A Phase 2 Study of Cladribine Add-on to Interferon-beta (IFN-beta) Therapy in Multiple Sclerosis (MS) Subjects With Active Disease (ONWARD)

• Sponsor: EMD Serono Research & Development Institute, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00436826
• Collaborator: (none)
• Enrollment: 172
• Locations: 39
• Arms: 6
• Actual Duration (Months): 64
• Patients Per Site: 4.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The goal of this study was to evaluate the safety, tolerability and effectiveness of oral cladribine when taken in combination with Interferon-beta (IFN-beta) therapy for the treatment of multiple sclerosis (MS).

This study randomized around 200 participants from approximately 50 sites located world-wide, who have experienced at least one relapse while taking IFN-beta therapy within 48 weeks prior to Screening, irrespective of disability progression. Secondary progressive multiple sclerosis (SPMS) participants, who were still experiencing relapses, and participants who have received disease modifying drugs (DMDs), other than IFN-beta therapy, during their MS treatment history, but were currently on IFN-beta therapy and have experienced active MS symptoms (at least 1 relapse) during the 48 weeks prior to Screening, were enrolled.

Participants were randomized in a 2:1 fashion to receive up to 4 cycles of oral cladribine or matching placebo in combination with IFN-beta therapy. Participants who completed the double-blind portion of the study were invited to participate in an open-label extension phase of matching study design.

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis	Drug: Cladribine; Drug: Placebo; Drug: Interferon-beta (IFN-beta)	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 172 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase II, Multicenter, Randomized, Double Blind, Placebo Controlled, Safety, Tolerability and Efficacy Study of Add-on Cladribine Tablet Therapy With Interferon-beta (IFN-β) Treatment in Multiple Sclerosis Subjects With Active Disease
• Actual Study Start Date: Nov 30, 2006
• Actual Primary Completion Date: Sep 30, 2011
• Actual Study Completion Date: Mar 31, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cladribine 3.5 mg/kg, IFN-beta (DB period) Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Drug: Cladribine; Participants were administered with cladribine tablets orally as cumulative dose.; Drug: Interferon-beta (IFN-beta); Participants received IFN-beta therapy (Rebif® new formulation [RNF] 44 microgram [mcg] three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during both DB period of 96 weeks and OL extension period of 48 weeks.; Other Names: Avonex® Betaseron® RNF
Placebo Comparator: Placebo, IFN-beta (DB period) Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.	Drug: Placebo; Participants were administered with placebo orally.; Drug: Interferon-beta (IFN-beta); Participants received IFN-beta therapy (Rebif® new formulation [RNF] 44 microgram [mcg] three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during both DB period of 96 weeks and OL extension period of 48 weeks.; Other Names: Avonex® Betaseron® RNF
Experimental: Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the open label (OL) extension (Ext.) period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.	Drug: Cladribine; Participants were administered with cladribine tablets orally as cumulative dose.; Drug: Interferon-beta (IFN-beta); Participants received IFN-beta therapy (Rebif® new formulation [RNF] 44 microgram [mcg] three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during both DB period of 96 weeks and OL extension period of 48 weeks.; Other Names: Avonex® Betaseron® RNF
Placebo Comparator: Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) Participants who received placebo initially and completed DB period entered in the OL Ext. period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.	Drug: Cladribine; Participants were administered with cladribine tablets orally as cumulative dose.; Drug: Placebo; Participants were administered with placebo orally.; Drug: Interferon-beta (IFN-beta); Participants received IFN-beta therapy (Rebif® new formulation [RNF] 44 microgram [mcg] three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during both DB period of 96 weeks and OL extension period of 48 weeks.; Other Names: Avonex® Betaseron® RNF
Experimental: Cladribine 3.5 mg/kg, IFN-beta (Safety follow up) Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the OL ext. safety follow up period. In this period, participants who did not meet eligibility criteria received only IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.	Drug: Cladribine; Participants were administered with cladribine tablets orally as cumulative dose.; Drug: Interferon-beta (IFN-beta); Participants received IFN-beta therapy (Rebif® new formulation [RNF] 44 microgram [mcg] three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during both DB period of 96 weeks and OL extension period of 48 weeks.; Other Names: Avonex® Betaseron® RNF
Placebo Comparator: Placebo, IFN-beta (Safety follow up) Participants who received placebo initially and completed DB period entered in the OL ext. safety follow up period. In this period, participants who did not meet eligibility criteria received only IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.	Drug: Placebo; Participants were administered with placebo orally.; Drug: Interferon-beta (IFN-beta); Participants received IFN-beta therapy (Rebif® new formulation [RNF] 44 microgram [mcg] three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during both DB period of 96 weeks and OL extension period of 48 weeks.; Other Names: Avonex® Betaseron® RNF

Outcome Measures

Primary Outcome Measures

1. Double Blind Period: Percentage of Participants With Grade 3 or 4 (Common Terminology Criteria for Adverse Events [CTCAE] v 4.0) Hematological or Liver Toxicity [Baseline up to Week 96]

   Percentage of participants with Grade 3 or 4 CTCAE v 4.0 toxicity on the following hematology and liver function parameters were reported: lymphocytes, cluster of differentiation 4 (CD4) cell, neutrophils, white blood cells, hemoglobin, Alanine transaminase (ALT), Aspartate transaminase (AST), Platelets and Bilirubin. According to CTCAE v 4.0: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death.

2. Double Blind Period: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) in Infections and Infestations System Organ Class (SOC) [Baseline up to Week 96]

   An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. An AE was considered as 'treatment emergent' if it occurred after the first drug administration of each period or if it was present prior to drug administration but exacerbated after the drug administration.TEAEs were entered in infections and infestations SOC as per medical dictionary for regulatory activities (MedDRA) version 11.0

3. Double Blind Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs [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. An AE was considered as 'treatment emergent' if it occurred after the first drug administration of each period or if it was present prior to drug administration but exacerbated after the drug administration. TEAEs included both Serious TEAEs and non-serious TEAEs.

4. Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity [Baseline up to Week 96]

   Time to first Grade 3 or 4 hematological toxicity or liver toxicity (lymphocytes, cluster of differentiation 4 (CD4) cell, neutrophils, white blood cells, hemoglobin, Alanine transaminase (ALT), Aspartate transaminase (AST), Platelets and Bilirubin) were estimated using the Kaplan-Meier method. According to CTCAE v 4.0: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death. 10th and 20th percentiles estimated from Kaplan-Meier survival curve. Due to the small number of events, estimates from Kaplan-Meier survival curves could only be derived for lower percentiles. The median (50th percentile) could not be estimated if less than 50% of the participants had an event during the time of the study. Accordingly, lower percentiles are presented according to the number of events observed.

5. Double Blind Period: Time to Recovery From Grade 3 or 4 Hematological Toxicity [Baseline up to Week 96]

   Time to recovery from grade 3 or 4 hematological were reported: lymphocytes, platelets, neutrophils, white blood cells and hemoglobin. According to CTCAE v 4.0: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death. Recovery" as "Recovery from a Grade 3 or 4 toxicity is defined as a return to a Grade 0 or 1.

6. Double Blind Period: Mean Changes in Lymphocytes, White Blood Cells (WBC), Neutrophils and Platelets Values From Baseline to Week 96 [Baseline, Week 96]

   Mean changes in lymphocytes, WBC, neutrophils and platelets from baseline to week 96 were reported.

7. Double Blind Period: Maximum Corrected QT Interval (QTc) [Baseline up to Week 96]

   Criteria for potential clinical concern in ECG parameters: Maximum corrected QT interval (QTc) in range of 450 to less than 480 millisecond (msec).

8. Double Blind Period: Mean Change From Baseline in Vital Signs- Systolic and Diastolic Blood Pressure [Baseline, Week 96]

   Mean change from baseline in vital signs- systolic and diastolic blood pressure was reported.

9. Double Blind Period: Mean Change From Baseline in Vital Signs- Pulse Rate [Baseline, Week 96]

   Mean change from baseline in vital signs- Pulse Rate was reported.

10. Double Blind Period: Mean Change From Baseline in Vital Signs- Weight [Baseline, Week 96]

    Mean change from baseline in vital signs- weight was reported.

11. Double Blind Period: Mean Change From Baseline in Vital Signs- Temperature [Baseline, Week 96]

    Mean change from baseline in vital signs- temperature was reported.

