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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
EMD Serono
ClinicalTrials.gov Identifier:
NCT00725985
First received: July 30, 2008
Last updated: June 21, 2012
Last verified: June 2012
  Purpose

A randomized, double-blind, clinical trial to assess the safety and efficacy of two doses of oral cladribine vs. placebo in subjects who had a first clinical demyelinating event (clinically isolated syndrome). Subjects 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 2 dosage regimens of oral cladribine vs. placebo on the time to conversion to Multiple Sclerosis (MS) (from randomization) according to the Poser criteria in subjects with a first clinical demyelinating event at high risk of converting to MS.


Condition Intervention Phase
Multiple Sclerosis
Drug: Oral cladribine
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by EMD Serono:

Primary Outcome Measures:
  • Time to conversion to clinically definite MS (from randomization), according to the Poser Criteria, defined by either a 2nd attack or a sustained increase (³1.5 points) in the EDSS score which will be determined during the initial treatment period. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • The single primary endpoint for the overall study, which will be determined during the Initial Treatment Period, is time to conversion to MS (from randomization), according to the revised McDonald criteria (2005). [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Enrollment: 617
Study Start Date: October 2008
Study Completion Date: June 2012
Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Low-dose oral cladribine
Drug: Oral cladribine
Low-dose oral cladribine - 1.75 mg/kg/year. Dosed once/week for 4 weeks at the start of a cycle.
Experimental: 2
High-dose oral cladribine
Drug: Oral cladribine
Low-dose oral cladribine - 3.5 mg/kg/year. Dosed once/week for 4 weeks at the start of a cycle.
Placebo Comparator: 3
Placebo
Drug: Placebo
Placebo will be administered to subjects. The placebo looks exactly like the active treatment.

Detailed Description:

This will be a randomized, double blind, three-arm, placebo-controlled, multi-centre trial to evaluate the safety and efficacy of oral cladribine versus placebo in the treatment of subjects who have sustained a first clinical demyelinating event within 75 days prior to the Screening. Subjects must have a minimum of 2 clinically silent lesions on the Screening 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, subjects will then proceed from the Initial Treatment Period to either the Maintenance Treatment Period (with open-label interferon-beta treatment) or Long-Term Follow-up Treatment 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 Initial Treatment Period, is time to conversion to MS (from randomization), according to the Poser criteria.

For every subject, 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.

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Be male or female between 18 and 55 years old, inclusive (see Appendix C)
  2. Must weigh between 40-120 kg, inclusive
  3. 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, other than a paresthesia, vegetative or cerebral dysfunction
  4. Has at least two clinically silent lesions on the T2-weighted MRI scan, at screening, with a size of at least 3 mm, at least one of which is ovoid or periventricular or infratentorial on screening MRI
  5. Has EDSS 0 - 5.0 for at least one time point during the screening period before start of treatment with blinded study medication
  6. Have no medical history or evidence of latent tuberculosis infection (LTBI) or active tubercular disease (TB), as evidenced by TB skin test and/or chest X-ray
  7. Hematological parameters must be normal (as defined by the central lab)
  8. 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 (i.e. less than1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence or vasectomized partner, or
    • be post-menopausal or surgically sterilized [Note: for Danish sites only, subjects should use a hormonal contraceptive or intrauterine device for the duration of the trial]
  9. If male, he must be willing to use contraception to avoid contributing to pregnancies throughout the entire duration of the study and for 90 days following the last dose of study medication
  10. Be willing and able to comply with study procedures for the duration of the study Voluntarily provide written informed consent, including, for USA, subject authorization under Health Insurance Portability and Accountability Act (HIPAA) (see Appendix J), prior to any study-related procedure that is not part of normal medical care, and with the understanding that the subject may withdraw consent at any time without prejudice to their future medical care.

Exclusion Criteria:

  1. Subject has a diagnosis of multiple sclerosis (per McDonald criteria, 2005)
  2. Subject has any other disease that could better explain the subject's signs and symptoms
  3. Subject has complete transverse myelitis or bilateral optic neuritis
  4. Subject uses or has used any other approved MS disease modifying drug (DMD)
  5. Subject has used any investigational drug or undergone an experimental procedure within 12 weeks prior to SD1 with the exclusion of MS drug
  6. Subject received oral or systemic corticosteroids or ACTH within 30 days prior to SD1
  7. Subject has abnormal total bilirubin, or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or alkaline phosphatase
  8. Subject suffers from current autoimmune disease
  9. Subject suffers from psychiatric illness (including history of, or current, severe depressive disorders and/or suicidal ideation) that in the opinion of the investigator creates undue risk to the subject or could affect compliance with the study protocol
  10. Subject suffers from major medical illness such as cardiac (e.g. 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
  11. Subject has a history of seizures
  12. Subject has a known allergy to cladribine, IFN-beta, the excipient(s) of the study medications, or to gadolinium-DTPA
  13. Has any renal condition that would preclude the administration of gadolinium (e.g. acute or chronic severe renal insufficiency (GFR < 30 mL/min/1.73m2)
  14. Has a history of chronic or clinically significant hematological abnormalities
  15. History of active or chronic infectious disease or any disease that compromises immune function (e.g. HIV+, HTLV-1, Lyme disease, LTBI or TB, insulin-dependent diabetes).
  16. Subject has previously been screened in this study thus signed an informed consent and than withdrawn
  17. Subject has received any immunomodulatory or immunosuppressive therapy) at any time prior to Screening, 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 (e.g. natalizumab, alemtuzumab/Campath, anti-CD4), intravenous immunoglobulin G (IVIG), cytokines or anti-cytokine therapy
  18. Subject has received experimental MS treatment
  19. Subject has a history of alcohol or drug abuse
  20. Subject has intolerance or any contraindication to both paracetamol (acetaminophen) and ibuprofen
  21. Inability to administer subcutaneous injections either by self or by caregiver
  22. 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) Have a positive stool heme-occult test at Screening
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00725985

