Clinical Trial Results:
Title: A multicenter, randomized, double-blind, placebo-controlled Phase 3 trial to evaluate efficacy and safety of lenabasum in diffuse cutaneous systemic sclerosis Design: This was a Phase 3, 2-part, randomised, double-blind, placebo-controlled, multicentre, interventional, parallel-dose study (Part A), followed by an open-label extension study (Part B), to assess the efficacy and safety of lenabasum in subjects with diffuse cutaneous systemic sclerosis (dcSSc). In Part A, subjects were randomised to receive blinded study product (lenabasum 5 mg twice daily [BID] or 20 mg BID, or placebo) for 52 weeks. Subjects treated with study product who completed Part A and a 31-day off treatment withdrawal period were rolled over to Part B. In Part B (open-label), subjects received powder-in-capsules of lenabasum 20 mg BID for up to 2 years.

Trial information Top of page
Trial identification
Sponsor protocol code	JBT101-SSc-002
Additional study identifiers
ISRCTN number	-
US NCT number	NCT02465437
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	Corbus Pharmaceuticals, Inc.
Sponsor organisation address	500 River Ridge Drive, Norwood, United States, MA 02062
Public contact	Corbus General Information, Corbus Pharmaceuticals, Inc., +1 617-963-0100, info@corbuspharma.com
Scientific contact	Corbus General Information, Corbus Pharmaceuticals, Inc., +1 617-963-0100, info@corbuspharma.com
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	17 Nov 2021
Is this the analysis of the primary completion data?	Yes
Primary completion date	14 Dec 2020
Global end of trial reached?	Yes
Global end of trial date	14 Dec 2020
Was the trial ended prematurely?	Yes
General information about the trial
Main objective of the trial	Part A: In all countries except Japan, the primary efficacy objective was to evaluate the efficacy of lenabasum compared to placebo in the treatment of SSc by assessing the American College of Rheumatology (ACR) Provisional Combined Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) score at Visit 11 (Week 52), comparing lenabasum 20 mg twice per day (BID) and placebo cohorts. In Japan, the primary efficacy objective was the change in mRSS at Visit 11 (Week 52), comparing lenabasum 20 mg BID and placebo cohorts. Part B: To evaluate the efficacy and safety of lenabasum in the treatment of dcSSc by evaluating changes in the CRISS at the end of the open-label follow-up period (Part B) compared with Part A baseline. In Part B, all subjects were treated with Lenabasum 20 mg twice daily (BID).
Protection of trial subjects	The final region-specific protocols, amendments or addendums, and informed consent documentation were reviewed and approved by the Ethics Committee at the investigational centre(s) participating in the study. This study was conducted in accordance with the international ethical principles originating in or derived from the Declaration of Helsinki and in compliance with the principles of the International Council for Harmonisation Good Clinical Practice. In addition, the guidelines from relevant regulatory authorities, applicable government regulations, and institutional research policies and procedures were followed.
Background therapy	Concomitant therapies taken for chronic treatment of pre-existing conditions could be continued during the study provided they were in accordance with the eligibility criteria. It was preferred that these medications be stabilised before entry and continued wherever practical without variation of dose or regimen during the study. Doses of non-corticosteoiod immunosuppressant medications had to be stable for ≥8 weeks at Screening. The intent was to allow all immunosuppressive medications that the subject had been receiving as standard-of-care by the treating physician, with the exception that doses of oral prednisone greater than 10 mg per day (or equivalent) were not permitted for at least 28 days prior to Visit 1. Intravenous prednisone was not permitted within 28 days before Visit 1. However, it was acknowledged that signs and symptoms of SSc may worsen or improve during this long-term study and adjustments in medications could have been required to provide the subject with best medical care.
Evidence for comparator	Part A: the randomised comparator was placebo. Subjects continued on immunosuppressive medications as needed, as detailed above. Part B: No comparator; this was an open-label treatment period with all patients treated with lenabasum 20 mg BID.
Actual start date of recruitment	29 Jan 2018
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	Yes
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Netherlands: 6
Country: Number of subjects enrolled	Poland: 33
Country: Number of subjects enrolled	Spain: 14
Country: Number of subjects enrolled	United Kingdom: 24
Country: Number of subjects enrolled	Germany: 18
Country: Number of subjects enrolled	Italy: 11
Country: Number of subjects enrolled	Switzerland: 4
Country: Number of subjects enrolled	Canada: 5
Country: Number of subjects enrolled	Japan: 35
Country: Number of subjects enrolled	Korea, Republic of: 31
Country: Number of subjects enrolled	Australia: 14
Country: Number of subjects enrolled	Israel: 35
Country: Number of subjects enrolled	United States: 135
Worldwide total number of subjects	365
EEA total number of subjects	82
Number of subjects enrolled per age group
In utero	0
Preterm newborn - gestational age < 37 wk	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	0
Adolescents (12-17 years)	0
Adults (18-64 years)	313
From 65 to 84 years	51
85 years and over	1

