History of Changes for Study: NCT02962895

Study Identification


Unique Protocol ID:	CVAY736A2201
Brief Title:	Safety and Efficacy of VAY736 in Patients With Primary Sjogren's Syndrome (pSS)
Official Title:	Study of Safety and Efficacy of Multiple VAY736 Doses in Patients With Moderate to Severe Primary Sjogren's Syndrome (pSS)
Secondary IDs:

Study Status


Record Verification:	July 2022
Overall Status:	Completed
Study Start:	June 27, 2017
Primary Completion:	June 30, 2020 [Actual]
Study Completion:	September 23, 2021 [Actual]

First Submitted:	November 3, 2016
First Submitted that Met QC Criteria:	November 9, 2016
First Posted:	November 15, 2016 [Estimate]

Last Update Submitted that Met QC Criteria:
Last Update Posted:	August 10, 2022 [Actual]

Study Description

Brief Summary:

The purpose of this study was to determine the dose-response relationship of VAY736 for key efficacy and safety parameters

Detailed Description:

This was a randomized, double-blind, placebo-controlled, multicenter, parallel-group trial that was divided into 4 study periods.

Period 1: A screening period of 4 weeks to assess patient eligibility. Patients could be re-screened only once, and no study-related re-screening procedure could be performed prior to written re-consent by the patient.

Period 2: A blinded treatment period of 24 weeks. At baseline, eligible patients were randomized to one of three ianalumab dose arms (VAY736 5 mg, 50 mg or 300 mg s.c.) or a placebo arm (placebo s.c.). Blinded study drug was administered every four weeks (q4w) for a 24-week period.

Except for Japan, randomization was stratified by baseline ESSDAI score (<10 or ≥10 based on weighted scores). Separate blocks of randomization numbers were generated for patients in Japan versus the other countries participating to ensure that Japanese patients were equally distributed across all treatment groups in the study.

The primary endpoint was assessed at the end of Period 2 (Week 24). Treatment assignment in Period 2 remained double-blinded until the end of Period 3.

Period 3: An extended blinded treatment period of 28 weeks. After Week 24 assessments, patients in the ianalumab 300 mg arm were re-randomized in a 1:1 ratio to either continue on ianalumab 300 mg s.c. q4w or switch to matching placebo up to Week 52. Patients who received placebo during Period 2 were switched to ianalumab 150 mg s.c q4w up to Week 52. Patients who received 5 mg and 50 mg s.c. in Period 2 proceeded directly to safety follow-up (Period 4). Treatment assignment in Period 3 remained double-blinded.

Period 4: A post-treatment safety follow-up period. Patients who prematurely discontinued the study treatment at any time point or completed the treatment as planned entered the safety follow-up period. The minimum required duration of follow-up in the study was 20 weeks from the last administration of the study treatment (mandatory follow-up). The maximum duration of the follow-up was 2 years from the last dose of the study treatment, and it was defined by the level of recovery of CD19+ B-cells: conditional follow up (with reduced visit frequency) until CD19+ B-cell levels return to at least 80% of baseline or 50 cells/µL, whichever occurred first. Patients who had not yet recovered their B-cell counts two years after last ianalumab dosing were discharged from the study and had undergone their End of Study (EoS) visit. Patients who were treated with another immunomodulatory or immunosuppressive treatment (e.g., azathioprine, cyclophosphamide, high dose glucocorticosteroids) after completion of the minimum 20-week safety follow-up period were excluded from further safety follow-up.

Study Design


Study Type:	Interventional
Primary Purpose:	Treatment
Study Phase:	Phase 2
Interventional Study Model:	Parallel Assignment
	This was a randomized, double-blind, placebo-controlled, multicenter, parallel-group trial which planned to enroll approximately 180 patients with moderate to severe primary Sjögren's syndrome. The study was divided into 4 study periods: Period 1: 4-week Screening to assess patient eligibility. Period 2: 24-week Blinded treatment period. Period 3: An extended blinded treatment period of 28 weeks. After Week 24 assessments, patients in the ianalumab 300 mg arm were re-randomized in a 1:1 ratio to either continue on ianalumab 300 mg s.c. q4w or switch to matching placebo up to Week 52. Period 4: Post-treatment safety follow-up period. Patients who prematurely discontinued the study treatment at any time point or completed the treatment as planned entered the safety follow-up period.
Number of Arms:	4
Masking:	Triple (Participant, Care Provider, Investigator)
Allocation:	Randomized
Enrollment:	190 [Actual]

Arms and Interventions

Arms	Assigned Interventions
Experimental: VAY736 dose 1 - 5mg VAY736 low	Biological: VAY736 VAY736
Experimental: VAY736 dose 2 - 50mg VAY736 medium	Biological: VAY736 VAY736
Experimental: VAY736 dose 3 - 300 mg VAY736 high	Biological: VAY736 VAY736
Placebo Comparator: Placebo Placebo control	Placebo Placebo control

Outcome Measures

[See Results Section.]


Primary Outcome Measures:
1.	Change From Baseline in ESSDAI Score at Week 24 [ Time Frame: Baseline, 24 weeks ] Dose response measured by change multi-dimensional disease activity as assessed by the physician. Score range is 0-123. Higher scores on the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) scale are associated with poorer health states A negative change from baseline indicates improvement in disease status.
Secondary Outcome Measures:
1.	Change From Baseline in ESSDAI Score at Weeks 4, 8, 12, and 16 [ Time Frame: Baseline, Weeks 4, 8, 12, and 16 ] Dose response measured by change multi-dimensional disease activity as assessed by the physician. Score range is 0-123. Higher scores on the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) scale are associated with poorer health states A negative change from baseline indicates improvement in disease status.
2.	Change From Baseline in ESSPRI Score at Week 24 [ Time Frame: Baseline, 24 weeks ] Change in quality of life measure by patient reported outcome (PRO) The EULAR Sjörgen's Syndrome Patient Reported Index (ESSPRI) is an established disease outcome measure for Sjögren's syndrome that is calculated by averaging the scales for pain, fatigue and dryness. The total score is the mean score of the 3 scales and ranges between 0 and 10 with higher values indicating more severity of symptoms. A negative change from baseline is a favourable outcome.
3.	Change From Baseline in ESSPRI Score at Weeks 4, 8, 12 and 16 [ Time Frame: Baseline, Weeks 4, 8, 12 and 16 ] Change in quality of life measure by patient reported outcome (PRO) The EULAR Sjörgen's Syndrome Patient Reported Index (ESSPRI) is an established disease outcome measure for Sjögren's syndrome that is calculated by averaging the scales for pain, fatigue and dryness. The total score is the mean score of the 3 scales and ranges between 0 and 10 with higher values indicating more severity of symptoms. A negative change from baseline is a favourable outcome.
4.	Change From Baseline in FACIT-F Score at Week 24 [ Time Frame: Baseline to 24 weeks ] Change in FACIT-F from baseline over 24 weeks as compared to placebo. The Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F v4) is a short, 13-item, easy-to-administer tool that measures an individual's level of fatigue during their usual daily activities over the previous week. The level of fatigue is measured on a four-point Likert scale (4 = not at all fatigued to 0 = very much fatigued). The global score ranges between 0 and 52, with higher scores indicating less fatigue.
5.	Change From Baseline in FACIT-F Score at Weeks 4, 8, 12 and 16 [ Time Frame: Baseline, Weeks 4, 8, 12 and 16 ] Change in FACIT-F from baseline as compared to placebo. The Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F v4) is a short, 13-item, easy-to-administer tool that measures an individual's level of fatigue during their usual daily activities over the previous week. The level of fatigue is measured on a four-point Likert scale (4 = not at all fatigued to 0 = very much fatigued). The global score ranges between 0 and 52, with higher scores indicating less fatigue.
6.	Change From Baseline in Salivary Flow Rate at Week 24 [ Time Frame: Baseline, 24 weeks ] Change from baseline in salivary flow rate (unstimulated and stimulated) at 24 weeks as compared to placebo. Unstimulated saliva is a mix of serous and mucous secretions coming primarily from the submandibular and minor salivary glands. The parotid gland produces the largest volume of stimulated saliva. Stimulated saliva accounts for 80-90% of daily salivary production.
7.	Change From SF-36 Physical Component (PCS) and Mental Component (MCS) at Week 24 [ Time Frame: Baseline, Week 24 ] Change from SF-36 physical component (PCS) and mental component (MCS) from baseline over 24 weeks as compared to placebo The SF36 includes 8 scale scores (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health) and two summary scores, the physical and mental component scores. The first four and last four scales comprise physical and mental component scores, respectively. The range of scores of the physical component (PCS) and mental component (MCS) is 0 (lowest or worst possible level of functioning) to 100 (highest or best possible level of functioning).
8.	Change From SF-36 Physical Component (PCS) and Mental Component (MCS) From Baseline to Weeks 4, 8, 12 and 16 [ Time Frame: Baseline, Weeks 4, 8, 12 and 16 ] Change from SF-36 physical component (PCS) and mental component (MCS) from baseline over to 16 weeks as compared to placebo The SF36 includes 8 scale scores (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health) and two summary scores, the physical and mental component scores. The first four and last four scales comprise physical and mental component scores, respectively. The range of scores of the physical component (PCS) and mental component (MCS) is 0 (lowest or worst possible level of functioning) to 100 (highest or best possible level of functioning).
9.	Change From Baseline in PhGA of Patient's Overall Disease Activity Using Patient Visual Analog Scale (VAS) at 24 Weeks [ Time Frame: Baseline, 24 weeks ] Change from baseline in PhGA of patient's overall disease activity (recorded by VAS) over 24 weeks as compared to placebo Physician global assessment of overall disease activity (PhGA) was performed using a 100 mm visual analogue scale (VAS) ranging from no disease activity (score 0) to maximal disease activity (score 100), after the question "Considering all the ways the disease affects your patient, draw a line on the scale for how well his or her condition is today". A negative change from baseline is a favourable outcome.
10.	Change From Baseline in PhGA of Patient's Overall Disease Activity Using Patient Visual Analog Scale (VAS) at Weeks 4, 8, 12 and 16 [ Time Frame: Baseline, Weeks 4, 8, 12 and 16 ] Change from baseline in PhGA of patient's overall disease activity (recorded by VAS) as compared to placebo Change from baseline in PhGA of patient's overall disease activity (recorded by VAS) over 16 weeks as compared to placebo Physician global assessment of overall disease activity (PhGA) was performed using a 100 mm visual analogue scale (VAS) ranging from no disease activity (score 0) to maximal disease activity (score 100), after the question "Considering all the ways the disease affects your patient, draw a line on the scale for how well his or her condition is today". A negative change from baseline is a favourable outcome.
11.	PaGA Score at Weeks 4, 8, 12, 16 and 24 [ Time Frame: Weeks 4, 8, 12, 16 and 24 ] Patient global assessment (PaGA) Score at Weeks 4, 8, 12, 16 and 24 The PaGA is a 5-point scale ranging from 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), to 4 (severe), incorporating an assessment of the severity of the disease by the patient
Quality Control Review Comment provided by the National Library of Medicine: The description of the scale or categories does not include sufficient information to understand the results reported.
12.	Change From Baseline in Whole Blood CD19+ B-cell Counts. Units: Percent Change From Baseline at Week 24 [ Time Frame: Baseline, Week 24 ] Change from baseline in whole blood CD19+ B-cell counts. Units: percent change from baseline VAY736 300 mg - Placebo includes patients who discontinued in Period 2 and entered Period 4 directly and patients who completed Period 2 and were re-randomized to placebo. Baseline is defined as the last assessment performed on or prior to the date of administration of the first dose of study treatment. Only patients with baseline measurement and at least one measurement post-baseline were included.
Quality Control Review Comment provided by the National Library of Medicine: The measure does not appear to include sufficient information to understand how outcomes are measured and reported. The Time Frame appears inconsistent with information provided here or in other parts of the record.
13.	Time to Recovery to Baseline Like Values for B-cell Counts [ Time Frame: Baseline to Week 24 ] Kaplan-Meier Analysis for Time to Recovery to Baseline like Values (defined as at least 80% of baseline counts or ≥ 50 cells/µL) for B-cell counts - Entire Study (FAS) VAY736 300 mg - Placebo includes patients who discontinued in Period 2 and entered Period 4 directly and patients who completed Period 2 and were re-randomized to placebo.
Quality Control Review Comment provided by the National Library of Medicine: The Time Frame appears inconsistent with information provided here or in other parts of the record.
14.	Peak Serum Concentration of VAY736 [ Time Frame: baseline to week 24 ] Pharmacokinetic Concentrations This outcome only applies to patients who received at least one dose of VAY739 (so not applicable to placebo)
Quality Control Review Comment provided by the National Library of Medicine: The Time Frame appears inconsistent with information provided here or in other parts of the record.

