CVAY736X2201: PD of VAY736 in Patients With Primary Sjögren's Syndrome

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02149420
• Collaborator: (none)
• Enrollment: 27
• Location: 1
• Arms: 3
• Actual Duration (Months): 44.6
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

This study was designed to evaluate the safety, tolerability, pharmacokinetics and therapeutic efficacy of a single intravenous infusion of VAY7346 monoclonal antibody in pSS patients

Condition or Disease	Intervention/Treatment	Phase
Primary Sjögren's Syndrome	Drug: VAY736; Drug: Placebo	Phase 2

Detailed Description

Patients were enrolled in 2 sequential cohorts:

Cohort 1: 6 patients received 3 mg/kg or Placebo (2:1 ratio) Cohort 2: 21 patients received 10 mg/kg, 3 mg/kg or Placebo (6:1:3 ratio)

At week 24 the blind was broken to assess continuation in the trial:

• If a patient received VAY736 and their B cell recovery was demonstrated at Week 24, then patients completed the trial.

• If a patient received VAY736 and their B cell recovery was NOT demonstrated at Week 24, then patients were followed up until B cell recovery was demonstrated

• If a patient received placebo, they were offered the option of receiving open-label VAY736 (10 mg/kg) in a separate treatment arm.

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Treatment was unblinded at an individual patient level at Week 24 to determine their progress in the study (follow-up, open-label VAY736 or End of Study Visit).
• Primary Purpose: Treatment
• Official Title: A Single Dose, Double-blind, Placebo-controlled, Parallel Study to Assess the Pharmacodynamics, Pharmacokinetics and Safety and Tolerability of VAY736 in Patients With Primary Sjögren's Syndrome
• Actual Study Start Date: May 23, 2014
• Actual Primary Completion Date: Feb 7, 2018
• Actual Study Completion Date: Feb 7, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: VAY736 3 mg/kg single dose iv of VAY736 at a dose of 3mg/kg	Drug: VAY736
Experimental: VAY736 10 mg/kg single dose iv of VAY736 at a dose of 10mg/kg	Drug: VAY736
Placebo Comparator: Placebo single dose iv of Placebo. At Week 24 patients were offered to receive open label VAY736 10 mg/kg.	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Change in EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) [Baseline, week 12]

   The effect of VAY736 on clinical disease activity was measured by the change in ESSDAI (EULAR Sjögren's syndrome disease activity index) between baseline and week 12. The instrument contains 12 organ-specific domains contributing to disease activity. For each domain, features of disease activity are scored in 3 or 4 levels according to their severity. These scores are then summed across the 12 domains in a weighted manner to provide the total score (range 0-123). A reduction from baseline indicates improvement in patients.

2. Overall Incidence of Adverse Events [Baseline to Week 24]

   Number of subjects with Adverse Events during the double blind treatment period.

Secondary Outcome Measures

1. Change in EULAR Sjögren's Syndrome Patient Response Index (ESSPRI) [Baseline, week 12]

   The ESSPRI is a patient self-reported outcome measure to assess dryness, limb pain, fatigue and mental fatigue, where each of the domains normally reported as 0 (not at all) to 10 (extremely severe). The final ESSPRI score is the average of three: dryness, pain and fatigue. A reduction from baseline indicates the improvement of symptoms. During the study all individual scores were reported as 1 to 10 instead. A linear transformation was reported to map the scores to the range of 0-10.

2. Change in Short Form (36) Health Survey (SF-36) [Baseline, week 12]

   The SF-36 is a 36-item, patient self-reported outcome measure (questionnaires) of patient health. The outcome of the questionnaires in eight scales results in two summary scores, physical component and mental component, both ranging from 0 - 100. An increase from baseline in either component summary score indicates reduced disease burden.

3. Change in Multidimensional Fatigue Inventory (MFI) [Baseline, week 12]

   The MFI is a patient self-reported outcome measure (questionnaires) to assess fatigue covering the following dimensions: General Fatigue, Physical Fatigue, Mental Fatigue, Reduced Motivation and Reduced Activity. Each dimension has a posible range from 4-20. A reduction from baseline in MFI indicates improvement.

4. Change in the Physician's Global Assessment of Overall Disease Activity by Means of Visual Analog Scale (VAS) [Baseline, week 12]

   The visual analogue scale used is a 100 mm VAS ranging from "no disease" (0 mm) to "maximal disease activity" (100 mm).

