A Study of Rebif® in Subjects With Relapsing Multiple Sclerosis

Study Overview
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Brief Summary
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This is an open-label, multi-center, 12-week, randomized, controlled, parallel group, Phase 4 study to assess whether the morning administration of interferon beta 1a (Rebif®) leads to a lower severity of flu-like symptoms (FLS) as compared to the evening administration, in subjects with relapsing multiple sclerosis (RMS).

Official Title
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Multicenter, Open-label, 12 Week, Phase IV Prospective Randomized Study Aimed at Evaluating Whether sc IFN Beta 1a (Rebif®) Administered in the Morning May Affect the Severity of Flu-like Syndrome and Patient-perceived Invisible Symptoms in Subjects With Relapsing Multiple Sclerosis

Conditions
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Multiple Sclerosis, Relapsing-Remitting

Intervention / Treatment
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* Drug: Rebif®
* Drug: Rebif®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females between 18 and 60 years of age Female subjects must be neither pregnant nor breast-feeding and must lack child-bearing potential. Furthermore, female subjects must not have been pregnant from at least three months prior to enter in the study Subjects have RMS according to the revised McDonald Criteria (2010) Subjects with an expanded disability status scale (EDSS) score of less than 6.0 Subjects naive to treatment and eligible for treatment with Rebif® 44 three times a week, or patients having received glatiramer acetate with a wash-out from at least one month, or patients having received treatment with natalizumab or fingolimod with a wash-out from at least three months Subjects able to self-inject treatment using RebiSmart® Subjects willing and able to comply with the protocol for the duration of the study Subjects have given written informed consent to take part in the study Exclusion Criteria: Subjects have any disease other than MS that could better explain his/her signs and symptoms Subjects who have received any immunosuppressive agents within 3 months prior to Baseline Subjects who have received any corticosteroids within 30 days prior to Baseline Subjects have a MS relapse within 30 days prior to Baseline Subjects have inadequate liver function and bone marrow reserve as defined in the protocol Subjects have moderate to severe renal impairment Subjects have any visual or physical impairment that precludes the subjects from self-injecting the treatment using RebiSmart® Subjects have hypersensitivity to natural or recombinant interferon, or to any of its excipients Subjects have any contra-indications to treatment with interferon (IFN) beta 1a according to Summary of Product Characteristics (SmPC) Subjects have any contra-indications to treatment with ibuprofen/paracetamol according to SmPC Obese subjects, defined by body mass index greater than 30 kilogram per square meter (kg/m^2) Subjects have participated in any other investigational trial within 30 days from Baseline Subjects have any other significant disease that in the Investigator's opinion would exclude the subject from the trial