12. Double Blind Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- Heart Rate [Baseline, Week 96]

    Mean change from baseline in ECG parameters- Heart Rate was reported.

13. Double Blind Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- PR, RR, QRS and OT Interval [Baseline, Week 96]

    Mean change from baseline in ECG parameters- PR, RR, QRS and OT interval was reported.

14. Double Blind Period: Mean Changes From Baseline in Hemoglobin Level to Week 96 [Baseline, Week 96]

    Mean changes in hemoglobin level from baseline to week 96 was reported.

15. Double Blind Period: Mean Changes From Baseline in CD4+ Count, CD8+ Count, and CD19+ to Week 96 [Baseline, Week 96]

    Mean changes CD4+ Count, CD8+ Count, and CD19+ from baseline to Week 96 were reported.

16. Double Blind Period: Mean Changes From Baseline in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) to Week 96 [Baseline, Week 96]

    Mean changes in ALT and AST from baseline to week 96 were reported.

17. Open Label Extension Period: Maximum Corrected QT Interval (Qtc) [Baseline up to Week 96]

    Criteria for potential clinical concern in ECG parameters: Maximum corrected QT interval (QTc) in range of 450 to less than 480 millisecond (msec).

18. Open Label Extension Period: Mean Change From Baseline in Vital Signs- Systolic and Diastolic Blood Pressure [Baseline, Week 72]

    Mean change from baseline in vital signs- systolic and diastolic blood pressure was reported.

19. Open Label Extension Period: Mean Change From Baseline in Vital Signs- Pulse Rate [Baseline, Week 72]

    Mean change from baseline in vital signs- Pulse Rate was reported.

20. Open Label Extension Period: Mean Change From Baseline in Vital Signs- Weight [Baseline, Week 72]

    Mean change from baseline in vital signs- weight was reported.

21. Open Label Extension Period: Mean Change From Baseline in Vital Signs- Temperature [Baseline, Week 72]

    Mean change from baseline in vital signs- temperature was reported.

22. Open Label Extension Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- Heart Rate [Baseline, Week 72]

    Mean change from baseline in ECG parameters- Heart Rate was reported.

23. Open Label Extension Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- PR, RR, QRS and OT Interval [Baseline, Week 72]

    Mean change from baseline in ECG parameters- PR, RR, QRS and OT interval was reported.

24. OLE and Safety Follow-up Period: Percentage of Participants With Grade 3 or 4 (Common Terminology Criteria for Adverse Events [CTCAE] v 4.0) Hematological or Liver Toxicity [Baseline (OLEP) up to Week 96]

    Percentage of participants with Grade 3 or 4 CTCAE v 4.0 toxicity on the following hematology and liver function parameters were reported: lymphocytes, cluster of differentiation 4 (CD4) cell, neutrophils, white blood cells, hemoglobin, Alanine transaminase (ALT), Aspartate transaminase (AST), Platelets and Bilirubin. According to CTCAE v 4.0: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death.

25. OLE and Safety Follow-up Period: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) in Infections and Infestations System Organ Class (SOC) [Baseline (OLEP) up to Week 96]

    An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. An AE was considered as 'treatment emergent' if it occurred after the first drug administration of each period or if it was present prior to drug administration but exacerbated after the drug administration.TEAEs were entered in infections and infestations SOC as per medical dictionary for regulatory activities (MedDRA) version 11.0

26. OLE and Safety Follow-up Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs [Baseline (OLEP) 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. An AE was considered as 'treatment emergent' if it occurred after the first drug administration of each period or if it was present prior to drug administration but exacerbated after the drug administration. TEAEs included both Serious TEAEs and non-serious TEAEs.

27. Open Label Extension Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity [Baseline up to Week 96]

    Time to first Grade 3 or 4 hematological toxicity or liver toxicity (lymphocytes, cluster of differentiation 4 (CD4+) cell, neutrophils, white blood cells, hemoglobin, Alanine transaminase (ALT), Aspartate transaminase (AST), Platelets and Bilirubin) were estimated using the Kaplan-Meier method. According to CTCAE v 4.0: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death. 10th and 20th percentiles estimated from Kaplan-Meier survival curve. Due to the small number of events, estimates from Kaplan-Meier survival curves could only be derived for lower percentiles. The median (50th percentile) could not be estimated if less than 50% of the participants had an event during the time of the study. Accordingly, lower percentiles are presented according to the number of events observed.

Secondary Outcome Measures

1. Double Blind Period: Number of Combined Unique Active (CUA) Lesions, Active Time Constant 2 (T2) Lesions, and Time Constant 1 (T1) Gadolinium Enhanced (Gd+) Lesions Per Participant Per Scan [Week 96]

   Number of CUA lesions, active T2 lesions, and T1 Gd+ lesions were measured by using magnetic resonance imaging (MRI) scans.

2. Double Blind Period: Mean Number of T1 Hypointense Lesions Per Participant Per Scan at Week 96 [Week 96]

   Mean number of T1 hypointense lesions per participant per scan at 96 weeks were reported. T1 hypointense lesions were measured by using magnetic resonance imaging (MRI) scans.

3. Double Blind Period: Percentage of Participants With no Active T2 Lesions at Week 96 [Week 96]

   Percentage of participants with no active T2 lesions at week 96 were reported. Active T2 lesions were measured by using magnetic resonance imaging (MRI) scans.

4. Double Blind Period: Percentage of Participants With no Active T1 Gd-Enhanced Lesions at Week 96 [Week 96]

   Percentage of participants with no active T1 Gd-enhanced lesions at week 96 were reported. Active T1 Gd-Enhanced lesions were measured by using magnetic resonance imaging (MRI) scans.

5. Double Blind Period: Mean Change in T2 Lesion Volume From Baseline to Week 96 [Baseline, Week 96]

   Mean change in T2 lesion volume From baseline to Week 96 were reported. T2 lesions were measured by using magnetic resonance imaging (MRI) scans.

6. Double Blind Period: Percent Change in Normalized Brain Volume From Baseline to Week 96 [Baseline, Week 96]

   Brain volume was measured using magnetic resonance imaging (MRI) scans of the brain. Percent change in normalized brain volume from baseline to week 96 was reported.

7. Double Blind Period: Mean Change in T1 Hypointense Lesion Volume From Baseline to Week 96 [Baseline, Week 96]

   Mean change in T1 hypointense lesion volume from baseline to week 96 was reported. T1 Hypointense lesions were measured by using magnetic resonance imaging (MRI) scans.

8. Double Blind Period: Annualized Qualifying Relapse Rate [Baseline up to Week 96]

   A qualifying relapse was defined as a 2-grade increase in at least one, or a 1-grade increase in at least two, Kurtzke Functional Systems excluding bowel/bladder or cognition changes, in the absence of fever lasting more than or equal to 24 hours, and preceded by more than or equal to 30 days of clinical stability or improvement. 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.

9. Double Blind Period: Percentage of Participants Qualifying Relapse-free [Baseline up to Week 96]

   A qualifying relapse was defined as a 2-grade increase in 1 or more Kurtzke Functional Systems (KFS) or a 1-grade increase in 2 or more KFS, excluding changes in bowel/bladder or cognition, in the absence of fever, lasting for >= 24 hours, and preceded by at least 30 days of clinical stability or improvement. Percentage of participants qualifying relapse-free were reported.

10. Double Blind Period and OLE Period: Time to 3-Month Sustained Expanded Disability Status Scale (EDSS) Progression [Baseline up to Week 96]

    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. Time to sustained disability progression was analyzed using a Cox proportional hazards model. 10th and 20th percentiles estimated from Kaplan-Meier survival curve. Due to the small number of events, estimates from Kaplan-Meier survival curves could only be derived for lower percentiles. The median (50th percentile) could not be estimated if less than 50% of the participants had an event during the time of the study. Accordingly, lower percentiles are presented according to the number of events observed.

11. Double Blind Period and OLE Period: Time to First Qualifying Relapse [Baseline up to Week 96]

    A qualifying relapse was defined as a 2-grade increase in at least one, or a 1-grade increase in at least two, Kurtzke Functional Systems excluding bowel/bladder or cognition changes, in the absence of fever lasting more than or equal to 24 hours, and preceded by more than or equal to 30 days of clinical stability or improvement. Time to first qualifying relapse were analyzed using a Cox proportional hazards model. 10th and 20th percentiles estimated from Kaplan-Meier survival curve. Due to the small number of events, estimates from Kaplan-Meier survival curves could only be derived for lower percentiles. The median (50th percentile) could not be estimated if less than 50% of the participants had an event during the time of the study. Accordingly, lower percentiles are presented according to the number of events observed.

