Effectiveness of Rebif® in Clinically Isolated Syndrome and Relapsing Multiple Sclerosis Using RebiSmart™

Study Overview
=================
Brief Summary
-----------------
This is a Phase 4, interventional, multicenter study of subcutaneous Rebif® (interferon beta-1a) using RebiSmart™ device to assess effectiveness and adherence of treatment in subjects with clinically isolated syndrome (CIS) or relapsing multiple sclerosis (RMS).

Official Title
-----------------
Prospective Phase IV Clinical Trial on Effectiveness of Rebif Treatment of CIS and RMS Patients in Romania Using Electronic Device RebiSmart™

Conditions
-----------------
Relapsing Multiple Sclerosis, Clinically Isolated Syndrome

Intervention / Treatment
-----------------
* Drug: Rebif


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male and female subjects between 18 to 65 years of age Female subjects must be neither pregnant nor breast-feeding and must lack child-bearing potential as defined in the protocol Subjects diagnosed with CIS or RMS according to the revised McDonald criteria (2010) Treatment-naive subjects or subjects treated with Rebif® multi-dose injected by RebiSmart™ for no longer than 6 weeks prior to Baseline visit Subjects that are able to self-inject with RebiSmart™ (in the opinion of the physician) Subjects with Expanded Disability Status Scale (EDSS) score less than (<) 6 (inclusive) at Baseline Signed informed consent and subject data collection form Exclusion Criteria: Subjects experiencing a relapse within 30 days before Baseline Participation in other studies within 30 days before Baseline Received any MS therapy within 6 months prior to study enrolment (for example, other disease-modifying drugs: immunomodulatory, immunosuppressive agents or combination therapy) with the exception of Rebif® multi-dose injected by RebiSmart™ Any visual or physical impairment that precludes the subject from self-injecting the treatment using the RebiSmart™ Pregnancy and breast-feeding Serious or acute heart disease such as uncontrolled cardiac dysrhythmias, uncontrolled angina pectoris, cardiomyopathy, or uncontrolled congestive heart failure, as per investigator opinion Current or past (within the last 2 years) history of alcohol or drug abuse Have any contra-indications to treatment with interferon beta-1a according to Summary of Product Characteristics

