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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00725985
First Posted: July 31, 2008
Last Update Posted: October 3, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
EMD Serono
  Purpose
A randomized, double-blind, clinical trial to assess the safety and efficacy of two doses of oral cladribine versus 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 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 subjects with first clinical demyelinating event at high risk of converting to MS.

Condition Intervention Phase
Multiple Sclerosis Drug: Cladribine Drug: Placebo Drug: Rebif® new formulation (RNF) Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, 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 Clinically Definite Multiple Sclerosis (CDMS) Conversion Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With CDMS [ Time Frame: Baseline up to Week 96 ]
    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. 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.


Secondary Outcome Measures:
  • 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 [ Time Frame: Baseline up to Week 96 ]
    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. % of participants with McDonald MS over time.

  • 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 [ Time Frame: Week 96 ]
    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.

  • Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to Week 96 ]
    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. Number of participants with AEs includes number of participants with both serious adverse events (SAEs) and non-SAEs.


Enrollment: 617
Actual Study Start Date: December 31, 2008
Study Completion Date: April 30, 2012
Primary Completion Date: July 31, 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cladribine 5.25 mg/kg Drug: Cladribine
Cladribine tablets will be administered as cumulative dose of 0.875 milligram per kilogram (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 mg/kg during the initial treatment period (ITP) of 96 weeks or until CDMS conversion, whichever occur first
Drug: Rebif® new formulation (RNF)
Participants who will convert to CDMS during ITP will enter in open-label maintenance period (OLMP) and receive RNF subcutaneously at a dose of 44 microgram (mcg) three times a week. Participants who will convert to CDMS during long-term follow-up (LTFU) period, will also receive RNF subcutaneously at a dose of 44 mcg three times a week
Experimental: Cladribine 3.5 mg/kg Drug: Cladribine
Cladribine tablets will be 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 will be 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 occur first
Drug: Rebif® new formulation (RNF)
Participants who will convert to CDMS during ITP will enter in open-label maintenance period (OLMP) and receive RNF subcutaneously at a dose of 44 microgram (mcg) three times a week. Participants who will convert to CDMS during long-term follow-up (LTFU) period, will also receive RNF subcutaneously at a dose of 44 mcg three times a week
Placebo Comparator: Placebo Drug: Placebo
Placebo matched to cladribine tablets will be 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 occur first
Drug: Rebif® new formulation (RNF)
Participants who will convert to CDMS during ITP will enter in open-label maintenance period (OLMP) and receive RNF subcutaneously at a dose of 44 microgram (mcg) three times a week. Participants who will convert to CDMS during long-term follow-up (LTFU) period, will also receive RNF subcutaneously at a dose of 44 mcg three times a week

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 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 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, subjects 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 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

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female between 18 and 55 years old, inclusive
  • Weighed between 40 to 120 kilogram (kg), inclusive
  • Subject 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
  • Subject 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
  • Subject has EDSS 0 - 5.0 at Screening
  • Subject 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
  • Subject 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, subjects should use a hormonal contraceptive or intrauterine device for the duration of the trial)
  • Male subjects 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
  • Subject has to provide written informed consent voluntarily, including, for United states of America (USA), subject authorization under Health Insurance Portability and Accountability Act (HIPAA), prior to any study-related procedure that is not part of normal medical care
  • Subject 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:

  • Subject has a diagnosis of MS (per McDonald criteria, 2005)
  • Subject has any other disease that could better explain the subject's signs and symptoms
  • Subject has complete transverse myelitis or bilateral optic neuritis
  • Subject using or has used any other approved MS disease modifying drug (DMD)
  • Subject has used any investigational drug or undergone an experimental procedure within 12 weeks prior to Study day 1
  • Subject 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.
  • Subject 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
  • Subject suffered from current autoimmune disease other than MS
  • Subject 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 subject or could affect compliance with the study protocol
  • Subject 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
  • Subject has a history of seizures not adequately controlled by medications
  • Subject has a known allergy to cladribine, interferon-beta, the excipient(s) of the study medications, or to gadolinium- diethylenetriamine penta-acetic acid (DTPA)
  • Subject 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])
  • Subject has a history of chronic or clinically significant hematological abnormalities
  • Subject 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).
  • Subject has previously been screened in this study (signed an informed consent) and then withdrawn
  • Subject 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
  • Subject has received experimental MS treatment
  • Subject has a history of alcohol or drug abuse
  • Subject has intolerance or any contraindication to both paracetamol (acetaminophen) and ibuprofen
  • Subject has inability to administer subcutaneous injections either by self or by caregiver
  • Subject 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)
  • Subject has a positive stool hemoccult test at Screening
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00725985


  Show 159 Study Locations
Sponsors and Collaborators
EMD Serono
Investigators
Study Director: Bettina Stubinski, MD Merck Serono S.A., Geneva
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: EMD Serono
ClinicalTrials.gov Identifier: NCT00725985     History of Changes
Other Study ID Numbers: 28821
First Submitted: July 30, 2008
First Posted: July 31, 2008
Results First Submitted: June 11, 2013
Results First Posted: October 10, 2013
Last Update Posted: October 3, 2017
Last Verified: September 2017

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

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