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.

BACKGROUND

Treatment with natalizumab once every 4 weeks is approved for patients with relapsing-remitting multiple sclerosis, but is associated with a risk of progressive multifocal leukoencephalopathy. Switching to extended-interval dosing is associated with lower progressive multifocal leukoencephalopathy risk, but the efficacy of this approach is unclear. We aimed to assess the safety and efficacy of natalizumab once every 6 weeks compared with once every 4 weeks in patients with relapsing-remitting multiple sclerosis.

METHODS

We did a randomised, controlled, open-label, phase 3b trial (NOVA) at 89 multiple sclerosis centres across 11 countries in the Americas, Europe, and Western Pacific. Included participants were aged 18-60 years with relapsing-remitting multiple sclerosis and had been treated with intravenous natalizumab 300 mg once every 4 weeks with no relapses for at least 12 months before randomisation, with no missed doses in the previous 3 months. Participants were randomly assigned (1:1), using a randomisation sequence generated by the study funder and contract personnel with interactive response technology, to switch to natalizumab once every 6 weeks or continue with once every 4 weeks. The centralised MRI reader, independent neurology evaluation committee, site examining neurologists, site backup examining neurologists, and site examining technicians were masked to study group assignments. The primary endpoint was the number of new or newly enlarging T2 hyperintense lesions at week 72, assessed in all participants who received at least one dose of assigned treatment and had at least one postbaseline MRI, relapse, or neurological examination or efficacy assessment. Missing primary endpoint data were handled under prespecified primary and secondary estimands: the primary estimand included all data, regardless of whether participants remained on the assigned treatment; the secondary estimand classed all data obtained after treatment discontinuation or study withdrawal as missing. Safety was assessed in all participants who received at least one dose of study treatment. Study enrolment is closed and an open-label extension study is ongoing. This study is registered with EudraCT, 2018-002145-11, and ClinicalTrials.gov, NCT03689972.

FINDINGS

Between Dec 26, 2018, and Aug 30, 2019, 605 patients were assessed for eligibility and 499 were enrolled and assigned to receive natalizumab once every 6 weeks (n=251) or once every 4 weeks (n=248). After prespecified adjustments for missing data, mean numbers of new or newly enlarging T2 hyperintense lesions at week 72 were 0·20 (95% CI 0·07-0·63) in the once every 6 weeks group and 0·05 (0·01-0·22) in the once every 4 weeks group (mean lesion ratio 4·24 [95% CI 0·86-20·85]; p=0·076) under the primary estimand, and 0·31 (95% CI 0·12-0·82) and 0·06 (0·01-0·31; mean lesion ratio 4·93 [95% CI 1·05-23·20]; p=0·044) under the secondary estimand. Two participants in the once every 6 weeks group with extreme new or newly enlarging T2 hyperintense lesion numbers (≥25) contributed most of the excess lesions. Adverse events occurred in 194 (78%) of 250 participants in the once every 6 weeks group and 190 (77%) of 247 in the once every 4 weeks group, and serious adverse events occurred in 17 (7%) and 17 (7%), respectively. No deaths were reported. There was one case of asymptomatic progressive multifocal leukoencephalopathy (without clinical signs) in the once every 6 weeks group, and no cases in the once every 4 weeks group; 6 months after diagnosis, the participant was without increased disability and remained classified as asymptomatic.

INTERPRETATION

We found a numerical difference in the mean number of new or newly enlarging T2 hyperintense lesions at week 72 between the once every 6 weeks and once every 4 weeks groups, which reached significance under the secondary estimand, but interpretation of statistical differences (or absence thereof) is limited because disease activity in the once every 4 weeks group was lower than expected. The safety profiles of natalizumab once every 6 weeks and once every 4 weeks were similar. Although this trial was not powered to assess differences in risk of progressive multifocal leukoencephalopathy, the occurrence of the (asymptomatic) case underscores the importance of monitoring and risk factor consideration in all patients receiving natalizumab.

FUNDING

Biogen.

