDMT is defined as a decrease from baseline of at least 4 points at any post-baseline assessment up to the Week 96 visit. mITT population consisted of all subjects in the ITT population who received at least one dose of study medication and have at least one baseline and post baseline efficacy assessment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 96
    End point values
    		 Ublituximab + Oral Placebo Teriflunomide + IV Placebo
    Number of subjects analysed
    271
    274
    Units: percentage of subjects
        number (not applicable)
    29.2
    31.8
    Statistical analysis title
    		 Percentage of Subjects with Impaired SDMT
    Comparison groups
    Ublituximab + Oral Placebo v Teriflunomide + IV Placebo
    Number of subjects included in analysis
    545
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4669 [7]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds Ratio (Ublituximab/Teriflunomide)
    Point estimate
    0.872
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.603
         upper limit
    		 1.261
    Notes
    [7] - Logistic regression model with treatment, region, baseline EDSS strata, and log-transformed baseline MRI counts (T1 unenhancing, T2, Gd enhancing) as covariates.

    Secondary: Percent Change From Baseline in Brain Volume

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    End point title
    		 Percent Change From Baseline in Brain Volume
    End point description
    mITT- MRI population included subjects in mITT population who have baseline and post-baseline MRI efficacy assessments. Overall number of subjects analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 96
    End point values
    		 Ublituximab + Oral Placebo Teriflunomide + IV Placebo
    Number of subjects analysed
    204
    207
    Units: percent change
        least squares mean (confidence interval 95%)
    -0.197 (-0.228 to -0.166)
    -0.125 (-0.155 to -0.095)
    Statistical analysis title
    		 Percent Change From Baseline in Brain Volume
    Comparison groups
    Teriflunomide + IV Placebo v Ublituximab + Oral Placebo
    Number of subjects included in analysis
    411
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [8]
    Method
    		 Mixed Model Repeated Measure (MMRM)
    Parameter type
    		 Least squares mean difference
    Point estimate
    -0.072
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.107
         upper limit
    		 -0.036
    Notes
    [8] - The model includes treatment, region, baseline EDSS strata, visit, treatment-by-visit interaction, and baseline volume (cube root transformed) as covariates and an unstructured covariance matrix.

    Secondary: Percentage of Subjects With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

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    End point title
    		 Percentage of Subjects With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
    End point description
    An adverse event (AE) is any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. A Serious AE is defined as any untoward medical occurrence that: results in death, is immediately life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, and/or causes a congenital anomaly/birth defect. A TEAE is an AE that starts or worsens after receiving study drug. Safety population included all subjects who received at least one dose of study drug (ublituximab or teriflunomide, with corresponding placebos).
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug through the end of the study (up to approximately 116 weeks)
    End point values
    		 Ublituximab + Oral Placebo Teriflunomide + IV Placebo
    Number of subjects analysed
    273
    275
    Units: percentage of subjects
    number (not applicable)
        TEAEs
    86.1
    89.1
        TESAEs
    11.4
    6.9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug through the end of the study (up to approximately 116 weeks)
    Adverse event reporting additional description
    All-Cause Mortality: All the enrolled subjects (i.e subjects exposed n=274, 275); Adverse Events: Safety population included all subjects who received at least one dose of study drug (ublituximab or teriflunomide, with corresponding placebos)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Ublituximab + Oral Placebo
    Reporting group description
    		 Subjects were administered ublituximab 150 milligrams (mg), intravenous (IV) infusion over 4 hours (h) on Day 1 followed by 450 mg over 1 h on Days 15, 168, 336 and 504 (Week 72) along with the oral placebo once daily (QD) from Day 1 up to the last day of Week 95.

    Reporting group title
    Teriflunomide + IV Placebo
    Reporting group description
    		 Subjects were administered teriflunomide 14 mg tablet, orally, QD from Day 1 up to the last day of Week 95 along with the placebo IV infusion on Days 1, 15, 168, 336 and 504 (Week 72).

