A Study of the Efficacy and Safety of Tocilizumab in Participants With Systemic Sclerosis (SSc)

Study Overview
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Brief Summary
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This study will assess the efficacy and safety of tocilizumab compared with placebo in participants with SSc across approximately 120 planned global study sites. The study will consist of a 48-week, double-blind, placebo-controlled period followed by a 48-week open-label treatment period. Participants will be assigned, in a 1:1 ratio, to double-blind treatment with active tocilizumab or matching placebo. In the open-label period, eligible participants from either arm may receive active tocilizumab.

Official Title
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A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Assess the Efficacy and Safety of Tocilizumab Versus Placebo in Patients With Systemic Sclerosis

Conditions
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Systemic Sclerosis

Intervention / Treatment
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* Drug: Placebo
* Drug: Tocilizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of SSc according to American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) criteria, meeting criteria for active disease and with total disease duration of less than or equal to (</=) 60 months mRSS of 10-35 units, inclusive Agreement to remain abstinent or use an effective contraceptive method among males and females with childbearing potential Exclusion Criteria: Pregnant or lactating females Major surgery within 8 weeks prior to screening Scleroderma limited to the face or areas distal to the elbows or knees Rheumatic autoimmune disease other than SSc Immunization with a live or attenuated vaccine within 4 weeks prior to Baseline Known hypersensitivity to human, humanized, or murine monoclonal antibodies Moderately severe nervous system, renal, endocrine, pulmonary, cardiovascular, or gastrointestinal (GI) disease not related to SSc, including diverticulitis or ulcerative lower GI disorders, or myocardial infarction (MI) within 6 months prior to screening Active or significant history of infection, including treatment with intravenous (IV) antibiotics within 4 weeks or oral antibiotics within 2 weeks prior to screening Significant history of tuberculosis (TB) Primary or secondary immunodeficiency Malignant disease, with the exception of excised/cured local basal or squamous cell carcinoma of the skin or carcinoma in situ of the uterine cervix History of drug or alcohol abuse

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: Double-Blind Placebo<br>Participants will receive double-blind matching placebo from Baseline to Week 47. Participants may then receive open-label tocilizumab from Weeks 48 to 96. | Drug: Placebo<br>* Participants will receive matching placebo subcutaneous (SC) injections once weekly for 48 weeks of double-blind treatment.<br>Drug: Tocilizumab<br>* Participants will receive 162 mg SC tocilizumab once weekly for 48 weeks of double-blind treatment. The same regimen will be given to all eligible participants for 48 weeks of open-label treatment.<br>|
| Experimental: Double-Blind Tocilizumab<br>Participants will receive double-blind tocilizumab from Baseline to Week 47. Participants may then receive open-label tocilizumab from Weeks 48 to 96. | Drug: Tocilizumab<br>* Participants will receive 162 mg SC tocilizumab once weekly for 48 weeks of double-blind treatment. The same regimen will be given to all eligible participants for 48 weeks of open-label treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Modified Rodnan Skin Score (mRSS) During Double-blind Period | The efficacy of TCZ vs placebo is evaluated in terms of in mean change in mRSS. Skin thickness will be assessed by palpation and rated using an mRSS that ranges from 0 (normal) to 3 (severe skin thickening) across 17 different body sites. The total score is the sum of the individual skin scores from all of these sites and ranges from 0 to 51 units. | From baseline to week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Greater Than or Equal to (>/=) 20%, 40%, or 60% Improvement in mRSS During Double-blind Period | The proportion of participants with threshold improvements in mRSS at Week 48 relative to baseline. | From Baseline to Week 48 | 
| Change From Baseline in Percent Predicted FVC (ppFVC) During Double-blind Period | FVC is pulmonary function test and will be conducted as per the study Pulmonary Function Manual, which is based on the American Thoracic Society/European Respiratory Society (ATS/ERS) Consensus Statement. FVC is the maximum amount of air exhaled from the lungs after taking the deepest breath possible. Patients perform three to eight exhalations into a spirometer with the highest value recorded. | Baseline to week 48 | 
