Cladribine vs other drugs in MS: Merging randomized trial with real-life data

doi:10.1212/NXI.0000000000000878

Observational Study

. 2020 Aug 14;7(6):e878.

doi: 10.1212/NXI.0000000000000878. Print 2020 Nov.

Cladribine vs other drugs in MS: Merging randomized trial with real-life data

Alessio Signori¹, Francesco Saccà¹, Roberta Lanzillo¹, Giorgia Teresa Maniscalco¹, Elisabetta Signoriello¹, Anna Maria Repice¹, Pietro Annovazzi¹, Damiano Baroncini¹, Marinella Clerico¹, Eleonora Binello¹, Raffaella Cerqua¹, Giorgia Mataluni¹, Paola Perini¹, Simona Bonavita¹, Luigi Lavorgna¹, Ignazio Roberto Zarbo¹, Alice Laroni¹, Lorena Pareja-Gutierrez¹, Sara La Gioia¹, Barbara Frigeni¹, Valeria Barcella¹, Jessica Frau¹, Eleonora Cocco¹, Giuseppe Fenu¹, Valentina Torri Clerici¹, Arianna Sartori¹, Sarah Rasia¹, Cinzia Cordioli¹, Maria Laura Stromillo¹, Alessia Di Sapio¹, Simona Pontecorvo¹, Roberta Grasso¹, Stefania Barone¹, Caterina Barrilà¹, Cinzia Valeria Russo¹, Sabrina Esposito¹, Domenico Ippolito¹, Doriana Landi¹, Andrea Visconti¹, Maria Pia Sormani²

