Multiple SclerosisPhase 2ONWARDNCT00436826
A Phase 2 Study of Cladribine Add-on to Interferon-beta (IFN-beta) Therapy in Multiple Sclerosis (MS) Subjects With Active Disease (ONWARD)
A Phase 2 study testing Cladribine and Interferon-beta (IFN-beta) in people with Multiple Sclerosis, run by EMD Serono Research & Development Institute, Inc. at 39 sites in 4 countries.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Multiple Sclerosis
- What is being tested?
- Cladribine and Interferon-beta (IFN-beta)
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 172 participants
- Where
- 39 sitesin 4 countries
- Study dates
- 30 Nov 2006to 31 Mar 2012
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
39 sites in 4 countries.
39 sites in 4 countries
United States21 sites
Research Site
Albuquerque, New Mexico
Research Site
Atlanta, Georgia
Research Site
Bethlehem, Pennsylvania
Research Site
Boston, Massachusetts
Research Site
Boulder, Colorado
Research Site
Burlington, Vermont
Research Site
Charlotte, North Carolina
Research Site
Cullman, Alabama
Research Site
Fort Collins, Colorado
Research Site
Houston, Texas
Research Site
Los Angeles, California
Research Site
Nashville, Tennessee
Research Site
Newark, New Jersey
Research Site
Peoria, Illinois
Research Site
Philadelphia, Pennsylvania
Research Site
Phoenix, Arizona
Research Site
Round Rock, Texas
Research Site
Scottsdale, Arizona
Research Site
St Louis, Missouri
Research Site
Tampa, Florida
Research Site
Winston-Salem, North Carolina
Russia7 sites
Research Site
Arkhangelsk
Research Site
Kazan'
Research Site
Moscow
Research Site
Novosibirsk
Research Site
Saint Petersburg
Research Site
Samara
Research Site
Smolensk
Spain7 sites
Research Site
Alicante
Research site
Barcelona
Research Site
Bilbao
Research Site
Madrid
Research Site
Málaga
Research Site
Santiago
Research Site
Seville
Italy4 sites
Research Site
Fidenza
Research Site
Milan
Research Site
Naples
Research Site
Rome
About this study
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
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.
- Conditions
- Multiple Sclerosis
- Being tested
- Cladribine, Placebo, Interferon-beta (IFN-beta)
- Keywords
- Multiple Sclerosis, Relapsing forms, Interferon-beta therapy
- Medical subject headings
- Multiple Sclerosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CladribineDrug
Participants were administered with cladribine tablets orally as cumulative dose.
PlaceboDrug
Participants were administered with placebo orally.
Interferon-beta (IFN-beta)Drug
Also called Avonex®, Betaseron®, RNF
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.
| Study group | Role | What they receive |
|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB period) | Experimental | 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. Receives: Drug: Cladribine; Drug: Interferon-beta (IFN-beta) |
| Placebo, IFN-beta (DB period) | Placebo comparator | 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. Receives: Drug: Placebo; Drug: Interferon-beta (IFN-beta) |
| Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | Experimental | 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. Receives: Drug: Cladribine; Drug: Interferon-beta (IFN-beta) |
| Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | Placebo comparator | 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. Receives: Drug: Cladribine; Drug: Placebo; Drug: Interferon-beta (IFN-beta) |
| Cladribine 3.5 mg/kg, IFN-beta (Safety follow up) | Experimental | 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. Receives: Drug: Cladribine; Drug: Interferon-beta (IFN-beta) |
| Placebo, IFN-beta (Safety follow up) | Placebo comparator | 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. Receives: Drug: Placebo; Drug: Interferon-beta (IFN-beta) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline up to Week 96
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
Measured: Baseline up to Week 96
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.
Measured: Baseline up to Week 96
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.
Measured: Baseline up to Week 96
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.
Measured: Baseline up to Week 96
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.
Measured: Baseline, Week 96
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).
Measured: Baseline up to Week 96
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.
Measured: Baseline, Week 96
Double Blind Period: Mean Change From Baseline in Vital Signs- Pulse Rate
Mean change from baseline in vital signs- Pulse Rate was reported.
Measured: Baseline, Week 96
Double Blind Period: Mean Change From Baseline in Vital Signs- Weight
Mean change from baseline in vital signs- weight was reported.
