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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02453256
Recruitment Status : Completed
First Posted : May 25, 2015
Results First Posted : April 3, 2019
Last Update Posted : March 9, 2020
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Systemic Sclerosis
Interventions Drug: Placebo
Drug: Tocilizumab
Enrollment 212
Recruitment Details  
Pre-assignment Details Overall 212 participants were randomized on to the study, 107 to the placebo arm and 105 to the tocilizumab arm. One participant in placebo arm withdrew consent prior to receiving any treatment and one participant in the tocilizumab arm was withdrawn due to randomization error prior to receiving any treatment.
Arm/Group Title Double-Blind Placebo, Then Open Label Tocilizumab Double-Blind Tocilizumab, Then Open Label Tocilizumab
Hide Arm/Group Description Participants received double-blind matching placebo from Baseline to Week 48. Participants then received open-label tocilizumab from Weeks 48 to 96. Participants received double-blind tocilizumab from Baseline to Week 48. Participants then received open-label tocilizumab from Weeks 48 to 96.
Period Title: Double Blind Period
Started 106 104
Completed 93 95
Not Completed 13 9
Reason Not Completed
Death             1             1
Adverse Event             3             2
Withdrawal by Subject             9             5
Other             0             1
Period Title: Open Label Period
Started 89 92
Completed 82 85
Not Completed 7 7
Reason Not Completed
Adverse Event             1             3
Death             0             1
Lost to Follow-up             1             0
Other             0             2
Withdrawal by Subject             5             1
Arm/Group Title Double-Blind Placebo, Then Tocilizumab Open Label Double-Blind Tocilizumab, Then Tocilizumab Open Label Total
Hide Arm/Group Description Participants received double-blind matching placebo from Baseline to Week 48. Participants then received open-label tocilizumab from Weeks 48 to 96. Participants received double-blind tocilizumab from Baseline to Week 48. Participants then received open-label tocilizumab from Weeks 48 to 96. Total of all reporting groups
Overall Number of Baseline Participants 106 104 210
Hide Baseline Analysis Population Description
The analysis was conducted on the safety population, i.e. all randomized patients who received at least one dose of study drug and provided data from at least one post dose safety assessment.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 106 participants 104 participants 210 participants
49.3  (12.6) 47.0  (12.2) 48.2  (12.4)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 106 participants 104 participants 210 participants
Female
90
  84.9%
81
  77.9%
171
  81.4%
Male
16
  15.1%
23
  22.1%
39
  18.6%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 106 participants 104 participants 210 participants
Hispanic or Latino
26
  24.5%
13
  12.5%
39
  18.6%
Not Hispanic or Latino
79
  74.5%
89
  85.6%
168
  80.0%
Unknown or Not Reported
1
   0.9%
2
   1.9%
3
   1.4%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 106 participants 104 participants 210 participants
American Indian or Alaska Native
3
   2.8%
1
   1.0%
4
   1.9%
Asian
9
   8.5%
16
  15.4%
25
  11.9%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
3
   2.8%
2
   1.9%
5
   2.4%
White
90
  84.9%
85
  81.7%
175
  83.3%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
1
   0.9%
0
   0.0%
1
   0.5%
1.Primary Outcome
Title Change in Modified Rodnan Skin Score (mRSS) During Double-blind Period
Hide Description 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.
Time Frame From baseline to week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the Intent-to-treat (ITT) population, i.e. all patients who were randomized and received any study drug.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Units on a scale
-4.41
(-5.96 to -2.86)
-6.14
(-7.71 to -4.57)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-Blind Placebo, Double-Blind Tocilizumab
Comments Difference in least square means between the TCZ group and the Placebo group at week 48. Null hypothesis: There is no difference between the TCZ group and the placebo group in mean change in mRSS from baseline to Week 48.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0983
Comments [Not Specified]
Method Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in least square means
Estimated Value -1.73
Confidence Interval (2-Sided) 95%
-3.78 to 0.32
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Percentage of Participants With Greater Than or Equal to (>/=) 20%, 40%, or 60% Improvement in mRSS During Double-blind Period
Hide Description The proportion of participants with threshold improvements in mRSS at Week 48 relative to baseline.
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the Intent-to-treat (ITT) population, i.e. all patients who were randomized and received any study drug.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
≥ 20%
50.0
(40.01 to 59.99)
72.1
(63.02 to 81.21)
≥ 40%
37.7
(28.04 to 47.44)
42.3
(32.33 to 52.28)
≥ 60%
22.6
(14.20 to 31.08)
17.3
(9.56 to 25.06)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-Blind Placebo, Double-Blind Tocilizumab
Comments This statistical analysis applies to participants with ≥ 20% improvement in mRSS.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0007
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Weighted difference
Estimated Value 21.91
Confidence Interval (2-Sided) 95%
9.2 to 34.6
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Double-Blind Placebo, Double-Blind Tocilizumab
Comments This statistical analysis applies to participants with ≥ 40% improvement in mRSS.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5139
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Weighted difference
Estimated Value 4.32
Confidence Interval (2-Sided) 95%
-8.7 to 17.3
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Double-Blind Placebo, Double-Blind Tocilizumab
Comments This statistical analysis applies to participants with ≥ 60% improvement in mRSS.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3276
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Weighted difference
Estimated Value -5.41
Confidence Interval (2-Sided) 95%
-16.2 to 5.4
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Change From Baseline in Percent Predicted FVC (ppFVC) During Double-blind Period
Hide Description 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.
Time Frame Baseline to week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the Intent-to-treat (ITT) population, i.e. all patients who were randomized and received any study drug.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Median (95% Confidence Interval)
Unit of Measure: Percent Predicted FVC
-3.910
(-4.820 to -1.620)
-0.600
(-2.380 to 0.880)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-Blind Placebo, Double-Blind Tocilizumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0015
Comments P-value from Van Elteren analysis stratified by IL-6 level (<10; >=10 pg/mL) at screening.
Method Van Elteren
Comments [Not Specified]
4.Secondary Outcome
Title Change in Forced Vital Capacity (FVC) During Double-blind Period
Hide Description 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.
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the Intent-to-treat (ITT) population, i.e. all patients who were randomized and received any study drug.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Liters of air
-0.19
(-0.25 to -0.13)
-0.02
(-0.09 to 0.04)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-Blind Placebo, Double-Blind Tocilizumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0001
Comments [Not Specified]
Method Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in least square means
Estimated Value 0.167
Confidence Interval (2-Sided) 95%
0.083 to 0.250
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Change in Health Assessment Questionnaire Disability Index (HAQ-DI) Score During Double-blind Period
Hide Description 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.
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the Intent-to-treat (ITT) population, i.e. all patients who were randomized and received any study drug.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Scores on a Scale
-0.06
(-0.16 to 0.05)
-0.11
(-0.22 to -0.01)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-Blind Placebo, Double-Blind Tocilizumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4489
Comments [Not Specified]
Method Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in least square means
Estimated Value -0.053
Confidence Interval (2-Sided) 95%
-0.192 to 0.085
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Change in Patient Global Assessment Score During Double-blind Period
Hide Description 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."
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the Intent-to-treat (ITT) population, i.e. all patients who were randomized and received any study drug.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mm
-7.66
(-12.31 to -3.02)
-10.10
(-14.79 to -5.41)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-Blind Placebo, Double-Blind Tocilizumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4339
Comments [Not Specified]
Method Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in least square means
Estimated Value -2.44
Confidence Interval (2-Sided) 95%
-8.57 to 3.70
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Change in Physician Global Assessment Score During Double-blind Period
Hide Description 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."
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the Intent-to-treat (ITT) population, i.e. all patients who were randomized and received any study drug.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mm
-19.99
(-24.76 to -15.22)
-22.45
(-27.33 to -17.57)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-Blind Placebo, Double-Blind Tocilizumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4378
Comments [Not Specified]
Method Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in least square means
Estimated Value -2.46
Confidence Interval (2-Sided) 95%
-8.72 to 3.79
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Time to Treatment Failure According to mRSS, FVC, or Protocol-Specified Event During Double-blind Period
Hide Description 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.
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the Intent-to-treat (ITT) population, i.e. all patients who were randomized and received any study drug.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(48.7 to NA)
NA [2] 
(NA to NA)
[1]
The median and upper limit of CI were not evaluable because of the low number of participants with events at Week 48.
[2]
The median, lower limit and upper limit of CI were not evaluable because of the low number of participants with events at Week 48.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-Blind Placebo, Double-Blind Tocilizumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0821
Comments [Not Specified]
Method Cox-proportional hazards model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.63
Confidence Interval (2-Sided) 95%
0.37 to 1.06
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Summary of Adverse Events During Double-blind Period
Hide Description 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
Time Frame From Baseline until Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Measure Type: Number
Unit of Measure: Percentage of Participants
At least one Adverse Event (AE) 77.4 85.6
Withdrawn from study due to an AE 3.8 2.9
Fatal AE 2.8 1.0
Serious Adverse Events (SAEs) 17.0 12.5
SAE leading to withdrawal from treatment 3.8 3.8
SAE leading to dose modification/interruption 6.6 2.9
SAE related to study drug 6.6 1.0
AE leading to withdrawal from treatment 10.4 5.8
AE leading to dose modification/interruption 25.5 19.2
AE related to study drug 34.9 46.2
Related AE leading to withdrawal from treatment 1.9 1.0
Related AE with dose modification/interruption 16.0 11.5
Infections and Infestations SAE 6.6 1.9
Infections and Infestations AE 50.0 51.9
Opportunistic Infections and Infestations AE 0.9 0.0
Malignancy AE 0.9 1.9
Malignancy AE (excluding NMSC) 0.9 1.9
At least one Hepatic SAE 0.0 0.0
At least one Stroke SAE 0.0 0.0
At least one Myocardial Infarction SAE 1.9 0.0
At least one Anaphylactic Reaction AE 0.0 0.0
Anaphylactic Reaction AE (Sampson's Criteria) 0.0 0.0
At least one Gastrointestinal Perforation SAE 0.0 0.0
At least one Bleeding SAE 0.9 0.0
At least one Demyelinating SAE 0.0 0.0
10.Secondary Outcome
Title Incidence and Severity of Adverse Events During Double-blind Period
Hide Description Adverse events listed according to MedDRA version 20.1 preferred terms and severity grade.
