Multiple Sclerosis
Conditions
Keywords
Multiple Sclerosis, Relapsing forms, Interferon-beta therapy
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.
Interventions
DRUGCladribine
Participants were administered with cladribine tablets orally as cumulative dose.
DRUGPlacebo
Participants were administered with placebo orally.
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.
Sponsors
EMD Serono Research & Development Institute, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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). |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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 |
| 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. |
| 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. |
| 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 |
| 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. |
| 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. |
| 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. |
| 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. |
| 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). |
| 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. |
| 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. |
| Double Blind Period: Mean Change From Baseline in Vital Signs- Weight | Baseline, Week 96 | Mean change from baseline in vital signs- weight was reported. |
| Double Blind Period: Mean Change From Baseline in Vital Signs- Temperature | Baseline, Week 96 | Mean change from baseline in vital signs- temperature was reported. |
| 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. |
| 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Italy, Russia, Spain, United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Cladribine 3.5 mg/kg, IFN-beta 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. | 124 |
| Placebo, IFN-beta 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. | 48 |
| Total | 172 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Double Blind Period (DBP) | Adverse Event | 2 | 0 | 0 | 0 | 0 | 0 |
| Double Blind Period (DBP) | Other | 10 | 11 | 0 | 0 | 0 | 0 |
| Double Blind Period (DBP) | Protocol Violation | 1 | 0 | 0 | 0 | 0 | 0 |
| Ext. Period (No Cladribine Treatment) | Sponsor's decision to terminate study | 0 | 0 | 0 | 0 | 51 | 7 |
| Ext. Period (With Cladribine Treatment) | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 | 0 |
| Ext. Period (With Cladribine Treatment) | Other un-specified | 0 | 0 | 46 | 25 | 0 | 0 |
Baseline characteristics
| Characteristic | Cladribine 3.5 mg/kg, IFN-beta | Placebo, IFN-beta | Total |
|---|---|---|---|
| Age, Continuous | 38.5 years STANDARD_DEVIATION 10.2 | 40.1 years STANDARD_DEVIATION 10.3 | 38.9 years STANDARD_DEVIATION 10.2 |
| Expanded disability status scale (EDSS) score | 2.9 unit on scale STANDARD_DEVIATION 1.2 | 3.0 unit on scale STANDARD_DEVIATION 1.2 | 2.9 unit on scale STANDARD_DEVIATION 1.2 |
| Number of Gadolinium-enhanced lesions | 1.1 lesions STANDARD_DEVIATION 4 | 0.6 lesions STANDARD_DEVIATION 1.2 | 0.9 lesions STANDARD_DEVIATION 3.4 |
| Number of Time constant 1 (T1) hypointense lesions | 9.0 lesions STANDARD_DEVIATION 9.2 | 9.3 lesions STANDARD_DEVIATION 9.9 | 9.1 lesions STANDARD_DEVIATION 9.3 |
| Sex: Female, Male Female | 84 Participants | 36 Participants | 120 Participants |
| Sex: Female, Male Male | 40 Participants | 12 Participants | 52 Participants |
| T1 Gd+ volume | 150.3 cubic millimetre (mm^3) STANDARD_DEVIATION 592.2 | 99.4 cubic millimetre (mm^3) STANDARD_DEVIATION 210 | 136.1 cubic millimetre (mm^3) STANDARD_DEVIATION 514.5 |
| T2 lesions volume | 10791.2 mm^3 STANDARD_DEVIATION 11298 | 13669.1 mm^3 STANDARD_DEVIATION 16605.2 | 11596.3 mm^3 STANDARD_DEVIATION 13013.5 |
| Time (years) from first attack to study Day 1 | 9.98 years STANDARD_DEVIATION 7.24 | 10.83 years STANDARD_DEVIATION 7.98 | 10.22 years STANDARD_DEVIATION 7.44 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 124 | 0 / 48 | 0 / 47 | 0 / 28 | 0 / 52 | 0 / 7 |
| other Total, other adverse events | 111 / 124 | 33 / 48 | 24 / 47 | 12 / 28 | 0 / 52 | 0 / 7 |
| serious Total, serious adverse events | 12 / 124 | 5 / 48 | 0 / 47 | 1 / 28 | 1 / 52 | 0 / 7 |
Outcome results
Primary
Double Blind Period: Maximum Corrected QT Interval (QTc)
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Maximum Corrected QT Interval (QTc) | 0.4381 Milliseconds | Standard Deviation 0.0194 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Maximum Corrected QT Interval (QTc) | 0.4361 Milliseconds | Standard Deviation 0.0176 |
Primary
Double Blind Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- Heart Rate
Mean change from baseline in ECG parameters- Heart Rate was reported.
