Personalized Extended Interval Dosing of Natalizumab in Relapsing Remitting Multiple Sclerosis

Relapsing Remitting Multiple Sclerosis Clinical Trial

— SUPERNEXT  

Official title:

Personalized Extended Interval Dosing of Natalizumab in Relapsing Remitting Multiple Sclerosis

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT04225312
• Other study ID #: NL70503.029.19
• Status: Enrolling by invitation
• Phase: Phase 4
• Start date: February 3, 2020
• Est. completion date: March 1, 2025

Study information

• Verified date: April 2023
• Source: Amsterdam UMC, location VUmc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 300
• Est. completion date: March 1, 2025
• Est. primary completion date: March 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Relapsing-Remitting
• Relapsing Remitting Multiple Sclerosis
• Sclerosis

Intervention

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.
• Standard interval dosing
Standard interval dosing in control group and historic group

Locations

Country	Name	City	State
Netherlands	Ziekenhuisgroep Twente hospital	Almelo
Netherlands	Flevoziekenhuis	Almere
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	Jeroen Bosch Hospital	Den Bosch
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

Sponsors (4)

Lead Sponsor	Collaborator
Amsterdam UMC, location VUmc	Innovatiefonds Zorgverzekeraars, Stichting MS Research, Stichting Treatmeds

Country where clinical trial is conducted

Netherlands, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change of T2 lesions on brain MRI	Assessing new/enlarging T2 lesions on brain MRI	Baseline, year 1, year 2
Secondary	Annualized relapse rate	Clinical relapses during personalized extended interval dosing	Baseline, year 1, year 2
Secondary	Disability progression during follow-up	Disability progression measured on the Expanded Disability Status Scale (EDSS); running form 0 (no disability) to 10 (death)	Baseline, year 1, year 2
Secondary	Cost analysis	Cost-utility analysis using EuroQol 5D (EQ-5D) and the Work Productivity and Activtiy Impairment Questionnaire (WPAI).	Baseline, year 1, year 2
Secondary	JC virus conversion	Annual conversion rate of the John Cunningham Virus (JCV)	6 monthly JCV measurement for two years
Secondary	Course JC virus index	Course of John Cunningham Virus (JCV) index in JCV positive patients	6 monthly JCV measurement for two years
Secondary	Natalizumab wearing-off effect	Occurrence of the natalizumab wearing-off effect	Baseline, year 1, year 2
Secondary	Stability of natalizumab trough concentration	Long-term stability of natalizumab trough concentration in personalized interval dosing	6 monthly natalizumab trough concentrations for two years
Secondary	Patient preference	Percentage of patients preferring personalized treatment over standard treatment and percentage staying on personalized treatment	Baseline
Secondary	Quality of life: MSIS-29	Quality of life on the Multiple Sclerosis Impact Scale (MSIS-29)	Baseline, year 1, year 2
Secondary	Satisfaction of treatment: TSQM	Satisfaction of treatment on the Treatment Satisfaction Questionnaire of Medication (TSQM)	Baseline, year 1, year 2
Secondary	Progressive multifocal leukoencephalopathy	Incidence of progressive multifocal leukoencephalopathy	Trough study completion, an average of 2 years
Secondary	Brain atrophy	Percentage of patients preferring personalized treatment over standard treatment and percentage staying on personalized treatment	Baseline, year 1, year 2
Secondary	Serum neurofilament light levels	Difference in serum neurofilament light levels with personalized interval dosing	Trough study completion, an average of 2 years