Eligibility


Minimum Age:	18 Years
Maximum Age:	75 Years
Sex:	All
Gender Based:
Accepts Healthy Volunteers:	No
Criteria:	Inclusion Criteria: Fulfilled revised American European Consensus Group criteria for pSS Seropositive at screening for anti-Ro/SSA antibodies Screening ESSDAI value >=6 scored from 7 domains: articular, cutaneous, glandular, lymphoadenopathy, constitutional, biologic and hematologic. Exclusion Criteria: Secondary Sjogren's syndrome Use of other investigational drugs Active viral, bacterial or other infections Positive hepatitis B, hepatitis C, HIV or tuberculosis test results at screening

Contacts/Locations


Study Officials:	Novartis Pharmaceuticals Study Director Novartis Pharmaceuticals
Locations:	United States, Florida
	Novartis Investigative Site Plantation, Florida, United States, 33324
	United States, Indiana
	Novartis Investigative Site Indianapolis, Indiana, United States, 46202
	United States, Maryland
	Novartis Investigative Site Baltimore, Maryland, United States, 21224
	United States, Massachusetts
	Novartis Investigative Site Boston, Massachusetts, United States, 02111
	United States, New York
	Novartis Investigative Site Rochester, New York, United States, 14618
	United States, Pennsylvania
	Novartis Investigative Site Pittsburgh, Pennsylvania, United States, 15213
	Novartis Investigative Site Wexford, Pennsylvania, United States, 15090
	United States, Texas
	Novartis Investigative Site Houston, Texas, United States, 77030
	Novartis Investigative Site San Antonio, Texas, United States, 78229
	Argentina
	Novartis Investigative Site Caba, Argentina, 1117
	Novartis Investigative Site Cordoba, Argentina, 5000
	Novartis Investigative Site Cordoba, Argentina, X5016KEH
	Argentina, Buenos Aires
	Novartis Investigative Site Ciudad Autonoma de Bs As, Buenos Aires, Argentina, C1055AAF
	Austria
	Novartis Investigative Site Graz, Austria, 8036
	Belgium
	Novartis Investigative Site Bruxelles, Belgium, 1070
	Novartis Investigative Site Leuven, Belgium, 3000
	Chile
	Novartis Investigative Site Santiago, Chile, 7500710
	Novartis Investigative Site Santiago, Chile, 8207257
	France
	Novartis Investigative Site Brest, France, 29200
	Novartis Investigative Site Lille, France, 59000
	Germany
	Novartis Investigative Site Berlin, Germany, 13353
	Novartis Investigative Site Freiburg, Germany, 79106
	Novartis Investigative Site Muenchen, Germany, 81377
	Novartis Investigative Site Wuerzburg, Germany, 97080
	Hungary
	Novartis Investigative Site Budapest, Hungary, H-1097
	Novartis Investigative Site Szeged, Hungary, 6720
	Israel
	Novartis Investigative Site Ramat Gan, Israel, 52621
	Italy, MI
	Novartis Investigative Site Rozzano, MI, Italy, 20089
	Italy, RM
	Novartis Investigative Site Roma, RM, Italy, 00161
	Italy, UD
	Novartis Investigative Site Udine, UD, Italy, 33100
	Japan, Aichi
	Novartis Investigative Site Nagoya, Aichi, Japan, 457 8510
	Japan, Nagasaki
	Novartis Investigative Site Sasebo-city, Nagasaki, Japan, 857-1165
	Japan, Tokyo
	Novartis Investigative Site Itabashi-ku, Tokyo, Japan, 173-8610
	Novartis Investigative Site Shinjuku-ku, Tokyo, Japan, 160 8582
	Netherlands
	Novartis Investigative Site Rotterdam, Netherlands, 3015 CE
	Poland
	Novartis Investigative Site Lublin, Poland, 20-954
	Portugal
	Novartis Investigative Site Almada, Portugal, 2801 951
	Novartis Investigative Site Lisboa, Portugal, 1050-034
	Novartis Investigative Site Lisboa, Portugal, 1649-035
	Novartis Investigative Site Porto, Portugal, 4099 001
	Romania
	Novartis Investigative Site Brasov, Romania, 500283
	Novartis Investigative Site Cluj Napoca, Romania, 400006
	Russian Federation
	Novartis Investigative Site Ekaterinburg, Russian Federation, 620028
	Novartis Investigative Site Orenburg, Russian Federation, 460000
	Novartis Investigative Site St Petersburg, Russian Federation, 190068
	Novartis Investigative Site St Petersburg, Russian Federation, 195257
	Spain
	Novartis Investigative Site Barcelona, Spain, 08041
	Spain, Pontevedra
	Novartis Investigative Site Vigo, Pontevedra, Spain, 36200
	Spain, Santa Cruz De Tenerife
	Novartis Investigative Site La Laguna, Santa Cruz De Tenerife, Spain, 38320
	Taiwan
	Novartis Investigative Site Kaohsiung, Taiwan, 81346
	Novartis Investigative Site Taichung, Taiwan, 40447
	Novartis Investigative Site Taichung, Taiwan, 40705
	Novartis Investigative Site Taipei, Taiwan, 11490
	United Kingdom
	Novartis Investigative Site Birmingham, United Kingdom, B15 2TH
	Novartis Investigative Site Liverpool, United Kingdom, L9 7AL
	United Kingdom, Essex
	Novartis Investigative Site Westcliff-on-Sea, Essex, United Kingdom, SS0 0RY

IPDSharing


Plan to Share IPD:	Yes Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
	Supporting Information:
	Time Frame:
	Access Criteria:
	URL:

Document Section


	Study Protocol Document Date: January 16, 2020 Uploaded: 07/13/2022 17:30 File Name: Prot_000.pdf
	Statistical Analysis Plan Document Date: July 27, 2019 Uploaded: 07/13/2022 17:33 File Name: SAP_001.pdf

Study Results

Participant Flow

Recruitment Details

190 Patients were enrolled from 56 centers in 19 countries.

Pre-assignment Details

Period one was the screening period and is not shown here.

