Relapsing Multiple Sclerosis
Conditions
Keywords
Ofatumumab, Relapsing multiple sclerosis, MS, RMS, CIS, RRMS, SPM, ocrelizumab, MRI, CD19 B, adult,, OMB157, open-label, rituximab
Brief summary
A single arm study evaluating the continued efficacy, safety and tolerability of ofatumumab in patients with relapsing multiple sclerosis who are transitioning from aCD20 mAb therapy
Detailed description
This was a single-arm, multicenter, prospective, study in participants with relapsing multiple sclerosis (MS) who had been previously treated with intravenous (i.v.) anti-CD20 monoclonal antibody (aCD20 mAb) therapy and had received at least 2 consecutive courses of intravenously administered ocrelizumab or rituximab every 6 months, and the last dose was within 4 to 9 months before Baseline/Day 1. In this study, participants could have enrolled only if discontinuing i.v. aCD20 mAb therapy for reasons other than lack of efficacy or due to certain treatment-emergent adverse events (TEAEs). Reasons for switching could have included but were not limited to physician/participant preference, access to commercial drug (e.g. insurance coverage issues), or for other logistical reasons (e.g. geographical relocation, travel, etc.). Eligible participants received open label ofatumumab 20 mg subcutaneous (s.c.) once monthly for 12 months following initial loading regimen of 20 mg s.c. doses on Days 1, 7, and 14. After the 12-Month Treatment Period there was a Telephone Safety Follow-up call 30 days after last dose of study treatment. The Core phase covered a 28-day Screening Period, 12-Month Treatment Period, and 30-Day Telephone Safety Follow-up. Upon completing the study, participants could opt to continue ofatumumab therapy through commercial services. Participants who did not continue into the ofatumumab commercial patient services hub within 1 month of the end of study visit or who did not switch to another therapy had to continue into the Post-Treatment Safety Follow-up period, consisting of every 3 month visits including B cell monitoring, until they were able to start on commercial ofatumumab, until they switched to another therapy, or until their B cells were repleted (defined as a B cell concentration greater than the individual participant's baseline value prior to starting the i.v. aCD20 mAb or greater than the lower limit of normal).
Interventions
DRUGOfatumumab
Investigational drug will be provided in an autoinjector for subcutaneous administration containing 20 mg ofatumumab (20 mg/0.4 ml)
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-label
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria: 1. Written informed consent must be obtained before any assessment is performed. 2. Male or female participants aged 18 to 60 years (inclusive) at screening. 3. Diagnosis of relapsing MS (RMS) according to the 2017 Revised McDonald criteria (Thompson et al. 2018), including CIS, RRMS or SPMS with disease activity as defined by (Lublin et al. 2014). 4. Disability status at Screening with an EDSS score of 0 to 5.5 (inclusive). 5. Received at least 2 courses of intravenous aCD20 mAb (loading doses are considered 1 course): • Participants currently treated with ocrelizumab must have received (meet all three criteria below): 1\. 2 fully infused initial 300 mg ocrelizumab iv infusions 2. At least 1 fully infused 600 mg ocrelizumab iv infusions 6 months (+/- one month) 3. Last fully infused ocrelizumab dose must have occurred within 4-9 months prior to baseline •Participants currently treated with rituximab must have received (meet both criteria below): 1. At least 2 fully infused courses of rituximab 500 mg - 1000 mg iv every 6 months (+/- one month). 1. Initial loading regimens of rituximab i.e. 500 mg - 1000 mg on day 1 and on day 15, are allowed but this is consider a single course and must be followed by additional infusion(s) every 6 months (+/- one month) 2. Last fully infused rituximab dose must have occurred within 4-9 months prior to baseline. 6\. Participants discontinuing aCD20 therapy for reasons including, but not limited to: physician/participant preference, access to commercial drug (e.g. insurance coverage issues) or for other logistical reasons (such as geographical relocation, travel, etc.) are eligible for this study. 7. Neurologically stable within 1 month prior to first study drug administration. 8\. Must be able to use a smart device or have a caregiver that can assist.