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	The first subject was randomised on 29 Jan 2018 and the last visit in Part B was 14 December 2020. In total, 365 subjects were randomised and treated worldwide, including 82 in the EEA and 135 in the USA. Baseline data is presented for randomised, treated patients.
Pre-assignment
Screening details	Screening occurred up to 28 days prior to Visit 1 of Part A of the study, to ensure patients met entry criteria. Patients were on stable background treatments for SSc, including background immunosuppressive therapy (IST), except cyclophosphamide. They were not to have started or increased their dose of IST therapy within 8 weeks of screening.
Period 1
Period 1 title	Randomised controlled trial (Part A)
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Double blind
Roles blinded	Subject, Investigator, Monitor, Data analyst, Carer, Assessor
Blinding implementation details	In Part A of the study, treatment with lenabasum (5 mg BID or 20 mg BID) or placebo was randomly assigned and blinded. Lenabasum and placebo capsules had similar physical appearance and were packaged, labelled, and handled so that patients and site staff were not able to distinguish treatments.
Arms
Are arms mutually exclusive	Yes
Arm title	Lenabasum 5 mg BID Part A
Arm description	Patients in Part A randomised to treatment with lenabasum 5 mg BID. Data presented represents the modified intent-to-treat (mITT) population.
Arm type	All treated patients
Investigational medicinal product name	Lenabasum 5 mg BID
Investigational medicinal product code
Other name
Pharmaceutical forms	Capsule
Routes of administration	Oral use
Dosage and administration details	5 mg Lenabasum, taken orally twice daily (total dose: 10 mg lenabasum per day)
Arm title	Lenabasum 20 mg BID Part A
Arm description	Patients in Part A randomised to treatment with lenabasum 20 mg BID. Data presented represents the modified intent-to-treat (mITT) population.
Arm type	Experimental
Investigational medicinal product name	Lenabasum 20 mg BID
Investigational medicinal product code
Other name
Pharmaceutical forms	Capsule
Routes of administration	Oral use
Dosage and administration details	20 mg Lenabasum, taken orally twice daily (total dose: 40 mg lenabasum per day)
Arm title	Placebo in Part A
Arm description	Patients in Part A randomised to treatment with placebo. Data presented represents the modified intent-to-treat (mITT) population.
Arm type	Experimental
Investigational medicinal product name	Placebo
Investigational medicinal product code
Other name
Pharmaceutical forms	Capsule
Routes of administration	Oral use
Dosage and administration details	Placebo, taken orally twice daily.
Number of subjects in period 1 Lenabasum 5 mg BID Part A Lenabasum 20 mg BID Part A Placebo in Part A Started 122 120 123 Completed 113 100 115 Not completed 9 20 8      Adverse event, serious fatal - 2 1      Consent withdrawn by subject 3 10 1      Physician decision - 2 -      Non-compliance with study 2 - -      Adverse event, non-fatal 1 5 6      Lack of efficacy - physician decision 1 - -      Lack of efficacy - withdrawal by subject 1 - -      Lost to follow-up 1 1 -
Period 2
Period 2 title	Open label extension (Part B)
Is this the baseline period?	No
Allocation method	Not applicable
Blinding used	Not blinded
Blinding implementation details	Part B was an open-label treatment period following on from Part A. All patients were treated with lenabasum 20 mg (no blinding required). Reporting groups present patients according to randomised treatment in Part A (lenabasum or placebo) as well as a group with the total patients in Part B (i.e., all patients appear twice in the reporting groups - once in one of the randomised groups AND once in the total group for Part B).
Arms
Are arms mutually exclusive	No
Arm title	Part B (Lenabasum in Part A)
Arm description	All patients treated with 20 mg lenabasum twice daily in Part B (patients who had been treated with either 5 mg or 20 lenabasum in Part A). This represents the safety population.
Arm type	Experimental
Investigational medicinal product name	Lenabasum 20 mg BID
Investigational medicinal product code
Other name
Pharmaceutical forms	Capsule
Routes of administration	Oral use
Dosage and administration details	20 mg Lenabasum, taken orally twice daily (total dose: 40 mg lenabasum per day)
Arm title	Part B (placebo in Part A)
Arm description	All patients treated with 20 mg lenabasum twice daily in Part B (patients who had been treated with placebo in Part A). This represents the safety population.
Arm type	Experimental
Investigational medicinal product name	Lenabasum 20 mg BID
Investigational medicinal product code
Other name
Pharmaceutical forms	Capsule
Routes of administration	Oral use
Dosage and administration details	20 mg Lenabasum, taken orally twice daily (total dose: 40 mg lenabasum per day)
Arm title	Part B (all patients)
Arm description	All patients treated with 20 mg lenabasum twice daily in Part B (patients who had been treated with either 5 mg or 20 lenabasum or placebo in Part A). This represents the safety population.
Arm type	Experimental
Investigational medicinal product name	Lenabasum 20 mg BID
Investigational medicinal product code
Other name
Pharmaceutical forms	Capsule
Routes of administration	Oral use
Dosage and administration details	20 mg Lenabasum, taken orally twice daily (total dose: 40 mg lenabasum per day)
Number of subjects in period 2 Part B (Lenabasum in Part A) Part B (placebo in Part A) Part B (all patients) Started 205 111 316 Completed 0 0 0 Not completed 205 111 316      Consent withdrawn by subject 6 2 8      Physician decision - 1 1      Study terminated by Sponsor 195 107 302      Adverse event, non-fatal 2 - 2      Lost to follow-up 1 - 1      Lack of efficacy 1 1 2

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Lenabasum 5 mg BID Part A
Reporting group description	Patients in Part A randomised to treatment with lenabasum 5 mg BID. Data presented represents the modified intent-to-treat (mITT) population.
Reporting group title	Lenabasum 20 mg BID Part A
Reporting group description	Patients in Part A randomised to treatment with lenabasum 20 mg BID. Data presented represents the modified intent-to-treat (mITT) population.
Reporting group title	Placebo in Part A
Reporting group description	Patients in Part A randomised to treatment with placebo. Data presented represents the modified intent-to-treat (mITT) population.
Reporting group values Lenabasum 5 mg BID Part A Lenabasum 20 mg BID Part A Placebo in Part A Total Number of subjects 122 120 123 365 Age categorical Units: Subjects     Adults (18-64 years) 102 107 104 313     From 65-84 years 20 12 19 51     85 years and over 0 1 0 1 Gender categorical Units: Subjects     Female 89 96 91 276     Male 33 24 32 89 Part A baseline mRSS total score modified Rodnan Skin Score Note, summary statistics were calculated for patients included in the analysis of mRSS score (i.e., the mITT population); consequently, 2 patients in the baseline reporting group (safety population) for Lenabasum 5 mg are not included in this table (N=120 for Lenabasum 5 mg). Units: mRSS score     arithmetic mean (standard deviation) 22.0 ± 7.35 22.1 ± 8.55 23.3 ± 8.68 - Part A baseline HAQ-DI score Health Assessment Questionnaire Disability Index Units: HAQ-DI score     arithmetic mean (standard deviation) 1.0719 ± 0.76468 1.1219 ± 0.78179 1.575 ± 0.76769 - Part A baseline FVC% predicted The FEV1/FVC Ratio (FVC%) parameter is calculated by dividing the measured FEV1 value by the measured FVC value. The predicted value shows the ratio expressed as a percentage. Units: percent     arithmetic mean (standard deviation) 79.481 ± 16.1321 81.279 ± 18.8347 78.925 ± 15.2292 -