Time Frame From Baseline until Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Measure Type: Number
Unit of Measure: Number of participants
NASOPHARYNGITIS GRADE 1 6 10
NASOPHARYNGITIS GRADE 2 2 3
URINARY TRACT INFECTION GRADE 1 5 1
URINARY TRACT INFECTION GRADE 2 5 3
URINARY TRACT INFECTION GRADE 3 0 1
GASTROENTERITIS GRADE 1 0 2
GASTROENTERITIS GRADE 2 2 4
HERPES ZOSTER GRADE 2 5 0
HERPES ZOSTER GRADE 3 0 2
PHARYNGITIS GRADE 1 2 1
PHARYNGITIS GRADE 2 2 2
INFECTED SKIN ULCER GRADE 1 0 1
INFECTED SKIN ULCER GRADE 2 1 3
INFECTED SKIN ULCER GRADE 3 1 0
BRONCHITIS GRADE 1 1 1
BRONCHITIS GRADE 2 1 2
INFLUENZA GRADE 1 1 2
INFLUENZA GRADE 2 1 1
LATENT TUBERCULOSIS GRADE 1 1 2
LATENT TUBERCULOSIS GRADE 2 0 2
PNEUMONIA GRADE 2 1 1
PNEUMONIA GRADE 3 3 0
RESPIRATORY TRACT INFECTION GRADE 1 1 1
RESPIRATORY TRACT INFECTION GRADE 2 0 1
RESPIRATORY TRACT INFECTION GRADE 3 1 0
SINUSITIS GRADE 1 1 0
SINUSITIS GRADE 2 1 1
SINUSITIS GRADE 3 0 1
WOUND INFECTION GRADE 1 0 2
WOUND INFECTION GRADE 2 1 0
WOUND INFECTION GRADE 3 1 0
CYSTITIS GRADE 1 0 1
CYSTITIS GRADE 2 0 2
LOCALISED INFECTION GRADE 1 1 0
LOCALISED INFECTION GRADE 2 2 0
ORAL CANDIDIASIS GRADE 1 2 1
PARONYCHIA GRADE 2 2 0
PARONYCHIA GRADE 3 1 0
VULVOVAGINAL MYCOTIC INFECTION GRADE 2 2 1
CANDIDA INFECTION GRADE 1 1 0
CANDIDA INFECTION GRADE 2 1 0
FOLLICULITIS GRADE 1 0 1
FOLLICULITIS GRADE 2 1 0
GASTROINTESTINAL INFECTION GRADE 2 2 0
HORDEOLUM GRADE 1 0 2
RHINITIS GRADE 2 1 1
SOFT TISSUE INFECTION GRADE 2 1 0
SOFT TISSUE INFECTION GRADE 4 1 0
TINEA PEDIS GRADE 1 0 1
TINEA PEDIS GRADE 2 0 1
VIRAL UPPER RESPIRATORY TRACT INFECTION GRADE 1 1 0
VIRAL UPPER RESPIRATORY TRACT INFECTION GRADE 2 1 0
ABSCESS JAW GRADE 3 1 0
ACUTE SINUSITIS GRADE 2 1 0
BACTERAEMIA GRADE 2 1 0
BODY TINEA GRADE 1 1 0
CAMPYLOBACTER GASTROENTERITIS GRADE 1 0 1
GASTROENTERITIS VIRAL GRADE 2 1 0
GASTROINTESTINAL BACTERIAL OVERGROWTH GRADE 2 1 0
GASTROINTESTINAL VIRAL INFECTION GRADE 1 1 0
GINGIVITIS GRADE 2 1 0
HERPES SIMPLEX GRADE 1 1 0
INFECTIOUS MONONUCLEOSIS GRADE 1 1 0
LARYNGITIS GRADE 1 1 0
LICE INFESTATION GRADE 3 0 1
OESOPHAGEAL CANDIDIASIS GRADE 2 1 0
ORAL HERPES GRADE 2 1 0
OSTEOMYELITIS GRADE 3 0 1
PELVIC INFLAMMATORY DISEASE GRADE 3 0 1
PERIODONTITIS GRADE 2 1 0
PERIORBITAL CELLULITIS GRADE 1 0 1
PHARYNGITIS STREPTOCOCCAL GRADE 1 1 0
PULMONARY TUBERCULOSIS GRADE 3 0 1
PULPITIS DENTAL GRADE 1 0 1
PYELONEPHRITIS CHRONIC GRADE 3 1 0
RASH PUSTULAR GRADE 1 0 1
RESPIRATORY TRACT INFECTION BACTERIAL GRADE 2 0 1
SEPSIS GRADE 3 1 0
SKIN BACTERIAL INFECTION GRADE 2 1 0
TONSILLITIS GRADE 2 0 1
TOOTH INFECTION GRADE 3 1 0
VIRAL INFECTION GRADE 1 0 1
WOUND INFECTION STAPHYLOCOCCAL GRADE 1 0 1
ARTHRALGIA GRADE 1 3 8
ARTHRALGIA GRADE 2 8 3
ARTHRALGIA GRADE 3 1 0
BACK PAIN GRADE 1 1 1
BACK PAIN GRADE 2 4 1
MUSCLE SPASMS GRADE 1 1 2
MUSCLE SPASMS GRADE 2 1 1
MUSCLE SPASMS GRADE 3 1 0
PAIN IN EXTREMITY GRADE 1 2 2
PAIN IN EXTREMITY GRADE 2 0 1
PAIN IN EXTREMITY GRADE 3 1 0
MUSCULOSKELETAL PAIN GRADE 1 1 0
MUSCULOSKELETAL PAIN GRADE 2 4 0
BURSITIS GRADE 1 3 0
BURSITIS GRADE 2 0 1
MYALGIA GRADE 1 1 0
MYALGIA GRADE 2 3 0
ARTHRITIS GRADE 2 2 1
INTERVERTEBRAL DISC PROTRUSION GRADE 1 1 1
INTERVERTEBRAL DISC PROTRUSION GRADE 2 0 1
MYOSITIS GRADE 1 1 0
MYOSITIS GRADE 2 1 1
OSTEOCHONDROSIS GRADE 1 1 2
FOOT DEFORMITY GRADE 1 1 1
SCLERODERMA GRADE 2 0 1
SCLERODERMA GRADE 4 1 0
SJOGREN'S SYNDROME GRADE 1 1 0
SJOGREN'S SYNDROME GRADE 2 1 0
SPINAL OSTEOARTHRITIS GRADE 1 0 1
SPINAL OSTEOARTHRITIS GRADE 2 1 0
EXTREMITY CONTRACTURE GRADE 1 1 0
FIBROMYALGIA GRADE 1 1 0
FLANK PAIN GRADE 1 0 1
JOINT STIFFNESS GRADE 1 0 1
JOINT SWELLING GRADE 2 1 0
MUSCLE CONTRACTURE GRADE 1 0 1
MUSCLE FATIGUE GRADE 1 1 0
MUSCULAR WEAKNESS GRADE 2 0 1
MUSCULOSKELETAL CHEST PAIN GRADE 1 1 0
MYOPATHY GRADE 1 1 0
NECK PAIN GRADE 2 1 0
OSTEOPENIA GRADE 1 0 1
OSTEOPOROSIS GRADE 2 0 1
OSTEOPOROTIC FRACTURE GRADE 2 1 0
PAIN IN JAW GRADE 1 1 0
POLYARTHRITIS GRADE 2 1 0
TENOSYNOVITIS GRADE 2 0 1
TENOSYNOVITIS STENOSANS GRADE 1 1 0
SKIN ULCER GRADE 1 5 8
SKIN ULCER GRADE 2 7 5
SKIN ULCER GRADE 3 0 2
PRURITUS GRADE 1 2 1
PRURITUS GRADE 2 2 5
RASH GRADE 1 4 2
RASH GRADE 2 3 0
ERYTHEMA GRADE 1 1 4
ECZEMA GRADE 1 0 2
ECZEMA GRADE 2 2 0
ROSACEA GRADE 1 0 1
ROSACEA GRADE 2 1 1
SKIN TIGHTNESS GRADE 1 2 1
DERMATITIS CONTACT GRADE 2 1 1
INGROWING NAIL GRADE 1 0 1
INGROWING NAIL GRADE 2 1 0
MACULE GRADE 1 1 1
NIGHT SWEATS GRADE 1 2 0
SKIN DISCOLOURATION GRADE 1 0 2
SKIN FISSURES GRADE 1 0 2
SKIN HYPERTROPHY GRADE 1 0 2
SKIN INDURATION GRADE 1 2 0
URTICARIA GRADE 1 0 1
URTICARIA GRADE 2 1 0
ALOPECIA GRADE 1 0 1
BLISTER GRADE 2 0 1
CHLOASMA GRADE 1 1 0
COLD SWEAT GRADE 1 1 0
DECUBITUS ULCER GRADE 2 0 1
DERMATITIS ACNEIFORM GRADE 1 0 1
DERMATITIS ATOPIC GRADE 1 0 1
DIGITAL PITTING SCAR GRADE 4 1 0
DRY SKIN GRADE 1 0 1
ECCHYMOSIS GRADE 3 1 0
EXCESSIVE GRANULATION TISSUE GRADE 3 0 1
HYPERTRICHOSIS GRADE 1 1 0
ONYCHOLYSIS GRADE 1 1 0
PAIN OF SKIN GRADE 1 1 0
PAPULE GRADE 1 1 0
RASH ERYTHEMATOUS GRADE 1 0 1
RASH MACULO-PAPULAR GRADE 3 0 1
SKIN DEPIGMENTATION GRADE 1 1 0
SKIN FIBROSIS GRADE 2 1 0
SKIN HYPOPIGMENTATION GRADE 1 1 0
SKIN OEDEMA GRADE 1 1 0
VITILIGO GRADE 2 1 0
DIARRHOEA GRADE 1 5 6
DIARRHOEA GRADE 2 3 0
GASTROOESOPHAGEAL REFLUX DISEASE GRADE 1 3 3
GASTROOESOPHAGEAL REFLUX DISEASE GRADE 2 2 1
NAUSEA GRADE 1 5 3
NAUSEA GRADE 2 1 0
ABDOMINAL PAIN GRADE 1 3 1
ABDOMINAL PAIN GRADE 2 1 0
ABDOMINAL PAIN GRADE 3 1 0
CONSTIPATION GRADE 1 2 2
CONSTIPATION GRADE 2 2 0
DYSPEPSIA GRADE 1 1 2
DYSPEPSIA GRADE 2 1 1
