Personalized Extended Interval Dosing of Natalizumab in Relapsing Remitting Multiple Sclerosis (SUPERNEXT)

April 25, 2023 updated by: Zoé van Kempen, Amsterdam UMC, location VUmc

Rationale: Natalizumab is an effective drug in the treatment for relapsing remitting multiple sclerosis (RRMS) and is approved by de FDA/EMA in a treatment regimen of 4-weekly 300mg natalizumab infusions. Natalizumab trough concentrations after a 4-weekly interval are high in the large majority of patients which implies a relative overdose in most patients. A recent randomized controlled trial (RCT) suggests natalizumab maintains a high level of effi-cacy in stable patients with RRMS switching to a 6 week interval. Our study group demon-strated that efficacy of natalizumab is maintained when the infusion interval is extended based on natalizumab trough concentrations (personalized extended interval dosing). This leads to fewer hospital visits, a decrease of healthcare costs and decrease of risk of compli-cations of natalizumab treatment.

Objective: Our objective is to test feasibility and validate safety of personalized extended interval dosing of natalizumab starting from 6 weeks in a large real-life cohort across the Netherlands.

Study design: Prospective national phase IV natalizumab cohort study.

Study population: All patients, aged 18 years or older, who are currently treated with natalizumab in the Netherlands for RRMS, with a minimum of 6 consecutive infusions.

Intervention: All patients currently included in the NEXT-MS trial will receive an adjusted personalized extended interval dosing treatment regimen of natalizumab based on natalizumab concentrations starting from an infusion interval of 6 weeks.

Main study parameters/endpoints: Our main study endpoint is the safety (defined by radiological disease activity) of personalized natalizumab dosing in a large real-life cohort across the Netherlands. Data will be collected regarding disease activity and disability progression. A cost analysis will be performed to show the extent of cost reduction. Patients will be annually followed to assess the influence of personalized dosing on JC virus conversion, JC virus index, incidence of progressive multifocal leukoencephalopathy, treatment satisfaction and quality of life. The influence of personalized dosing on pharmacokinetics will be monitored.

Study Overview

Status

Enrolling by invitation

Conditions

Intervention / Treatment

Detailed Description

This a national open label phase IV natalizumab cohort study. Our aim is that the large majority of natalizumab treated RRMS patients who are currently treated with PEID in The Netherlands will continue in this study with a treatment interval ≥6 weeks. We will continue the NEXT-MS study with 24 participating centers. The study duration is two years. This study will contain the PEID group, a control group and a historic control group. Participants will decide in which group they will participate as this is an open label, non-randomized study. We have chosen this design as we expect the large majority of patients wanting a personalized natalizumab treatment for the following reasons. Others and our own study group have studied personalized and extended dosing of natalizumab treatment, all indicating that this is a safe approach. Data from the NOVA trial support this approach. As we see a drastic reduction of PML risk with extended interval dosing there is a growing trend internationally to personalized/extended interval dosing. Furthermore, there is an increasing wish in patients and physicians for personalized treatment to increase patient convenience and lowering costs of expensive medication and healthcare.

Based on recent data from the NOVA-trial and data from our preliminary analyses, all patients in the PEID group will continue with personalized dosing with an interval ≥6 weeks. The PEID study group will receive a personalized treatment with the aim of a natalizumab trough concentration of 5μg/ml.

If patients do not desire a personalized treatment, they will be asked informed consent for the use of their patient data and for the questionnaires as the control group. As this introduces a bias, the PEID group will be compared to a historical cohort of Amsterdam MS Center.

Furthermore, the patients of the control group will be asked to donate blood once for measuring of natalizumab trough concentration.

As of April 2021, the European Commission has granted marketing authorization for SC in-jection of natalizumab. As pharmacokinetics and pharmacodynamics between SC and IV ad-ministration resulted in comparable trough natalizumab serum concentration and a4-integrin receptor saturation, patients who desire a switch from IV administration to SC administration will have the opportunity to continue the study in the same study group.

Study Type

Interventional

Enrollment (Anticipated)

300

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Netherlands
      • Almelo, Netherlands
        • Ziekenhuisgroep Twente hospital
      • Almere, Netherlands
        • Flevoziekenhuis
      • Amsterdam, Netherlands
        • OLVG
      • Amsterdam, Netherlands
        • Amsterdam UMC, location VUmc
      • Arnhem, Netherlands
        • Rijnstate Hospital
      • Assen, Netherlands
        • Wilhelmina Hospital Assen
      • Breda, Netherlands
        • Amphia Hospital
      • Delft, Netherlands
        • Reinier de Graaf Hospital
      • Den Bosch, Netherlands
        • Jeroen Bosch Hospital
      • Doetinchem, Netherlands
        • Slingeland Hospital
      • Groningen, Netherlands
        • University Medical Center Groningen
      • Groningen, Netherlands
        • Ommelander Hospital Groningen
      • Haarlem, Netherlands
        • Spaarne Gasthuis Hospital
      • Harderwijk, Netherlands
        • Sint-Jansdal Hospital
      • Leeuwarden, Netherlands
        • Medisch Centrum Leeuwarden
      • Leiden, Netherlands
        • Alrijne Hospital
      • Maastricht, Netherlands
        • Maasstad Hospital
      • Nijmegen, Netherlands
        • Canisius Wilhelmina Hospital
      • Rotterdam, Netherlands
        • Erasmus Medical Center
      • The Hague, Netherlands
        • Haaglanden Medical Center
      • Tilburg, Netherlands
        • Elizabeth TweeSteden Hospital
      • Utrecht, Netherlands
        • Diakonessenhuis
      • Utrecht, Netherlands
        • St. Antonius Hospital
      • Zwolle, Netherlands
        • Isala