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	Lenabasum 5 mg BID Part A
Reporting group description	Patients in Part A randomised to treatment with lenabasum 5 mg BID. Data presented represents the modified intent-to-treat (mITT) population.
Reporting group title	Lenabasum 20 mg BID Part A
Reporting group description	Patients in Part A randomised to treatment with lenabasum 20 mg BID. Data presented represents the modified intent-to-treat (mITT) population.
Reporting group title	Placebo in Part A
Reporting group description	Patients in Part A randomised to treatment with placebo. Data presented represents the modified intent-to-treat (mITT) population.
Reporting group title	Part B (Lenabasum in Part A)
Reporting group description	All patients treated with 20 mg lenabasum twice daily in Part B (patients who had been treated with either 5 mg or 20 lenabasum in Part A). This represents the safety population.
Reporting group title	Part B (placebo in Part A)
Reporting group description	All patients treated with 20 mg lenabasum twice daily in Part B (patients who had been treated with placebo in Part A). This represents the safety population.
Reporting group title	Part B (all patients)
Reporting group description	All patients treated with 20 mg lenabasum twice daily in Part B (patients who had been treated with either 5 mg or 20 lenabasum or placebo in Part A). This represents the safety population.

End points Top of page

Primary: ACR CRISS Score (Improvement Probability) - Part A Top of page
End point title	ACR CRISS Score (Improvement Probability) - Part A
End point description
End point type	Primary
End point timeframe	The ACR CRISS Score (Improvement Probability) at Visit 11 (Week 52).
End point values Lenabasum 5 mg BID Part A Lenabasum 20 mg BID Part A Placebo in Part A Number of subjects analysed 113 100 115 Units: ACR CRISS score     median (inter-quartile range (Q1-Q3)) 0.8270 (0.0700 to 0.9880) 0.8880 (0.0610 to 0.9970) 0.8870 (0.0710 to 0.9990)
Statistical analysis title	Lenabasum 20 mg vs Placebo
Statistical analysis description	A comparison of median ACR CRISS scores between the 20 mg lenabasum group and the placebo group.
Comparison groups	Lenabasum 20 mg BID Part A v Placebo in Part A
Number of subjects included in analysis	215
Analysis specification	Pre-specified
Analysis type	superiority [1]
P-value	= 0.4972
Method	Mixed models analysis
Confidence interval
Notes [1] - Combined inference statistics. Each imputation dataset is analysed using mixed models for repeated measures (MMRM) on the ranked ACR CRISS score with region, disease duration (≤ 24 months vs > 24 months), Baseline mycophenolate use (Yes vs No), visit, treatment, and treatment-by-visit interaction as fixed effects and Baseline mRSS as a covariate.
Statistical analysis title	Lenabasum 5 mg vs Placebo
Statistical analysis description	A comparison of median ACR CRISS scores between the 5 mg lenabasum group and the placebo group.
Comparison groups	Lenabasum 5 mg BID Part A v Placebo in Part A
Number of subjects included in analysis	228
Analysis specification	Pre-specified
Analysis type	superiority [2]
P-value	= 0.3486
Method	Mixed models analysis
Confidence interval
Notes [2] - Combined inference statistics. Each imputation dataset is analysed using mixed models for repeated measures (MMRM) on the ranked ACR CRISS score with region, disease duration (≤ 24 months vs > 24 months), Baseline mycophenolate use (Yes vs No), visit, treatment, and treatment-by-visit interaction as fixed effects and Baseline mRSS as a covariate.

Primary: ACR CRISS Score (Improvement Probability) - Part A Top of page

Secondary: Change in mRSS Score - Part A Top of page
End point title	Change in mRSS Score - Part A
End point description	Change in mRSS score from baseline in subjects treated with lenabasum 5 mg or 20 mg BID and placebo BID in Part A of the study. This was a secondary endpoint for the study, but the primary endpoint for patients in Japan.
End point type	Secondary
End point timeframe	Change from baseline to Visit 11 (Week 52).
End point values Lenabasum 5 mg BID Part A Lenabasum 20 mg BID Part A Placebo in Part A Number of subjects analysed 113 100 115 Units: mRSS Score     arithmetic mean (standard deviation) -7.1 ± 6.24 -6.7 ± 6.59 -8.1 ± 7.72
Statistical analysis title	Lenabasum 20 mg vs Placebo
Statistical analysis description	A comparison of mean mRSS scores between the 20 mg lenabasum group and the placebo group.
Comparison groups	Lenabasum 20 mg BID Part A v Placebo in Part A
Number of subjects included in analysis	215
Analysis specification	Pre-specified
Analysis type	superiority [3]
P-value	= 0.1183
Method	Mixed models analysis
Parameter type	LS Mean Difference
Confidence interval
level	95%
sides	2-sided
lower limit	-0.4
upper limit	3.3
Notes [3] - Based on an MMRM with region, disease duration (≤ 24 months vs > 24 months), Baseline mycophenolate use (Yes vs No), visit, treatment, and treatment-by-visit interaction as fixed effects and Baseline mRSS as a covariate.
Statistical analysis title	Lenabasum 5 mg vs Placebo
Statistical analysis description	A comparison of mean mRSS scores between the 5 mg lenabasum group and the placebo group.
Comparison groups	Placebo in Part A v Lenabasum 5 mg BID Part A
Number of subjects included in analysis	228
Analysis specification	Pre-specified
Analysis type	superiority [4]
P-value	= 0.5036
Method	Mixed models analysis
Parameter type	LS Mean Difference
Confidence interval
level	95%
sides	2-sided
lower limit	-1.2
upper limit	2.4
Notes [4] - Based on an MMRM with region, disease duration (≤ 24 months vs > 24 months), Baseline mycophenolate use (Yes vs No), visit, treatment, and treatment-by-visit interaction as fixed effects and Baseline mRSS as a covariate.