Affiliations

¹ From the Department of Health Sciences (A. Signori, M.P.S.), Section of Biostatistics, University of Genoa; Department of Neurosciences (F.S., R.L., C.V.R.), Reproductive Sciences and Odontostomatology, Multiple Sclerosis Center, Federico II University, Naples; Neurological Clinic and Multiple Sclerosis Center of "AORN A.Cardarelli" (G.T.M.), Naples; Centro di Sclerosi Multipla (E.S.), II Clinica Neurologica, Università della Campania "Luigi Vanvitelli," Napoli; 2nd Neurology Unit and CRRSM (Regional Referral Multiple Sclerosis Center) (A.M.R.), Careggi University Hospital, University of Florence; Multiple Sclerosis Study Center (P.A., D.B.), ASST Valle Olona, PO di Gallarate (VA); Clinical and Biological Sciences Department (M.C.), Neurology Unit, University of Torino, San Luigi Gonzaga Hospital, Orbassano; Centro SM (E.B.), Dipartimento di Neuroscienze, Ospedale Universitario Città della Salute e della Scienza di Torino; Neurological Clinic (R.C.), Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona; Policlinic Tor Vergata (G.M., D.L.), Rome; The Multiple Sclerosis Center of the Veneto Region (P.P.), Department of Neurosciences, University of Padua; Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences (S. Bonavita, L.L., S.E., D.I.), University of Campania Luigi Vanvitelli, Naples; Department of Clinical and Experimental Medicine (I.R.Z.), University of Sassari; Department Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (A.L.), Center of Excellence for Biomedical Research (CEBR), University of Genova; Neuroimmunology and Neuromuscular Diseases Unit (L.P.-G., V.T.C.), IRCCS Foundation Carlo Besta Neurological Institute, Milan; Centro Sclerosi Multipla ASST Papa Giovanni XXIII di Bergamo (S.L.G., B.F., V.B.); Department of Medical Science and Public Health (J.F., E.C., G.F.), University of Cagliari; Neurology Clinic (A. Sartori), Department of Medical, Surgical, and Health Sciences, University of Trieste; Multiple Sclerosis Center (S.R., C.C.), ASST Spedali Civili, PO di Montichiari (BS); Department of Medicine, Surgery and Neuroscience (M.L.S.), University of Siena; 2nd Neurology Unit and CReSM (Regional Referral Multiple Sclerosis Center) (A.D.S.), AOU San Luigi Gonzaga, Orbassano, Torino; Regina Montis Regalis Hospital (A.D.S.), Mondovì; Department of Neurology and Psychiatry (S.P.), Sapienza University, Rome; Neurologia Universitaria OORR (R.G.), Foggia; Institute of Neurology (S. Barone), University Magna Graecia of Catanzaro; Department of Neurology (C.B.), Valduce Hospital, Como; Merck Serono S.p.A. (A.V.), Rome; and IRCCS Ospedale Policlinico San Martino (A.L., M.P.S.), Genova, Italy.
² From the Department of Health Sciences (A. Signori, M.P.S.), Section of Biostatistics, University of Genoa; Department of Neurosciences (F.S., R.L., C.V.R.), Reproductive Sciences and Odontostomatology, Multiple Sclerosis Center, Federico II University, Naples; Neurological Clinic and Multiple Sclerosis Center of "AORN A.Cardarelli" (G.T.M.), Naples; Centro di Sclerosi Multipla (E.S.), II Clinica Neurologica, Università della Campania "Luigi Vanvitelli," Napoli; 2nd Neurology Unit and CRRSM (Regional Referral Multiple Sclerosis Center) (A.M.R.), Careggi University Hospital, University of Florence; Multiple Sclerosis Study Center (P.A., D.B.), ASST Valle Olona, PO di Gallarate (VA); Clinical and Biological Sciences Department (M.C.), Neurology Unit, University of Torino, San Luigi Gonzaga Hospital, Orbassano; Centro SM (E.B.), Dipartimento di Neuroscienze, Ospedale Universitario Città della Salute e della Scienza di Torino; Neurological Clinic (R.C.), Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona; Policlinic Tor Vergata (G.M., D.L.), Rome; The Multiple Sclerosis Center of the Veneto Region (P.P.), Department of Neurosciences, University of Padua; Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences (S. Bonavita, L.L., S.E., D.I.), University of Campania Luigi Vanvitelli, Naples; Department of Clinical and Experimental Medicine (I.R.Z.), University of Sassari; Department Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (A.L.), Center of Excellence for Biomedical Research (CEBR), University of Genova; Neuroimmunology and Neuromuscular Diseases Unit (L.P.-G., V.T.C.), IRCCS Foundation Carlo Besta Neurological Institute, Milan; Centro Sclerosi Multipla ASST Papa Giovanni XXIII di Bergamo (S.L.G., B.F., V.B.); Department of Medical Science and Public Health (J.F., E.C., G.F.), University of Cagliari; Neurology Clinic (A. Sartori), Department of Medical, Surgical, and Health Sciences, University of Trieste; Multiple Sclerosis Center (S.R., C.C.), ASST Spedali Civili, PO di Montichiari (BS); Department of Medicine, Surgery and Neuroscience (M.L.S.), University of Siena; 2nd Neurology Unit and CReSM (Regional Referral Multiple Sclerosis Center) (A.D.S.), AOU San Luigi Gonzaga, Orbassano, Torino; Regina Montis Regalis Hospital (A.D.S.), Mondovì; Department of Neurology and Psychiatry (S.P.), Sapienza University, Rome; Neurologia Universitaria OORR (R.G.), Foggia; Institute of Neurology (S. Barone), University Magna Graecia of Catanzaro; Department of Neurology (C.B.), Valduce Hospital, Como; Merck Serono S.p.A. (A.V.), Rome; and IRCCS Ospedale Policlinico San Martino (A.L., M.P.S.), Genova, Italy. mariapia.sormani@unige.it.

PMID: 32801167
PMCID: PMC7641098
DOI: 10.1212/NXI.0000000000000878

Observational Study

Cladribine vs other drugs in MS: Merging randomized trial with real-life data

Alessio Signori et al. Neurol Neuroimmunol Neuroinflamm. 2020.

. 2020 Aug 14;7(6):e878.

doi: 10.1212/NXI.0000000000000878. Print 2020 Nov.