DYSPHAGIA GRADE 1 2 2
DYSPHAGIA GRADE 2 0 1
STOMATITIS GRADE 1 1 1
STOMATITIS GRADE 2 1 0
VOMITING GRADE 1 1 1
VOMITING GRADE 3 0 1
ABDOMINAL DISCOMFORT GRADE 1 0 1
ABDOMINAL DISCOMFORT GRADE 2 1 0
ABDOMINAL DISTENSION GRADE 1 1 0
ABDOMINAL DISTENSION GRADE 2 1 0
ABDOMINAL PAIN UPPER GRADE 1 1 1
DENTAL CARIES GRADE 2 1 1
FAECES SOFT GRADE 1 1 1
HAEMORRHOIDS GRADE 1 1 0
HAEMORRHOIDS GRADE 2 1 0
TOOTHACHE GRADE 2 2 0
ANAL HAEMORRHAGE GRADE 2 1 0
CHRONIC GASTRITIS GRADE 1 1 0
DIVERTICULUM INTESTINAL GRADE 1 0 1
DRY MOUTH GRADE 2 0 1
DUODENITIS GRADE 1 0 1
GASTRIC DISORDER GRADE 1 0 1
GASTRIC POLYPS GRADE 1 1 0
GASTRITIS GRADE 2 1 0
HAEMATOCHEZIA GRADE 1 0 1
ILEUS PARALYTIC GRADE 3 1 0
LOOSE TOOTH GRADE 1 0 1
OESOPHAGEAL DISORDER GRADE 1 1 0
OESOPHAGEAL HYPOMOTILITY GRADE 2 0 1
PERIODONTAL DISEASE GRADE 2 1 0
PNEUMATOSIS INTESTINALIS GRADE 2 0 1
RANULA GRADE 1 0 1
SWOLLEN TONGUE GRADE 2 0 1
FATIGUE GRADE 1 3 7
FATIGUE GRADE 2 4 1
OEDEMA PERIPHERAL GRADE 1 2 1
OEDEMA PERIPHERAL GRADE 2 1 0
ASTHENIA GRADE 1 2 0
ASTHENIA GRADE 3 1 0
CALCINOSIS GRADE 1 1 2
INJECTION SITE ERYTHEMA GRADE 1 0 1
INJECTION SITE ERYTHEMA GRADE 2 0 1
INJECTION SITE ERYTHEMA GRADE 3 0 1
INJECTION SITE REACTION GRADE 1 0 1
INJECTION SITE REACTION GRADE 2 1 1
PAIN GRADE 2 1 0
PAIN GRADE 3 0 1
PAIN GRADE 4 1 0
CHEST PAIN GRADE 1 2 0
CYST GRADE 1 1 0
CYST GRADE 2 1 0
INFLUENZA LIKE ILLNESS GRADE 1 1 1
DEATH GRADE 5 0 1
FEELING HOT GRADE 1 0 1
GRANULOMA GRADE 1 1 0
INJECTION SITE EXTRAVASATION GRADE 1 0 1
INJECTION SITE INDURATION GRADE 2 0 1
INJECTION SITE PRURITUS GRADE 2 0 1
MALAISE GRADE 1 0 1
NODULE GRADE 1 1 0
PERIPHERAL SWELLING GRADE 2 1 0
PYREXIA GRADE 1 1 0
SENSATION OF FOREIGN BODY GRADE 1 0 1
VESSEL PUNCTURE SITE PAIN GRADE 1 0 1
WEIGHT DECREASED GRADE 1 3 1
WEIGHT DECREASED GRADE 2 3 2
ALANINE AMINOTRANSFERASE INCREASED GRADE 1 0 2
ALANINE AMINOTRANSFERASE INCREASED GRADE 2 2 0
ALANINE AMINOTRANSFERASE INCREASED GRADE 3 0 2
ASPARTATE AMINOTRANSFERASE INCREASED GRADE 1 0 2
ASPARTATE AMINOTRANSFERASE INCREASED GRADE 2 2 0
ASPARTATE AMINOTRANSFERASE INCREASED GRADE 3 0 1
HEPATIC ENZYME INCREASED GRADE 1 1 0
HEPATIC ENZYME INCREASED GRADE 2 1 1
HEPATIC ENZYME INCREASED GRADE 3 1 0
WEIGHT INCREASED GRADE 1 2 2
TRANSAMINASES INCREASED GRADE 1 0 1
TRANSAMINASES INCREASED GRADE 2 2 0
BLOOD CHOLESTEROL INCREASED GRADE 1 0 1
BLOOD CHOLESTEROL INCREASED GRADE 2 0 1
UPPER RESPIRATORY TRACT INFECTION GRADE 1 4 7
UPPER RESPIRATORY TRACT INFECTION GRADE 2 7 4
UPPER RESPIRATORY TRACT INFECTION GRADE 3 0 1
BLOOD CREATINE PHOSPHOKINASE INCREASED GRADE 1 0 1
BLOOD CREATINE PHOSPHOKINASE INCREASED GRADE 2 0 1
BLOOD BILIRUBIN INCREASED GRADE 1 0 1
BLOOD URINE PRESENT GRADE 2 1 0
CAROTID INTIMA-MEDIA THICKNESS INCREASED GRADE 1 1 0
COMPUTERISED TOMOGRAM THORAX ABNORMAL GRADE 2 1 0
HAEMOGLOBIN DECREASED GRADE 2 1 0
LIVER FUNCTION TEST ABNORMAL GRADE 2 0 1
LOW DENSITY LIPOPROTEIN INCREASED GRADE 2 0 1
PROTEIN URINE PRESENT GRADE 2 1 0
TRANSFERRIN SATURATION INCREASED GRADE 1 0 1
TUBERCULIN TEST POSITIVE GRADE 2 1 0
URINE BILIRUBIN INCREASED GRADE 2 1 0
UROBILINOGEN URINE INCREASED GRADE 2 1 0
WHITE BLOOD CELLS URINE POSITIVE GRADE 1 1 0
COUGH GRADE 1 3 1
COUGH GRADE 2 2 2
INTERSTITIAL LUNG DISEASE GRADE 1 3 0
INTERSTITIAL LUNG DISEASE GRADE 2 5 0
DYSPNOEA GRADE 1 1 1
DYSPNOEA GRADE 2 2 2
EPISTAXIS GRADE 1 3 1
EPISTAXIS GRADE 2 0 1
DYSPNOEA EXERTIONAL GRADE 1 1 0
DYSPNOEA EXERTIONAL GRADE 2 1 0
DYSPNOEA EXERTIONAL GRADE 3 1 0
OROPHARYNGEAL PAIN GRADE 1 1 1
OROPHARYNGEAL PAIN GRADE 2 1 0
PRODUCTIVE COUGH GRADE 1 2 0
DYSPHONIA GRADE 1 1 0
HAEMOPTYSIS GRADE 1 0 1
PAINFUL RESPIRATION GRADE 1 1 0
PLEURAL EFFUSION GRADE 4 1 0
PNEUMONITIS GRADE 2 1 0
RHINITIS ALLERGIC GRADE 1 1 0
RHINORRHOEA GRADE 1 1 0
HEADACHE GRADE 1 3 3
HEADACHE GRADE 2 4 0
DIZZINESS GRADE 1 2 2
DIZZINESS GRADE 2 1 1
NEUROPATHY PERIPHERAL GRADE 2 2 0
POST HERPETIC NEURALGIA GRADE 2 2 0
CARPAL TUNNEL SYNDROME GRADE 1 1 0
DYSGEUSIA GRADE 1 1 0
HYPOAESTHESIA GRADE 1 1 0
HYPOKINESIA GRADE 3 0 1
MEMORY IMPAIRMENT GRADE 1 0 1
NERVE COMPRESSION GRADE 1 1 0
NEURALGIA GRADE 1 1 0
PARAESTHESIA GRADE 1 0 1
PARKINSONISM GRADE 2 1 0
PRESYNCOPE GRADE 1 0 1
RADICULAR PAIN GRADE 1 0 1
SENSORY LOSS GRADE 1 1 0
SOMNOLENCE GRADE 1 0 1
LIMB INJURY GRADE 1 2 1
LIMB INJURY GRADE 2 2 0
LIMB INJURY GRADE 3 0 1
FALL GRADE 1 0 1
FALL GRADE 2 0 2
EAR INJURY GRADE 1 0 2
LACERATION GRADE 1 1 0
LACERATION GRADE 2 1 0
SCAR GRADE 1 0 1
SCAR GRADE 2 1 0
WOUND GRADE 1 0 1
WOUND GRADE 2 1 0
ANIMAL BITE GRADE 2 0 1
ANKLE FRACTURE GRADE 1 0 1
ARTHROPOD STING GRADE 1 1 0
CONTUSION GRADE 1 0 1
CRANIOCEREBRAL INJURY GRADE 2 1 0
EXCORIATION GRADE 1 0 1
FACE INJURY GRADE 1 0 1
INJURY CORNEAL GRADE 2 1 0
JOINT INJURY GRADE 3 0 1
LIGAMENT SPRAIN GRADE 1 0 1
LIMB TRAUMATIC AMPUTATION GRADE 3 0 1
MENISCUS INJURY GRADE 3 0 1
MUSCLE RUPTURE GRADE 2 0 1
MUSCLE STRAIN GRADE 2 1 0
ROAD TRAFFIC ACCIDENT GRADE 1 0 1
SKIN ABRASION GRADE 1 1 0
SPINAL COMPRESSION FRACTURE GRADE 2 1 0
THERMAL BURN GRADE 1 0 1
ANAEMIA GRADE 1 3 0
ANAEMIA GRADE 2 2 1
ANAEMIA GRADE 3 1 0
IRON DEFICIENCY ANAEMIA GRADE 1 1 0
IRON DEFICIENCY ANAEMIA GRADE 2 1 0
IRON DEFICIENCY ANAEMIA GRADE 3 0 1
LYMPHOPENIA GRADE 2 0 1
LYMPHOPENIA GRADE 3 1 0
NEUTROPENIA GRADE 2 0 1
NEUTROPENIA GRADE 3 1 0
ANAEMIA MEGALOBLASTIC GRADE 2 1 0
EOSINOPHILIA GRADE 1 0 1
LEUKOCYTOSIS GRADE 1 1 0
LEUKOPENIA GRADE 2 0 1
LYMPHADENOPATHY MEDIASTINAL GRADE 2 1 0
MICROANGIOPATHIC HAEMOLYTIC ANAEMIA GRADE 2 0 1
MICROCYTIC ANAEMIA GRADE 1 0 1
THROMBOCYTOPENIA GRADE 1 0 1
