Phase 2
N=172
A Phase 2 Study of Cladribine Add-on to Interferon-beta (IFN-beta) Therapy in Multiple Sclerosis (MS) Subjects With Active Disease (ONWARD)
Multiple Sclerosis
Bottom Line
View on ClinicalTrials.gov: NCT00436826 ↗Enrolled (actual)
172
Serious AEs
6.2%
Results posted
Jul 2013
Primary outcome: Primary: 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 — 63.71; 2.08; 2.42; 0.00 Percentage of participants
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- Cladribine (Drug); Placebo (Drug); Interferon-beta (IFN-beta) (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- EMD Serono Research & Development Institute, Inc.
- Primary completion
- Sep 2011
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY 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 |
63.71; 2.08; 2.42; 0.00; 10.48; 0.00 | — |
| PRIMARY Double Blind Period: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) in Infections and Infestations System Organ Class (SOC) |
61.3; 54.2 | — |
| PRIMARY Double Blind Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs |
119; 36; 12; 5 | — |
| PRIMARY Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity |
1.61; NA; 2.00; NA; NA; NA | — |
| PRIMARY Double Blind Period: Time to Recovery From Grade 3 or 4 Hematological Toxicity |
19.50; 31.27; 41.17; 56.75; 142.53; 28.00 | — |
| PRIMARY Double Blind Period: Mean Changes in Lymphocytes, White Blood Cells (WBC), Neutrophils and Platelets Values From Baseline to Week 96 |
-0.8; 0.0; -29.8; -12.4; -1.5; -0.4 | — |
| PRIMARY Double Blind Period: Maximum Corrected QT Interval (QTc) |
0.4381; 0.4361 | — |
| PRIMARY Double Blind Period: Mean Change From Baseline in Vital Signs- Systolic and Diastolic Blood Pressure |
-0.6; 0.0; -0.6; -2.2 | — |
| PRIMARY Double Blind Period: Mean Change From Baseline in Vital Signs- Pulse Rate |
1.0; 0.4 | — |
| PRIMARY Double Blind Period: Mean Change From Baseline in Vital Signs- Weight |
-0.6; -0.4 | — |
| PRIMARY Double Blind Period: Mean Change From Baseline in Vital Signs- Temperature |
-0.1; -0.1 | — |
| PRIMARY Double Blind Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- Heart Rate |
-3.114; 1.981 | — |
| PRIMARY Double Blind Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- PR, RR, QRS and OT Interval |
0.0001; 0.0033; 0.0361; -0.0272; 0.0028; 0.0043 | — |
| PRIMARY Double Blind Period: Mean Changes From Baseline in Hemoglobin Level to Week 96 |
-2.9; -2.5 | — |
| PRIMARY Double Blind Period: Mean Changes From Baseline in CD4+ Count, CD8+ Count, and CD19+ to Week 96 |
-604.1; 7.1; -137.8; 23.9; 22.0; 30.7 | — |
| PRIMARY Double Blind Period: Mean Changes From Baseline in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) to Week 96 |
-3.0; 1.3; -1.7; 1.1 | — |
| PRIMARY Open Label Extension Period: Maximum Corrected QT Interval (Qtc) |
0.4370; 0.4317 | — |
| PRIMARY Open Label Extension Period: Mean Change From Baseline in Vital Signs- Systolic and Diastolic Blood Pressure |
0.3; -1.7 | — |
| PRIMARY Open Label Extension Period: Mean Change From Baseline in Vital Signs- Pulse Rate |
4.7 | — |
| PRIMARY Open Label Extension Period: Mean Change From Baseline in Vital Signs- Weight |
-9.4 | — |
| PRIMARY Open Label Extension Period: Mean Change From Baseline in Vital Signs- Temperature |
-0.3 | — |
| PRIMARY Open Label Extension Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- Heart Rate |
-4.889 | — |
| PRIMARY Open Label Extension Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- PR, RR, QRS and OT Interval |
-0.0044; 0.0643; -0.0026; 0.0109 | — |
| PRIMARY 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 |
48.9; 28.6; 3.9; 0.00; 0.00; 0.00 | — |
| PRIMARY OLE and Safety Follow-up Period: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) in Infections and Infestations System Organ Class (SOC) |
38.3; 21.4; 11.5; 0 | — |
| PRIMARY OLE and Safety Follow-up Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs |
37; 19; 22; 0; 0; 1 | — |
| PRIMARY Open Label Extension Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity |
0.30; 0.36; 1.64; 2.23; NA; NA | — |
| SECONDARY 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 |
0.06; 0.34; 0.55; 1.12; 0.53; 1.04 | — |
| SECONDARY Double Blind Period: Mean Number of T1 Hypointense Lesions Per Participant Per Scan at Week 96 |
0.28; 0.43 | — |
| SECONDARY Double Blind Period: Percentage of Participants With no Active T2 Lesions at Week 96 |
56.2; 29.2 | — |
| SECONDARY Double Blind Period: Percentage of Participants With no Active T1 Gd-Enhanced Lesions at Week 96 |
86.0; 56.3 | — |
| SECONDARY Double Blind Period: Mean Change in T2 Lesion Volume From Baseline to Week 96 |
-2007.2; -1224.6 | — |
| SECONDARY Double Blind Period: Percent Change in Normalized Brain Volume From Baseline to Week 96 |
-1.01; -1.42 | — |
| SECONDARY Double Blind Period: Mean Change in T1 Hypointense Lesion Volume From Baseline to Week 96 |
-481.8; -263.0 | — |
| SECONDARY Double Blind Period: Annualized Qualifying Relapse Rate |
0.12; 0.32 | <0.001 sig |
| SECONDARY Double Blind Period: Percentage of Participants Qualifying Relapse-free |
75.0; 52.1 | — |
| SECONDARY Double Blind Period and OLE Period: Time to 3-Month Sustained Expanded Disability Status Scale (EDSS) Progression |
244; 484; 87; 85; NA; 0 | — |
| SECONDARY Double Blind Period and OLE Period: Time to First Qualifying Relapse |
239; 252; 255; 155; NA; 481 | — |
| SECONDARY Double Blind Period: Mean Change in New T1 Gd+ Lesions From Baseline to Week 96 |
-1.0; -0.3 | — |
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 myelosup
Data sourced from ClinicalTrials.gov (NCT00436826). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.