Long-Term Outcomes and Durability of Effect Following Treatment With Cladribine Tablets for MS (CLASSIC-MS)

Evaluating the Long-Term Outcomes and Durability of Effect Following Treatment With Cladribine Tablets for MS: An Exploratory Phase IV Ambispective Study of Patients Who Previously Participated in the CLARITY/CLARITY-EXT and ORACLE MS Clinical Trials (CLASSIC-MS)

The objective of this study was to collect data both retrospectively and prospectively in order to evaluate the long-term outcomes, durability of effect, and real-world treatment patterns following treatment with Cladribine Tablets or placebo in participants with multiple sclerosis (MS) who were previously participated in the parent studies (ORACLE MS and CLARITY/CLARITY-EXT).

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis (MS)
• Intervention / Treatment: Other: Data Collection

• Study Type: Interventional
• Enrollment (Actual): 662
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • Camperdown, Australia
    • University of Sydney
• Austria
  • Linz, Austria
    • Barmherzige Brueder Konventspital Linz - Abteilung fuer Neurologie
• Belgium
  • Hasselt, Belgium
    • Limburgs Universitair Centrum
  • Seraing, Belgium
    • University Hospital of Liege
• Bulgaria
  • Pleven, Bulgaria
    • Military Medical Academy - MHAT - Pleven
  • Shumen, Bulgaria
    • MHAT - Shumen, AD
  • Sofia, Bulgaria
    • MHAT - "National Heart Hospital" EAD - Multiple Clinics
  • Sofia, Bulgaria
    • University Hospital "Saint Naum"
  • Stara Zagora, Bulgaria
    • Multiprofile Hospital for Active Treatment - Stara Zagora
• Canada
  • Burnaby, Canada
    • Burnaby Hospital Vancouver
  • Gatineau, Canada
    • Clinique Neuro-Outaouais
  • Greenfield Park, Canada
    • Recherche Sepmus, Inc.
  • Ottawa, Canada
    • The Ottawa Hospital - General Campus
• Croatia
  • Split, Croatia
    • Clinical Hospital Centar Split
  • Varaždin, Croatia
    • General Hospital Varazdin
• Czechia
  • Hradec Kralove, Czechia
    • Privatni ordinace - neurologie - Nestatni zdravotnicke zarizeni
  • Olomouc, Czechia
    • Fakultni nemocnice Olomouc - Neurologicka klinika
  • Ostrava-Poruba, Czechia
    • Fakultni nemocnice Ostrava - Dept of Neurology
  • Praha 2, Czechia
    • Vseobecna fakultni nemocnice v Praze - Dept of Neurologicka klinika 1.LF UK a VFN v Praze
  • Praha 5, Czechia
    • Fakultni nemocnice v Motole - Interní klinika 2. LF UK a FN Motol
  • Teplice, Czechia
    • Krajska zdravotni, a.s. - Nemocnice Teplice, o.z. - Neurologicke oddeleni
• Estonia
  • Tallinn, Estonia
    • Astra Team Clinic
  • Tartu, Estonia
    • Tartu University Hospital
• Finland
  • Turku, Finland
    • Neuro NEO Oy - NEO Research
• France
  • Lille, France
    • Hopital Roger Salengro - CHU Lille - service de neurologie D
  • Nimes, France
    • CHU de Nîmes - Hôpital Carémeau - Service de Neurologie
  • Rennes cedex 09, France
    • CHU Rennes - Hopital Pontchaillou - Neurologie - Clinique Neurologique
• Georgia
  • Tbilisi, Georgia
    • Ltd. Pineo Medical Ecosystem
  • Tbilisi, Georgia
    • S. Khechinashvili University Clinic
• Germany
  • Duesseldorf, Germany
    • Heinrich-Heine-Universitaet Duesseldorf - Klinik fuer Nephrologie
  • Hanover, Germany
    • Diakoniekrankenhaus Henriettenstiftung GgmBH
  • Regensburg, Germany
    • Klinik und Poliklinik für Neurologie
  • Rostock, Germany
    • Universitaetsmedizin Rostock - Klinik und Poliklinik fuer Neurologie
• Italy
  • Bari, Italy
    • Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari - Neurofisiopatologia
  • Catania, Italy
    • A.O.U. Policlinico V. Emanuele - Presidio Gaspare Rodolico - Clinica Neurologica I
  • Chieti, Italy
    • Ospedale Clinicizzato SS. Annunziata - Centro Regionale Sclerosi Multipla
  • Gallarate, Italy
    • Azienda Socio Sanitaria Territoriale della Valle Olona (presidio di Gallarate)
  • Genova, Italy
    • Azienda Ospadaliero Universitaria San Martino - PARENT
  • Milano, Italy
    • Ospedale San Raffaele - U.O. di Neurologia
  • Napoli, Italy
    • Azienda Ospedaliera Universitaria "Federico II" - Gastroenterologia Pediatrica
  • Orbassano, Italy
    • Azienda Ospedaliero_Universitaria S. Luigi Gonzaga - Centro di Riferimento Regionale Sclerosi Multipla
  • Pavia, Italy
    • Fondazione Istituto Neurologico Casimiro Mondino - Unità Complessa Malattie Cerebrovascolari/Stroke U
  • Roma, Italy
    • Azienda Ospedaliera San Camillo Forlanini
  • Roma, Italy
    • Azienda Ospedaliera Universitaria Policlinico Tor Vergata - Dip. Neuroscienze-Centro per la Sclerosi Multipla
  • Rome, Italy
    • Ospedale Sant'Andrea di Roma - MS Center
• Korea, Republic of
  • Goyang-si, Korea, Republic of
    • National Cancer Center
  • Seoul, Korea, Republic of
    • Severance Hospital, Yonsei University
• Lebanon
  • Beirut, Lebanon
    • American University of Beirut Medical Center
  • Beirut, Lebanon
    • Bellevue Medical Center
• Lithuania
  • Kaunas, Lithuania
    • Hospital of Lithuanian University of Health Sciences Kaunas Clinics - Neurology Clinic
• Norway
  • Haukeland, Norway
    • Department of Neurology, Haukeland University