12. Double Blind Period: Mean Change in New T1 Gd+ Lesions From Baseline to Week 96 [Baseline, Week 96]

    Mean change in new T1 Gd+ lesions from baseline to week 96 was reported.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Be male or female, 18 to 65 years of age (inclusive)

• Weigh between 40 to 120 kilogram (kg), (inclusive)

• Have definite MS, as confirmed by the revised McDonald criteria 2005, and have relapsing forms of MS, such as relapsing-remitting multiple sclerosis (RRMS) or SPMS with superimposed relapses

• Have experienced at least one relapse within 48 weeks prior to Screening, while receiving IFN-beta treatments (Rebif® 44mcg three times a week, subcutaneously; Avonex®30 mcg every week, intramuscular; or Betaseron® 250 mcg every other day, subcutaneously)

• Have a minimum time on IFN-beta therapy of 48-consecutive weeks prior to Screening. Participants who switched from one IFN-beta therapy to another in the 48 weeks preceding Screening may be entered into the study if they have been on a stable regimen of their current IFN-beta therapy for a minimum of 3 months prior to Screening

• Be clinically stable (other than MS relapse) during the 28 days preceding Screening

• The following hematological parameters must be normal (as defined below, inclusively) within 28 days of first dosing of blinded study medication at study day 1 (SD 1)

• Hemoglobin=11.6 to 16.2 gram per deciliter (g/dL)

• Leukocytes (total white blood cells [WBC])=4.1 to 12.3*10^3 per microliter (/UL)

• Absolute lymphocytes count (ALC)= 1.02 to 3.36*10^3/UL

• Absolute neutrophil count (ANC)=2.03 to 8.36*10^3/UL

• Platelet count=140 to 450*10^3/UL

• Have no medical history or evidence of latent tuberculosis infection (LTBI) or active tubercular disease (TB), as evidenced by TB skin test or chest X-ray

• Have an expanded disability status scale (EDSS) from 1.0-5.5, inclusive

• Have no prior exposure to immunosuppressive or cytotoxic agents (with the exception of steroids for MS flare management, or intravenous immunoglobulin-G [IVIG] after allowed wash-out periods

• If female, 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 6 months (6 menstrual cycles) following completion of the last dose of study medication. A highly effective method of contraception is defined as one 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 (IUDs), sexual abstinence or a vasectomized partner. For the purpose of this trial, women of childbearing potential are defined as: All female participants after puberty unless they are post-menopausal for at least 2 years, or are surgically sterile

• If male, must be willing to use contraception to avoid pregnancies throughout the entire duration of 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

• Have not met any of the exclusion criteria outlined below; and

• Have voluntarily provided written informed consent, 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, and with the understanding that the participant may withdraw consent at any time without prejudice to future medical care

• Other protocol defined inclusion criteria may apply

Exclusion Criteria:

• Has primary progressive multiple sclerosis (PPMS) or SPMS without relapses forms

• Has prior or current malignancy other than medically documented complete excision of basal cell skin cancer no less than 5 years prior to Screening

• Has a history of chronic or clinically significant hematological abnormalities

• Prior use of cladribine, fingolimod, teriflunimide, laquinimod, mitoxantrone, campath-1h, cyclophosphamide, azathioprine, methotrexate, daclizumab, natalizumab, lymphoid irradiation, bone marrow transplantation or myelosuppressive/cytotoxic therapy

• Use of cytokine or anti-cytokine therapy or plasmapheresis within 3 months prior to SD 1

• Treatment with IVIG within 30 days of Screening

• Treatment with oral or parenteral corticosteroids 30 days of Screening

• Treatment with adrenocorticotropic hormone within 28 days prior to SD 1

• Use of any investigational drug (other than Rebif® New Formulation [RNF], Avonex® or Betaferon®) or experimental procedure within 6 months prior to SD 1

• Has inadequate liver function, defined by a total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) or alkaline phosphatase greater than 2.5 times the upper limit of the normal values

• Suffers from major medical illness such as cardiac, endocrinologic, hepatic, immunologic (other than MS), metabolic, renal, pulmonary, gastrointestinal, dermatologic, or other major disease that would preclude the administration of oral cladribine

• Suffers from major 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 participant or could affect compliance with the study protocol

• Has history of active or chronic infectious disease or any disease which compromises immune function (for example, human immunodeficiency virus [HIV]+, human T-lymphotropic virus [HTLV-1], Lyme disease, LTBI or TB)

• Has an allergy or hypersensitivity to gadolinium, to cladribine or any of its excipients, or IFN-beta or any of its excipient(s)

• Has any renal condition that would preclude the administration of gadolinium (for example, acute or chronic severe renal insufficiency [glomerular filtration rate less than 30 milliliter per minute {mL/min} per 1.73 square meter {m^2}])

• Has a positive stool hemoccult test at Screening

• Has a history of seizures not adequately controlled by treatment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Cullman	Alabama	United States
2	Research Site	Phoenix	Arizona	United States
3	Research Site	Scottsdale	Arizona	United States
4	Research Site	Los Angeles	California	United States
5	Research Site	Boulder	Colorado	United States
6	Research Site	Fort Collins	Colorado	United States
7	Research Site	Tampa	Florida	United States
8	Research Site	Atlanta	Georgia	United States
9	Research Site	Peoria	Illinois	United States
10	Research Site	Boston	Massachusetts	United States
11	Research Site	Saint Louis	Missouri	United States
12	Research Site	Newark	New Jersey	United States
13	Research Site	Albuquerque	New Mexico	United States
14	Research Site	Charlotte	North Carolina	United States
15	Research Site	Winston-Salem	North Carolina	United States
16	Research Site	Bethlehem	Pennsylvania	United States
17	Research Site	Philadelphia	Pennsylvania	United States
18	Research Site	Nashville	Tennessee	United States
19	Research Site	Houston	Texas	United States
20	Research Site	Round Rock	Texas	United States
21	Research Site	Burlington	Vermont	United States
22	Research Site	Fidenza		Italy
23	Research Site	Milan		Italy
24	Research Site	Napoli		Italy
25	Research Site	Rome		Italy
26	Research Site	Arkhangelsk		Russian Federation
27	Research Site	Kazan		Russian Federation
28	Research Site	Moscow		Russian Federation
29	Research Site	Novosibirsk		Russian Federation
30	Research Site	Samara		Russian Federation
31	Research Site	Smolensk		Russian Federation
32	Research Site	St. Petersburg		Russian Federation
33	Research Site	Alicante		Spain
34	Research site	Barcelona		Spain
35	Research Site	Bilbao		Spain
36	Research Site	Madrid		Spain
37	Research Site	Malaga		Spain
38	Research Site	Santiago		Spain
39	Research Site	Seville		Spain

Sponsors and Collaborators

• EMD Serono Research & Development Institute, Inc.

Investigators

• Study Director: Medical Responsible, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

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

Publications

None provided.

• Responsible Party: EMD Serono Research & Development Institute, Inc.
• ClinicalTrials.gov Identifier: NCT00436826
• Other Study ID Numbers: 26593; 2006-003366-33
• First Posted: Feb 19, 2007
• Last Update Posted: Oct 12, 2020
• Last Verified: Oct 1, 2020

• Keywords provided by EMD Serono Research & Development Institute, Inc.: Multiple Sclerosis; Relapsing forms; Interferon-beta therapy
• Additional relevant MeSH terms: Multiple Sclerosis; Sclerosis; Interferons; Interferon-beta; Cladribine; Interferon beta-1b

Study Results

Participant Flow

Pre-assignment Detail	Initially 42 participants randomized under original protocol but enrollment terminated because of hematological toxicities. Protocol amendment 1 and 2 were implemented and enrolled 172 participants. Protocol amendment 5 was generated, resulting in discontinuation of Cladribine and reduction of Extension period and Safety Follow up to 48 weeks.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)	Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)	Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)	Cladribine 3.5 mg/kg, IFN-beta (Safety Follow up)	Placebo, IFN-beta (Safety Follow up)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.	Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the open label (OL) extension (Ext.) period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.	Participants who received placebo initially and completed DB period entered in the OL Ext. period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.	Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the OL ext. safety follow up period. In this period, participants who did not meet eligibility criteria received only IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.	Participants who received placebo initially and completed DB period entered in the OL ext. safety follow up period. In this period, participants who did not meet eligibility criteria received only IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.
Period Title: Double Blind Period (DBP)
STARTED	124	48	0	0	0	0
COMPLETED	111	37	0	0	0	0
NOT COMPLETED	13	11	0	0	0	0
Period Title: Double Blind Period (DBP)
STARTED	0	0	47	28	0	0
COMPLETED	0	0	1	2	0	0
NOT COMPLETED	0	0	46	26	0	0
Period Title: Double Blind Period (DBP)
STARTED	0	0	0	0	52	7
COMPLETED	0	0	0	0	1	0
NOT COMPLETED	0	0	0	0	51	7

