Oral Cladribine in Early Multiple Sclerosis (MS) (ORACLE MS)

A Phase III, Randomized, Double-blind, Placebo-controlled, Multi-center Clinical Trial of Oral Cladribine in Subjects With a First Clinical Event at High Risk of Converting to MS

A randomized, double-blind, clinical trial to assess the safety and efficacy of two doses of oral cladribine versus placebo in participants who had a first clinical demyelinating event (clinically isolated syndrome). Participants in either the cladribine or placebo group may also enter treatment periods with open-label interferon-beta or open-label cladribine depending upon the disease status. The primary objective of this study is to evaluate the effect of two dosage regimens of oral cladribine versus placebo on the time to conversion to multiple sclerosis (MS) (from randomization) according to the Poser criteria in participants with first clinical demyelinating event at high risk of converting to MS.

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Drug: Cladribine; Drug: Rebif® new formulation (RNF); Drug: Placebo

Detailed Description

This will be a randomized, double blind, three-arm, placebo-controlled, multi-center trial to evaluate the safety and efficacy of oral cladribine versus placebo in the treatment of participants who have sustained a first clinical demyelinating event within 75 days prior to the Screening. Participants must have a minimum of 2 clinically silent lesions on the Screening magnetic resonance imaging (MRI).

The study will include a pre-study evaluation period (Screening period: between 10 and 28 days prior to the start of treatment with blinded study medication (oral cladribine or placebo).

Depending upon the clinical course of their MS, participants will then proceed from the ITP to either the Maintenance Treatment Period (with open-label interferon-beta treatment) or LTFU period (with either open-label low-dose cladribine or no additional treatment (if no progression to MS has been noted after the initial treatment period). The single primary endpoint for the overall study, which will be determined during the ITP, is time to conversion to MS (from randomization), according to the Poser criteria.

For every participants, eligibility for study enrollment and entry into each of the study periods, and diagnosis of conversion to either McDonald MS or CDMS must be confirmed and approved by a Sponsor appointed study Adjudication Committee.

