Study to Assess the Efficacy and Safety of Ublituximab in Participants With Relapsing Forms of Multiple Sclerosis (RMS) - Clinical Trial for Relapsing Multiple Sclerosis (RMS) | NCT03277248

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Primary Purpose

Status

Completed

Phase

Phase 3

Locations

United States

Study Type

Interventional

Intervention

Ublituximab

Teriflunomide

Oral Placebo

IV Placebo

About this trial

This is an interventional treatment trial for Relapsing Multiple Sclerosis (RMS)

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Diagnosis of relapsing multiple sclerosis (RMS) (McDonald Criteria 2010)
Active disease
Expanded disability status scale (EDSS) 0 - 5.5 (inclusive) at screening

Exclusion Criteria:

Treatment with prior Anti-cluster of differentiate 20 (CD20) or other B cell directed treatment
Treatment with the following therapies at any time prior to randomization: alemtuzumab, natalizumab, teriflunomide, leflunomide and Stem cell transplantation
Diagnosed with primary progressive multiple sclerosis (PPMS)
Pregnant or nursing

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Ublituximab + Oral Placebo

Teriflunomide + IV Placebo

Arm Description

Participants received ublituximab intravenous (IV) infusion, 150 milligrams (mg) 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 tablet, once daily (QD) from Day 1 up to the last day of Week 95.

Participants received 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).

Outcomes

Primary Outcome Measures

Annualized Relapse Rate (ARR)

ARR is defined as the number of Independent Relapse Adjudication Committee (IRAP)-confirmed relapses per participant year. The estimate of ARR for a treatment group is the total number of relapses for participants in the respective treatment group divided by the sum of treatment duration for participants in that specific treatment group.

Secondary Outcome Measures

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

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.

Total Number of New and Enlarging T2 Hyperintense Lesions (NELs) Per MRI Scan Per Participant

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.

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

12-week CDP is defined as an increase in EDSS at least 1 point higher than the 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. The EDSS is based on a standard neurological examination, (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, and cerebral) and ambulation function system assessments. The 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.

Percentage of Participants With No Evidence of Disease Activity (NEDA)

A participant with NEDA is defined as a participant 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.

Percentage of Participants With Impaired Symbol Digit Modalities Test (SDMT)

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 of at least 4 points from baseline at any post-baseline assessment up to the Week 96 visit.

Percent Change From Baseline in Brain Volume

Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)

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. TEAEs are AEs that start or worsen after receiving the study drug.

Full Information

NCT ID

NCT03277248

First Posted

September 7, 2017

Last Updated

November 11, 2021

Sponsor

TG Therapeutics, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT03277248

Brief Title

Study to Assess the Efficacy and Safety of Ublituximab in Participants With Relapsing Forms of Multiple Sclerosis (RMS)

Acronym

ULTIMATE II

Official Title

Phase III: UbLiTuximab in Multiple Sclerosis Treatment Effects (ULTIMATE II STUDY)

Study Type

Interventional

2. Study Status

Record Verification Date

November 2021

Overall Recruitment Status

Completed

Study Start Date

August 25, 2017 (Actual)

Primary Completion Date

August 4, 2020 (Actual)

Study Completion Date

November 12, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

TG Therapeutics, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

No

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This study determines the Annualized Relapse Rate (ARR) in participants with RMS after 96 weeks (approximately 2 years) treatment with intravenous (IV) infusion of ublituximab/oral placebo compared to 14 mg oral teriflunomide/IV placebo.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Relapsing Multiple Sclerosis (RMS)

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Model Description

Randomized, multi-center, double-blinded, active-controlled study

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

Double-blinded, active-controlled study

Allocation

Randomized

Enrollment

545 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Ublituximab + Oral Placebo

Arm Type

Experimental

Arm Description

Participants received ublituximab intravenous (IV) infusion, 150 milligrams (mg) 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 tablet, once daily (QD) from Day 1 up to the last day of Week 95.

Arm Title

Teriflunomide + IV Placebo

Arm Type

Active Comparator

Arm Description

Participants received 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).

Intervention Type

Biological

Intervention Name(s)

Ublituximab

Other Intervention Name(s)

TG-1101

Intervention Description

Administered as an IV infusion.

Intervention Type

Drug

Intervention Name(s)

Teriflunomide

Intervention Description

Film coated tablets administered orally.

Intervention Type

Drug

Intervention Name(s)

Oral Placebo

Intervention Description

Administered orally.

Intervention Type

Drug

Intervention Name(s)

IV Placebo

Intervention Description

Administered as an IV Infusion.

Primary Outcome Measure Information:

Title

Annualized Relapse Rate (ARR)

Description

ARR is defined as the number of Independent Relapse Adjudication Committee (IRAP)-confirmed relapses per participant year. The estimate of ARR for a treatment group is the total number of relapses for participants in the respective treatment group divided by the sum of treatment duration for participants in that specific treatment group.

