Secondary Progressive Multiple Sclerosis
Conditions
Keywords
COVID-19, SARS-CoV-2 mRNA vaccine, Siponimod, Secondary Progressive Multiple Sclerosis, SPMS, adult, MS
Brief summary
The purpose of this study was to understand whether participants could mount an immune response to SARS-CoV-2 modRNA vaccines administered either during continuous siponimod treatment or during a treatment break versus while on treatment with first-line DMTS or no current MS treatment..
Detailed description
This was a three cohort, multicenter, open-label, study of 60 planned (optionally up to 90) multiple sclerosis (MS) patients who were on treatment with siponimod or a first-line disease modifying therapy (DMT) or without MS treatment planning to undergo a SARS-CoV-2 modRNA vaccination as part of clinical routine. * The first cohort enrolled participants who did not interrupt their siponimod therapy for the purpose of a SARS-CoV-2 modRNA vaccination. * The second cohort enrolled participants who interrupted their siponimod therapy for the purpose of a SARS-CoV-2 modRNA vaccination for approximately 2-3 months * The third cohort enrollled participants who received modRNA vaccination while on treatment with the following first-line DMTs (dimethylfumarate, glatirameracetate, interferons, teriflunomide) or no current treatment in clinical routine. The study consists of a screening period, vaccination period and investigational period. During the screening period of up to one month eligibility and SARS-CoV-2 antibodies at baseline were assessed. The 3-4 week vaccination period started with first dose of modRNA vaccine on Day 1 and ended with second dose of modRNA vaccine 3-4 weeks after first dose depending on EU SmPC. The investigational period lasted 12 months, during which blood samples for primary and secondary endpoint analyses were drawn at 1 week (Visit 1), 1 Month (Visit 2) and 6 months (Visit 3) after completion of vaccination (i.e. second dose of vaccine). 12 months after completion of vaccination a COVID-19 follow-up call was scheduled. As patients were treated according to clinical routine, the start of treatment was defined as the date the informed consent was signed. Booster vaccinations were allowed as per local regulations, physician's discretion and as part of clinical routine. This booster may have been any type of SARS-CoV2 vaccine and introduction of a treatment break for the purpose of booster vaccination was at the discretion of the treating physician or patient for all three cohorts. In case of booster vaccinations an additional blood sample was collected 1 month after the booster vaccination (booster Visit). The planned study duration for each participant was 56-64 weeks, depending on the length of the screening period. The study investigated the development of functional anti-SARS-CoV-2 antibodies and T-cell titers for six months after the participants' vaccination.
Interventions
DRUGBAF312
taken orally once per day (dose depends on CYP2C9 genotype)
DRUGBaseline disease modifying therapies (DMTs)
DMTs: Dimethylfumarate, glatirameracetate, interferon, teriflunomode according to respective SmPC
BIOLOGICALBNT162
Administerd according to the respective EU SmPC at the discretion of the treating physician independent of AMA-VACC. If suggested by local regulations and performed as part of clinical routine any type of booster/refresher vaccination (e.g. mRNA, vector, peptide) was allowed in this study.
BIOLOGICALmRNA-1273
Administerd according to the respective EU SmPC at the discretion of the treating physician independent of AMA-VACC. If suggested by local regulations and performed as part of clinical routine any type of booster/refresher vaccination (e.g. mRNA, vector, peptide) was allowed in this study
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Secondary Progressive Multiple Sclerosis (SPMS) diagnosis or with Relapsing Remitting Multiple Sclerosis (RRMS) at risk to develop SPMS (at the discretion of the treating physician) * on stable MS treatment (Siponimod, dimethylfumarate, glatirameracetate, interferon, teriflunomode) or no current treatment * no recent treatment changes
Exclusion criteria
* prior or current COVID-19 disease * SARS-CoV-2 antibodies at screening Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Seroconversion One Week After Receiving Second Vaccine (EAS) | At 1 week after vaccination period (defined as 1 week after second dose of vaccine) | Participants who had detectable SARS-CoV-2 serum functional antibodies one week after second dose of vaccine. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| SARS-CoV-2 Functional Antibodies (% Inhibition) by Visits (SAF/EAS) | Baseline; Week 1, Month 1 and Month 6 after second dose of vaccine; 1 month after booster (up to Month 12 after second dose of vaccine) | Measurement of antibody-mediated blockage (i.e. presence of functional SARS-CoV-2 antibodies) was performed to quantify functional SARS-CoV-2 neutralizing antibodies and was calculated as % inhibition to the in-assay control. |
| Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Baseline; Week 1, Month 1 and Month 6 after second dose of vaccine; 1 month after booster (up to Month 12 after second dose of vaccine) | The release of IFNg or IL-2 after stimulation with a SARS-CoV-2/PAN corona peptide-mix measured by enzyme-linked immunosorbent spot (ELIspot) assay from peripheral blood mononuclear cells indicates the presence of SARS-CoV-2 reactive T-cells, i.e. a T-cell response. |
Countries
Germany
Participant flow
Pre-assignment details
All participants screened were enrolled, there were no screen failures.