Time frame: Baseline, Week 96
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- Heart Rate | -3.114 beats per minutes | Standard Deviation 8.99 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- Heart Rate | 1.981 beats per minutes | Standard Deviation 7.857 |
Primary
Double Blind Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- PR, RR, QRS and OT Interval
Mean change from baseline in ECG parameters- PR, RR, QRS and OT interval was reported.
Time frame: Baseline, Week 96
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- PR, RR, QRS and OT Interval | PR Interval | 0.0001 milliseconds | Standard Deviation 0.0094 |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- PR, RR, QRS and OT Interval | RR Interval | 0.0361 milliseconds | Standard Deviation 0.1068 |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- PR, RR, QRS and OT Interval | QRS Interval | 0.0028 milliseconds | Standard Deviation 0.006 |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- PR, RR, QRS and OT Interval | QT Interval | 0.0135 milliseconds | Standard Deviation 0.0214 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- PR, RR, QRS and OT Interval | QT Interval | 0.0037 milliseconds | Standard Deviation 0.0189 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- PR, RR, QRS and OT Interval | PR Interval | 0.0033 milliseconds | Standard Deviation 0.0108 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- PR, RR, QRS and OT Interval | QRS Interval | 0.0043 milliseconds | Standard Deviation 0.0054 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- PR, RR, QRS and OT Interval | RR Interval | -0.0272 milliseconds | Standard Deviation 0.1175 |
Primary
Double Blind Period: Mean Change From Baseline in Vital Signs- Pulse Rate
Mean change from baseline in vital signs- Pulse Rate was reported.
Time frame: Baseline, Week 96
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Mean Change From Baseline in Vital Signs- Pulse Rate | 1.0 beats per minutes | Standard Deviation 11.6 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Mean Change From Baseline in Vital Signs- Pulse Rate | 0.4 beats per minutes | Standard Deviation 9.2 |
Primary
Double Blind Period: Mean Change From Baseline in Vital Signs- Systolic and Diastolic Blood Pressure
Mean change from baseline in vital signs- systolic and diastolic blood pressure was reported.
Time frame: Baseline, Week 96
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Mean Change From Baseline in Vital Signs- Systolic and Diastolic Blood Pressure | Systolic Blood Pressure | -0.6 Millimeter of mercury (mm*hg) | Standard Deviation 13.2 |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Mean Change From Baseline in Vital Signs- Systolic and Diastolic Blood Pressure | Diastolic Blood Pressure | -0.6 Millimeter of mercury (mm*hg) | Standard Deviation 10.1 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Mean Change From Baseline in Vital Signs- Systolic and Diastolic Blood Pressure | Systolic Blood Pressure | 0.0 Millimeter of mercury (mm*hg) | Standard Deviation 13.1 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Mean Change From Baseline in Vital Signs- Systolic and Diastolic Blood Pressure | Diastolic Blood Pressure | -2.2 Millimeter of mercury (mm*hg) | Standard Deviation 8.9 |
Primary
Double Blind Period: Mean Change From Baseline in Vital Signs- Temperature
Mean change from baseline in vital signs- temperature was reported.
Time frame: Baseline, Week 96
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Mean Change From Baseline in Vital Signs- Temperature | -0.1 Degree celsius | Standard Deviation 0.3 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Mean Change From Baseline in Vital Signs- Temperature | -0.1 Degree celsius | Standard Deviation 0.4 |
Primary
Double Blind Period: Mean Change From Baseline in Vital Signs- Weight
Mean change from baseline in vital signs- weight was reported.
Time frame: Baseline, Week 96
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Mean Change From Baseline in Vital Signs- Weight | -0.6 Kilogram | Standard Deviation 8 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Mean Change From Baseline in Vital Signs- Weight | -0.4 Kilogram | Standard Deviation 5 |
Primary
Double Blind Period: Mean Changes From Baseline in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) to Week 96
Mean changes in ALT and AST from baseline to week 96 were reported.
Time frame: Baseline, Week 96
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Mean Changes From Baseline in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) to Week 96 | ALT | -3.0 Units per liter | Standard Deviation 11.5 |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Mean Changes From Baseline in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) to Week 96 | AST | -1.7 Units per liter | Standard Deviation 6.9 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Mean Changes From Baseline in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) to Week 96 | ALT | 1.3 Units per liter | Standard Deviation 11.5 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Mean Changes From Baseline in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) to Week 96 | AST | 1.1 Units per liter | Standard Deviation 6.2 |
Primary
Double Blind Period: Mean Changes From Baseline in CD4+ Count, CD8+ Count, and CD19+ to Week 96
Mean changes CD4+ Count, CD8+ Count, and CD19+ from baseline to Week 96 were reported.