  • Trondheim, Norway
    • St Olavs Hospital - PARENT
• Poland
  • Gdansk, Poland
    • Szpital im. Mikołaja Kopernika - Neurology
  • Gdansk, Poland
    • Uniwersyteckie Centrum Kliniczne - Dept of Neurology
  • Lublin, Poland
    • Prof. Dr. med. Zbigniew Stelmasiak Specjalistyczny Gabinet Neurologiczny
  • Poznań, Poland
    • Szpital Kliniczny im.Heliodora Swiecickiego Uniwersytetu Medycznego im.K. Marcinkowskiego w Poznaniu - Dept of Neurology
  • Warszawa, Poland
    • Instytut Psychiatrii i Neurologii
• Portugal
  • Lisboa, Portugal
    • Centro Hospitalar de Lisboa Central, E.P.E. - Hospital de Santo António dos Capuchos - Serviço de Neurologia
• Romania
  • Bucaresti, Romania
    • SC Sana Monitoring SRL.
  • Targu Mures, Romania
    • Spitalul Clinic Judetean de Urgenta Targu Mures - Sectia Clinica Neurologie I
  • Timisoara, Romania
    • Spitalul Clinic Judetean de Urgenta "Pius Branzeu" Timisoara - Clinica de Neurologie II
• Russian Federation
  • Kemerovo, Russian Federation
    • SAIH "Kemerovo Regional Clinical Hospital" - PARENT
  • Kursk, Russian Federation
    • BMI "Kursk Regional Clinical Hospital"
  • Moscow, Russian Federation
    • NHI "Central Clinical Hospital #2 of JSC "Russian Railways" n.a. N.A. Semashko
  • Moscow, Russian Federation
    • SBIH of Moscow "City Clinical Hospital # 24" - Branch 1
  • Moscow, Russian Federation
    • SBIH of Moscow region " Moscow Regional Scientific and Research Clinical Institute n.a. M.F. Vladimi
  • Nizhny Novgorod, Russian Federation
    • Medis
  • Novosibirsk, Russian Federation
    • RSHI"State Novosibirsk Regional Clinical Hospital"
  • Rostov-on-don, Russian Federation
    • SEIHPE "Rostov State Medical University of MoH of RF"
  • Saint-Petersburg, Russian Federation
    • LLC " International Clinic MEDEM"
  • Saint-Petersburg, Russian Federation
    • Pavlov First Saint Petersburg State Medical University - PARENT
  • Saint-Petersburg, Russian Federation
    • SBIH "Leningrad Regional Clinical Hospital"
  • Samara, Russian Federation
    • SBIH "Samara Regional Clinical Hospital n.a. V.D. Seredavin
  • Saratov, Russian Federation
    • SBEI HPE "Saratov State Medical University n.a. V. I. Razumovskiy" of the MoH of the RF
  • Smolensk, Russian Federation
    • RSBIH "Smolensk Regional Clinical Hospital"
  • St. Petersburg, Russian Federation
    • Saint-Petersburg SU on b.o. City Multifield Hospital #2 - Intensive Pulmonology and Thoracal Surgery
  • Tomsk, Russian Federation
    • Siberian State Medical University
  • Tyumen, Russian Federation
    • Regional Multiple Sclerosis Centre b/o CC ECM "Neftyanik" - Neurology
  • Yaroslavl, Russian Federation
    • SBHI of Yaroslavl Region "Clinical Hospital # 8" - Cardiology
• Serbia
  • Belgrade, Serbia
    • Clinical Center of Serbia
  • Nis, Serbia
    • Clinical Center Nis - Clinic of Neurology
• Spain
  • Córdoba, Spain
    • Hospital Universitario Reina Sofia
  • Santa Cruz de Tenerife, Spain
    • Hospital Universitario Nuestra Señora de la Candelaria - Servicio de Neurologia
• Sweden
  • Göteborg, Sweden
    • Sahlgrenska Sjukhuset
• Switzerland
  • Lausanne, Switzerland
    • (CHUV), Centre Hospitalier Universitaire Vaudois - Departement des Neurosciences Cliniques
• Tunisia
  • Monastir, Tunisia
    • Hôpital Fattouma Bourghiba
  • Sfax, Tunisia
    • Hôpital Habib Bourguiba - Service de Neurologie
  • Tunis, Tunisia
    • Hopital Militaire de Tunis
• Ukraine
  • Kharkiv, Ukraine
    • SI Institute of Neurology, Psychiatry and Narcology of NAMSU - Dept of Neuroinfections and Multiple Sclerosis
  • Vinnytsia, Ukraine
    • Vinnitsa State Medical University - Neurology dept
• United Kingdom
  • Nottingham, United Kingdom
    • Nottingham University Hospital - Division of Clinical Neurology
  • Sheffield, United Kingdom
    • Royal Hallamshire Hospital - Dept of Neurology
• United States
  • Georgia
    • Atlanta, Georgia, United States, 30327
      • MS Center of Atlanta
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland, Baltimore - Maryland Center for MS
  • New York
    • Latham, New York, United States, 12110
      • Empire Neurology, PC - Empire Neurology PC
  • North Dakota
    • Fargo, North Dakota, United States, 58103
      • Sanford Neuro Health Center - Neurology
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • OMRF
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19106
      • Rowan University School of Osteopathic Medicine - Department of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participants with relapsing remitting multiple sclerosis (RRMS) randomised in CLARITY/CLARITY-EXT clinical trial(s) who have received greater than or equal to (>=) 1 course of in investigational medicinal product (IMP) Cladribine Tablets or placebo
• Participants with their first clinical demyelinating event randomised in ORACLE MS clinical trial who have received >= 1 course of IMP Cladribine Tablets or placebo
• Participants who has sign informed consent which includes compliance with the requirements and restrictions listed in the informed consent form and this protocol