• Study Type: Interventional
• Enrollment (Actual): 617
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Godoy Cruz, Argentina
    • Instituto Médico Rodriguez Alfici
  • Rosario, Argentina
    • Fundacion Rosarina de Neurorehabilitacion
• Austria
  • Linz, Austria
    • Krankenhaus der Barmherzigen Brüder
• Belgium
  • Brugge, Belgium
    • Algemeen Ziekenhuis St Jan
  • Brussels, Belgium
    • Cliniques Universitaires St-Luc
  • Bruxelles, Belgium
    • Hôpital Erasme
  • Liège, Belgium
    • CHU de Liege - Domaine Universitaire du Sart Tilman,
• Bosnia and Herzegovina
  • Sarajevo, Bosnia and Herzegovina
    • Clinical Center University of Sarajevo
• Bulgaria
  • Pleven, Bulgaria
    • Military Medical Academy- Sofia (MMA)
  • Rousse, Bulgaria
    • MBAL Rousse AD 1st
  • Sofia, Bulgaria
    • Tokuda Hospital
  • Sofia, Bulgaria
    • Military Medical Academy
  • Sofia, Bulgaria
    • Central Clinic Hospital
  • Sofia, Bulgaria
    • National Heart Hospital
  • Sofia, Bulgaria
    • Second MHAT
  • Sofia, Bulgaria
    • University Hospital St Naum
  • Veliko Tarnovo, Bulgaria
    • Medical Centre Centromed 2000
• Canada
  • Ottawa, Canada
    • Ottawa General Hospital
• Croatia
  • Varazdin, Croatia
    • General Hospital Varazdin
  • Zagreb, Croatia
    • University Hospital Zagreb
• Czechia
  • Brno, Czechia
    • Faculty hospital Brno
  • Hradec Kralove, Czechia
    • Neurological dept of Faculty
  • Ostrava, Czechia
    • Fakultni nemocnice s poliklinikou Ostrava
  • Prague, Czechia
    • Faculty Hospital Motol
  • Prague, Czechia
    • Klinika Vseobecne
  • Teplice, Czechia
    • Nemocnice Teplice
• Estonia
  • Tallinn, Estonia
    • East Tallinn Central Hospital
  • Tallinn, Estonia
    • West Tallinn Central Hospital
• Finland
  • Hyvinkaa, Finland
    • HUS Hyvinkaa Central Hospital
  • Oulu, Finland
    • OYKS Neurologian Klinikka
  • Seinajoki, Finland
    • Neurologian Klinikka Seinajoen Keskussairaala
  • Tampere, Finland
    • Tampere University Hospital
  • Turku, Finland
    • Turun Yliopistollinen Keskussairaala Rakennus 3 1
• France
  • Lille Cedex, France
    • CHU de Lille
  • Nantes, France
    • CHU de Nantes
  • Reims Cedex, France
    • American Memorial Hospital
• Georgia
  • Tbilisi, Georgia
    • David Tatishvili Medical Center
  • Tbilisi, Georgia
    • Medical Center Health
  • Tbilisi, Georgia
    • S. Khechinashvili Tbilisi State Medical University
• Germany
  • Heidelberg, Germany
    • Universitaetsklinikum und Medizinische Fakultaet Heidelberg
  • Marburg, Germany
    • Philipps-Universitaet Marburg
• India
  • Coimbatore, India
    • Kovai Medical Centre and Hospital
  • Lucknow, India
    • Sanjay Gandhi Post Graduate Institute of Medical Sciences
  • Mangalore, India
    • Mallikatta Neuro and Research Centre
  • Karnataka
    • Bangalore, Karnataka, India
      • M S Ramaiah Medical College Hospital
    • Bangalore, Karnataka, India
      • St.John's Medical College and Hospital
  • Kerala
    • Kochi, Kerala, India
      • Amrita Institute of Medical Sciences and Research
• Italy
  • Ancona, Italy
    • Ospedale Regionale Torrette
  • Bari, Italy
    • Università de Bari
  • Cagliari, Italy
    • Ospedale Binaghi Centro Sclerosi Multipla
  • Catania, Italy
    • Azienda Ospedaliera Garibaldi
  • Catania, Italy
    • Dipartimento di Neuroscienze
  • Chieti, Italy
    • Università G. d'Annunzio
  • Gallarate, Italy
    • Ospedale San Antonio Abate
  • Genova, Italy
    • Universita degli Studi di Genova
  • Gussago, Italy
    • Ospedale e casa di riposo P. Richiedei
  • Milano, Italy
    • Ospedale San Raffaele
  • Napoli, Italy
    • Dipartimento di Scienze Neurologiche
  • Orbassano, Italy
    • Azienda Sanitaria Ospedaliera San Luigi Gonzaga
  • Palermo, Italy
    • Villa Sofia Hospital Azienda Ospedaliera Villa Sofia P.zza Salerno e Resuttana 1
  • Pavia, Italy
    • Istituto Neurologico C. Mondino
  • Roma, Italy
    • Azienda Ospedaliera S. Camillo Forlanini
  • Roma, Italy
    • Azienda Ospedaliera Universitaria Policlinico Tor Vergata
  • Roma, Italy
    • Università di Roma La Sapienza
• Korea, Republic of
  • Gyeonggi-do, Korea, Republic of
    • National Cancer Center, Department of Neurology,
  • Seoul, Korea, Republic of
    • Department of Neurology, 50 Ilwon-dong, Gangnam-gu
  • Seoul, Korea, Republic of
    • Department of Neurology, Asan Medical Center, 388-1 Pungnap 2-dong, Songpa-gu
  • Seoul, Korea, Republic of
    • Seoul National University Hospital, Department of Neurology
  • Seoul, Korea, Republic of
    • Yonsei University Medical Center, Department of Neurology, Yonsei University Medical Center
• Lebanon
  • Beirut, Lebanon
    • American University of Beirut
• North Macedonia
  • Skopje, North Macedonia
    • Clinic of Neurology "Klinicki Centar"
• Norway
  • Bergen, Norway
    • Helse Bergen HF Kvinneklinikken Haukeland Universitetssykehus Jonas
  • Trondheim, Norway
    • Regionsykehuset I Trondheim, Nevrologisk avd.
• Poland
  • Bydgoszcz, Poland
    • 10 Wojskowy Szpital Kliniczny
  • Gdansk, Poland
    • Wojewodzki Szpital Specjalistyczny im. M. Kopernika
  • Krakow, Poland
    • Niepubliczny Zespol Opieki Zdrowotnej
  • Lodz, Poland
    • Medical Academy of Lodz
  • Lublin, Poland
    • Panstwowy Szpital Kliniczny
  • Olsztyn, Poland
    • Wojewodzki Szpital Specjalistyczny Oddział Neurologii z Pododdziałem Udarowym
  • Poznan, Poland
    • Medical Academy
  • Warsaw, Poland
    • Medical Academy II
  • Warsaw, Poland
    • Medical Academy
• Portugal
  • Amadora, Portugal
    • Hospital Fernando da Fonseca
  • Coimbra, Portugal
    • Hospitais da universidade de Coimbra
  • Lisboa, Portugal
    • Hospital de Santa Maria
  • S. Martinho Do Bispo, Portugal
    • Centro Hospitalar de Coimbra
• Romania
  • Bucharest, Romania
    • "Dr. Carol Davilla" Military Clinical Hospital
  • Bucharest, Romania
    • Centrul Medical Sana
  • Targu-Mures, Romania
    • Spitalul Clinic Judetean Mures
  • Timisoara, Romania
    • County Hospital Timisoara
• Russian Federation
  • Chelyabinsk, Russian Federation
    • Municipal Healthcare Institution "City Clinical Hospital #3"
  • Ekaterinburg, Russian Federation
    • State Healthcare Institution "Sverdlovsk Regional Clinical Hospital #1"
  • Kaluga, Russian Federation
    • State Healthcare Institution "Kaluga Regional Hospital"
  • Kazan, Russian Federation
    • State Medical Institution "Republican Rehabilitation Clinic of Tatarstan Ministry of Health"
  • Kemerovo, Russian Federation
    • State Healthcare Institution "Kemerovo Regional Clinical Hospital"
  • Kursk, Russian Federation
    • State Medical Institution " Jursk Regional Clinical Hospital"