Time frame: Baseline, Week 96
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Mean Changes From Baseline in CD4+ Count, CD8+ Count, and CD19+ to Week 96 | CD4+ | -604.1 Cells per microliter | Standard Deviation 301.3 |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Mean Changes From Baseline in CD4+ Count, CD8+ Count, and CD19+ to Week 96 | CD8+ | -137.8 Cells per microliter | Standard Deviation 178.1 |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Mean Changes From Baseline in CD4+ Count, CD8+ Count, and CD19+ to Week 96 | CD19+ | 22.0 Cells per microliter | Standard Deviation 141.2 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Mean Changes From Baseline in CD4+ Count, CD8+ Count, and CD19+ to Week 96 | CD4+ | 7.1 Cells per microliter | Standard Deviation 344.7 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Mean Changes From Baseline in CD4+ Count, CD8+ Count, and CD19+ to Week 96 | CD8+ | 23.9 Cells per microliter | Standard Deviation 188.3 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Mean Changes From Baseline in CD4+ Count, CD8+ Count, and CD19+ to Week 96 | CD19+ | 30.7 Cells per microliter | Standard Deviation 121.5 |
Primary
Double Blind Period: Mean Changes From Baseline in Hemoglobin Level to Week 96
Mean changes in hemoglobin level from baseline to week 96 was reported.
Time frame: Baseline, Week 96
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Mean Changes From Baseline in Hemoglobin Level to Week 96 | -2.9 gram per liter (g/L) | Standard Deviation 8.1 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Mean Changes From Baseline in Hemoglobin Level to Week 96 | -2.5 gram per liter (g/L) | Standard Deviation 10.6 |
Primary
Double Blind Period: Mean Changes in Lymphocytes, White Blood Cells (WBC), Neutrophils and Platelets Values From Baseline to Week 96
Mean changes in lymphocytes, WBC, neutrophils and platelets from baseline to week 96 were reported.
Time frame: Baseline, Week 96
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Mean Changes in Lymphocytes, White Blood Cells (WBC), Neutrophils and Platelets Values From Baseline to Week 96 | Lymphocytes | -0.8 10^9 cells per liter | Standard Deviation 0.5 |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Mean Changes in Lymphocytes, White Blood Cells (WBC), Neutrophils and Platelets Values From Baseline to Week 96 | Platelet | -29.8 10^9 cells per liter | Standard Deviation 37.9 |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Mean Changes in Lymphocytes, White Blood Cells (WBC), Neutrophils and Platelets Values From Baseline to Week 96 | WBC | -1.5 10^9 cells per liter | Standard Deviation 1.8 |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Mean Changes in Lymphocytes, White Blood Cells (WBC), Neutrophils and Platelets Values From Baseline to Week 96 | Neutrophils | -0.7 10^9 cells per liter | Standard Deviation 1.6 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Mean Changes in Lymphocytes, White Blood Cells (WBC), Neutrophils and Platelets Values From Baseline to Week 96 | Neutrophils | -0.4 10^9 cells per liter | Standard Deviation 1.2 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Mean Changes in Lymphocytes, White Blood Cells (WBC), Neutrophils and Platelets Values From Baseline to Week 96 | Lymphocytes | 0.0 10^9 cells per liter | Standard Deviation 0.7 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Mean Changes in Lymphocytes, White Blood Cells (WBC), Neutrophils and Platelets Values From Baseline to Week 96 | WBC | -0.4 10^9 cells per liter | Standard Deviation 1.6 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Mean Changes in Lymphocytes, White Blood Cells (WBC), Neutrophils and Platelets Values From Baseline to Week 96 | Platelet | -12.4 10^9 cells per liter | Standard Deviation 56.9 |
Primary
Double Blind Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
An AE was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered. SAE: Any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was a medically important condition. 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
Population: 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 | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 119 Participants |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with Serious TEAEs | 12 Participants |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 36 Participants |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with Serious TEAEs | 5 Participants |
Primary
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
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
Population: Safety population: all randomized participants who received at least 1 dose of study drug in DBP and had follow-up safety data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | 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 | Grade 3 or 4 Bilirubin toxicity | 0.00 Percentage of participants |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | 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 | Grade 3 or 4 Lymphocyte toxicity | 63.71 Percentage of participants |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | 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 | Grade 3 or 4 Hemoglobin toxicity | 2.42 Percentage of participants |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | 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 | Grade 3 or 4 White Blood Cell toxicity | 10.48 Percentage of participants |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | 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 | Grade 3 or 4 Neutrophil toxicity | 12.10 Percentage of participants |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | 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 | Grade 3 or 4 CD4+ toxicity | 50.81 Percentage of participants |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | 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 | Grade 3 or 4 AST toxicity | 0.81 Percentage of participants |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | 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 | Grade 3 or 4 ALT toxicity | 0.81 Percentage of participants |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | 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 | Grade 3 or 4 Platelet toxicity | 0.00 Percentage of participants |