Participants by arm
| Arm | Count |
|---|---|
| Siponimod - Continuous Continuous treatment with siponimod (oral, daily, dose depending on CYP2C9 genotype: 2mg or 1 mg) during SARS-CoV-2 mRNA vaccination | 17 |
| Siponimod- Interrupted Siponimod (oral, daily, dose depending on CYP2C9 genotype: 2mg or 1 mg) with treatment interruption (for approx. 2-3 months) for the purpose of a SARS-CoV-2 mRNA vaccination | 4 |
| DMT or no MS Treatment Baseline disease modifying treatments (DMTs) or no multiple sclerosis treatment during SARS-CoV-2 mRNA vaccination | 20 |
| Total | 41 |
Baseline characteristics
| Characteristic | Siponimod- Interrupted | Total | Siponimod - Continuous | DMT or no MS Treatment |
|---|---|---|---|---|
| Age, Continuous | 55.8 years STANDARD_DEVIATION 2.2 | 51.8 years STANDARD_DEVIATION 10.2 | 54.6 years STANDARD_DEVIATION 5.8 | 48.6 years STANDARD_DEVIATION 12.9 |
| Multiple sclerosis diagnosis Active RRMS (with acute exacerbation or progression) | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Multiple sclerosis diagnosis Active SPMS (with acute exacerbation or progression) | 3 Participants | 6 Participants | 3 Participants | 0 Participants |
| Multiple sclerosis diagnosis MS Multiple sclerosis, not specified | 0 Participants | 6 Participants | 0 Participants | 6 Participants |
| Multiple sclerosis diagnosis RRMS Relapsing remitting multiple sclerosis | 0 Participants | 11 Participants | 0 Participants | 11 Participants |
| Multiple sclerosis diagnosis SPMS Secondary progressive multiple sclerosis | 1 Participants | 17 Participants | 14 Participants | 2 Participants |
| Race/Ethnicity, Customized African | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Caucasian | 3 participants | 34 participants | 14 participants | 17 participants |
| Race/Ethnicity, Customized Missing | 0 participants | 3 participants | 2 participants | 1 participants |
| Race/Ethnicity, Customized Other | 1 participants | 4 participants | 1 participants | 2 participants |
| Sex: Female, Male Female | 3 Participants | 32 Participants | 13 Participants | 16 Participants |
| Sex: Female, Male Male | 1 Participants | 9 Participants | 4 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 4 | 0 / 20 |
| other Total, other adverse events | 10 / 17 | 3 / 4 | 16 / 20 |
| serious Total, serious adverse events | 1 / 17 | 1 / 4 | 1 / 20 |
Outcome results
Primary
Percentage of Participants Achieving Seroconversion One Week After Receiving Second Vaccine (EAS)
Participants who had detectable SARS-CoV-2 serum functional antibodies one week after second dose of vaccine.
Time frame: At 1 week after vaccination period (defined as 1 week after second dose of vaccine)
Population: Efficacy analysis set (EAS) - all participants who had a valid primary endpoint (i. e. determination of functional antibodies to SARS-CoV-2 at Week 1 after second dose of vaccine)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Siponimod - Continuous | Percentage of Participants Achieving Seroconversion One Week After Receiving Second Vaccine (EAS) | 52.9 percentage of participants |
| Siponimod- Interrupted | Percentage of Participants Achieving Seroconversion One Week After Receiving Second Vaccine (EAS) | 75.0 percentage of participants |
| DMT or no MS Treatment | Percentage of Participants Achieving Seroconversion One Week After Receiving Second Vaccine (EAS) | 90.0 percentage of participants |
Secondary
Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS
The release of IFNg or IL-2 after stimulation with a SARS-CoV-2/PAN corona peptide-mix measured by enzyme-linked immunosorbent spot (ELIspot) assay from peripheral blood mononuclear cells indicates the presence of SARS-CoV-2 reactive T-cells, i.e. a T-cell response.