Baseline Characteristics

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta	Placebo, IFN-beta	Total
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 milligram per kilogram (mg/kg) over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 mg/kg along with IFN-beta therapy (Rebif® new formulation [RNF] 44 microgram [mcg] three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the double blind (DB) period of 96 weeks. After completing DB period, participants entered in OL extension period. In OL extension period, participant who met eligibility criteria received OL oral cladribine 3.5 mg/kg and participants who did not meet the eligibility criteria received IFN-beta only and were followed for safety only.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the double blind (DB) period of 96 weeks. After completing DB period, participants entered in OL extension period. In OL extension period, participant who met eligibility criteria received OL oral cladribine 3.5 mg/kg and participants participants who did not meet the eligibility criteria received IFN-beta only and were followed for safety only.	Total of all reporting groups
Overall Participants	124	48	172
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	38.5 (10.2)	40.1 (10.3)	38.9 (10.2)
Sex: Female, Male (Count of Participants)
Female	84 67.7%	36 75%	120 69.8%
Male	40 32.3%	12 25%	52 30.2%
Time (years) from first attack to study Day 1 (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	9.98 (7.24)	10.83 (7.98)	10.22 (7.44)
Expanded disability status scale (EDSS) score (unit on scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [unit on scale]	2.9 (1.2)	3.0 (1.2)	2.9 (1.2)
Number of Gadolinium-enhanced lesions (lesions) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [lesions]	1.1 (4.0)	0.6 (1.2)	0.9 (3.4)
Number of Time constant 1 (T1) hypointense lesions (lesions) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [lesions]	9.0 (9.2)	9.3 (9.9)	9.1 (9.3)
T1 Gd+ volume (cubic millimetre (mm^3)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cubic millimetre (mm^3)]	150.3 (592.2)	99.4 (210.0)	136.1 (514.5)
T2 lesions volume (mm^3) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm^3]	10791.2 (11298.0)	13669.1 (16605.2)	11596.3 (13013.5)

Outcome Measures

1. Primary Outcome

Title	Double Blind Period: Percentage of Participants With Grade 3 or 4 (Common Terminology Criteria for Adverse Events [CTCAE] v 4.0) Hematological or Liver Toxicity
Description	Percentage of participants with Grade 3 or 4 CTCAE v 4.0 toxicity on the following hematology and liver function parameters were reported: lymphocytes, cluster of differentiation 4 (CD4) cell, neutrophils, white blood cells, hemoglobin, Alanine transaminase (ALT), Aspartate transaminase (AST), Platelets and Bilirubin. According to CTCAE v 4.0: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death.
Time Frame	Baseline up to Week 96

Outcome Measure Data

Analysis Population Description

Safety population: all randomized participants who received at least 1 dose of study drug in DBP and had follow-up safety data.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Measure Participants	124	48
Grade 3 or 4 Lymphocyte toxicity	63.71 51.4%	2.08 4.3%
Grade 3 or 4 Hemoglobin toxicity	2.42 2%	0.00 0%
Grade 3 or 4 White Blood Cell toxicity	10.48 8.5%	0.00 0%
Grade 3 or 4 Neutrophil toxicity	12.10 9.8%	2.08 4.3%
Grade 3 or 4 CD4+ toxicity	50.81 41%	2.08 4.3%
Grade 3 or 4 AST toxicity	0.81 0.7%	0.00 0%
Grade 3 or 4 ALT toxicity	0.81 0.7%	2.08 4.3%
Grade 3 or 4 Platelet toxicity	0.00 0%	0.00 0%
Grade 3 or 4 Bilirubin toxicity	0.00 0%	0.00 0%

2. Primary Outcome

Title	Double Blind Period: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) in Infections and Infestations System Organ Class (SOC)
Description	An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. An AE was considered as 'treatment emergent' if it occurred after the first drug administration of each period or if it was present prior to drug administration but exacerbated after the drug administration.TEAEs were entered in infections and infestations SOC as per medical dictionary for regulatory activities (MedDRA) version 11.0
Time Frame	Baseline up to Week 96

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least one dose of study medication in the DBP and had follow-up safety data.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Measure Participants	124	48
Number [Percentage of participants]	61.3 49.4%	54.2 112.9%

3. Primary Outcome

Title	Double Blind Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
Description	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. An AE was considered as 'treatment emergent' if it occurred after the first drug administration of each period or if it was present prior to drug administration but exacerbated after the drug administration. TEAEs included both Serious TEAEs and non-serious TEAEs.
Time Frame	Baseline up to Week 96

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least one dose of study medication in the DBP and had follow-up safety data.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Measure Participants	124	48
Participants with TEAEs	119 96%	36 75%
Participants with Serious TEAEs	12 9.7%	5 10.4%

4. Primary Outcome

Title	Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity
Description	Time to first Grade 3 or 4 hematological toxicity or liver toxicity (lymphocytes, cluster of differentiation 4 (CD4) cell, neutrophils, white blood cells, hemoglobin, Alanine transaminase (ALT), Aspartate transaminase (AST), Platelets and Bilirubin) were estimated using the Kaplan-Meier method. According to CTCAE v 4.0: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death. 10th and 20th percentiles estimated from Kaplan-Meier survival curve. Due to the small number of events, estimates from Kaplan-Meier survival curves could only be derived for lower percentiles. The median (50th percentile) could not be estimated if less than 50% of the participants had an event during the time of the study. Accordingly, lower percentiles are presented according to the number of events observed.
Time Frame	Baseline up to Week 96

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least one dose of study medication in the DBP and had follow-up safety data. Here "Number of Participants analyzed"= participants evaluable for this outcome measure and "number analyzed"= participants who were evaluable for specified category.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Measure Participants	79	2
10th percentile: Lymphocytes toxicity	1.61	NA
20th percentile: Lymphocytes toxicity	2.00	NA
10th percentile:Hemoglobin toxicity	NA
20th percentile:Hemoglobin toxicity	NA
10th percentile: White Blood Cell toxicity	17.74
20th percentile: White Blood Cell toxicity	NA
10th percentile: Neutrophil toxicity	12.55	NA
20th percentile: Neutrophil toxicity	NA	NA
10th percentile: CD4+ count toxicity	1.87	NA
20th percentile: CD4+ count toxicity	2.99	NA
10th percentile: AST toxicity	NA
20th percentile: AST toxicity	NA
10th percentile: ALT toxicity	NA	NA
20th percentile: ALT toxicity	NA	NA

5. Primary Outcome

Title	Double Blind Period: Time to Recovery From Grade 3 or 4 Hematological Toxicity
Description	Time to recovery from grade 3 or 4 hematological were reported: lymphocytes, platelets, neutrophils, white blood cells and hemoglobin. According to CTCAE v 4.0: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death. Recovery" as "Recovery from a Grade 3 or 4 toxicity is defined as a return to a Grade 0 or 1.
Time Frame	Baseline up to Week 96

Outcome Measure Data

Analysis Population Description

Safety population: all randomized participants who received at least 1 dose of study drug in DBP and had follow-up safety data. Here "Number of Participants analyzed"= participants evaluable for this outcome measure and "number analyzed"= participants who had a Grade 3 or 4 abnormality and evaluable at specified category.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Measure Participants	76	2
Hemoglobin	19.50 (10.61)
White Blood Cell	31.27 (27.69)
Neutrophil	41.17 (37.90)	56.75 (30.76)
Lymphocyte	142.53 (109.86)	28.00

6. Primary Outcome

Title	Double Blind Period: Mean Changes in Lymphocytes, White Blood Cells (WBC), Neutrophils and Platelets Values From Baseline to Week 96
Description	Mean changes in lymphocytes, WBC, neutrophils and platelets from baseline to week 96 were reported.
Time Frame	Baseline, Week 96