Arm/Group Title	Placebo	VAY736 5 mg	VAY736 50 mg	VAY736 150 mg	VAY736 300 mg	VAY736 - Placebo 300 mg	VAY736 300 mg - VAY736 300 mg
Arm/Group Description	Placebo control	VAY736 low	VAY736 medium	Placebo in Period 2 and VAY736 150 mg in Period 3	VAY736 high	VAY736 300 mg in Period 2 and Placebo in Period 3	VAY736 300 mg in Period 2 and Period 3

Period Title: Period 2 - Randomized Set
Started	49	47	47	0	47	0	0
Completed	47	42	43	0	46	0	0
Not Completed	2	5	4	0	1	0	0
Reason Not Completed
Withdrawal by Subject	1	1	2	0	0	0	0
Withdrawal of Informed Consent	0	1	0	0	0	0	0
Adverse Event	0	2	2	0	0	0	0
New therapy for indication	1	0	0	0	0	0	0
Non-compliance with treatment	0	1	0	0	0	0	0
Pregnancy	0	0	0	0	1	0	0

Period Title: Period 3 - Randomized Set
Started	0	0	0	47	0	22	21
Completed	0	0	0	42	0	22	17
Not Completed	0	0	0	5	0	0	4
Reason Not Completed
Patient/guardian decision	0	0	0	0	0	0	1
Adverse Event	0	0	0	5	0	0	2
Pregnancy	0	0	0	0	0	0	1

Period Title: Period 4
Started	2	47	47	46	4	22	20
Completed	2	41	43	42	1	20	20
Not Completed	0	6	4	4	3	2	0
Reason Not Completed
Lack of Efficacy	0	1	0	0	0	0	0
Lost to Follow-up	0	0	0	1	0	0	0
New therapy for indication	0	0	0	1	0	0	0
Withdrawal of informed consent	0	3	1	0	2	0	0
Withdrawal by Subject	0	2	3	2	1	2	0

Baseline Characteristics

Arm/Group Title

Placebo

VAY736 5 mg

VAY736 50 mg

VAY736 300 mg

Total

Arm/Group Description

Placebo control

VAY736 low

VAY736 medium

VAY736 high

Total of all reporting groups

Overall Number of Baseline Participants

190

Baseline Analysis Population Description

Age, Categorical^[1]

Measure Type: Count of Participants
Unit of measure: Participants

Number Analyzed

49 Participants

47 Participants

190 Participants

<=18 years

Between 18 and 65 years

91.84%

78.72%

89.36%

82.98%

163

85.79%

>=65 years

8.16%

21.28%

10.64%

17.02%

14.21%

[1]	Measure Description: Randomized Set

Age, Continuous

Mean (Standard Deviation)
Unit of measure: Years

Number Analyzed

49 Participants

47 Participants

190 Participants

47.9(12.44)

52.5(13.64)

51.0(11.12)

49.1(15.41)

50.9(13.48)

Sex: Female, Male

Measure Type: Count of Participants
Unit of measure: Participants

Number Analyzed

49 Participants

47 Participants

190 Participants

Female

95.92%

97.87%

87.23%

97.87%

180

94.74%

Male

4.08%

2.13%

12.77%

2.13%

5.26%

Race/Ethnicity, Customized

Measure Type: Count of Participants
Unit of measure: Participants

Number Analyzed

49 Participants

47 Participants

190 Participants

Asian

8.16%

6.38%

21.28%

10.64%

11.58%

Black or African American

2.13%

0.53%

White

89.8%

89.36%

78.72%

89.36%

165

86.84%

Unknown

2.04%

0.53%

Quality Control Review Comment provided by the National Library of Medicine:

The number of participants analyzed appears inconsistent with data here or in other parts of the record.

Outcome Measures

1. Primary Outcome:

Title

Change From Baseline in ESSDAI Score at Week 24

Description

Dose response measured by change multi-dimensional disease activity as assessed by the physician.

Score range is 0-123. Higher scores on the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) scale are associated with poorer health states

A negative change from baseline indicates improvement in disease status.

Time Frame

Baseline, 24 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): comprised of all patients in the Randomised Set to whom study treatment was assigned. Following the intent-to-treat principle, patients were analyzed according to the treatment assigned to at randomization.


Arm/Group Title	Placebo	VAY736 5 mg	VAY736 50 mg	VAY736 300 mg
Arm/Group Description	Placebo control	VAY736 low	VAY736 medium	VAY736 300 mg high dose
Overall Number of Participants Analyzed	49	47	47	47
Least Squares Mean (Standard Error) Unit of Measure: Scores on a scale	-6.39(0.808)	-5.64(0.850)	-6.93(0.836)	-8.30(0.828)

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 5 mg
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.5161
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	Confidence intervals and p-values derived from a mixed model for repeated measures (MMRM)


Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.75
	Confidence Interval	(2-sided) 95% -1.52 to 3.02
	Estimation Comments	[Not specified]

Statistical Analysis 2


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 50 mg
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.6332
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	Confidence intervals and p-values derived from a mixed model for repeated measures (MMRM)


Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.55
	Confidence Interval	(2-sided) 95% -2.80 to 1.71
	Estimation Comments	[Not specified]

Statistical Analysis 3


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 300 mg
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.0921
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	Confidence intervals and p-values derived from a mixed model for repeated measures (MMRM)


Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-1.92
	Confidence Interval	(2-sided) 95% -4.15 to 0.32
	Estimation Comments	[Not specified]

2. Secondary Outcome:

Title

Change From Baseline in ESSDAI Score at Weeks 4, 8, 12, and 16

Description

Dose response measured by change multi-dimensional disease activity as assessed by the physician.

Score range is 0-123. Higher scores on the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) scale are associated with poorer health states

A negative change from baseline indicates improvement in disease status.

Time Frame

Baseline, Weeks 4, 8, 12, and 16

Outcome Measure Data

Analysis Population Description


Arm/Group Title		Placebo	VAY736 5 mg	VAY736 50 mg	VAY736 300 mg
Arm/Group Description		Placebo control	VAY736 low	VAY736 medium	VAY736 300 mg high dose
Overall Number of Participants Analyzed		49	47	47	47
Least Squares Mean (Standard Error) Unit of Measure: Scores on a scale
Week 4	Number Analyzed	Participants	Participants	Participants	Participants
Week 4		-3.73(0.626)	-2.28(0.661)	-3.37(0.638)	-4.53(0.651)
Week 8	Number Analyzed	Participants	Participants	Participants	Participants
Week 8		-4.13(0.704)	-4.65(0.733)	-4.73(0.720)	-6.38(0.717)
Week 12	Number Analyzed	Participants	Participants	Participants	Participants
Week 12		-5.45(0.721)	-4.89(0.762)	-5.69(0.739)	-6.64(0.739)
Week 16	Number Analyzed	Participants	Participants	Participants	Participants
Week 16		-6.08(0.818)	-5.67(0.852)	-6.17(0.835)	-6.99(0.836)

3. Secondary Outcome:

Title

Change From Baseline in ESSPRI Score at Week 24

Description

Change in quality of life measure by patient reported outcome (PRO)

The EULAR Sjörgen's Syndrome Patient Reported Index (ESSPRI) is an established disease outcome measure for Sjögren's syndrome that is calculated by averaging the scales for pain, fatigue and dryness. The total score is the mean score of the 3 scales and ranges between 0 and 10 with higher values indicating more severity of symptoms. A negative change from baseline is a favourable outcome.

Time Frame

Baseline, 24 weeks

Outcome Measure Data

Analysis Population Description

FAS


Arm/Group Title	Placebo	VAY736 5 mg	VAY736 50 mg	VAY736 300 mg
Arm/Group Description	Placebo control	VAY736 low	VAY736 medium	VAY736 high
Overall Number of Participants Analyzed	49	47	47	47
Least Squares Mean (Standard Error) Unit of Measure: Scores on a scale	-1.71(0.288)	-1.39(0.304)	-1.70(0.301)	-1.77(0.295)

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 5 mg
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.4457
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.32
	Confidence Interval	(2-sided) 95% -0.50 to 1.13
	Estimation Comments	[Not specified]

Statistical Analysis 2


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 50 mg
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.301
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	0.01
	Confidence Interval	(2-sided) 95% -0.79 to 0.82
	Estimation Comments	[Not specified]

Statistical Analysis 3


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 300 mg
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.8858
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-0.06
	Confidence Interval	(2-sided) 95% -0.86 to 0.74
	Estimation Comments	[Not specified]

4. Secondary Outcome:

Title

Change From Baseline in ESSPRI Score at Weeks 4, 8, 12 and 16

Description

Change in quality of life measure by patient reported outcome (PRO)

Time Frame

Baseline, Weeks 4, 8, 12 and 16

Outcome Measure Data

Analysis Population Description

FAS


Arm/Group Title		Placebo	VAY736 5 mg	VAY736 50 mg	VAY736 300 mg
Arm/Group Description		Placebo control	VAY736 low	VAY736 medium	VAY736 high
Overall Number of Participants Analyzed		49	47	47	47
Least Squares Mean (Standard Error) Unit of Measure: Scores on a scale
Week 4	Number Analyzed	Participants	Participants	Participants	Participants
Week 4		-0.54(0.236)	-0.67(0.247)	-0.80(0.241)	-0.88(0.242)
Week 8	Number Analyzed	Participants	Participants	Participants	Participants
Week 8		-0.94(0.242)	-0.84(0.255)	-1.06(0.251)	-1.8(0.248)
Week 12	Number Analyzed	Participants	Participants	Participants	Participants
Week 12		-1.42(0.265)	-1.36(0.279)	-1.44(0.273)	-1.23(0.270)
Week 16	Number Analyzed	Participants	Participants	Participants	Participants
Week 16		-1.77(0.263)	-1.27(0.275)	-1.55(0.271)	-1.55(0.270)

5. Secondary Outcome:

Title

Change From Baseline in FACIT-F Score at Week 24

Description

Change in FACIT-F from baseline over 24 weeks as compared to placebo. The Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F v4) is a short, 13-item, easy-to-administer tool that measures an individual's level of fatigue during their usual daily activities over the previous week. The level of fatigue is measured on a four-point Likert scale (4 = not at all fatigued to 0 = very much fatigued). The global score ranges between 0 and 52, with higher scores indicating less fatigue.