  • Moscow, Russian Federation
    • Moscow State Healthcare Institution City Clinical Hospital #11
  • Moscow, Russian Federation
    • Non-State Healthcare Institution "Central Clinical Hospital #2 named after N.A. Semasko of Russian Railways"
  • Moscow, Russian Federation
    • State Educational Institute of Higher Professional Education "I.M. Sechenov Moscow Medical Academy of Roszdrav" Russia based on A. Ya. Kozhevnikov Nervous Disease Clinic
  • Nizhny Novgorod, Russian Federation
    • Municipal Treatment Prophylactic Institution "City Hospital #33"
  • Novosibirsk, Russian Federation
    • Federal State Institution " Siberian Reginal Medical Center of Roszdarv"
  • Novosibirsk, Russian Federation
    • State institution Science Research Institute Clinical and Experimental Lymphology of Russian Academy of Medical Sciences
  • Rostov-on-Don, Russian Federation
    • State Educational Institute of Higher Professional Education "Rostov State Medical University of Roszdrav"
  • Rostov-on-Don, Russian Federation
    • State Healthcare Institution "Rostov Region Clinical Hospital"
  • Saint-Petersburg, Russian Federation
    • State Educational Institution of Higher Professional Education "Military Medical Academy named after S. M. Korov of Dept of Defense of Russian Federation based on Clinic of Neurology of State Institution
  • Samara, Russian Federation
    • State Educational Institution of Higher Professional Education "Samara State Medical University of Roszdrav" on State Healthcare Institution "Samara Regional Clinical Hospital named after M. I. Kalinin"
  • Saratov, Russian Federation
    • State Educational Institution of Higher Professional Education "Saratov State Medical University of Roszdrav" based on Clincial Hosptial #3 of Saratov State Medical University
  • Smolensk, Russian Federation
    • Regional State Healthcare Institution "State Smolensk Region Clinical Hospital"
  • St Petersburg, Russian Federation
    • Institute of Human Brain of Russian Academy of Science Dept. of Multiple Sclerosis
  • St Petersburg, Russian Federation
    • International Clinic and Hospital, Neurology
  • St. Petersburg, Russian Federation
    • St. Petersburg State Healthcare Institution "Multifield City Hospital #2"
  • Tomsk, Russian Federation
    • State Educational Institution of Higher Professional Education "Siberian State Medical University of Roszdrav"
  • Tyumen, Russian Federation
    • Closed joint-stock society Medical sanitary unit "Nephtaynik" based the hospital
  • Vladimir, Russian Federation
    • Vladimir Regional State Healthcare Institution "Regional Clinical Hospital"
  • Yaroslavl, Russian Federation
    • Municipal Healthcare Institution "Yaroslavi Clinical Hospital #8"
• Serbia
  • Belgrade, Serbia
    • Clinical Centre of Serbia
  • Belgrade, Serbia
    • Hospital for Prevention and Treatment of Cerebro-Vascular Diseases
  • Niš, Serbia
    • Clinical Centre Nis
• Singapore
  • Singapore, Singapore
    • National Neuroscience Institute (TTSH Campus)
• Spain
  • Cordoba, Spain
    • Hospital Reina Sofía Cordoba
  • Sta. Cruz de Tenerife, Spain
    • Hospital Universitario Nuestra Señora de La Candelaria
• Sweden
  • Goteborg, Sweden
    • Sahlgrenskasjukhuset
  • Stockholm, Sweden
    • Karolinska University Hospital
  • Umea, Sweden
    • Umeå University Hospital
• Taiwan
  • Taipei, Taiwan
    • Taipei Veterans
  • Taoyuan, Taiwan
    • Chang Gung Medical Foundation- Linkou Branch No5
• Thailand
  • Khon Kaen, Thailand
    • Srinagarind Hospital
• Turkey
  • Izmir, Turkey
    • Dokuz Eylul University
  • Samsun, Turkey
    • Ondokuz Mayis Üniversitesi
• Ukraine
  • Kharkiv, Ukraine
    • State Established "Institute of Neurology, Psychiatry and Narcology of the AMS of Ukraine", Depart of Neurinfections and Multiple Sclorosis
  • Kiev, Ukraine
    • Institue for Clinical Radiology of the State Establishment "Research Centre for Radiation Medicine of the AMS of Ukraino" Depart of Radiation Psychoneurology
  • Vinnitsa, Ukraine
    • Vinnylsia Regional Psychoneurological Hosptial Named After O. I Yushchenko, Neurological Depart, Vinnytsia National Medical University Named After M. I. Pirogov, Chair of Neurology
• United Arab Emirates
  • Dubai, United Arab Emirates
    • Rashid hospital
• United Kingdom
  • London, United Kingdom
    • Kings College London
• United States
  • Arizona
    • Phoenix, Arizona, United States
      • Hope Research Institute Medical Plaza LLC Desert Hills
  • California
    • Newport Beach, California, United States
      • Multiple Sclerosis Center Drive, Neurology Suite 701
  • Colorado
    • Denver, Colorado, United States
      • University of Colorado at Denver Health Sciences
    • Fort Collins, Colorado, United States
      • Fort Collins Neurology
  • Florida
    • Melbourne, Florida, United States
      • MS Center of Brevard MIMA Centry Research Associates
    • Tampa, Florida, United States
      • University of South Florida
  • Georgia
    • Atlanta, Georgia, United States
      • MS Center of Atlanta
  • Iowa
    • Des Moines, Iowa, United States
      • Bruce Hughes West Building
  • Michigan
    • Clinton Township, Michigan, United States
      • Michigan Neurology Associates
    • Detroit, Michigan, United States
      • Henry Ford Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States
      • University of Minnesota
  • Montana
    • Great Falls, Montana, United States
      • Dennis Dietrich
  • New Jersey
    • Stratford, New Jersey, United States
      • University of Medicine and Dentistry of New Jersey School of Neurology
  • New York
    • Albany, New York, United States
      • Upstate Clinical Research LLC 3
    • Great Neck, New York, United States
      • Neurological Specialists of Long Island
    • New York, New York, United States
      • Multiple Sclerosis Center of Northeastern NY
    • Patchogue, New York, United States
      • Comprehensive MS Care Clinic at South Shore Multiple Sclerosis
  • North Carolina
    • Charlotte, North Carolina, United States
      • Carolinas Medical Center
  • North Dakota
    • Fargo, North Dakota, United States
      • Meritcare Neuroscience Center Neurology
  • Ohio
    • Cincinnati, Ohio, United States
      • University of Cincinnati
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
      • MS Center of Oklahoma
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States
      • Neurology and Sleep Medicine
  • Washington
    • Seattle, Washington, United States
      • Swedish Medical Center Cherry Hill
    • Tacoma, Washington, United States
      • Neurology & Neurological Association of Tacoma

