A Study of Participants With Relapsing-Remitting Multiple Sclerosis (RRMS)

Study Overview
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Brief Summary
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To look at the ability of LY2127399 to reduce magnetic resonance imaging (MRI) lesions at 12, 16, 20, and 24 weeks compared to placebo.

Official Title
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Multiple Subcutaneous Doses of LY2127399, an Anti-BAFF Human Antibody, in Subjects With Relapsing-Remitting Multiple Sclerosis

Conditions
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Relapsing-Remitting Multiple Sclerosis

Intervention / Treatment
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* Drug: LY2127399
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 through 64 years of age diagnosed with RRMS, who can walk without aid or rest for at least 200 meters (approximately 1/10 of a mile). Women who can become pregnant must use birth control. Exclusion Criteria: Have had a live vaccination within 12 weeks before randomization, or intend to have a live vaccination during the course of the study. Have had had recent surgery or are scheduled to have surgery during the study. Are immunocompromised or have evidence of active infection [such as hepatitis, tuberculosis or, human immunodeficiency virus (HIV)]. Have been on certain drugs that are being studied for RRMS or have recently received prescription drugs to treat RRMS. Have had a recent serious infection. Have serious or uncontrolled illnesses other than RRMS. Have clinically significant blood test values. Have multiple or severe drug allergies. Have contraindications for MRI scanning or claustrophobia (fear of an enclosed space) that cannot be managed.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Injection: Every 4 weeks in the placebo arm for 24 weeks (Weeks 0, 4, 8, 12, 16, and 20) for a total of 6 doses. Every 4 weeks in the LY2127399 arms [4 milligrams (mg) LY2127399 / 12 weeks and 120 mg LY2127399 / 12 weeks] for 24 weeks (except Week 0 and Week 12). | Drug: Placebo<br>* Administered via Injection<br>|
| Experimental: 4 mg LY2127399 / 4 weeks<br>Injection: 6 doses, one every 4 weeks for 24 weeks. | Drug: LY2127399<br>* Administered via Injection<br>|
| Experimental: 40 mg LY2127399 / 4 weeks<br>Injection: 6 doses, one every 4 weeks for 24 weeks. | Drug: LY2127399<br>* Administered via Injection<br>|
| Experimental: 120 mg LY2127399 / 4 weeks<br>Injection: 6 doses, one every 4 weeks for 24 weeks. | Drug: LY2127399<br>* Administered via Injection<br>|
| Experimental: 4 mg LY2127399 / 12 weeks<br>Drug: LY2127399 Injection: 2 doses, one every 12 weeks for 24 weeks. Drug: Placebo Injection: Every 4 weeks for 24 weeks (except Week 0 and Week 12). | Drug: LY2127399<br>* Administered via Injection<br>Drug: Placebo<br>* Administered via Injection<br>|
| Experimental: 120 mg LY2127399 / 12 weeks<br>Drug: LY2127399 Injection: 2 doses, one every 12 weeks for 24 weeks. Drug: Placebo Injection: Every 4 weeks for 24 weeks (except Week 0 and Week 12). | Drug: LY2127399<br>* Administered via Injection<br>Drug: Placebo<br>* Administered via Injection<br>|
| Experimental: 12 mg LY2127399 / 4 weeks<br>Injection: 6 doses, one every 4 weeks for 24 weeks. | Drug: LY2127399<br>* Administered via Injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Number of Gd-Enhancing T1-Weighted MRI Lesions Per Scan Averaged During Weeks 12, 16, 20, and 24 | Lesions were measured using Gd-enhancing T1-weighted MRI scans. The number of T1-weighted lesions per scan was obtained from the number of T1-weighted lesions observed during a specified week divided by the number of scans performed that same week. To obtain the number of T1-weighted lesions per scan averaged during Weeks 12, 16, 20, and 24, the number of lesions per scan at each week was summed and then divided by the number of visits with non-missing lesion counts. | Weeks 12, 16, 20, and 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Number of Gd-Enhancing T1-Weighted MRI Lesions Per Scan | Lesions were measured using Gd-enhancing T1-weighted MRI scans. The number of T1-weighted lesions per scan was obtained from the number of T1-weighted lesions observed during a specified week divided by the number of scans performed that same week. Least squares (LS) mean was calculated using an analysis of variance (ANOVA). | Baseline, Weeks 4, 8, 12, 16, 20, 24, 36, and 48 | 