| Change in Forced Vital Capacity (FVC) During Double-blind Period | FVC is pulmonary function test and will be conducted as per the study Pulmonary Function Manual, which is based on the American Thoracic Society/European Respiratory Society (ATS/ERS) Consensus Statement. FVC is the maximum amount of air exhaled from the lungs after taking the deepest breath possible. Patients perform three to eight exhalations into a spirometer with the highest value recorded. | From Baseline to Week 48 | 
| Change in Health Assessment Questionnaire Disability Index (HAQ-DI) Score During Double-blind Period | The Health Assessment Questionnaire Disability Index (HAQ-DI) consists of 20 questions referring to eight component sets consisting of dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. Each item is scored on a 4-point scale from 0 to 3: 0 = Without any difficulty; 1 = With some difficulty; 2 = With much difficulty; 3 = Unable to do. Overall score was computed as the sum of component set scores and divided by the number of component sets answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty. The total score indicates the patient's self-assessed level of disability. This outcome measure represents the change in mean score from baseline. A negative change from baseline indicates improvement. | From Baseline to Week 48 | 
| Change in Patient Global Assessment Score During Double-blind Period | The Patient's Global Assessment represents the patient's overall assessment of current SSc status on a 100-mm horizontal visual analogue scale (VAS), ranging from 0 on the extreme left end of the scale indicating has no effect at all (symptom free), and 100 on the extreme right end indicating worst possible effect. | From Baseline to Week 48 | 
| Change in Physician Global Assessment Score During Double-blind Period | The Physician's Global Assessment is to be completed on the basis of examination and overall assessment of the patient. The physician's assessment of the patient's SSc status will be scored on a 100-mm horizontal visual analogue scale (VAS), ranging from 0 on the extreme left end of the scale indicating has no effect at all (symptom free), and 100 on the extreme right end indicating worst possible effect. | From Baseline to Week 48 | 
| Time to Treatment Failure According to mRSS, FVC, or Protocol-Specified Event During Double-blind Period | Time to treatment failure is defined as the time from randomization to the time of death, decline in percent-predicted FVC > 10% relative to baseline, > 20% increase in mRSS and an increase in mRSS of equal to or more than 5 points, or occurrence of a predefined SSc-related complication as adjudicated by the Clinical Adjudication Committee (whichever occurs first) during the 48-week double-blind treatment period. The median TTF was not estimable and is not presented for either treatment arm because of the low number of patients with events at Week 48. | From Baseline to Week 48 | 
| Summary of Adverse Events During Double-blind Period | Summary of key safety results including Adverse Events of Special Interest (AESI). All adverse events categorized according to MedDRA version 20.1. NMSC = Non-Melanoma Skin Cancer | From Baseline until Week 48 | 
| Incidence and Severity of Adverse Events During Double-blind Period | Adverse events listed according to MedDRA version 20.1 preferred terms and severity grade. | From Baseline until Week 48 | 
| Number of Participants With Adverse Events Leading to Death During Double-blind Period | Reason of death is coded using MedDRA 20.1 | From Baseline up to Week 48 | 
| Frequency of Serious Systemic Sclerosis (SSC) Related Complications During Double-blind Period | Adverse event terms coded using MedDRA 20.1. Includes only those serious events adjudicated as SSC-related complications by an independent external committee. | From Baseline up to Week 48 | 
| Incidence of Haematology and Hepatic Laboratory Parameters During Double-blind Period | A laboratory event occurred if the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grade for a post-baseline laboratory measurement increased from baseline. | From Baseline up to Week 48 | 
| Percentage of Participants With Change in Digital Ulcer Count During Double-blind Period | A digital ulcer is defined as an ulcer at or distal to the MCP joint on either the dorsal or volar surface, with loss of surface epithelialization. This does not include fissures, cracks, or calcium extrusions from calcinosis cutis. The number of fingers (0-10) with digital ulcers and the number of digital (or finger) ulcers will be counted and recorded by the investigator. | From Baseline to Week 48 | 
