Multiple Sclerosis, Relapsing-Remitting
Conditions
Brief summary
The purpose of the study is to determine if cladribine tablets are a safe and effective treatment for relapsing-remitting multiple sclerosis (RRMS).
Detailed description
This is a randomized, double-blind, three-arm, placebo-controlled, multi-center study. The study includes a pre-study evaluation period (up to 28 days prior to the start of treatment); an initial treatment period from Week 1 to 48; and a re-treatment period during Week 49 to 96. During the initial treatment period (Week 1 to 48), eligible subjects are equally randomized by a central randomization system to receive either a) cladribine at a low dose (0.875 milligram per kilogram per course \[mg/kg/course\] for two courses plus placebo for two courses); b) cladribine at a high dose (0.875 mg/kg/course for four courses); or c) placebo (four courses). During the re-treatment period (Weeks 49 to 96), subjects received either a) cladribine at a low dose (0.875 mg/kg/course for two courses); or b) placebo (two courses). For all randomized subjects, there is a rescue option of treatment with Rebif® (interferon beta-1a 44 microgram (mcg) given subcutaneously three times a week), if the subject experienced more than one qualifying relapse, and/or experienced a sustained increase in their EDSS score of greater than or equal to (\>=) 1 point, or \>=1.5 points if baseline EDSS score is 0, (over a period of three months or greater), during a calendar year beginning at Week 24. To maintain the blind, there is a treating physician who view clinical laboratory results and assess adverse events and safety information, and an independent blinded evaluating physician who will perform neurological exams. A central neuroradiology center, also blinded to treatment, will assess magnetic resonance imaging (MRI) evaluations.
Interventions
DRUGCladribine 5.25 mg/kg
Cladribine tablet will be administered as cumulative dose of 0.875 milligram per kilogram (mg/kg) over a course of 4 or 5 consecutive days of 28-day period at Week 1, 5, 9, 13, 48, and 52 resulting in total cladribine dose of 5.25 mg/kg during the treatment period of 96 weeks.
DRUGCladribine 3.5 mg/kg
Cladribine tablet will be administered as cumulative dose of 0.875 mg/kg over a course of 4 or 5 consecutive days of 28-day period at Weeks 1, 5, 48, and 52 and placebo matched to cladribine tablet will be administered at Week 9 and 13 resulting in total cladribine dose of 3.5 mg/kg during the treatment period of 96 weeks.
OTHERPlacebo
Placebo matched to cladribine tablet will be administered over a course of 4 or 5 consecutive days of 28-day period at Weeks 1, 5, 9, 13, 48 and 52 during the treatment period of 96 weeks.
Sponsors
EMD Serono
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Male or female, between 18 and 65 years of age (inclusive, at time of informed consent) * Has definite MS according to the McDonald criteria * Has relapsing-remitting disease with 1 or more relapses within 12 months prior to Study Day 1 * Must have been clinically stable and not has a relapse within 28 days prior to Study Day 1 * Has MRI consistent with MS at the pre-study evaluation according to the Fazekas criteria * Has a EDSS score from 0 to 5.5, inclusive * Weighed between 40-120 kilogram (kg), inclusive * If female, she must: 1. be post-menopausal or surgically sterilized; or 2. uses a hormonal contraceptive, intra uterine device, diaphragm with spermicide, or condom with spermicide, for the duration of the study; and 3. be neither pregnant nor breast-feeding * If male, he must be willing to use contraception to avoid pregnancies * Be willing and able to comply with study procedures for the duration of the study * Voluntarily provides written informed consent, and for United states of America (USA) sites only, a subject authorization under Health Insurance Portability and Accountability Act (HIPAA)