Authors

Affiliations

¹ From the Department of Health Sciences (A. Signori, M.P.S.), Section of Biostatistics, University of Genoa; Department of Neurosciences (F.S., R.L., C.V.R.), Reproductive Sciences and Odontostomatology, Multiple Sclerosis Center, Federico II University, Naples; Neurological Clinic and Multiple Sclerosis Center of "AORN A.Cardarelli" (G.T.M.), Naples; Centro di Sclerosi Multipla (E.S.), II Clinica Neurologica, Università della Campania "Luigi Vanvitelli," Napoli; 2nd Neurology Unit and CRRSM (Regional Referral Multiple Sclerosis Center) (A.M.R.), Careggi University Hospital, University of Florence; Multiple Sclerosis Study Center (P.A., D.B.), ASST Valle Olona, PO di Gallarate (VA); Clinical and Biological Sciences Department (M.C.), Neurology Unit, University of Torino, San Luigi Gonzaga Hospital, Orbassano; Centro SM (E.B.), Dipartimento di Neuroscienze, Ospedale Universitario Città della Salute e della Scienza di Torino; Neurological Clinic (R.C.), Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona; Policlinic Tor Vergata (G.M., D.L.), Rome; The Multiple Sclerosis Center of the Veneto Region (P.P.), Department of Neurosciences, University of Padua; Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences (S. Bonavita, L.L., S.E., D.I.), University of Campania Luigi Vanvitelli, Naples; Department of Clinical and Experimental Medicine (I.R.Z.), University of Sassari; Department Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (A.L.), Center of Excellence for Biomedical Research (CEBR), University of Genova; Neuroimmunology and Neuromuscular Diseases Unit (L.P.-G., V.T.C.), IRCCS Foundation Carlo Besta Neurological Institute, Milan; Centro Sclerosi Multipla ASST Papa Giovanni XXIII di Bergamo (S.L.G., B.F., V.B.); Department of Medical Science and Public Health (J.F., E.C., G.F.), University of Cagliari; Neurology Clinic (A. Sartori), Department of Medical, Surgical, and Health Sciences, University of Trieste; Multiple Sclerosis Center (S.R., C.C.), ASST Spedali Civili, PO di Montichiari (BS); Department of Medicine, Surgery and Neuroscience (M.L.S.), University of Siena; 2nd Neurology Unit and CReSM (Regional Referral Multiple Sclerosis Center) (A.D.S.), AOU San Luigi Gonzaga, Orbassano, Torino; Regina Montis Regalis Hospital (A.D.S.), Mondovì; Department of Neurology and Psychiatry (S.P.), Sapienza University, Rome; Neurologia Universitaria OORR (R.G.), Foggia; Institute of Neurology (S. Barone), University Magna Graecia of Catanzaro; Department of Neurology (C.B.), Valduce Hospital, Como; Merck Serono S.p.A. (A.V.), Rome; and IRCCS Ospedale Policlinico San Martino (A.L., M.P.S.), Genova, Italy.
² From the Department of Health Sciences (A. Signori, M.P.S.), Section of Biostatistics, University of Genoa; Department of Neurosciences (F.S., R.L., C.V.R.), Reproductive Sciences and Odontostomatology, Multiple Sclerosis Center, Federico II University, Naples; Neurological Clinic and Multiple Sclerosis Center of "AORN A.Cardarelli" (G.T.M.), Naples; Centro di Sclerosi Multipla (E.S.), II Clinica Neurologica, Università della Campania "Luigi Vanvitelli," Napoli; 2nd Neurology Unit and CRRSM (Regional Referral Multiple Sclerosis Center) (A.M.R.), Careggi University Hospital, University of Florence; Multiple Sclerosis Study Center (P.A., D.B.), ASST Valle Olona, PO di Gallarate (VA); Clinical and Biological Sciences Department (M.C.), Neurology Unit, University of Torino, San Luigi Gonzaga Hospital, Orbassano; Centro SM (E.B.), Dipartimento di Neuroscienze, Ospedale Universitario Città della Salute e della Scienza di Torino; Neurological Clinic (R.C.), Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona; Policlinic Tor Vergata (G.M., D.L.), Rome; The Multiple Sclerosis Center of the Veneto Region (P.P.), Department of Neurosciences, University of Padua; Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences (S. Bonavita, L.L., S.E., D.I.), University of Campania Luigi Vanvitelli, Naples; Department of Clinical and Experimental Medicine (I.R.Z.), University of Sassari; Department Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (A.L.), Center of Excellence for Biomedical Research (CEBR), University of Genova; Neuroimmunology and Neuromuscular Diseases Unit (L.P.-G., V.T.C.), IRCCS Foundation Carlo Besta Neurological Institute, Milan; Centro Sclerosi Multipla ASST Papa Giovanni XXIII di Bergamo (S.L.G., B.F., V.B.); Department of Medical Science and Public Health (J.F., E.C., G.F.), University of Cagliari; Neurology Clinic (A. Sartori), Department of Medical, Surgical, and Health Sciences, University of Trieste; Multiple Sclerosis Center (S.R., C.C.), ASST Spedali Civili, PO di Montichiari (BS); Department of Medicine, Surgery and Neuroscience (M.L.S.), University of Siena; 2nd Neurology Unit and CReSM (Regional Referral Multiple Sclerosis Center) (A.D.S.), AOU San Luigi Gonzaga, Orbassano, Torino; Regina Montis Regalis Hospital (A.D.S.), Mondovì; Department of Neurology and Psychiatry (S.P.), Sapienza University, Rome; Neurologia Universitaria OORR (R.G.), Foggia; Institute of Neurology (S. Barone), University Magna Graecia of Catanzaro; Department of Neurology (C.B.), Valduce Hospital, Como; Merck Serono S.p.A. (A.V.), Rome; and IRCCS Ospedale Policlinico San Martino (A.L., M.P.S.), Genova, Italy. mariapia.sormani@unige.it.