| Placebo, IFN-beta (DB Period) | 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 | Grade 3 or 4 ALT toxicity | 2.08 Percentage of participants |
| Placebo, IFN-beta (DB Period) | 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 | Grade 3 or 4 CD4+ toxicity | 2.08 Percentage of participants |
| Placebo, IFN-beta (DB Period) | 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 | Grade 3 or 4 Lymphocyte toxicity | 2.08 Percentage of participants |
| Placebo, IFN-beta (DB Period) | 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 | Grade 3 or 4 Bilirubin toxicity | 0.00 Percentage of participants |
| Placebo, IFN-beta (DB Period) | 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 | Grade 3 or 4 Hemoglobin toxicity | 0.00 Percentage of participants |
| Placebo, IFN-beta (DB Period) | 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 | Grade 3 or 4 AST toxicity | 0.00 Percentage of participants |
| Placebo, IFN-beta (DB Period) | 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 | Grade 3 or 4 White Blood Cell toxicity | 0.00 Percentage of participants |
| Placebo, IFN-beta (DB Period) | 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 | Grade 3 or 4 Platelet toxicity | 0.00 Percentage of participants |
| Placebo, IFN-beta (DB Period) | 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 | Grade 3 or 4 Neutrophil toxicity | 2.08 Percentage of participants |
Primary
Double Blind Period: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) in Infections and Infestations System Organ Class (SOC)
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) in Infections and Infestations System Organ Class (SOC) | 61.3 Percentage of participants |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) in Infections and Infestations System Organ Class (SOC) | 54.2 Percentage of participants |
Primary
Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 20th percentile: CD4+ count toxicity | 2.99 Months |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 10th percentile: White Blood Cell toxicity | 17.74 Months |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 10th percentile: AST toxicity | NA Months |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 20th percentile: AST toxicity | NA Months |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 10th percentile: ALT toxicity | NA Months |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 20th percentile: White Blood Cell toxicity | NA Months |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 20th percentile: ALT toxicity | NA Months |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 10th percentile: Lymphocytes toxicity | 1.61 Months |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 10th percentile: Neutrophil toxicity | 12.55 Months |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 20th percentile: Lymphocytes toxicity | 2.00 Months |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 20th percentile: Neutrophil toxicity | NA Months |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 10th percentile:Hemoglobin toxicity | NA Months |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 10th percentile: CD4+ count toxicity | 1.87 Months |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 20th percentile:Hemoglobin toxicity | NA Months |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 20th percentile: ALT toxicity | NA Months |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 10th percentile: Lymphocytes toxicity | NA Months |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 20th percentile: Lymphocytes toxicity | NA Months |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 10th percentile: Neutrophil toxicity | NA Months |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 20th percentile: Neutrophil toxicity | NA Months |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 10th percentile: CD4+ count toxicity | NA Months |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 20th percentile: CD4+ count toxicity | NA Months |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 10th percentile: ALT toxicity | NA Months |
Primary
Double Blind Period: Time to Recovery From Grade 3 or 4 Hematological Toxicity
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Time to Recovery From Grade 3 or 4 Hematological Toxicity | Hemoglobin | 19.50 Days | Standard Deviation 10.61 |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Time to Recovery From Grade 3 or 4 Hematological Toxicity | White Blood Cell | 31.27 Days | Standard Deviation 27.69 |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Time to Recovery From Grade 3 or 4 Hematological Toxicity | Neutrophil | 41.17 Days | Standard Deviation 37.9 |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Time to Recovery From Grade 3 or 4 Hematological Toxicity | Lymphocyte | 142.53 Days | Standard Deviation 109.86 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Time to Recovery From Grade 3 or 4 Hematological Toxicity | Neutrophil | 56.75 Days | Standard Deviation 30.76 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Time to Recovery From Grade 3 or 4 Hematological Toxicity | Lymphocyte | 28.00 Days | — |
Primary
OLE and Safety Follow-up Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
An AE was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered. SAE: Any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was a medically important condition. 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