5. Change in the Patient's Global Assessment of Overall Disease Activity by Means of Visual Analog Scale (VAS) [Baseline, week 12]

   The visual analogue scale used is a 100 mm VAS ranging from "no disease" (0 mm) to "maximal disease activity" (100 mm).

6. VAY736 Serum Concentration - AUCinf [0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks.]

   The area under the serum concentration-time curve from time zero to infinity [mass × time / volume]. The concentration of VAY736 was measured in the serum.

7. VAY736 Serum Concentration - AUClast [0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks.]

   The area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration [mass × time / volume]. The concentration of VAY736 was measured in the serum.

8. VAY736 Serum Concentration - CL [0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks.]

   The systemic (or total body) clearance from serum following intravenous administration [volume / time]. The concentration of VAY736 was measured in the serum.

9. VAY736 Serum Concentration - Cmax [0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks.]

   The observed maximum serum concentration following drug administration [mass / volume]. The concentration of VAY736 was measured in the serum.

10. VAY736 Serum Concentration - T1/2 [0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks.]

    Apparent terminal half-life, determined as the ln2/lambda_z or 0.693/lambda_z. The concentration of VAY736 was measured in the serum.

11. VAY736 Serum Concentration - Tmax [0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks.]

    The time to reach the maximum concentration after drug administration [time]. The concentration of VAY736 was measured in the serum.

12. VAY736 Serum Concentration - Vz [0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks.]

    The volume of distribution during the terminal elimination phase following intravenous administration [volume]. The concentration of VAY736 was measured in the serum.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

INCLUSION CRITERIA:

• Fulfilled revised European US consensus criteria for pSS

• ESSDAI value ≥ 6

• Elevated serum titers at screening of ANA (≥ 1:160)

• Seropositive at screening for anti-SSA and/or anti-SSB antibodies

• Stimulated whole salivary flow rate at screening of > 0 mL/min

EXCLUSION CRITERIA:

• Prior or previous use of (specific dosages and intervals prior to study start may apply): B-cell depleting therapy (e.g., rituximab), Prednisone, anti-BAFF mAb, CTLA4-Fc Ig (abatacept), anti-TNF-α mAb, cyclophosphamide, azathioprine and medications known to cause dry mouth.

Hydroxychloroquine or methotrexate in a consistent dose for ≥ 3 months prior to randomization is allowed

• Active or recent history of clinically significant infection

• Vaccination within 2 month prior to study

• History of primary or secondary immunodeficiency

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Berlin		Germany	10117

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Oct 31, 2016
• Statistical Analysis Plan - Jan 11, 2017

More Information

Additional Information:

• A Plain Language Trial Summary is available on novartisclinicaltrials.com

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02149420
• Other Study ID Numbers: CVAY736X2201; 2013-000250-22
• First Posted: May 29, 2014
• Last Update Posted: Oct 4, 2021
• Last Verified: Sep 1, 2021

• Keywords provided by Novartis Pharmaceuticals: primary Sjögren's syndrome, pharmacodynamics
• Additional relevant MeSH terms: Sjogren's Syndrome; Syndrome

Study Results

Participant Flow

Recruitment Details	A total of 27 patients were enrolled and randomized into the study at one site in Germany.
Pre-assignment Detail	The patients were enrolled in 2 sequential cohorts: Cohort 1: Six patients were randomized to receive a single dose iv of VAY736 at a dose of 3mg/kg or placebo at a 2:1 ratio. Cohort 2: Twenty one patients were randomized to receive a single iv dose of VAY736 at a dose of 10.0 mg/kg or 3.0 mg/kg or placebo at a 6:1:3 ratio.

Arm/Group Title	Placebo	VAY736 3 mg/kg	VAY736 10 mg/kg
Arm/Group Description	single dose iv of Placebo (+ Option to receive Open label VAY736 10 mg/kg at Week 24)	single dose iv of VAY736 at a dose of 3mg/kg	single dose iv of VAY736 at a dose of 10mg/kg
Period Title: Core Study
STARTED	9	6	12
Safety Analysis Set	9	6	12
PK Analysis Set	5	6	12
PD (Pharmacodynamics) Analysis Set	9	6	12
COMPLETED	9	5	10
NOT COMPLETED	0	1	2
Period Title: Core Study
STARTED	5	0	0
COMPLETED	4	0	0
NOT COMPLETED	1	0	0

