A Phase 2 Study of Cladribine Add-on to Interferon-beta (IFN-beta) Therapy in Multiple Sclerosis (MS) Subjects With Active Disease (ONWARD)
NCT ID: NCT00436826
Last Updated: 2020-10-12
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE2
172 participants
INTERVENTIONAL
2006-11-30
2012-03-31
Brief Summary
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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.
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
TRIPLE
Study Groups
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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.
Cladribine
Participants were administered with cladribine tablets orally as cumulative dose.
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.
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.
Placebo
Participants were administered with placebo orally.
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.
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.
Cladribine
Participants were administered with cladribine tablets orally as cumulative dose.
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.
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.
Cladribine
Participants were administered with cladribine tablets orally as cumulative dose.
Placebo
Participants were administered with placebo orally.
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.
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.
Cladribine
Participants were administered with cladribine tablets orally as cumulative dose.
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.
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.
Placebo
Participants were administered with placebo orally.
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.
Interventions
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Cladribine
Participants were administered with cladribine tablets orally as cumulative dose.
Placebo
Participants were administered with placebo orally.
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 Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
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
18 Years
65 Years
ALL
No
Sponsors
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EMD Serono Research & Development Institute, Inc.
INDUSTRY
Responsible Party
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Principal Investigators
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Medical Responsible
Role: STUDY_DIRECTOR
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Locations
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Research Site
Cullman, Alabama, United States
Research Site
Phoenix, Arizona, United States
Research Site
Scottsdale, Arizona, United States
Research Site
Los Angeles, California, United States
Research Site
Boulder, Colorado, United States
Research Site
Fort Collins, Colorado, United States
Research Site
Tampa, Florida, United States
Research Site
Atlanta, Georgia, United States
Research Site
Peoria, Illinois, United States
Research Site
Boston, Massachusetts, United States
Research Site
St Louis, Missouri, United States
Research Site
Newark, New Jersey, United States
Research Site
Albuquerque, New Mexico, United States
Research Site
Charlotte, North Carolina, United States
Research Site
Winston-Salem, North Carolina, United States
Research Site
Bethlehem, Pennsylvania, United States
Research Site
Philadelphia, Pennsylvania, United States
Research Site
Nashville, Tennessee, United States
Research Site
Houston, Texas, United States
Research Site
Round Rock, Texas, United States
Research Site
Burlington, Vermont, United States
Research Site
Fidenza, , Italy
Research Site
Milan, , Italy
Research Site
Napoli, , Italy
Research Site
Rome, , Italy
Research Site
Arkhangelsk, , Russia
Research Site
Kazan', , Russia
Research Site
Moscow, , Russia
Research Site
Novosibirsk, , Russia
Research Site
Saint Petersburg, , Russia
Research Site
Samara, , Russia
Research Site
Smolensk, , Russia
Research Site
Alicante, , Spain
Research site
Barcelona, , Spain
Research Site
Bilbao, , Spain
Research Site
Madrid, , Spain
Research Site
Málaga, , Spain
Research Site
Santiago, , Spain
Research Site
Seville, , Spain
Countries
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References
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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.
Montalban 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.
Related Links
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Trial Awareness and Transparency website
US Medical Information website, Medical Resources
Other Identifiers
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2006-003366-33
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
26593
Identifier Type: -
Identifier Source: org_study_id
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