Exclusion criteria
* Has secondary progressive MS (SPMS) or primary progressive MS (PPMS) * Prior use of disease modifying drugs (DMDs) within the last 3 months, or 2 or more prior treatment failures with DMDs on the basis of efficacy * Has significant leukopenia (white blood cell count less than 0.5 times the lower limit of normal of the central laboratory) within 28 days prior to Study Day 1 * Has received cladribine, mitoxantrone, total lymphoid irradiation, myelosuppressive therapy, campath-1h, cyclophosphamide, azathioprine, methotrexate or natalizumab * Has received oral or systemic corticosteroids or adrenocorticotropic hormone within 28 days prior to Study Day 1 * Has compromised immune function or infection * Has received oral or systemic corticosteroids or adrenocorticotropic hormone within 28 days prior to Study Day 1 * Has received cytokine-based therapy, intravenous immunoglobulin therapy, or plasmapheresis within 3 months prior to Study Day 1 * Has platelet and absolute neutrophil counts below the lower limit of normal range within 28 days prior to Study Day 1 * Has prior or current history of malignancy * Has a history of persistent anemia, leukopenia, neutropenia, or thrombocytopenia after immunosuppressive therapy * Has systemic disease that, in the opinion of the Investigator, might interfere with subject safety, compliance or evaluation of the condition under Study (for example, insulin-dependent diabetes, Lyme disease, clinically significant cardiac, hepatic, or renal disease, Human Immunodeficiency Virus, or Human T-Cell Lymphotrophic Virus Type-1) * Has a psychiatric disorder that, in the opinion of the Investigator, was unstable or would preclude safe participation in the study * Has allergy or hypersensitivity to gadolinium, to cladribine or any of its excipients * Has used any investigational drug or experimental procedure within 6 months prior to Study Day 1
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Qualifying Relapse Rate | Week 96 | A qualifying relapse was defined as an increase of 2 points in at least one functional system of the expanded disability status scale (EDSS) or an increase of 1 point in at least two functional systems (excluding changes in bowel or bladder function or cognition) in the absence of fever, lasting for at least 24 hours and to have been preceded by at least 30 days of clinical stability or improvement. Expanded disability status scale (EDSS) assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to multiple sclerosis \[MS\]) was calculated. The annualized relapse rate for each treatment group was calculated as the total number of confirmed relapses divided by the total number of days on study multiplied by 365.25. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Relapse-free Participants | Week 96 | A qualifying relapse was defined as an increase of 2 points in at least one functional system of the EDSS or an increase of 1 point in at least two functional systems (excluding changes in bowel or bladder function or cognition) in the absence of fever, lasting for at least 24 hours and to have been preceded by at least 30 days of clinical stability or improvement. Expanded disability status scale (EDSS) assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. |
| Time to Disability Progression | Baseline up to Week 96 | Time to disability progression was defined as the time to a sustained increase in EDSS score of at least 1 point if baseline EDSS score between 0.5 and 4.5 inclusively, or at least 1.5 points if the baseline EDSS score was 0, or at least 0.5 point if the baseline EDSS score was at least 5, over a period of at least three months. Expanded disability status scale (EDSS) assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. Tenth Percentile of time to sustained increase in EDSS score was reported using Kaplan-Meier survival curve. |
| Mean Number of Combined Unique (CU) Lesions, Active Time Constant 2 (T2) Lesions, and Active Time Constant 1 (T1) Gadolinium-Enhanced (Gd+) Lesions Per Participant Per Scan | Week 96 | Mean Number of CU lesions, active T2 lesions, and active T1 Gd+ lesions were measured by using magnetic resonance imaging (MRI) scans. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cladribine 5.25 mg/kg Cladribine tablet administered as cumulative dose of 0.875 milligram per kilogram (mg/kg) over a course of 4 or 5 consecutive days of 28-day period at Week 1, 5, 9, 13, 48, and 52 resulting in total cladribine dose of 5.25 mg/kg during the treatment period of 96 weeks. | 456 |
| Cladribine 3.5 mg/kg Cladribine tablet administered as cumulative dose of 0.875 mg/kg over a course of 4 or 5 consecutive days of 28-day period at Week 1, 5, 48, and 52 and placebo matched to cladribine tablet was administered at Week 9 and 13 resulting in total cladribine dose of 3.5 mg/kg during the treatment period of 96 weeks. | 433 |
| Placebo Placebo matched to cladribine tablet administered over a course of 4 or 5 consecutive days of 28-day period at Week 1, 5, 9, 13, 48 and 52 during the treatment period of 96 weeks. | 437 |
| Total | 1,326 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 9 | 5 | 5 |
| Overall Study | Death | 1 | 1 | 2 |
| Overall Study | Disease progression | 4 | 5 | 21 |
| Overall Study | Lost to Follow-up | 11 | 8 | 4 |
| Overall Study | Other | 21 | 12 | 15 |
| Overall Study | Protocol Violation | 4 | 4 | 10 |
Baseline characteristics
| Characteristic | Cladribine 5.25 mg/kg | Cladribine 3.5 mg/kg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 39.1 years STANDARD_DEVIATION 9.9 | 37.9 years STANDARD_DEVIATION 10.3 | 38.7 years STANDARD_DEVIATION 9.9 | 38.6 years STANDARD_DEVIATION 10 |
| Sex: Female, Male Female | 312 Participants | 298 Participants | 288 Participants | 898 Participants |
| Sex: Female, Male Male | 144 Participants | 135 Participants | 149 Participants | 428 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 324 / 454 | 286 / 430 | 242 / 435 |
| serious Total, serious adverse events | 41 / 454 | 36 / 430 | 28 / 435 |
Outcome results
Primary
Annualized Qualifying Relapse Rate
A qualifying relapse was defined as an increase of 2 points in at least one functional system of the expanded disability status scale (EDSS) or an increase of 1 point in at least two functional systems (excluding changes in bowel or bladder function or cognition) in the absence of fever, lasting for at least 24 hours and to have been preceded by at least 30 days of clinical stability or improvement. Expanded disability status scale (EDSS) assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to multiple sclerosis \[MS\]) was calculated. The annualized relapse rate for each treatment group was calculated as the total number of confirmed relapses divided by the total number of days on study multiplied by 365.25.
Time frame: Week 96
Population: The intention-to-treat (ITT) population included all participants who were randomized in the study.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Cladribine 5.25 mg/kg | Annualized Qualifying Relapse Rate | 0.15 relapses per year | 95% Confidence Interval 0.58 |
| Cladribine 3.5 mg/kg | Annualized Qualifying Relapse Rate | 0.14 relapses per year | 95% Confidence Interval 0.59 |
| Placebo | Annualized Qualifying Relapse Rate | 0.33 relapses per year | 95% Confidence Interval 0.88 |
p-value: <0.00195% CI: [0.35, 0.54]Wald Chi-square test
p-value: <0.00195% CI: [0.34, 0.54]Wald Chi-square test
Secondary
Mean Number of Combined Unique (CU) Lesions, Active Time Constant 2 (T2) Lesions, and Active Time Constant 1 (T1) Gadolinium-Enhanced (Gd+) Lesions Per Participant Per Scan
Mean Number of CU lesions, active T2 lesions, and active T1 Gd+ lesions were measured by using magnetic resonance imaging (MRI) scans.