Baseline Characteristics

Arm/Group Title	Placebo	VAY736 3 mg/kg	VAY736 10 mg/kg	Total
Arm/Group Description	single dose iv of Placebo	single dose iv of VAY736 at a dose of 3mg/kg	single dose iv of VAY736 at a dose of 10mg/kg	Total of all reporting groups
Overall Participants	9	6	12	27
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	46.7 (11.29)	46.8 (8.75)	55.3 (13.35)	50.5 (12.16)
Sex: Female, Male (Count of Participants)
Female	7 77.8%	5 83.3%	11 91.7%	23 85.2%
Male	2 22.2%	1 16.7%	1 8.3%	4 14.8%
Race/Ethnicity, Customized (Number) [Number]
Caucasian	9 100%	6 100%	12 100%	27 100%

Outcome Measures

1. Primary Outcome

Title	Change in EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI)
Description	The effect of VAY736 on clinical disease activity was measured by the change in ESSDAI (EULAR Sjögren's syndrome disease activity index) between baseline and week 12. The instrument contains 12 organ-specific domains contributing to disease activity. For each domain, features of disease activity are scored in 3 or 4 levels according to their severity. These scores are then summed across the 12 domains in a weighted manner to provide the total score (range 0-123). A reduction from baseline indicates improvement in patients.
Time Frame	Baseline, week 12

Outcome Measure Data

Analysis Population Description

PD analysis set

Arm/Group Title	Placebo	VAY736 3 mg/kg	VAY736 10 mg/kg	VAY736 Combined
Arm/Group Description	single dose iv of Placebo	single dose iv of VAY736 at a dose of 3mg/kg	single dose iv of VAY736 at a dose of 10mg/kg	Combining VAY736 3mg/kg and VAY736 10mg/kg
Measure Participants	9	6	12	18
Baseline	11.1 (4.08)	14.5 (9.44)	11.5 (4.38)	12.5 (6.38)
Week 12	10.2 (5.29)	10.7 (7.69)	10.0 (5.36)	10.2 (6.01)
Change from Baseline to Week 12	-0.9 (2.98)	-3.8 (8.66)	-1.5 (3.00)	-2.3 (5.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, VAY736 Combined
	Comments	Per protocol the primary analysis was between placebo and the combined VAY736 groups at Week 12.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.678
	Comments
	Method	repeated measures Bayesian analysis
	Comments	with baseline as a covariate
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.93
	Confidence Interval	(2-Sided) 95%; -5.007 to 3.180
	Parameter Dispersion	Type: Standard Deviation; Value: 2.058
	Estimation Comments

2. Secondary Outcome

Title	Change in EULAR Sjögren's Syndrome Patient Response Index (ESSPRI)
Description	The ESSPRI is a patient self-reported outcome measure to assess dryness, limb pain, fatigue and mental fatigue, where each of the domains normally reported as 0 (not at all) to 10 (extremely severe). The final ESSPRI score is the average of three: dryness, pain and fatigue. A reduction from baseline indicates the improvement of symptoms. During the study all individual scores were reported as 1 to 10 instead. A linear transformation was reported to map the scores to the range of 0-10.
Time Frame	Baseline, week 12

Outcome Measure Data

Analysis Population Description

PD analysis set

Arm/Group Title	Placebo	VAY736 3 mg/kg	VAY736 10 mg/kg
Arm/Group Description	single dose iv of Placebo	single dose iv of VAY736 at a dose of 3mg/kg	single dose iv of VAY736 at a dose of 10mg/kg
Measure Participants	9	6	12
Baseline	5.967 (2.2179)	6.049 (1.2759)	6.235 (1.5379)
Week 12	5.926 (1.5822)	6.173 (1.4753)	4.568 (2.5966)
Change from Baseline to Week 12	-0.041 (1.7805)	0.123 (1.0120)	-1.667 (1.8918)

3. Secondary Outcome

Title	Change in Short Form (36) Health Survey (SF-36)
Description	The SF-36 is a 36-item, patient self-reported outcome measure (questionnaires) of patient health. The outcome of the questionnaires in eight scales results in two summary scores, physical component and mental component, both ranging from 0 - 100. An increase from baseline in either component summary score indicates reduced disease burden.
Time Frame	Baseline, week 12