Exclusion Criteria:

• Participants who has any uncontrolled disease state other than MS, that in the Investigator's opinion, constitutes an inappropriate risk or a contraindication for participation in the study or that could interfere with the study objectives, conduct, or evaluation
• For study participants at selected sites where MRI assessment will be conducted following exclusion criteria will apply to MRI assessments only:
• Female study participants who are pregnant
• Participants who are taking Cladribine Tablets as part of another study at the time of the start of this study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Cohort A; The participants previously enrolled in parent studies CLARITY (NCT00213135), CLARITY-EXT (NCT00641537), ORACLE (NCT00725985) and had received Cladribine tablet and Placebo were invited up to 2 visit for follow-up/data collection.	Other: Data Collection; No study treatment was administered as part of this study

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Using Wheelchair or Being Bedridden Assessed by Expanded Disability Status Scale (EDSS) Score 7.0 or Higher	EDSS is a scale based on standardized neurological examination which comprised of optic, brain stem, pyramidal, cerebellar, sensory & cerebral functions, as well as walking ability. EDDS is a scale from 0-10 that evaluates a person with Multiple Sclerosis (MS) disability/neurologic function level where 0=normal and 10=death due to MS. Score of 7.0 is defined as unable to walk beyond approximately 5 meters even with aid, essentially restricted to wheelchair; wheels self in standard wheelchair and transfers alone; up and about in wheelchair some 12 hours a day. Score of 8.0 is defined as Essentially restricted to bed or chair or perambulated in wheelchair, but may be out of bed itself much of the day; retains many self-care functions; generally has effective use of arms.	3 months prior to study visit 1. Retrospectively from end of parent study (NCT00213135, NCT00641537 and NCT00725985) to study visit 1 (study visit 1 occurred up to 3 months from screening)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Expanded Disability Status Scale (EDSS) Score 6.0 or Higher	EDSS is a scale based on standardized neurological examination which comprised of optic, brain stem, pyramidal, cerebellar, sensory & cerebral functions, as well as walking ability. EDDS is a scale from 0-10 that evaluates a person with MS disability/neurologic function level where 0= normal and 10= death due to MS. Score of 6.0 is defined as "intermittent or unilateral constant assistance (cane, crutch and brace) required to walk about 100 meters with or without resting".	At study visit 1. Retrospectively after last IMP administration from parent study (NCT00213135, NCT00641537 and NCT00725985) to study visit 1 (study visit 1 occurred up to 3 months from screening)
Clinical and Demographic Characteristic: Age, Disease Duration	Clinical and demographic characteristics including age and disease duration is reported in the form of long term responders and non-responder. Here long term responder is defined as study participants not requiring disease modifying drug (DMD) 4 years or later following their last dose of IMP in parent study. Non-responder is defined as study participants requiring DMD less than 4 years following their last dose of IMP in parent study.	At study visit 1, occurred up to 3 months from screening (Retrospective analysis of medical record of parent study-NCT00213135, NCT00641537 and NCT00725985)
Number of Participants in Each Category of Clinical and Demographic Characteristics	Clinical and demographic characteristics included gender, race, disease classification (relapsing remitting multiple sclerosis [RRMS], Secondary Progressive Multiple Sclerosis [SPMS], unknown & no MS disease), Prior use of DMDs & high-disease activity (HAD) status, education level and employment status. Number of participants in each category of clinical and demographic characteristics were reported in form of long term responders & non-responder. Here long term responder is defined as participants not requiring DMD 4 years or later following their last dose of IMP in parent study. Non-responder is defined as study participants requiring DMD < 4 years following their last dose of IMP in parent study.	At study visit 1, occurred up to 3 months from screening (Retrospective analysis of medical record of parent study-NCT00213135, NCT00641537 and NCT00725985)