Time Frame

Baseline to 24 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): comprised of all patients in the RAN to whom study treatment was assigned. Following the intent-to-treat principle, patients were analyzed according to the treatment assigned to at randomization and by actual stratum at baseline. FAS was used for all efficacy variables, unless otherwise stated.


Arm/Group Title	Placebo	VAY736 5 mg	VAY736 50 mg	VAY736 300 mg
Arm/Group Description	Placebo control	VAY736 low	VAY736 medium	VAY736 high
Overall Number of Participants Analyzed	49	47	47	47
Least Squares Mean (Standard Error) Unit of Measure: Scores on a scale	9.05(1.404)	7.12(1.502)	6.48(1.518)	9.36(1.436)

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 5 mg
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.3424
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	Confidence intervals and p-values are derived from a mixed model for repeated measures (MMRM)


Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.93
	Confidence Interval	(2-sided) 95% -5.93 to 2.07
	Estimation Comments	[Not specified]

Statistical Analysis 2


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 50 mg
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.2092
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	Confidence intervals and p-values are derived from a mixed model for repeated measures (MMRM)


Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-2.56
	Confidence Interval	(2-sided) 95% -6.58 to 1.45
	Estimation Comments	[Not specified]

Statistical Analysis 3


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 300 mg
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.8740
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	Confidence intervals and p-values are derived from a mixed model for repeated measures (MMRM)


Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.31
	Confidence Interval	(2-sided) 95% -3.58 to 4.20
	Estimation Comments	[Not specified]

6. Secondary Outcome:

Title

Change From Baseline in FACIT-F Score at Weeks 4, 8, 12 and 16

Description

Change in FACIT-F from baseline as compared to placebo. The Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F v4) is a short, 13-item, easy-to-administer tool that measures an individual's level of fatigue during their usual daily activities over the previous week. The level of fatigue is measured on a four-point Likert scale (4 = not at all fatigued to 0 = very much fatigued). The global score ranges between 0 and 52, with higher scores indicating less fatigue.

Time Frame

Baseline, Weeks 4, 8, 12 and 16

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Placebo	VAY736 5 mg	VAY736 50 mg	VAY736 300 mg
Arm/Group Description	Placebo control	VAY736 low	VAY736 medium	VAY736 high
Overall Number of Participants Analyzed	48	42	39	46
Mean (Standard Deviation) Unit of Measure: Scores on a scale
Week 4	3.78(1.175)	6.32(1.239)	3.12(1.229)	3.39(1.203)
Week 8	5.49(1.222)	6.36(1.297)	3.93(1.303)	5.98(1.250)
Week 12	6.25(1.349)	8.17(1.429)	5.73(1.427)	6.05(1.374)
Week 16	8.56(1.284)	7.09(1.357)	6.86(1.359)	8.30(1.318)

7. Secondary Outcome:

Title

Change From Baseline in Salivary Flow Rate at Week 24

Description

Change from baseline in salivary flow rate (unstimulated and stimulated) at 24 weeks as compared to placebo.

Unstimulated saliva is a mix of serous and mucous secretions coming primarily from the submandibular and minor salivary glands. The parotid gland produces the largest volume of stimulated saliva. Stimulated saliva accounts for 80-90% of daily salivary production.

Time Frame

Baseline, 24 weeks

Outcome Measure Data

Analysis Population Description

FAS: The overall number of participants analyzed represents the FAS. The number analyzed per row represents participants with data available at each assessment.


Arm/Group Title		Placebo	VAY736 5 mg	VAY736 50 mg	VAY736 300 mg
Arm/Group Description		Placebo control	VAY736 low	VAY736 medium	VAY736 high
Overall Number of Participants Analyzed		49	47	47	47
Least Squares Mean (Standard Error) Unit of Measure: mL/min
Stimulated	Number Analyzed	Participants	Participants	Participants	Participants
Stimulated		0.05(0.067)	0.16(0.074)	0.18(0.071)	0.25(0.98)
Unstimulated	Number Analyzed	Participants	Participants	Participants	Participants
Unstimulated		0.12(0.20)	0.12(0.17)	0.10(0.13)	0.25(0.069)

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 5 mg
	Comments	Stimulated
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.2710
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	Confidence intervals and p-values derived from a mixed model for repeated measures (MMRM)


Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.11
	Confidence Interval	(2-sided) 95% -0.08 to 0.30
	Estimation Comments	[Not specified]

Statistical Analysis 2


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 50 mg
	Comments	Stimulated
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.1618
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	Confidence intervals and p-values derived from a mixed model for repeated measures (MMRM)


Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.13
	Confidence Interval	(2-sided) 95% -0.05 to 0.32
	Estimation Comments	[Not specified]

Statistical Analysis 3


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 300 mg
	Comments	Stimulated
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.0374
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	Confidence intervals and p-values derived from a mixed model for repeated measures (MMRM)


Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.20
	Confidence Interval	(2-sided) 95% 0.01 to 0.38
	Estimation Comments	[Not specified]

Statistical Analysis 4


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 5 mg
	Comments	Unstimulated
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.9559
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	Confidence intervals and p-values derived from a mixed model for repeated measures (MMRM)


Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.00
	Confidence Interval	(2-sided) 95% -0.09 to 0.09
	Estimation Comments	[Not specified]

Statistical Analysis 5


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 50 mg
	Comments	Unstimulated
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.9290
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	Confidence intervals and p-values derived from a mixed model for repeated measures (MMRM)


Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.01
	Confidence Interval	(2-sided) 95% -0.09 to 0.08
	Estimation Comments	[Not specified]

Statistical Analysis 6


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 300 mg
	Comments	Unstimulated
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.7276
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	Confidence intervals and p-values derived from a mixed model for repeated measures (MMRM)


Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.01
	Confidence Interval	(2-sided) 95% -0.10 to 0.07
	Estimation Comments	[Not specified]

8. Secondary Outcome:

Title

Change From SF-36 Physical Component (PCS) and Mental Component (MCS) at Week 24

Description

Change from SF-36 physical component (PCS) and mental component (MCS) from baseline over 24 weeks as compared to placebo

The SF36 includes 8 scale scores (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health) and two summary scores, the physical and mental component scores. The first four and last four scales comprise physical and mental component scores, respectively. The range of scores of the physical component (PCS) and mental component (MCS) is 0 (lowest or worst possible level of functioning) to 100 (highest or best possible level of functioning).

Time Frame

Baseline, Week 24

Outcome Measure Data

Analysis Population Description

FAS:FAS: The overall number of participants analyzed represents the FAS. The number analyzed per row represents participants with data available at each assessment.


Arm/Group Title		Placebo	VAY736 5 mg	VAY736 50 mg	VAY736 300 mg
Arm/Group Description		Placebo control	low dose	medium dose	VAY736 high
Overall Number of Participants Analyzed		49	47	47	47
Least Squares Mean (Standard Error) Unit of Measure: Scores on a scale
Mental Component Score	Number Analyzed	Participants	Participants	Participants	Participants
Mental Component Score		4.63(1.259)	3.61(1.350)	5.31(1.367)	5.63(1.286)
Physical Component Score	Number Analyzed	Participants	Participants	Participants	Participants
Physical Component Score		3.66(0.952)	4.79(1.019)	2.66(1.026)	5.50(0.972)

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 5 mg
	Comments	Mental Component Score
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.5768
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.02
	Confidence Interval	(2-sided) 95% -4.61 to 2.57
	Estimation Comments	[Not specified]

Statistical Analysis 2


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 50 mg
	Comments	Mental Component Score
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.7113
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.68
	Confidence Interval	(2-sided) 95% -2.93 to 4.28
	Estimation Comments	[Not specified]

Statistical Analysis 3


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 300 mg
	Comments	Mental Component Score
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.5722
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	1.00
	Confidence Interval	(2-sided) 95% -2.49 to 4.48
	Estimation Comments	[Not specified]

Statistical Analysis 4


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 5 mg
	Comments	Physical Component Score
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.4138
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	1.84
	Confidence Interval	(2-sided) 95% -1.59 to 3.83
	Estimation Comments	[Not specified]

Statistical Analysis 5


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 50 mg
	Comments	Physical Component Score
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.4663
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.00
	Confidence Interval	(2-sided) 95% -3.72 to 1.71
	Estimation Comments	[Not specified]

Statistical Analysis 6


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 300 mg
	Comments	Physical Component Score
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.1694
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	1.84
	Confidence Interval	(2-sided) 95% -0.79 to 4.47
	Estimation Comments	[Not specified]

9. Secondary Outcome:

Title

Change From SF-36 Physical Component (PCS) and Mental Component (MCS) From Baseline to Weeks 4, 8, 12 and 16

Description

Change from SF-36 physical component (PCS) and mental component (MCS) from baseline over to 16 weeks as compared to placebo

Time Frame

Baseline, Weeks 4, 8, 12 and 16

Outcome Measure Data

Analysis Population Description

FAS:FAS: The overall number of participants analyzed represents the FAS. The number analyzed per row represents participants with data available at each assessment.