| Percentage of Participants With Positive Anti-Tocilizumab Assay Result at Baseline | Incidence of anti-Tocilizumab at baseline | Baseline | 
| Percentage of Participants With Positive Anti-Tocilizumab Assay Post-Baseline up to Week 48 | Incidence of anti-Tocilizumab antibodies during the study relative to the prevalence of anti-Tocilizumab antibodies at baseline. Samples that are positive for anti-TCZ in the screening assay will be further analyzed by a confirmation assay to confirm specificity. If the confirmation assay is positive, two additional tests will be performed: a neutralizing assay for the ability to inhibit the activity of TCZ and a test for anti -TCZ of the IgE isotype. | Double-blind period (up to Week 48) | 
| Correlation Between Anti-Tocilizumab Antibody Status and Outcome Measures Pertaining to the Efficacy, Safety, and Pharmacokinetics of Tocilizumab | Pre-specified analysis of the relationship between Anti-Tocilizumab Antibody status and safety, efficacy, and PK endpoints were not analyzed via subgroup analyses as there was only 1 patient with ADA-positive status. | Baseline; during Weeks 8, 16, 24, 36, 48, 96, and/or at treatment discontinuation (up to 96 weeks); and 8 weeks after treatment discontinuation (up to 104 weeks overall) | 
| Erythrocyte Sedimentation Rate (ESR), Mean, From Baseline to Week 48 | Erythrocyte Sedimentation Rate (ESR) levels predose at baseline and at subsequent time points after initiation of study drug. | From Predose up to Week 48 | 
| Erythrocyte Sedimentation Rate (ESR), Median, From Baseline to Week 48 | Erythrocyte Sedimentation Rate (ESR) levels predose at baseline and at subsequent time points after initiation of study drug. | From Baseline to Week 48 | 
| Serum Interleukin (IL)-6 Level, Mean, From Baseline to Week 48 | Serum Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug. | From Baseline to Week 48 | 
| Serum Interleukin (IL)-6 Level, Median, From Baseline to Week 48 | Serum Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug. | From Baseline to Week 48 | 
| Serum Interleukin (IL)-6 Level, Mean Change From Baseline to Week 48 | Serum Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug. | From Baseline to Week 48 | 
| Serum Interleukin (IL)-6 Level, Median Change From Baseline to Week 48 | Serum Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug. | From Baseline to Week 48 | 
| Serum Soluble Interleukin (IL)-6 Receptor Level, Mean, From Baseline to Week 48 | Serum soluble Interleukin (IL)-6 receptor levels predose at baseline and at subsequent time points after initiation of study drug. | From Baseline to Week 48 | 
| Serum Soluble Interleukin (IL)-6 Receptor Level, Median, From Baseline to Week 48 | Serum soluble Interleukin (IL)-6 receptor levels predose at baseline and at subsequent time points after initiation of study drug. | From Baseline to Week 48 | 
| Serum Soluble Interleukin (IL)-6 Receptor Level, Mean Change From Baseline to Week 48 | Serum soluble Interleukin (IL)-6 receptor levels predose at baseline and at subsequent time points after initiation of study drug. | From Baseline to Week 48 | 
| Serum Soluble Interleukin (IL)-6 Receptor Level, Median Change From Baseline to Week 48 | Serum soluble Interleukin (IL)-6 receptor levels predose at baseline and at subsequent time points after initiation of study drug. | From Baseline to Week 48 | 
| Serum C-Reactive Protein (CRP) Level, Mean, From Baseline to Week 48 | Serum C-Reactive Protein (CRP) levels predose at baseline and at subsequent time points after initiation of study drug. | From Baseline up to Week 48 | 
| Serum C-Reactive Protein (CRP) Level, Median, From Baseline to Week 48 | Serum C-Reactive Protein (CRP) levels predose at baseline and at subsequent time points after initiation of study drug. | From Baseline up to Week 48 | 
| Serum Tocilizumab Concentration, Mean, From Baseline to Week 48 | Predose observed serum TCZ concentration at baseline and at specified timepoints thereafter | From Baseline to Week 48 | 
| Serum Tocilizumab Concentration, Median, From Baseline to Week 48 | Predose observed serum TCZ concentration at baseline and at specified timepoints thereafter | From Baseline to Week 48 | 
| Correlation Between Low Serum Tocilizumab Exposure and Mean Modified Rodnan Skin Score (mRSS) From Baseline to Week 48 | In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-<41 ug/ml, Medium = 41-<=61.1 ug/ml, High = 61.1-<=145 ug/ml. | From Baseline to Week 48 | 
| Correlation Between Low Serum Tocilizumab Exposure and Median Modified Rodnan Skin Score (mRSS) From Baseline to Week 48 | In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-<41 ug/ml, Medium = 41-<=61.1 ug/ml, High = 61.1-<=145 ug/ml. | From Baseline to Week 48 | 