Time frame: Baseline; Week 1, Month 1 and Month 6 after second dose of vaccine; 1 month after booster (up to Month 12 after second dose of vaccine)
Population: Safety analysis set (received any study drug) and efficacy analysis set (participants with a valid primary endpoint)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Siponimod - Continuous | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 1/Week 1 missing value n=17,4,20 | 2 participants |
| Siponimod - Continuous | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 1 Month after booster not reactive n=16,4,18 | 10 participants |
| Siponimod - Continuous | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 2/Month 1 missing value n=16,4,20 | 0 participants |
| Siponimod - Continuous | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 3/Month 6 reactive n=17,4,20 | 4 participants |
| Siponimod - Continuous | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 2/Month 1 reactive n=16,4,20 | 0 participants |
| Siponimod - Continuous | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Screening missing value n=17,4,20 | 7 participants |
| Siponimod - Continuous | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 2/Month 1 not reactive n=16,4,20 | 16 participants |
| Siponimod - Continuous | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Screening not reactive n=17,4,20 | 10 participants |
| Siponimod - Continuous | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 1 Month after booster reactive n=16,4,18 | 4 participants |
| Siponimod - Continuous | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 1/Week 1 reactive n=17,4,20 | 7 participants |
| Siponimod - Continuous | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Screening reactive n=17,4,20 | 0 participants |
| Siponimod - Continuous | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 3/Month 6 missing value n=17,4,20 | 2 participants |
| Siponimod - Continuous | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 1/Week 1 not reactive n=17,4,20 | 8 participants |
| Siponimod - Continuous | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 1 Month after booster missing value n=16,4,18 | 2 participants |
| Siponimod - Continuous | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 3/Month 6 not reactive n=17,4,20 | 11 participants |
| Siponimod- Interrupted | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 1/Week 1 reactive n=17,4,20 | 3 participants |
| Siponimod- Interrupted | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Screening reactive n=17,4,20 | 0 participants |
| Siponimod- Interrupted | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Screening not reactive n=17,4,20 | 3 participants |
| Siponimod- Interrupted | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Screening missing value n=17,4,20 | 1 participants |
| Siponimod- Interrupted | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 1/Week 1 not reactive n=17,4,20 | 1 participants |
| Siponimod- Interrupted | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 1/Week 1 missing value n=17,4,20 | 0 participants |
| Siponimod- Interrupted | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 2/Month 1 reactive n=16,4,20 | 1 participants |
| Siponimod- Interrupted | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 2/Month 1 not reactive n=16,4,20 | 3 participants |
| Siponimod- Interrupted | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 2/Month 1 missing value n=16,4,20 | 0 participants |
| Siponimod- Interrupted | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 3/Month 6 reactive n=17,4,20 | 1 participants |
| Siponimod- Interrupted | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 3/Month 6 not reactive n=17,4,20 | 3 participants |
| Siponimod- Interrupted | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 3/Month 6 missing value n=17,4,20 | 0 participants |
| Siponimod- Interrupted | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 1 Month after booster reactive n=16,4,18 | 2 participants |
| Siponimod- Interrupted | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 1 Month after booster not reactive n=16,4,18 | 2 participants |
| Siponimod- Interrupted | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 1 Month after booster missing value n=16,4,18 | 0 participants |
| DMT or no MS Treatment | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 1/Week 1 not reactive n=17,4,20 | 8 participants |
| DMT or no MS Treatment | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 1 Month after booster missing value n=16,4,18 | 0 participants |
| DMT or no MS Treatment | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 3/Month 6 not reactive n=17,4,20 | 5 participants |
| DMT or no MS Treatment | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 1/Week 1 reactive n=17,4,20 | 12 participants |
| DMT or no MS Treatment | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 1 Month after booster not reactive n=16,4,18 | 3 participants |
| DMT or no MS Treatment | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 3/Month 6 missing value n=17,4,20 | 1 participants |
| DMT or no MS Treatment | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Screening missing value n=17,4,20 | 0 participants |
| DMT or no MS Treatment | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 2/Month 1 reactive n=16,4,20 | 14 participants |
| DMT or no MS Treatment | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Screening reactive n=17,4,20 | 1 participants |
| DMT or no MS Treatment | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 2/Month 1 not reactive n=16,4,20 | 6 participants |
| DMT or no MS Treatment | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 1/Week 1 missing value n=17,4,20 | 0 participants |
| DMT or no MS Treatment | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 1 Month after booster reactive n=16,4,18 | 15 participants |
| DMT or no MS Treatment | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 2/Month 1 missing value n=16,4,20 | 0 participants |
| DMT or no MS Treatment | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Screening not reactive n=17,4,20 | 19 participants |
| DMT or no MS Treatment | Number of Patients Reactive to INFg or IL-2 SARS-CoV-2 by Visit SAF/EAS | Visit 3/Month 6 reactive n=17,4,20 | 14 participants |
Secondary
SARS-CoV-2 Functional Antibodies (% Inhibition) by Visits (SAF/EAS)
Measurement of antibody-mediated blockage (i.e. presence of functional SARS-CoV-2 antibodies) was performed to quantify functional SARS-CoV-2 neutralizing antibodies and was calculated as % inhibition to the in-assay control.