Secondary: Change in mRSS Score - Part A Top of page

Secondary: Change in HAQ-DI Score - Part A Top of page
End point title	Change in HAQ-DI Score - Part A
End point description	Change in HAQ-DI score from baseline in subjects treated with lenabasum 5 mg or 20 mg BID and placebo BID in Part A of the study.
End point type	Secondary
End point timeframe	Change from baseline to Visit 11 (Week 52).
End point values Lenabasum 5 mg BID Part A Lenabasum 20 mg BID Part A Placebo in Part A Number of subjects analysed 112 99 114 Units: HAQ-DI Score     arithmetic mean (standard deviation) -0.0603 ± 0.39170 -0.1326 ± 0.43625 -0.1272 ± 0.46770
Statistical analysis title	Lenabasum 20 mg vs Placebo
Statistical analysis description	A comparison of HAQ-DI scores between the 20 mg lenabasum group and the placebo group.
Comparison groups	Lenabasum 20 mg BID Part A v Placebo in Part A
Number of subjects included in analysis	213
Analysis specification	Pre-specified
Analysis type	superiority [5]
P-value	= 0.7449
Method	Mixed models analysis
Parameter type	LS Mean Difference
Confidence interval
level	95%
sides	2-sided
lower limit	-0.095
upper limit	0.1328
Notes [5] - Based on an MMRM with region, disease duration (≤ 24 months vs > 24 months), Baseline mycophenolate use (Yes vs No), visit, treatment, and treatment-by-visit interaction as fixed effects and Baseline HAQ-DI score as a covariate.
Statistical analysis title	Lenabasum 5 mg vs Placebo
Statistical analysis description	A comparison of HAQ-DI scores between the 5 mg lenabasum group and the placebo group.
Comparison groups	Placebo in Part A v Lenabasum 5 mg BID Part A
Number of subjects included in analysis	226
Analysis specification	Pre-specified
Analysis type	superiority [6]
P-value	= 0.3216
Method	Mixed models analysis
Parameter type	LS Mean Difference
Confidence interval
level	95%
sides	2-sided
lower limit	-0.0557
upper limit	0.1691
Notes [6] - Based on an MMRM with region, disease duration (≤ 24 months vs > 24 months), Baseline mycophenolate use (Yes vs No), visit, treatment, and treatment-by-visit interaction as fixed effects and Baseline HAQ-DI score as a covariate.

Secondary: Change in HAQ-DI Score - Part A Top of page

Secondary: Change in FVC% predicted value - Part A Top of page
End point title	Change in FVC% predicted value - Part A
End point description	Change in FVC% predicted values from baseline in subjects treated with lenabasum 5 mg or 20 mg BID and placebo BID in Part A of the study.
End point type	Secondary
End point timeframe	Change from baseline to Visit 11 (Week 52).
End point values Lenabasum 5 mg BID Part A Lenabasum 20 mg BID Part A Placebo in Part A Number of subjects analysed 112 99 112 Units: change in percentage score     arithmetic mean (standard deviation) -2.248 ± 6.2099 -1.602 ± 6.9106 -0.993 ± 8.6840
Statistical analysis title	Lenabasum 20 mg vs Placebo
Statistical analysis description	A comparison of FVC% predicted scores between the 20 mg lenabasum group and the placebo group.
Comparison groups	Lenabasum 20 mg BID Part A v Placebo in Part A
Number of subjects included in analysis	211
Analysis specification	Pre-specified
Analysis type	superiority [7]
P-value	= 0.5393
Method	Mixed models analysis
Parameter type	LS Mean Difference
Confidence interval
level	95%
sides	2-sided
lower limit	-2.509
upper limit	1.315
Notes [7] - Based on an MMRM with region, disease duration (≤ 24 months vs > 24 months), Baseline mycophenolate use (Yes vs No), visit, treatment, and treatment-by-visit interaction as fixed effects and Baseline FVC % predicted as a covariate.
Statistical analysis title	Lenabasum 5 mg vs Placebo
Statistical analysis description	A comparison of FVC% predicted scores between the 5 mg lenabasum group and the placebo group.
Comparison groups	Placebo in Part A v Lenabasum 5 mg BID Part A
Number of subjects included in analysis	224
Analysis specification	Pre-specified
Analysis type	superiority [8]
P-value	= 0.5158
Method	Mixed models analysis
Parameter type	LS Mean Difference
Confidence interval
level	95%
sides	2-sided
lower limit	-2.497
upper limit	1.256
Notes [8] - Based on an MMRM with region, disease duration (≤ 24 months vs > 24 months), Baseline mycophenolate use (Yes vs No), visit, treatment, and treatment-by-visit interaction as fixed effects and Baseline FVC % predicted as a covariate.

Secondary: Change in FVC% predicted value - Part A Top of page

Secondary: Change in FVC absolute value - Part A Top of page
End point title	Change in FVC absolute value - Part A
End point description	Change in FVC absolute values from baseline in subjects treated with lenabasum 5 mg or 20 mg BID and placebo BID in Part A of the study.
End point type	Secondary
End point timeframe	Change from baseline to Visit 11 (Week 52).
End point values Lenabasum 5 mg BID Part A Lenabasum 20 mg BID Part A Placebo in Part A Number of subjects analysed 112 99 112 Units: litre(s)     arithmetic mean (standard deviation) -0.105 ± 0.2516 -0.075 ± 0.2655 -0.043 ± 0.3124
Statistical analysis title	Lenabasum 20 mg vs Placebo
Statistical analysis description	A comparison of FVC absolute scores between the 20 mg lenabasum group and the placebo group.
Comparison groups	Lenabasum 20 mg BID Part A v Placebo in Part A
Number of subjects included in analysis	211
Analysis specification	Pre-specified
Analysis type	superiority [9]
P-value	= 0.3219
Method	Mixed models analysis
Parameter type	LS Mean Difference
Confidence interval
level	95%
sides	2-sided
lower limit	-0.11
upper limit	0.036
Notes [9] - Based on an MMRM with region, disease duration (≤ 24 months vs > 24 months), Baseline mycophenolate use (Yes vs No), visit, treatment, and treatment-by-visit interaction as fixed effects and Baseline FVC as a covariate.
Statistical analysis title	Lenabasum 5 mg vs Placebo
Statistical analysis description	A comparison of FVC absolute scores between the 5 mg lenabasum group and the placebo group.
Comparison groups	Placebo in Part A v Lenabasum 5 mg BID Part A
Number of subjects included in analysis	224
Analysis specification	Pre-specified
Analysis type	superiority [10]
P-value	= 0.3175
Method	Mixed models analysis
Parameter type	LS Mean Difference
Confidence interval
level	95%
sides	2-sided
lower limit	-0.108
upper limit	0.035
Notes [10] - Based on an MMRM with region, disease duration (≤ 24 months vs > 24 months), Baseline mycophenolate use (Yes vs No), visit, treatment, and treatment-by-visit interaction as fixed effects and Baseline FVC as a covariate.