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female between 18 and 55 years old, inclusive
• Weighed between 40 to 120 kilogram (kg), inclusive
• Participant has experienced a single, first clinical event suggestive of MS within 75 days prior to the Screening visit, (clock starts 24 hours after onset). The event must be a new neurological abnormality present for at least 24 hours, either mono- or polysymptomatic
• Participant has at least two clinically silent lesions on the T2-weighted MRI scan, at screening, with a size of at least 3 millimeter (mm), at least one of which is ovoid or periventricular or infratentorial on screening MRI
• Participant has EDSS 0 - 5.0 at Screening
• Participant has no medical history or evidence of latent tuberculosis infection (LTBI) or active tubercular disease, as evidenced by the Mantoux tuberculosis (TB) skin test or a comparable sensitive test according to local regulations/guidelines (if the Mantoux test is not available), and/or a chest X-ray
• Participant has normal hematological parameters at Screening, as defined by the central laboratory that performed all the assessments

• If female, she must:

  • be neither pregnant nor breast-feeding, nor attempting to conceive and
  • use a highly effective method of contraception throughout the entire duration of the study and for 90 days following completion of the last dose of study medication. A highly effective method of contraception is defined as those which result in a low failure rate (that is less than 1 percent per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices, sexual abstinence or vasectomized partner, or
  • be post-menopausal or surgically sterilized (Note: for Danish sites only, participants should use a hormonal contraceptive or intrauterine device for the duration of the trial)
• Male participants must be willing to use contraception to avoid impregnating partners throughout the study, and for 90 days following the last dose of study medication
• Be willing and able to comply with study procedures for the duration of the study
• Participant has to provide written informed consent voluntarily, including, for United states of America (USA), participant authorization under Health Insurance Portability and Accountability Act (HIPAA), prior to any study-related procedure that is not part of normal medical care
• Participant has refused any treatment already available for clinically isolated syndrome (CIS) such as interferons or glatiramer acetate, at the time of entry into the Initial Treatment Period of this study