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study: 1. Participants that have demonstrated suboptimal response to aCD20 therapy to include: a. Signs of MRI activity, defined as ≥ 2 active Gd+ T1 lesions, or any new or newly enlarging T2 lesions, documented within the past 6 months * If a prior MRI within the last 6 months is not available, then new or newly enlarging T2 lesions should be considered not documented and the patient may continue screening b. Documented relapse while on stable, previous aCD20 treatment. * Relapses during the first 3 months of intravenous aCD20 therapy are allowable if the participant is then relapse-free for the 12 months following the relapse while on intravenous aCD20 therapy c. Any signs of clinical worsening as measured by EDSS or any clinical measure documented within the last 6 months 2. Discontinuing aCD20 mAb therapy due to the following treatment- emergent adverse events: 1. Severe infusion-related reactions (Grade 3 or above) 2. Recurrent infections defined as ≥ 2 severe infections or ≥ 3 respiratory infections or the need for ≥ 2 courses of antibiotics since starting aCD20 therapy, if the Investigator believes this is related to therapy. 3. Decreased IgG requiring treatment with Intravenous immunoglobulin 3. Participants with primary progressive MS (Polman et al 2011) or SPMS without disease activity (Lublin et al 2014). 4. Participants meeting criteria for neuromyelitis optica (Wingerchuk et al 2015). 5. Pregnant or nursing (lactating) women 6. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for at least 6 months after stopping study medication. 7. Participants with active chronic disease (or stable but treated with immune therapy) of the immune system other than MS (e.g. rheumatoid arthritis, scleroderma, Sjögren's syndrome, Crohn's disease, ulcerative colitis, etc.) or with immunodeficiency syndrome (hereditary immune deficiency, drug-induced immune deficiency). 8. Participants with active systemic bacterial, viral or fungal infections, or known to have acquired immunodeficiency syndrome (AIDS). 9. Participants with neurological symptoms consistent with PML or with confirmed PML. 10. Participants at risk of developing or having reactivation of syphilis or tuberculosis 11. Participants at risk of developing or having reactivation of hepatitis. 12. Have received any live or live-attenuated vaccines (including for varicella-zoster virus or measles) within 4 weeks prior to first study drug administration. a. There is presently no contraindication for the use of an inactivated, viral-vector-or mRNA based Sars-CoV-2 vaccine in patients who are immunocompromised. However, different Sars-CoV-2 vaccines may have various mechanisms of action and different associated potential risks. Please review local prescribing information of any specific Sars-CoV-2 vaccine and comply with local prescribing information requirements for specific contra-indications and special warnings and precautions for use.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With no Change or a Reduction From Baseline in the Number of Gadolinium Enhancing (GdE) Lesions at Month 12 Using Non-responder Imputation | Baseline (assessed at screening visit), Month 12 | Magnetic Resonance Imaging (MRI) was used to measure presence of new or reduction in number of gadolinium enhancing T1 lesions. Each MRI scan was previewed by a local neuroradiologist. The quality of each scan performed was assessed by a central MRI reading center and evaluated for quality, completeness and adherence to the protocol. A nonresponder imputation (NRI) for missing data approach was applied. NRI assumes that a participant was a treatment failure, i.e. non-responder, if they did not have a valid Month 12 MRI assessment, or if they discontinued the study prematurely and did not have a valid Month 12 MRI assessment. |
| Percentage of Participants With no Change or a Reduction From Baseline in the Number of Gadolinium Enhancing (GdE) Lesions at Month 12 Based on Observed Data | Baseline (assessed at screening visit), Month 12 | Magnetic Resonance Imaging (MRI) was used to measure presence of new or reduction in number of gadolinium enhancing T1 lesions. Each MRI scan was previewed by a local neuroradiologist. The quality of each scan performed was assessed by a central MRI reading center and evaluated for quality, completeness and adherence to the protocol. A sensitivity analysis of the primary endpoint was performed based on an observed data approach. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in CD20+ CD3+ T Cell Counts Obtained by FACS | Baseline, Month 6, Month 12 | Changes from baseline in lymphocytes, including total CD19+ B cell counts and CD20+CD3+ T cell counts, were obtained by fluorescence-activated cell sorting (FACS), which is a specific type of flow cytometry. |