Outcome Measure Data

Analysis Population Description

PD analysis set

Arm/Group Title	Placebo	VAY736 3 mg/kg	VAY736 10 mg/kg
Arm/Group Description	single dose iv of Placebo	single dose iv of VAY736 at a dose of 3mg/kg	single dose iv of VAY736 at a dose of 10mg/kg
Measure Participants	9	6	12
Physical component score: Baseline	46.886 (6.3905)	39.445 (4.2857)	46.015 (9.3533)
Physical component score: Week 12	44.788 (8.3513)	45.493 (7.3060)	47.671 (9.2804)
Physical component score: Change from Baseline	-2.098 (7.9084)	6.048 (4.7189)	1.656 (5.4113)
Mental component score: Baseline	36.913 (15.2776)	37.517 (6.8994)	43.628 (11.3667)
Mental component score: Week 12	41.012 (13.2991)	40.170 (11.9815)	46.700 (11.3182)
Mental component score: Change from Baseline	4.099 (5.3361)	2.653 (17.1261)	3.073 (11.5823)

4. Secondary Outcome

Title	Change in Multidimensional Fatigue Inventory (MFI)
Description	The MFI is a patient self-reported outcome measure (questionnaires) to assess fatigue covering the following dimensions: General Fatigue, Physical Fatigue, Mental Fatigue, Reduced Motivation and Reduced Activity. Each dimension has a posible range from 4-20. A reduction from baseline in MFI indicates improvement.
Time Frame	Baseline, week 12

Outcome Measure Data

Analysis Population Description

PD analysis set

Arm/Group Title	Placebo	VAY736 3 mg/kg	VAY736 10 mg/kg
Arm/Group Description	single dose iv of Placebo	single dose iv of VAY736 at a dose of 3mg/kg	single dose iv of VAY736 at a dose of 10mg/kg
Measure Participants	9	6	12
General Fatigue: Baseline	14.0 (4.72)	17.0 (2.37)	15.9 (3.34)
General Fatigue: Week 12	12.8 (4.84)	14.2 (6.40)	12.4 (3.99)
General Fatigue: Change from Baseline	-1.2 (1.64)	-2.8 (5.04)	-3.5 (4.12)
Physical Fatigue: Baseline	12.9 (4.14)	15.7 (2.34)	14.2 (3.41)
Physical Fatigue: Week 12	12.2 (3.99)	11.2 (5.15)	10.4 (4.66)
Physical Fatigue: Change from Baseline	-0.7 (1.32)	-4.5 (6.57)	-3.8 (4.77)
Mental Fatigue: Baseline	11.9 (4.78)	14.3 (3.78)	13.0 (3.28)
Mental Fatigue: Week 12	11.7 (4.12)	11.3 (4.18)	9.8 (5.17)
Mental Fatigue: Change from Baseline	-0.2 (2.95)	-3.0 (6.07)	-3.2 (5.84)
Reduced motivation: Baseline	12.4 (4.93)	12.3 (3.93)	10.9 (2.68)
Reduced motivation: Week 12	12.0 (5.32)	10.0 (4.52)	9.8 (4.97)
Reduced motivation: Change from Baseline	-0.4 (2.40)	-2.3 (4.50)	-1.1 (4.56)
Reduced activity: Baseline	11.8 (2.86)	10.8 (1.72)	12.2 (2.69)
Reduced activity: Week 12	10.4 (3.81)	8.7 (3.61)	9.3 (5.08)
Reduced activity: Change from Baseline	-1.3 (1.80)	-2.2 (4.83)	-2.9 (4.25)

5. Secondary Outcome

Title	Change in the Physician's Global Assessment of Overall Disease Activity by Means of Visual Analog Scale (VAS)
Description	The visual analogue scale used is a 100 mm VAS ranging from "no disease" (0 mm) to "maximal disease activity" (100 mm).
Time Frame	Baseline, week 12

Outcome Measure Data

Analysis Population Description

PD analysis set

Arm/Group Title	Placebo	VAY736 3 mg/kg	VAY736 10 mg/kg
Arm/Group Description	single dose iv of Placebo	single dose iv of VAY736 at a dose of 3mg/kg	single dose iv of VAY736 at a dose of 10mg/kg
Measure Participants	9	6	12
Baseline	57.3 (17.73)	66.2 (17.53)	65.0 (11.74)
Week 12	59.8 (23.35)	43.0 (23.82)	48.5 (17.33)
Change from Baseline to Week 12	2.4 (12.21)	-23.2 (31.10)	-16.5 (18.96)