Exclusion Criteria:

• Participant has a diagnosis of MS (per McDonald criteria, 2005)
• Participant has any other disease that could better explain the participant's signs and symptoms
• Participant has complete transverse myelitis or bilateral optic neuritis
• Participant using or has used any other approved MS disease modifying drug (DMD)
• Participant has used any investigational drug or undergone an experimental procedure within 12 weeks prior to Study day 1
• Participant received oral or systemic corticosteroids or adrenocorticotropic hormone (ACTH) within 30 days prior to screening MRI. The MRI had to be performed 30 days after the oral or systemic corticosteroids or ACTH treatment. In case this interfered with MRI timing the screening period could be extended accordingly.
• Participant has abnormal total bilirubin, or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or alkaline phosphatase greater than 2.5 times the upper limit of normal
• Participant suffered from current autoimmune disease other than MS
• Participant suffered from psychiatric illness (including history of, or concurrent, severe depressive disorders and/or suicidal ideation) that in the opinion of the investigator creates undue risk to the participant or could affect compliance with the study protocol
• Participant suffered from major medical illness such as cardiac (for example angina, congestive heart failure or arrhythmia), endocrinologic, hepatic, immunologic, metabolic, renal, pulmonary, gastrointestinal, dermatologic, or other major disease that would preclude the administration of oral cladribine
• Participant has a history of seizures not adequately controlled by medications
• Participant has a known allergy to cladribine, interferon-beta, the excipient(s) of the study medications, or to gadolinium- diethylenetriamine penta-acetic acid (DTPA)
• Participant has any renal condition that would preclude the administration of gadolinium (for example acute or chronic severe renal insufficiency (glomerular filtration rate [GFR] less than 30 milliliter per minute per 1.73 square meter [mL/min/1.73 m^2])
• Participant has a history of chronic or clinically significant hematological abnormalities
• Participant has a history of active or chronic infectious disease or any disease that compromises immune function (for example human immunodeficiency virus positive [HIV+], human T-lymphotrophic virus [HTLV-1], Lyme disease, latent tuberculosis infection [LTBI] or TB, insulin-dependent diabetes).
• Participant has previously been screened in this study (signed an informed consent) and then withdrawn
• Participant has received any immunomodulatory or immunosuppressive therapy) at any time prior to Study Day 1, including, but not limited to, the following products: any interferon, glatiramer acetate (Copolymer I), cyclophosphamide, cyclosporine, methotrexate, linomide, azathioprine, mitoxantrone, teriflunomide, laquinimod, cladribine, total lymphoid irradiation, anti-lymphocyte monoclonal antibody treatment (for example natalizumab, alemtuzumab/Campath, anti-cluster of differentiation 4 [CD4]), intravenous immunoglobulin G (IVIG), cytokines or anti-cytokine therapy
• Participant has received experimental MS treatment
• Participant has a history of alcohol or drug abuse
• Participant has intolerance or any contraindication to both paracetamol (acetaminophen) and ibuprofen
• Participant has inability to administer subcutaneous injections either by self or by caregiver
• Participant has prior or current malignancy (with the exception of in situ basal or squamous cell skin cancer surgically removed without recurrence for at least five years)
• Participant has a positive stool hemoccult test at Screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