Arm/Group Title		Placebo	VAY736 5 mg	VAY736 50 mg	VAY736 300 mg
Arm/Group Description		Placebo control	low dose	medium dose	VAY736 high
Overall Number of Participants Analyzed		49	47	47	47
Least Squares Mean (Standard Error) Unit of Measure: Scores on a scale
Week 4 - Mental Component Score	Number Analyzed	Participants	Participants	Participants	Participants
Week 4 - Mental Component Score		0.49(1.091)	1.89(1.151)	2.46(1.149)	2.18(1.116)
Week 8 - Mental Component Score	Number Analyzed	Participants	Participants	Participants	Participants
Week 8 - Mental Component Score		2.65(2.267)	3.80(1.341)	4.65(1.363)	3.35(1.294)
Week 12 - Mental Component Score	Number Analyzed	Participants	Participants	Participants	Participants
Week 12 - Mental Component Score		2.89(1.188)	5.42(1.264)	3.94(1.265)	4.59(1.207)
Week 16 - Mental Component Score	Number Analyzed	Participants	Participants	Participants	Participants
Week 16 - Mental Component Score		4.60(1.214)	3.00(1.281)	5.57(1.291)	5.46(1.247)
Week 4 - Physical Component Score	Number Analyzed	Participants	Participants	Participants	Participants
Week 4 - Physical Component Score		3.35(0.844)	3.94(0.889)	1.14(0.878)	1.98(0.863)
Week 8 - Physical Component Score	Number Analyzed	Participants	Participants	Participants	Participants
Week 8 - Physical Component Score		3.83(0.894)	4.56(0.949)	3.48(0.941)	3.47(0.909)
Week 12 - Physical Component Score	Number Analyzed	Participants	Participants	Participants	Participants
Week 12 - Physical Component Score		3.83(0.894)	4.56(0.949)	3.48(0.941)	3.47(0.909)
Week 16 - Physical Component Score	Number Analyzed	Participants	Participants	Participants	Participants
Week 16 - Physical Component Score		4.72(0.968)	4.67(1.020)	3.32(1.021)	4.57(0.993)

10. Secondary Outcome:

Title

Change From Baseline in PhGA of Patient's Overall Disease Activity Using Patient Visual Analog Scale (VAS) at 24 Weeks

Description

Change from baseline in PhGA of patient's overall disease activity (recorded by VAS) over 24 weeks as compared to placebo

Physician global assessment of overall disease activity (PhGA) was performed using a 100 mm visual analogue scale (VAS) ranging from no disease activity (score 0) to maximal disease activity (score 100), after the question "Considering all the ways the disease affects your patient, draw a line on the scale for how well his or her condition is today".

A negative change from baseline is a favourable outcome.

Time Frame

Baseline, 24 weeks

Outcome Measure Data

Analysis Population Description

FAS


Arm/Group Title	Placebo	VAY736 5 mg	VAY736 50 mg	VAY736 300 mg
Arm/Group Description	Placebo control	VAY736 5 mg low dose	VAY736 medium dose	VAY736 high dose
Overall Number of Participants Analyzed	49	47	47	47
Least Squares Mean (Standard Error) Unit of Measure: Scores on a scale	-23.64(2.601)	-27.81(2.751)	-28.13(2.700)	-31.99(2.630)

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 5 mg
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.2671
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	Confidence intervals and p-values derived from a mixed model for repeated measures (MMRM)


Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-4.17
	Confidence Interval	(2-sided) 95% -11.56 to 3.22
	Estimation Comments	[Not specified]

Statistical Analysis 2


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 50 mg
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.2248
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	Confidence intervals and p-values derived from a mixed model for repeated measures (MMRM)


Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-4.49
	Confidence Interval	(2-sided) 95% -11.78 to 2.79
	Estimation Comments	[Not specified]

Statistical Analysis 3


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 300 mg
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.0224
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	Confidence intervals and p-values derived from a mixed model for repeated measures (MMRM)


Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-8.36
	Confidence Interval	(2-sided) 95% -15.51 to -1.20
	Estimation Comments	[Not specified]

11. Secondary Outcome:

Title

Change From Baseline in PhGA of Patient's Overall Disease Activity Using Patient Visual Analog Scale (VAS) at Weeks 4, 8, 12 and 16

Description

Change from baseline in PhGA of patient's overall disease activity (recorded by VAS) as compared to placebo

Change from baseline in PhGA of patient's overall disease activity (recorded by VAS) over 16 weeks as compared to placebo

A negative change from baseline is a favourable outcome.

Time Frame

Baseline, Weeks 4, 8, 12 and 16

Outcome Measure Data

Analysis Population Description

FAS


Arm/Group Title		Placebo	VAY736 5 mg	VAY736 50 mg	VAY736 300 mg
Arm/Group Description		Placebo control	VAY736 5 mg low dose	VAY736 medium dose	VAY736 high dose
Overall Number of Participants Analyzed		49	47	47	47
Least Squares Mean (Standard Error) Unit of Measure: Scores on a scale
Week 4	Number Analyzed	Participants	Participants	Participants	Participants
Week 4		-12.49(2.327)	-10.50(2.445)	-12.38(2.361)	-18.67(2.367)
Week 8	Number Analyzed	Participants	Participants	Participants	Participants
Week 8		-18.54(2.239)	-16.53(2.338)	-22.12(2.374)	-24.85(2.289)
Week 12	Number Analyzed	Participants	Participants	Participants	Participants
Week 12		-21.01(2.299)	-20.72(2.413)	-25.35(2.341)	-27.25(2.305)
Week 16	Number Analyzed	Participants	Participants	Participants	Participants
Week 16		-19.44(2.572)	-24.49(2.687)	-24.77(2.676)	-25.77(2.633)

12. Secondary Outcome:

Title

PaGA Score at Weeks 4, 8, 12, 16 and 24

Description

Patient global assessment (PaGA) Score at Weeks 4, 8, 12, 16 and 24

The PaGA is a 5-point scale ranging from 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), to 4 (severe), incorporating an assessment of the severity of the disease by the patient

Time Frame

Weeks 4, 8, 12, 16 and 24

Quality Control Review Comment provided by the National Library of Medicine:

The description of the scale or categories does not include sufficient information to understand the results reported.

Outcome Measure Data

Analysis Population Description

FAS


Arm/Group Title		Placebo	VAY736 5 mg	VAY736 50 mg	VAY736 300 mg
Arm/Group Description		Placebo control	VAY736 low	VAY736 medium	VAY736 300 mg high dose
Overall Number of Participants Analyzed		49	47	47	47
Least Squares Mean (Standard Error) Unit of Measure: Scores on a scale
Week 4	Number Analyzed	Participants	Participants	Participants	Participants
Week 4		-9.42(2.850)	-10.02(2.992)	-5.96(2.969)	-8.96(2.906)
Week 8	Number Analyzed	Participants	Participants	Participants	Participants
Week 8		-9.74(3.035)	-11.48(3.214)	-8.70(3.271)	-15.27(3.091)
Week 12	Number Analyzed	Participants	Participants	Participants	Participants
Week 12		-11.45(3.064)	-17.51(3.244)	-11.73(3.234)	-13.57(3.105)
Week 16	Number Analyzed	Participants	Participants	Participants	Participants
Week 16		-16.26(3.194)	-17.56(3.361)	-14.86(3.375)	-15.78(3.271)
Week 24	Number Analyzed	Participants	Participants	Participants	Participants
Week 24		-15.11(3.405)	-12.83(3.648)	-11.85(3.704)	-19.87(3.470)

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 5 mg
	Comments	Baseline, Week 24
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.6457
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	2.27
	Confidence Interval	(2-sided) 95% -7.46 to 12.00
	Estimation Comments	[Not specified]

Statistical Analysis 2


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 50 mg
	Comments	Baseline, Week 24
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.5132
	Comments	[Not specified]
	Method	LS Mean Difference
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	3.26
	Confidence Interval	(2-sided) 95% -6.55 to 13.06
	Estimation Comments	[Not specified]

Statistical Analysis 3


Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 300 mg
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	95
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-4.77
	Confidence Interval	(2-sided) 95% -14.21 to 4.68
	Estimation Comments	[Not specified]

13. Secondary Outcome:

Title

Change From Baseline in Whole Blood CD19+ B-cell Counts. Units: Percent Change From Baseline at Week 24

Description

Change from baseline in whole blood CD19+ B-cell counts. Units: percent change from baseline

VAY736 300 mg - Placebo includes patients who discontinued in Period 2 and entered Period 4 directly and patients who completed Period 2 and were re-randomized to placebo.

Baseline is defined as the last assessment performed on or prior to the date of administration of the first dose of study treatment. Only patients with baseline measurement and at least one measurement post-baseline were included.

Time Frame

Baseline, Week 24

Quality Control Review Comment provided by the National Library of Medicine:

The measure does not appear to include sufficient information to understand how outcomes are measured and reported.
The Time Frame appears inconsistent with information provided here or in other parts of the record.