Population: 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 | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | OLE and Safety Follow-up Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 37 Participants |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | OLE and Safety Follow-up Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with Serious TEAEs | 0 Participants |
| Placebo, IFN-beta (DB Period) | OLE and Safety Follow-up Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with Serious TEAEs | 1 Participants |
| Placebo, IFN-beta (DB Period) | OLE and Safety Follow-up Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 19 Participants |
| Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | OLE and Safety Follow-up Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 22 Participants |
| Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | OLE and Safety Follow-up Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with Serious TEAEs | 1 Participants |
| Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | OLE and Safety Follow-up Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 0 Participants |
| Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | OLE and Safety Follow-up Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with Serious TEAEs | 0 Participants |
Primary
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
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | 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 | Grade 3 or 4 CD4+ toxicity | 66.0 Percentage of participants |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | 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 | Grade 3 or 4 Hemoglobin toxicity | 0.00 Percentage of participants |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | 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 | Grade 3 or 4 AST toxicity | 0.00 Percentage of participants |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | 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 | Grade 3 or 4 ALT toxicity | 0.00 Percentage of participants |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | 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 | Grade 3 or 4 Bilirubin toxicity | 0.00 Percentage of participants |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | 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 | Grade 3 or 4 White Blood Cell toxicity | 4.3 Percentage of participants |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | 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 | Grade 3 or 4 Lymphocyte toxicity | 48.9 Percentage of participants |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | 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 | Grade 3 or 4 Neutrophil toxicity | 6.4 Percentage of participants |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | 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 | Grade 3 or 4 Platelet toxicity | 0.00 Percentage of participants |
| Placebo, IFN-beta (DB Period) | 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 | Grade 3 or 4 Neutrophil toxicity | 14.3 Percentage of participants |
| Placebo, IFN-beta (DB Period) | 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 | Grade 3 or 4 White Blood Cell toxicity | 3.6 Percentage of participants |
| Placebo, IFN-beta (DB Period) | 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 | Grade 3 or 4 ALT toxicity | 3.6 Percentage of participants |
| Placebo, IFN-beta (DB Period) | 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 | Grade 3 or 4 Bilirubin toxicity | 0.00 Percentage of participants |
| Placebo, IFN-beta (DB Period) | 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 | Grade 3 or 4 AST toxicity | 0.00 Percentage of participants |
| Placebo, IFN-beta (DB Period) | 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 | Grade 3 or 4 Hemoglobin toxicity | 0.00 Percentage of participants |
| Placebo, IFN-beta (DB Period) | 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 | Grade 3 or 4 Platelet toxicity | 0.00 Percentage of participants |
| Placebo, IFN-beta (DB Period) | 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 | Grade 3 or 4 Lymphocyte toxicity | 28.6 Percentage of participants |
| Placebo, IFN-beta (DB Period) | 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 | Grade 3 or 4 CD4+ toxicity | 21.4 Percentage of participants |
| Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | 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 | Grade 3 or 4 Bilirubin toxicity | 0.00 Percentage of participants |
| Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | 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 | Grade 3 or 4 Lymphocyte toxicity | 3.9 Percentage of participants |
| Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | 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 | Grade 3 or 4 Hemoglobin toxicity | 2.0 Percentage of participants |
| Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | 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 | Grade 3 or 4 White Blood Cell toxicity | 0.00 Percentage of participants |
| Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | 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 | Grade 3 or 4 Neutrophil toxicity | 0.00 Percentage of participants |
| Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | 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 | Grade 3 or 4 CD4+ toxicity | 14.0 Percentage of participants |
| Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | 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 | Grade 3 or 4 AST toxicity | 0.00 Percentage of participants |
| Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | 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 | Grade 3 or 4 ALT toxicity | 0.00 Percentage of participants |
| Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | 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 | Grade 3 or 4 Platelet toxicity | 0.00 Percentage of participants |
| Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | 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 | Grade 3 or 4 Lymphocyte toxicity | 0.00 Percentage of participants |
| Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | 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 | Grade 3 or 4 ALT toxicity | 0.00 Percentage of participants |
| Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | 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 | Grade 3 or 4 Neutrophil toxicity | 0.00 Percentage of participants |
| Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | 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 | Grade 3 or 4 White Blood Cell toxicity | 0.00 Percentage of participants |
| Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | 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 | Grade 3 or 4 Bilirubin toxicity | 0.00 Percentage of participants |
| Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | 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 | Grade 3 or 4 Platelet toxicity | 0.00 Percentage of participants |
| Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | 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 | Grade 3 or 4 Hemoglobin toxicity | 0.00 Percentage of participants |
| Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | 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 | Grade 3 or 4 AST toxicity | 0.00 Percentage of participants |
| Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | 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 | Grade 3 or 4 CD4+ toxicity | 0.00 Percentage of participants |
Primary
OLE and Safety Follow-up Period: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) in Infections and Infestations System Organ Class (SOC)
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | OLE and Safety Follow-up Period: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) in Infections and Infestations System Organ Class (SOC) | 38.3 Percentage of participants |
| Placebo, IFN-beta (DB Period) | OLE and Safety Follow-up Period: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) in Infections and Infestations System Organ Class (SOC) | 21.4 Percentage of participants |
| Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | OLE and Safety Follow-up Period: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) in Infections and Infestations System Organ Class (SOC) | 11.5 Percentage of participants |
| Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | OLE and Safety Follow-up Period: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) in Infections and Infestations System Organ Class (SOC) | 0 Percentage of participants |
Primary
Open Label Extension Period: Maximum Corrected QT Interval (Qtc)
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Open Label Extension Period: Maximum Corrected QT Interval (Qtc) | 0.4370 Milliseconds | Standard Deviation 0.0219 |
| Placebo, IFN-beta (DB Period) | Open Label Extension Period: Maximum Corrected QT Interval (Qtc) | 0.4317 Milliseconds | Standard Deviation 0.0181 |
Primary
Open Label Extension Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- Heart Rate
Mean change from baseline in ECG parameters- Heart Rate was reported.
Time frame: Baseline, Week 72
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Open Label Extension Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- Heart Rate | -4.889 beats per minutes | Standard Deviation 6.16 |
Primary
Open Label Extension Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- PR, RR, QRS and OT Interval
Mean change from baseline in ECG parameters- PR, RR, QRS and OT interval was reported.
Time frame: Baseline, Week 72
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Open Label Extension Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- PR, RR, QRS and OT Interval | PR Interval | -0.0044 milliseconds | Standard Deviation 0.0108 |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Open Label Extension Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- PR, RR, QRS and OT Interval | RR Interval | 0.0643 milliseconds | Standard Deviation 0.0721 |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Open Label Extension Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- PR, RR, QRS and OT Interval | QRS Interval | -0.0026 milliseconds | Standard Deviation 0.009 |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Open Label Extension Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- PR, RR, QRS and OT Interval | QT Interval | 0.0109 milliseconds | Standard Deviation 0.0206 |
Primary
Open Label Extension Period: Mean Change From Baseline in Vital Signs- Pulse Rate
Mean change from baseline in vital signs- Pulse Rate was reported.
Time frame: Baseline, Week 72
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Open Label Extension Period: Mean Change From Baseline in Vital Signs- Pulse Rate | 4.7 beats per minutes | Standard Deviation 11.5 |
Primary
Open Label Extension Period: Mean Change From Baseline in Vital Signs- Systolic and Diastolic Blood Pressure
Mean change from baseline in vital signs- systolic and diastolic blood pressure was reported.
Time frame: Baseline, Week 72
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Open Label Extension Period: Mean Change From Baseline in Vital Signs- Systolic and Diastolic Blood Pressure | Systolic Blood Pressure | 0.3 Millimeter of mercury (mm*hg) | Standard Deviation 10.2 |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Open Label Extension Period: Mean Change From Baseline in Vital Signs- Systolic and Diastolic Blood Pressure | Diastolic Blood Pressure | -1.7 Millimeter of mercury (mm*hg) | Standard Deviation 5 |
Primary
Open Label Extension Period: Mean Change From Baseline in Vital Signs- Temperature
Mean change from baseline in vital signs- temperature was reported.
Time frame: Baseline, Week 72
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Open Label Extension Period: Mean Change From Baseline in Vital Signs- Temperature | -0.3 Degree celsius | Standard Deviation 0.3 |
Primary
Open Label Extension Period: Mean Change From Baseline in Vital Signs- Weight
Mean change from baseline in vital signs- weight was reported.