Secondary: Change in FVC absolute value - Part A Top of page

Secondary: ACR CRISS Score (Improvement Probability) - Part B Top of page
End point title	ACR CRISS Score (Improvement Probability) - Part B
End point description	All patients treated with 20 mg lenabasum twice daily in Part B (patients who had been treated with either 5 mg or 20 lenabasum or placebo in Part A).
End point type	Secondary
End point timeframe	The ACR CRISS Score (Improvement Probability) at Visit 10B (Week 68) related to baseline in Part A.
End point values Part B (Lenabasum in Part A) Part B (placebo in Part A) Part B (all patients) Number of subjects analysed 12 5 17 Units: ACR CRISS Score     median (full range (min-max)) 0.9835 (0.052 to 1.000) 0.9990 (0.640 to 1.000) 0.9920 (0.052 to 1.000)
No statistical analyses for this end point

Secondary: ACR CRISS Score (Improvement Probability) - Part B Top of page

Secondary: Change in mRSS Score - Part B Top of page
End point title	Change in mRSS Score - Part B
End point description	Change in mRSS score from Part A baseline in subjects treated with lenabasum 20 mg BID in Part B of the study.
End point type	Secondary
End point timeframe	Change from Part A baseline to Visit 10B (Week 68).
End point values Part B (Lenabasum in Part A) Part B (placebo in Part A) Part B (all patients) Number of subjects analysed 12 6 18 Units: mRSS Score     arithmetic mean (standard deviation) -10.3 ± 5.24 -14.7 ± 6.95 -11.7 ± 6.05
No statistical analyses for this end point

Secondary: Change in mRSS Score - Part B Top of page

Secondary: Change in HAQ-DI Score - Part B Top of page
End point title	Change in HAQ-DI Score - Part B
End point description	Change in HAQ-DI score from Part A baseline in subjects treated with lenabasum 20 mg BID in Part B of the study.
End point type	Secondary
End point timeframe	Change from Part A baseline to Visit 10B (Week 68).
End point values Part B (Lenabasum in Part A) Part B (placebo in Part A) Part B (all patients) Number of subjects analysed 9 5 14 Units: HAQ-DI Score     arithmetic mean (standard deviation) -0.4861 ± 0.39747 -0.3250 ± 0.54199 -0.4286 ± 0.44048
No statistical analyses for this end point

Secondary: Change in HAQ-DI Score - Part B Top of page

Secondary: Change in FVC% predicted value - Part B Top of page
End point title	Change in FVC% predicted value - Part B
End point description	Change in FVC% predicted value from Part A baseline in subjects treated with lenabasum 20 mg BID in Part B of the study.
End point type	Secondary
End point timeframe	Change from Part A baseline to Visit 10B (Week 68).
End point values Part B (Lenabasum in Part A) Part B (placebo in Part A) Part B (all patients) Number of subjects analysed 12 5 17 Units: change in percentage score     arithmetic mean (standard deviation) -0.185 ± 6.8241 -0.494 ± 3.2118 -0.276 ± 5.8835
No statistical analyses for this end point

Secondary: Change in FVC% predicted value - Part B Top of page

Secondary: Change in FVC absolute value - Part B Top of page
End point title	Change in FVC absolute value - Part B
End point description	Change in FVC absolute value from Part A baseline in subjects treated with lenabasum 20 mg BID in Part B of the study.
End point type	Secondary
End point timeframe	Change from Part A baseline to Visit 10B (Week 68).
End point values Part B (Lenabasum in Part A) Part B (placebo in Part A) Part B (all patients) Number of subjects analysed 12 5 17 Units: litre(s)     arithmetic mean (standard deviation) -0.028 ± 0.2253 -0.088 ± 0.1432 -0.046 ± 0.2020
No statistical analyses for this end point

