Personalized Extended Interval Dosing of Natalizumab in Relapsing Remitting Multiple Sclerosis
Overview
- Phase
- Phase 4
- Intervention
- Personalized extended interval dosing of natalizumab
- Conditions
- Relapsing Remitting Multiple Sclerosis
- Sponsor
- Amsterdam UMC, location VUmc
- Enrollment
- 300
- Locations
- 24
- Primary Endpoint
- Change of T2 lesions on brain MRI
- Status
- Enrolling By Invitation
- Last Updated
- 3 years ago
Overview
Brief Summary
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.
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.
Investigators
Zoé van Kempen
Principal investigator
Amsterdam UMC, location VUmc
Eligibility Criteria
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)
Arms & Interventions
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.
Intervention: Personalized extended interval dosing of natalizumab
Standard interval dosing
Patients who prefer to stay on standard interval dosing.
Intervention: Standard interval dosing
Historic cohort
Historic cohort of natalizumab treated patients on standard interval dosing.
Intervention: Standard interval dosing
Outcomes
Primary Outcomes
Change of T2 lesions on brain MRI
Time Frame: Baseline, year 1, year 2
Assessing new/enlarging T2 lesions on brain MRI
Secondary Outcomes
- Quality of life: MSIS-29(Baseline, year 1, year 2)
- Satisfaction of treatment: TSQM(Baseline, year 1, year 2)
- Progressive multifocal leukoencephalopathy(Trough study completion, an average of 2 years)
- Serum neurofilament light levels(Trough study completion, an average of 2 years)
- Brain atrophy(Baseline, year 1, year 2)
- JC virus conversion(6 monthly JCV measurement for two years)
- Course JC virus index(6 monthly JCV measurement for two years)
- Patient preference(Baseline)
- Annualized relapse rate(Baseline, year 1, year 2)
- Disability progression during follow-up(Baseline, year 1, year 2)
- Cost analysis(Baseline, year 1, year 2)
- Natalizumab wearing-off effect(Baseline, year 1, year 2)
- Stability of natalizumab trough concentration(6 monthly natalizumab trough concentrations for two years)