| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsing multiple sclerosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| relapsing multiple sclerosis |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10048393 |
| E.1.2 | Term | Multiple sclerosis relapse |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Core Phase:
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. |
|
| E.2.2 | Secondary objectives of the trial |
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:
o Time to first relapse
o 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.
...
See the complete list of objectives including Extension Phase objectives in the protocol |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Core Phase:
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 randomization.
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 contraindication.
Fingolimod Extension Phase:
Criterion 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 Core Phase on or off study drug
Criterion apply 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. |
|
| E.4 | Principal exclusion criteria |
Core Phase:
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 critieria for neuromyelitis optica (Wingerchuk et al 2006) or tested positive for aquaporin 4 (AQP4) at Screening.
5. 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 or teriflunomide within 3.5 months prior to randomization
o Immunosuppressive/immunomodulatory medications such as azathioprine, methotrexate, laquinimod, ofatumumab, ocrelizumab within 6 months prior to randomization
o Alemtuzumab, cladribine, cyclophosphamide, mitoxantrone or rituximab at any time
o Fingolimod at any time
o The following antiarrhythmic drugs at Screening: Class Ia (e.g. quinidine, disopyramide) or Class III (e.g. amiodarone, sotalol) anti-arrhythmics
o 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-heartrate 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 varicella-zoster 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, such as:
o History of symptomatic bradycardia or recurrent syncope
o Known ischaemic heart disease
o 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).
o Cerebrovascular disease
o History of myocardial infarction
o Congestive heart failure
o History of cardiac arrest
o Uncontrolled hypertension despite prescribed medications
o Resting (sitting) heart rate <55 bpm (in patients 12 years or older) and <60 bpm (in patients below 12 years)
o Severe untreated sleep apnea.
o Sick sinus syndrome or sino-atrial heart block
o 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.
o 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:
o anti-HAV IgM
o HBs Ag and/or anti-HBc IgM
o anti-HCV IgG or HCV-RNA PCR
o anti- HEV IgM (if positive IgG: do HEV-RNA PCR: if negative, patient can be included)
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.
....
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| To evaluate the efficacy of fingolimod relative to intramuscular interferon B-1a in reducing the frequency of relapses as assess by the annualized relapse rate (ARR) in children/adolescent MS patients aged 10 to less than 18 years treated for up to 24 months. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| To evaluate the efficacy of fingolimode relative to IFN B-1a in reducing the number of new/newly enlarging T2 (n/ne T2)lesions in children/adolescent MS patients aged 10 to less than 18 years treated for up to 24 months |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Belarus |
| Brazil |
| Bulgaria |
| Canada |
| Croatia |
| Estonia |
| France |
| Germany |
| Italy |
| Latvia |
| Lithuania |
| Mexico |
| Netherlands |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Slovakia |
| South Africa |
| Spain |
| Sweden |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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