    Serious adverse events
    		 Ublituximab + Oral Placebo Teriflunomide + IV Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    31 / 273 (11.36%)
    19 / 275 (6.91%)
         number of deaths (all causes)
    2
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Varicose vein
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Medical device removal
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Ectopic pregnancy
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 275 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst ruptured
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 275 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 275 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Affective disorder
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental disorder
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 275 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Acoustic neuritis
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 275 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological symptom
         subjects affected / exposed
    1 / 273 (0.37%)
    4 / 275 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Oesophageal achalasia
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 275 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 275 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rosacea
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 275 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 275 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 275 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 275 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 275 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 275 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bullous erysipelas
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 273 (0.73%)
    1 / 275 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system enteroviral infection
         subjects affected / exposed
    2 / 273 (0.73%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lyme disease
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 275 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Measles
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningoencephalitis viral
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 273 (1.10%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 275 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salpingitis
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 275 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 275 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ublituximab + Oral Placebo Teriflunomide + IV Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    197 / 273 (72.16%)
    181 / 275 (65.82%)
    Investigations
    Lymphocyte count decreased
         subjects affected / exposed
    33 / 273 (12.09%)
    8 / 275 (2.91%)
         occurrences all number
    33
    8
    Aspartate aminotransferase increased
         subjects affected / exposed
    14 / 273 (5.13%)
    4 / 275 (1.45%)
         occurrences all number
    23
    4
    Alanine aminotransferase increased
         subjects affected / exposed
    12 / 273 (4.40%)
    16 / 275 (5.82%)
         occurrences all number
    17
    26
    Vascular disorders
    Hypertension
         subjects affected / exposed
    12 / 273 (4.40%)
    23 / 275 (8.36%)
         occurrences all number
    18
    33
    Nervous system disorders
    Headache
         subjects affected / exposed
    84 / 273 (30.77%)
    59 / 275 (21.45%)
         occurrences all number
    254
    189
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    27 / 273 (9.89%)
    4 / 275 (1.45%)
         occurrences all number
    28
    5
    Neutropenia
         subjects affected / exposed
    11 / 273 (4.03%)
    15 / 275 (5.45%)
         occurrences all number
    14
    22
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    41 / 273 (15.02%)
    13 / 275 (4.73%)
         occurrences all number
    46
    18
    Chills
         subjects affected / exposed
    19 / 273 (6.96%)
    1 / 275 (0.36%)
         occurrences all number
    20
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    29 / 273 (10.62%)
    15 / 275 (5.45%)
         occurrences all number
    43
    22
    Diarrhoea
         subjects affected / exposed
    19 / 273 (6.96%)
    26 / 275 (9.45%)
         occurrences all number
    43
    33
    Abdominal pain
         subjects affected / exposed
    15 / 273 (5.49%)
    9 / 275 (3.27%)
         occurrences all number
    21
    17
    Abdominal pain upper
         subjects affected / exposed
    7 / 273 (2.56%)
    14 / 275 (5.09%)
         occurrences all number
    12
    21
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    6 / 273 (2.20%)
    36 / 275 (13.09%)
         occurrences all number
    8
    40
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    16 / 273 (5.86%)
    30 / 275 (10.91%)
         occurrences all number
    19
    41
    Pain in extremity
         subjects affected / exposed
    15 / 273 (5.49%)
    12 / 275 (4.36%)
         occurrences all number
    22
    19
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    34 / 273 (12.45%)
    44 / 275 (16.00%)
         occurrences all number
    59
    82
    Respiratory tract infection viral
         subjects affected / exposed
    20 / 273 (7.33%)
    8 / 275 (2.91%)
         occurrences all number
    36
    12
    Rhinitis
         subjects affected / exposed
    18 / 273 (6.59%)
    8 / 275 (2.91%)
         occurrences all number
    23
    9
    Upper respiratory tract infection
         subjects affected / exposed
    16 / 273 (5.86%)
    15 / 275 (5.45%)
         occurrences all number
    16
    22
    Urinary tract infection
         subjects affected / exposed
    11 / 273 (4.03%)
    16 / 275 (5.82%)
         occurrences all number
    24
    25

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Jun 2017
    •A sentence was added to include additional analysis of relapses from a more specific timeframe. The sentence reads as follows: “Relapses that occur after study drugs are withdrawn will be assessed over the remainder of the study period and this data will be utilized as part of additional sensitivity analysis (described in the statistical plan) as long as the subject has not withdrawn their consent to be in the trial.” • The interface between IRAP and the study sites were updated to as follows: “IRAP adjudicates each case based on all available data provided for that case and members are not permitted to contact the site or the sponsor for additional information.” • The change in EDSS score for defining progression of disability were updated to state as follows: “…if a subject experiences at least 1.0 point increase on the EDSS when a baseline score is < 5.5…”. • The assessment tables stipulated as EDSS must be assessed 1 day prior to randomization. • Intent to treat definition was updated in the body of the protocol. • Now included a hierarchy analysis, sensitivity analysis for secondary endpoints and subjects who withdraw from study. • The timeframe of relapse assessment was further defined. • Interim sample size reassessment for relapses was further defined. • Minor typographical errors.
    03 Aug 2017
    •Included information regarding a new vial size for ublituximab. • Updated sections to reflect changes in adverse events as reported in the revised Investigator Brochure. • Minor typographical errors.
    17 Jan 2020
    • Clarification of the exclusion criteria to avoid potential misinterpretation. • Clarification regarding the active comparator to confirm bioequivalent teriflunomide product is used in the study. • Clarification on MRI and Pharmacokinetic (PK) windows. • Minor administrative revisions to remove inconsistencies. • Advise for subjects to seek immediate medical help and inform the investigator if they experience signs or symptoms of an infection. • Provided information on TG1101-RMS303 which was the Open Label Extension of TG1101-RMS301 and TG1101-RMS302.
    04 Sep 2020
    •Updated Secondary Endpoints. •Updated Tertiary Endpoints. •Specified timing of teriflunomide elimination procedure post discontinuation from study treatment. •Added reference to pharmacists as site team members. •Defined Treating Neurologist Medically Confirmed relapses. • Added requirement to re-consent subjects upon Treating Neurologist medically confirmed relapse. • Added guidance to assessments during dosing delay due to lab abnormalities and suspected relapse. • Provided definition of Infusion Related Reaction and that they will be analyzed separately. • Listed and clarified all pooled analysis. • Further defined Treatment Emergent Adverse Events Replaced protocol list of Adverse Events of Special Interest with reference to valid IB.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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