Exploring the Immune Response to SARS-CoV-2 modRNA Vaccines in Patients With Secondary Progressive Multiple Sclerosis (AMA-VACC) (AMA-VACC)

An Open-label Multicenter Study to Assess Response to SARS-CoV-2 modRNA Vaccines in Participants With Secondary Progressive Multiple Sclerosis Treated With Mayzent (Siponimod)

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..

Study Overview

• Status: Completed
• Conditions: Secondary Progressive Multiple Sclerosis
• Intervention / Treatment: Drug: BAF312; Drug: Baseline disease modifying therapies (DMTs); Biological: BNT162; Biological: mRNA-1273

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.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Bogen, Germany, 94327
    • Novartis Investigative Site
  • Chemnitz, Germany, 09117
    • Novartis Investigative Site
  • Dresden, Germany, 01307
    • Novartis Investigative Site
  • Düsseldorf, Germany, 40211
    • Novartis Investigative Site
  • Neuburg an der Donau, Germany, 86633
    • Novartis Investigative Site
  • Pforzheim, Germany, 75172
    • Novartis Investigative Site
  • Regensburg, Germany, 93059
    • Novartis Investigative Site
  • Ruelzheim, Germany, 76761
    • Novartis Investigative Site
  • Ulm, Germany, 89073
    • Novartis Investigative Site
  • Sachsen
    • Mittweida, Sachsen, Germany, 09648
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Siponimod - continuous; Continuous treatment with siponimod (oral, daily, dose depending on CYP2C9 genotype: 2mg or 1 mg) during SARS-CoV-2 mRNA vaccination	Drug: BAF312; taken orally once per day (dose depends on CYP2C9 genotype); Other Names: Siponimod; Biological: BNT162; 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.; Other Names: Comirnaty®; Biological: mRNA-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; Other Names: Spikevax®
Experimental: 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	Drug: BAF312; taken orally once per day (dose depends on CYP2C9 genotype); Other Names: Siponimod; Biological: BNT162; 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.; Other Names: Comirnaty®; Biological: mRNA-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; Other Names: Spikevax®
Active Comparator: Comparator; Baseline DMTs or no treatment during SARS-CoV-2 mRNA vaccination	Drug: Baseline disease modifying therapies (DMTs); DMTs: Dimethylfumarate, glatirameracetate, interferon, teriflunomode according to respective SmPC; Biological: BNT162; 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.; Other Names: Comirnaty®; Biological: mRNA-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; Other Names: Spikevax®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	At 1 week after vaccination period (defined as 1 week after second dose of vaccine)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Ziemssen T, Groth M, Rauser B, Bopp T. Assessing the immune response to SARS-CoV-2 mRNA vaccines in siponimod-treated patients: a nonrandomized controlled clinical trial (AMA-VACC). Ther Adv Neurol Disord. 2022 Nov 8;15:17562864221135305. doi: 10.1177/17562864221135305. eCollection 2022.

Helpful Links

• Patient Lay Trial Summary

Study record dates

Study Major Dates

• Study Start (Actual): April 19, 2021
• Primary Completion (Actual): September 6, 2021
• Study Completion (Actual): August 15, 2022

Study Registration Dates

• First Submitted: March 8, 2021
• First Submitted That Met QC Criteria: March 8, 2021
• First Posted (Actual): March 11, 2021

Study Record Updates

• Last Update Posted (Actual): June 20, 2024
• Last Update Submitted That Met QC Criteria: June 17, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: adult; MS; COVID-19; Secondary Progressive Multiple Sclerosis; SPMS; Siponimod; SARS-CoV-2 mRNA vaccine
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Neoplasms; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Disease Attributes; Neoplastic Processes; Chronic Disease; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis; Neoplasm Metastasis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Sphingosine 1 Phosphate Receptor Modulators; Siponimod
• Other Study ID Numbers: CBAF312ADE03; 2020-005752-38 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

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/.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No