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rebif in Relapsing Multiple Sclerosis (RMS) Subjects<br> | Drug: Rebif<br>* Rebif will be administered at a dose of 44 microgram (mcg) subcutaneously using RebiSmart auto-injector three times a week for a total duration up to 12 months.<br>* Other names: Interferon beta-1a;|
| Experimental: Rebif in Clinically Isolated Syndromes (CIS) Subjects<br> | Drug: Rebif<br>* Rebif will be administered at a dose of 44 microgram (mcg) subcutaneously using RebiSmart auto-injector three times a week for a total duration up to 12 months.<br>* Other names: Interferon beta-1a;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Relapse-free RMS Subjects | A relapse was defined as the appearance of a new symptom or worsening of an old symptom, attributable to multiple sclerosis (MS), accompanied by an appropriate new neurological abnormality or focal neurological dysfunction lasting at least 24 hours in the absence of fever, and preceded by stability or improvement for at least 30 days. Relapse-free RMS subjects were those who did not had relapse during 12 month treatment period. Data was planned to be reported for Rebif in RMS Subjects arm. | Month 12 | 
| Time to the First Relapse for CIS Subjects | A relapse was defined as the appearance of a new symptom or worsening of an old symptom, attributable to MS, accompanied by an appropriate new neurological abnormality or focal neurological dysfunction lasting at least 24 hours in the absence of fever, and preceded by stability or improvement for at least 30 days. Time to the first relapse was defined as the duration from start of the treatment until first relapse. Data was planned to be reported for Rebif in CIS Subjects arm. | Baseline up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With Treatment Adherence | According to the World Health Organisation (WHO), treatment adherence is defined as both compliance (taking the medication in the correct dose and according to the schedule prescribed) and persistency (maintenance of the drug regimen over the long-term). Percentage of subjects with treatment adherence under different categories (<=50%, >50-75%, >75-90%, >90%) were presented. | Month 12 | 
| Percentage of Subjects With Relapse by Adherence Category | A relapse was defined as the appearance of a new symptom or worsening of an old symptom, attributable to multiple sclerosis (MS), accompanied by an appropriate new neurological abnormality or focal neurological dysfunction lasting at least 24 hours in the absence of fever, and preceded by stability or improvement for at least 30 days. According to the World Health Organisation (WHO), treatment adherence is defined as both compliance (taking the medication in the correct dose and according to the schedule prescribed) and persistency (maintenance of the drug regimen over the long-term). Percentage of subjects with relapses by adherence categories (<=50%, >50-75%, >75-90%, >90%) were presented. Adherence missing are the subjects who withdrew before 12 months and who did not have any relapses before withdrawal. | Month 12 | 
| Percentage of Subjects Who Prematurely Terminated Treatment and Reasons | Percentage of subjects who prematurely terminated treatment and reasons were presented. | Baseline up to 12 months | 
| Percentage of Subjects Free From Clinical Disease Activity | Expanded Disability Status Scale is abbreviated as EDSS. | Baseline up to 12 months | 
| Percentage of Subjects Free From Disability Progression | Expanded Disability Status Scale is abbreviated as EDSS. | Baseline up to 12 months | 
| Mean Number of Relapses in RMS Subjects | A relapse was defined as the appearance of a new symptom or worsening of an old symptom, attributable to multiple sclerosis (MS), accompanied by an appropriate new neurological abnormality or focal neurological dysfunction lasting at least 24 hours in the absence of fever, and preceded by stability or improvement for at least 30 days. | Month 12 | 
| Number of Subjects With Reasons of Missed Injections | Number of subjects with the reasons of missed injections were presented. Aspartate transaminase and alanine transaminase are abbreviated as ALT and AST respectively. Glutamic oxaloacetic transaminase and glutamic pyruvic transaminase are abbreviated as GOT and GPT respectively. | Baseline up to 12 months | 
| Overall Evaluation of RebiSmart Use as Assessed by Investigator | Evaluation of RebiSmart was categorized under very easy, quite easy, Neither easy nor difficult, very difficult and missing | Month 12 | 
| Healthcare Resource Utilization Questionnaire - Number of Visits to Clinic by Subjects Due to Multiple Sclerosis (MS) | Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of visits to clinic by subjects due to MS were presented. | Month 12 | 
| Healthcare Resource Utilization Questionnaire - Number of Subjects Visiting Different Types of Doctors During Their Clinical Visit | Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Subjects who took consultations with specialists, general practitioners for MS were presented. | Month 12 | 
| Healthcare Resource Utilization Questionnaire - Number of Visits by Healthcare Professional to Subjects' Home | Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of visits by healthcare professional to subjects' home were presented. | Month 12 | 
| Healthcare Resource Utilization Questionnaire - Number of Times Subjects Visited Emergency Room Due to Multiple Sclerosis (MS) | Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of times subjects visited emergency room due to MS were presented. | Month 12 | 
| Healthcare Resource Utilization Questionnaire - Number of Days Subjects Hospitalized Due to Multiple Sclerosis (MS) | Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of days subjects hospitalized due to MS were presented. | Month 12 | 
| Healthcare Resource Utilization Questionnaire -Number of Subjects Who Paid Someone to Assist Them Due to Multiple Sclerosis (MS) | Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of subjects who paid someone to assist them due to MS were presented. | Month 12 | 
| Healthcare Resource Utilization Questionnaire - Number of Days Per Week Assistant Worked For Subject Due to Multiple Sclerosis (MS) | Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of days per week assistant worked for subject due to MS were presented. | Month 12 | 
| Healthcare Resource Utilization Questionnaire - Number of Hours Per Day Assistant Worked for Subject Due to Multiple Sclerosis (MS) | Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of hours per week assistant worked for subject due to MS were presented. | Month 12 | 
| Healthcare Resource Utilization Questionnaire - Number of Subjects Whose Relatives or Friends Missed Work Due to Subjects' Multiple Sclerosis (MS) | Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of subjects whose relatives or friends missed work due to subjects' MS were presented. | Month 12 | 
| Healthcare Resource Utilization Questionnaire - Number of Working Days Missed by Relative or Friend Due to Subjects' Multiple Sclerosis (MS) | Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of working days missed by relative or friend due to subjects' MS were presented. | Month 12 | 
| Healthcare Resource Utilization Questionnaire - Number of Subjects Who Missed Any Full Days From Work Due to Multiple Sclerosis (MS). | Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of subjects who missed any full days from work due to MS were presented. | Month 12 | 
| Healthcare Resource Utilization Questionnaire - Number of Full Days Missed From Work by Subjects | Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of full days missed from work by subjects were presented. | Month 12 | 
| Healthcare Resource Utilization Questionnaire - Number of Subjects Who Missed Any Partial Days From Work Due to Multiple Sclerosis (MS). | Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of subjects who missed any partial days from work due to MS were presented. | Month 12 | 
| Healthcare Resource Utilization Questionnaire - Number of Hours Per Day Missed From Work by Subjects | Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of hours per day missed from work by subjects were presented. | Month 12 | 
| Healthcare Resource Utilization Questionnaire - Number of Subjects Accomplished Less Work Due to Multiple Sclerosis (MS) | Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of subjects accomplished less work due to MS were presented. | Month 12 | 
| Healthcare Resource Utilization Questionnaire - Number of Subjects With Percentage of Work Completed Despite of Multiple Sclerosis (MS) | Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Amount of work done by subjects in spite of multiple sclerosis was presented under different percentages (0-100%) | Month 12 | 
| Number of Subjects With Medication Adherence Based on Morisky Medication Adherence Score | The Morisky Medication Adherence Scale (MMAS) is a valid and reliable instrument that consists of 8 items that measure medication adherence. The scores of the MMAS-8 range from 0 to 8. This self-report scale consists of 7 items answered with a yes or no and 1 item with a 5-point Likert scale. A score below 6 indicates low adherence, a score between 6 to < 8 indicates medium adherence and a score of 8 indicates high adherence. | Month 12 | 
| Number of Subjects With Adverse Event or Adverse Drug Reaction (AE/ADR), Serious AE/ADR, AE/ADR Leading to Death and AE/ADR Leading to Early Termination | An AE was any untoward medical occurrence in a subject or clinical investigation in a subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An ADR was any unfavourable or unintended response (adverse event) that could possibly be related to drug treatment. An SAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. AE/ADR was planned to be reported for both the arms together. | Baseline up to 12 months | 
| Expanded Disability Status Scale (EDSS) Score | EDSS is an ordinal scale in half-point increments that qualifies disability in participants with MS. It consists of 8 ordinal rating scales assessing seven functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS). | Baseline, Month 12 | 
| Body Mass Index (BMI) | BMI was defined as weight in kilogram (kg) divided by height in square meter (m^2). | Baseline, Month 12 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
RebiSmart™, Relapsing multiple sclerosis, Clinically isolated syndrome, RMS, CIS, Rebif®, Interferon beta-1a