Outcome Measure Data

Analysis Population Description

Safety population: all randomized participants who received at least 1 dose of study drug in DBP and had follow-up safety data. Here "Number of Participants analyzed"= participants evaluable for this outcome measure and "number analyzed"= participants who were evaluable for specified category.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Measure Participants	102	33
Lymphocytes	-0.8 (0.5)	0.0 (0.7)
Platelet	-29.8 (37.9)	-12.4 (56.9)
WBC	-1.5 (1.8)	-0.4 (1.6)
Neutrophils	-0.7 (1.6)	-0.4 (1.2)

7. Primary Outcome

Title	Double Blind Period: Maximum Corrected QT Interval (QTc)
Description	Criteria for potential clinical concern in ECG parameters: Maximum corrected QT interval (QTc) in range of 450 to less than 480 millisecond (msec).
Time Frame	Baseline up to Week 96

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least one dose of study medication in the DB period and had follow-up safety data.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Measure Participants	124	48
Mean (Standard Deviation) [Milliseconds]	0.4381 (0.0194)	0.4361 (0.0176)

8. Primary Outcome

Title	Double Blind Period: Mean Change From Baseline in Vital Signs- Systolic and Diastolic Blood Pressure
Description	Mean change from baseline in vital signs- systolic and diastolic blood pressure was reported.
Time Frame	Baseline, Week 96

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least one dose of study medication in the DB period and had follow-up safety data. Here "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Measure Participants	113	38
Systolic Blood Pressure	-0.6 (13.2)	0.0 (13.1)
Diastolic Blood Pressure	-0.6 (10.1)	-2.2 (8.9)

9. Primary Outcome

Title	Double Blind Period: Mean Change From Baseline in Vital Signs- Pulse Rate
Description	Mean change from baseline in vital signs- Pulse Rate was reported.
Time Frame	Baseline, Week 96

Outcome Measure Data

Analysis Population Description

Safety population: all randomized participants who received at least 1 dose of study drug in DBP and had follow-up safety data. Here "Number of Participants analyzed"= participants evaluable for this outcome measure.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Measure Participants	112	38
Mean (Standard Deviation) [beats per minutes]	1.0 (11.6)	0.4 (9.2)

10. Primary Outcome

Title	Double Blind Period: Mean Change From Baseline in Vital Signs- Weight
Description	Mean change from baseline in vital signs- weight was reported.
Time Frame	Baseline, Week 96

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least one dose of study medication in the DB period and had follow-up safety data. Here "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Measure Participants	111	38
Mean (Standard Deviation) [Kilogram]	-0.6 (8.0)	-0.4 (5.0)

11. Primary Outcome

Title	Double Blind Period: Mean Change From Baseline in Vital Signs- Temperature
Description	Mean change from baseline in vital signs- temperature was reported.
Time Frame	Baseline, Week 96

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least one dose of study medication in the DB period and had follow-up safety data. Here "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Measure Participants	112	38
Mean (Standard Deviation) [Degree celsius]	-0.1 (0.3)	-0.1 (0.4)

12. Primary Outcome

Title	Double Blind Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- Heart Rate
Description	Mean change from baseline in ECG parameters- Heart Rate was reported.
Time Frame	Baseline, Week 96

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least one dose of study medication in the DB period and had follow-up safety data. Here "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Measure Participants	37	22
Mean (Standard Deviation) [beats per minutes]	-3.114 (8.990)	1.981 (7.857)

13. Primary Outcome

Title	Double Blind Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- PR, RR, QRS and OT Interval
Description	Mean change from baseline in ECG parameters- PR, RR, QRS and OT interval was reported.
Time Frame	Baseline, Week 96

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least one dose of study medication in the DB period and had follow-up safety data. Here "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Measure Participants	37	22
PR Interval	0.0001 (0.0094)	0.0033 (0.0108)
RR Interval	0.0361 (0.1068)	-0.0272 (0.1175)
QRS Interval	0.0028 (0.0060)	0.0043 (0.0054)
QT Interval	0.0135 (0.0214)	0.0037 (0.0189)

14. Primary Outcome

Title	Double Blind Period: Mean Changes From Baseline in Hemoglobin Level to Week 96
Description	Mean changes in hemoglobin level from baseline to week 96 was reported.
Time Frame	Baseline, Week 96

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least one dose of study medication in the DB period and had follow-up safety data. Here "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Measure Participants	102	33
Mean (Standard Deviation) [gram per liter (g/L)]	-2.9 (8.1)	-2.5 (10.6)

15. Primary Outcome

Title	Double Blind Period: Mean Changes From Baseline in CD4+ Count, CD8+ Count, and CD19+ to Week 96
Description	Mean changes CD4+ Count, CD8+ Count, and CD19+ from baseline to Week 96 were reported.
Time Frame	Baseline, Week 96

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least one dose of study medication in the DB period and had follow-up safety data. Here "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Measure Participants	99	31
CD4+	-604.1 (301.3)	7.1 (344.7)
CD8+	-137.8 (178.1)	23.9 (188.3)
CD19+	22.0 (141.2)	30.7 (121.5)

16. Primary Outcome

Title	Double Blind Period: Mean Changes From Baseline in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) to Week 96
Description	Mean changes in ALT and AST from baseline to week 96 were reported.
Time Frame	Baseline, Week 96

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least one dose of study medication in the DB period and had follow-up safety data. Here "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Measure Participants	102	32
ALT	-3.0 (11.5)	1.3 (11.5)
AST	-1.7 (6.9)	1.1 (6.2)

17. Secondary Outcome

Title	Double Blind Period: Number of Combined Unique Active (CUA) Lesions, Active Time Constant 2 (T2) Lesions, and Time Constant 1 (T1) Gadolinium Enhanced (Gd+) Lesions Per Participant Per Scan
Description	Number of CUA lesions, active T2 lesions, and T1 Gd+ lesions were measured by using magnetic resonance imaging (MRI) scans.
Time Frame	Week 96

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants who had received at least one dose of study medication in the DB period. Here "Number of Participants analyzed"= participants evaluable for this outcome measure.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Measure Participants	121	48
T1 Gd+ lesions	0.06 (0.37)	0.34 (0.87)
CUA lesions	0.55 (1.27)	1.12 (1.94)
T2 lesions	0.53 (1.26)	1.04 (1.81)

18. Secondary Outcome

Title	Double Blind Period: Mean Number of T1 Hypointense Lesions Per Participant Per Scan at Week 96
Description	Mean number of T1 hypointense lesions per participant per scan at 96 weeks were reported. T1 hypointense lesions were measured by using magnetic resonance imaging (MRI) scans.
Time Frame	Week 96

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants who had received at least one dose of study medication in the DB period. Here "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Measure Participants	121	48
Mean (Standard Deviation) [Lesions]	0.28 (0.63)	0.43 (1.00)

19. Secondary Outcome

Title	Double Blind Period: Percentage of Participants With no Active T2 Lesions at Week 96
Description	Percentage of participants with no active T2 lesions at week 96 were reported. Active T2 lesions were measured by using magnetic resonance imaging (MRI) scans.
Time Frame	Week 96

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants who had received at least one dose of study medication in the DB period. Here "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Measure Participants	121	48
Number [Percentage of Participants]	56.2 45.3%	29.2 60.8%

20. Secondary Outcome

Title	Double Blind Period: Percentage of Participants With no Active T1 Gd-Enhanced Lesions at Week 96
Description	Percentage of participants with no active T1 Gd-enhanced lesions at week 96 were reported. Active T1 Gd-Enhanced lesions were measured by using magnetic resonance imaging (MRI) scans.
Time Frame	Week 96

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants who had received at least one dose of study medication in the DB period. Here "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Measure Participants	121	48
Number [Percentage of Participants]	86.0 69.4%	56.3 117.3%

21. Secondary Outcome

Title	Double Blind Period: Mean Change in T2 Lesion Volume From Baseline to Week 96
Description	Mean change in T2 lesion volume From baseline to Week 96 were reported. T2 lesions were measured by using magnetic resonance imaging (MRI) scans.
Time Frame	Baseline, Week 96

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants who had received at least one dose of study medication in the DB period. Here "Number of participants analyzed" signifies those participants who were evaluated for this outcome measure.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Measure Participants	105	37
Mean (Standard Deviation) [cubic millimeters (mm^3)]	-2007.2 (3718.3)	-1224.6 (7056.3)