| Number of Participants With Suicidal Ideation or Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) | Baseline (all prior history), Post-baseline (up to Month 12) | The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire that assesses suicidal ideation and suicidal behavior. The suicidal ideation section includes 5 items (Categories 1 to 5), and the suicidal behavior section includes 5 items (Categories 6 to 10). Additionally, there is one item about Self-injurious behavior, without suicidal intent. The C-SSRS was given multiple times throughout the study from baseline up to Month 12. The number of participants who answered 'Yes' to any of the items in C-SSRS at baseline and at any timepoint post-baseline is summarized in this record. Baseline refers to all prior history. |
| Number of Participants Who Continued Study Treatment From Baseline to Months 6 and 12 | Baseline, Month 6, Month 12 | Retention on study treatment from baseline to Month 6 and to Month 12 was based on the number of participants who continued study treatment. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | From first dose of study drug (Day 1) up to 30 days after last dose (Month 13) | TEAEs are defined as any adverse events (AEs) that started on or after the day of first dose of study drug, or before 30 days after the treatment end date, if severity at baseline was missing or if postbaseline severity was greater than baseline severity. |
| Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) Scores at Baseline, Month 6 and Month 12 | Baseline, Month 6, Month 12 | The Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) is a 9-item general instrument that measures the major dimensions of satisfaction with a medication. The questionnaire consists of 3 domains: effectiveness (items 1 to 3), convenience (items 4 to 6) and global satisfaction (items 7 to 9). The scores of each domain range from 0 to 100 with higher scores representing higher satisfaction on that domain. |
| Change From Baseline in CD19+ B Cell Counts Obtained by FACS | Baseline, Month 6, Month 12 | Changes from baseline in lymphocytes, including total CD19+ B cell counts and CD20+CD3+ T cell counts, were obtained by fluorescence-activated cell sorting (FACS), which is a specific type of flow cytometry. |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
This study is conducted in 20 sites in the United States.
Pre-assignment details
The study had a Core phase and a Post-Treatment Safety Follow-up (FU). The Core phase covered a 28-day Screening Period, 12-Month Treatment Period, and 30-Day Telephone Safety FU. Upon completing the study, participants could opt to continue ofatumumab therapy through commercial services. Those not continuing with commercial ofatumumab or switching therapies entered the Post-Treatment Safety FU period.
Participants by arm
| Arm | Count |
|---|---|
| Ofatumumab 20 mg Subcutaneous injection of ofatumumab 20 mg on Day 1, Day 7, Day 14 and thereafter once monthly starting at Month 1 and up to Month 12. | 102 |
| Total | 102 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Core Phase | Adverse Event | 5 |
| Core Phase | Enrolled subjects not treated | 9 |
| Core Phase | Lost to Follow-up | 1 |
| Core Phase | Physician Decision | 1 |
| Core Phase | Subject decision | 6 |
Baseline characteristics
| Characteristic | Ofatumumab 20 mg |
|---|---|
| Age, Continuous | 43.51 years STANDARD_DEVIATION 8.244 |
| Race/Ethnicity, Customized Asian | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 20 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race/Ethnicity, Customized White | 78 Participants |
| Sex: Female, Male Female | 69 Participants |
| Sex: Female, Male Male | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 102 |
| other Total, other adverse events | 53 / 102 |
| serious Total, serious adverse events | 6 / 102 |
Outcome results
Primary
Percentage of Participants With no Change or a Reduction From Baseline in the Number of Gadolinium Enhancing (GdE) Lesions at Month 12 Based on Observed Data
Magnetic Resonance Imaging (MRI) was used to measure presence of new or reduction in number of gadolinium enhancing T1 lesions. Each MRI scan was previewed by a local neuroradiologist. The quality of each scan performed was assessed by a central MRI reading center and evaluated for quality, completeness and adherence to the protocol. A sensitivity analysis of the primary endpoint was performed based on an observed data approach.
