A Phase 4 interventional study of BAF312 and Baseline disease modifying therapies (DMTs) in Secondary Progressive Multiple Sclerosis, sponsored by Novartis Pharmaceuticals. Completed at 10 sites in Germany. Open to participants aged 18 Years to 100 Years. Per ClinicalTrials.gov, last updated 2024-06-20.
Sponsored by Novartis Pharmaceuticals · Phase 4, Interventional, and Treatment
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..
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 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.
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Exclusion Criteria:
Continuous treatment with siponimod (oral, daily, dose depending on CYP2C9 genotype: 2mg or 1 mg) during SARS-CoV-2 mRNA vaccination
Drug: BAF312 · Biological: BNT162 · Biological: mRNA-1273
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
Drug: BAF312 · Biological: BNT162 · Biological: mRNA-1273
Baseline DMTs or no treatment during SARS-CoV-2 mRNA vaccination
Drug: Baseline disease modifying therapies (DMTs) · Biological: BNT162 · Biological: mRNA-1273
taken orally once per day (dose depends on CYP2C9 genotype)
Also known as: Siponimod
DMTs: Dimethylfumarate, glatirameracetate, interferon, teriflunomode according to respective SmPC
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.
Also known as: Comirnaty®
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
Also known as: Spikevax®
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)
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)
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)
| Milestone | Siponimod - Continuous | Siponimod- Interrupted | DMT or no MS Treatment |
|---|---|---|---|
| Started | 17 | 4 | 20 |
| Completed | 17 | 4 | 20 |
| Not completed | 0 | 0 | 0 |
Participants who had detectable SARS-CoV-2 serum functional antibodies one week after second dose of vaccine.
| percentage of participants | Siponimod - Continuous | Siponimod- Interrupted | DMT or no MS Treatment |
|---|---|---|---|
| Percentage of Participants Achieving Seroconversion One Week After Receiving Second Vaccine (EAS) | 52.9 (27.8 to 77.0) | 75.0 (19.4 to 99.4) | 90.0 (68.3 to 98.8) |
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.
| antibody titer levels (% inhibition) | Siponimod - Continuous | Siponimod- Interrupted | DMT or no MS Treatment |
|---|---|---|---|
| Screening n=17,4,20 | -3.8 ± 5.0 | -0.3 ± 11.1 | -2.6 ± 8.2 |
| Visit 1/Week 1 n=17,4,20 | 38.1 ± 34.8 | 64.0 ± 41.8 | 82.6 ± 26.7 |
| Visit 2/Month 1 n=16,4,20 | 40.1 ± 27.2 | 87.5 ± 16.4 | 86.8 ± 21.5 |
| Visit 3/Month 6 n=16,4,20 | 43.2 ± 32.8 | 68.3 ± 34.5 | 77.3 ± 27.1 |
| 1 Month after booster n=16,4,18 | 62.3 ± 30.3 | 96.5 ± 2.4 | 96.8 ± 2.8 |
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.
