Clinical trial NCT04225312: Personalized Extended Interval Dosing of Natalizumab in Relapsing Remitting Multiple Sclerosis
Official title: Personalized Extended Interval Dosing of Natalizumab in Relapsing Remitting Multiple Sclerosis
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Relapsing Remitting Multiple Sclerosis
Keywords: Natalizumab
Extended interval dosing
Lead sponsor: Amsterdam UMC, location VUmc
Sponsor class: OTHER
Collaborators: name: Stichting MS Research
name: Innovatiefonds Zorgverzekeraars
name: Stichting Treatmeds
First posted: 2020-01-13
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective national phase IV natalizumab cohort study
Primary purpose: TREATMENT

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.

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)

Primary outcomes:
measure: Change of T2 lesions on brain MRI
timeFrame: Baseline, year 1, year 2
Secondary outcomes:
measure: Annualized relapse rate
timeFrame: Baseline, year 1, year 2
measure: Disability progression during follow-up
timeFrame: Baseline, year 1, year 2
measure: Cost analysis
timeFrame: Baseline, year 1, year 2
measure: JC virus conversion
timeFrame: 6 monthly JCV measurement for two years
measure: Course JC virus index
timeFrame: 6 monthly JCV measurement for two years
measure: Natalizumab wearing-off effect
timeFrame: Baseline, year 1, year 2
measure: Stability of natalizumab trough concentration
timeFrame: 6 monthly natalizumab trough concentrations for two years
measure: Patient preference
timeFrame: Baseline
measure: Quality of life: MSIS-29
timeFrame: Baseline, year 1, year 2
measure: Satisfaction of treatment: TSQM
timeFrame: Baseline, year 1, year 2
measure: Progressive multifocal leukoencephalopathy
timeFrame: Trough study completion, an average of 2 years
measure: Brain atrophy
timeFrame: Baseline, year 1, year 2
measure: Serum neurofilament light levels
timeFrame: Trough study completion, an average of 2 years
Other outcomes:
Locations:
city: Almelo
country: Netherlands
facility: Ziekenhuisgroep Twente hospital
city: Almere
country: Netherlands
facility: Flevoziekenhuis
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC, location VUmc
city: Amsterdam
country: Netherlands
facility: OLVG
city: Arnhem
country: Netherlands
facility: Rijnstate Hospital
city: Assen
country: Netherlands
facility: Wilhelmina hospital Assen
city: Breda
country: Netherlands
facility: Amphia Hospital
city: Delft
country: Netherlands
facility: Reinier de Graaf hospital
city: Den Bosch
country: Netherlands
facility: Jeroen Bosch Hospital
city: Doetinchem
country: Netherlands
facility: Slingeland Hospital
city: Groningen
country: Netherlands
facility: Ommelander Hospital Groningen
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Haarlem
country: Netherlands
facility: Spaarne gasthuis hospital
city: Harderwijk
country: Netherlands
facility: Sint-Jansdal Hospital
city: Leeuwarden
country: Netherlands
facility: Medisch Centrum Leeuwarden
city: Leiden
country: Netherlands
facility: Alrijne Hospital
city: Maastricht
country: Netherlands
facility: Maasstad hospital
city: Nijmegen
country: Netherlands
facility: Canisius Wilhelmina Hospital
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
city: The Hague
country: Netherlands
facility: Haaglanden Medical Center
city: Tilburg
country: Netherlands
facility: Elizabeth tweesteden Hospital
city: Utrecht
country: Netherlands
facility: Diakonessenhuis
city: Utrecht
country: Netherlands
facility: St. Antonius Hospital
city: Zwolle
country: Netherlands
facility: Isala
Study officials:
References:
citation: 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.