22. Secondary Outcome

Title	Double Blind Period: Percent Change in Normalized Brain Volume From Baseline to Week 96
Description	Brain volume was measured using magnetic resonance imaging (MRI) scans of the brain. Percent change in normalized brain volume from baseline to week 96 was reported.
Time Frame	Baseline, Week 96

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants who had received at least one dose of study medication in the DB period. Here "Number of participants analyzed" signifies those participants who were evaluated for this outcome measure.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Measure Participants	15	6
Mean (Standard Deviation) [Percent Change]	-1.01 (1.03)	-1.42 (0.73)

23. Secondary Outcome

Title	Double Blind Period: Mean Change in T1 Hypointense Lesion Volume From Baseline to Week 96
Description	Mean change in T1 hypointense lesion volume from baseline to week 96 was reported. T1 Hypointense lesions were measured by using magnetic resonance imaging (MRI) scans.
Time Frame	Baseline, Week 96

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants who had received at least one dose of study medication in the DB period. Here "Number of participants analyzed" signifies those participants who were evaluated for this outcome measure.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Measure Participants	105	37
Mean (Standard Deviation) [millimeter cubic]	-481.8 (1097.2)	-263.0 (1678.3)

24. Secondary Outcome

Title	Double Blind Period: Annualized Qualifying Relapse Rate
Description	A qualifying relapse was defined as a 2-grade increase in at least one, or a 1-grade increase in at least two, Kurtzke Functional Systems excluding bowel/bladder or cognition changes, in the absence of fever lasting more than or equal to 24 hours, and preceded by more than or equal to 30 days of clinical stability or improvement. 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.
Time Frame	Baseline up to Week 96

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants who had received at least one dose of study medication in the DB period.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Measure Participants	124	48
Number (95% Confidence Interval) [relapses per year]	0.12	0.32

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cladribine 3.5 mg/kg, IFN-beta (DB Period), Placebo, IFN-beta (DB Period)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wald Chi-square
	Comments
Method of Estimation	Estimation Parameter	Relative Risk
	Estimated Value	0.37
	Confidence Interval	(2-Sided) 95%; 0.22 to 0.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

25. Secondary Outcome

Title	Double Blind Period: Percentage of Participants Qualifying Relapse-free
Description	A qualifying relapse was defined as a 2-grade increase in 1 or more Kurtzke Functional Systems (KFS) or a 1-grade increase in 2 or more KFS, excluding changes in bowel/bladder or cognition, in the absence of fever, lasting for >= 24 hours, and preceded by at least 30 days of clinical stability or improvement. Percentage of participants qualifying relapse-free were reported.
Time Frame	Baseline up to Week 96

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants who had received at least one dose of study medication in the DB period.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Measure Participants	124	48
Number [Percentage of Participants]	75.0 60.5%	52.1 108.5%

26. Secondary Outcome

Title	Double Blind Period and OLE Period: Time to 3-Month Sustained Expanded Disability Status Scale (EDSS) Progression
Description	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. Time to sustained disability progression was analyzed using a Cox proportional hazards model. 10th and 20th percentiles estimated from Kaplan-Meier survival curve. Due to the small number of events, estimates from Kaplan-Meier survival curves could only be derived for lower percentiles. The median (50th percentile) could not be estimated if less than 50% of the participants had an event during the time of the study. Accordingly, lower percentiles are presented according to the number of events observed.
Time Frame	Baseline up to Week 96

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants who had received at least one dose of study medication in the DB period. Here "Number of Participants analyzed"= participants evaluable for this outcome measure and "number analyzed"= participants who were evaluable for specified category.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)	Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)	Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.	Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the open label (OL) extension (Ext.) period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.	Participants who received placebo initially and completed DB period entered in the OL Ext. period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.
Measure Participants	19	6	10	5
10th percentile	244	484	87	85
20th percentile	NA	0	246	0

27. Secondary Outcome

Title	Double Blind Period and OLE Period: Time to First Qualifying Relapse
Description	A qualifying relapse was defined as a 2-grade increase in at least one, or a 1-grade increase in at least two, Kurtzke Functional Systems excluding bowel/bladder or cognition changes, in the absence of fever lasting more than or equal to 24 hours, and preceded by more than or equal to 30 days of clinical stability or improvement. Time to first qualifying relapse were analyzed using a Cox proportional hazards model. 10th and 20th percentiles estimated from Kaplan-Meier survival curve. Due to the small number of events, estimates from Kaplan-Meier survival curves could only be derived for lower percentiles. The median (50th percentile) could not be estimated if less than 50% of the participants had an event during the time of the study. Accordingly, lower percentiles are presented according to the number of events observed.
Time Frame	Baseline up to Week 96

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants who had received at least one dose of study medication in the DB period. Here "Number of Participants analyzed"= participants evaluable for this outcome measure and "number analyzed"= participants who were evaluable for specified category.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)	Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)	Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.	Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the open label (OL) extension (Ext.) period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.	Participants who received placebo initially and completed DB period entered in the OL Ext. period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.
Measure Participants	23	16	4	4
10th percentile	239	252	255	155
20th percentile	NA	481	0	0

28. Primary Outcome

Title	Open Label Extension Period: Maximum Corrected QT Interval (Qtc)
Description	Criteria for potential clinical concern in ECG parameters: Maximum corrected QT interval (QTc) in range of 450 to less than 480 millisecond (msec).
Time Frame	Baseline up to Week 96

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least one dose of study medication in the DB period and had follow-up safety data. Here "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)	Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)
Arm/Group Description	Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the open label (OL) extension (Ext.) period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.	Participants who received placebo initially and completed DB period entered in the OL Ext. period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.
Measure Participants	47	27
Mean (Standard Deviation) [Milliseconds]	0.4370 (0.0219)	0.4317 (0.0181)

29. Primary Outcome

Title	Open Label Extension Period: Mean Change From Baseline in Vital Signs- Systolic and Diastolic Blood Pressure
Description	Mean change from baseline in vital signs- systolic and diastolic blood pressure was reported.
Time Frame	Baseline, Week 72

Outcome Measure Data

Analysis Population Description

Safety population was used. Here "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure. Only those participants with data available at the specified time point were reported.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)	Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)
Arm/Group Description	Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the open label (OL) extension (Ext.) period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.	Participants who received placebo initially and completed DB period entered in the OL Ext. period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.
Measure Participants	3	0
Systolic Blood Pressure	0.3 (10.2)
Diastolic Blood Pressure	-1.7 (5.0)

30. Primary Outcome

Title	Open Label Extension Period: Mean Change From Baseline in Vital Signs- Pulse Rate
Description	Mean change from baseline in vital signs- Pulse Rate was reported.
Time Frame	Baseline, Week 72

Outcome Measure Data

Analysis Population Description

Safety population: all randomized participants who received at least 1 dose of study drug in DBP and had follow-up safety data. Here "Number of Participants analyzed"= participants evaluable for this outcome measure. Only those participants with data available at the specified time point were reported.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)	Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)
Arm/Group Description	Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the open label (OL) extension (Ext.) period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.	Participants who received placebo initially and completed DB period entered in the OL Ext. period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.
Measure Participants	3	0
Mean (Standard Deviation) [beats per minutes]	4.7 (11.5)

31. Primary Outcome

Title	Open Label Extension Period: Mean Change From Baseline in Vital Signs- Weight
Description	Mean change from baseline in vital signs- weight was reported.
Time Frame	Baseline, Week 72

Outcome Measure Data

Analysis Population Description

Safety population was used. Here "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure. Only those participants with data available at the specified time point were reported.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)	Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)
Arm/Group Description	Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the open label (OL) extension (Ext.) period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.	Participants who received placebo initially and completed DB period entered in the OL Ext. period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.
Measure Participants	3	0
Mean (Standard Deviation) [Kilogram]	-9.4 (6.9)

32. Primary Outcome

Title	Open Label Extension Period: Mean Change From Baseline in Vital Signs- Temperature
Description	Mean change from baseline in vital signs- temperature was reported.
Time Frame	Baseline, Week 72

Outcome Measure Data

Analysis Population Description

Safety population was used. Here "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure. Only those participants with data available at the specified time point were reported.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)	Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)
Arm/Group Description	Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the open label (OL) extension (Ext.) period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.	Participants who received placebo initially and completed DB period entered in the OL Ext. period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.
Measure Participants	3	0
Mean (Standard Deviation) [Degree celsius]	-0.3 (0.3)