| participants | Siponimod - Continuous | Siponimod- Interrupted | DMT or no MS Treatment |
|---|---|---|---|
| Screening reactive n=17,4,20 | 0 | 0 | 1 |
| Screening not reactive n=17,4,20 | 10 | 3 | 19 |
| Screening missing value n=17,4,20 | 7 | 1 | 0 |
| Visit 1/Week 1 reactive n=17,4,20 | 7 | 3 | 12 |
| Visit 1/Week 1 not reactive n=17,4,20 | 8 | 1 | 8 |
| Visit 1/Week 1 missing value n=17,4,20 | 2 | 0 | 0 |
| Visit 2/Month 1 reactive n=16,4,20 | 0 | 1 | 14 |
| Visit 2/Month 1 not reactive n=16,4,20 | 16 | 3 | 6 |
| Visit 2/Month 1 missing value n=16,4,20 | 0 | 0 | 0 |
| Visit 3/Month 6 reactive n=17,4,20 | 4 | 1 | 14 |
| Visit 3/Month 6 not reactive n=17,4,20 | 11 | 3 | 5 |
| Visit 3/Month 6 missing value n=17,4,20 | 2 | 0 | 1 |
| Visit 1 Month after booster reactive n=16,4,18 | 4 | 2 | 15 |
| Visit 1 Month after booster not reactive n=16,4,18 | 10 | 2 | 3 |
| Visit 1 Month after booster missing value n=16,4,18 | 2 | 0 | 0 |
Collected over Adverse events were reported from screening visit for a maximum of 69 weeks.. Non-serious events are listed at a 2% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Siponimod Continuous | 0/17 (0%) | 1/17 (5.9%) | 10/17 (58.8%) |
| Siponimod Interrupted | 0/4 (0%) | 1/4 (25%) | 3/4 (75%) |
| DMT or No MS Treatment | 0/20 (0%) | 1/20 (5%) | 16/20 (80%) |
| Event | Siponimod Continuous | Siponimod Interrupted | DMT or No MS Treatment |
|---|---|---|---|
| EpilepsyNervous system disorders | 0/17 | 1/4 | 0/20 |
| Escherichia urinary tract infectionInfections and infestations | 1/17 | 0/4 | 0/20 |
| Acute sinusitisInfections and infestations | 0/17 | 0/4 | 1/20 |
| Gastroenteritis rotavirusInfections and infestations | 0/17 | 0/4 | 1/20 |
| Event | Siponimod Continuous | Siponimod Interrupted | DMT or No MS Treatment |
|---|---|---|---|
| LymphopeniaBlood and lymphatic system disorders | 3/17 | 1/4 | 0/20 |
| ChillsGeneral disorders | 0/17 | 1/4 | 1/20 |
| Influenza like illnessGeneral disorders | 0/17 | 1/4 | 2/20 |
| Peripheral swellingGeneral disorders | 0/17 | 1/4 | 0/20 |
| COVID-19Infections and infestations | 4/17 | 0/4 | 5/20 |
| Urinary tract infectionInfections and infestations | 1/17 | 1/4 | 0/20 |
| Blood glucose decreasedInvestigations | 0/17 | 1/4 | 0/20 |
| Blood pressure increasedInvestigations | 0/17 | 1/4 | 1/20 |
| Liver function test increasedInvestigations | 2/17 | 1/4 | 0/20 |
| Pain in extremityMusculoskeletal and connective tissue disorders | 2/17 | 1/4 | 2/20 |
| Age, Continuous(years) | Siponimod - Continuous | Siponimod- Interrupted | DMT or no MS Treatment | Total |
|---|---|---|---|---|
| Mean | 54.6 ± 5.8 | 55.8 ± 2.2 | 48.6 ± 12.9 | 51.8 ± 10.2 |
| Sex: Female, Male(Participants) | Siponimod - Continuous | Siponimod- Interrupted | DMT or no MS Treatment | Total |
|---|---|---|---|---|
| Female | 13 | 3 | 16 | 32 |
| Male | 4 | 1 | 4 | 9 |
| Race/Ethnicity, Customized(participants) | Siponimod - Continuous | Siponimod- Interrupted | DMT or no MS Treatment | Total |
|---|---|---|---|---|
| Caucasian | 14 | 3 | 17 | 34 |
| African | 0 | 0 | 0 | 0 |
| Other | 1 | 1 | 2 | 4 |
| Missing | 2 | 0 | 1 | 3 |
| Multiple sclerosis diagnosis(Participants) | Siponimod - Continuous | Siponimod- Interrupted | DMT or no MS Treatment | Total |
|---|---|---|---|---|
| SPMS Secondary progressive multiple sclerosis | 14 | 1 | 2 | 17 |
| RRMS Relapsing remitting multiple sclerosis | 0 | 0 | 11 | 11 |
| Active SPMS (with acute exacerbation or progression) | 3 | 3 | 0 | 6 |
| MS Multiple sclerosis, not specified | 0 | 0 | 6 | 6 |
| Active RRMS (with acute exacerbation or progression) | 0 | 0 | 1 | 1 |
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Plan to share: Yes — Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on https://www.clinicalstudydatarequest.com/.
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