DECREASED APPETITE GRADE 1 4 1
DYSLIPIDAEMIA GRADE 1 0 2
DYSLIPIDAEMIA GRADE 2 1 1
HYPERCHOLESTEROLAEMIA GRADE 1 0 1
HYPERCHOLESTEROLAEMIA GRADE 2 0 1
HYPERTRIGLYCERIDAEMIA GRADE 2 1 1
DIABETES MELLITUS GRADE 2 1 0
DIABETIC KETOACIDOSIS GRADE 4 1 0
DIABETIC METABOLIC DECOMPENSATION GRADE 1 0 1
FOLATE DEFICIENCY GRADE 1 0 1
GOUT GRADE 2 1 0
HYPERGLYCAEMIA GRADE 3 1 0
HYPERLIPIDAEMIA GRADE 1 0 1
HYPONATRAEMIA GRADE 1 1 0
IRON DEFICIENCY GRADE 2 1 0
OBESITY GRADE 1 0 1
WEIGHT FLUCTUATION GRADE 1 1 0
PALPITATIONS GRADE 1 4 1
PALPITATIONS GRADE 3 0 1
BUNDLE BRANCH BLOCK RIGHT GRADE 1 1 0
BUNDLE BRANCH BLOCK RIGHT GRADE 2 0 1
PERICARDIAL EFFUSION GRADE 1 1 0
PERICARDIAL EFFUSION GRADE 2 1 0
ACUTE MYOCARDIAL INFARCTION GRADE 3 1 0
ANGINA PECTORIS GRADE 3 0 1
ATRIAL FIBRILLATION GRADE 3 1 0
ATRIAL TACHYCARDIA GRADE 2 1 0
BRADYCARDIA GRADE 1 0 1
CARDIAC FAILURE GRADE 3 0 1
CARDIAC FAILURE CHRONIC GRADE 5 1 0
MICROVASCULAR CORONARY ARTERY DISEASE GRADE 2 1 0
MYOCARDIAL INFARCTION GRADE 5 1 0
MYOCARDITIS GRADE 5 1 0
PERICARDITIS GRADE 2 1 0
SUPRAVENTRICULAR EXTRASYSTOLES GRADE 1 1 0
TACHYCARDIA GRADE 1 1 0
ANXIETY GRADE 1 2 1
ANXIETY GRADE 2 1 0
INSOMNIA GRADE 1 2 1
STRESS GRADE 1 1 1
ADJUSTMENT DISORDER GRADE 3 1 0
DEPRESSED MOOD GRADE 3 0 1
DEPRESSION GRADE 1 0 1
GENERALISED ANXIETY DISORDER GRADE 2 1 0
SLEEP DISORDER GRADE 1 1 0
CHALAZION GRADE 1 0 2
GLAUCOMA GRADE 1 0 1
GLAUCOMA GRADE 3 1 0
BLEPHARITIS GRADE 2 0 1
CATARACT GRADE 3 1 0
CONJUNCTIVAL HAEMORRHAGE GRADE 1 1 0
DRY EYE GRADE 1 0 1
EYELID OEDEMA GRADE 1 0 1
KERATITIS GRADE 2 0 1
VISUAL IMPAIRMENT GRADE 1 0 1
RAYNAUD'S PHENOMENON GRADE 1 1 3
RAYNAUD'S PHENOMENON GRADE 2 1 0
BLOOD PRESSURE FLUCTUATION GRADE 1 0 1
HYPERTENSION GRADE 2 0 1
HYPOTENSION GRADE 2 1 0
PERIPHERAL ISCHAEMIA GRADE 2 0 1
THROMBOPHLEBITIS GRADE 2 0 1
VASCULITIS GRADE 2 1 0
ACUTE KIDNEY INJURY GRADE 3 1 0
DYSURIA GRADE 1 1 0
HAEMATURIA GRADE 1 1 0
NEPHROLITHIASIS GRADE 3 0 1
RENAL COLIC GRADE 2 0 1
RENAL CYST GRADE 1 1 0
RENAL PAIN GRADE 2 1 0
SCLERODERMA RENAL CRISIS GRADE 3 0 1
AMENORRHOEA GRADE 1 0 1
BREAST CYST GRADE 1 1 0
CERVICAL POLYP GRADE 1 0 1
ERECTILE DYSFUNCTION GRADE 2 1 0
GENITAL RASH GRADE 2 1 0
MENSTRUATION IRREGULAR GRADE 1 1 0
OVARIAN CYST RUPTURED GRADE 2 1 0
PENILE PAIN GRADE 1 1 0
B-CELL LYMPHOMA GRADE 3 0 1
BENIGN BONE NEOPLASM GRADE 3 1 0
BENIGN LUNG NEOPLASM GRADE 1 0 1
BREAST CANCER GRADE 3 0 1
LUNG ADENOCARCINOMA GRADE 4 1 0
SKIN PAPILLOMA GRADE 2 0 1
FOOD ALLERGY GRADE 2 0 1
HYPERSENSITIVITY GRADE 1 0 1
TYPE I HYPERSENSITIVITY GRADE 2 0 1
MICROSTOMIA GRADE 1 1 0
MICROSTOMIA GRADE 2 0 1
PRESBYACUSIS GRADE 1 0 1
VERTIGO GRADE 1 1 0
HYPOTHYROIDISM GRADE 1 0 1
THYROID MASS GRADE 1 1 0
HEPATIC STEATOSIS GRADE 1 0 1
NEEDLE ISSUE GRADE 1 0 1
CATARACT OPERATION GRADE 3 1 0
11.Secondary Outcome
Title Number of Participants With Adverse Events Leading to Death During Double-blind Period
Hide Description Reason of death is coded using MedDRA 20.1
Time Frame From Baseline up to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Measure Type: Number
Unit of Measure: Number of participants
CARDIAC FAILURE CHRONIC 1 0
MYOCARDITIS 1 0
MYOCARDIAL INFARCTION 1 0
DEATH 0 1
12.Secondary Outcome
Title Frequency of Serious Systemic Sclerosis (SSC) Related Complications During Double-blind Period
Hide Description Adverse event terms coded using MedDRA 20.1. Includes only those serious events adjudicated as SSC-related complications by an independent external committee.
Time Frame From Baseline up to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Measure Type: Number
Unit of Measure: Number of Participants
CARDIAC FAILURE 0 1
CARDIAC FAILURE CHRONIC 1 0
MICROVASCULAR CORONARY ARTERY DISEASE 1 0
MYOCARDITIS 1 0
INFECTED SKIN ULCER 1 0
OSTEOMYELITIS 0 1
WOUND INFECTION 0 1
ILEUS PARALYTIC 1 0
PAIN 1 0
WEIGHT DECREASED 0 1
SCLERODERMA 1 0
HYPOKINESIA 0 1
ADJUSTMENT DISORDER 1 0
SCLERODERMA RENAL CRISIS 0 1
DIGITAL PITTING SCAR 1 0
13.Secondary Outcome
Title Incidence of Haematology and Hepatic Laboratory Parameters During Double-blind Period
Hide Description 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.
Time Frame From Baseline up to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Measure Type: Number
Unit of Measure: Number of Participants
High Alkaline Phosphatase 7 1
High SGPT/ALT 17 32
High SGOT/AST 17 24
Low Neutrophils, Segmented, Abs 2 27
Low Platelet 0 9
High Bilirubin 1 13
14.Secondary Outcome
Title Percentage of Participants With Change in Digital Ulcer Count During Double-blind Period
Hide Description 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.
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Measure Type: Number
Unit of Measure: Percentage of participants
No change 85.4 87.2
Increase by 1 3.4 5.3
Increase by 2 1.1 1.1
Increase by 3 0 0
Increase by 4 0 0
Increase by >4 1.1 0
Decrease by 1 3.4 4.3
Decrease by 2 3.4 0
Decrease by 3 0 1.1
Decrease by 4 1.1 0
Decrease by >4 0 0
Baseline missing 1.1 1.1
15.Secondary Outcome
Title Percentage of Participants With Positive Anti-Tocilizumab Assay Result at Baseline
Hide Description Incidence of anti-Tocilizumab at baseline
Time Frame Baseline
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Measure Type: Number
Unit of Measure: Percentage of Participants
5.9 2.9
16.Secondary Outcome
Title Percentage of Participants With Positive Anti-Tocilizumab Assay Post-Baseline up to Week 48
Hide Description 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.