Secondary: Change in FVC absolute value - Part B Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	From baseline to the end of the study. Part A comprised a 52-week double-bind treatment period. Part B was an open-label period with all patients treated with lenabasum (20 mg twice daily) for up to 2 years.
Adverse event reporting additional description	Part A: Mean durations of exposure were 331.9 days and 349.8 days for lenabasum 20 mg and 5 mg BID, respectively, and 348.2 days for placebo. Part B of the study was terminated early (primary efficacy endpoint in Part A was not met). The mean duration of exposure in Part B was 266.1 days (min, max: 1, 560).
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	23.1
Reporting groups
Reporting group title	Lenabasum 5 mg BID Part A
Reporting group description	Patients in Part A randomised to treatment with lenabasum 5 mg BID.
Reporting group title	Lenabasum 20 mg BID Part A
Reporting group description	Patients in Part A randomised to treatment with lenabasum 20 mg BID.
Reporting group title	Placebo Part A
Reporting group description	Patients in Part A randomised to treatment with placebo.
Reporting group title	Part B lenabasum 20 mg BID (Lenabasum in Part A)
Reporting group description	All patients in Part B were treated with 20 mg lenabasum BID (open label).
Reporting group title	Part B 20 mg lenabasum BID (placebo in Part A)
Reporting group description	All patients in Part B were treated with 20 mg lenabasum BID (open label).
Reporting group title	Part B 20 mg lenabasum BID (all patients)
Reporting group description	All patients in Part B were treated with 20 mg lenabasum BID (open label), regardless of double-blind treatment assignment in Part A.
Serious adverse events Lenabasum 5 mg BID Part A Lenabasum 20 mg BID Part A Placebo Part A Part B lenabasum 20 mg BID (Lenabasum in Part A) Part B 20 mg lenabasum BID (placebo in Part A) Part B 20 mg lenabasum BID (all patients) Total subjects affected by serious adverse events      subjects affected / exposed 10 / 122 (8.20%) 11 / 120 (9.17%) 18 / 123 (14.63%) 16 / 205 (7.80%) 9 / 111 (8.11%) 25 / 316 (7.91%)      number of deaths (all causes) 0 1 1 0 0 0      number of deaths resulting from adverse events 0 1 1 0 0 0 Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 0 / 205 (0.00%) 1 / 111 (0.90%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 1 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Breast cancer      subjects affected / exposed 0 / 122 (0.00%) 2 / 120 (1.67%) 0 / 123 (0.00%) 1 / 205 (0.49%) 0 / 111 (0.00%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 2 0 / 0 0 / 1 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Colorectal cancer      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 0 / 205 (0.00%) 1 / 111 (0.90%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 1 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Epstein-Barr virus associated lymphoma      subjects affected / exposed 0 / 122 (0.00%) 1 / 120 (0.83%) 0 / 123 (0.00%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Lung neoplasm      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 1 / 123 (0.81%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Lung neoplasm malignant      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 1 / 123 (0.81%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Ovarian cancer metastatic      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 1 / 123 (0.81%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0 Squamous cell carcinoma of skin      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 1 / 205 (0.49%) 1 / 111 (0.90%) 2 / 316 (0.63%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1 0 / 1 0 / 2      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Thyroid cancer      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 1 / 123 (0.81%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Vascular disorders Hypertension      subjects affected / exposed 0 / 122 (0.00%) 1 / 120 (0.83%) 0 / 123 (0.00%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Leriche syndrome      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 0 / 205 (0.00%) 1 / 111 (0.90%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 1 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Peripheral ischaemia      subjects affected / exposed 0 / 122 (0.00%) 1 / 120 (0.83%) 0 / 123 (0.00%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 2 0 / 0 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 General disorders and administration site conditions Asthenia      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 1 / 123 (0.81%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Chest pain      subjects affected / exposed 0 / 122 (0.00%) 1 / 120 (0.83%) 0 / 123 (0.00%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Pain      subjects affected / exposed 0 / 122 (0.00%) 1 / 120 (0.83%) 0 / 123 (0.00%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Peripheral swelling      subjects affected / exposed 1 / 122 (0.82%) 0 / 120 (0.00%) 0 / 123 (0.00%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Pyrexia      subjects affected / exposed 2 / 122 (1.64%) 0 / 120 (0.00%) 0 / 123 (0.00%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 2 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Reproductive system and breast disorders Uterine polyp      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 1 / 205 (0.49%) 0 / 111 (0.00%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Respiratory, thoracic and mediastinal disorders Dyspnoea      subjects affected / exposed 1 / 122 (0.82%) 0 / 120 (0.00%) 0 / 123 (0.00%) 1 / 205 (0.49%) 0 / 111 (0.00%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 1 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Hypoxia      subjects affected / exposed 0 / 122 (0.00%) 1 / 120 (0.83%) 0 / 123 (0.00%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0 0 / 0 Interstitial lung disease      subjects affected / exposed 1 / 122 (0.82%) 0 / 120 (0.00%) 0 / 123 (0.00%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Organising pneumonia      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 1 / 123 (0.81%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Pulmonary arterial hypertension      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 1 / 123 (0.81%) 1 / 205 (0.49%) 0 / 111 (0.00%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 1 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Sleep apnoea syndrome      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 1 / 205 (0.49%) 0 / 111 (0.00%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Injury, poisoning and procedural complications Concussion      subjects affected / exposed 1 / 122 (0.82%) 0 / 120 (0.00%) 0 / 123 (0.00%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Femur fracture      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 1 / 205 (0.49%) 0 / 111 (0.00%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Procedural haemorrhage      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 0 / 205 (0.00%) 1 / 111 (0.90%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 1 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Radius fracture      subjects affected / exposed 1 / 122 (0.82%) 0 / 120 (0.00%) 0 / 123 (0.00%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Cardiac disorders Acute myocardial infarction      subjects affected / exposed 0 / 122 (0.00%) 1 / 120 (0.83%) 0 / 123 (0.00%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Aortic valve stenosis      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 