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

EMD Serono Research & Development Institute, Inc.172 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

172

Conditions

Multiple Sclerosis

Interventions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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.

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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).

Time frame: 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.

Time frame: 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.

Time frame: Baseline, Week 96

Double Blind Period: Mean Change From Baseline in Vital Signs- Weight

Mean change from baseline in vital signs- weight was reported.

Time frame: Baseline, Week 96

Double Blind Period: Mean Change From Baseline in Vital Signs- Temperature

Mean change from baseline in vital signs- temperature was reported.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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).

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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

Time frame: 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)

Time frame: Baseline (OLEP) up to Week 96

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

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.

Time frame: Baseline up to Week 96

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

Number of CUA lesions, active T2 lesions, and T1 Gd+ lesions were measured by using magnetic resonance imaging (MRI) scans.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline, Week 96

Double Blind Period: Mean Change in T1 Hypointense Lesion Volume From Baseline to Week 96

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

Overview

Conditions

Interventions

Eligibility

Locations (39)

Outcomes

Primary Outcomes

Secondary Outcomes