Assignment 2010). 2. AIM OF THE STUDY The aim

Assignment B3: Clinical
Development Phase III


The used article is ”Oral Fingolimod or Intramuscular Interferon for Relapsing
Multiple Sclerosis” (Cohen & Barkhof, 2010).

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The aim of the study
is to evaluate the efficacy, safety and tolerability of oral fingolimod
compared with intramuscular interferon during a 12-month observation

Indication area and reference drug
The indication area
is Relapsing Remitting Multiple Sclerosis (RRMS). The reference drug is interferon
beta-1a (Avonex)

The intended therapeutic action of the study
Oral fingolimod prevents normal lymphocyte egress from lymphoid tissues, thus
reducing the infiltration of autoaggressive lymphocytes into the Central
Nervous System (CNS), where they would cause inflammation and tissue damage. This
action of fingolimod is primarily mediated by modulation of sphingosine-1-phosphate-receptor
1 (S1P1). An oral treatment option for RRMS is also highly desirable by

Interferon beta-1a intramuscular
injection is used to reduce the number of episodes of symptoms and slow the
development of disability in patients with RRMS. It is a immunomodulator. It is
not known how interferon beta-1a works to treat MS.

The primary efficacy end point was the Annualized Relapse Rate (ARR),
which was defined as the number of confirmed relapses during a 12-month period.
The two key secondary end points were the number of new or enlarged
hyperintense lesions on T2-weighted MRI scans at 12 months and the
time to confirmed disability progression.

It is a
12-month, phase 3, multicentre, randomized, double-blind, double dummy,
parallel-group study. Randomization was performed centrally in blocks of six
within each site and was stratified according to site. During the trial,
patients, study personnel, MRI evaluators, steering-committee members, and the
study statistician were unaware of study-group assignments and leukocyte
counts. Capsules, syringes, and packaging materials for active and placebo
treatments were indistinguishable. Patients were instructed to cover injection
sites at visits and not to discuss adverse events with clinical evaluators. An
independent physician monitored patients after the first dose of the oral study
drug was administered. Employees of the sponsor working independently of the
study team monitored first-dose safety data. An independent data and safety
monitoring board evaluated overall safety in the fingolimod phase 3 program.


Characteristics and numbers of subjects

Inclusion criteria:

Aged between 18 and 55 years.

Diagnosed with RRMS

Had at least one documented relapse during
previous year or at least two during previous 2 years.

A score of 0 to 5.5 on the Expanded Disability
Status Scale (EDSS).

Exclusion criteria:

A documented relapse or corticosteroid
treatment within 30 days before randomization

Active infection

Macular edema

History with immunosuppressive drugs

Clinically significant coexisting systemic


A total of 1280 patients
enrolled the study.


Duration of the study
The duration of the
study is 12 months.

Time of measuring clinical endpoints

Primary endpoint: The ARR are measured during a period of 12 months
throughout the treatment with fingolimod or interferon beta-1a  

Secondary endpoint 1: MRI scans are obtained at
screening and at 12 months.

Secondary endpoint 2: The time to confirmed disability
progression are measured during a period of 12 months. EDSS scores are determined
every 3 months

The considerations for dosages and route of
administration of the study drug
The route of
administration of the study drug is oral, with a daily dose of either 1.25 or
0.5 mg.

Route and dose of reference drug
The route of the
reference drug is intramuscular, with weekly dose of 30g.

Which medical centers were involved?
A total of 172 clinical
centers in 18 countries were involved.

A total of 1153 patients completed the study.

Relapse rates:
There was a significantly greater reduction of the ARR in both fingolimod
groups. Relapse-related measures also significantly favoured fingolimod .The ARR
for fingolimod 0.5mg was 0.16 and the ARR for interferon beta-1a was 0.33
(P<0.001). The percentage of patients without relapses was 83% for fingolimod 0.5mg and 70% for interferon beta-1a (p<0.001). ·         MRI outcomes: Patients in the two fingolimod groups had significantly fewer new or enlarged lesions on T2-weighted images and T1-weighted images at 12 months than patients receiving interferon (p=0.002). The mean percent reduction in brain volume from baseline to 12 months was significantly lower in the two fingolimod groups than in the interferon group ·         Disability: There were no significant differences seen in the progression of disability among the study groups. Adverse events: Adverse events were similar in the three groups. Approximately 90% of these events were mild or moderate. The most serious adverse events were in the group receiving fingolimod 1.25 mg. The most common serious events in this group were bradycardia and atrioventricular block.   7. THE CONCLUSIONS THAT COULD BE DRAWN FROM THE RESULTS This study showed that once-daily oral fingolimod had a superior efficacy to interferon beta-1a administered by weekly intramuscular injection. Fingolimod was associated with adverse events, some of which may be dose-related. 8. THE CONSEQUENCES AND IMPLICATIONS OF THIS STUDY Oral fingolimod 0.5 mg daily was approved in the European Union in 2011 for the treatment of Relapsing-Remitting Multiple Sclerosis (RRMS). Fingolimod is associated with adverse events. When a patient takes the first dose of fingolimod, the heart rate of the patient is expected to slow down. Therefore, the patient has to be observed and monitored for at least six hours by a doctor (Gilenya, n.d.). The possibility of serious cardiac and other rare adverse events justified the decision of the European Medicines Agency (EMA) to approve the drug as a second-line treatment for MS patients who are not responsive to first-line therapy (Gajofatto, 2015). 9. OPINION ON THE ETHICS OF THIS STUDY In this study they did not use a placebo. Both groups received a treatment. The study was also conducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and the principles of the Declaration of Helsinki. Also, all patients provided written informed consent before any study-related procedure was performed.