Oral Cladribine in Early Multiple Sclerosis (MS)

EMD Serono Research & Development Institute, Inc.617 enrolled

Overview

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.

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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.

Time frame: ITP: Baseline up to Week 96

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline, Week 48

ITP: Number of T1 Hypointense Lesions

Number of T1 Hypointense lesions were measured by using magnetic resonance imaging (MRI) scans.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline up to Week 96

LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Number of Relapses

Time frame: Baseline up to Week 48

LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Number of Relapses

Time frame: 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.

Time frame: Baseline up to Week 96

OLMP: Percentage of Relapse-Free Participants

Time frame: 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.

Time frame: ITP: Baseline up to Week 96

Oral Cladribine in Early Multiple Sclerosis (MS)

Overview

Conditions

Interventions

Eligibility

Locations (158)

Outcomes

Primary Outcomes

Secondary Outcomes