| Total Number of New Gd-Enhancing T1-Weighted MRI Lesions Per Scan | Lesions were measured using Gd-enhancing T1-weighted MRI scans. The number of new T1-weighted lesions per scan was obtained from the number new T1-weighted lesions observed during a specified week divided by the number of scans performed that same week. | Weeks 4, 8, 12, 16, 20, 24, 36, and 48 | 
| Total Number of New or Newly Enlarging T2-Weighted MRI Lesions | Lesions were measured using T2-weighted proton density MRI scans. | Weeks 4, 8, 12, 16, 20, 24, 36, and 48 | 
| Total Volume of T2-Weighted MRI Lesions | The total volume of T2-weighted lesions was measured using T2-weighted proton density MRI scans. LS mean was calculated using an ANOVA model. | Weeks 4, 8, 12, 16, 20, 24, 36, and 48 | 
| Expanded Disability Status Scale (EDSS) | The EDSS is a rating scale for quantifying disability in multiple sclerosis (MS) participants. The EDSS has 8 functional systems (pyramidal, cerebellar, brain stem, sensory, bowel and bladder, visual, cerebral, and other) each rated on a scale from 0 (normal) to 5 (severe disability) or 0 (normal) to 6 (severe disability). The EDSS score was computed based on an algorithm of these components, and scores ranged from 0.0 (normal neurological exam) to 10.0 (death due to MS) in increments of 0.5. | Weeks 12, 24, and 48 | 
| Time to First Relapse | A confirmed relapse was defined as the appearance of 1 or more new neurological symptom(s) attributable to MS or the worsening of 1 or more previously observed symptoms. This change in clinical state was to last at least 48 hours and be immediately preceded by an improving neurological state of at least 30 days from onset of previous relapse. New or worsening neurological symptoms were accompanied by objective EDSS changes on examination (an increase from baseline of at least 1 point on the EDSS, at least 1 point on 2 EDSS functional systems, or at least 2 points on 1 EDSS functional system). A relapse may or may not have required systemic corticosteroid treatment. If a relapse did not occur during the specified time frame, the time to the first confirmed relapse was censored to the date of the participant's last available visit at or prior to Week 24, Week 48, and Week 48 for the respective time frames. | Baseline through Week 24, Baseline through Week 48, and Week 24 through Week 48 | 
| Percentage of Relapse-Free Participants | A confirmed relapse was defined as the appearance of 1 or more new neurological symptom(s) attributable to MS or the worsening of 1 or more previously observed symptoms. This change in clinical state was to last at least 48 hours and be immediately preceded by an improving neurological state of at least 30 days from onset of previous relapse. New or worsening neurological symptoms were accompanied by objective EDSS changes on examination (an increase from baseline of at least 1 point on the EDSS, at least 1 point on 2 EDSS functional systems, or at least 2 points on 1 EDSS functional system). A relapse may or may not have required systemic corticosteroid treatment. Percentage of relapse-free participants=[(number of participants who did not relapse)/(number of pts assessed)]*100. | Week 24, Week 48, end of study treatment [Week 24 or early discontinuation (ED)], and end of follow-up (Week 48 or ED) | 
| Annualized Relapse Rate (ARR) at Week 24 and Week 48 | The number of confirmed relapses per year, ARR=[(number of relapses from baseline through Week 24 or baseline through Week 48)/(the time in days between the same interval)]*365.25. A confirmed relapse was defined as the appearance of 1 or more new neurological symptom(s) attributable to MS or the worsening of 1 or more previously observed symptoms. This change in clinical state was to last at least 48 hours and be immediately preceded by an improving neurological state of at least 30 days from onset of previous relapse. New or worsening neurological symptoms were accompanied by objective EDSS changes on examination (an increase from baseline of at least 1 point on the EDSS, at least 1 point on 2 EDSS functional systems, or at least 2 points on 1 EDSS functional system). A relapse may or may have not required systemic corticosteroid treatment. | Baseline through Week 24 and Baseline through Week 48 | 
