Official Title
Personalized Extended Interval Dosing of Natalizumab in Relapsing Remitting Multiple Sclerosis
Phase
Phase 4Lead Sponsor
Free University of AmsterdamStudy Type
InterventionalStatus
RecruitingIndication/Condition
Relapsing Remitting Multiple SclerosisIntervention/Treatment
Personalized extended interval dosing of natalizumab ...Study Participants
300Rationale: Natalizumab is an effective drug in the treatment for relapsing remitting multiple sclerosis (RRMS) and is approved in the 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. The investigators have demonstrated 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 complications of natalizumab treatment.
Objective: The objective is to test feasibility and validate safety of personalized extended interval dosing of natalizumab 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: Patients will receive a personalized extended interval dosing (4-8 weeks) based on two natalizumab trough concentrations in the standard 4 week interval.
Main study parameters/endpoints: The 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 John Cunningham virus (JCV) conversion, JCV index, incidence of progressive multifocal leukoencephalopathy and treatment satisfaction and quality of life. The influence of personalized dosing on pharmacokinetics will be monitored. Furthermore, personalized extended interval dosing will be studied in a subgroup with the aim to explore lower than previously studied trough values of natalizumab.
The proposed trial is a national open label phase IV natalizumab cohort study. The large majority of natalizumab treated RRMS patients in The Netherlands will be asked to participate in this study by their treating neurologist. The study will start with approximately 15 participating centers and expand the study with amendments of more participating centers. The study duration is two years, with an extension phase of another two years. This study will contain a main study group with a control group ,a smaller study subgroup and a historic control group. Participants will decide in which group they will participate as this is an open label, non-randomized study. This design was chosen as it was expected that the large majority of patients wanting a personalized natalizumab treatment for the following reasons. Other research groups studied personalized and extended dosing of natalizumab treatment, all indicating that this is a safe approach. A drastic reduction of PML risk with extended interval dosing causes 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.
For the study subgroup with a lower aim of trough concentration, only completely stable patients will be included, in this way the patients will be their own control, expecting no recurrence of disease activity. The latter design is equal to a previous study on personalized EID. If patients desire a personalized natalizumab treatment and have been treated with ≥6 consecutive natalizumab infusions, they have the opportunity of entering the study as a participant of the main PEID study group or the low PEID study group. The main PEID study group will receive a personalized treatment with the aim of a natalizumab trough concentration of 10µg/ml. Patients in the low PEID study group have 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 main study 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 and natalizumab antibodies.
As of April 2021, the European Commission has granted marketing authorization for SC injec-tion 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.
An interim analysis will be performed after the 100th patient completes the first year of PEID and after 200 patients complete the first year of PEID.
Personalized extended interval dosing of natalizumab based on natalizumab trough concentration
Standard interval dosing in control group and historic group
Personalized dosing based on natalizumab trough concentration with an aim of natalizumab trough concentration of 10mcg/ml.
Personalized dosing based on natalizumab trough concentration with a lower aim of natalizumab trough concentration of 5mcg/ml.
Patients who prefer to stay on standard interval dosing.
Historic cohort of natalizumab treated patients on standard interval dosing.
Inclusion Criteria: Diagnosis of relapsing remitting multiple sclerosis according to the 2017 criteria21 6 or more consecutive natalizumab infusions 18 years or older Agreed to participate (written informed consent) Disease stability (radiological and clinical) ≥ 12 months (only in low personalized extended interval dosing group) 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)