Informations de copyright

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Déclaration de conflit d'intérêts

Declaration of interests JFF reports personal compensation for consulting activities from Biogen and Octave; and compensation (paid to institution) for data safety monitoring or advisory boards from Biogen, Genentech, and Novartis. GD reports personal compensation for scientific advisory boards and funding for travel or speaker honoraria from Biogen, Bristol-Myers Squibb, Merck Serono, Novartis, Sanofi Genzyme, and Teva Pharmaceuticals; and research grants (paid to institution) from Biogen, Merck Serono, Novartis, and Sanofi Genzyme. LZR reports personal compensation for advisory board activities from Biogen, Genentech, and Novartis; and research support from Biogen, Celgene, and Genentech. JAC reports personal compensation for consulting from Biogen, Bristol-Myers Squibb, Convelo, Genentech, Janssen, NervGen, Novartis, and PSI; for speaking from H3 Communications; and for serving as an Editor of Multiple Sclerosis Journal. DLA reports consulting fees from Albert Charitable Trust, Alexion Pharma, Biogen, Celgene, Frequency Therapeutics, Genentech, Med-Ex Learning, Merck, Novartis, Population Council, Receptos, Roche, and Sanofi Aventis; grants from Biogen, Immunotec, and Novartis; and equity interest in NeuroRx. HB reports personal compensation for consulting from Oxford Health Policy Forum; compensation (paid to institution) for advisory board membership or speaker bureaus from Biogen, Merck, Novartis, Roche, and UCB Pharma; research support (paid to institution) from Biogen, Merck, Novartis, and Roche; and honorarium (paid to institution) for serving on NOVA trial steering committee. GC reports serving on data and safety monitoring boards for AstraZeneca, Avexis, Biolinerx, Brainstorm Cell Therapeutics, Bristol-Myers Squibb–Celgene, CSL Behring, Galmed, GreenValley Pharma, Mapi, Merck, Merck–Pfizer, Opko Biologics, OncoImmune, Neurim, Novartis, Orphazyme, Sanofi, Reata, Teva Pharmaceuticals, VielaBio, Vivus, the National Heart, Lung, and Blood Institute (Protocol Review Committee), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Obstetric Pharmacology Research Unit oversight committee); consulting or advisory boards for Biodelivery Sciences International, Biogen, Click Therapeutics, Genzyme, Genentech, GW Pharmaceuticals, Immunic, Klein-Buendel, MedDay, MedImmune, Neurogenesis, Novartis, Osmotica, Perception Neurosciences, Recursion–Cerexis, Rekover, Roche, and TG Therapeutics; is employed by the University of Alabama at Birmingham, Birmingham, AL, USA; and is president of Pythagoras, a private consulting company located in Birmingham, AL, USA. GG reports consulting or speaker fees from AbbVie, Aslan, Atara Bio, Biogen, Bristol-Myers Squibb–Celgene, GlaxoSmithKline, GW Pharma, Janssen–Actelion, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co, Merck KGaA–EMD Serono, Novartis, Sanofi Genzyme, Roche–Genentech, and Teva Pharmaceuticals. JK reports speaker and consulting fees from Biogen, Genzyme, Merck Serono, Novartis, Roche, and Teva Pharmaceuticals. HW reports honoraria for consulting or speaking from AbbVie, Actelion, Alexion, Argenx, Biogen, Bristol-Myers Squibb, Cognomed, EMD Serono, Evgen, F Hoffmann-La Roche, Idorsia, IGES, Immunic, Immunovant, Janssen, Johnson & Johnson, MedDay, Merck Serono, Novartis, Roche, Sanofi Genzyme, the Swiss Multiple Sclerosis Society, Teva Pharmaceuticals, and UCB; travel support from Alexion, Biogen, Biologix, Cognomed, F Hoffmann-La Roche, Gemeinnützige Hertie-Stiftung, Genzyme, Merck, Novartis, Roche Pharma, Teva Pharmaceuticals, and WebMD Global; and research support from Biogen, GlaxoSmithKline, Roche, and Sanofi Genzyme. KS, GK, RK, and NC report support from Biogen as employees; and hold stock or stock options in Biogen. SX is a former employee of Biogen.