Time Frame Double-blind period (up to Week 48)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Measure Type: Number
Unit of Measure: Percentage of Participants
Positive Anti-TCZ Assay Number Analyzed 101 participants 104 participants
0.0 2.9
Positive Confirmation Assay Number Analyzed 101 participants 104 participants
0.0 1.0
Positive Neutralizing Assay Number Analyzed 101 participants 104 participants
0.0 1.0
Positive IgE Assay Number Analyzed 101 participants 104 participants
0.0 0.0
17.Secondary Outcome
Title Correlation Between Anti-Tocilizumab Antibody Status and Outcome Measures Pertaining to the Efficacy, Safety, and Pharmacokinetics of Tocilizumab
Hide Description 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.
Time Frame 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)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Median (Full Range)
Unit of Measure: Units on a scale
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
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.
18.Secondary Outcome
Title Erythrocyte Sedimentation Rate (ESR), Mean, From Baseline to Week 48
Hide Description Erythrocyte Sedimentation Rate (ESR) levels predose at baseline and at subsequent time points after initiation of study drug.
Time Frame From Predose up to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Mean (Standard Deviation)
Unit of Measure: mm/hr
Baseline Number Analyzed 103 participants 100 participants
34.72  (18.49) 34.83  (16.29)
Week 4 Number Analyzed 96 participants 98 participants
31.38  (19.00) 14.29  (12.98)
Week 24 Number Analyzed 98 participants 94 participants
28.49  (20.86) 8.46  (8.63)
Week 48 Number Analyzed 88 participants 90 participants
26.59  (18.62) 10.82  (15.53)
19.Secondary Outcome
Title Erythrocyte Sedimentation Rate (ESR), Median, From Baseline to Week 48
Hide Description Erythrocyte Sedimentation Rate (ESR) levels predose at baseline and at subsequent time points after initiation of study drug.
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Median (Inter-Quartile Range)
Unit of Measure: mm/hr
Baseline Number Analyzed 103 participants 100 participants
33.0
(23.00 to 43.00)
33.50
(26.00 to 42.00)
Week 4 Number Analyzed 96 participants 98 participants
30.00
(16.50 to 39.50)
9.50
(4.00 to 23.00)
Week 24 Number Analyzed 98 participants 94 participants
25.00
(12.00 to 36.00)
5.00
(3.00 to 8.00)
Week 48 Number Analyzed 88 participants 90 participants
22.50
(14.00 to 31.50)
5.50
(3.00 to 12.00)
20.Secondary Outcome
Title Serum Interleukin (IL)-6 Level, Mean, From Baseline to Week 48
Hide Description Serum Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug.
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Mean (Standard Deviation)
Unit of Measure: pg/mL
Baseline Number Analyzed 106 participants 104 participants
11.83  (19.74) 13.88  (43.77)
Week 4 Number Analyzed 95 participants 99 participants
13.41  (29.98) 143.97  (427.01)
Week 8 Number Analyzed 95 participants 94 participants
14.21  (26.82) 111.44  (280.34)
Week 16 Number Analyzed 93 participants 88 participants
15.40  (24.26) 66.20  (70.50)
Week 24 Number Analyzed 85 participants 85 participants
11.81  (24.05) 62.74  (53.40)
Week 36 Number Analyzed 73 participants 83 participants
9.32  (15.23) 62.15  (68.08)
Week 48 Number Analyzed 78 participants 80 participants
9.25  (15.14) 53.98  (57.25)
21.Secondary Outcome
Title Serum Interleukin (IL)-6 Level, Median, From Baseline to Week 48
Hide Description Serum Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug.
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Median (Full Range)
Unit of Measure: pg/mL
Baseline Number Analyzed 106 participants 104 participants
5.21
(0.0 to 15.0)
4.65
(0.0 to 419.0)
Week 4 Number Analyzed 95 participants 99 participants
5.31
(0.0 to 246.0)
56.50
(0.0 to 3260.0)
Week 8 Number Analyzed 95 participants 94 participants
5.15
(0.0 to 214.0)
58.65
(0.0 to 2650.0)
Week 16 Number Analyzed 93 participants 88 participants
5.01
(0.0 to 117.0)
48.25
(0.0 to 494.0)
Week 24 Number Analyzed 85 participants 85 participants
3.53
(0.0 to 151.0)
47.90
(0.0 to 286.0)
Week 36 Number Analyzed 73 participants 83 participants
4.01
(0.0 to 107.0)
46.30
(14.8 to 608.0)
Week 48 Number Analyzed 78 participants 80 participants
3.85
(0.0 to 80.5)
43.45
(0.0 to 439.0)
22.Secondary Outcome
Title Serum Interleukin (IL)-6 Level, Mean Change From Baseline to Week 48
Hide Description Serum Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug.
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Mean (Standard Deviation)
Unit of Measure: pg/mL
Week 4 Number Analyzed 95 participants 99 participants
1.11  (28.78) 130.60  (395.93)
Week 8 Number Analyzed 95 participants 94 participants
2.43  (31.00) 97.22  (237.43)
Week 16 Number Analyzed 93 participants 88 participants
3.07  (31.71) 57.10  (62.62)
Week 24 Number Analyzed 85 participants 85 participants
0.13  (30.63) 53.33  (46.81)
Week 36 Number Analyzed 73 participants 83 participants
-3.48  (23.23) 52.26  (55.81)
Week 48 Number Analyzed 78 participants 80 participants
-1.60  (21.54) 40.01  (29.89)
23.Secondary Outcome
Title Serum Interleukin (IL)-6 Level, Median Change From Baseline to Week 48
Hide Description Serum Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug.
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Median (Full Range)
Unit of Measure: pg/mL
Week 4 Number Analyzed 95 participants 99 participants
-0.12
(-150.0 to 202.7)
52.41
(-27.4 to 2841.0)
Week 8 Number Analyzed 95 participants 94 participants
0.83
(-148.6 to 210.5)
52.35
(-9.8 to 2231.0)
Week 16 Number Analyzed 93 participants 88 participants
0.34
(-148.5 to 114.5)
42.35
(-6.0 to 494.0)
Week 24 Number Analyzed 85 participants 85 participants
0.00
(-148.5 to 144.9)
41.21
(-8.0 to 284.0)
Week 36 Number Analyzed 73 participants 83 participants
0.00
(-148.2 to 63.3)
41.20
(0.9 to 474.0)
Week 48 Number Analyzed 78 participants 80 participants
0.00
(-150.0 to 46.0)
32.96
(-11.8 to 138)
24.Secondary Outcome
Title Serum Soluble Interleukin (IL)-6 Receptor Level, Mean, From Baseline to Week 48
Hide Description Serum soluble Interleukin (IL)-6 receptor levels predose at baseline and at subsequent time points after initiation of study drug.
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Mean (Standard Deviation)
Unit of Measure: ng/mL
Baseline Number Analyzed 101 participants 101 participants
42.16  (32.41) 42.22  (14.56)
Week 4 Number Analyzed 103 participants 102 participants
46.07  (73.52) 486.58  (122.94)
Week 8 Number Analyzed 103 participants 101 participants
45.71  (57.95) 546.59  (142.58)
Week 16 Number Analyzed 102 participants 96 participants
47.81  (68.22) 583.87  (164.36)
Week 24 Number Analyzed 95 participants 95 participants
41.35  (15.17) 587.28  (153.90)
Week 36 Number Analyzed 89 participants 93 participants
38.13  (11.22) 589.59  (140.63)
Week 48 Number Analyzed 91 participants 90 participants
49.27  (76.97) 571.48  (167.85)
25.Secondary Outcome
Title Serum Soluble Interleukin (IL)-6 Receptor Level, Median, From Baseline to Week 48
Hide Description Serum soluble Interleukin (IL)-6 receptor levels predose at baseline and at subsequent time points after initiation of study drug.
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Median (Full Range)
Unit of Measure: ng/mL
Baseline Number Analyzed 101 participants 101 participants
37.10
(17.0 to 340.0)
39.00
(20.1 to 97.2)
Week 4 Number Analyzed 103 participants 102 participants
38.10
(19.4 to 775.0)
482.50
(42.0 to 773.0)
Week 8 Number Analyzed 103 participants 101 participants
37.20
(17.6 to 612.0)
536.00
(30.5 to 873.0)
Week 16 Number Analyzed 102 participants 96 participants
38.95
(20.6 to 711.0)
589.50
(27.4 to 1290.0)
Week 24 Number Analyzed 95 participants 95 participants
39.30
(19.5 to 99.8)
590.00
(23.2 to 945.0)
Week 36 Number Analyzed 89 participants 93 participants
36.20
(21.1 to 67.5)
591.00
(45.4 to 970.0)
Week 48 Number Analyzed 91 participants 90 participants
36.00
(19.2 to 596.0)
576.50
(23.4 to 973.0)
26.Secondary Outcome
Title Serum Soluble Interleukin (IL)-6 Receptor Level, Mean Change From Baseline to Week 48
Hide Description Serum soluble Interleukin (IL)-6 receptor levels predose at baseline and at subsequent time points after initiation of study drug.
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Mean (Standard Deviation)
Unit of Measure: ng/mL
Week 4 Number Analyzed 99 participants 99 participants
3.96  (79.00) 444.23  (120.90)
Week 8 Number Analyzed 99 participants 98 participants
3.31  (65.47) 501.09  (140.42)
Week 16 Number Analyzed 98 participants 93 participants
6.04  (77.69) 539.21  (165.63)
Week 24 Number Analyzed 91 participants 92 participants
-1.29  (35.46) 540.98  (152.70)
Week 36 Number Analyzed 85 participants 90 participants
-4.31  (35.92) 544.89  (142.95)
Week 48 Number Analyzed 87 participants 87 participants
7.23  (86.81) 525.66  (165.53)
27.Secondary Outcome
Title Serum Soluble Interleukin (IL)-6 Receptor Level, Median Change From Baseline to Week 48
Hide Description Serum soluble Interleukin (IL)-6 receptor levels predose at baseline and at subsequent time points after initiation of study drug.
