Multiple Sclerosis
Conditions
Keywords
pediatric, multiple sclerosis, fingolimod, pre-pubertal, low weight, children, adolescent, MS, core phase, extension phase, younger cohort
Brief summary
To evaluate the safety and efficacy of fingolimod vs. interferon beta-1a i.m. in pediatric patients with multiple sclerosis (MS)
Detailed description
The study is divided into a Core Phase, which includes the Double-Blind Treatment Period, and an Extension Phase in which all patients will be treated with fingolimod. The Core Phase is a 24-month, double-blind, randomized, active-controlled, parallel-group multicenter study phase to evaluate the efficacy and safety of fingolimod compared to IFN β-1a in children/adolescent patients aged 10-17 years old with MS. The Extension Phase is a 60-month (5 year) study phase for patients who complete the Core Phase of the study and meet all inclusion/exclusion criteria and for patients who will be recruited in the younger cohort to participate in the Extension Phase. The 'younger cohort' refers to the population of pediatric patients fulfilling any single one or a combination of the following criteria: being ≤12 years of age, or weighing ≤40 kg, or being prepubertal (i.e. pubertal status of Tanner stage \<2). The recruitment of the younger cohort (up to 25 patients) was requested as a post- approval health authority commitment
Interventions
DRUGInterferon beta-1a
Administration once weekly via i.m. injections.
DRUGFingolimod
Administrated orally once daily: 0.5 mg capsule for patients over 40 kg or 0.25 mg capsule for patients 40 kg or less.
DRUGPlacebo capsule
Matching placebo capsule required for double-dummy masking to blind formulations.
DRUGPlacebo i.m. injection
Matching placebo i.m. injection required for double-dummy masking to blind formulations.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
There are 2 arms in the core phase. In the extension phase all participants are receiving open-label.study drug. A third arm has been added to enroll up to 25 new younger patients per HA post approval commitment.
Eligibility
Sex/Gender
ALL
Age
10 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria Core Phase: * diagnosis of multiple sclerosis * at least one MS relapse during the previous year or two MS relapses in the previous 2 years or evidence of Gd enhancing lesions on MRI within 6 months EDSS score of 0 to 5.5, inclusive Key
Exclusion criteria
Core Phase: * patients with progressive MS * patients with an active, chronic disease of the immune system other than MS * patients meeting the definition of ADEM * patients with severe cardiac disease or significant findings on the screening ECG. * patients with severe renal insufficiency Key Inclusion Criteria Extension Phase: Applies to all patients participating in the Core Phase and then entering the Extension Phase. 1. Patients that originally met Core Phase Inclusion criteria and completed the Core phase on or off of study drug. Applies to patients newly recruited to participate in the Extension Phase. * All newly recruited patients' that enroll directly into the Extension Phase must fulfill the local country health authority product label approved for pediatric age group for inclusion criteria. * Central review (including initial MRI report) of the diagnosis of pediatric MS will be required for all newly recruited patients. Key
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Relapses in Patients Treated for up to 24 Months | 24 months | Frequency of relapses assessed by the annualized relapse rate (ARR). The ARR is defined as the average number of confirmed relapses per year (total number of confirmed relapses divided by the total days in the study multiplied by 365.25). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| New/Newly Enlarged T2 Lesions | 24 months | Annualized rate of the number of new/newly enlarged T2 lesions up to Month 24 |
| Time to First Relapse | 24 months | Time to first relapse was determined. |
| Proportion of Patients Relapse-free | 24 months | Proportion of patients relapse-free was determined |
| T1 Gd- Enhancing Lesions | 24 months | Number of T1 Gd-enhancing lesions per scan up to Month 24 |
| Pharmacokinetics (Cavg) of Fingolimod-P | 24 months | Cavg (average drug concentration over the dose interval) will be evaluated. |
| Pharmacokinetic/Pharmacodynamic Relationship for Fingolimod-P to Lymphocyte Levels | 24 months | Population PK/PD modeling approaches were used to relate the individual fingolimod-P concentrations to lymphocyte counts. |
Countries
Australia, Austria, Brazil, Bulgaria, Canada, Croatia, Estonia, France, Germany, Italy, Latvia, Lithuania, Mexico, Netherlands, Poland, Puerto Rico, Romania, Russia, Serbia, Slovakia, Spain, Turkey (Türkiye), Ukraine, United Kingdom, United States
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Participant flow
Pre-assignment details
This study is divided into a core phase and extension phase. In the core phase, patients were randomized to Fingolimod or Interferon beta-1a in a 1:1 ratio. The core phase disposition is reported for interim results disclosure. Upon completion of the extension phase, the extension disposition will be reported.
Participants by arm
| Arm | Count |
|---|---|
| Fingolimod Fingolimod was administered orally once daily at a dose of either 0.5 mg or 0.25 mg (depending on patient's body weight) with the aim to achieve systemic exposure in range of that in adults at the licensed 0.5 mg dose. | 107 |
| Interferon Beta-1a An intramuscular (IM) injection of Interferon beta-1a was administered once weekly. | 108 |
| Total | 215 |
Baseline characteristics
| Characteristic | Interferon Beta-1a | Total | Fingolimod |
|---|---|---|---|
| Age, Continuous | 15.4 Years STANDARD_DEVIATION 1.6 | 15.3 Years STANDARD_DEVIATION 1.81 | 15.2 Years STANDARD_DEVIATION 2 |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 5 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 7 Participants | 2 Participants |
| Race (NIH/OMB) White | 97 Participants | 197 Participants | 100 Participants |
| Sex: Female, Male Female | 64 Participants | 134 Participants | 70 Participants |
| Sex: Female, Male Male | 44 Participants | 81 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 107 | 0 / 107 |
| other Total, other adverse events | 82 / 107 | 94 / 107 |
| serious Total, serious adverse events | 19 / 107 | 10 / 107 |
Outcome results
Primary
Frequency of Relapses in Patients Treated for up to 24 Months
Frequency of relapses assessed by the annualized relapse rate (ARR). The ARR is defined as the average number of confirmed relapses per year (total number of confirmed relapses divided by the total days in the study multiplied by 365.25).
Time frame: 24 months
Population: Full analysis set (FAS): The FAS was comprised of all randomized patients with assigned treatments who received at least one dose of study medication.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Fingolimod | Frequency of Relapses in Patients Treated for up to 24 Months | 0.122 Confirmed relapse per year |
| Interferon Beta-1a | Frequency of Relapses in Patients Treated for up to 24 Months | 0.675 Confirmed relapse per year |
p-value: <0.001Negative binomial regression model
Secondary
New/Newly Enlarged T2 Lesions
Annualized rate of the number of new/newly enlarged T2 lesions up to Month 24
Time frame: 24 months
Secondary
Pharmacokinetic/Pharmacodynamic Relationship for Fingolimod-P to Lymphocyte Levels
Population PK/PD modeling approaches were used to relate the individual fingolimod-P concentrations to lymphocyte counts.
Time frame: 24 months
Secondary
Pharmacokinetics (Cavg) of Fingolimod-P
Cavg (average drug concentration over the dose interval) will be evaluated.
Time frame: 24 months
Secondary
Proportion of Patients Relapse-free
Proportion of patients relapse-free was determined
Time frame: 24 months
Secondary
T1 Gd- Enhancing Lesions
Number of T1 Gd-enhancing lesions per scan up to Month 24
Time frame: 24 months
Secondary
Time to First Relapse
Time to first relapse was determined.
Time frame: 24 months