Clinical trial NCT00436826: A Phase 2 Study of Cladribine Add-on to Interferon-beta (IFN-beta) Therapy in Multiple Sclerosis (MS) Subjects With Active Disease (ONWARD)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Sclerosis
Keywords: Multiple Sclerosis
Relapsing forms
Interferon-beta therapy
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
First posted: 2007-02-19
Enrollment: 172
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
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
timeFrame: Baseline up to Week 96
measure: Double Blind Period: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) in Infections and Infestations System Organ Class (SOC)
timeFrame: Baseline up to Week 96
measure: Double Blind Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
timeFrame: Baseline up to Week 96
measure: Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity
timeFrame: Baseline up to Week 96
measure: Double Blind Period: Time to Recovery From Grade 3 or 4 Hematological Toxicity
timeFrame: Baseline up to Week 96
measure: Double Blind Period: Mean Changes in Lymphocytes, White Blood Cells (WBC), Neutrophils and Platelets Values From Baseline to Week 96
timeFrame: Baseline, Week 96
measure: Double Blind Period: Maximum Corrected QT Interval (QTc)
timeFrame: Baseline up to Week 96
measure: Double Blind Period: Mean Change From Baseline in Vital Signs- Systolic and Diastolic Blood Pressure
timeFrame: Baseline, Week 96
measure: Double Blind Period: Mean Change From Baseline in Vital Signs- Pulse Rate
timeFrame: Baseline, Week 96
measure: Double Blind Period: Mean Change From Baseline in Vital Signs- Weight
timeFrame: Baseline, Week 96
measure: Double Blind Period: Mean Change From Baseline in Vital Signs- Temperature
timeFrame: Baseline, Week 96
measure: Double Blind Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- Heart Rate
timeFrame: Baseline, Week 96
measure: Double Blind Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- PR, RR, QRS and OT Interval
timeFrame: Baseline, Week 96
measure: Double Blind Period: Mean Changes From Baseline in Hemoglobin Level to Week 96
timeFrame: Baseline, Week 96
measure: Double Blind Period: Mean Changes From Baseline in CD4+ Count, CD8+ Count, and CD19+ to Week 96
timeFrame: Baseline, Week 96
measure: Double Blind Period: Mean Changes From Baseline in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) to Week 96
timeFrame: Baseline, Week 96
measure: Open Label Extension Period: Maximum Corrected QT Interval (Qtc)
timeFrame: Baseline up to Week 96
measure: Open Label Extension Period: Mean Change From Baseline in Vital Signs- Systolic and Diastolic Blood Pressure
timeFrame: Baseline, Week 72
measure: Open Label Extension Period: Mean Change From Baseline in Vital Signs- Pulse Rate
timeFrame: Baseline, Week 72
measure: Open Label Extension Period: Mean Change From Baseline in Vital Signs- Weight
timeFrame: Baseline, Week 72
measure: Open Label Extension Period: Mean Change From Baseline in Vital Signs- Temperature
timeFrame: Baseline, Week 72
measure: Open Label Extension Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- Heart Rate
timeFrame: Baseline, Week 72
measure: Open Label Extension Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- PR, RR, QRS and OT Interval
timeFrame: Baseline, Week 72
measure: 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
timeFrame: Baseline (OLEP) up to Week 96
measure: OLE and Safety Follow-up Period: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) in Infections and Infestations System Organ Class (SOC)
timeFrame: Baseline (OLEP) up to Week 96
measure: OLE and Safety Follow-up Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
timeFrame: Baseline (OLEP) up to Week 96
measure: Open Label Extension Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity
timeFrame: Baseline up to Week 96
Secondary outcomes:
measure: 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
timeFrame: Week 96
measure: Double Blind Period: Mean Number of T1 Hypointense Lesions Per Participant Per Scan at Week 96
timeFrame: Week 96
measure: Double Blind Period: Percentage of Participants With no Active T2 Lesions at Week 96
timeFrame: Week 96
measure: Double Blind Period: Percentage of Participants With no Active T1 Gd-Enhanced Lesions at Week 96
timeFrame: Week 96
measure: Double Blind Period: Mean Change in T2 Lesion Volume From Baseline to Week 96
timeFrame: Baseline, Week 96
measure: Double Blind Period: Percent Change in Normalized Brain Volume From Baseline to Week 96
timeFrame: Baseline, Week 96
measure: Double Blind Period: Mean Change in T1 Hypointense Lesion Volume From Baseline to Week 96
timeFrame: Baseline, Week 96
measure: Double Blind Period: Annualized Qualifying Relapse Rate
timeFrame: Baseline up to Week 96
measure: Double Blind Period: Percentage of Participants Qualifying Relapse-free
timeFrame: Baseline up to Week 96
measure: Double Blind Period and OLE Period: Time to 3-Month Sustained Expanded Disability Status Scale (EDSS) Progression
timeFrame: Baseline up to Week 96
measure: Double Blind Period and OLE Period: Time to First Qualifying Relapse
timeFrame: Baseline up to Week 96
measure: Double Blind Period: Mean Change in New T1 Gd+ Lesions From Baseline to Week 96
timeFrame: Baseline, Week 96
Other outcomes:
Locations:
city: Cullman
country: United States
facility: Research Site
state: Alabama
city: Phoenix
country: United States
facility: Research Site
state: Arizona
city: Scottsdale
country: United States
facility: Research Site
state: Arizona
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Boulder
country: United States
facility: Research Site
state: Colorado
city: Fort Collins
country: United States
facility: Research Site
state: Colorado
city: Tampa
country: United States
facility: Research Site
state: Florida
city: Atlanta
country: United States
facility: Research Site
state: Georgia
city: Peoria
country: United States
facility: Research Site
state: Illinois
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Saint Louis
country: United States
facility: Research Site
state: Missouri
city: Newark
country: United States
facility: Research Site
state: New Jersey
city: Albuquerque
country: United States
facility: Research Site
state: New Mexico
city: Charlotte
country: United States
facility: Research Site
state: North Carolina
city: Winston-Salem
country: United States
facility: Research Site
state: North Carolina
city: Bethlehem
country: United States
facility: Research Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: Research Site
state: Pennsylvania
city: Nashville
country: United States
facility: Research Site
state: Tennessee
city: Houston
country: United States
facility: Research Site
state: Texas
city: Round Rock
country: United States
facility: Research Site
state: Texas
city: Burlington
country: United States
facility: Research Site
state: Vermont
city: Fidenza
country: Italy
facility: Research Site
city: Milan
country: Italy
facility: Research Site
city: Napoli
country: Italy
facility: Research Site
city: Rome
country: Italy
facility: Research Site
city: Arkhangelsk
country: Russian Federation
facility: Research Site
city: Kazan
country: Russian Federation
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Novosibirsk
country: Russian Federation
facility: Research Site
city: Samara
country: Russian Federation
facility: Research Site
city: Smolensk
country: Russian Federation
facility: Research Site
city: St. Petersburg
country: Russian Federation
facility: Research Site
city: Alicante
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research site
city: Bilbao
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Malaga
country: Spain
facility: Research Site
city: Santiago
country: Spain
facility: Research Site
city: Seville
country: Spain
facility: Research Site
Study officials:
affiliation: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.