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Median (Full Range)
Unit of Measure: ng/mL
Week 4 Number Analyzed 99 participants 99 participants
0.20
(-318.4 to 709.5)
437.80
(-13.4 to 724.3)
Week 8 Number Analyzed 99 participants 98 participants
0.20
(-305.9 to 560.8)
489.90
(-14.1 to 823.0)
Week 16 Number Analyzed 98 participants 93 participants
0.25
(-316.4 to 679.0)
542.30
(-28.0 to 1248.7)
Week 24 Number Analyzed 91 participants 92 participants
1.20
(-316.6 to 51.6)
547.50
(-32.2 to 909.9)
Week 36 Number Analyzed 85 participants 90 participants
-0.40
(-315.7 to 24.1)
541.70
(-26.6 to 942.9)
Week 48 Number Analyzed 87 participants 87 participants
-0.70
(-317.9 to 560.2)
532.20
(-0.4 to 945.9)
28.Secondary Outcome
Title Serum C-Reactive Protein (CRP) Level, Mean, From Baseline to Week 48
Hide Description Serum C-Reactive Protein (CRP) levels predose at baseline and at subsequent time points after initiation of study drug.
Time Frame From Baseline up to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Mean (Standard Deviation)
Unit of Measure: mg/L
Baseline Number Analyzed 106 participants 104 participants
7.43  (12.61) 9.00  (14.76)
Week 4 Number Analyzed 102 participants 101 participants
9.81  (20.79) 0.85  (2.52)
Week 24 Number Analyzed 100 participants 97 participants
9.89  (13.99) 0.56  (1.19)
Week 48 Number Analyzed 90 participants 93 participants
7.52  (12.80) 1.58  (6.22)
29.Secondary Outcome
Title Serum C-Reactive Protein (CRP) Level, Median, From Baseline to Week 48
Hide Description Serum C-Reactive Protein (CRP) levels predose at baseline and at subsequent time points after initiation of study drug.
Time Frame From Baseline up to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 104
Median (Inter-Quartile Range)
Unit of Measure: mg/L
Baseline Number Analyzed 106 participants 104 participants
3.82
(1.19 to 8.69)
4.05
(1.30 to 9.48)
Week 4 Number Analyzed 102 participants 101 participants
3.71
(1.27 to 8.83)
0.20
(0.20 to 0.50)
Week 24 Number Analyzed 100 participants 97 participants
4.15
(1.43 to 13.10)
0.20
(0.20 to 0.47)
Week 48 Number Analyzed 90 participants 93 participants
3.67
(1.26 to 7.78)
0.20
(0.20 to 0.59)
30.Secondary Outcome
Title Serum Tocilizumab Concentration, Mean, From Baseline to Week 48
Hide Description Predose observed serum TCZ concentration at baseline and at specified timepoints thereafter
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The PK population includes all patients who received at least one TCZ injection and had at least one PK sample with detectable results.
Arm/Group Title Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 103
Mean (Standard Deviation)
Unit of Measure: ug/mL
Baseline Number Analyzed 100 participants
0.00  (0.03)
Week 4 Number Analyzed 102 participants
30.92  (15.24)
Week 8 Number Analyzed 100 participants
41.82  (17.66)
Week 16 Number Analyzed 93 participants
50.98  (23.33)
Week 24 Number Analyzed 93 participants
54.34  (26.24)
Week 36 Number Analyzed 91 participants
53.55  (29.25)
Week 48 Number Analyzed 88 participants
54.67  (29.79)
31.Secondary Outcome
Title Serum Tocilizumab Concentration, Median, From Baseline to Week 48
Hide Description Predose observed serum TCZ concentration at baseline and at specified timepoints thereafter
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The PK population includes all patients who received at least one TCZ injection and had at least one PK sample with detectable results.
Arm/Group Title Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 103
Median (Full Range)
Unit of Measure: ug/mL
Baseline Number Analyzed 100 participants
0.00
(0.0 to 0.2)
Week 4 Number Analyzed 102 participants
28.70
(0.4 to 86.8)
Week 8 Number Analyzed 100 participants
39.25
(8.3 to 97.6)
Week 16 Number Analyzed 93 participants
47.40
(9.5 to 120.0)
Week 24 Number Analyzed 93 participants
52.60
(7.6 to 117.0)
Week 36 Number Analyzed 91 participants
52.50
(4.0 to 138.0)
Week 48 Number Analyzed 88 participants
52.10
(0.4 to 145.0)
32.Secondary Outcome
Title Correlation Between Low Serum Tocilizumab Exposure and Mean Modified Rodnan Skin Score (mRSS) From Baseline to Week 48
Hide Description 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.
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 30
Mean (Standard Deviation)
Unit of Measure: Units on a scale
Baseline Number Analyzed 106 participants 30 participants
20.4  (6.95) 20.3  (5.56)
Week 8 Number Analyzed 102 participants 30 participants
18.6  (7.78) 17.9  (5.84)
Week 16 Number Analyzed 101 participants 29 participants
17.9  (8.71) 16.2  (5.58)
Week 24 Number Analyzed 99 participants 30 participants
16.9  (9.38) 14.7  (5.61)
Week 36 Number Analyzed 94 participants 30 participants
16.2  (10.24) 13.2  (4.97)
Week 48 Number Analyzed 92 participants 30 participants
14.8  (9.89) 12.2  (6.03)
33.Secondary Outcome
Title Correlation Between Low Serum Tocilizumab Exposure and Median Modified Rodnan Skin Score (mRSS) From Baseline to Week 48
Hide Description 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.
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 30
Median (Full Range)
Unit of Measure: Units on a scale
Baseline Number Analyzed 106 participants 30 participants
19.0
(10 to 40)
20.0
(11 to 31)
Week 8 Number Analyzed 102 participants 30 participants
18.0
(4 to 43)
16.0
(9 to 34)
Week 16 Number Analyzed 101 participants 29 participants
17.0
(0 to 38)
15.0
(8 to 30)
Week 24 Number Analyzed 99 participants 30 participants
16.0
(0 to 42)
14.0
(6 to 29)
Week 36 Number Analyzed 94 participants 30 participants
14.0
(0 to 47)
13.5
(5 to 27)
Week 48 Number Analyzed 92 participants 30 participants
14.0
(0 to 43)
12.5
(2 to 30)
34.Secondary Outcome
Title Correlation Between Medium Serum Tocilizumab Exposure and Mean Modified Rodnan Skin Score (mRSS) From Baseline to Week 48
Hide Description 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.
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 29
Mean (Standard Deviation)
Unit of Measure: Units on a scale
Baseline Number Analyzed 106 participants 29 participants
20.4  (6.95) 19.1  (6.24)
Week 8 Number Analyzed 102 participants 29 participants
18.6  (7.78) 17.2  (6.17)
Week 16 Number Analyzed 101 participants 29 participants
17.9  (8.71) 16.2  (6.10)
Week 24 Number Analyzed 99 participants 29 participants
16.9  (9.38) 14.6  (6.66)
Week 36 Number Analyzed 94 participants 28 participants
16.2  (10.24) 13.4  (6.20)
Week 48 Number Analyzed 92 participants 29 participants
14.8  (9.89) 11.6  (5.72)
35.Secondary Outcome
Title Correlation Between Medium Serum Tocilizumab Exposure and Median Modified Rodnan Skin Score (mRSS) From Baseline to Week 48
Hide Description 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.
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 29
Median (Full Range)
Unit of Measure: Units on a scale
Baseline Number Analyzed 106 participants 29 participants
19.0
(10 to 40)
18.0
(10 to 35)
Week 8 Number Analyzed 102 participants 29 participants
18.0
(4 to 43)
17.0
(5 to 31)
Week 16 Number Analyzed 101 participants 29 participants
17.0
(0 to 38)
16.0
(5 to 27)
Week 24 Number Analyzed 99 participants 29 participants
16.0
(0 to 42)
14.0
(3 to 28)
Week 36 Number Analyzed 94 participants 28 participants
14.0
(0 to 47)
13.0
(2 to 25)
Week 48 Number Analyzed 92 participants 29 participants
14.0
(0 to 43)
11.0
(0 to 24)
36.Secondary Outcome
Title Correlation Between High Serum Tocilizumab Exposure and Mean Modified Rodnan Skin Score (mRSS) From Baseline to Week 48
Hide Description 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.
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 29
Mean (Standard Deviation)
Unit of Measure: Units on a scale
Baseline Number Analyzed 106 participants 29 participants
20.4  (6.95) 19.8  (6.82)
Week 8 Number Analyzed 102 participants 28 participants
18.6  (7.78) 17.9  (7.35)
Week 16 Number Analyzed 101 participants 29 participants
17.9  (8.71) 16.7  (7.31)
Week 24 Number Analyzed 99 participants 29 participants
16.9  (9.38) 15.6  (7.50)
Week 36 Number Analyzed 94 participants 28 participants
16.2  (10.24) 13.7  (7.07)
Week 48 Number Analyzed 92 participants 29 participants
14.8  (9.89) 12.8  (7.20)
37.Secondary Outcome
Title Correlation Between High Serum Tocilizumab Exposure and Median Modified Rodnan Skin Score (mRSS) From Baseline to Week 48
Hide Description 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.
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 106 29
Median (Full Range)
Unit of Measure: Units on a scale
Baseline Number Analyzed 106 participants 29 participants
19.0
(10 to 40)
19.0
(11 to 33)
Week 8 Number Analyzed 102 participants 28 participants
18.0
(4 to 43)
17.5
(5 to 32)
Week 16 Number Analyzed 101 participants 29 participants
17.0
(0 to 38)
15.0
(6 to 33)
Week 24 Number Analyzed 99 participants 29 participants
16.0
(0 to 42)
15.0
(2 to 31)
Week 36 Number Analyzed 94 participants 28 participants
14.0
(0 to 47)
11.0
(4 to 30)
Week 48 Number Analyzed 92 participants 29 participants
14.0
(0 to 43)
11.0
(4 to 34)
38.Secondary Outcome
Title Change in Mean Modified Rodnan Skin Score (mRSS) at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48
Hide Description 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.