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Diagnosis of relapsing remitting multiple sclerosis according to the 2017 criteria
  • 6 or more consecutive natalizumab infusions
  • 18 years or older
  • Agreed to participate (written informed consent)

Exclusion Criteria:

  • High titer natalizumab (>100 arbitrary units (AU)/ml) antibodies
  • Contraindication for frequent magnetic resonance imaging (MRI) (ie, pacemaker or other contraindicated implanted metal devices, or have claustrophobia that cannot be medically managed)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Personalized extended interval dosing
Patients will be receiving a personalized dosing schedule from 6 weeks, which will be further extended if the trough level exceeds 10 ug/ml.
Drug: Personalized extended interval dosing of natalizumab
Personalized extended interval dosing of natalizumab with a schedule from every 6 weeks, which will be further extended if the trough level exceeds 10 ug/ml.
Other Names:
  • EID
Other: Standard interval dosing
Patients who prefer to stay on standard interval dosing.
Drug: Standard interval dosing
Standard interval dosing in control group and historic group
Other Names:
  • SID
Other: Historic cohort
Historic cohort of natalizumab treated patients on standard interval dosing.
Drug: Standard interval dosing
Standard interval dosing in control group and historic group
Other Names:
  • SID

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change of T2 lesions on brain MRI
Time Frame: Baseline, year 1, year 2
Assessing new/enlarging T2 lesions on brain MRI
Baseline, year 1, year 2

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Annualized relapse rate
Time Frame: Baseline, year 1, year 2
Clinical relapses during personalized extended interval dosing
Baseline, year 1, year 2
Disability progression during follow-up
Time Frame: Baseline, year 1, year 2
Disability progression measured on the Expanded Disability Status Scale (EDSS); running form 0 (no disability) to 10 (death)
Baseline, year 1, year 2
Cost analysis
Time Frame: Baseline, year 1, year 2
Cost-utility analysis using EuroQol 5D (EQ-5D) and the Work Productivity and Activtiy Impairment Questionnaire (WPAI).
Baseline, year 1, year 2
JC virus conversion
Time Frame: 6 monthly JCV measurement for two years
Annual conversion rate of the John Cunningham Virus (JCV)
6 monthly JCV measurement for two years
Course JC virus index
Time Frame: 6 monthly JCV measurement for two years
Course of John Cunningham Virus (JCV) index in JCV positive patients
6 monthly JCV measurement for two years
Natalizumab wearing-off effect
Time Frame: Baseline, year 1, year 2
Occurrence of the natalizumab wearing-off effect
Baseline, year 1, year 2
Stability of natalizumab trough concentration
Time Frame: 6 monthly natalizumab trough concentrations for two years
Long-term stability of natalizumab trough concentration in personalized interval dosing
6 monthly natalizumab trough concentrations for two years
Patient preference
Time Frame: Baseline
Percentage of patients preferring personalized treatment over standard treatment and percentage staying on personalized treatment
Baseline
Quality of life: MSIS-29
Time Frame: Baseline, year 1, year 2
Quality of life on the Multiple Sclerosis Impact Scale (MSIS-29)
Baseline, year 1, year 2
Satisfaction of treatment: TSQM
Time Frame: Baseline, year 1, year 2
Satisfaction of treatment on the Treatment Satisfaction Questionnaire of Medication (TSQM)
Baseline, year 1, year 2
Progressive multifocal leukoencephalopathy
Time Frame: Trough study completion, an average of 2 years
Incidence of progressive multifocal leukoencephalopathy
Trough study completion, an average of 2 years
Brain atrophy
Time Frame: Baseline, year 1, year 2
Percentage of patients preferring personalized treatment over standard treatment and percentage staying on personalized treatment
Baseline, year 1, year 2
Serum neurofilament light levels
Time Frame: Trough study completion, an average of 2 years
Difference in serum neurofilament light levels with personalized interval dosing
Trough study completion, an average of 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Amsterdam UMC, location VUmc

Collaborators

Innovatiefonds Zorgverzekeraars
Stichting MS Research
Stichting Treatmeds

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 3, 2020

Primary Completion (Anticipated)

March 1, 2025

Study Completion (Anticipated)

March 1, 2025

Study Registration Dates

First Submitted

January 3, 2020

First Submitted That Met QC Criteria

January 9, 2020

First Posted (Actual)

January 13, 2020

Study Record Updates

Last Update Posted (Actual)

April 27, 2023

Last Update Submitted That Met QC Criteria

April 25, 2023

Last Verified

April 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NL70503.029.19

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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