A Study of RoActemra/Actemra (Tocilizumab) Versus Placebo in Patients With Systemic Sclerosis

Study Overview
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Brief Summary
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This multicenter, randomized, double-blind, placebo-controlled, two-arm, parallel-group study will evaluate the efficacy and safety of RoActemra/Actemra (tocilizumab) in participants with systemic sclerosis. Participants will be randomized to receive either RoActemra/Actemra 162 mg subcutaneously weekly or placebo for 48 weeks. From Week 48 to Week 96, all participants will receive open-label RoActemra/Actemra 162 mg subcutaneously weekly. Anticipated time on study treatment is 96 weeks.

Official Title
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A Phase II/III, Multicenter, Randomized, Double-blind, Placebo-controlled Study To Assess The Efficacy And Safety Of Tocilizumab Versus Placebo In Patients With Systemic Sclerosis

Conditions
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Sclerosis, Systemic

Intervention / Treatment
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* Drug: Placebo
* Drug: tocilizumab [RoActemra/Actemra]
* Drug: tocilizumab [RoActemra/Actemra]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients, >/= 18 years of age Systemic sclerosis, as defined by American College of Rheumatology (1980) criteria Disease duration of </= 60 months (defined as time from first non-Raynaud phenomenon manifestation) >/= 15 and </= 40 mRSS units at screening Active disease, as defined by protocol Uninvolved skin at injection sites Negative pregnancy test for a female subject of childbearing potential Exclusion Criteria: Major surgery (including joint surgery) within 8 weeks prior to and/or during study enrollment Rheumatic autoimmune disease other than systemic sclerosis Skin thickening (scleroderma) limited to areas distal to the elbows or knees at screening Previous treatment with tocilizumab History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies Severe cardiopulmonary disease Known active current or history of recurrent infections Use of any investigational, biologic, or immunosuppressive therapies including intra-articular or parenteral corticosteroids prior to study enrollment as specified in the protocol As specified in the protocol, any current or past medical condition or medical history involving but not limited to the nervous, renal, pulmonary, endocrine, and gastrointestinal organ systems determined by the Principal Investigator to pose a significant safety risk to any subject while participating in the study Primary or secondary immunodeficiency