12

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cladribine 5.25 mg/kg (ITP); Cladribine tablets administered as cumulative dose of 0.875 mg/kg over a course of 5 consecutive days at Weeks 1, 5, 9, 13, 48, and 52 resulting in total cladribine dose of 5.25 milligrams per kilograms (mg/kg) during the ITP of 96 weeks or until clinically definite multiple sclerosis (CDMS) conversion, whichever occurred first.	Drug: Cladribine; Cladribine tablets were administered until CDMS conversion, whichever occur first.; Drug: Rebif® new formulation (RNF); Participants who converted to CDMS during ITP entered in open-label maintenance period (OLMP) and received RNF subcutaneously at a dose of 44 microgram (mcg) three times a week. Participants who converted to CDMS during long-term follow-up (LTFU) period, received RNF subcutaneously at a dose of 44 mcg three times a week.
Experimental: Cladribine 3.5 mg/kg (ITP); Cladribine tablets administered as cumulative dose of 0.875 mg/kg over a course of 5 consecutive days at Weeks 1, 5, 48, 52 and placebo matched to cladribine tablets was administered at Week 9 and 13 resulting in total cladribine dose of 3.5 mg/kg during the ITP of 96 weeks or until CDMS conversion, whichever occurred first.	Drug: Cladribine; Cladribine tablets were administered until CDMS conversion, whichever occur first.; Drug: Rebif® new formulation (RNF); Participants who converted to CDMS during ITP entered in open-label maintenance period (OLMP) and received RNF subcutaneously at a dose of 44 microgram (mcg) three times a week. Participants who converted to CDMS during long-term follow-up (LTFU) period, received RNF subcutaneously at a dose of 44 mcg three times a week.
Placebo Comparator: Placebo (ITP); Placebo matched to cladribine tablets administered over a course of 5 consecutive days at Weeks 1, 5, 9, 13, 48 and 52 during the ITP of 96 weeks or until CDMS conversion, whichever occurred first.	Drug: Rebif® new formulation (RNF); Participants who converted to CDMS during ITP entered in open-label maintenance period (OLMP) and received RNF subcutaneously at a dose of 44 microgram (mcg) three times a week. Participants who converted to CDMS during long-term follow-up (LTFU) period, received RNF subcutaneously at a dose of 44 mcg three times a week.; Drug: Placebo; Placebo matched to cladribine tablets were administered.
Experimental: Cladribine 5.25 mg/kg, Rebif (OLMP); Participants who received cladribine 5.25 mg/kg and converted to CDMS during ITP entered in open-label maintenance period (OLMP) and received Rebif® new formulation (RNF) subcutaneously at a dose of 44 microgram (mcg) three times a week for up to 96 weeks. Due to trial termination, the OLMP duration was reduced for some participants.	Drug: Cladribine; Cladribine tablets were administered until CDMS conversion, whichever occur first.; Drug: Rebif® new formulation (RNF); Participants who converted to CDMS during ITP entered in open-label maintenance period (OLMP) and received RNF subcutaneously at a dose of 44 microgram (mcg) three times a week. Participants who converted to CDMS during long-term follow-up (LTFU) period, received RNF subcutaneously at a dose of 44 mcg three times a week.
Experimental: Cladribine 3.5 mg/kg, Rebif (OLMP); Participants who received cladribine 3.5 mg/kg and converted to CDMS during ITP entered in OLMP and received RNF subcutaneously at a dose of 44 mcg three times a week for up to 96 weeks. Due to trial termination, the OLMP duration was reduced for some participants.	Drug: Cladribine; Cladribine tablets were administered until CDMS conversion, whichever occur first.; Drug: Rebif® new formulation (RNF); Participants who converted to CDMS during ITP entered in open-label maintenance period (OLMP) and received RNF subcutaneously at a dose of 44 microgram (mcg) three times a week. Participants who converted to CDMS during long-term follow-up (LTFU) period, received RNF subcutaneously at a dose of 44 mcg three times a week.
Experimental: Placebo, Rebif (OLMP); Participants who received placebo and converted to CDMS during ITP entered in OLMP and received RNF subcutaneously at a dose of 44 mcg three times a week for up to 96 weeks. Due to trial termination, the OLMP duration was reduced for some participants.	Drug: Placebo; Placebo matched to cladribine tablets were administered.
Experimental: Cladribine 5.25 mg/kg, Rebif, Cladribine 3.5 mg/kg (LTFU); Participants who received cladribine 5.25 mg/kg and did not convert to CDMS during ITP, entered in long-term follow-up (LTFU) period. Participants who converted to McDonald multiple sclerosis (MS) during ITP or during LTFU period received open-label cladribine tablets (3.5 mg/kg) during LTFU period. Participants who converted to CDMS during LTFU received RNF subcutaneously at a dose of 44 mcg three times a week for the remaining LTFU period. Under the original study design, total duration of LTFU period was up to 96 weeks. The LTFU duration was reduced due to trial termination. Following the notice of trial termination, no further open label cladribine treatment was administered during the LTFU.	Drug: Cladribine; Cladribine tablets were administered until CDMS conversion, whichever occur first.; Drug: Rebif® new formulation (RNF); Participants who converted to CDMS during ITP entered in open-label maintenance period (OLMP) and received RNF subcutaneously at a dose of 44 microgram (mcg) three times a week. Participants who converted to CDMS during long-term follow-up (LTFU) period, received RNF subcutaneously at a dose of 44 mcg three times a week.
Experimental: Cladribine 3.5 mg/kg, Rebif, Cladribine 3.5 mg/kg (LTFU); Participants who received cladribine 3.5 mg/kg and did not convert to CDMS during ITP, entered in long-term follow-up (LTFU) period. Participants who converted to McDonald multiple sclerosis (MS) during ITP or during LTFU period received open-label cladribine tablets (3.5 mg/kg) during LTFU period. Participants who converted to CDMS during LTFU received RNF subcutaneously at a dose of 44 mcg three times a week for the remaining LTFU period. Under the original study design, total duration of LTFU period was up to 96 weeks. The LTFU duration was reduced due to trial termination. Following the notice of trial termination, no further open label cladribine treatment was administered during the LTFU.	Drug: Cladribine; Cladribine tablets were administered until CDMS conversion, whichever occur first.; Drug: Rebif® new formulation (RNF); Participants who converted to CDMS during ITP entered in open-label maintenance period (OLMP) and received RNF subcutaneously at a dose of 44 microgram (mcg) three times a week. Participants who converted to CDMS during long-term follow-up (LTFU) period, received RNF subcutaneously at a dose of 44 mcg three times a week.
Experimental: Placebo, Rebif, Cladribine 3.5 mg/kg (LTFU); Participants who received placebo and did not convert to CDMS during ITP, entered in long-term follow-up (LTFU) period. Participants who converted to McDonald multiple sclerosis (MS) during ITP or during LTFU period received open-label cladribine tablets (3.5 mg/kg) during LTFU period. Participants who converted to CDMS during LTFU received RNF subcutaneously at a dose of 44 mcg three times a week for the remaining LTFU period. Under the original study design, total duration of LTFU period was up to 96 weeks. The LTFU duration was reduced due to trial termination. Following the notice of trial termination, no further open label cladribine treatment was administered during the LTFU.	Drug: Placebo; Placebo matched to cladribine tablets were administered.
Experimental: Cladribine 5.25 mg/kg, Rebif (LTFU); Participants who received cladribine 5.25 mg/kg and did not convert to CDMS during ITP, entered in LTFU period. Participants who did not convert to McDonald MS during ITP did not receive any treatment during LTFU period. Participants who converted to CDMS during LTFU period received RNF subcutaneously at a dose of 44 mcg three times a week for the remaining LTFU period. Under the original study design, total duration of LTFU period was up to 96 weeks. The LTFU duration was reduced due to trial termination. Following the notice of trial termination, no further open label cladribine treatment was administered during the LTFU.	Drug: Cladribine; Cladribine tablets were administered until CDMS conversion, whichever occur first.; Drug: Rebif® new formulation (RNF); Participants who converted to CDMS during ITP entered in open-label maintenance period (OLMP) and received RNF subcutaneously at a dose of 44 microgram (mcg) three times a week. Participants who converted to CDMS during long-term follow-up (LTFU) period, received RNF subcutaneously at a dose of 44 mcg three times a week.
Experimental: Cladribine 3.5 mg/kg, Rebif (LTFU); Participants who received cladribine 3.5 mg/kg and did not convert to CDMS during ITP, entered in LTFU period. Participants who did not convert to McDonald MS during ITP did not receive any treatment during LTFU period. Participants who converted to CDMS during LTFU period received RNF subcutaneously at a dose of 44 mcg three times a week for the remaining LTFU period. Under the original study design, total duration of LTFU period was up to 96 weeks. The LTFU duration was reduced due to trial termination. Following the notice of trial termination, no further open label cladribine treatment was administered during the LTFU.	Drug: Cladribine; Cladribine tablets were administered until CDMS conversion, whichever occur first.; Drug: Rebif® new formulation (RNF); Participants who converted to CDMS during ITP entered in open-label maintenance period (OLMP) and received RNF subcutaneously at a dose of 44 microgram (mcg) three times a week. Participants who converted to CDMS during long-term follow-up (LTFU) period, received RNF subcutaneously at a dose of 44 mcg three times a week.
Experimental: Placebo, Rebif (LTFU); Participants who received placebo and did not convert to CDMS during ITP, entered in LTFU period. Participants who did not convert to McDonald MS during ITP did not receive any treatment during LTFU period. Participants who convert to CDMS during LTFU period received RNF subcutaneously at a dose of 44 mcg three times a week for the remaining LTFU period. Under the original study design, total duration of LTFU period was up to 96 weeks. The LTFU duration was reduced due to trial termination. Following the notice of trial termination, no further open label cladribine treatment was administered during the LTFU.	Drug: Placebo; Placebo matched to cladribine tablets were administered.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ITP: Time to Clinically Definite Multiple Sclerosis (CDMS) Conversion Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With CDMS	CDMS according to the Poser criteria is defined as the occurrence of a second attack or a sustained increase in the expanded disability status scale (EDSS) Score. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to Multiple Sclerosis [MS]) was calculated. Sustained EDSS progression was defined as an increase in the EDSS score of greater than or equal to (>=) 1 point if baseline EDSS was between >= 1.0 and less than or equal to (=<) 4.5; or >= 1.5 points if baseline EDSS was 0, or >= 0.5 if baseline EDSS >= 5.0 over a period of at least 3 months. Kaplan-Meier estimates were provided for of the cumulative (cum.) percentage (%) of participants with CDMS over time. The probability of patients remaining event-free over time (from randomization) in each of the three treatment groups was displayed in the form of survival curves estimated using the non-parametric Kaplan-Meier method.	ITP: Baseline up to Week 96