PMID: 32801167
PMCID: PMC7641098
DOI: 10.1212/NXI.0000000000000878

Abstract

Objective: Cladribine tablets were tested against placebo in randomized controlled trials (RCTs). In this study, the effectiveness of cladribine vs other approved drugs in patients with relapsing-remitting MS (RRMS) was compared by matching RCT to observational data.

Methods: Data from the pivotal trial assessing cladribine tablets vs placebo (CLARITY) were propensity score matched to data from the Italian multicenter database i-MuST. This database included 3,150 patients diagnosed between 2010 and 2018 at 24 Italian MS centers who started a disease-modifying drug. The annualized relapse rate (ARR) over 2 years from treatment start and the 24-week confirmed disability progression were compared between patients treated with cladribine and other approved drugs (interferon, glatiramer acetate, fingolimod, natalizumab, and dimethyl fumarate), with comparisons with placebo as a reference. Treatment effects were estimated by the inverse probability weighting negative binomial regression model for ARR and Cox model for disability progression. The treatment effect has also been evaluated according to baseline disease activity.

Results: All weighted baseline characteristics were well balanced between groups. All drugs tested had an effect vs placebo close to that detected in the RCT. Patients treated with cladribine had a significantly lower ARR compared with interferon (relapse ratio [RR] = 0.48; p < 0.001), glatiramer acetate (RR = 0.49; p < 0.001), and dimethyl fumarate (RR = 0.6; p = 0.001); a similar ARR to that with fingolimod (RR = 0.74; p = 0.24); and a significantly higher ARR than natalizumab (RR = 2.13; p = 0.014), confirming results obtained by indirect treatment comparisons from RCTs (network meta-analyses). The relative effect of cladribine tablets 10 mg (cumulative dose 3.5 mg/kg over 2 years) was higher in patients with high disease activity vs all treatments except fingolimod and natalizumab. Effects on disability progression were largely nonsignificant, probably due to lack of power for such analysis.

