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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
EMD Serono
ClinicalTrials.gov Identifier:
NCT00436826
First received: February 15, 2007
Last updated: August 4, 2013
Last verified: August 2013
  Purpose

The goal of this study is 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 will randomize around 200 subjects 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) subjects, who are still experiencing relapses, and subjects who have received disease modifying drugs (DMDs), other than IFN-beta therapy, during their MS treatment history, but are currently on IFN-beta therapy and have experienced active MS symptoms (at least 1 relapse) during the 48 weeks prior to Screening, may also be enrolled.

Subjects will be randomized in a 2:1 fashion to receive up to 4 cycles of oral cladribine or matching placebo in combination with IFN-beta therapy. Subjects who complete the double-blind portion of the study will be invited to participate in an open-label extension phase of matching study design. Total participation is 96 weeks in double blind period, and up to 48 weeks in open label extension phase.


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

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, 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

Resource links provided by NLM:


Further study details as provided by EMD Serono:

Primary Outcome Measures:
  • Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to Week 96 ] [ Designated as safety issue: Yes ]
    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.

  • Percentage of Participants With Grade 3 or 4 (Common Terminology Criteria for Adverse Events [CTCAE]) Hematological or Liver Toxicity [ Time Frame: Baseline up to Week 96 ] [ Designated as safety issue: Yes ]
    Percentage of participants with Grade 3 or 4 CTCAE 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) and Aspartate transaminase (AST). According to CTCAE: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death

  • Percentage of Participants With Adverse Events in Infections and Infestations System Organ Class (SOC) [ Time Frame: Baseline up to Week 96 ] [ Designated as safety issue: Yes ]
    Adverse Events were entered in infections and infestations SOC as per medical dictionary for regulatory activities (MedDRA) version 11.0


Secondary Outcome Measures:
  • Number of Qualifying Relapses [ Time Frame: Baseline up to Week 96 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    Number of CUA lesions, active T2 lesions, and T1 Gd+ lesions were measured by using magnetic resonance imaging (MRI) scans

  • Annualized Qualifying Relapse Rate [ Time Frame: Baseline up to Week 96 ] [ Designated as safety issue: No ]
    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.


Enrollment: 214
Study Start Date: November 2006
Study Completion Date: March 2012
Primary Completion Date: September 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cladribine 3.5 mg/kg, IFN-beta Drug: Cladribine
Subjects will receive cladribine tablets orally as cumulative dose of 0.875 milligram per kilogram (mg/kg) over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 mg/kg during the double blind (DB) period of 96 weeks. Subjects who will complete the DB period will to enter in open label (OL) extension period, if they meet the eligibility criteria they will be given total cladribine dose of 3.5 mg/kg over 48 weeks.
Drug: Interferon-beta (IFN-beta)
Subjects will receive 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 Drug: Placebo
Subjects will receive matching placebo 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 matching placebo dose of 3.5 mg/kg during the DB period of 96 weeks.
Drug: Interferon-beta (IFN-beta)
Subjects will receive 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

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
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. Subjects 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 subjects 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), subject 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 subject 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 subject or could affect compliance with the study protocol
  • Has history of active or chronic infectious disease or any disease which compromises immune function (for example, human immunodeficiency virus [HIV]+, human T-lymphotropic virus [HTLV-1], Lyme disease, LTBI or TB)
  • Has an allergy or hypersensitivity to gadolinium, to cladribine or any of its excipients, or IFN-beta or any of its excipient(s)
  • Has any renal condition that would preclude the administration of gadolinium (for example, acute or chronic severe renal insufficiency [glomerular filtration rate less than 30 milliliter per minute {mL/min} per 1.73 square meter {m^2}])
  • Has a positive stool hemoccult test at Screening
  • Has a history of seizures not adequately controlled by treatment
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00436826

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Sponsors and Collaborators
EMD Serono
  More Information

No publications provided

Responsible Party: EMD Serono
ClinicalTrials.gov Identifier: NCT00436826     History of Changes
Other Study ID Numbers: 26593, 2006-003366-33
Study First Received: February 15, 2007
Results First Received: March 28, 2013
Last Updated: August 4, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by EMD Serono:
Multiple Sclerosis
Relapsing forms
Interferon-beta therapy

Additional relevant MeSH terms:
Multiple Sclerosis
Sclerosis
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Pathologic Processes
Interferon-beta
Interferons
Cladribine
Interferon beta-1b
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antiviral Agents
Anti-Infective Agents
Immunologic Factors
Physiological Effects of Drugs
Immunosuppressive Agents
Adjuvants, Immunologic

ClinicalTrials.gov processed this record on September 14, 2014