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ITP: Time to Develop Multiple Sclerosis (MS) Conversion According to the Revised McDonald Criteria (2005) Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With McDonald MS	The McDonald criteria use dissemination in time and space established by magnetic resonance imaging (MRI) findings to provide a clinical diagnosis for MS. Dissemination in time is established by a new time constant 2 (T2) or gadolinium enhanced (Gd+) lesion found on a repeat MRI. Dissemination in space is established by the presence of any 3 of the following: 1 Gd+ lesion or 9 T2 bright lesions if there is no enhancement; greater than or equal to 1 infratentorial lesion; greater than or equal to 1 juxtacortical lesion; greater than or equal to 3 periventricular lesions. Kaplan-Meier estimates were provided for the cum. percentage (%) of participants with McDonald MS over time.	ITP: Baseline up to Week 96
ITP: Number of Combined Unique Active (CUA) Lesions, New or Enlarging Time Constant 2 (T2) Lesions, and New or Persisting Time Constant 1 (T1) Gadolinium Enhanced (Gd+) Lesions Per Participant Per Scan	Number of CUA lesions, new or enlarging T2 lesions, and new or persisting T1 Gd+ lesions were measured by using magnetic resonance imaging (MRI) scans.	ITP: Baseline up to Week 96
OLMP: Time to 3 Month Confirmed Expanded Disability Status Scale (EDSS) Progression From Randomization Represented by Kaplan-Meier Estimates of Probability of Disability Progression	EDSS progression is based on a standardized neurological exam and focuses on symptoms that commonly occur in Multiple Sclerosis (MS). Overall scores ranges from 0.0 (normal) to 10.0 (death due to MS). A sustained progression on EDSS score was defined as an EDSS progression confirmed into two consecutive assessment. Probability of disability progression at different time points was estimated using Kaplan-Meier method on the time to disability progression defined as the time from randomization to first EDSS increase.	OLMP: Day 1, 90, 180, 270, 360, 450, 540, 630, 720 and 810
LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Time to Conversion to Multiple Sclerosis (MS) According to the 2005 McDonald Criteria	The McDonald criteria use dissemination in time and space established by magnetic resonance imaging (MRI) findings to provide a clinical diagnosis for MS. Dissemination in time is established by a new time constant 2 (T2) or gadolinium enhanced (Gd+) lesion found on a repeat MRI.	Time from Randomization up to 1217 days
LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) According to Poser Criteria	CDMS according to the Poser criteria is defined as the occurrence of a second attack or a sustained increase in the expanded disability status scale (EDSS) Score. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. Sustained EDSS progression was defined as an increase in the EDSS score of greater than or equal to (>=) 1 point if baseline EDSS was between >= 1.0 and less than or equal to (=<) 4.5; or >= 1.5 points if baseline EDSS was 0, or >= 0.5 if baseline EDSS >= 5.0 over a period of at least 3 months.	Time from Randomization up to 1217 days
LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) According to Poser Criteria	CDMS according to the Poser criteria is defined as the occurrence of a second attack or a sustained increase in the expanded disability status scale (EDSS) Score. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. Sustained EDSS progression was defined as an increase in the EDSS score of greater than or equal to (>=) 1 point if baseline EDSS was between >= 1.0 and less than or equal to (=<) 4.5; or >= 1.5 points if baseline EDSS was 0, or >= 0.5 if baseline EDSS >= 5.0 over a period of at least 3 months.	Time from Randomization up to 1217 days
ITP: Percentage of Participants Converting to Clinically Definite Multiple Sclerosis (CDMS) as Per Poser Criteria	Clinically definite multiple sclerosis (CDMS) according to the Poser criteria is defined as the occurrence of a second attack or a sustained increase in the expanded disability status scale (EDSS) Score. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. Sustained EDSS progression was defined as an increase in the EDSS score of greater than or equal to (>=) 1 point if baseline EDSS was between >= 1.0 and less than or equal to (=<) 4.5; or >= 1.5 points if baseline EDSS was 0, or >= 0.5 if baseline EDSS >= 5.0 over a period of at least 3 months. The percentage of participants who converted to CDMS are reported here.	ITP: Baseline up to week 96
ITP: Percentage of Participants Converting to McDonald Multiple Sclerosis (MS) (2005)	Percentage of participants converting to mcDonald multiple sclerosis (2005) were reported.	ITP: Baseline up to week 96
ITP: Number of New or Persisting Gd-enhanced Lesions	Number of new or persisting Gd-enhanced lesions were measured by using magnetic resonance imaging (MRI) scans.	ITP: Week 13, 24, 36, 48, 60, 72, 84 and 96
OLMP: Number of New or Persisting Gd-enhanced Lesions	Number of new or persisting Gd-Enhanced lesions were measured by using magnetic resonance imaging (MRI) scans.	OLMP: Baseline, Week 24, 48, 72 and 96
LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Number of New or Persisting Gd-enhanced Lesions	Number of new or persisting Gd-Enhanced lesions were measured by using magnetic resonance imaging (MRI) scans.	LTFU: Baseline, Week 13, 24 and 36
LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Number of New or Persisting Gd-enhanced Lesions	Number of new or persisting Gd-Enhanced lesions were measured by using magnetic resonance imaging (MRI) scans.	LTFU: Baseline, Week 13, 24, 36 and 48
ITP: Number of New or Enlarging T2 Lesions	Number of new or enlarging T2 lesions were measured by using magnetic resonance imaging (MRI) scans.	ITP: Week 13, 24, 36, 48, 60, 72, 84 and 96
OLMP: Number of New or Enlarging T2 Lesions	Number of new or enlarging T2 lesions were measured by using magnetic resonance imaging (MRI) scans.	OLMP: Baseline, Week 24, 48, 72 and 96
LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Number of New or Enlarging T2 Lesions	Number of new or enlarging T2 Lesions were measured by using magnetic resonance imaging (MRI) scans.	LTFU: Baseline, Week 13, 24 and 36
LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Number of New or Enlarging T2 Lesions	Number of new or enlarging T2 lesions were measured by using magnetic resonance imaging (MRI) scans.	LTFU: Baseline, Week 13, 24, 36 and 48
ITP: Number of Combined Unique Active (CUA) Magnetic Resonance Imaging (MRI) Lesions	Number of CUA lesions were measured by using magnetic resonance imaging (MRI) scans.	ITP: Week 13, 24, 36, 48, 60, 72, 84 and 96
OLMP: Number of Combined Unique Active (CUA) Magnetic Resonance Imaging (MRI) Lesions	Number of combined unique active (CUA) lesions were measured by using magnetic resonance imaging (MRI) scans.	OLMP: Baseline, Week 24, 48, 72 and 96
LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Number of Combined Unique Active (CUA) Magnetic Resonance Imaging (MRI) Lesions	Number of CUA MRI lesions were measured by using magnetic resonance imaging (MRI) scans.	LTFU: Baseline, Week 13, 24 and 36
LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Number of Combined Unique Active (CUA) Magnetic Resonance Imaging (MRI) Lesions	Number of CUA lesions were measured by using magnetic resonance imaging (MRI) scans.	LTFU: Baseline, Week 13, 24, 36 and 48
ITP: Change From Baseline in Volume of T1 Gd-Enhanced Lesions	Change in volume of T1 Gd-Enhanced lesions was measured by using magnetic resonance imaging (MRI) scans.	ITP: Baseline, Week 96
OLMP: Mean Volume of T1 Gd-Enhanced Lesions and Changes From Baseline in Volume of T1 Gd-Enhanced Lesions	Volume of T1 Gd-Enhanced lesions was measured by using magnetic resonance imaging (MRI) scans.	OLMP: Baseline, Week 24, 48, 72 and 96
LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Mean Volume of T1 Gd-Enhanced Lesions and Changes From Baseline in Volume of T1 Gd-Enhanced Lesions	Volume of T1 Gd-Enhanced lesions was measured by using magnetic resonance imaging (MRI) scans.	LTFU: Baseline, Week 13, 24 and 36
LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Mean Volume of T1 Gd-Enhanced Lesions and Changes From Baseline in Volume of T1 Gd-Enhanced Lesions	Volume of T1 Gd-Enhanced lesions was measured by using magnetic resonance imaging (MRI) scans.	LTFU: Baseline, Week 13, 24, 36 and 48
ITP: Changes From Baseline in Volume of T2 Lesions	Change in volume of T2 lesions from baseline was measured by using magnetic resonance imaging (MRI) scans.	ITP: Baseline, Week 48 and 96
OLMP: Mean Volume of T2 Lesions and Changes From Baseline in Volume of T2 Lesions	Volume of T2 lesions was measured by using magnetic resonance imaging (MRI) scans.	OLMP: Baseline, Week 48 and 96
LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Mean Volume of T2 Lesions	Volume of T2 lesions was measured by using magnetic resonance imaging (MRI) scans.	LTFU: Baseline (Day 1)
LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Mean Volume of T2 Lesions and Changes From Baseline in Volume of T2 Lesions	Volume of T2 lesions was measured by using magnetic resonance imaging (MRI) scans.	Baseline, Week 48
ITP: Number of T1 Hypointense Lesions	Number of T1 Hypointense lesions were measured by using magnetic resonance imaging (MRI) scans.	ITP: Baseline, Week 48 and 96
OLMP: Number of T1 Hypointense Lesions	Number of T1 Hypointense lesions were measured by using magnetic resonance imaging (MRI) scans.	OLMP: Baseline, Week 48 and 96
LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Number of T1 Hypointense Lesions	Number of T1 Hypointense lesions were measured by using magnetic resonance imaging (MRI) scans.	LTFU: Baseline (Day 1)
LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Number of T1 Hypointense Lesions	Number of T1 Hypointense lesions were measured by using magnetic resonance imaging (MRI) scans.	LTFU: Baseline, Week 48
ITP: Percentage of Participants With no New or Persisting T1 Gd-Enhanced Lesions	T1 Gd-enhanced lesions were measured by using magnetic resonance imaging (MRI) scans. Percentage of participants with no new or persisting T1 Gd-enhanced lesions were reported.	ITP: Baseline up to Week 96
OLMP: Percentage of Participants With no New or Persisting T1 Gd-Enhanced Lesions	T1 Gd-enhanced lesions were measured by using magnetic resonance imaging (MRI) scans. Percentage of participants with no new or persisting T1 Gd-enhanced lesions were reported.	OLMP: Baseline up to Week 96
LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Percentage of Participants With no New or Persisting T1 Gd-Enhanced Lesions	T1 Gd-enhanced lesions were measured by using magnetic resonance imaging (MRI) scans. Percentage of participants with no new or persisting T1 Gd-enhanced lesions were reported.	LTFU: Baseline up to Week 48
LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Percentage of Participants With no New or Persisting T1 Gd-Enhanced Lesions	T1 Gd-enhanced lesions were measured by using magnetic resonance imaging (MRI) scans. Percentage of participants with no new or persisting T1 Gd-enhanced lesions were reported.	Baseline up to Week 48
ITP: Percentage of Participants With no New or Enlarging T2 Lesions	T2 lesions were measured by using magnetic resonance imaging (MRI) scans. Percentage of participants with no new or enlarging T2 lesions were reported.	ITP: Baseline up to Week 96
OLMP: Percentage of Participants With no New or Enlarging T2 Lesions	T2 Gd-enhanced lesions were measured by using magnetic resonance imaging (MRI) scans. Percentage of participants with no new or enlarging T2 Lesions were reported.	OLMP: Baseline up to 96
LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Percentage of Participants With no New or Enlarging T2 Lesions	Enlarging T2 Lesions were measured by using magnetic resonance imaging (MRI) scans. Percentage of participants with no New or Enlarging T2 Lesions were reported.	Baseline up to Week 48
LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Percentage of Participants With no New or Enlarging T2 Lesions	Enlarging T2 lesions were measured by using magnetic resonance imaging (MRI) scans. Percentage of participants with no New or Enlarging T2 lesions were reported.	LTFU: Baseline up to Week 48
ITP: Percent Change From Baseline in Brain Volume	Brain volume was measured by using magnetic resonance imaging (MRI) scans. Percent change from baseline in brain volume at Week 48 and 96 was reported.	ITP: Baseline, Week 48 and 96
OLMP: Percent Change From Baseline in Brain Volume	Brain volume was measured by using magnetic resonance imaging (MRI) scans. Percent change from baseline in brain volume at Week 48 and 96 was reported.	OLMP: Baseline, Week 48 and 96
OLMP: Number of Relapses	Relapse was defined as new, worsening or recurrent neurological symptoms attributed to multiple sclerosis that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days.	Baseline up to Week 96
LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Number of Relapses	Relapse was defined as new, worsening or recurrent neurological symptoms attributed to multiple sclerosis that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days.	Baseline up to Week 48
LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Number of Relapses	Relapse was defined as new, worsening or recurrent neurological symptoms attributed to multiple sclerosis that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days.	Baseline up to Week 48
OLMP: Annualized Relapse Rate	The annualized relapse rate for each treatment group was the mean of the annualized relapse rates for all the participants in the group, calculated as the total number of confirmed relapses divided by the total number of days on study multiplied by 365.25. Where, Relapse was defined as new, worsening or recurrent neurological symptoms attributed to multiple sclerosis that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days.	Baseline up to Week 96
OLMP: Percentage of Relapse-Free Participants	Relapse was defined as new, worsening or recurrent neurological symptoms attributed to multiple sclerosis that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days. Percentage of relapse-free participants were reported.	Baseline up to Week 96
ITP: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs	An AE was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered. SAE: Any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was a medically important condition. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs include both Serious TEAEs and non-serious TEAEs. Number of Participants with TEAEs and serious TEAEs were reported.	ITP: Baseline up to Week 96

