Novartis FTY720D Fingolimod

Overview

Status: Not yet recruiting
Keywords: Fingolimod , Multiple Sclerosis
IRB Number: 00065076
Specialty: Pediatric Neurology
Sub Specialties:

Brief Summary

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.

 

Primary objective

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

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

  • 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 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.

Principal Investigator: Michael Lloyd
Department: Pediatric Neurology
Co Investigator:

Contact Information

Name:JoAnn Narus
Phone: 801-585-7497
Email: joann.narus@hsc.utah.edu

Inclusion Criteria

Patients eligible for inclusion in this study have to fulfill all of the following criteria:

  • Written informed consent must be obtained before any assessment is performed.
  • Male and female patients aged 10-17 years old, inclusive (i.e., have not yet had their 18th birthday) at randomization.
  • A diagnosis of MS as defined by the revised consensus definition for pediatric MS,(Krupp et al 2013, Polman et al 2011).

- Central review of the diagnosis of pediatric MS will be required for all patients prior to randomization.

  • At least one MS relapse during the previous year or two MS relapses in the previous two years, preceding enrollment to the study.
  • Expanded Disability Status Scale (EDSS) score of 0 to 5.5, inclusive.

Exclusion Criteria

Patients fulfilling any of the following criteria are not eligible for inclusion in this study:

  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.
  3. Patients with widespread and symmetric white matter alterations in the Screening MRI suggestive of other demyelinating disorders (e.g. metabolic disorders, mitochondrial disorders).
  4. Patients meeting the definition of ADEM  (Krupp et al. 2013); patients meeting criteria for neuromyelitis optica (Wingerchuk et al 2006) or tested positive for aquaporin 4 (AQP4) at screening.
  5. Patients who have detectable antibodies to IFN β at Screening.
  6. Patients treated with:

o Systemic corticosteroids or adrenocorticotropic hormone (ACTH) in the 30 days prior to Screening MRI scan
o High dose intravenous immunoglobulin within 2 months prior to randomization
o Natalizumab within 3 months prior to randomization

  • Immunosuppressive/immunomodulatory medications such as cladribine, cyclophosphamide, mitoxantrone, azathioprine, methotrexate, rituximab, ofatumumab, ocrelizumab, alemtuzamub, teriflunomide or dimethyl fumarate 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.
  • Systemic corticosteroids or adrenocorticotropic hormone (ACTH) in the 30 days prior to Screening
  • High dose intravenous immunoglobulin within 2 months prior to randomization
  • Natalizumab within 3 months prior to randomization

7.  Patients diagnosed with macular edema during the pre-randomization phase

8.  Patients with active systemic bacterial, viral or fungal infections, including tuberculosis.

9.  Patients who have not completed their vaccination schedule based on the local recommendations.

10. Patients who are negative for varicella-zoster virus, mumps, measles, rubella, diptheria, tetanus or pertussis IgG antibodies at screening.

11. Patients who have received any live or live attenuated vaccines (including for varicella-zoster virus or measles) within one month prior to randomization.

12. Patients with a history or presence of malignancy.

13. Patients with any medically unstable condition, as assessed by the investigator.

14. Patients with any severe cardiac disease or significant findings on the screening ECG, such as:

  • 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 signifcant).
  • 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
  • QTc 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 Pointes.
  • Second degree Mobitz type II or higher AV block

15. 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).

16. 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 ( if positive IgG: do HEV-RNA PCR: if negative, patient can be included)

17. Patients with any of the following hepatic conditions:

  • Chronic liver or biliary disease, acute or chronic pancreatitis, with the exception of Gilbert's syndrome
  • Liver enzymes (ALT, AST, alkaline phosphatase, GCT, total and conjugated bilirubin) >1 x upper limit of normal (ULN) range for age (unless elevations occur in the context of Gilbert's disease).  Patients currently treated with IFN beta or glatiramer acetate and have ALT/AST <2 x ULN and total or conjugated bilirubin <1.5 x ULN (i.e. elevation in context of the treatment)  may be included if deemed appropriate by the investigator

18. Patients with severe renal insufficiency (GFR <30 ml/min/1.73 m2).

19. Patients with lymphocyte count < 800 cells/mm3.

20. 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

21. Patients unable to undergo MRI scans, including claustrophobia or history of hypersensitivity to gadolinium-DTPA.

22. 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 test.

23. 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.

24. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes.

25. 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.

26. Patients who have received an investigational drug within 180 days or 5 half-lives or randomization, whichever is longer.