Measured: Baseline, Week 96
Double Blind Period: Mean Change From Baseline in Vital Signs- Temperature
Mean change from baseline in vital signs- temperature was reported.
Measured: Baseline, Week 96
Double Blind Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- Heart Rate
Mean change from baseline in ECG parameters- Heart Rate was reported.
Measured: Baseline, Week 96
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.
Measured: Baseline, Week 96
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.
Measured: Baseline, Week 96
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.
Measured: Baseline, Week 96
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.
Measured: Baseline, Week 96
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).
Measured: Baseline up to Week 96
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.
Measured: Baseline, Week 72
Open Label Extension Period: Mean Change From Baseline in Vital Signs- Pulse Rate
Mean change from baseline in vital signs- Pulse Rate was reported.
Measured: Baseline, Week 72
Open Label Extension Period: Mean Change From Baseline in Vital Signs- Weight
Mean change from baseline in vital signs- weight was reported.
Measured: Baseline, Week 72
Open Label Extension Period: Mean Change From Baseline in Vital Signs- Temperature
Mean change from baseline in vital signs- temperature was reported.
Measured: Baseline, Week 72
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.
Measured: Baseline, Week 72
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.
Measured: Baseline, Week 72
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.
Measured: Baseline (OLEP) up to Week 96
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
Measured: Baseline (OLEP) up to Week 96
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.
Measured: Baseline (OLEP) up to Week 96
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.
Measured: Baseline up to Week 96
Secondary outcomes (12)
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.
Measured: Week 96
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.
Measured: Week 96
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.
Measured: Week 96
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.
Measured: Week 96
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.
Measured: Baseline, Week 96
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.
Measured: Baseline, Week 96
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.
Measured: Baseline, Week 96
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.
Measured: Baseline up to Week 96
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.
Measured: Baseline up to Week 96
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.
Measured: Baseline up to Week 96
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.
Measured: Baseline up to Week 96
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.
Measured: Baseline, Week 96
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Feb 2007 (estimated)
- Study start30 Nov 2006
- Primary completion30 Sep 2011
- Study completion31 Mar 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Multiple SclerosisStudies of the same condition, open and under way.
- More trials run by EMD Serono Research & Development Institute, Inc.The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 172 participants (actual)
Sponsor and investigators
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Medical Responsible, Study director, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00436826
- Sponsor's protocol ID
- 26593
- Other IDs
- 2006-003366-33
- Acronym
- ONWARD
- Status last verified
- Oct 2020
- First submitted
- 15 Feb 2007
- Last updated
- 12 Oct 2020
- Results posted
- Yes, on ClinicalTrials.gov
Publications
Giovannoni G, Galazka A, Schick R, Leist T, Comi G, Montalban X, Damian D, Dangond F, Cook S. Pregnancy Outcomes During the Clinical Development Program of Cladribine in Multiple Sclerosis: An Integrated Analysis of Safety. Drug Saf. 2020 Jul;43(7):635-643. doi: 10.1007/s40264-020-00948-x.
PubMed 32447743Montalban X, Leist TP, Cohen BA, Moses H, Campbell J, Hicking C, Dangond F. Cladribine tablets added to IFN-beta in active relapsing MS: The ONWARD study. Neurol Neuroimmunol Neuroinflamm. 2018 Jul 11;5(5):e477. doi: 10.1212/NXI.0000000000000477. eCollection 2018 Sep.