Time Frame

Up to 96 weeks

Secondary Outcome Measure Information:

Title

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

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.

Time Frame

Weeks 12, 24, 48, and 96

Title

Total Number of New and Enlarging T2 Hyperintense Lesions (NELs) Per MRI Scan Per Participant

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.

Time Frame

Weeks 24, 48, and 96

Title

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

Description

12-week CDP is defined as an increase in EDSS at least 1 point higher than the 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. The EDSS is based on a standard neurological examination, (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, and cerebral) and ambulation function system assessments. The 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.

Time Frame

Up to Week 96

Title

Percentage of Participants With No Evidence of Disease Activity (NEDA)

Description

A participant with NEDA is defined as a participant 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.

Time Frame

From Week 24 to Week 96

Title

Percentage of Participants With Impaired Symbol Digit Modalities Test (SDMT)

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 of at least 4 points from baseline at any post-baseline assessment up to the Week 96 visit.

Time Frame

Baseline to Week 96

Title

Percent Change From Baseline in Brain Volume

Time Frame

Baseline to Week 96

Title

Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)

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. TEAEs are AEs that start or worsen after receiving the study drug.

Time Frame

From the first dose of study drug through the end of the study (up to approximately 116 weeks)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

55 Years

Accepts Healthy Volunteers

No

Eligibility Criteria

Inclusion Criteria: Diagnosis of relapsing multiple sclerosis (RMS) (McDonald Criteria 2010) Active disease Expanded disability status scale (EDSS) 0 - 5.5 (inclusive) at screening Exclusion Criteria: Treatment with prior Anti-cluster of differentiate 20 (CD20) or other B cell directed treatment Treatment with the following therapies at any time prior to randomization: alemtuzumab, natalizumab, teriflunomide, leflunomide and Stem cell transplantation Diagnosed with primary progressive multiple sclerosis (PPMS) Pregnant or nursing

Facility Information:

Facility Name

TG Therapeutics RMS Investigational Trial site

City

Phoenix

State/Province

Arizona

ZIP/Postal Code

58018

Country

United States

Facility Name

TG Therapeutics RMS Investigational Trial Site

City

Aurora

State/Province

Colorado

ZIP/Postal Code

80045

Country

United States

Facility Name

TG Therapeutics RMS Investigational Trial Site

City

Tampa

State/Province

Florida

ZIP/Postal Code

33612

Country

United States

Facility Name

TG Therapeutics RMS Investigational Trial Site

City

Lexington

State/Province

Kentucky

ZIP/Postal Code

40513

Country

United States

Facility Name

TG Therapeutics RMS Investigational Trial Site

City

Chesterfield

State/Province

Missouri

ZIP/Postal Code

63017

Country

United States

Facility Name

TG Therapeutics RMS Investigational Trial Site

City

Las Vegas

State/Province

Nevada

ZIP/Postal Code

89106

Country

United States

Facility Name

TG Therapeutics RMS Investigational Trial Site

City

Teaneck

State/Province

New Jersey

ZIP/Postal Code

07666

Country

United States

Facility Name

TG Therapeutics RMS Investigational Trial Site

City

Albuquerque

State/Province

New Mexico

ZIP/Postal Code

87131

Country

United States

Facility Name

TG Therapeutics RMS Investigational Trial Site

City

Patchogue

State/Province

New York

ZIP/Postal Code

11772

Country

United States

Facility Name

TG Therapeutics RMS Investigational Trial site

City

Columbus

State/Province

Ohio

ZIP/Postal Code

43221

Country

United States

Facility Name

TG Therapeutics RMS Investigational Trial Site

City

Pittsburgh

State/Province

Pennsylvania

ZIP/Postal Code

15212

Country

United States

Facility Name

TG Therapeutics RMS Investigational Trial site

City

San Antonio

State/Province

Texas

ZIP/Postal Code

78258

Country

United States

Facility Name

TG Therapeutics RMS Investigational Trial site

City

Seattle

State/Province

Washington

ZIP/Postal Code

98122

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Undecided

IPD Sharing Plan Description

Data will be shared after study completion via publication.

Citations:

PubMed Identifier

36001711

Citation

Steinman L, Fox E, Hartung HP, Alvarez E, Qian P, Wray S, Robertson D, Huang D, Selmaj K, Wynn D, Cutter G, Mok K, Hsu Y, Xu Y, Weiss MS, Bosco JA, Power SA, Lee L, Miskin HP, Cree BAC; ULTIMATE I and ULTIMATE II Investigators. Ublituximab versus Teriflunomide in Relapsing Multiple Sclerosis. N Engl J Med. 2022 Aug 25;387(8):704-714. doi: 10.1056/NEJMoa2201904.

Results Reference

derived

Study to Assess the Efficacy and Safety of Ublituximab in Participants With Relapsing Forms of Multiple Sclerosis (RMS) (ULTIMATE II)

Relapsing Multiple Sclerosis (RMS)

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial