Novartis FTY720D Fingolimod
|Principal Investigator: MichaelLloyd|
|Keywords: Fingolimod , Multiple Sclerosis||Department: Pediatric Neurology|
|IRB Number: 00065076||Co Investigator:|
|Specialty: Pediatric Neurology|
The purpose of this study is to seek regulatory approval for use of fingolimod in a pediatric population with MS aged 10 to less than 18 years old. This study is conducted in line with the Pediatric Investigational Plan agreed with the EMA (under EU pediatric regulation (EC) No 1901/2006) and the post-marketing requirements in the US.
To evaluate the efficacy of fingolimod relative to intramuscular IFN β-1a in reducing the frequency of relapses as assessed by the annualized relapse rate in children/adolescent MS patients aged 10 to less than 18 years treated for up to 24 months.
Key secondary objective - Core Phase
To evaluate the efficacy of fingolimod relative to IFN β-1a in reducing the number of new/newly enlarging T2 (n/neT2) lesions in children/adolescent MS patients aged 10 to less than 18 years treated for up to 24 months.
Other secondary objectives
- To evaluate the safety of fingolimod relative to IFN β-1a in children/adolescent MS patients.
- To evaluate the effect of fingolimod relative to IFN β-1a in children/adolescent MS patients on other relapse-related parameters:
- Time to first relapse
- Proportion of patients relapse-free
- To evaluate the effect of fingolimod relative to IFN β-1a in children/adolescent MS patients on T1 Gd-enhancing lesions on brain MRI.
- To study the pharmacokinetics of fingolimod and fingolimod-P in children/adolescent MS patients treated for up to 24 months.
- To study the pharmacokinetic/pharmacodynamic relationship for key efficacy and safety outcomes in children/adolescent MS patients treated for up to 24 months.
Exploratory objectives - Core Phase
• To explore the effects of fingolimod relative to IFN β-1a on other MRI measures
including change in total T2 hyperintense and T1 hypointense lesion volumes, new T1
hypointense lesion count, combined unique active (CUA) lesion count and brain volume
change in children/adolescent MS patients.
• To explore the effects of fingolimod relative to IFN β-1a on safety and efficacy
parameters in the subset of pre-pubertal children with MS.
• To explore the effects of fingolimod relative to IFN β-1a in children/adolescent MS
patients treated for up to 24 months on physical and sexual development.
• To explore the effects of fingolimod relative to IFN β-1a on measures of cognition and
health related quality of life.
Fingolimod Extension Phase:
To examine long-term safety, tolerability and efficacy parameters in patients treated with
To examine the effects of fingolimod on safety, tolerability and efficacy parameters in patients
who were treated with inferferon-β-1a in the Core Phase.
To explore the long term effects of fingolimod in patients on physical and sexual
Population: Male and female patients with multiple sclerosis (MS) aged 10 to less than 18 years will
be included in this Core Phase study. Patients will be recruited into two cohorts based on their puberty
status (pre-pubertal, pubertal). The study will be conducted in centers worldwide. Approximately 190 patients
will be randomized to receive either fingolimod or IFN β-1a.
The population of the Extension Phase will consist of patients who complete 24 months participation in
the Core Phase
Patients who complete the Core Phase on study drug will be allowed to enter the Extension
Phase without any further criteria.
Patients who complete the Core Phase but prematurely discontinued study drug during the
Core Phase for any reason will be assessed for eligibility in the Extension Phase based on
the exclusion criteria.
1. Written informed consent must be obtained before any assessment is performed.
2. Male and female patients aged 10-17 years old*, inclusive (i.e., have not yet had their 18th
birthday) at randomization.
3. A diagnosis of MS as defined by the revised consensus definition for pediatric MS (Krupp et al 2013, Polman et al 2011),
4. Central review of the diagnosis of pediatric MS will be required for all patients prior to
5. At least one MS relapse/attack during the previous year or two MS relapses in the
previous two years prior to screening or evidence of one or more Gd enhancing lesions on
MRI within 6 months prior to randomization (including screening MRI).
6. Expanded Disability Status Scale (EDSS) score of 0 to 5.5, inclusive.
*Exception: If, in a specific country, use of interferon-β-1a IM in children below a certain age
is included in the Contraindications section of Avonex (interferon-β-1a IM) local product
information, inclusion of such patients is not permitted in that country. E.g. the Russian
Avonex product information lists use in children below the age of 12 years as a
Fingolimod Extension Phase:
Criterion applies to all patients entering the Extension Phase.
1. Patients that originally met Core Phase Inclusion criteria and completed the Core phase on or
off of study drug.
1. Patients with progressive MS.
2. Patients with an active, chronic disease (or stable but treated with immune therapy) of the
immune system other than MS (e.g. Sjögren’s disease, systemic lupus erythematosus) or
with a known immunodeficiency syndrome (AIDS, hereditary immune deficiency, drug
induced immune deficiency) or tested positive for HIV at Screening.
3. Patients with widespread and symmetric white matter alterations in the Screening MRI
suggestive of other demyelinating disorders (e.g. metabolic disorders, mitochondrial
4. Patients meeting the definition of ADEM (Krupp et al. 2013); patients meeting critieria for
neuromyelitis optica (Wingerchuk et al 2006) or tested positive for aquaporin 4 (AQP4) at
5. Patients treated with:
• Systemic corticosteroids or adrenocorticotropic hormone (ACTH) in the 30 days prior
to Screening MRI scan
• High dose intravenous immunoglobulin within 2 months prior to randomization
• Natalizumab within 3 months or teriflunomide within 3 ½ months prior to
• Immunosuppressive/immunomodulatory medications such as, azathioprine,
methotrexate, laquinimod, ofatumumab, ocrelizumab within 6 months prior to
• Alemtuzumab, cladribine, cyclophosphamide, mitoxantrone or rituximab at any time
• Fingolimod at any time
• The following antiarrhythmic drugs at Screening: Class Ia (e.g. quinidine,
disopyramide) or Class III (e.g. amiodarone, sotalol) anti-arrhythmics
• Concurrently treated with heart-rate-lowering drugs at Screening e.g.: Beta blockers,
heart-rate lowering calcium channel blockers (e.g. verapamil, diltiazem or ivabradine),
digoxin, anticholinesteratic agents, pilocarpine. Advice from a cardiologist should be
sought regarding the switch to non-heart-rate lowering medicinal products.
6. Patients diagnosed with macular edema during the pre-randomization phase
7. Patients with active systemic bacterial, viral or fungal infections, including tuberculosis.
8. Patients without acceptable evidence of immunity to varicella-zoster virus, mumps,
measles, rubella, diphtheria, tetanus and pertussis at Randomization (See Appendix 3
Guidance on vaccinations for guidance on acceptable evidence of immunity and
requirements for serologic testing).
9. Patients who have received any live or live attenuated vaccines (including for varicellazoster
virus or measles) within one month prior to randomization.
10. Patients with a history or presence of malignancy.
11. Patients with any medically unstable condition, as assessed by the investigator.
12. Patients with any severe cardiac disease or significant findings on the screening ECG,
• History of symptomatic bradycardia or recurrent syncope
• Known ischaemic heart disease
• History of congenital heart disease (except conditions such as small patent ductus
arteriosus, atrial septal defect, ventricular septal defect, or an ECG or rhythm
abnormality, which have been assessed by a pediatric cardiologist and considered to
be clinically insignificant).