| Correlation Between Medium Serum Tocilizumab Exposure and Mean Modified Rodnan Skin Score (mRSS) From Baseline to Week 48 | In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-<41 ug/ml, Medium = 41-<=61.1 ug/ml, High = 61.1-<=145 ug/ml. | From Baseline to Week 48 | 
| Correlation Between Medium Serum Tocilizumab Exposure and Median Modified Rodnan Skin Score (mRSS) From Baseline to Week 48 | In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-<41 ug/ml, Medium = 41-<=61.1 ug/ml, High = 61.1-<=145 ug/ml. | From Baseline to Week 48 | 
| Correlation Between High Serum Tocilizumab Exposure and Mean Modified Rodnan Skin Score (mRSS) From Baseline to Week 48 | In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-<41 ug/ml, Medium = 41-<=61.1 ug/ml, High = 61.1-<=145 ug/ml. | From Baseline to Week 48 | 
| Correlation Between High Serum Tocilizumab Exposure and Median Modified Rodnan Skin Score (mRSS) From Baseline to Week 48 | In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-<41 ug/ml, Medium = 41-<=61.1 ug/ml, High = 61.1-<=145 ug/ml. | From Baseline to Week 48 | 
| Change in Mean Modified Rodnan Skin Score (mRSS) at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48 | In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-<41 ug/ml, Medium = 41-<=61.1 ug/ml, High = 61.1-<=145 ug/ml. | From Baseline to Week 48 | 
| Change in Median Modified Rodnan Skin Score (mRSS), at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48 | In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-<41 ug/ml, Medium = 41-<=61.1 ug/ml, High = 61.1-<=145 ug/ml. | From Baseline to Week 48 | 
| Change in Mean Percent Predicted Forced Vital Capacity (ppFVC), at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48 | In order to characterize exposure-efficacy relationships, ppFVC scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-<41 ug/ml, Medium = 41-<=61.1 ug/ml, High = 61.1-<=145 ug/ml. | From Baseline to Week 48 | 
| Change in Median Percent Predicted Forced Vital Capacity (ppFVC), at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48 | In order to characterize exposure-efficacy relationships, ppFVC scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-<41 ug/ml, Medium = 41-<=61.1 ug/ml, High = 61.1-<=145 ug/ml. | From Baseline to Week 48 | 
| Summary of Adverse Events Up to Week 96 | Summary of key safety results including Adverse Events of Special Interest (AESI). All adverse events categorized according to MedDRA version 21.1. NMSC = Non-Melanoma Skin Cancer | Up to Week 96 | 
| Incidence and Severity of Adverse Events Up to Week 96 | Adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) severity grade: 1 = mild, 2 = moderate, 3 = severe and/or requiring medical intervention but not life-threatening, 4 = life-threatening consequences, and 5 = death. | Up to Week 96 | 
| Number of Participants With Adverse Events Leading to Death Up to Week 96 |  | Up to Week 96 | 
| Percentage of Participants With Change in Digital Ulcer Count at Week 96 | A digital ulcer is defined as an ulcer at or distal to the MCP joint on either the dorsal or volar surface, with loss of surface epithelialization. This does not include fissures, cracks, or calcium extrusions from calcinosis cutis. The number of fingers (0-10) with digital ulcers and the number of digital (or finger) ulcers will be counted and recorded by the investigator. | From Baseline to Week 96 | 
| Percentage of Participants With Positive Anti-Tocilizumab Assay Post-Baseline From Week 48 to 96 | Reported were the percentage of participants with post-baseline treatment-induced anti-TCZ antibodies. Positive samples underwent additional analyses: a neutralizing assay for the ability to inhibit the activity of TCZ and a test for anti -TCZ of the IgE isotype. | Open-label period from Week 48 to 96 | 
| Erythrocyte Sedimentation Rate (ESR) Up to Week 96 | Erythrocyte Sedimentation Rate (ESR) levels predose at baseline and at subsequent time points after initiation of study drug. | Up to Week 96 | 
| Serum Interleukin (IL)-6 Level, Mean, From Baseline to Week 96 | Serum Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug. | Up to Week 96 | 
| Serum Soluble Interleukin (IL)-6 Receptor Level, Mean, Up to Week 96 | Serum Soluble Interleukin (IL)-6 receptor levels predose at baseline and at subsequent time points after initiation of study drug. | Up to Week 96 | 
| Serum C-Reactive Protein (CRP) Level, Mean, Up to Week 96 | Serum C-Reactive Protein (CRP) levels predose at baseline and at subsequent time points after initiation of study drug. | From Baseline up to Week 96 | 
| Serum Tocilizumab Concentration, Mean, Up to Week 96 | Predose observed serum TCZ concentration at baseline and at specified timepoints thereafter | Up to Week 96 |