1 / 123 (0.81%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Cardiac failure      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 1 / 205 (0.49%) 0 / 111 (0.00%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Cardiac failure congestive      subjects affected / exposed 0 / 122 (0.00%) 1 / 120 (0.83%) 1 / 123 (0.81%) 1 / 205 (0.49%) 0 / 111 (0.00%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 1 0 / 1 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Myocardial ischaemia      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 0 / 205 (0.00%) 1 / 111 (0.90%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 1 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Myocarditis      subjects affected / exposed 1 / 122 (0.82%) 1 / 120 (0.83%) 1 / 123 (0.81%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 1 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Pericardial effusion      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 1 / 205 (0.49%) 0 / 111 (0.00%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Supraventricular tachycardia      subjects affected / exposed 1 / 122 (0.82%) 0 / 120 (0.00%) 0 / 123 (0.00%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Nervous system disorders Spondylitic myelopathy      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 1 / 123 (0.81%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Transient global amnesia      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 1 / 205 (0.49%) 0 / 111 (0.00%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Blood and lymphatic system disorders Anaemia      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 2 / 123 (1.63%) 0 / 205 (0.00%) 1 / 111 (0.90%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 2 0 / 0 0 / 1 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Iron deficiency anaemia      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 1 / 123 (0.81%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Gastrointestinal disorders Enteritis      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 0 / 205 (0.00%) 1 / 111 (0.90%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 1 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Faecaloma      subjects affected / exposed 0 / 122 (0.00%) 1 / 120 (0.83%) 0 / 123 (0.00%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Gastritis      subjects affected / exposed 0 / 122 (0.00%) 1 / 120 (0.83%) 0 / 123 (0.00%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Gastrointestinal inflammation      subjects affected / exposed 0 / 122 (0.00%) 1 / 120 (0.83%) 0 / 123 (0.00%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Haematemesis      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 1 / 123 (0.81%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 4 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Ileus paralytic      subjects affected / exposed 0 / 122 (0.00%) 1 / 120 (0.83%) 0 / 123 (0.00%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Intestinal ischaemia      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 1 / 123 (0.81%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Oesophageal food impaction      subjects affected / exposed 0 / 122 (0.00%) 1 / 120 (0.83%) 0 / 123 (0.00%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Upper gastrointestinal haemorrhage      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 1 / 123 (0.81%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Volvulus      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 1 / 205 (0.49%) 0 / 111 (0.00%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Hepatobiliary disorders Cholecystitis acute      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 1 / 205 (0.49%) 1 / 111 (0.90%) 2 / 316 (0.63%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1 1 / 1 1 / 2      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Skin and subcutaneous tissue disorders Scleroderma associated digital ulcer      subjects affected / exposed 5 / 122 (4.10%) 1 / 120 (0.83%) 1 / 123 (0.81%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 5 0 / 1 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Renal and urinary disorders Scleroderma renal crisis      subjects affected / exposed 1 / 122 (0.82%) 0 / 120 (0.00%) 2 / 123 (1.63%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 2 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Musculoskeletal and connective tissue disorders Intervertebral disc protrusion      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 0 / 205 (0.00%) 1 / 111 (0.90%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 1 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Joint contracture      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 0 / 205 (0.00%) 1 / 111 (0.90%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 1 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Osteochondritis      subjects affected / exposed 1 / 122 (0.82%) 0 / 120 (0.00%) 0 / 123 (0.00%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Systemic scleroderma      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 1 / 123 (0.81%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Tenosynovitis      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 0 / 205 (0.00%) 1 / 111 (0.90%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 1 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Vertebral foraminal stenosis      subjects affected / exposed 1 / 122 (0.82%) 0 / 120 (0.00%) 0 / 123 (0.00%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Infections and infestations COVID-19      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 1 / 205 (0.49%) 0 / 111 (0.00%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Cellulitis      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 1 / 205 (0.49%) 0 / 111 (0.00%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Clostridium difficile colitis      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 1 / 123 (0.81%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Device related infection      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 1 / 123 (0.81%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Diarrhoea infectious      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 0 / 205 (0.00%) 1 / 111 (0.90%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 1 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Diverticulitis      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 1 / 123 (0.81%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Gastroenteritis      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 1 / 205 (0.49%) 0 / 111 (0.00%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Gastroenteritis clostridial      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 1 / 205 (0.49%) 0 / 111 (0.00%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Herpes zoster      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 1 / 205 (0.49%) 0 / 111 (0.00%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 1 / 1 0 / 0 1 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Infected skin ulcer      subjects affected / exposed 1 / 122 (0.82%) 0 / 120 (0.00%) 0 / 123 (0.00%) 1 / 205 (0.49%) 0 / 111 (0.00%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 2 0 / 0 0 / 0 0 / 1 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Localised infection      subjects affected / exposed 1 / 122 (0.82%) 0 / 120 (0.00%) 0 / 123 (0.00%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 4 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Osteomyelitis      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 