Time frame: Baseline (assessed at screening visit), Month 12
Population: Participants in the Full Analysis Set with a value for the outcome measure at both baseline and Month 12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ofatumumab 20 mg | Percentage of Participants With no Change or a Reduction From Baseline in the Number of Gadolinium Enhancing (GdE) Lesions at Month 12 Based on Observed Data | 100 percentage of participants |
Primary
Percentage of Participants With no Change or a Reduction From Baseline in the Number of Gadolinium Enhancing (GdE) Lesions at Month 12 Using Non-responder Imputation
Magnetic Resonance Imaging (MRI) was used to measure presence of new or reduction in number of gadolinium enhancing T1 lesions. Each MRI scan was previewed by a local neuroradiologist. The quality of each scan performed was assessed by a central MRI reading center and evaluated for quality, completeness and adherence to the protocol. A nonresponder imputation (NRI) for missing data approach was applied. NRI assumes that a participant was a treatment failure, i.e. non-responder, if they did not have a valid Month 12 MRI assessment, or if they discontinued the study prematurely and did not have a valid Month 12 MRI assessment.
Time frame: Baseline (assessed at screening visit), Month 12
Population: Participants in the Full Analysis Set with a value for the outcome measure at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ofatumumab 20 mg | Percentage of Participants With no Change or a Reduction From Baseline in the Number of Gadolinium Enhancing (GdE) Lesions at Month 12 Using Non-responder Imputation | 86.6 percentage of participants |
Secondary
Change From Baseline in CD19+ B Cell Counts Obtained by FACS
Changes from baseline in lymphocytes, including total CD19+ B cell counts and CD20+CD3+ T cell counts, were obtained by fluorescence-activated cell sorting (FACS), which is a specific type of flow cytometry.
Time frame: Baseline, Month 6, Month 12
Population: Participants in the Safety Analysis Set with an available value for the outcome measure at both baseline and the corresponding time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ofatumumab 20 mg | Change From Baseline in CD19+ B Cell Counts Obtained by FACS | Month 6 | -24.45 CD19+ B cells * 10^6/L | Standard Deviation 58.295 |
| Ofatumumab 20 mg | Change From Baseline in CD19+ B Cell Counts Obtained by FACS | Month 12 | -17.53 CD19+ B cells * 10^6/L | Standard Deviation 52.182 |
Secondary
Change From Baseline in CD20+ CD3+ T Cell Counts Obtained by FACS
Changes from baseline in lymphocytes, including total CD19+ B cell counts and CD20+CD3+ T cell counts, were obtained by fluorescence-activated cell sorting (FACS), which is a specific type of flow cytometry.
Time frame: Baseline, Month 6, Month 12
Population: Participants in the Safety Analysis Set with an available value for the outcome measure at both baseline and the corresponding time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ofatumumab 20 mg | Change From Baseline in CD20+ CD3+ T Cell Counts Obtained by FACS | Month 6 | -11.144 CD20+ CD3+ T cells * 10^6/L | Standard Deviation 39.152 |
| Ofatumumab 20 mg | Change From Baseline in CD20+ CD3+ T Cell Counts Obtained by FACS | Month 12 | -2.590 CD20+ CD3+ T cells * 10^6/L | Standard Deviation 32.1112 |
Secondary
Number of Participants Who Continued Study Treatment From Baseline to Months 6 and 12
Retention on study treatment from baseline to Month 6 and to Month 12 was based on the number of participants who continued study treatment.
Time frame: Baseline, Month 6, Month 12
Population: Full Analysis Set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ofatumumab 20 mg | Number of Participants Who Continued Study Treatment From Baseline to Months 6 and 12 | Month 6 | 95 Participants |
| Ofatumumab 20 mg | Number of Participants Who Continued Study Treatment From Baseline to Months 6 and 12 | Month 12 | 89 Participants |
Secondary
Number of Participants With Suicidal Ideation or Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS)
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire that assesses suicidal ideation and suicidal behavior. The suicidal ideation section includes 5 items (Categories 1 to 5), and the suicidal behavior section includes 5 items (Categories 6 to 10). Additionally, there is one item about Self-injurious behavior, without suicidal intent. The C-SSRS was given multiple times throughout the study from baseline up to Month 12. The number of participants who answered 'Yes' to any of the items in C-SSRS at baseline and at any timepoint post-baseline is summarized in this record. Baseline refers to all prior history.