6. Secondary Outcome

Title	Change in the Patient's Global Assessment of Overall Disease Activity by Means of Visual Analog Scale (VAS)
Description	The visual analogue scale used is a 100 mm VAS ranging from "no disease" (0 mm) to "maximal disease activity" (100 mm).
Time Frame	Baseline, week 12

Outcome Measure Data

Analysis Population Description

PD analysis set

Arm/Group Title	Placebo	VAY736 3 mg/kg	VAY736 10 mg/kg
Arm/Group Description	single dose iv of Placebo	single dose iv of VAY736 at a dose of 3mg/kg	single dose iv of VAY736 at a dose of 10mg/kg
Measure Participants	9	6	12
Baseline	56.2 (24.86)	67.2 (13.69)	59.8 (24.30)
Week 12	55.2 (21.57)	44.2 (22.75)	40.8 (20.49)
Change from Baseline to Week 12	-1.0 (17.71)	-23.0 (25.73)	-19.0 (21.08)

7. Secondary Outcome

Title	VAY736 Serum Concentration - AUCinf
Description	The area under the serum concentration-time curve from time zero to infinity [mass × time / volume]. The concentration of VAY736 was measured in the serum.
Time Frame	0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks.

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	VAY736 3 mg/kg	VAY736 10 mg/kg	Open Label VAY736
Arm/Group Description	single dose iv of VAY736 at a dose of 3mg/kg	single dose iv of VAY736 at a dose of 10mg/kg	Open label VAY736 10mg/kg
Measure Participants	6	12	5
Median (Full Range) [day*ug/mL]	389	1140	971

8. Secondary Outcome

Title	VAY736 Serum Concentration - AUClast
Description	The area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration [mass × time / volume]. The concentration of VAY736 was measured in the serum.
Time Frame	0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks.

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	VAY736 3 mg/kg	VAY736 10 mg/kg	Open Label VAY736
Arm/Group Description	single dose iv of VAY736 at a dose of 3mg/kg	single dose iv of VAY736 at a dose of 10mg/kg	Open label VAY736 10mg/kg
Measure Participants	6	12	5
Median (Full Range) [day*ug/mL]	385	1140	971

9. Secondary Outcome

Title	VAY736 Serum Concentration - CL
Description	The systemic (or total body) clearance from serum following intravenous administration [volume / time]. The concentration of VAY736 was measured in the serum.
Time Frame	0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks.

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	VAY736 3 mg/kg	VAY736 10 mg/kg	Open Label VAY736
Arm/Group Description	single dose iv of VAY736 at a dose of 3mg/kg	single dose iv of VAY736 at a dose of 10mg/kg	Open label VAY736 10mg/kg
Measure Participants	6	12	5
Median (Full Range) [L/day]	0.594	0.584	0.686

10. Secondary Outcome

Title	VAY736 Serum Concentration - Cmax
Description	The observed maximum serum concentration following drug administration [mass / volume]. The concentration of VAY736 was measured in the serum.
Time Frame	0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks.

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	VAY736 3 mg/kg	VAY736 10 mg/kg	Open Label VAY736
Arm/Group Description	single dose iv of VAY736 at a dose of 3mg/kg	single dose iv of VAY736 at a dose of 10mg/kg	Open label VAY736 10mg/kg
Measure Participants	6	12	5
Median (Full Range) [ug/mL]	65.0	213	205

11. Secondary Outcome

Title	VAY736 Serum Concentration - T1/2
Description	Apparent terminal half-life, determined as the ln2/lambda_z or 0.693/lambda_z. The concentration of VAY736 was measured in the serum.
Time Frame	0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks.

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	VAY736 3 mg/kg	VAY736 10 mg/kg	Open Label VAY736
Arm/Group Description	single dose iv of VAY736 at a dose of 3mg/kg	single dose iv of VAY736 at a dose of 10mg/kg	Open label VAY736 10mg/kg
Measure Participants	6	12	5
Median (Full Range) [days]	8.43	9.51	11.0

12. Secondary Outcome

Title	VAY736 Serum Concentration - Tmax
Description	The time to reach the maximum concentration after drug administration [time]. The concentration of VAY736 was measured in the serum.
Time Frame	0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks.