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rebif® Morning Administration<br> | Drug: Rebif®<br>* Rebif® will be administered at a dose of 44 microgram (mcg) subcutaneously three times a week in the morning using RebiSmart® self-injector device for 12 weeks.<br>|
| Experimental: Rebif® Evening Administration<br> | Drug: Rebif®<br>* Rebif® will be administered at a dose of 44 mcg subcutaneously three times a week in the evening using RebiSmart® self-injector device for 12 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in Multiple Sclerosis Treatment Concern Questionnaire (MSTCQ) Flu Like Symptom (FLS) Score Between Rebif Morning Administration and Rebif Evening Administration Groups at Week 12 | The MSTCQ was used as a tool to measure treatment satisfaction, focusing on the attributes specific to multiple sclerosis (MS) medications. The FLS subscale of MSTCQ was defined as the sum of the scores for questions 13 to 16 with a minimum possible total FLS score = 1 and a maximum possible total FLS score = 20. Lower score indicates lower flu like symptoms and better satisfaction. Difference between Rebif Morning Administration and Rebif Evening Administration groups at Week 12 is presented in statistical analysis section. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in Multiple Sclerosis Treatment Concern Questionnaire (MSTCQ) Flu Like Symptom (FLS) Score Between Rebif Morning Administration and Rebif Evening Administration Groups at Week 4 and 8 | The MSTCQ was used as a tool to measure treatment satisfaction, focusing on the attributes specific to multiple sclerosis (MS) medications. The FLS subscale of MSTCQ was defined as the sum of the scores for questions 13 to 16 with a minimum possible total FLS score = 1 and a maximum possible total FLS score = 20. Lower score indicates lower flu like symptoms and better satisfaction. Difference between Rebif Morning Administration and Rebif Evening Administration groups at Week 4 and 8 is presented in statistical analysis section. | Week 4 and 8 | 
| Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Discontinuation | An adverse event (AE) was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the treatment. A serious adverse event (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. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. | Baseline up to Week 12 | 
| Difference in Multiple Sclerosis Treatment Concern Questionnaire (MSTCQ) Subscale Scores Between Rebif Morning Administration and Rebif Evening Administration Groups at Week 4, 8 and 12 | MSTCQ was used as a tool to measure treatment satisfaction, focusing on attributes specific to MS medications. Following sub-scales were assessed: Injection site reactions (ISRs), Global side-effects, Benefits, Pain, Visual Analog Scale (VAS), and Rating of Pain. ISR subscale was defined as sum of scores for questions 17 to 20, with a minimum possible total score of 4 and a maximum possible total score of 20. Global side-effects subscale was defined as sum of scores for questions 21 to 23 with minimum possible total score of 3 and a maximum possible total score of 15. Benefits (question 35); description of pain (question 36); VAS (question 37); rating of pain (question 38) subscales ranged from minimum possible score of 1 and a maximum possible total score of 5. For each of the subscales, lower scores indicated better satisfaction. Difference between both the groups at Week 4, 8 and 12 for individual sub-scales is presented in statistical analysis section. | Week 4, 8 and 12 | 
| Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Score at Week 4, 8 and 12 | HADS was used to measure depression and anxiety in subjects. The scale was limited to 14 questions. Seven of the items related to anxiety and 7 related to depression. Each item on the questionnaire was scored from 0-3 giving a total score between 0 and 21 for either anxiety or depression where higher score indicates more anxiety/depression. | Baseline, Week 4, 8 and 12 | 
| Change From Baseline in Fatigue Severity Scale (FSS) Score at Week 4, 8 and 12 | FSS is a method designed to assess disabling fatigue in all the individuals. The Fatigue Severity Scale is a 9-item questionnaire developed to assess the level of fatigue due to neurological disease, were each item assessed on a 1-7 scale (1= no fatigue and 7= severe fatigue). The total score was calculated as the average of individual 9-items and ranged from 1 to 7 with a higher value indicating greater impairment due to fatigue. | Baseline, Week 4, 8 and 12 | 
| Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) Score at Week 4, 8 and 12 | PSQI is a self-rated questionnaire which assess sleep quality and disturbances over a 1-month interval using seven clinically derived components of sleep difficulties: sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction. PSQI is a summary of 7 components. Each component is scored from 0 to 3, therefore PSQI has a range of 0 (better) to 21 (worse). Interpretation of the PSQI is that a score less than 5 is associated with good sleep quality and a score of 5 or greater is associated with poor sleep quality. | Baseline, Week 4, 8 and 12 | 
| Change From Baseline in Multiple Sclerosis International Quality of Life (MusiQOL) Score at Week 4, 8 and 12 | The MusiQoL is a validated 31-item questionnaire describing 9 dimensions: activities of daily living (8 items); psychological well-being (4 items); symptoms (3 items); relationships with friends (4 items); relationships with family (3 items); relationship with healthcare system (3 items); sentimental and sexual life (2 items); coping (2 items); and rejection (2 items). Each of the questions was answered using a 6-point Likert scale ranging from 1 (never/not at all) to 6 (always/very much). The scores of each dimension were obtained by computing mean of the item scores of dimension with negatively worded item scores reversed so that higher scores indicated higher health-related quality of life (QoL). All 9 dimension scores were linearly transformed to a 0 to 100 scale and the average of the 9 dimensions was used to give a Global Score ranging from 0 to 100, where higher scores indicated higher health-related quality of life (QoL). | Baseline, Week 4, 8 and 12 | 
| Percentage of Subjects With Treatment Adherence at Week 4, 8 and 12 | Adherence to treatment was calculated as 100 x the number of completed injections the subject administered divided by the expected number of injections. Treatment adherence was divided in two categories: percentage of subjects with less than (<) 80 percent adherence and percentage of subjects with more than or equal to (>=) 80 percent adherence. | Week 4, 8 and 12 | 
| Change From Baseline in Circulating Levels of Cytokines at Week 12 | Results are presented for three cytokines: leptin, resistin and adiponectin. | Baseline and Week 12 | 
| Correlation Between Change From Baseline in Circulating Levels of Cytokines (Leptin, Resistin and Adiponectin) and in Flu Like Symptom (FLS) Score at Week 12 | Correlation was assessed by using Pearson correlation coefficient. The MSTCQ was used as a tool to measure treatment satisfaction, focusing on the attributes specific to MS medications. The FLS subscale of MSTCQ was defined as the sum of the scores for questions 13 to 16 with a minimum possible total FLS score = 1 and a maximum possible total FLS score = 20. Lower score indicates lower flu like symptoms and better satisfaction. | Baseline and Week 12 | 
| Correlation Between Change From Baseline in Circulating Levels of Cytokines and in Other MSTCQ Items, HADS, FSS, PSQI and MusiQOL Scores at Week 12 | Correlation was assessed by using Pearson correlation coefficient. MSTCQ, HADS, FSS, PSQI and MusiQOL are described in the above endpoints. Following abbreviations used in the categories: Global side-effects (GLOBSE); description of pain (PAINDESCR). | Baseline and Week 12 | 
| Change From Baseline in Cytokines (Leptin and Resistin) Levels at Week 12 | Results are presented for cytokines: leptin and resistin. | Baseline and Week 12 | 
| Change From Baseline in Cytokine (Adiponectin) Level at Week 12 |  | Baseline and Week 12 | 
| Change From Baseline in Hormone-Like Cytokine (Interleukin-6, 10 and 12) Levels at Week 12 |  | Baseline and Week 12 | 
| Change From Baseline in Total Sleep Time (TST) and Rapid Eye Movement (REM) Sleep Time at Week 12 | Polysomnography (PSG) was performed for subjects who participated in the sub study. PSG is a multi-parametric test used in the study of sleep and as a diagnostic tool in sleep medicine. Total sleep time is the total of all REM and non-REM sleep in a sleep episode. | Baseline and Week 12 | 
| Correlation Between Change From Baseline in Cytokines (Leptin, Resistin and Adiponectin) and Hormone-like Cytokine Levels (Interleukin-6, 10 and 12), and TST and REM Sleep Time at Week 12 | Correlations between change from baseline at Week 12 in TST or REM sleep and the area under the curve (AUC) calculated using the trapezoidal method for cytokine levels (i.e., leptin, resistin, adiponectin, Interleukin (IL)-12, IL 10, and IL 6) were analyzed using Pearson's correlation coefficient. Polysomnography (PSG) was performed for subjects who participated in the sub study. | Baseline and Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Sclerosis, Relapsing-Remitting, Interferon beta 1a, Rebif®