Time frame: Baseline (all prior history), Post-baseline (up to Month 12)
Population: Safety Analysis Set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ofatumumab 20 mg | Number of Participants With Suicidal Ideation or Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) | Baseline: Any suicidal ideation (Categories 1 to 5) | 18 Participants |
| Ofatumumab 20 mg | Number of Participants With Suicidal Ideation or Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) | Baseline: Any suicidal behavior (Categories 6 to 10) | 6 Participants |
| Ofatumumab 20 mg | Number of Participants With Suicidal Ideation or Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) | Baseline: Any suicidal ideation or behavior (Categories 1 to 10) | 19 Participants |
| Ofatumumab 20 mg | Number of Participants With Suicidal Ideation or Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) | Baseline: Self-injurious behavior, without suicidal intent | 4 Participants |
| Ofatumumab 20 mg | Number of Participants With Suicidal Ideation or Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) | Post-baseline: Any suicidal ideation (Categories 1 to 5) | 4 Participants |
| Ofatumumab 20 mg | Number of Participants With Suicidal Ideation or Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) | Post-baseline: Any suicidal behavior (Categories 6 to 10) | 0 Participants |
| Ofatumumab 20 mg | Number of Participants With Suicidal Ideation or Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) | Post-baseline: Any suicidal ideation or behavior (Categories 1 to 10) | 4 Participants |
| Ofatumumab 20 mg | Number of Participants With Suicidal Ideation or Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) | Post-baseline: Self-injurious behavior, without suicidal intent | 0 Participants |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
TEAEs are defined as any adverse events (AEs) that started on or after the day of first dose of study drug, or before 30 days after the treatment end date, if severity at baseline was missing or if postbaseline severity was greater than baseline severity.
Time frame: From first dose of study drug (Day 1) up to 30 days after last dose (Month 13)
Population: Safety Analysis Set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ofatumumab 20 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Participants with AEs (any AE, regardless of seriousness) | 86 Participants |
| Ofatumumab 20 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Participants with serious adverse events (SAEs) | 6 Participants |
Secondary
Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) Scores at Baseline, Month 6 and Month 12
The Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) is a 9-item general instrument that measures the major dimensions of satisfaction with a medication. The questionnaire consists of 3 domains: effectiveness (items 1 to 3), convenience (items 4 to 6) and global satisfaction (items 7 to 9). The scores of each domain range from 0 to 100 with higher scores representing higher satisfaction on that domain.
Time frame: Baseline, Month 6, Month 12
Population: Participants in the Full Analysis Set with an available value for the outcome measure at each time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ofatumumab 20 mg | Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) Scores at Baseline, Month 6 and Month 12 | TSQM-9 Effectiveness Score - Baseline | 61.11 Score on scale |
| Ofatumumab 20 mg | Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) Scores at Baseline, Month 6 and Month 12 | TSQM-9 Effectiveness Score - Month 6 | 66.67 Score on scale |
| Ofatumumab 20 mg | Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) Scores at Baseline, Month 6 and Month 12 | TSQM-9 Effectiveness Score - Month 12 | 66.67 Score on scale |
| Ofatumumab 20 mg | Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) Scores at Baseline, Month 6 and Month 12 | TSQM-9 Convenience Score - Baseline | 61.11 Score on scale |
| Ofatumumab 20 mg | Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) Scores at Baseline, Month 6 and Month 12 | TSQM-9 Convenience Score - Month 6 | 88.89 Score on scale |
| Ofatumumab 20 mg | Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) Scores at Baseline, Month 6 and Month 12 | TSQM-9 Convenience Score - Month 12 | 86.11 Score on scale |
| Ofatumumab 20 mg | Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) Scores at Baseline, Month 6 and Month 12 | TSQM-9 Global Satisfaction Score - Baseline | 63.89 Score on scale |
| Ofatumumab 20 mg | Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) Scores at Baseline, Month 6 and Month 12 | TSQM-9 Global Satisfaction Score - Month 6 | 77.78 Score on scale |
| Ofatumumab 20 mg | Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) Scores at Baseline, Month 6 and Month 12 | TSQM-9 Global Satisfaction Score - Month 12 | 42.22 Score on scale |