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	VAY736 3 mg/kg	VAY736 10 mg/kg	Open Label VAY736
Arm/Group Description	single dose iv of VAY736 at a dose of 3mg/kg	single dose iv of VAY736 at a dose of 10mg/kg	Open label VAY736 10mg/kg
Measure Participants	6	12	5
Median (Full Range) [hours]	2.03	2.03	2.10

13. Secondary Outcome

Title	VAY736 Serum Concentration - Vz
Description	The volume of distribution during the terminal elimination phase following intravenous administration [volume]. The concentration of VAY736 was measured in the serum.
Time Frame	0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks.

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	VAY736 3 mg/kg	VAY736 10 mg/kg	Open Label VAY736
Arm/Group Description	single dose iv of VAY736 at a dose of 3mg/kg	single dose iv of VAY736 at a dose of 10mg/kg	Open label VAY736 10mg/kg
Measure Participants	6	12	5
Median (Full Range) [L]	7.83	8.68	10.3

14. Primary Outcome

Title	Overall Incidence of Adverse Events
Description	Number of subjects with Adverse Events during the double blind treatment period.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Safety analysis set

Arm/Group Title	Placebo	VAY736 3 mg/kg	VAY736 10 mg/kg	VAY736 Combined
Arm/Group Description	single dose iv of Placebo	single dose iv of VAY736 at a dose of 3mg/kg	single dose iv of VAY736 at a dose of 10mg/kg	Combining VAY736 3mg/kg and VAY736 10mg/kg
Measure Participants	9	6	12	18
Subjects with AEs	8 88.9%	6 100%	11 91.7%	17 63%
Subjects with AEs within 24hr of infusion	2 22.2%	6 100%	11 91.7%	17 63%
Subjects with AEs post 24hr of infusion	8 88.9%	6 100%	8 66.7%	14 51.9%
Subjects with Study drug-related AEs	5 55.6%	6 100%	11 91.7%	17 63%
Subjects with Infusion related AEs	1 11.1%	6 100%	9 75%	15 55.6%