• Cerebrovascular disease
• History of myocardial infarction
• Congestive heart failure
• History of cardiac arrest
• Uncontrolled hypertension despite prescribed medications
• Resting (sitting) heart rate <55 bpm (in patients 12 years or older) and <60 bpm (in
patients below 12 years)
• Severe untreated sleep apnea
• Sick sinus syndrome or sino-atrial heart block
• QTcF interval >450 msec in males and >460 msec in females or relevant risk factors
for QT prolongation (e.g. hypokalaemia, hypomagnesemia, congenital QT
prolongation) or treatment with QT prolonging drugs with a known risk of Torsades
de pointes (e.g. citalopram, chlorpromazine, haloperidol, methadone, erythromycin)
or history of familial long QT syndrome or known family history of Torsades de
• Second degree Mobitz type II or higher AV block
13. Patients with any pulmonary conditions, as determined by the investigator, including
severe asthma defined as per the 2010 WHO uniform definition on severe asthma
(Bousquet et al 2010).
14. Positive results of screening period testing for serological markers for hepatitis A, B, C
and E indicating acute or chronic infection:
• anti-HAV IgM
• HBs Ag and/or anti-HBc IgM
• anti-HCV IgG or HCV-RNA PCR
• anti- HEV IgM or IgG (if positive IgG: do HEV-RNA PCR: if negative, patient can
15. Patients with any of the following hepatic conditions:
• Chronic liver or biliary disease, acute or chronic pancreatitis, with the exception of
• Liver enzymes
• ALT, AST, alkaline phosphatase, GGT, >2 x upper limit of normal (ULN) range
for age (for pre-pubertal patients > 1 X ULN or > 2X ULN if currently treated
with IFN or glatiramer acetate). Elevations of alkaline phosphatase should not be
used in isolation to exclude subjects, and would require Investigator discretion.
• Bilirubin elevations not in the context of Gilberts Syndrome: Total and
conjugated bilirubin >1.5 X ULN (for pre-pubertal patients >1 X ULN or > 1.5 X
ULN if currently treated with IFN or glatiramer acetate).
16. Patients with severe renal insufficiency (GFR <30 ml/min/1.73 m2).
17. Patients with lymphocyte count < 800 cells (mm3).
18. Patients with any of the following neurologic/psychiatric disorder:
• History of any type of epileptic seizure(s) as well as psychogenic non-epileptic
seizure(s) during the past 12 months before screening;
• History of substance abuse (drug or alcohol) or any other factor (i.e., serious
psychiatric condition) that may interfere with the subject’s ability to cooperate and
comply with the study procedures;
• Progressive neurological disorder, other than MS, which may affect participation in
the study or require the use of medications not allowed by the protocol
19. Patients unable to undergo MRI scans, including claustrophobia or history of
hypersensitivity to gadolinium-DTPA.
20. Pregnant or nursing females, where pregnancy is defined as the state of a female after
conception and until the termination of gestation, confirmed by a positive HCG laboratory
21. Female patients of childbearing potential, defined as all females physiologically capable
of becoming pregnant, unless they agree to abstinence or, if sexually active, the use of
contraception as defined in Section 6.6.
22. History of hypersensitivity to any of the study drugs or to drugs of similar chemical
23. Patients with a score of “yes” on item 4 or 5 of the Suicidal Ideation section of the
C-SSRS, if this ideation occurred in the past 6 months, or with a score of “yes” on any
item of the Suicidal Behavior section, except for “Non-Suicidal Self Injurious Behavior”,
if this behavior occurred in the past 2 years.
24. Patients who have received an investigational drug or therapy within 180 days or
5 half-lives of randomization, whichever is longer.
No additional exclusions may be applied by the investigator, in order to ensure that the
study population will be representative of all eligible patients.
Fingolimod Extension Phase:
Criteria apply to patients who completed the Core Phase, but prematurely discontinued study drug.
1. Premature discontinuation of the study drug during the Core Phase due to an adverse event,
serious adverse event, laboratory abnormality or conditions leading to permanent study drug
discontinuation due to safety reasons as described in the protocol.
Note: If a patient was discontinued due to lack of efficacy in the Core Phase, the patient may be
offered the option to enter the extension trial if the investigator determines it is in the patient’s
best interest when considering all available treatment options.
2. Patients with known new events or concomitant medications that would exclude them from
the Core Phase exclusion criteria. Serological or other additional tests will not be required.