Locations
United States, Massachusetts
Research Site
Rockland, Massachusetts, United States
Korea, Republic of
Natonal Cancer Center, Department of Neurology,
Gyeonggi-do, 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
Department of Neurology, 50 Ilwon-dong, Gangnam-gu
Seoul, Korea, Republic of
Yonsei University Medical Center, Department of Neurology, Yonsei University Medical Center
Seoul, Korea, Republic of
Lebanon
American University of Beirut
Beirut, Lebanon
Russian Federation
Municipal Healthcare Institution "City Clinical Hospital #3"
Chelyabinsk, Russian Federation
State Healthcare Institution "Sverdlovsk Regional Clinical Hospital #1"
Ekaterinburg, Russian Federation
State Medical Institution "Republican Rehabilitation Clinic of Tatarstan Ministry of Health"
Kazan, Russian Federation
State Healthcare Institution "Kemerovo Regional Clinical Hospital"
Kemerovo, Russian Federation
State Medical Institution " Jursk Regional Clinical Hospital"
Kursk, Russian Federation
State Healthcare Institution "Kaluga Regional Hospital"
Laluga, 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
Moscow, Russian Federation
Moscow State Healthcare Institution City Clinical Hospital #11
Moscow, Russian Federation
Municipal Treatment Prophylactic Institution "City Hospital #33"
Nizhny Novgorod, Russian Federation
Federal State Institution " Siberian Reginal Medical Center of Roszdarv"
Novosibirsk, Russian Federation
State Healthcare Institution "Rostov Region Clinical Hospital"
Rostov-on-Don, Russian Federation
State Educational Institute of Higher Professional Education "Rostov State Medical University of Roszdrav"
Rostov-on-Don, 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
Saint-Petersburg, 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"
Samara, 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
Saratov, Russian Federation
Regional State Healthcare Institution "State Smolensk Region Clinical Hospital"
Smolensk, Russian Federation
St. Petersburg State Healthcare Institution "Multifield City Hospital #2"
St. Petersburg, Russian Federation
State Educational Institution of Higher Professional Education "Siberian State Medical University of Roszdrav"
Tomsk, Russian Federation
Closed joint-stock society Medical sanitary unit "Nephtaynik" based the hospital
Tyumen, Russian Federation
Vladimir Regional State Healthcare Institution "Regional Clinical Hospital"
Vladimir, Russian Federation
Municipal Healthcare Institution "Yaroslavi Clinical Hospital #8"
Yaroslavi, Russian Federation
Saudi Arabia
King Abdullah International Medical Research Center, King Saud Ben Abdulazziz University for Health Sciences, and National Guard Health Affairs
Riyadh, Saudi Arabia
Thailand
Northern Neuroscience Center, Faculty of Medicine Maharaj Nakorn Chiang Mai Hospital
Chiang Mai, Thailand
Ukraine
State Established "Institute of Neurology, Psychiatry and Narcology of the AMS of Ukraine", Depart of Neurinfections and Multiple Sclorosis
Kharkiv, Ukraine
Institue for Clinical Radiology of the State Establishment "Research Centre for Radiation Medicine of the AMS of Ukraino" Depart of Radiation Psychoneurology
Kylv, Ukraine
Vinnylsia Regional Psychoneurological Hosptial Named After O. I Yushchenko, Neurological Depart, Vinnytsia National Medical University Named After M. I. Pirogov, Chair of Neurology
Vinnytsia, Ukraine
Sponsors and Collaborators
EMD Serono
Investigators
Study Director: Bettina Stubinski, MD Merck Serono S.A., Geneva
  More Information

No publications provided

Responsible Party: EMD Serono
ClinicalTrials.gov Identifier: NCT00725985     History of Changes
Other Study ID Numbers: 28821
Study First Received: July 30, 2008
Last Updated: June 21, 2012
Health Authority: United States: Food and Drug Administration
Algeria: Ministry of Health
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Australia: Human Research Ethics Committee
Austria: Agency for Health and Food Safety
Belgium: Federal Agency for Medicinal Products and Health Products
Bulgaria: Ministry of Health
Canada: Health Canada
Chile: Comisión Nacional de Investigación Científica y Tecnológica
Croatia: Ministry of Health and Social Care
Czech Republic: State Institute for Drug Control
Estonia: The State Agency of Medicine
Finland: Finnish Medicines Agency
France: Ministry of Health
Germany: Federal Institute for Drugs and Medical Devices
Greece: National Organization of Medicines
India: Ministry of Health
Ireland: Ministry of Health
Italy: National Institute of Health
Korea: Food and Drug Administration
Lebanon: Ministry of Public Health
Lithuania: State Medicine Control Agency - Ministry of Health
Macedonia: Ethics Committee
Mexico: Ministry of Health
Norway: Norwegian Medicines Agency
Poland: Ministry of Health
Portugal: National Pharmacy and Medicines Institute
Romania: National Medicines Agency
Serbia and Montenegro: Agency for Drugs and Medicinal Devices
Singapore: Health Sciences Authority
Spain: Ministry of Health
Sweden: Medical Products Agency
Switzerland: Federal Office of Public Health
Taiwan: National Bureau of Controlled Drugs
Thailand: Food and Drug Administration
Turkey: Ministry of Health
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by EMD Serono:
Clinically Isolated Syndrome (CIS)
Early MS
Multiple Sclerosis

Additional relevant MeSH terms:
Multiple Sclerosis
Sclerosis
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Pathologic Processes
Cladribine
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on June 18, 2013