Time frame: Baseline, Week 72
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Open Label Extension Period: Mean Change From Baseline in Vital Signs- Weight | -9.4 Kilogram | Standard Deviation 6.9 |
Primary
Open Label Extension Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Open Label Extension Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 20th percentile: Neutrophil toxicity | NA Months |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Open Label Extension Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 20th percentile: White Blood Cell toxicity | NA Months |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Open Label Extension Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 10th percentile: CD4+ count toxicity | 0.92 Months |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Open Label Extension Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 10th percentile: White Blood Cell toxicity | NA Months |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Open Label Extension Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 20th percentile: CD4+ count toxicity | 0.99 Months |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Open Label Extension Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 10th percentile: Neutrophil toxicity | NA Months |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Open Label Extension Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 20th percentile: Lymphocytes toxicity | 1.64 Months |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Open Label Extension Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 10th percentile: Lymphocytes toxicity | 0.30 Months |
| Placebo, IFN-beta (DB Period) | Open Label Extension Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 20th percentile: CD4+ count toxicity | 7.00 Months |
| Placebo, IFN-beta (DB Period) | Open Label Extension Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 10th percentile: ALT toxicity | NA Months |
| Placebo, IFN-beta (DB Period) | Open Label Extension Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 20th percentile: ALT toxicity | NA Months |
| Placebo, IFN-beta (DB Period) | Open Label Extension Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 10th percentile: Lymphocytes toxicity | 0.36 Months |
| Placebo, IFN-beta (DB Period) | Open Label Extension Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 20th percentile: Lymphocytes toxicity | 2.23 Months |
| Placebo, IFN-beta (DB Period) | Open Label Extension Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 10th percentile: White Blood Cell toxicity | NA Months |
| Placebo, IFN-beta (DB Period) | Open Label Extension Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 20th percentile: White Blood Cell toxicity | NA Months |
| Placebo, IFN-beta (DB Period) | Open Label Extension Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 10th percentile: Neutrophil toxicity | 0.92 Months |
| Placebo, IFN-beta (DB Period) | Open Label Extension Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 20th percentile: Neutrophil toxicity | NA Months |
| Placebo, IFN-beta (DB Period) | Open Label Extension Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity | 10th percentile: CD4+ count toxicity | 2.96 Months |
Secondary
Double Blind Period and OLE Period: Time to 3-Month Sustained Expanded Disability Status Scale (EDSS) Progression
EDSS progression is based on a standardized neurological exam and focuses on symptoms that commonly occur in Multiple Sclerosis (MS). Overall scores ranges from 0.0 (normal) to 10.0 (death due to MS). A sustained progression on EDSS score was defined as an EDSS progression confirmed into two consecutive assessment. 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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period and OLE Period: Time to 3-Month Sustained Expanded Disability Status Scale (EDSS) Progression | 10th percentile | 244 Days |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period and OLE Period: Time to 3-Month Sustained Expanded Disability Status Scale (EDSS) Progression | 20th percentile | NA Days |
| Placebo, IFN-beta (DB Period) | Double Blind Period and OLE Period: Time to 3-Month Sustained Expanded Disability Status Scale (EDSS) Progression | 20th percentile | 0 Days |
| Placebo, IFN-beta (DB Period) | Double Blind Period and OLE Period: Time to 3-Month Sustained Expanded Disability Status Scale (EDSS) Progression | 10th percentile | 484 Days |
| Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | Double Blind Period and OLE Period: Time to 3-Month Sustained Expanded Disability Status Scale (EDSS) Progression | 10th percentile | 87 Days |
| Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | Double Blind Period and OLE Period: Time to 3-Month Sustained Expanded Disability Status Scale (EDSS) Progression | 20th percentile | 246 Days |
| Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | Double Blind Period and OLE Period: Time to 3-Month Sustained Expanded Disability Status Scale (EDSS) Progression | 10th percentile | 85 Days |
| Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | Double Blind Period and OLE Period: Time to 3-Month Sustained Expanded Disability Status Scale (EDSS) Progression | 20th percentile | 0 Days |
Secondary
Double Blind Period and OLE Period: Time to First Qualifying Relapse
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period and OLE Period: Time to First Qualifying Relapse | 20th percentile | NA Days |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period and OLE Period: Time to First Qualifying Relapse | 10th percentile | 239 Days |
| Placebo, IFN-beta (DB Period) | Double Blind Period and OLE Period: Time to First Qualifying Relapse | 10th percentile | 252 Days |
| Placebo, IFN-beta (DB Period) | Double Blind Period and OLE Period: Time to First Qualifying Relapse | 20th percentile | 481 Days |
| Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | Double Blind Period and OLE Period: Time to First Qualifying Relapse | 10th percentile | 255 Days |
| Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | Double Blind Period and OLE Period: Time to First Qualifying Relapse | 20th percentile | 0 Days |
| Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | Double Blind Period and OLE Period: Time to First Qualifying Relapse | 20th percentile | 0 Days |
| Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | Double Blind Period and OLE Period: Time to First Qualifying Relapse | 10th percentile | 155 Days |
Secondary
Double Blind Period: Annualized Qualifying Relapse Rate
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
Population: ITT population included all randomized participants who had received at least one dose of study medication in the DB period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Annualized Qualifying Relapse Rate | 0.12 relapses per year |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Annualized Qualifying Relapse Rate | 0.32 relapses per year |
p-value: <0.00195% CI: [0.22, 0.63]Wald Chi-square
Secondary
Double Blind Period: Mean Change in New T1 Gd+ Lesions From Baseline to Week 96
Mean change in new T1 Gd+ lesions from baseline to week 96 was reported.
