Personalized Extended Interval Dosing of Natalizumab in Relapsing Remitting Multiple Sclerosis

NCT ID: NCT04225312

Last Updated: 2023-04-27

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 300 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-02-03
• Study Completion Date: 2025-03-01

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.

Conditions

Relapsing Remitting Multiple Sclerosis

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Personalized extended interval dosing of natalizumab

Intervention Type: DRUG

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.

Standard interval dosing

Patients who prefer to stay on standard interval dosing.

Group Type: OTHER

Standard interval dosing

Intervention Type: DRUG

Standard interval dosing in control group and historic group

Historic cohort

Historic cohort of natalizumab treated patients on standard interval dosing.

Group Type: OTHER

Standard interval dosing

Intervention Type: DRUG

Standard interval dosing in control group and historic group

Interventions

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.

Intervention Type: DRUG

Standard interval dosing

Standard interval dosing in control group and historic group

Intervention Type: DRUG

Other Intervention Names

EID; SID

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)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Stichting MS Research

UNKNOWN

Sponsor Role: collaborator

Innovatiefonds Zorgverzekeraars

OTHER

Sponsor Role: collaborator

Stichting Treatmeds

UNKNOWN

Sponsor Role: collaborator

Amsterdam UMC, location VUmc

OTHER

Sponsor Role: lead

Responsible Party

Zoé van Kempen

Principal investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Jeroen Bosch Hospital

's-Hertogenbosch, , Netherlands

Ziekenhuisgroep Twente hospital

Almelo, , Netherlands

Flevoziekenhuis

Almere Stad, , Netherlands

Amsterdam UMC, location VUmc

Amsterdam, , Netherlands

OLVG

Amsterdam, , Netherlands

Rijnstate Hospital

Arnhem, , Netherlands

Wilhelmina hospital Assen

Assen, , Netherlands

Amphia Hospital

Breda, , Netherlands

Reinier de Graaf hospital

Delft, , Netherlands

Slingeland Hospital

Doetinchem, , Netherlands

Ommelander Hospital Groningen

Groningen, , Netherlands

University Medical Center Groningen

Groningen, , Netherlands

Spaarne gasthuis hospital

Haarlem, , Netherlands

Sint-Jansdal Hospital

Harderwijk, , Netherlands

Medisch Centrum Leeuwarden

Leeuwarden, , Netherlands

Alrijne Hospital

Leiden, , Netherlands

Maasstad hospital

Maastricht, , Netherlands

Canisius Wilhelmina Hospital

Nijmegen, , Netherlands

Erasmus Medical Center

Rotterdam, , Netherlands

Haaglanden Medical Center

The Hague, , Netherlands

Elizabeth tweesteden Hospital

Tilburg, , Netherlands

Diakonessenhuis

Utrecht, , Netherlands

St. Antonius Hospital

Utrecht, , Netherlands

Isala

Zwolle, , Netherlands

Countries

Netherlands

References

Foley JF, Defer G, Ryerson LZ, Cohen JA, Arnold DL, Butzkueven H, Cutter G, Giovannoni G, Killestein J, Wiendl H, Smirnakis K, Xiao S, Kong G, Kuhelj R, Campbell N; NOVA study investigators. Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): a randomised, controlled, open-label, phase 3b trial. Lancet Neurol. 2022 Jul;21(7):608-619. doi: 10.1016/S1474-4422(22)00143-0. Epub 2022 Apr 25.

Reference Type: BACKGROUND

PMID: 35483387 (View on PubMed)

Toorop AA, van Lierop ZY, Gelissen LM, Hoitsma E, Zeinstra EM, van Rooij LC, van Munster CE, Vennegoor A, Mostert JP, Wokke BH, Kalkers NF, Hoogervorst EL, van Eijk JJ, Roosendaal CM, Kragt JJ, Eurelings M, van Genugten J, Nielsen J, Sinnige L, Kloosterziel ME, Arnoldus EP, van Dijk GW, Bouvy WH, Wessels MH, Boonkamp L, Strijbis EM, van Oosten BW, De Jong BA, Lissenberg-Witte BI, Barkhof F, Moraal B, Teunissen CE, Rispens T, Uitdehaag BM, Killestein J, van Kempen ZL. Prospective trial of natalizumab personalised extended interval dosing by therapeutic drug monitoring in relapsing-remitting multiple sclerosis (NEXT-MS). J Neurol Neurosurg Psychiatry. 2024 Apr 12;95(5):392-400. doi: 10.1136/jnnp-2023-332119.

Reference Type: DERIVED

PMID: 37963723 (View on PubMed)

Other Identifiers

NL70503.029.19

Identifier Type: -

Identifier Source: org_study_id