Outcome Measure Data

Analysis Population Description

FAS


Arm/Group Title	VAY736 5 mg	VAY736 50 mg	Placebo - VAY150 mg	VAY736 300 mg - Placebo	VAY736 300 mg - VAY736 300 mg
Arm/Group Description	VAY736 low	VAY736 medium	Placebo control	VAY736 high	VAY736 300 mg
Overall Number of Participants Analyzed	47	47	49	26	21
Least Squares Mean (Standard Error) Unit of Measure: pg/mL	150.36(16.229)	241.14(16.040)	-1.17(15.053)	265.77(20.407)	251.28(22508)

14. Secondary Outcome:

Title

Time to Recovery to Baseline Like Values for B-cell Counts

Description

Kaplan-Meier Analysis for Time to Recovery to Baseline like Values (defined as at least 80% of baseline counts or ≥ 50 cells/µL) for B-cell counts - Entire Study (FAS)

VAY736 300 mg - Placebo includes patients who discontinued in Period 2 and entered Period 4 directly and patients who completed Period 2 and were re-randomized to placebo.

Time Frame

Baseline to Week 24

Quality Control Review Comment provided by the National Library of Medicine:

The Time Frame appears inconsistent with information provided here or in other parts of the record.

Outcome Measure Data

Analysis Population Description

FAS


Arm/Group Title	VAY736 5 mg	VAY736 50 mg	Placebo - VAY150 mg	VAY736 300 mg - Placebo	VAY736 300 mg - VAY736 300 mg
Arm/Group Description	VAY736 low	VAY736 medium	Placebo control	VAY736 high	VAY736 300 mg
Overall Number of Participants Analyzed	47	47	49	26	21
Median (95% Confidence Interval) Unit of Measure: months	3.8(2.7 to 5.2)	4.8(4.7 to 6.6)	6.8(5.0 to 9.2)	8.4(6.8 to 9.1)	6.5(4.9 to 7.5)

15. Secondary Outcome:

Title

Peak Serum Concentration of VAY736

Description

Pharmacokinetic Concentrations

This outcome only applies to patients who received at least one dose of VAY739 (so not applicable to placebo)

Time Frame

baseline to week 24

Quality Control Review Comment provided by the National Library of Medicine:

The Time Frame appears inconsistent with information provided here or in other parts of the record.

Outcome Measure Data

Analysis Population Description

Safety set (SAF): included all patients who received at least one dose of study medication. Patients were analyzed according to treatment received and the actual stratum at baseline. The safety set was used in the analysis of all safety variables.


Arm/Group Title	VAY736 5 mg	VAY736 50 mg	VAY736 300 mg	VAY736 300 mg - Placebo	VAY736 300 mg - VAY736 300 mg
Arm/Group Description	VAY736 low	VAY736 medium	VAY736 300 mg high dose	VAY736 300 mg - Placebo	VAY736 300 mg - VAY736 300 mg
Overall Number of Participants Analyzed	47	47	4	21	22
Mean (Standard Deviation) Unit of Measure: ug/mL	0.0747(0.203)	0.475(0.380)	1.46(0.596)	2.15(1.47)	1.94(1.53)

Adverse Events


Time Frame	AEs were collected from first dose of study treatment until end of study treatment at week 24 and then up to 28 weeks
Adverse Event Reporting Description	Adverse Events (AEs) are any untoward sign or symptom that occurs during the study treatment
Quality Control Review Comment provided by the National Library of Medicine: The Time Frame appears inconsistent with information provided here or in other parts of the record.