Time frame: Baseline; Week 1, Month 1 and Month 6 after second dose of vaccine; 1 month after booster (up to Month 12 after second dose of vaccine)
Population: Safety analysis set (received any study drug) and efficacy analysis set (participants with a valid primary endpoint)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Siponimod - Continuous | SARS-CoV-2 Functional Antibodies (% Inhibition) by Visits (SAF/EAS) | Visit 3/Month 6 n=16,4,20 | 43.2 antibody titer levels (% inhibition) | Standard Deviation 32.8 |
| Siponimod - Continuous | SARS-CoV-2 Functional Antibodies (% Inhibition) by Visits (SAF/EAS) | Visit 2/Month 1 n=16,4,20 | 40.1 antibody titer levels (% inhibition) | Standard Deviation 27.2 |
| Siponimod - Continuous | SARS-CoV-2 Functional Antibodies (% Inhibition) by Visits (SAF/EAS) | Screening n=17,4,20 | -3.8 antibody titer levels (% inhibition) | Standard Deviation 5 |
| Siponimod - Continuous | SARS-CoV-2 Functional Antibodies (% Inhibition) by Visits (SAF/EAS) | Visit 1/Week 1 n=17,4,20 | 38.1 antibody titer levels (% inhibition) | Standard Deviation 34.8 |
| Siponimod - Continuous | SARS-CoV-2 Functional Antibodies (% Inhibition) by Visits (SAF/EAS) | 1 Month after booster n=16,4,18 | 62.3 antibody titer levels (% inhibition) | Standard Deviation 30.3 |
| Siponimod- Interrupted | SARS-CoV-2 Functional Antibodies (% Inhibition) by Visits (SAF/EAS) | Visit 2/Month 1 n=16,4,20 | 87.5 antibody titer levels (% inhibition) | Standard Deviation 16.4 |
| Siponimod- Interrupted | SARS-CoV-2 Functional Antibodies (% Inhibition) by Visits (SAF/EAS) | Screening n=17,4,20 | -0.3 antibody titer levels (% inhibition) | Standard Deviation 11.1 |
| Siponimod- Interrupted | SARS-CoV-2 Functional Antibodies (% Inhibition) by Visits (SAF/EAS) | Visit 1/Week 1 n=17,4,20 | 64.0 antibody titer levels (% inhibition) | Standard Deviation 41.8 |
| Siponimod- Interrupted | SARS-CoV-2 Functional Antibodies (% Inhibition) by Visits (SAF/EAS) | Visit 3/Month 6 n=16,4,20 | 68.3 antibody titer levels (% inhibition) | Standard Deviation 34.5 |
| Siponimod- Interrupted | SARS-CoV-2 Functional Antibodies (% Inhibition) by Visits (SAF/EAS) | 1 Month after booster n=16,4,18 | 96.5 antibody titer levels (% inhibition) | Standard Deviation 2.4 |
| DMT or no MS Treatment | SARS-CoV-2 Functional Antibodies (% Inhibition) by Visits (SAF/EAS) | 1 Month after booster n=16,4,18 | 96.8 antibody titer levels (% inhibition) | Standard Deviation 2.8 |
| DMT or no MS Treatment | SARS-CoV-2 Functional Antibodies (% Inhibition) by Visits (SAF/EAS) | Visit 3/Month 6 n=16,4,20 | 77.3 antibody titer levels (% inhibition) | Standard Deviation 27.1 |
| DMT or no MS Treatment | SARS-CoV-2 Functional Antibodies (% Inhibition) by Visits (SAF/EAS) | Screening n=17,4,20 | -2.6 antibody titer levels (% inhibition) | Standard Deviation 8.2 |
| DMT or no MS Treatment | SARS-CoV-2 Functional Antibodies (% Inhibition) by Visits (SAF/EAS) | Visit 2/Month 1 n=16,4,20 | 86.8 antibody titer levels (% inhibition) | Standard Deviation 21.5 |
| DMT or no MS Treatment | SARS-CoV-2 Functional Antibodies (% Inhibition) by Visits (SAF/EAS) | Visit 1/Week 1 n=17,4,20 | 82.6 antibody titer levels (% inhibition) | Standard Deviation 26.7 |