Collaborators and Investigators

• Sponsor: EMD Serono Research & Development Institute, Inc.
• Investigators: Study Director: Bettina Stubinski, MD, Merck Serono S.A., Geneva

Publications and helpful links

General Publications

• Giovannoni G, Galazka A, Schick R, Leist T, Comi G, Montalban X, Damian D, Dangond F, Cook S. Pregnancy Outcomes During the Clinical Development Program of Cladribine in Multiple Sclerosis: An Integrated Analysis of Safety. Drug Saf. 2020 Jul;43(7):635-643. doi: 10.1007/s40264-020-00948-x.
• Oh J, Walker B, Giovannoni G, Jack D, Dangond F, Nolting A, Aldridge J, Lebson LA, Leist TP. Side effects that occurred early in people with multiple sclerosis during the first year of treatment with cladribine tablets: a plain language summary. Neurodegener Dis Manag. 2022 Feb 1;12(1):1-7. doi: 10.2217/nmt-2021-0041. Epub 2022 Jan 12.
• Giovannoni G, Coyle PK, Vermersch P, Walker B, Aldridge J, Nolting A, Galazka A, Lemieux C, Leist TP. Integrated Lymphopenia Analysis in Younger and Older Patients With Multiple Sclerosis Treated With Cladribine Tablets. Front Immunol. 2021 Dec 24;12:763433. doi: 10.3389/fimmu.2021.763433. eCollection 2021.
• Freedman MS, Leist TP, Comi G, Cree BA, Coyle PK, Hartung HP, Vermersch P, Damian D, Dangond F. The efficacy of cladribine tablets in CIS patients retrospectively assigned the diagnosis of MS using modern criteria: Results from the ORACLE-MS study. Mult Scler J Exp Transl Clin. 2017 Oct 9;3(4):2055217317732802. doi: 10.1177/2055217317732802. eCollection 2017 Oct-Dec.
• Leist TP, Comi G, Cree BA, Coyle PK, Freedman MS, Hartung HP, Vermersch P, Casset-Semanaz F, Scaramozza M; oral cladribine for early MS (ORACLE MS) Study Group. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurol. 2014 Mar;13(3):257-67. doi: 10.1016/S1474-4422(14)70005-5. Epub 2014 Feb 4.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): December 31, 2008
• Primary Completion (Actual): July 31, 2011
• Study Completion (Actual): April 30, 2012

Study Registration Dates

• First Submitted: July 30, 2008
• First Submitted That Met QC Criteria: July 30, 2008
• First Posted (Estimate): July 31, 2008

Study Record Updates

• Last Update Posted (Actual): March 22, 2021
• Last Update Submitted That Met QC Criteria: February 24, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Multiple Sclerosis; Clinically Isolated Syndrome (CIS); Early MS
• 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; Physiological Effects of Drugs; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Cladribine
• Other Study ID Numbers: 28821