Arm/Group Title	VAY736 5 mg 24 Weeks	VAY736 50 mg 24 Weeks	VAY736 150 mg 28 Weeks	VAY736 300 mg 24 Weeks	VAY736 300 mg 52 Weeks	Any VAY736 300 mg	Any VAY736
Arm/Group Description	VAY736 5 mg 24 Weeks	VAY736 50 mg 24 Weeks	VAY736 150 mg 28 Weeks	VAY736 300 mg 24 Weeks	VAY736 300 mg 52 Weeks	Any VAY736 300 mg	Any VAY736
Quality Control Review Comment provided by the National Library of Medicine: The arms/groups appear inconsistent with information in other parts of the record. Each arm/group should be described separately, or a valid explanation provided.
All-Cause Mortality
	VAY736 5 mg 24 Weeks	VAY736 50 mg 24 Weeks	VAY736 150 mg 28 Weeks	VAY736 300 mg 24 Weeks	VAY736 300 mg 52 Weeks	Any VAY736 300 mg	Any VAY736
	Affected / At Risk (%)	Affected / At Risk (%)	Affected / At Risk (%)	Affected / At Risk (%)	Affected / At Risk (%)	Affected / At Risk (%)	Affected / At Risk (%)
Total	0 / 47 (0%)	0 / 47 (0%)	0 / 47 (0%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	0 / 188 (0%)
Serious Adverse Events
	VAY736 5 mg 24 Weeks	VAY736 50 mg 24 Weeks	VAY736 150 mg 28 Weeks	VAY736 300 mg 24 Weeks	VAY736 300 mg 52 Weeks	Any VAY736 300 mg	Any VAY736
	Affected / At Risk (%)	Affected / At Risk (%)	Affected / At Risk (%)	Affected / At Risk (%)	Affected / At Risk (%)	Affected / At Risk (%)	Affected / At Risk (%)
Total	3 / 47 (6.38%)	7 / 47 (14.89%)	9 / 47 (19.15%)	5 / 26 (19.23%)	5 / 21 (23.81%)	10 / 47 (21.28%)	29 / 188 (15.43%)
Blood and lymphatic system disorders
Anaemia ^{† A}	0 / 47 (0%)	0 / 47 (0%)	0 / 47 (0%)	1 / 26 (3.85%)	0 / 21 (0%)	1 / 47 (2.13%)	1 / 188 (0.53%)
Leukopenia ^{† A}	0 / 47 (0%)	1 / 47 (2.13%)	0 / 47 (0%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	1 / 188 (0.53%)
Ear and labyrinth disorders
Deafness neurosensory ^{† A}	0 / 47 (0%)	0 / 47 (0%)	0 / 47 (0%)	1 / 26 (3.85%)	0 / 21 (0%)	1 / 47 (2.13%)	1 / 188 (0.53%)
Gastrointestinal disorders
Pancreatic disorder ^{† A}	0 / 47 (0%)	0 / 47 (0%)	1 / 47 (2.13%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	1 / 188 (0.53%)
Hepatobiliary disorders
Cholelithiasis ^{† A}	0 / 47 (0%)	0 / 47 (0%)	0 / 47 (0%)	0 / 26 (0%)	2 / 21 (9.52%)	2 / 47 (4.26%)	2 / 188 (1.06%)
Immune system disorders
Cell-mediated immune deficiency ^{† A}	0 / 47 (0%)	0 / 47 (0%)	1 / 47 (2.13%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	1 / 188 (0.53%)
Infections and infestations
Appendicitis ^{† A}	0 / 47 (0%)	1 / 47 (2.13%)	0 / 47 (0%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	1 / 188 (0.53%)
Bronchitis ^{† A}	0 / 47 (0%)	0 / 47 (0%)	1 / 47 (2.13%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	1 / 188 (0.53%)
COVID-19 ^{† A}	0 / 47 (0%)	0 / 47 (0%)	0 / 47 (0%)	1 / 26 (3.85%)	0 / 21 (0%)	1 / 47 (2.13%)	1 / 188 (0.53%)
COVID-19 pneumonia ^{† A}	0 / 47 (0%)	0 / 47 (0%)	0 / 47 (0%)	1 / 26 (3.85%)	0 / 21 (0%)	1 / 47 (2.13%)	1 / 188 (0.53%)
Candida infection ^{† A}	1 / 47 (2.13%)	0 / 47 (0%)	0 / 47 (0%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	1 / 188 (0.53%)
Pneumonia ^{† A}	0 / 47 (0%)	0 / 47 (0%)	1 / 47 (2.13%)	0 / 26 (0%)	1 / 21 (4.76%)	1 / 47 (2.13%)	2 / 188 (1.06%)
Respiratory syncytial virus bronchiolitis ^{† A}	0 / 47 (0%)	0 / 47 (0%)	1 / 47 (2.13%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	1 / 188 (0.53%)
Sinusitis ^{† A}	0 / 47 (0%)	0 / 47 (0%)	1 / 47 (2.13%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	1 / 188 (0.53%)
Tubo-ovarian abscess ^{† A}	0 / 47 (0%)	1 / 47 (2.13%)	0 / 47 (0%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	1 / 188 (0.53%)
Wound infection ^{† A}	0 / 47 (0%)	1 / 47 (2.13%)	0 / 47 (0%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	1 / 188 (0.53%)
Injury, poisoning and procedural complications
Femoral neck fracture ^{† A}	1 / 47 (2.13%)	0 / 47 (0%)	0 / 47 (0%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	1 / 188 (0.53%)
Injection related reaction ^{† A}	0 / 47 (0%)	0 / 47 (0%)	1 / 47 (2.13%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	1 / 188 (0.53%)
Thoracic vertebral fracture ^{† A}	0 / 47 (0%)	1 / 47 (2.13%)	0 / 47 (0%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	1 / 188 (0.53%)
Traumatic fracture ^{† A}	0 / 47 (0%)	0 / 47 (0%)	0 / 47 (0%)	0 / 26 (0%)	1 / 21 (4.76%)	1 / 47 (2.13%)	1 / 188 (0.53%)
Investigations
Weight decreased ^{† A}	0 / 47 (0%)	0 / 47 (0%)	0 / 47 (0%)	1 / 26 (3.85%)	0 / 21 (0%)	1 / 47 (2.13%)	1 / 188 (0.53%)
Musculoskeletal and connective tissue disorders
Arthralgia ^{† A}	0 / 47 (0%)	0 / 47 (0%)	1 / 47 (2.13%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	1 / 188 (0.53%)
Osteoarthritis ^{† A}	0 / 47 (0%)	0 / 47 (0%)	1 / 47 (2.13%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	1 / 188 (0.53%)
Sjogren's syndrome ^{† A}	0 / 47 (0%)	1 / 47 (2.13%)	0 / 47 (0%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	1 / 188 (0.53%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer metastatic ^{† A}	1 / 47 (2.13%)	0 / 47 (0%)	0 / 47 (0%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	1 / 188 (0.53%)
Extranodal marginal zone B-cell lymphoma (MALT type) ^{† A}	0 / 47 (0%)	0 / 47 (0%)	1 / 47 (2.13%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	1 / 188 (0.53%)
Nervous system disorders
Migraine ^{† A}	0 / 47 (0%)	0 / 47 (0%)	0 / 47 (0%)	0 / 26 (0%)	1 / 21 (4.76%)	1 / 47 (2.13%)	1 / 188 (0.53%)
Seizure ^{† A}	0 / 47 (0%)	1 / 47 (2.13%)	0 / 47 (0%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	1 / 188 (0.53%)
Syncope ^{† A}	0 / 47 (0%)	1 / 47 (2.13%)	0 / 47 (0%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	1 / 188 (0.53%)
Product Issues
Device breakage ^{† A}	0 / 47 (0%)	0 / 47 (0%)	0 / 47 (0%)	1 / 26 (3.85%)	0 / 21 (0%)	1 / 47 (2.13%)	1 / 188 (0.53%)
Renal and urinary disorders
Renal colic ^{† A}	0 / 47 (0%)	0 / 47 (0%)	1 / 47 (2.13%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	1 / 188 (0.53%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism ^{† A}	0 / 47 (0%)	0 / 47 (0%)	0 / 47 (0%)	1 / 26 (3.85%)	0 / 21 (0%)	1 / 47 (2.13%)	1 / 188 (0.53%)
Skin and subcutaneous tissue disorders
Pruritus ^{† A}	0 / 47 (0%)	0 / 47 (0%)	0 / 47 (0%)	1 / 26 (3.85%)	0 / 21 (0%)	1 / 47 (2.13%)	1 / 188 (0.53%)
Rash ^{† A}	0 / 47 (0%)	0 / 47 (0%)	1 / 47 (2.13%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	1 / 188 (0.53%)
Vascular disorders
Vasculitis ^{† A}	0 / 47 (0%)	0 / 47 (0%)	1 / 47 (2.13%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	1 / 188 (0.53%)
†Indicates events were collected by systematic assessment. ATerm from vocabulary, MedDRA (24.0)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	VAY736 5 mg 24 Weeks	VAY736 50 mg 24 Weeks	VAY736 150 mg 28 Weeks	VAY736 300 mg 24 Weeks	VAY736 300 mg 52 Weeks	Any VAY736 300 mg	Any VAY736
	Affected / At Risk (%)	Affected / At Risk (%)	Affected / At Risk (%)	Affected / At Risk (%)	Affected / At Risk (%)	Affected / At Risk (%)	Affected / At Risk (%)
Total	41 / 47 (87.23%)	37 / 47 (78.72%)	41 / 47 (87.23%)	24 / 26 (92.31%)	20 / 21 (95.24%)	44 / 47 (93.62%)	163 / 188 (86.7%)
Blood and lymphatic system disorders
Iron deficiency anaemia ^{† A}	1 / 47 (2.13%)	3 / 47 (6.38%)	0 / 47 (0%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	4 / 188 (2.13%)
Leukopenia ^{† A}	3 / 47 (6.38%)	2 / 47 (4.26%)	4 / 47 (8.51%)	2 / 26 (7.69%)	4 / 21 (19.05%)	6 / 47 (12.77%)	15 / 188 (7.98%)
Lymphopenia ^{† A}	4 / 47 (8.51%)	4 / 47 (8.51%)	3 / 47 (6.38%)	1 / 26 (3.85%)	1 / 21 (4.76%)	2 / 47 (4.26%)	13 / 188 (6.91%)
Neutropenia ^{† A}	5 / 47 (10.64%)	1 / 47 (2.13%)	2 / 47 (4.26%)	2 / 26 (7.69%)	2 / 21 (9.52%)	4 / 47 (8.51%)	12 / 188 (6.38%)
Ear and labyrinth disorders
Vertigo ^{† A}	1 / 47 (2.13%)	1 / 47 (2.13%)	1 / 47 (2.13%)	0 / 26 (0%)	2 / 21 (9.52%)	2 / 47 (4.26%)	5 / 188 (2.66%)
Gastrointestinal disorders