Clinical Characteristic: Expanded Disability Status Scale (EDSS) Score	EDSS is a scale based on standardized neurological examination which comprised of optic, brain stem, pyramidal, cerebellar, sensory & cerebral functions, as well as walking ability. EDSS scores range from 0.0 (normal) to 10.0 (dead). Clinical characteristics of EDSS score in form of long-term responders & non-responder was reported for at parent study baseline (based on retrospective data collection [based on chart review] at study visit 1) & study visit 1. Here long term responder is defined as study participants not requiring DMD 4 years or later following their last dose of IMP in parent study. Non-responder is defined as study participants requiring DMD < 4 years following their last dose of IMP in parent study.	At study visit 1, occurred up to 3 months from screening (Retrospective analysis of medical record of parent study-NCT00213135, NCT00641537 and NCT00725985)
Clinical Characteristic: Number of Relapses	Relapse was defined as participant-reported symptoms & objectively observed signs typical of an acute inflammatory demyelinating event in CNS, developing acutely or sub-acutely with duration of at least 24 hours, in absence of fever or infection. Clinical characteristics of number of relapses during last year before enrollment of parent study (it is reported based on retrospective data collection [based on chart review] at study visit 1) in the form of long-term responders & non-responder was reported. Here long term responder is defined as study participants not requiring DMD 4 years or later following their last dose of IMP in parent study. Non-responder is defined as study participants requiring DMD less than 4 years following their last dose of IMP in parent study.	At study visit 1, occurred up to 3 months from screening (Retrospective analysis of medical record of parent study-NCT00213135, NCT00641537 and NCT00725985)
Number of Total T1-weighted (T1-W) Lesions	Total number of T1-W lesion were measured by Using magnetic resonance imaging (MRI) Scans. Here long term responder is defined as study participants not requiring DMD 4 years or later following their last dose of IMP in parent study. Non-responder is defined as study participants requiring DMD less than 4 years following their last dose of IMP in parent study.	At study visit 2, within 6 months from screening (Retrospective analysis of medical record of parent study-NCT00213135, NCT00641537 and NCT00725985)
Number of Total T2-weighted (T2-W) Lesions	Total number of T2-W lesion were measured by Using magnetic resonance imaging (MRI) Scans. Here long term responder is defined as study participants not requiring DMD 4 years or later following their last dose of IMP in parent study. Non-responder is defined as study participants requiring DMD less than 4 years following their last dose of IMP in parent study.	At study visit 2, within 6 months from screening (Retrospective analysis of medical record of parent study-NCT00213135, NCT00641537 and NCT00725985)
T1-weighted (T1-W) Lesion Volume	T1-W lesion volume were measured by Using magnetic resonance imaging (MRI) Scans. Here long term responder is defined as study participants not requiring DMD 4 years or later following their last dose of IMP in parent study. Non-responder is defined as study participants requiring DMD less than 4 years following their last dose of IMP in parent study.	At study visit 2, within 6 months from screening (Retrospective analysis of medical record of parent study-NCT00213135, NCT00641537 and NCT00725985)
T2-weighted (T2-W) Lesion Volume	T2-W lesion volume were measured by Using magnetic resonance imaging (MRI) Scans. Here long term responder is defined as study participants not requiring DMD 4 years or later following their last dose of IMP in parent study. Non-responder is defined as study participants requiring DMD less than 4 years following their last dose of IMP in parent study.	At study visit 2, within 6 months from screening (Retrospective analysis of medical record of parent study-NCT00213135, NCT00641537 and NCT00725985)
Total Brain Volume	Brain volume were measured by Using magnetic resonance imaging (MRI) Scans. Here long term responder is defined as study participants not requiring DMD 4 years or later following their last dose of IMP in parent study. Non-responder is defined as study participants requiring DMD less than 4 years following their last dose of IMP in parent study.	At study visit 2, within 6 months from screening (Retrospective analysis of medical record of parent study-NCT00213135, NCT00641537 and NCT00725985)