Time frame: Baseline, Week 96
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Mean Change in New T1 Gd+ Lesions From Baseline to Week 96 | -1.0 Lesions | Standard Deviation 4.4 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Mean Change in New T1 Gd+ Lesions From Baseline to Week 96 | -0.3 Lesions | Standard Deviation 1.1 |
Secondary
Double Blind Period: Mean Change in T1 Hypointense Lesion Volume From Baseline to 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.
Time frame: Baseline, Week 96
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Mean Change in T1 Hypointense Lesion Volume From Baseline to Week 96 | -481.8 millimeter cubic | Standard Deviation 1097.2 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Mean Change in T1 Hypointense Lesion Volume From Baseline to Week 96 | -263.0 millimeter cubic | Standard Deviation 1678.3 |
Secondary
Double Blind Period: Mean Change in T2 Lesion Volume From Baseline to 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.
Time frame: Baseline, Week 96
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Mean Change in T2 Lesion Volume From Baseline to Week 96 | -2007.2 cubic millimeters (mm^3) | Standard Deviation 3718.3 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Mean Change in T2 Lesion Volume From Baseline to Week 96 | -1224.6 cubic millimeters (mm^3) | Standard Deviation 7056.3 |
Secondary
Double Blind Period: Mean Number of T1 Hypointense Lesions Per Participant Per Scan at 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.
Time frame: Week 96
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Mean Number of T1 Hypointense Lesions Per Participant Per Scan at Week 96 | 0.28 Lesions | Standard Deviation 0.63 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Mean Number of T1 Hypointense Lesions Per Participant Per Scan at Week 96 | 0.43 Lesions | Standard Deviation 1 |
Secondary
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
Number of CUA lesions, active T2 lesions, and T1 Gd+ lesions were measured by using magnetic resonance imaging (MRI) scans.
Time frame: Week 96
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | 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 | T1 Gd+ lesions | 0.06 Lesions | Standard Deviation 0.37 |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | 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 | CUA lesions | 0.55 Lesions | Standard Deviation 1.27 |
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | 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 | T2 lesions | 0.53 Lesions | Standard Deviation 1.26 |
| Placebo, IFN-beta (DB Period) | 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 | T1 Gd+ lesions | 0.34 Lesions | Standard Deviation 0.87 |
| Placebo, IFN-beta (DB Period) | 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 | CUA lesions | 1.12 Lesions | Standard Deviation 1.94 |
| Placebo, IFN-beta (DB Period) | 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 | T2 lesions | 1.04 Lesions | Standard Deviation 1.81 |
Secondary
Double Blind Period: Percentage of Participants Qualifying Relapse-free
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
Population: ITT population included all randomized participants who had received at least one dose of study medication in the DB period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Percentage of Participants Qualifying Relapse-free | 75.0 Percentage of Participants |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Percentage of Participants Qualifying Relapse-free | 52.1 Percentage of Participants |
Secondary
Double Blind Period: Percentage of Participants With no Active T1 Gd-Enhanced Lesions at 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.
Time frame: Week 96
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Percentage of Participants With no Active T1 Gd-Enhanced Lesions at Week 96 | 86.0 Percentage of Participants |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Percentage of Participants With no Active T1 Gd-Enhanced Lesions at Week 96 | 56.3 Percentage of Participants |
Secondary
Double Blind Period: Percentage of Participants With no Active T2 Lesions at 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.
Time frame: Week 96
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Percentage of Participants With no Active T2 Lesions at Week 96 | 56.2 Percentage of Participants |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Percentage of Participants With no Active T2 Lesions at Week 96 | 29.2 Percentage of Participants |
Secondary
Double Blind Period: Percent Change in Normalized Brain Volume From Baseline to 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.
Time frame: Baseline, Week 96
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB Period) | Double Blind Period: Percent Change in Normalized Brain Volume From Baseline to Week 96 | -1.01 Percent Change | Standard Deviation 1.03 |
| Placebo, IFN-beta (DB Period) | Double Blind Period: Percent Change in Normalized Brain Volume From Baseline to Week 96 | -1.42 Percent Change | Standard Deviation 0.73 |