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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00436826
Recruitment Status : Completed
First Posted : February 19, 2007
Results First Posted : July 1, 2013
Last Update Posted : October 12, 2020
Sponsor:
Information provided by (Responsible Party):
EMD Serono ( EMD Serono Research & Development Institute, Inc. )

Brief Summary:

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

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

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


Condition or disease Intervention/treatment Phase
Multiple Sclerosis Drug: Cladribine Drug: Placebo Drug: Interferon-beta (IFN-beta) Phase 2

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

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cladribine 3.5 mg/kg, IFN-beta (DB period)
Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.
Drug: Cladribine
Participants were administered with cladribine tablets orally as cumulative dose.

Drug: Interferon-beta (IFN-beta)
Participants received IFN-beta therapy (Rebif® new formulation [RNF] 44 microgram [mcg] three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during both DB period of 96 weeks and OL extension period of 48 weeks.
Other Names:
  • Avonex®
  • Betaseron®
  • RNF

Placebo Comparator: Placebo, IFN-beta (DB period)
Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Drug: Placebo
Participants were administered with placebo orally.

Drug: Interferon-beta (IFN-beta)
Participants received IFN-beta therapy (Rebif® new formulation [RNF] 44 microgram [mcg] three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during both DB period of 96 weeks and OL extension period of 48 weeks.
Other Names:
  • Avonex®
  • Betaseron®
  • RNF

Experimental: Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)
Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the open label (OL) extension (Ext.) period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.
Drug: Cladribine
Participants were administered with cladribine tablets orally as cumulative dose.

Drug: Interferon-beta (IFN-beta)
Participants received IFN-beta therapy (Rebif® new formulation [RNF] 44 microgram [mcg] three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during both DB period of 96 weeks and OL extension period of 48 weeks.
Other Names:
  • Avonex®
  • Betaseron®
  • RNF

Placebo Comparator: Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)
Participants who received placebo initially and completed DB period entered in the OL Ext. period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.
Drug: Cladribine
Participants were administered with cladribine tablets orally as cumulative dose.

Drug: Placebo
Participants were administered with placebo orally.

Drug: Interferon-beta (IFN-beta)
Participants received IFN-beta therapy (Rebif® new formulation [RNF] 44 microgram [mcg] three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during both DB period of 96 weeks and OL extension period of 48 weeks.
Other Names:
  • Avonex®
  • Betaseron®
  • RNF

Experimental: Cladribine 3.5 mg/kg, IFN-beta (Safety follow up)
Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the OL ext. safety follow up period. In this period, participants who did not meet eligibility criteria received only IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.
Drug: Cladribine
Participants were administered with cladribine tablets orally as cumulative dose.

Drug: Interferon-beta (IFN-beta)
Participants received IFN-beta therapy (Rebif® new formulation [RNF] 44 microgram [mcg] three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during both DB period of 96 weeks and OL extension period of 48 weeks.
Other Names:
  • Avonex®
  • Betaseron®
  • RNF

Placebo Comparator: Placebo, IFN-beta (Safety follow up)
Participants who received placebo initially and completed DB period entered in the OL ext. safety follow up period. In this period, participants who did not meet eligibility criteria received only IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.
Drug: Placebo
Participants were administered with placebo orally.

Drug: Interferon-beta (IFN-beta)
Participants received IFN-beta therapy (Rebif® new formulation [RNF] 44 microgram [mcg] three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during both DB period of 96 weeks and OL extension period of 48 weeks.
Other Names:
  • Avonex®
  • Betaseron®
  • RNF




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

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

  3. Double Blind Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs [ Time Frame: Baseline up to Week 96 ]
    An AE was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered. SAE: Any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was a medically important condition. An AE was considered as 'treatment emergent' if it occurred after the first drug administration of each period or if it was present prior to drug administration but exacerbated after the drug administration. TEAEs included both Serious TEAEs and non-serious TEAEs.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

  26. OLE and Safety Follow-up Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs [ Time Frame: Baseline (OLEP) up to Week 96 ]
    An AE was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered. SAE: Any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was a medically important condition. An AE was considered as 'treatment emergent' if it occurred after the first drug administration of each period or if it was present prior to drug administration but exacerbated after the drug administration. TEAEs included both Serious TEAEs and non-serious TEAEs.

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


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

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

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

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

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

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

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

  8. Double Blind Period: Annualized Qualifying Relapse Rate [ Time Frame: Baseline up to Week 96 ]
    A qualifying relapse was defined as a 2-grade increase in at least one, or a 1-grade increase in at least two, Kurtzke Functional Systems excluding bowel/bladder or cognition changes, in the absence of fever lasting more than or equal to 24 hours, and preceded by more than or equal to 30 days of clinical stability or improvement. The annualized relapse rate for each treatment group was the mean of the annualized relapse rates for all the participants in the group, calculated as the total number of confirmed relapses divided by the total number of days on study multiplied by 365.25.