Collaborators and Investigators

• Sponsor: EMD Serono Research & Development Institute, Inc.
• Collaborators: Merck KGaA, Darmstadt, Germany
• Investigators: Study Director: Medical Responsible, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Publications and helpful links

General Publications

• Giovannoni G, Boyko A, Correale J, Edan G, Freedman MS, Montalban X, Rammohan K, Stefoski D, Yamout B, Leist T, Aydemir A, Borsi L, Verdun di Cantogno E. Long-term follow-up of patients with relapsing multiple sclerosis from the CLARITY/CLARITY Extension cohort of CLASSIC-MS: An ambispective study. Mult Scler. 2023 May;29(6):719-730. doi: 10.1177/13524585231161494. Epub 2023 Apr 3.

Helpful Links

• US Medical Information website, Medical Resources
• Trial Awareness and Transparency website

Study record dates

Study Major Dates

• Study Start (Actual): August 15, 2019
• Primary Completion (Actual): February 27, 2021
• Study Completion (Actual): May 13, 2021

Study Registration Dates

• First Submitted: May 22, 2019
• First Submitted That Met QC Criteria: May 22, 2019
• First Posted (Actual): May 23, 2019

Study Record Updates

• Last Update Posted (Actual): October 31, 2023
• Last Update Submitted That Met QC Criteria: October 26, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Multiple Sclerosis; Cladribine; High Disease Activity
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis
• Other Study ID Numbers: MS700568_0026; 2019-000069-19 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Per company policy, following approval of a new product or a new indication for an approved product in both the EU and the US, EMD Serono will share study protocols, anonymized patient level and study level data and redacted clinical study reports from clinical trials in patients with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website https://www.emdgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html
• IPD Sharing Time Frame: Within six months after the approval of a new product or a new indication for an approved product in both the United States and the European Union
• IPD Sharing Access Criteria: Qualified scientific and medical researchers can request the data. Such requests must be submitted in writing to the company's portal and will be internally reviewed regarding criteria for researchers' qualification and legitimacy of the research proposal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No