PubMed 30027104
Study at a glance
From the registry record, last updated by the sponsor on 12 Oct 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00436826
- Acronym / sponsor ID
- ONWARD / 26593
- Conditions
- Multiple Sclerosis
- Keywords
- Multiple Sclerosis, Relapsing forms, Interferon-beta therapy
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 172 participants (actual)
- Lead sponsor
- EMD Serono Research & Development Institute, Inc.Industry (pharma, biotech, devices)
- Study start
- 30 Nov 2006 (actual)
- Primary completion
- 30 Sep 2011 (actual)
- Study completion
- 31 Mar 2012 (actual)
- First posted
- 19 Feb 2007 (estimated)
- Results
- Posted 1 Jul 2013
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| Cladribine 3.5 mg/kg, IFN-beta (DB period) | Experimental | Drug: Cladribine, Drug: Interferon-beta (IFN-beta)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. |
| Placebo, IFN-beta (DB period) | Placebo comparator | Drug: Placebo, Drug: Interferon-beta (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 DB period of 96 weeks. |
| Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | Experimental | Drug: Cladribine, Drug: Interferon-beta (IFN-beta)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. |
| Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) | Placebo comparator | Drug: Cladribine, Drug: Placebo, Drug: Interferon-beta (IFN-beta)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. |
| Cladribine 3.5 mg/kg, IFN-beta (Safety follow up) | Experimental | Drug: Cladribine, Drug: Interferon-beta (IFN-beta)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. |
| Placebo, IFN-beta (Safety follow up) | Placebo comparator | Drug: Placebo, Drug: Interferon-beta (IFN-beta)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. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (23 listed)
- 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
Key exclusion criteria (17 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CladribineParticipants were administered with cladribine tablets orally as cumulative dose. | Drug | Cladribine 3.5 mg/kg, IFN-beta (DB period), Cladribine 3.5 mg/kg, IFN-beta (Safety follow up), Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext), Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) |
| PlaceboParticipants were administered with placebo orally. | Drug | Placebo, IFN-beta (DB period), Placebo, IFN-beta (Safety follow up), Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) |
| Interferon-beta (IFN-beta)Also: Avonex®, Betaseron®, RNFParticipants 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. | Drug | Cladribine 3.5 mg/kg, IFN-beta (DB period), Cladribine 3.5 mg/kg, IFN-beta (Safety follow up), Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext), Placebo, IFN-beta (DB period), Placebo, IFN-beta (Safety follow up), Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) |
Primary outcome
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.
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
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
12 secondary outcomes
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
Double Blind Period: Mean Number of T1 Hypointense Lesions Per Participant Per Scan at Week 96
Time frame: Week 96
Double Blind Period: Percentage of Participants With no Active T2 Lesions at Week 96
Time frame: Week 96
Double Blind Period: Percentage of Participants With no Active T1 Gd-Enhanced Lesions at Week 96
Time frame: Week 96
Double Blind Period: Mean Change in T2 Lesion Volume From Baseline to Week 96
Time frame: Baseline, Week 96
Double Blind Period: Percent Change in Normalized Brain Volume From Baseline to Week 96
Time frame: Baseline, Week 96
Double Blind Period: Mean Change in T1 Hypointense Lesion Volume From Baseline to Week 96
Time frame: Baseline, Week 96
Double Blind Period: Annualized Qualifying Relapse Rate
Time frame: Baseline up to Week 96
Double Blind Period: Percentage of Participants Qualifying Relapse-free
Time frame: Baseline up to Week 96
Double Blind Period and OLE Period: Time to 3-Month Sustained Expanded Disability Status Scale (EDSS) Progression
Time frame: Baseline up to Week 96
Double Blind Period and OLE Period: Time to First Qualifying Relapse
Time frame: Baseline up to Week 96
Double Blind Period: Mean Change in New T1 Gd+ Lesions From Baseline to Week 96
Time frame: Baseline, Week 96
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Oct 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 32447743Giovannoni G, Galazka A, Schick R, Leist T, Comi G, Montalban X, Damian D, Dangond F, Cook S. Pregnancy Outcomes During the Clinical Development Program of Cladribine in Multiple Sclerosis: An Integrated Analysis of Safety. Drug Saf. 2020 Jul;43(7):635-643. doi: 10.1007/s40264-020-00948-x.
- Derived from this study: PubMed 30027104Montalban X, Leist TP, Cohen BA, Moses H, Campbell J, Hicking C, Dangond F. Cladribine tablets added to IFN-beta in active relapsing MS: The ONWARD study. Neurol Neuroimmunol Neuroinflamm. 2018 Jul 11;5(5):e477. doi: 10.1212/NXI.0000000000000477. eCollection 2018 Sep.
- Trial Awareness and Transparency websiteLink provided by the sponsor.
- US Medical Information website, Medical ResourcesLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Responsible study director
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
39 sites in 4 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Cladribine and Interferon-beta (IFN-beta) in people with Multiple Sclerosis, run by EMD Serono Research & Development Institute, Inc. at 39 sites in 4 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 23 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 Oct 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 39 sites in United States, Russia, Spain, Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 1 Jul 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). The study lists 27 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00436826, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Oct 2020; AzTrials last refreshed its copy on 6 Nov 2026.