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

  10. Double Blind Period and OLE Period: Time to 3-Month Sustained Expanded Disability Status Scale (EDSS) Progression [ Time Frame: Baseline up to Week 96 ]
    EDSS progression is based on a standardized neurological exam and focuses on symptoms that commonly occur in Multiple Sclerosis (MS). Overall scores ranges from 0.0 (normal) to 10.0 (death due to MS). A sustained progression on EDSS score was defined as an EDSS progression confirmed into two consecutive assessment. Time to sustained disability progression was analyzed using a Cox proportional hazards model. 10th and 20th percentiles estimated from Kaplan-Meier survival curve. Due to the small number of events, estimates from Kaplan-Meier survival curves could only be derived for lower percentiles. The median (50th percentile) could not be estimated if less than 50% of the participants had an event during the time of the study. Accordingly, lower percentiles are presented according to the number of events observed.

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

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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Be male or female, 18 to 65 years of age (inclusive)
  • Weigh between 40 to 120 kilogram (kg), (inclusive)
  • Have definite MS, as confirmed by the revised McDonald criteria 2005, and have relapsing forms of MS, such as relapsing-remitting multiple sclerosis (RRMS) or SPMS with superimposed relapses
  • Have experienced at least one relapse within 48 weeks prior to Screening, while receiving IFN-beta treatments (Rebif® 44mcg three times a week, subcutaneously; Avonex®30 mcg every week, intramuscular; or Betaseron® 250 mcg every other day, subcutaneously)
  • Have a minimum time on IFN-beta therapy of 48-consecutive weeks prior to Screening. Participants who switched from one IFN-beta therapy to another in the 48 weeks preceding Screening may be entered into the study if they have been on a stable regimen of their current IFN-beta therapy for a minimum of 3 months prior to Screening
  • Be clinically stable (other than MS relapse) during the 28 days preceding Screening
  • The following hematological parameters must be normal (as defined below, inclusively) within 28 days of first dosing of blinded study medication at study day 1 (SD 1)

    • Hemoglobin=11.6 to 16.2 gram per deciliter (g/dL)
    • Leukocytes (total white blood cells [WBC])=4.1 to 12.3*10^3 per microliter (/UL)
    • Absolute lymphocytes count (ALC)= 1.02 to 3.36*10^3/UL
    • Absolute neutrophil count (ANC)=2.03 to 8.36*10^3/UL
    • Platelet count=140 to 450*10^3/UL
  • Have no medical history or evidence of latent tuberculosis infection (LTBI) or active tubercular disease (TB), as evidenced by TB skin test or chest X-ray
  • Have an expanded disability status scale (EDSS) from 1.0-5.5, inclusive
  • Have no prior exposure to immunosuppressive or cytotoxic agents (with the exception of steroids for MS flare management, or intravenous immunoglobulin-G [IVIG] after allowed wash-out periods
  • If female, must:

    • be neither pregnant nor breast-feeding, nor attempting to conceive, and
    • use a highly effective method of contraception throughout the entire duration of the study and for 6 months (6 menstrual cycles) following completion of the last dose of study medication. A highly effective method of contraception is defined as one which result in a low failure rate (that is, less than 1 percent per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or a vasectomized partner. For the purpose of this trial, women of childbearing potential are defined as: All female participants after puberty unless they are post-menopausal for at least 2 years, or are surgically sterile
  • If male, must be willing to use contraception to avoid pregnancies throughout the entire duration of the study and for 90 days following the last dose of study medication
  • Be willing and able to comply with study procedures for the duration of the study
  • Have not met any of the exclusion criteria outlined below; and
  • Have voluntarily provided written informed consent, including, for United states of America (USA), participant authorization under Health Insurance Portability and Accountability Act (HIPAA), prior to any study-related procedure that is not part of normal medical care, and with the understanding that the participant may withdraw consent at any time without prejudice to future medical care
  • Other protocol defined inclusion criteria may apply

Exclusion Criteria:

  • Has primary progressive multiple sclerosis (PPMS) or SPMS without relapses forms
  • Has prior or current malignancy other than medically documented complete excision of basal cell skin cancer no less than 5 years prior to Screening
  • Has a history of chronic or clinically significant hematological abnormalities
  • Prior use of cladribine, fingolimod, teriflunimide, laquinimod, mitoxantrone, campath-1h, cyclophosphamide, azathioprine, methotrexate, daclizumab, natalizumab, lymphoid irradiation, bone marrow transplantation or myelosuppressive/cytotoxic therapy
  • Use of cytokine or anti-cytokine therapy or plasmapheresis within 3 months prior to SD 1
  • Treatment with IVIG within 30 days of Screening
  • Treatment with oral or parenteral corticosteroids 30 days of Screening
  • Treatment with adrenocorticotropic hormone within 28 days prior to SD 1
  • Use of any investigational drug (other than Rebif® New Formulation [RNF], Avonex® or Betaferon®) or experimental procedure within 6 months prior to SD 1
  • Has inadequate liver function, defined by a total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) or alkaline phosphatase greater than 2.5 times the upper limit of the normal values
  • Suffers from major medical illness such as cardiac, endocrinologic, hepatic, immunologic (other than MS), metabolic, renal, pulmonary, gastrointestinal, dermatologic, or other major disease that would preclude the administration of oral cladribine
  • Suffers from major psychiatric illness (including history of, or current, severe depressive disorders and/or suicidal ideation) that in the opinion of the investigator creates undue risk to the participant or could affect compliance with the study protocol
  • Has history of active or chronic infectious disease or any disease which compromises immune function (for example, human immunodeficiency virus [HIV]+, human T-lymphotropic virus [HTLV-1], Lyme disease, LTBI or TB)
  • Has an allergy or hypersensitivity to gadolinium, to cladribine or any of its excipients, or IFN-beta or any of its excipient(s)
  • Has any renal condition that would preclude the administration of gadolinium (for example, acute or chronic severe renal insufficiency [glomerular filtration rate less than 30 milliliter per minute {mL/min} per 1.73 square meter {m^2}])
  • Has a positive stool hemoccult test at Screening
  • Has a history of seizures not adequately controlled by treatment

Information from the National Library of Medicine

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

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00436826


Locations
Layout table for location information
United States, Alabama
Research Site
Cullman, Alabama, United States
United States, Arizona
Research Site
Phoenix, Arizona, United States
Research Site
Scottsdale, Arizona, United States
United States, California
Research Site
Los Angeles, California, United States
United States, Colorado
Research Site
Boulder, Colorado, United States
Research Site
Fort Collins, Colorado, United States
United States, Florida
Research Site
Tampa, Florida, United States
United States, Georgia
Research Site
Atlanta, Georgia, United States
United States, Illinois
Research Site
Peoria, Illinois, United States
United States, Massachusetts
Research Site
Boston, Massachusetts, United States
United States, Missouri
Research Site
Saint Louis, Missouri, United States
United States, New Jersey
Research Site
Newark, New Jersey, United States
United States, New Mexico
Research Site
Albuquerque, New Mexico, United States
United States, North Carolina
Research Site
Charlotte, North Carolina, United States
Research Site
Winston-Salem, North Carolina, United States
United States, Pennsylvania
Research Site
Bethlehem, Pennsylvania, United States
Research Site
Philadelphia, Pennsylvania, United States
United States, Tennessee
Research Site
Nashville, Tennessee, United States
United States, Texas
Research Site
Houston, Texas, United States
Research Site
Round Rock, Texas, United States
United States, Vermont
Research Site
Burlington, Vermont, United States
Italy
Research Site
Fidenza, Italy
Research Site
Milan, Italy
Research Site
Napoli, Italy
Research Site
Rome, Italy
Russian Federation
Research Site
Arkhangelsk, Russian Federation
Research Site
Kazan, Russian Federation
Research Site
Moscow, Russian Federation
Research Site
Novosibirsk, Russian Federation
Research Site
Samara, Russian Federation
Research Site
Smolensk, Russian Federation
Research Site
St. Petersburg, Russian Federation
Spain
Research Site
Alicante, Spain
Research site
Barcelona, Spain
Research Site
Bilbao, Spain
Research Site
Madrid, Spain
Research Site
Malaga, Spain
Research Site
Santiago, Spain
Research Site
Seville, Spain
Sponsors and Collaborators
EMD Serono Research & Development Institute, Inc.
Investigators
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Study Director: Medical Responsible Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: EMD Serono Research & Development Institute, Inc.
ClinicalTrials.gov Identifier: NCT00436826    
Other Study ID Numbers: 26593
2006-003366-33 ( EudraCT Number )
First Posted: February 19, 2007    Key Record Dates
Results First Posted: July 1, 2013
Last Update Posted: October 12, 2020
Last Verified: October 2020
Keywords provided by EMD Serono ( EMD Serono Research & Development Institute, Inc. ):
Multiple Sclerosis
Relapsing forms
Interferon-beta therapy
Additional relevant MeSH terms:
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Multiple Sclerosis
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Interferons
Interferon-beta
Cladribine
Interferon beta-1b
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunologic Factors
Physiological Effects of Drugs
Immunosuppressive Agents
Adjuvants, Immunologic