Conclusion: In patients with RRMS, cladribine tablets showed lower ARR compared with matched patients who started interferon, glatiramer acetate, or dimethyl fumarate; was similar to fingolimod; and was higher than natalizumab. The beneficial effect of cladribine tablets was generally amplified in the subgroup of patients with high disease activity.

Classification of evidence: This study provides Class III evidence that for patients with RRMS, cladribine-treated patients had lower ARR compared with interferon, glatiramer acetate, or dimethyl fumarate; similar ARR compared with fingolimod; and higher ARR compared with natalizumab.

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Figures

**Figure 1. ARR ratio of cladribine vs other treatments**
ARR = annualized relapse rate; DMF = dimethyl fumarate; FTY = fingolimod; GA = glatiramer acetate; IFN = interferon β; NTZ = natalizumab.

**Figure 2. Relapse rate ratio of cladribine vs each other treatment according to HDA subgroups**
ARR = annualized relapse rate; CLAD = cladribine; DMD = disease-modifying drug; DMF = dimethyl fumarate; FTY = fingolimod; GA = glatiramer acetate; HDA, high disease activity; IFN = interferon β; NTZ = natalizumab; RR = relapse ratio.

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References

1. Thompson AJ, Baranzini SE, Geurts J, et al. . Multiple sclerosis. Lancet 2018;391:1622–1636. - PubMed
1. Baker D, Pryce G, Herrod SS, Schmierer K. Potential mechanisms of action related to the efficacy and safety of cladribine. Mult Scler Relat Disord 2019;30:176–186. - PubMed
1. Giovannoni G, Comi G, Cook S, et al. . CLARITY Study Group. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med 2010;362:416–426. - PubMed
1. Giovannoni G, Soelberg Sorensen P, Cook S, et al. . Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: results from the randomized extension trial of the CLARITY study. Mult Scler 2018;24:1594–1604. - PubMed
1. Saccà F, Lanzillo R, Signori A, et al. . Determinants of therapy switch in multiple sclerosis treatment-naive patients: a real-life study. Mult Scler 2019;25:1263–1272. - PubMed

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[1] Thompson AJ, Baranzini SE, Geurts J, et al. . Multiple sclerosis. Lancet 2018;391:1622–1636. - PubMed

[2] Thompson AJ, Baranzini SE, Geurts J, et al. . Multiple sclerosis. Lancet 2018;391:1622–1636. - PubMed

[3] Baker D, Pryce G, Herrod SS, Schmierer K. Potential mechanisms of action related to the efficacy and safety of cladribine. Mult Scler Relat Disord 2019;30:176–186. - PubMed

[4] Baker D, Pryce G, Herrod SS, Schmierer K. Potential mechanisms of action related to the efficacy and safety of cladribine. Mult Scler Relat Disord 2019;30:176–186. - PubMed

[5] Giovannoni G, Comi G, Cook S, et al. . CLARITY Study Group. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med 2010;362:416–426. - PubMed

[6] Giovannoni G, Comi G, Cook S, et al. . CLARITY Study Group. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med 2010;362:416–426. - PubMed

[7] Giovannoni G, Soelberg Sorensen P, Cook S, et al. . Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: results from the randomized extension trial of the CLARITY study. Mult Scler 2018;24:1594–1604. - PubMed

[8] Giovannoni G, Soelberg Sorensen P, Cook S, et al. . Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: results from the randomized extension trial of the CLARITY study. Mult Scler 2018;24:1594–1604. - PubMed

[9] Saccà F, Lanzillo R, Signori A, et al. . Determinants of therapy switch in multiple sclerosis treatment-naive patients: a real-life study. Mult Scler 2019;25:1263–1272. - PubMed

[10] Saccà F, Lanzillo R, Signori A, et al. . Determinants of therapy switch in multiple sclerosis treatment-naive patients: a real-life study. Mult Scler 2019;25:1263–1272. - PubMed

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Cladribine vs other drugs in MS: Merging randomized trial with real-life data

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Cladribine vs other drugs in MS: Merging randomized trial with real-life data

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