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 92 30
Mean (Standard Deviation)
Unit of Measure: Units on a scale
Low Exposure Number Analyzed 92 participants 30 participants
-5.3  (7.77) -8.0  (5.85)
Medium Exposure Number Analyzed 92 participants 29 participants
-5.3  (7.77) -7.5  (5.06)
High Exposure Number Analyzed 92 participants 29 participants
-5.3  (7.77) -7.0  (6.26)
39.Secondary Outcome
Title Change in Median Modified Rodnan Skin Score (mRSS), at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48
Hide Description 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.
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 92 30
Median (Full Range)
Unit of Measure: Units on a scale
Low Exposure
-5.5
(-25 to 22)
-8.0
(-19 to 4)
Medium Exposure
-5.5
(-25 to 22)
-7.0
(-18 to 2)
High Exposure
-5.5
(-25 to 22)
-6.0
(-20 to 6)
40.Secondary Outcome
Title Change in Mean Percent Predicted Forced Vital Capacity (ppFVC), at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48
Hide Description 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.
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 91 29
Mean (Standard Deviation)
Unit of Measure: Percent
Low Exposure Number Analyzed 91 participants 28 participants
-4.264  (8.155) 0.144  (6.474)
Medium Exposure Number Analyzed 91 participants 28 participants
-4.264  (8.155) -0.161  (6.440)
High Exposure Number Analyzed 91 participants 29 participants
-4.264  (8.155) -0.297  (7.895)
41.Secondary Outcome
Title Change in Median Percent Predicted Forced Vital Capacity (ppFVC), at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48
Hide Description 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.
Time Frame From Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 91 29
Median (Full Range)
Unit of Measure: Percent
Low Exposure Number Analyzed 91 participants 28 participants
-3.910
(-31.47 to 13.47)
0.525
(-14.25 to 11.38)
Medium Exposure Number Analyzed 91 participants 28 participants
-3.910
(-31.47 to 13.47)
-1.600
(-13.83 to 17.00)
High Exposure Number Analyzed 91 participants 29 participants
-3.910
(-31.47 to 13.47)
0.000
(-10.55 to 19.69)
42.Secondary Outcome
Title Summary of Adverse Events Up to Week 96
Hide Description 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
Time Frame Up to Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab Placebo, Then Tocilizumab Open Label Tocilizumab, Then Tocilizumab Open Label
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants who received placebo during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.
Participants who received tocilizumab during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.
Overall Number of Participants Analyzed 106 104 89 92
Measure Type: Number
Unit of Measure: Percentage of participants
At least one Adverse Event (AE) 77.4 85.6 77.5 71.7
Withdrawn from study due to an AE 12.3 6.7 1.1 1.1
Fatal AE 2.8 1.0 1.1 1.1
Serious Adverse Events (SAEs) 17.0 12.5 7.9 10.9
SAE leading to withdrawal from treatment 5.7 4.8 1.1 1.1
SAE leading to dose modification/interruption 5.7 2.9 4.5 3.3
SAE related to study drug 6.6 1.0 3.4 3.3
AE leading to withdrawal from treatment 12.3 6.7 1.1 1.1
AE leading to dose modification/interruption 26.4 19.2 28.1 22.8
AE related to study drug 34.0 46.2 33.7 34.8
Related AE leading to withdrawal from treatment 1.9 1.0 1.1 1.1
Related AE with dose modification/interruption 17.0 11.5 12.4 14.1
Serious Infections and Infestations AEs 6.6 1.9 3.4 1.1
Infections and Infestations AEs 50.0 52.9 46.1 39.1
Opportunistic Infections AEs 0.9 1.0 0 1.1
Malignancy AEs 0.9 1.9 0 1.1
Malignancy AEs (excluding NMSC) 0.9 1.9 0 1.1
Serious Hepatic AEs 0 0 0 0
Serious Stroke AEs 0 0 0 0
Serious Myocardial Infarction AEs 1.9 0 0 0
Anaphylactic Reaction AEs 0 0 0 0
Anaphylactic Reaction AEs (Sampson's Criteria) 0 0 0 0
Serious Gastrointestinal Perforation AEs 0 0 0 0
Serious Bleeding AEs 0.9 0 0 0
Serious Demyelinating AEs 0 0 0 0
43.Secondary Outcome
Title Incidence and Severity of Adverse Events Up to Week 96
Hide Description 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.
Time Frame Up to Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab Placebo, Then Tocilizumab Open Label Tocilizumab, Then Tocilizumab Open Label
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants who received placebo during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.
Participants who received tocilizumab during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.
Overall Number of Participants Analyzed 106 104 89 92
Measure Type: Number
Unit of Measure: Number of participants
Grade 1 61 78 60 53
Grade 2 63 53 41 35
Grade 3 21 18 9 8
Grade 4 7 0 4 5
Grade 5 3 1 1 1
44.Secondary Outcome
Title Number of Participants With Adverse Events Leading to Death Up to Week 96
Hide Description [Not Specified]
Time Frame Up to Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab Placebo, Then Tocilizumab Open Label Tocilizumab, Then Tocilizumab Open Label
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants who received placebo during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.
Participants who received tocilizumab during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.
Overall Number of Participants Analyzed 106 104 89 92
Measure Type: Number
Unit of Measure: Number of participants
CARDIAC FAILURE CHRONIC 1 0 0 0
MYOCARDITIS 1 0 0 0
MYOCARDIAL INFARCTION 1 0 0 0
DEATH 0 1 0 0
BRAIN INJURY 0 0 1 0
PULMONARY HYPERTENSION 0 0 0 1
45.Secondary Outcome
Title Percentage of Participants With Change in Digital Ulcer Count at Week 96
Hide Description 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.
Time Frame From Baseline to Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab Placebo, Then Tocilizumab Open Label Tocilizumab, Then Tocilizumab Open Label
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants who received placebo during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.
Participants who received tocilizumab during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.
Overall Number of Participants Analyzed 106 104 89 92
Measure Type: Number
Unit of Measure: Percentage of participants
No change 0 0 91.1 83.3
Increase by 1 0 0 0 4.8
Increase by 2 0 0 0 1.2
Increase by 3 0 0 0 1.2
Increase by 4 0 0 0 0
Increase by >4 0 0 0 1.2
Decrease by 1 0 0 3.8 4.8
Decrease by 2 0 0 2.5 0
Decrease by 3 0 0 1.3 1.2
Decrease by 4 0 0 1.3 1.2
Decrease by >4 0 0 0 0
Baseline missing 0 0 0 1.2
46.Secondary Outcome
Title Percentage of Participants With Positive Anti-Tocilizumab Assay Post-Baseline From Week 48 to 96
Hide Description 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.
Time Frame Open-label period from Week 48 to 96
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population: received at least one dose of study drug and provide data from at least one post dose safety assessment. Only samples from the Double Blind TCZ, then Open Label TCZ were measured by the lab after week 48. Data for the Double Blind Period were reported at the time of Primary Results disclosure up to Week 48.
Arm/Group Title Tocilizumab, Then Tocilizumab Open Label
Hide Arm/Group Description:
Participants who received tocilizumab during the double blind period from Baseline to Week 47, received tocilizumab from Week 48 to Week 96.
Overall Number of Participants Analyzed 92
Measure Type: Number
Unit of Measure: Percentage of Participants
Treatment-Induced Anti-TCZ Antibodies 0.0
Anti-TCZ Antibodies of Neutralizing Potential 0.0
Anti-TCZ Antibodies of IgE 0.0
47.Secondary Outcome
Title Erythrocyte Sedimentation Rate (ESR) Up to Week 96
Hide Description Erythrocyte Sedimentation Rate (ESR) levels predose at baseline and at subsequent time points after initiation of study drug.
Time Frame Up to Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab Placebo, Then Tocilizumab Open Label Tocilizumab, Then Tocilizumab Open Label
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants who received placebo during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.
Participants who received tocilizumab during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.
Overall Number of Participants Analyzed 103 100 82 89
Mean (Standard Deviation)
Unit of Measure: mm/hr
Baseline Number Analyzed 103 participants 100 participants 0 participants 0 participants
34.72  (18.49) 34.83  (16.29)
Week 4 Number Analyzed 96 participants 98 participants 0 participants 0 participants
31.38  (19.00) 14.29  (12.98)
Week 24 Number Analyzed 98 participants 94 participants 0 participants 0 participants
28.49  (20.86) 8.46  (8.63)
Week 48 Number Analyzed 91 participants 93 participants 0 participants 0 participants
26.23  (18.53) 10.89  (15.39)
Week 72 Number Analyzed 0 participants 0 participants 82 participants 89 participants
9.54  (9.47) 8.29  (10.13)
Week 96 Number Analyzed 0 participants 0 participants 79 participants 85 participants
9.67  (8.67) 8.06  (8.86)
48.Secondary Outcome
Title Serum Interleukin (IL)-6 Level, Mean, From Baseline to Week 96
Hide Description Serum Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug.
Time Frame Up to Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab Placebo, Then Tocilizumab Open Label Tocilizumab, Then Tocilizumab Open Label
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants who received placebo during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.
Participants who received tocilizumab during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.