Time frame: Week 96
Population: The ITT population included all participants who were randomized in the study.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Cladribine 5.25 mg/kg | Mean Number of Combined Unique (CU) Lesions, Active Time Constant 2 (T2) Lesions, and Active Time Constant 1 (T1) Gadolinium-Enhanced (Gd+) Lesions Per Participant Per Scan | Active T1 Gd+ lesions | 0.11 lesions | Standard Error 0.05 |
| Cladribine 5.25 mg/kg | Mean Number of Combined Unique (CU) Lesions, Active Time Constant 2 (T2) Lesions, and Active Time Constant 1 (T1) Gadolinium-Enhanced (Gd+) Lesions Per Participant Per Scan | CU lesions | 0.38 lesions | Standard Error 0.08 |
| Cladribine 5.25 mg/kg | Mean Number of Combined Unique (CU) Lesions, Active Time Constant 2 (T2) Lesions, and Active Time Constant 1 (T1) Gadolinium-Enhanced (Gd+) Lesions Per Participant Per Scan | Active T2 lesions | 0.33 lesions | Standard Error 0.06 |
| Cladribine 3.5 mg/kg | Mean Number of Combined Unique (CU) Lesions, Active Time Constant 2 (T2) Lesions, and Active Time Constant 1 (T1) Gadolinium-Enhanced (Gd+) Lesions Per Participant Per Scan | Active T1 Gd+ lesions | 0.12 lesions | Standard Error 0.05 |
| Cladribine 3.5 mg/kg | Mean Number of Combined Unique (CU) Lesions, Active Time Constant 2 (T2) Lesions, and Active Time Constant 1 (T1) Gadolinium-Enhanced (Gd+) Lesions Per Participant Per Scan | CU lesions | 0.43 lesions | Standard Error 0.08 |
| Cladribine 3.5 mg/kg | Mean Number of Combined Unique (CU) Lesions, Active Time Constant 2 (T2) Lesions, and Active Time Constant 1 (T1) Gadolinium-Enhanced (Gd+) Lesions Per Participant Per Scan | Active T2 lesions | 0.38 lesions | Standard Error 0.07 |
| Placebo | Mean Number of Combined Unique (CU) Lesions, Active Time Constant 2 (T2) Lesions, and Active Time Constant 1 (T1) Gadolinium-Enhanced (Gd+) Lesions Per Participant Per Scan | CU lesions | 1.72 lesions | Standard Error 0.08 |
| Placebo | Mean Number of Combined Unique (CU) Lesions, Active Time Constant 2 (T2) Lesions, and Active Time Constant 1 (T1) Gadolinium-Enhanced (Gd+) Lesions Per Participant Per Scan | Active T2 lesions | 1.43 lesions | Standard Error 0.06 |
| Placebo | Mean Number of Combined Unique (CU) Lesions, Active Time Constant 2 (T2) Lesions, and Active Time Constant 1 (T1) Gadolinium-Enhanced (Gd+) Lesions Per Participant Per Scan | Active T1 Gd+ lesions | 0.91 lesions | Standard Error 0.05 |
Secondary
Percentage of Relapse-free Participants
A qualifying relapse was defined as an increase of 2 points in at least one functional system of the EDSS or an increase of 1 point in at least two functional systems (excluding changes in bowel or bladder function or cognition) in the absence of fever, lasting for at least 24 hours and to have been preceded by at least 30 days of clinical stability or improvement. Expanded disability status scale (EDSS) assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated.
Time frame: Week 96
Population: The ITT population included all participants who were randomized in the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cladribine 5.25 mg/kg | Percentage of Relapse-free Participants | 78.9 percentage of participants |
| Cladribine 3.5 mg/kg | Percentage of Relapse-free Participants | 79.7 percentage of participants |
| Placebo | Percentage of Relapse-free Participants | 60.9 percentage of participants |
Secondary
Time to Disability Progression
Time to disability progression was defined as the time to a sustained increase in EDSS score of at least 1 point if baseline EDSS score between 0.5 and 4.5 inclusively, or at least 1.5 points if the baseline EDSS score was 0, or at least 0.5 point if the baseline EDSS score was at least 5, over a period of at least three months. Expanded disability status scale (EDSS) assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. Tenth Percentile of time to sustained increase in EDSS score was reported using Kaplan-Meier survival curve.
Time frame: Baseline up to Week 96
Population: The ITT population included all participants who were randomized in the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cladribine 5.25 mg/kg | Time to Disability Progression | 13.6 months |
| Cladribine 3.5 mg/kg | Time to Disability Progression | 13.6 months |
| Placebo | Time to Disability Progression | 10.8 months |