Abdominal pain ^{† A}	0 / 47 (0%)	3 / 47 (6.38%)	1 / 47 (2.13%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	4 / 188 (2.13%)
Diarrhoea ^{† A}	3 / 47 (6.38%)	3 / 47 (6.38%)	2 / 47 (4.26%)	3 / 26 (11.54%)	4 / 21 (19.05%)	7 / 47 (14.89%)	15 / 188 (7.98%)
Dyspepsia ^{† A}	1 / 47 (2.13%)	0 / 47 (0%)	0 / 47 (0%)	2 / 26 (7.69%)	0 / 21 (0%)	2 / 47 (4.26%)	3 / 188 (1.6%)
Gastrooesophageal reflux disease ^{† A}	1 / 47 (2.13%)	4 / 47 (8.51%)	0 / 47 (0%)	0 / 26 (0%)	1 / 21 (4.76%)	1 / 47 (2.13%)	6 / 188 (3.19%)
Mouth ulceration ^{† A}	1 / 47 (2.13%)	0 / 47 (0%)	0 / 47 (0%)	2 / 26 (7.69%)	0 / 21 (0%)	2 / 47 (4.26%)	3 / 188 (1.6%)
Vomiting ^{† A}	1 / 47 (2.13%)	1 / 47 (2.13%)	1 / 47 (2.13%)	2 / 26 (7.69%)	0 / 21 (0%)	2 / 47 (4.26%)	5 / 188 (2.66%)
General disorders
Asthenia ^{† A}	0 / 47 (0%)	0 / 47 (0%)	0 / 47 (0%)	2 / 26 (7.69%)	0 / 21 (0%)	2 / 47 (4.26%)	2 / 188 (1.06%)
Influenza like illness ^{† A}	0 / 47 (0%)	4 / 47 (8.51%)	1 / 47 (2.13%)	2 / 26 (7.69%)	2 / 21 (9.52%)	4 / 47 (8.51%)	9 / 188 (4.79%)
Injection site reaction ^{† A}	4 / 47 (8.51%)	9 / 47 (19.15%)	17 / 47 (36.17%)	13 / 26 (50%)	14 / 21 (66.67%)	27 / 47 (57.45%)	57 / 188 (30.32%)
Oedema peripheral ^{† A}	0 / 47 (0%)	2 / 47 (4.26%)	0 / 47 (0%)	2 / 26 (7.69%)	1 / 21 (4.76%)	3 / 47 (6.38%)	5 / 188 (2.66%)
Pyrexia ^{† A}	0 / 47 (0%)	1 / 47 (2.13%)	3 / 47 (6.38%)	3 / 26 (11.54%)	0 / 21 (0%)	3 / 47 (6.38%)	7 / 188 (3.72%)
Infections and infestations
Acute sinusitis ^{† A}	3 / 47 (6.38%)	0 / 47 (0%)	2 / 47 (4.26%)	0 / 26 (0%)	1 / 21 (4.76%)	1 / 47 (2.13%)	6 / 188 (3.19%)
Bronchitis ^{† A}	3 / 47 (6.38%)	3 / 47 (6.38%)	4 / 47 (8.51%)	2 / 26 (7.69%)	2 / 21 (9.52%)	4 / 47 (8.51%)	14 / 188 (7.45%)
Conjunctivitis ^{† A}	3 / 47 (6.38%)	5 / 47 (10.64%)	2 / 47 (4.26%)	2 / 26 (7.69%)	0 / 21 (0%)	2 / 47 (4.26%)	12 / 188 (6.38%)
Cystitis ^{† A}	0 / 47 (0%)	1 / 47 (2.13%)	2 / 47 (4.26%)	2 / 26 (7.69%)	1 / 21 (4.76%)	3 / 47 (6.38%)	6 / 188 (3.19%)
Gastroenteritis ^{† A}	1 / 47 (2.13%)	2 / 47 (4.26%)	1 / 47 (2.13%)	2 / 26 (7.69%)	1 / 21 (4.76%)	3 / 47 (6.38%)	7 / 188 (3.72%)
Influenza ^{† A}	0 / 47 (0%)	1 / 47 (2.13%)	0 / 47 (0%)	1 / 26 (3.85%)	3 / 21 (14.29%)	4 / 47 (8.51%)	5 / 188 (2.66%)
Nasopharyngitis ^{† A}	7 / 47 (14.89%)	4 / 47 (8.51%)	11 / 47 (23.4%)	5 / 26 (19.23%)	4 / 21 (19.05%)	9 / 47 (19.15%)	31 / 188 (16.49%)
Oral candidiasis ^{† A}	0 / 47 (0%)	0 / 47 (0%)	1 / 47 (2.13%)	2 / 26 (7.69%)	1 / 21 (4.76%)	3 / 47 (6.38%)	4 / 188 (2.13%)
Oral herpes ^{† A}	4 / 47 (8.51%)	2 / 47 (4.26%)	2 / 47 (4.26%)	1 / 26 (3.85%)	3 / 21 (14.29%)	4 / 47 (8.51%)	12 / 188 (6.38%)
Parotitis ^{† A}	2 / 47 (4.26%)	0 / 47 (0%)	3 / 47 (6.38%)	1 / 26 (3.85%)	0 / 21 (0%)	1 / 47 (2.13%)	6 / 188 (3.19%)
Sinusitis ^{† A}	5 / 47 (10.64%)	3 / 47 (6.38%)	7 / 47 (14.89%)	2 / 26 (7.69%)	1 / 21 (4.76%)	3 / 47 (6.38%)	18 / 188 (9.57%)
Tracheobronchitis ^{† A}	1 / 47 (2.13%)	0 / 47 (0%)	0 / 47 (0%)	1 / 26 (3.85%)	2 / 21 (9.52%)	3 / 47 (6.38%)	4 / 188 (2.13%)
Upper respiratory tract infection ^{† A}	7 / 47 (14.89%)	9 / 47 (19.15%)	7 / 47 (14.89%)	8 / 26 (30.77%)	2 / 21 (9.52%)	10 / 47 (21.28%)	33 / 188 (17.55%)
Urinary tract infection ^{† A}	9 / 47 (19.15%)	5 / 47 (10.64%)	7 / 47 (14.89%)	2 / 26 (7.69%)	3 / 21 (14.29%)	5 / 47 (10.64%)	26 / 188 (13.83%)
Viral upper respiratory tract infection ^{† A}	1 / 47 (2.13%)	1 / 47 (2.13%)	0 / 47 (0%)	2 / 26 (7.69%)	0 / 21 (0%)	2 / 47 (4.26%)	4 / 188 (2.13%)
Injury, poisoning and procedural complications
Animal bite ^{† A}	0 / 47 (0%)	0 / 47 (0%)	0 / 47 (0%)	1 / 26 (3.85%)	2 / 21 (9.52%)	3 / 47 (6.38%)	3 / 188 (1.6%)
Arthropod bite ^{† A}	0 / 47 (0%)	2 / 47 (4.26%)	1 / 47 (2.13%)	0 / 26 (0%)	2 / 21 (9.52%)	2 / 47 (4.26%)	5 / 188 (2.66%)
Fall ^{† A}	0 / 47 (0%)	0 / 47 (0%)	2 / 47 (4.26%)	1 / 26 (3.85%)	2 / 21 (9.52%)	3 / 47 (6.38%)	5 / 188 (2.66%)
Injection related reaction ^{† A}	6 / 47 (12.77%)	5 / 47 (10.64%)	7 / 47 (14.89%)	2 / 26 (7.69%)	2 / 21 (9.52%)	4 / 47 (8.51%)	22 / 188 (11.7%)
Wound ^{† A}	0 / 47 (0%)	1 / 47 (2.13%)	0 / 47 (0%)	0 / 26 (0%)	2 / 21 (9.52%)	2 / 47 (4.26%)	3 / 188 (1.6%)
Investigations
Blood creatinine increased ^{† A}	3 / 47 (6.38%)	1 / 47 (2.13%)	1 / 47 (2.13%)	1 / 26 (3.85%)	0 / 21 (0%)	1 / 47 (2.13%)	6 / 188 (3.19%)
Lymphocyte count decreased ^{† A}	4 / 47 (8.51%)	0 / 47 (0%)	1 / 47 (2.13%)	0 / 26 (0%)	2 / 21 (9.52%)	2 / 47 (4.26%)	7 / 188 (3.72%)
Neutrophil count decreased ^{† A}	3 / 47 (6.38%)	0 / 47 (0%)	1 / 47 (2.13%)	1 / 26 (3.85%)	1 / 21 (4.76%)	2 / 47 (4.26%)	6 / 188 (3.19%)
White blood cell count decreased ^{† A}	3 / 47 (6.38%)	1 / 47 (2.13%)	0 / 47 (0%)	1 / 26 (3.85%)	1 / 21 (4.76%)	2 / 47 (4.26%)	6 / 188 (3.19%)
Musculoskeletal and connective tissue disorders
Arthralgia ^{† A}	3 / 47 (6.38%)	1 / 47 (2.13%)	6 / 47 (12.77%)	2 / 26 (7.69%)	3 / 21 (14.29%)	5 / 47 (10.64%)	15 / 188 (7.98%)
Back pain ^{† A}	3 / 47 (6.38%)	4 / 47 (8.51%)	6 / 47 (12.77%)	4 / 26 (15.38%)	2 / 21 (9.52%)	6 / 47 (12.77%)	19 / 188 (10.11%)
Joint swelling ^{† A}	2 / 47 (4.26%)	0 / 47 (0%)	0 / 47 (0%)	2 / 26 (7.69%)	1 / 21 (4.76%)	3 / 47 (6.38%)	5 / 188 (2.66%)
Muscle spasms ^{† A}	0 / 47 (0%)	2 / 47 (4.26%)	0 / 47 (0%)	0 / 26 (0%)	2 / 21 (9.52%)	2 / 47 (4.26%)	4 / 188 (2.13%)
Myalgia ^{† A}	2 / 47 (4.26%)	0 / 47 (0%)	4 / 47 (8.51%)	1 / 26 (3.85%)	2 / 21 (9.52%)	3 / 47 (6.38%)	9 / 188 (4.79%)
Osteoarthritis ^{† A}	0 / 47 (0%)	0 / 47 (0%)	0 / 47 (0%)	2 / 26 (7.69%)	0 / 21 (0%)	2 / 47 (4.26%)	2 / 188 (1.06%)
Pain in extremity ^{† A}	3 / 47 (6.38%)	4 / 47 (8.51%)	2 / 47 (4.26%)	2 / 26 (7.69%)	0 / 21 (0%)	2 / 47 (4.26%)	11 / 188 (5.85%)
Sjogren's syndrome ^{† A}	0 / 47 (0%)	4 / 47 (8.51%)	1 / 47 (2.13%)	0 / 26 (0%)	2 / 21 (9.52%)	2 / 47 (4.26%)	7 / 188 (3.72%)
Nervous system disorders
Dizziness ^{† A}	2 / 47 (4.26%)	1 / 47 (2.13%)	0 / 47 (0%)	2 / 26 (7.69%)	2 / 21 (9.52%)	4 / 47 (8.51%)	7 / 188 (3.72%)
Headache ^{† A}	5 / 47 (10.64%)	5 / 47 (10.64%)	4 / 47 (8.51%)	4 / 26 (15.38%)	2 / 21 (9.52%)	6 / 47 (12.77%)	20 / 188 (10.64%)
Polyneuropathy ^{† A}	0 / 47 (0%)	0 / 47 (0%)	0 / 47 (0%)	2 / 26 (7.69%)	0 / 21 (0%)	2 / 47 (4.26%)	2 / 188 (1.06%)
Psychiatric disorders
Insomnia ^{† A}	0 / 47 (0%)	0 / 47 (0%)	3 / 47 (6.38%)	0 / 26 (0%)	3 / 21 (14.29%)	3 / 47 (6.38%)	6 / 188 (3.19%)
Renal and urinary disorders
Dysuria ^{† A}	0 / 47 (0%)	0 / 47 (0%)	1 / 47 (2.13%)	2 / 26 (7.69%)	0 / 21 (0%)	2 / 47 (4.26%)	3 / 188 (1.6%)
Respiratory, thoracic and mediastinal disorders
Cough ^{† A}	3 / 47 (6.38%)	0 / 47 (0%)	2 / 47 (4.26%)	2 / 26 (7.69%)	0 / 21 (0%)	2 / 47 (4.26%)	7 / 188 (3.72%)
Nasal congestion ^{† A}	0 / 47 (0%)	0 / 47 (0%)	0 / 47 (0%)	2 / 26 (7.69%)	0 / 21 (0%)	2 / 47 (4.26%)	2 / 188 (1.06%)
Oropharyngeal pain ^{† A}	0 / 47 (0%)	0 / 47 (0%)	1 / 47 (2.13%)	0 / 26 (0%)	2 / 21 (9.52%)	2 / 47 (4.26%)	3 / 188 (1.6%)
Productive cough ^{† A}	0 / 47 (0%)	0 / 47 (0%)	1 / 47 (2.13%)	2 / 26 (7.69%)	0 / 21 (0%)	2 / 47 (4.26%)	3 / 188 (1.6%)
Skin and subcutaneous tissue disorders
Pruritus ^{† A}	2 / 47 (4.26%)	1 / 47 (2.13%)	2 / 47 (4.26%)	2 / 26 (7.69%)	1 / 21 (4.76%)	3 / 47 (6.38%)	8 / 188 (4.26%)
Rash ^{† A}	6 / 47 (12.77%)	3 / 47 (6.38%)	2 / 47 (4.26%)	2 / 26 (7.69%)	2 / 21 (9.52%)	4 / 47 (8.51%)	15 / 188 (7.98%)
Vascular disorders
Hypertension ^{† A}	4 / 47 (8.51%)	2 / 47 (4.26%)	2 / 47 (4.26%)	0 / 26 (0%)	0 / 21 (0%)	0 / 47 (0%)	8 / 188 (4.26%)
†Indicates events were collected by systematic assessment. ATerm from vocabulary, MedDRA (24.0)

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Certain Agreements:
Principal Investigators are NOT employed by the organization sponsoring the study. There IS an agreement between the Principal Investigator and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.
Results Point of Contact:
Name/Official Title:	Study Director
Organization:	Novartis Pharmaceuticals
Phone:	+1 (862) 778-8300
Email:	novartis.email@novartis.com