Overall Number of Participants Analyzed 106 104 79 79
Mean (Standard Deviation)
Unit of Measure: pg/mL
Baseline Number Analyzed 106 participants 104 participants 0 participants 0 participants
11.85  (19.73) 13.86  (43.78)
Week 4 Number Analyzed 95 participants 98 participants 0 participants 0 participants
13.41  (29.98) 144.75  (429.14)
Week 8 Number Analyzed 95 participants 94 participants 0 participants 0 participants
14.21  (26.82) 111.44  (280.34)
Week 16 Number Analyzed 93 participants 88 participants 0 participants 0 participants
15.40  (24.26) 66.20  (70.50)
Week 24 Number Analyzed 85 participants 85 participants 0 participants 0 participants
11.81  (24.05) 62.74  (53.40)
Week 36 Number Analyzed 73 participants 83 participants 0 participants 0 participants
9.32  (15.23) 62.15  (68.08)
Week 48 Number Analyzed 81 participants 82 participants 0 participants 0 participants
9.10  (14.88) 53.34  (56.80)
Week 96 Number Analyzed 0 participants 0 participants 79 participants 79 participants
62.60  (57.21) 52.03  (46.51)
49.Secondary Outcome
Title Serum Soluble Interleukin (IL)-6 Receptor Level, Mean, Up to Week 96
Hide Description Serum Soluble Interleukin (IL)-6 receptor levels predose at baseline and at subsequent time points after initiation of study drug.
Time Frame Up to Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab Placebo, Then Tocilizumab Open Label Tocilizumab, Then Tocilizumab Open Label
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants who received placebo during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.
Participants who received tocilizumab during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.
Overall Number of Participants Analyzed 103 102 79 85
Mean (Standard Deviation)
Unit of Measure: ng/mL
Baseline Number Analyzed 100 participants 102 participants 0 participants 0 participants
42.23  (32.56) 42.15  (14.50)
Week 4 Number Analyzed 103 participants 101 participants 0 participants 0 participants
46.07  (73.52) 487.70  (123.02)
Week 8 Number Analyzed 103 participants 101 participants 0 participants 0 participants
45.71  (57.95) 546.59  (142.58)
Week 16 Number Analyzed 102 participants 96 participants 0 participants 0 participants
47.81  (68.22) 583.87  (164.36)
Week 24 Number Analyzed 95 participants 95 participants 0 participants 0 participants
41.35  (15.17) 587.28  (153.90)
Week 36 Number Analyzed 89 participants 93 participants 0 participants 0 participants
38.13  (11.22) 589.59  (140.63)
Week 48 Number Analyzed 93 participants 92 participants 0 participants 0 participants
49.51  (76.17) 566.49  (175.25)
Week 96 Number Analyzed 0 participants 0 participants 79 participants 85 participants
558.38  (256.86) 565.31  (159.82)
50.Secondary Outcome
Title Serum C-Reactive Protein (CRP) Level, Mean, Up to Week 96
Hide Description Serum C-Reactive Protein (CRP) levels predose at baseline and at subsequent time points after initiation of study drug.
Time Frame From Baseline up to Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab Placebo, Then Tocilizumab Open Label Tocilizumab, Then Tocilizumab Open Label
Hide Arm/Group Description:
Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Participants who received placebo during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.
Participants who received tocilizumab during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.
Overall Number of Participants Analyzed 106 104 83 90
Mean (Standard Deviation)
Unit of Measure: mg/L
Baseline Number Analyzed 106 participants 104 participants 0 participants 0 participants
7.42  (12.62) 8.99  (14.76)
Week 4 Number Analyzed 103 participants 103 participants 0 participants 0 participants
10.05  (20.82) 0.85  (2.50)
Week 24 Number Analyzed 100 participants 97 participants 0 participants 0 participants
9.89  (13.99) 0.56  (1.19)
Week 48 Number Analyzed 93 participants 96 participants 0 participants 0 participants
7.40  (12.62) 1.75  (6.43)
Week 72 Number Analyzed 0 participants 0 participants 82 participants 90 participants
0.57  (0.80) 0.92  (3.61)
Week 96 Number Analyzed 0 participants 0 participants 83 participants 86 participants
0.90  (2.73) 0.97  (5.08)
51.Secondary Outcome
Title Serum Tocilizumab Concentration, Mean, Up to Week 96
Hide Description Predose observed serum TCZ concentration at baseline and at specified timepoints thereafter
Time Frame Up to Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
The PK population included all participants who received at least one TCZ injection and had at least one PK sample with detectable results. Only samples from the Double Blind TCZ, then Open Label TCZ were measured by the lab after week 48. Data for the Double Blind Period were reported at the time of Primary Results disclosure up to Week 48.
Arm/Group Title Double-Blind Tocilizumab, Then Open Label Tocilizumab
Hide Arm/Group Description:
Participants received double-blind tocilizumab from Baseline to Week 48. Participants then received open-label tocilizumab from Weeks 48 to 96.
Overall Number of Participants Analyzed 101
Mean (Standard Deviation)
Unit of Measure: ug/mL
Baseline Number Analyzed 101 participants
0.00  (0.03)
Week 4 Number Analyzed 101 participants
30.76  (15.23)
Week 8 Number Analyzed 100 participants
41.82  (17.66)
Week 16 Number Analyzed 93 participants
50.98  (23.33)
Week 24 Number Analyzed 93 participants
54.34  (26.24)
Week 36 Number Analyzed 91 participants
53.55  (29.25)
Week 48 Number Analyzed 89 participants
54.87  (29.69)
Week 96 Number Analyzed 82 participants
49.99  (26.19)
Time Frame Up to Week 96
Adverse Event Reporting Description The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
 
Arm/Group Title Double-Blind Placebo Double-Blind Tocilizumab Placebo, Then Tocilizumab Open Label Tocilizumab, Then Tocilizumab Open Label
Hide Arm/Group Description Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96. Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96. Participants who received placebo during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96. Participants who received tocilizumab during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.
All-Cause Mortality
Double-Blind Placebo Double-Blind Tocilizumab Placebo, Then Tocilizumab Open Label Tocilizumab, Then Tocilizumab Open Label
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   3/106 (2.83%)      1/104 (0.96%)      1/89 (1.12%)      1/92 (1.09%)    
Hide Serious Adverse Events
Double-Blind Placebo Double-Blind Tocilizumab Placebo, Then Tocilizumab Open Label Tocilizumab, Then Tocilizumab Open Label
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   18/106 (16.98%)      13/104 (12.50%)      7/89 (7.87%)      10/92 (10.87%)    
Blood and lymphatic system disorders         
ANAEMIA MEGALOBLASTIC  1  1/106 (0.94%)  1 0/104 (0.00%)  0 0/89 (0.00%)  0 0/92 (0.00%)  0
LYMPHADENOPATHY MEDIASTINAL  1  1/106 (0.94%)  1 0/104 (0.00%)  0 0/89 (0.00%)  0 0/92 (0.00%)  0
Cardiac disorders         
ACUTE MYOCARDIAL INFARCTION  1  1/106 (0.94%)  1 0/104 (0.00%)  0 0/89 (0.00%)  0 0/92 (0.00%)  0
ANGINA PECTORIS  1  0/106 (0.00%)  0 1/104 (0.96%)  1 0/89 (0.00%)  0 0/92 (0.00%)  0
ARRHYTHMIA  1  0/106 (0.00%)  0 0/104 (0.00%)  0 1/89 (1.12%)  1 0/92 (0.00%)  0
ATRIAL FIBRILLATION  1  1/106 (0.94%)  2 0/104 (0.00%)  0 0/89 (0.00%)  0 0/92 (0.00%)  0
CARDIAC FAILURE  1  0/106 (0.00%)  0 1/104 (0.96%)  1 0/89 (0.00%)  0 0/92 (0.00%)  0
CARDIAC FAILURE CHRONIC  1  1/106 (0.94%)  1 0/104 (0.00%)  0 0/89 (0.00%)  0 0/92 (0.00%)  0
CARDIAC TAMPONADE  1  0/106 (0.00%)  0 0/104 (0.00%)  0 1/89 (1.12%)  1 0/92 (0.00%)  0
CARDIO-RESPIRATORY ARREST  1  0/106 (0.00%)  0 0/104 (0.00%)  0 1/89 (1.12%)  1 0/92 (0.00%)  0
CONGESTIVE CARDIOMYOPATHY  1  0/106 (0.00%)  0 0/104 (0.00%)  0 0/89 (0.00%)  0 1/92 (1.09%)  1
MICROVASCULAR CORONARY ARTERY DISEASE  1  1/106 (0.94%)  1 0/104 (0.00%)  0 0/89 (0.00%)  0 0/92 (0.00%)  0
MYOCARDIAL INFARCTION  1  1/106 (0.94%)  1 0/104 (0.00%)  0 0/89 (0.00%)  0 0/92 (0.00%)  0
MYOCARDITIS  1  1/106 (0.94%)  1 0/104 (0.00%)  0 0/89 (0.00%)  0 0/92 (0.00%)  0
Eye disorders         
RETINAL VEIN THROMBOSIS  1  0/106 (0.00%)  0 0/104 (0.00%)  0 0/89 (0.00%)  0 1/92 (1.09%)  1
Gastrointestinal disorders         
GASTRITIS EROSIVE  1  0/106 (0.00%)  0 0/104 (0.00%)  0 0/89 (0.00%)  0 1/92 (1.09%)  1
ILEUS PARALYTIC  1  1/106 (0.94%)  1 0/104 (0.00%)  0 0/89 (0.00%)  0 0/92 (0.00%)  0
RECTAL PROLAPSE  1  0/106 (0.00%)  0 0/104 (0.00%)  0 1/89 (1.12%)  1 0/92 (0.00%)  0
General disorders         
DEATH  1  0/106 (0.00%)  0 1/104 (0.96%)  1 0/89 (0.00%)  0 0/92 (0.00%)  0
PAIN  1  1/106 (0.94%)  1 0/104 (0.00%)  0 0/89 (0.00%)  0 0/92 (0.00%)  0
Infections and infestations         
INFECTED SKIN ULCER  1  1/106 (0.94%)  1 0/104 (0.00%)  0 0/89 (0.00%)  0 0/92 (0.00%)  0
INFECTIVE TENOSYNOVITIS  1  0/106 (0.00%)  0 0/104 (0.00%)  0 1/89 (1.12%)  1 0/92 (0.00%)  0
OSTEOMYELITIS  1  0/106 (0.00%)  0 1/104 (0.96%)  1 0/89 (0.00%)  0 0/92 (0.00%)  0
OTITIS MEDIA  1