33. Primary Outcome

Title	Open Label Extension Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- Heart Rate
Description	Mean change from baseline in ECG parameters- Heart Rate was reported.
Time Frame	Baseline, Week 72

Outcome Measure Data

Analysis Population Description

Safety population was used. Here "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure. Only those participants with data available at the specified time point were reported.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)	Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)
Arm/Group Description	Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the open label (OL) extension (Ext.) period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.	Participants who received placebo initially and completed DB period entered in the OL Ext. period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.
Measure Participants	6	0
Mean (Standard Deviation) [beats per minutes]	-4.889 (6.160)

34. Primary Outcome

Title	Open Label Extension Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- PR, RR, QRS and OT Interval
Description	Mean change from baseline in ECG parameters- PR, RR, QRS and OT interval was reported.
Time Frame	Baseline, Week 72

Outcome Measure Data

Analysis Population Description

Safety population was used. Here "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure. Only those participants with data available at the specified time point were reported.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)	Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)
Arm/Group Description	Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the open label (OL) extension (Ext.) period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.	Participants who received placebo initially and completed DB period entered in the OL Ext. period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.
Measure Participants	6	0
PR Interval	-0.0044 (0.0108)
RR Interval	0.0643 (0.0721)
QRS Interval	-0.0026 (0.0090)
QT Interval	0.0109 (0.0206)

35. Secondary Outcome

Title	Double Blind Period: Mean Change in New T1 Gd+ Lesions From Baseline to Week 96
Description	Mean change in new T1 Gd+ lesions from baseline to week 96 was reported.
Time Frame	Baseline, Week 96

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants who had received at least one dose of study medication in the DB period. Here "Number of participants analyzed" signifies those participants who were evaluated for this outcome measure.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)	Placebo, IFN-beta (DB Period)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.	Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Measure Participants	105	37
Mean (Standard Deviation) [Lesions]	-1.0 (4.4)	-0.3 (1.1)

36. Primary Outcome

Title	OLE and Safety Follow-up Period: Percentage of Participants With Grade 3 or 4 (Common Terminology Criteria for Adverse Events [CTCAE] v 4.0) Hematological or Liver Toxicity
Description	Percentage of participants with Grade 3 or 4 CTCAE v 4.0 toxicity on the following hematology and liver function parameters were reported: lymphocytes, cluster of differentiation 4 (CD4) cell, neutrophils, white blood cells, hemoglobin, Alanine transaminase (ALT), Aspartate transaminase (AST), Platelets and Bilirubin. According to CTCAE v 4.0: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death.
Time Frame	Baseline (OLEP) up to Week 96

Outcome Measure Data

Analysis Population Description

Safety population: all randomized participants who received at least 1 dose of study drug in DBP and had follow-up safety data. Here "Number of Participants analyzed"= participants evaluable for this outcome measure and "number analyzed"= participants who were evaluable for specified category.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)	Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)	Cladribine 3.5 mg/kg, IFN-beta (Safety Follow up)	Placebo, IFN-beta (Safety Follow up)
Arm/Group Description	Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the open label (OL) extension (Ext.) period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.	Participants who received placebo initially and completed DB period entered in the OL Ext. period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.	Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the OL ext. safety follow up period. In this period, participants who did not meet eligibility criteria received only IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.	Participants who received placebo initially and completed DB period entered in the OL ext. safety follow up period. In this period, participants who did not meet eligibility criteria received only IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.
Measure Participants	47	28	51	7
Grade 3 or 4 Lymphocyte toxicity	48.9 39.4%	28.6 59.6%	3.9 2.3%	0.00 NaN
Grade 3 or 4 Hemoglobin toxicity	0.00 0%	0.00 0%	2.0 1.2%	0.00 NaN
Grade 3 or 4 White Blood Cell toxicity	4.3 3.5%	3.6 7.5%	0.00 0%	0.00 NaN
Grade 3 or 4 Neutrophil toxicity	6.4 5.2%	14.3 29.8%	0.00 0%	0.00 NaN
Grade 3 or 4 CD4+ toxicity	66.0 53.2%	21.4 44.6%	14.0 8.1%	0.00 NaN
Grade 3 or 4 AST toxicity	0.00 0%	0.00 0%	0.00 0%	0.00 NaN
Grade 3 or 4 ALT toxicity	0.00 0%	3.6 7.5%	0.00 0%	0.00 NaN
Grade 3 or 4 Platelet toxicity	0.00 0%	0.00 0%	0.00 0%	0.00 NaN
Grade 3 or 4 Bilirubin toxicity	0.00 0%	0.00 0%	0.00 0%	0.00 NaN

37. Primary Outcome

Title	OLE and Safety Follow-up Period: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) in Infections and Infestations System Organ Class (SOC)
Description	An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. An AE was considered as 'treatment emergent' if it occurred after the first drug administration of each period or if it was present prior to drug administration but exacerbated after the drug administration.TEAEs were entered in infections and infestations SOC as per medical dictionary for regulatory activities (MedDRA) version 11.0
Time Frame	Baseline (OLEP) up to Week 96

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least one dose of study medication in the DBP and had follow-up safety data.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)	Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)	Cladribine 3.5 mg/kg, IFN-beta (Safety Follow up)	Placebo, IFN-beta (Safety Follow up)
Arm/Group Description	Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the open label (OL) extension (Ext.) period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.	Participants who received placebo initially and completed DB period entered in the OL Ext. period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.	Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the OL ext. safety follow up period. In this period, participants who did not meet eligibility criteria received only IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.	Participants who received placebo initially and completed DB period entered in the OL ext. safety follow up period. In this period, participants who did not meet eligibility criteria received only IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.
Measure Participants	47	28	52	7
Number [Percentage of participants]	38.3 30.9%	21.4 44.6%	11.5 6.7%	0 NaN

38. Primary Outcome

Title	OLE and Safety Follow-up Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
Description	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. An AE was considered as 'treatment emergent' if it occurred after the first drug administration of each period or if it was present prior to drug administration but exacerbated after the drug administration. TEAEs included both Serious TEAEs and non-serious TEAEs.
Time Frame	Baseline (OLEP) up to Week 96

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least one dose of study medication in the DBP and had follow-up safety data.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)	Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)	Cladribine 3.5 mg/kg, IFN-beta (Safety Follow up)	Placebo, IFN-beta (Safety Follow up)
Arm/Group Description	Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the open label (OL) extension (Ext.) period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.	Participants who received placebo initially and completed DB period entered in the OL Ext. period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.	Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the OL ext. safety follow up period. In this period, participants who did not meet eligibility criteria received only IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.	Participants who received placebo initially and completed DB period entered in the OL ext. safety follow up period. In this period, participants who did not meet eligibility criteria received only IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.
Measure Participants	47	28	52	7
Participants with TEAEs	37 29.8%	19 39.6%	22 12.8%	0 NaN
Participants with Serious TEAEs	0 0%	1 2.1%	1 0.6%	0 NaN

39. Primary Outcome

Title	Open Label Extension Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity
Description	Time to first Grade 3 or 4 hematological toxicity or liver toxicity (lymphocytes, cluster of differentiation 4 (CD4+) cell, neutrophils, white blood cells, hemoglobin, Alanine transaminase (ALT), Aspartate transaminase (AST), Platelets and Bilirubin) were estimated using the Kaplan-Meier method. According to CTCAE v 4.0: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death. 10th and 20th percentiles estimated from Kaplan-Meier survival curve. Due to the small number of events, estimates from Kaplan-Meier survival curves could only be derived for lower percentiles. The median (50th percentile) could not be estimated if less than 50% of the participants had an event during the time of the study. Accordingly, lower percentiles are presented according to the number of events observed.
Time Frame	Baseline up to Week 96

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least one dose of study medication in the DBP and had follow-up safety data. Here "Number of Participants analyzed"= participants evaluable for this outcome measure and "number analyzed"= participants who were evaluable for specified category.

Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)	Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)
Arm/Group Description	Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the open label (OL) extension (Ext.) period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.	Participants who received placebo initially and completed DB period entered in the OL Ext. period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.
Measure Participants	31	8
10th percentile: Lymphocytes toxicity	0.30	0.36
20th percentile: Lymphocytes toxicity	1.64	2.23
10th percentile: White Blood Cell toxicity	NA	NA
20th percentile: White Blood Cell toxicity	NA	NA
10th percentile: Neutrophil toxicity	NA	0.92
20th percentile: Neutrophil toxicity	NA	NA
10th percentile: CD4+ count toxicity	0.92	2.96
20th percentile: CD4+ count toxicity	0.99	7.00
10th percentile: ALT toxicity	NA
20th percentile: ALT toxicity	NA

Adverse Events

Time Frame	DB Period: Baseline up to Week 96; OL Extension Period and Safety follow-up period: Baseline up to Week 96
Adverse Event Reporting Description	An adverse event (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.
Arm/Group Title	Cladribine 3.5 mg/kg, IFN-beta (DB Period)		Placebo, IFN-beta (DB Period)		Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)		Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)		Cladribine 3.5 mg/kg, IFN-beta (Safety Follow up)		Placebo, IFN-beta (Safety Follow up)
Arm/Group Description	Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.		Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.		Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the open label (OL) extension (Ext.) period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.		Participants who received placebo initially and completed DB period entered in the OL Ext. period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.		Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the OL ext. safety follow up period. In this period, participants who did not meet eligibility criteria received only IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.		Participants who received placebo initially and completed DB period entered in the OL ext. safety follow up period. In this period, participants who did not meet eligibility criteria received only IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.
All Cause Mortality
	Cladribine 3.5 mg/kg, IFN-beta (DB Period)		Placebo, IFN-beta (DB Period)		Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)		Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)		Cladribine 3.5 mg/kg, IFN-beta (Safety Follow up)		Placebo, IFN-beta (Safety Follow up)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/124 (0%)		0/48 (0%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Serious Adverse Events
	Cladribine 3.5 mg/kg, IFN-beta (DB Period)		Placebo, IFN-beta (DB Period)		Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)		Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)		Cladribine 3.5 mg/kg, IFN-beta (Safety Follow up)		Placebo, IFN-beta (Safety Follow up)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/124 (9.7%)		5/48 (10.4%)		0/47 (0%)		1/28 (3.6%)		1/52 (1.9%)		0/7 (0%)
Gastrointestinal disorders
Anal fissure	1/124 (0.8%)		0/48 (0%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Pancreatitis acute	1/124 (0.8%)		0/48 (0%)		0/47 (0%)		0/28 (0%)		1/52 (1.9%)		0/7 (0%)
General disorders
Non-cardiac chest pain	0/124 (0%)		1/48 (2.1%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Hepatobiliary disorders
Cholecystitis	2/124 (1.6%)		0/48 (0%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Hepatic cyst	0/124 (0%)		1/48 (2.1%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Infections and infestations
Genital herpes	1/124 (0.8%)		0/48 (0%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Human ehrlichiosis	1/124 (0.8%)		0/48 (0%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Pyelonephritis acute	1/124 (0.8%)		0/48 (0%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Urinary tract infection	1/124 (0.8%)		0/48 (0%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Injury, poisoning and procedural complications
Traumatic haematoma	0/124 (0%)		0/48 (0%)		0/47 (0%)		1/28 (3.6%)		0/52 (0%)		0/7 (0%)
Ulna fracture	0/124 (0%)		0/48 (0%)		0/47 (0%)		1/28 (3.6%)		0/52 (0%)		0/7 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/124 (0%)		0/48 (0%)		0/47 (0%)		1/28 (3.6%)		0/52 (0%)		0/7 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign breast neoplasm	1/124 (0.8%)		0/48 (0%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Lipoma	1/124 (0.8%)		0/48 (0%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Melanocytic naevus	1/124 (0.8%)		0/48 (0%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Seborrhoeic keratosis	1/124 (0.8%)		0/48 (0%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Skin papilloma	1/124 (0.8%)		0/48 (0%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Nervous system disorders
Grand mal convulsion	1/124 (0.8%)		0/48 (0%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Status epilepticus	1/124 (0.8%)		0/48 (0%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	0/124 (0%)		1/48 (2.1%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Renal and urinary disorders
Atonic urinary bladder	1/124 (0.8%)		0/48 (0%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Hydronephrosis	1/124 (0.8%)		0/48 (0%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Nephrolithiasis	1/124 (0.8%)		0/48 (0%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Reproductive system and breast disorders
Menometrorrhagia	1/124 (0.8%)		0/48 (0%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Skin and subcutaneous tissue disorders
Skin lesion	0/124 (0%)		1/48 (2.1%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Surgical and medical procedures
Abortion induced	0/124 (0%)		1/48 (2.1%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	Cladribine 3.5 mg/kg, IFN-beta (DB Period)		Placebo, IFN-beta (DB Period)		Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)		Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)		Cladribine 3.5 mg/kg, IFN-beta (Safety Follow up)		Placebo, IFN-beta (Safety Follow up)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	111/124 (89.5%)		33/48 (68.8%)		24/47 (51.1%)		12/28 (42.9%)		0/52 (0%)		0/7 (0%)
Blood and lymphatic system disorders
Lymphopenia	50/124 (40.3%)		0/48 (0%)		11/47 (23.4%)		2/28 (7.1%)		0/52 (0%)		0/7 (0%)
Neutropenia	13/124 (10.5%)		3/48 (6.3%)		3/47 (6.4%)		3/28 (10.7%)		0/52 (0%)		0/7 (0%)
Leukopenia	14/124 (11.3%)		0/48 (0%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Gastrointestinal disorders
Nausea	18/124 (14.5%)		6/48 (12.5%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Diarrhoea	9/124 (7.3%)		1/48 (2.1%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Vomiting	4/124 (3.2%)		3/48 (6.3%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Dyspepsia	2/124 (1.6%)		3/48 (6.3%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
General disorders
Influenza like illness	13/124 (10.5%)		4/48 (8.3%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Pyrexia	13/124 (10.5%)		4/48 (8.3%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Fatigue	7/124 (5.6%)		3/48 (6.3%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Pain	2/124 (1.6%)		4/48 (8.3%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Infections and infestations
Nasopharyngitis	28/124 (22.6%)		8/48 (16.7%)		3/47 (6.4%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Upper respiratory tract infection	14/124 (11.3%)		8/48 (16.7%)		3/47 (6.4%)		1/28 (3.6%)		0/52 (0%)		0/7 (0%)
Sinusitis	15/124 (12.1%)		6/48 (12.5%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Urinary tract infection	14/124 (11.3%)		5/48 (10.4%)		1/47 (2.1%)		4/28 (14.3%)		0/52 (0%)		0/7 (0%)
Influenza	7/124 (5.6%)		4/48 (8.3%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Bronchitis	7/124 (5.6%)		2/48 (4.2%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Herpes zoster	7/124 (5.6%)		0/48 (0%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Injury, poisoning and procedural complications
Fall	0/124 (0%)		0/48 (0%)		1/47 (2.1%)		2/28 (7.1%)		0/52 (0%)		0/7 (0%)
Investigations
Lymphocyte count decreased	13/124 (10.5%)		0/48 (0%)		4/47 (8.5%)		1/28 (3.6%)		0/52 (0%)		0/7 (0%)
Alanine aminotransferase increased	2/124 (1.6%)		3/48 (6.3%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Musculoskeletal and connective tissue disorders
Back pain	10/124 (8.1%)		4/48 (8.3%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Pain in extremity	12/124 (9.7%)		0/48 (0%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Arthralgia	8/124 (6.5%)		2/48 (4.2%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Nervous system disorders
Headache	31/124 (25%)		10/48 (20.8%)		6/47 (12.8%)		1/28 (3.6%)		0/52 (0%)		0/7 (0%)
Dizziness	6/124 (4.8%)		3/48 (6.3%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Pregnancy, puerperium and perinatal conditions
Pregnancy	1/124 (0.8%)		3/48 (6.3%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Psychiatric disorders
Depression	7/124 (5.6%)		2/48 (4.2%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Insomnia	5/124 (4%)		3/48 (6.3%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	8/124 (6.5%)		4/48 (8.3%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Pharyngolaryngeal pain	7/124 (5.6%)		3/48 (6.3%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Sinus congestion	1/124 (0.8%)		3/48 (6.3%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)
Skin and subcutaneous tissue disorders
Rash	6/124 (4.8%)		3/48 (6.3%)		0/47 (0%)		0/28 (0%)		0/52 (0%)		0/7 (0%)

Limitations/Caveats

The 96-week DB treatment period of study was completed as planned, and safety and exploratory efficacy results are presented here. The duration of OL Ext. period was reduced for some participants, following termination of the development program.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.