1 / 123 (0.81%) 1 / 205 (0.49%) 0 / 111 (0.00%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 3 0 / 1 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Pneumonia      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 3 / 123 (2.44%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 1 / 3 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Salmonellosis      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 1 / 205 (0.49%) 0 / 111 (0.00%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Sepsis      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 1 / 205 (0.49%) 0 / 111 (0.00%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Skin infection      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 0 / 123 (0.00%) 1 / 205 (0.49%) 0 / 111 (0.00%) 1 / 316 (0.32%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Tonsillitis      subjects affected / exposed 1 / 122 (0.82%) 0 / 120 (0.00%) 0 / 123 (0.00%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 Urinary tract infection      subjects affected / exposed 0 / 122 (0.00%) 0 / 120 (0.00%) 1 / 123 (0.81%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0 0 / 0
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events Lenabasum 5 mg BID Part A Lenabasum 20 mg BID Part A Placebo Part A Part B lenabasum 20 mg BID (Lenabasum in Part A) Part B 20 mg lenabasum BID (placebo in Part A) Part B 20 mg lenabasum BID (all patients) Total subjects affected by non serious adverse events      subjects affected / exposed 110 / 122 (90.16%) 110 / 120 (91.67%) 106 / 123 (86.18%) 152 / 205 (74.15%) 69 / 111 (62.16%) 221 / 316 (69.94%) Investigations Weight decreased      subjects affected / exposed 3 / 122 (2.46%) 7 / 120 (5.83%) 6 / 123 (4.88%) 4 / 205 (1.95%) 3 / 111 (2.70%) 7 / 316 (2.22%)      occurrences all number 4 7 6 4 3 7 Cardiac disorders Palpitations      subjects affected / exposed 3 / 122 (2.46%) 7 / 120 (5.83%) 5 / 123 (4.07%) 3 / 205 (1.46%) 1 / 111 (0.90%) 4 / 316 (1.27%)      occurrences all number 4 7 6 3 1 4 Nervous system disorders Dizziness      subjects affected / exposed 11 / 122 (9.02%) 22 / 120 (18.33%) 6 / 123 (4.88%) 16 / 205 (7.80%) 9 / 111 (8.11%) 25 / 316 (7.91%)      occurrences all number 12 29 6 17 11 28 Headache      subjects affected / exposed 14 / 122 (11.48%) 17 / 120 (14.17%) 9 / 123 (7.32%) 5 / 205 (2.44%) 5 / 111 (4.50%) 10 / 316 (3.16%)      occurrences all number 15 20 12 5 5 10 Paraesthesia      subjects affected / exposed 8 / 122 (6.56%) 3 / 120 (2.50%) 2 / 123 (1.63%) 2 / 205 (0.98%) 1 / 111 (0.90%) 3 / 316 (0.95%)      occurrences all number 8 4 2 2 2 4 General disorders and administration site conditions Fatigue      subjects affected / exposed 10 / 122 (8.20%) 10 / 120 (8.33%) 7 / 123 (5.69%) 9 / 205 (4.39%) 4 / 111 (3.60%) 13 / 316 (4.11%)      occurrences all number 10 12 8 9 4 13 Gastrointestinal disorders Constipation      subjects affected / exposed 8 / 122 (6.56%) 2 / 120 (1.67%) 5 / 123 (4.07%) 8 / 205 (3.90%) 2 / 111 (1.80%) 10 / 316 (3.16%)      occurrences all number 8 2 6 8 2 10 Diarrhoea      subjects affected / exposed 16 / 122 (13.11%) 21 / 120 (17.50%) 18 / 123 (14.63%) 13 / 205 (6.34%) 10 / 111 (9.01%) 23 / 316 (7.28%)      occurrences all number 18 26 20 15 12 27 Dry mouth      subjects affected / exposed 7 / 122 (5.74%) 6 / 120 (5.00%) 2 / 123 (1.63%) 7 / 205 (3.41%) 2 / 111 (1.80%) 9 / 316 (2.85%)      occurrences all number 7 6 2 7 2 9 Dysphagia      subjects affected / exposed 9 / 122 (7.38%) 2 / 120 (1.67%) 0 / 123 (0.00%) 5 / 205 (2.44%) 1 / 111 (0.90%) 6 / 316 (1.90%)      occurrences all number 9 2 0 5 1 6 Gastrooesophageal reflux disease      subjects affected / exposed 5 / 122 (4.10%) 7 / 120 (5.83%) 8 / 123 (6.50%) 4 / 205 (1.95%) 5 / 111 (4.50%) 9 / 316 (2.85%)      occurrences all number 5 8 8 4 6 10 Mouth ulceration      subjects affected / exposed 2 / 122 (1.64%) 6 / 120 (5.00%) 0 / 123 (0.00%) 2 / 205 (0.98%) 1 / 111 (0.90%) 3 / 316 (0.95%)      occurrences all number 2 6 0 2 1 3 Nausea      subjects affected / exposed 5 / 122 (4.10%) 17 / 120 (14.17%) 13 / 123 (10.57%) 10 / 205 (4.88%) 7 / 111 (6.31%) 17 / 316 (5.38%)      occurrences all number 5 21 13 11 8 19 Vomiting      subjects affected / exposed 7 / 122 (5.74%) 15 / 120 (12.50%) 7 / 123 (5.69%) 8 / 205 (3.90%) 4 / 111 (3.60%) 12 / 316 (3.80%)      occurrences all number 7 22 11 9 5 14 Respiratory, thoracic and mediastinal disorders Cough      subjects affected / exposed 7 / 122 (5.74%) 9 / 120 (7.50%) 9 / 123 (7.32%) 4 / 205 (1.95%) 0 / 111 (0.00%) 4 / 316 (1.27%)      occurrences all number 7 9 10 5 0 5 Dyspnoea      subjects affected / exposed 7 / 122 (5.74%) 3 / 120 (2.50%) 3 / 123 (2.44%) 6 / 205 (2.93%) 0 / 111 (0.00%) 6 / 316 (1.90%)      occurrences all number 7 3 3 6 0 6 Oropharyngeal pain      subjects affected / exposed 8 / 122 (6.56%) 2 / 120 (1.67%) 3 / 123 (2.44%) 6 / 205 (2.93%) 1 / 111 (0.90%) 7 / 316 (2.22%)      occurrences all number 8 2 4 6 1 7 Skin and subcutaneous tissue disorders Pruritus      subjects affected / exposed 10 / 122 (8.20%) 12 / 120 (10.00%) 9 / 123 (7.32%) 11 / 205 (5.37%) 2 / 111 (1.80%) 13 / 316 (4.11%)      occurrences all number 11 15 10 11 3 14 Scleroderma associated digital ulcer      subjects affected / exposed 21 / 122 (17.21%) 15 / 120 (12.50%) 18 / 123 (14.63%) 25 / 205 (12.20%) 14 / 111 (12.61%) 39 / 316 (12.34%)      occurrences all number 62 45 36 44 23 67 Skin ulcer      subjects affected / exposed 7 / 122 (5.74%) 5 / 120 (4.17%) 3 / 123 (2.44%) 6 / 205 (2.93%) 2 / 111 (1.80%) 8 / 316 (2.53%)      occurrences all number 10 5 7 9 2 11 Renal and urinary disorders Haematuria      subjects affected / exposed 4 / 122 (3.28%) 6 / 120 (5.00%) 0 / 123 (0.00%) 0 / 205 (0.00%) 0 / 111 (0.00%) 0 / 316 (0.00%)      occurrences all number 5 8 0 0 0 0 Musculoskeletal and connective tissue disorders Arthralgia      subjects affected / exposed 15 / 122 (12.30%) 12 / 120 (10.00%) 20 / 123 (16.26%) 9 / 205 (4.39%) 11 / 111 (9.91%) 20 / 316 (6.33%)      occurrences all number 17 15 26 10 14 24 Back pain      subjects affected / exposed 8 / 122 (6.56%) 5 / 120 (4.17%) 5 / 123 (4.07%) 6 / 205 (2.93%) 2 / 111 (1.80%) 8 / 316 (2.53%)      occurrences all number 9 5 7 6 2 8 Pain in extremity      subjects affected / exposed 8 / 122 (6.56%) 9 / 120 (7.50%) 6 / 123 (4.88%) 3 / 205 (1.46%) 4 / 111 (3.60%) 7 / 316 (2.22%)      occurrences all number 8 10 6 3 5 8 Infections and infestations Infected skin ulcer      subjects affected / exposed 5 / 122 (4.10%) 4 / 120 (3.33%) 7 / 123 (5.69%) 4 / 205 (1.95%) 3 / 111 (2.70%) 7 / 316 (2.22%)      occurrences all number 7 4 9 5 3 8 Nasopharyngitis      subjects affected / exposed 25 / 122 (20.49%) 18 / 120 (15.00%) 10 / 123 (8.13%) 15 / 205 (7.32%) 4 / 111 (3.60%) 19 / 316 (6.01%)      occurrences all number 42 21 16 16 4 20 Sinusitis      subjects affected / exposed 5 / 122 (4.10%) 6 / 120 (5.00%) 4 / 123 (3.25%) 1 / 205 (0.49%) 1 / 111 (0.90%) 2 / 316 (0.63%)      occurrences all number 7 6 4 1 1 2 Upper respiratory tract infection      subjects affected / exposed 18 / 122 (14.75%) 17 / 120 (14.17%) 20 / 123 (16.26%) 15 / 205 (7.32%) 8 / 111 (7.21%) 23 / 316 (7.28%)      occurrences all number 20 23 25 17 11 28 Urinary tract infection      subjects affected / exposed 10 / 122 (8.20%) 13 / 120 (10.83%) 5 / 123 (4.07%) 11 / 205 (5.37%) 3 / 111 (2.70%) 14 / 316 (4.43%)      occurrences all number 13 18 6 14 3 17 Viral upper respiratory tract infection      subjects affected / exposed 3 / 122 (2.46%) 6 / 120 (5.00%) 1 / 123 (0.81%) 1 / 205 (0.49%) 1 / 111 (0.90%) 2 / 316 (0.63%)      occurrences all number 3 6 1 1 1 2