| Multiple Sclerosis Functional Composite Scale (MSFC) | The MSFC is a composite scale consisting of 3 components [Timed 25-Foot Walk, 9-Hole Peg Test (9-HPT), and 3-Second Paced Auditory Serial Addition Test (PASAT-3)]. The Timed 25-Foot Walk was a quantitative measure of lower extremity function. The 9-HPT was a quantitative measure of upper extremity (arm and hand) function. The PASAT-3 was a measure of cognitive function that specifically assessed auditory information processing speed and flexibility, as well as calculation ability. Component scores ranged from 0 to 60 and were converted to standard scores (z-scores). The MSFC score was calculated as the average of the 3 standardized component scores. Higher MSFC scores reflected better neurological function. | Weeks 12, 24, and 48 | 
| Visual Analog Scale (VAS) of Wellbeing | The VAS is a 100-millimeter (mm) horizontal line marked with 0 mm = poor and 100 mm = excellent. Participants were asked to assess their wellbeing by making a vertical mark on the scale. The score was computed as the distance from 0 mm to the vertical mark. | Weeks 12, 24, and 48 | 
| 16-Item Quick Inventory for Depressive Symptomatology Self Report (QIDS-SR16) | The QIDS-SR16 is a 16-item participant-rated measure of depressive symptomatology. Each item corresponds to 1 of 9 criterion domains for depression: change in sleep disturbance [question (Q) 1 through Q4], sad mood (Q5), decrease or increase in appetite and weight (Q6 through Q9), concentration (Q10), self-criticism (Q11), suicidal ideation (Q12), interest (Q13), energy/fatigue (Q14), and psychomotor agitation and retardation (Q15 and Q16). Each question was scored 0 (no problems) to 3 (increased symptoms). The total score=(the highest score from Q1 through Q4)+(Q5 score)+(the highest score from Q6 through Q9)+(the total score for each Q10 through Q14)+(the highest score from Q15 and Q16). A total score of 0 through 5 was considered no depression likely, 6 through 10 was mild depression, 11 through 15 was moderate depression, 16 through 20 was severe depression, and 21 or over was very severe depression. | Weeks 12, 24, and 48 | 
| Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) Component Scores | The SF-36 was a 36-item, health-related survey that assessed participant's quality of life on 8 domains: physical functioning, bodily pain, role limitations due to physical problems, role limitations due to emotional problems, general health, mental health, social functioning, vitality and 2 component scores (mental and physical health). Domain scores were calculated by summing individual items for each domain and transforming scores into 0 to 100 scale; higher scores indicated better health status or function. The mental component summary (MCS) score, based on SF-36 domains, consisted of social functioning, vitality, mental health, and role-emotional scales (range: 0 to 100). The physical component summary (PCS) score, based on SF-36 domains, consisted of physical functioning, bodily pain, role-physical, and general health scales (range: 0 to 100). | Weeks 12, 24, and 48 | 
| Pharmacokinetics (PK): Area Under the Concentration-Time Curve for Dosing Interval at Steady State (AUCtau,ss) | AUCtau,ss was obtained by conducting a simulation consisting of 1000 participants, which were then used to determine the noncompartmental PK parameters for each regimen. | Week 0: Day 1, 2, or 3 and Weeks 1, 4, 8, 12, 16, 20, 24, 30, 36, and 40. | 
| Percentage of Participants With Anti-LY2127399 Antibodies [Anti-Drug Antibodies (ADA)] | The percentage of participants with ADA=[(number of participants who had ADA)/(number of participants assessed)]*100. | Baseline, Weeks 4, 12, 24, 48, 60, 72, 84, 96, and 108 | 
| Pharmacodynamics: Change From Baseline in Peripheral Blood B Cell Subsets (Absolute Cell Counts) | Cell surface marker cluster designation (CD)19, CD27, and immunoglobulin D (IgD) expression levels were used to define the various B cell subsets. Cell surface markers were defined as being either present (+) or absent (-). Peripheral blood B cell subsets included: mature naive B cells (CD19+IgD+CD27-); immature/transitional (immature/tran) B cells (CD19+IgD-CD27-); switched memory B cells (CD19+IgD-CD27+); and non-switched memory B cells (CD19+IgD+CD27+). A positive or negative change indicated an increase or decrease, respectively in B cell count. | Baseline, Day 2, Weeks (Wks) 1, 4, 12, 24, 36, and 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsing, Remitting, Multiple Sclerosis, Multiple, Sclerosis, MS, LY2127399