Ages Eligible for Study
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Minimum Age: 18 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> | Drug: Placebo<br>* Subcutaneously weekly, Weeks 0-48<br>Drug: tocilizumab [RoActemra/Actemra]<br>* 162 mg subcutaneously weekly, Week 48-96<br>|
| Experimental: Tocilizumab<br> | Drug: tocilizumab [RoActemra/Actemra]<br>* 162 mg subcutaneously weekly, Weeks 0-48<br>Drug: tocilizumab [RoActemra/Actemra]<br>* 162 mg subcutaneously weekly, Week 48-96<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Modified Rodnan Skin Score (mRSS) at Week 24 | Skin thickness was assessed by the mRSS. The mRSS was rated with scores ranging from 0 (normal) to 3 (severe skin thickening) across 17 different sites. The total score was the sum of the individual skin scores in the 17 body areas (e.g., face, hands, fingers; proximal area of the arms, distal area of the arms, thorax, abdomen; proximal area of the legs, and distal area of the legs, feet), giving a range of 0-51 units and had been validated for participants with systemic sclerosis (SSc). A negative change from baseline showed improvement. | Baseline, Week 24 | 
| Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to Week 8 after last dose that were absent before treatment or that worsened relative to pretreatment state. | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Physical Function Assessed by Scleroderma Health Assessment Questionnaire Disability Index (SHAQ-DI) | SHAQ-DI assessed five scleroderma-specific visual analogue scale (VAS) items to explore the impact of participant's disease. These items were developed to measure the effect of scleroderma on five elements of disease that could have a great impact on a participant's daily activities. Each VAS item was rated separately (0-100 millimeters [mm]), with higher scores indicating more severe disease. The five items were: 1) intestinal disease, 2) breathing problem, 3) Raynaud syndrome, 4) finger ulcers, and 5) overall disease. | Baseline, Weeks 24 and 48 | 
| Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 24 and Week 48 | The HAQ-DI scale consisted of 20 questions referring to eight component sets: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. The total score indicated the participant's self-assessed level of disability. There are four possible responses for each component: 0 = without any difficulty; 1 = with some difficulty; 2 = with much difficulty; 3 = unable to do. The HAQ-DI was the sum of the domain scores, divided by the number of domains that have a score (i.e. the average score), with total range of 0 to 3, higher scores showing larger functional limitation. | Baseline, Weeks 24 and 48 | 
| Change From Baseline in Clinician's Global Assessment at Week 24 and Week 48 | The Clinician's Global Assessment evaluated the overall impact of SSc on the participant as assessed by the physician on a VAS with scores ranging from 0 to 100 mm, with higher scores indicating worse disease in terms of severity, damage, or overall disease, but there was no standardization for the scale. | Baseline, Weeks 24 and 48 | 
| Change From Baseline in Patient's Global Assessment at Week 24 and Week 48 | The Patient's Global Assessment was a patient's reported outcome that represented the participant's overall assessment of his or her current SSc on a 100 mm horizontal VAS scale (0 mm to 100 mm), with higher scores indicating worsening disease. | Baseline, Weeks 24 and 48 | 
| Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 24 and Week 48 | This FACIT-Fatigue Scale was a 13-item measure with participants scoring each item on a 5-point scale (0 to 4) up to 52 points. The endpoint measured was fatigue. On this scale, a numerical increase indicated an improvement in the participant's condition. | Baseline, Weeks 24 and 48 | 
| Change From Baseline in 5-D Itch Scale at Week 24 and Week 48 | The 5-D Itch Scale contained five domains of duration, degree, direction, disability, and distribution. The endpoint of the scale was pruritus. Each domain was scored on a 5-point scale, the scores of each of the five domains were achieved separately and then summed together to obtain a total 5-D score. 5-D scores ranged between 5 (no pruritus) and 25 (most severe pruritus). | Baseline, Weeks 24 and 48 | 
| Change From Baseline in mRSS at Week 48 | Skin thickness was assessed by the mRSS. The mRSS was rated with scores ranging from 0 (normal) to 3 (severe skin thickening) across 17 different sites. The total score was the sum of the individual skin scores in the 17 body areas (e.g., face, hands, fingers; proximal area of the arms, distal area of the arms, thorax, abdomen; proximal area of the legs, and distal area of the legs, feet), giving a range of 0-51 units and had been validated for participants with systemic sclerosis (SSc). A negative change from baseline showed improvement. | Baseline, Week 48 | 
| Percentage of Participants Who Maintained or Improved in mRSS From Week 24 to Week 48 | Skin thickness was assessed by the mRSS. The mRSS was rated with scores ranging from 0 (normal) to 3 (severe skin thickening) across 17 different sites. The total score was the sum of the individual skin scores in the 17 body areas (e.g., face, hands, fingers; proximal area of the arms, distal area of the arms, thorax, abdomen; proximal area of the legs, and distal area of the legs, feet), giving a range of 0-51 units and had been validated for participants with systemic sclerosis (SSc). A negative change from baseline showed improvement. Percentage of participants with an improvement in mRSS at Week 24 (change from baseline <0) that maintained or further improved at Week 48 were reported as Yes and No with Yes = improvers at week 24 that had a change from baseline in mRSS at Week 48 <= change from baseline at Week 24. | Week 48 | 
| Change From Baseline in Tender Joint Count 28 (TJC28) | Joint tenderness was evaluated as per assessment of 28 joints. Joints on both sides of the body, including shoulders, elbows, wrists, 10 metacarpal phalangeal (MCP) joints, 10 proximal interphalangeal joint (PIP) joints, and both knees, were assessed. Joints were classified as not tender = 0 or tender = 1. Observed data was presented for this outcome measure. | Baseline, Weeks 3, 8, 16, 24, 32, 40, and 48 | 
| Area Under the Concentration-Time Curve (AUC) From Time 0 to 168 Hour (AUC0-168) | AUC was a measure of the serum concentration of the drug over time which was measured in micrograms times (*) hour per milliliters (µg*hr/mL). It is used to characterize drug absorption. | Pre-dose, 24, 48, 72, 96, 120 or 144, and 168 hours post dose for Baseline and Week 16 | 
| Mean Serum Concentrations of Interleukin (IL)-6 by Visit | Observed data was presented for this outcome measure. | Baseline, Weeks 1, 2, 3, 8, 16, 24, and 48 | 
| Mean Serum Concentrations of Soluble IL-6 Receptor (R) by Visit | Observed data was presented for this outcome measure. | Baseline, Weeks 1, 2, 3, 8, 16, 24, and 48 | 
| Percentage of Participants With Anti-Tocilizumab Antibody |  | Baseline, and post-baseline (up to Week 48) |