Adverse Events

Time Frame	Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date subject has provided informed consent until end of study (Week 28 or when B cell recovery was demonstrated, up to 3 years).
Adverse Event Reporting Description	All AEs were reported until week 52. After week 52 only AEs related to VAY736 and AEs related to infection, potential malignant events and neutropenia were recorded.
Arm/Group Title	Placebo		VAY736 3mg/kg		VAY736 10mg/kg		Open Label VAY736 10mg/kg
Arm/Group Description	Placebo		VAY736 3mg/kg		VAY736 10mg/kg		Open label VAY736 10mg/kg
All Cause Mortality
	Placebo		VAY736 3mg/kg		VAY736 10mg/kg		Open Label VAY736 10mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/6 (0%)		0/12 (0%)		0/5 (0%)
Serious Adverse Events
	Placebo		VAY736 3mg/kg		VAY736 10mg/kg		Open Label VAY736 10mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/9 (11.1%)		2/6 (33.3%)		0/12 (0%)		1/5 (20%)
Gastrointestinal disorders
Colitis	1/9 (11.1%)		0/6 (0%)		0/12 (0%)		0/5 (0%)
Inguinal hernia	0/9 (0%)		0/6 (0%)		0/12 (0%)		1/5 (20%)
Infections and infestations
Appendicitis	1/9 (11.1%)		0/6 (0%)		0/12 (0%)		0/5 (0%)
Injury, poisoning and procedural complications
Jaw fracture	0/9 (0%)		1/6 (16.7%)		0/12 (0%)		0/5 (0%)
Reproductive system and breast disorders
Ovarian cyst torsion	0/9 (0%)		1/6 (16.7%)		0/12 (0%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		VAY736 3mg/kg		VAY736 10mg/kg		Open Label VAY736 10mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/9 (100%)		6/6 (100%)		11/12 (91.7%)		5/5 (100%)
Blood and lymphatic system disorders
Iron deficiency anaemia	0/9 (0%)		0/6 (0%)		1/12 (8.3%)		0/5 (0%)
Cardiac disorders
Palpitations	0/9 (0%)		0/6 (0%)		0/12 (0%)		1/5 (20%)
Eye disorders
Chalazion	0/9 (0%)		1/6 (16.7%)		0/12 (0%)		0/5 (0%)
Keratitis	0/9 (0%)		1/6 (16.7%)		0/12 (0%)		0/5 (0%)
Vitreous detachment	1/9 (11.1%)		0/6 (0%)		0/12 (0%)		1/5 (20%)
Gastrointestinal disorders
Abdominal pain	0/9 (0%)		1/6 (16.7%)		0/12 (0%)		0/5 (0%)
Auriculotemporal syndrome	0/9 (0%)		1/6 (16.7%)		0/12 (0%)		0/5 (0%)
Noninfective sialoadenitis	1/9 (11.1%)		0/6 (0%)		0/12 (0%)		0/5 (0%)
Toothache	0/9 (0%)		0/6 (0%)		0/12 (0%)		1/5 (20%)
General disorders
Fatigue	0/9 (0%)		0/6 (0%)		1/12 (8.3%)		0/5 (0%)
Non-cardiac chest pain	2/9 (22.2%)		0/6 (0%)		0/12 (0%)		0/5 (0%)
Immune system disorders
Seasonal allergy	0/9 (0%)		1/6 (16.7%)		0/12 (0%)		0/5 (0%)
Infections and infestations
Bronchitis	0/9 (0%)		0/6 (0%)		0/12 (0%)		1/5 (20%)
Conjunctivitis	0/9 (0%)		0/6 (0%)		1/12 (8.3%)		1/5 (20%)
Cystitis	0/9 (0%)		0/6 (0%)		1/12 (8.3%)		0/5 (0%)
Gastroenteritis	0/9 (0%)		0/6 (0%)		1/12 (8.3%)		0/5 (0%)
Gastrointestinal infection	1/9 (11.1%)		0/6 (0%)		1/12 (8.3%)		0/5 (0%)
Influenza	0/9 (0%)		1/6 (16.7%)		1/12 (8.3%)		0/5 (0%)
Nasopharyngitis	2/9 (22.2%)		5/6 (83.3%)		4/12 (33.3%)		5/5 (100%)
Oral herpes	1/9 (11.1%)		0/6 (0%)		0/12 (0%)		0/5 (0%)
Otitis media	0/9 (0%)		1/6 (16.7%)		0/12 (0%)		1/5 (20%)
Sinusitis	1/9 (11.1%)		0/6 (0%)		1/12 (8.3%)		0/5 (0%)
Tooth infection	1/9 (11.1%)		1/6 (16.7%)		0/12 (0%)		0/5 (0%)
Urogenital infection bacterial	1/9 (11.1%)		0/6 (0%)		0/12 (0%)		0/5 (0%)
Injury, poisoning and procedural complications
Infusion related reaction	1/9 (11.1%)		6/6 (100%)		9/12 (75%)		3/5 (60%)
Ligament rupture	1/9 (11.1%)		0/6 (0%)		0/12 (0%)		0/5 (0%)
Limb injury	1/9 (11.1%)		0/6 (0%)		0/12 (0%)		0/5 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/9 (0%)		2/6 (33.3%)		0/12 (0%)		0/5 (0%)
Back pain	0/9 (0%)		0/6 (0%)		1/12 (8.3%)		0/5 (0%)
Musculoskeletal pain	0/9 (0%)		1/6 (16.7%)		0/12 (0%)		0/5 (0%)
Myalgia	0/9 (0%)		0/6 (0%)		1/12 (8.3%)		0/5 (0%)
Rotator cuff syndrome	0/9 (0%)		1/6 (16.7%)		0/12 (0%)		0/5 (0%)
Sjogren's syndrome	1/9 (11.1%)		1/6 (16.7%)		0/12 (0%)		1/5 (20%)
Synovitis	1/9 (11.1%)		1/6 (16.7%)		0/12 (0%)		0/5 (0%)
Nervous system disorders
Dizziness	0/9 (0%)		0/6 (0%)		0/12 (0%)		1/5 (20%)
Headache	3/9 (33.3%)		2/6 (33.3%)		2/12 (16.7%)		1/5 (20%)
Psychiatric disorders
Insomnia	0/9 (0%)		1/6 (16.7%)		0/12 (0%)		0/5 (0%)
Reproductive system and breast disorders
Postmenopausal haemorrhage	0/9 (0%)		1/6 (16.7%)		0/12 (0%)		0/5 (0%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	1/9 (11.1%)		1/6 (16.7%)		0/12 (0%)		1/5 (20%)
Skin and subcutaneous tissue disorders
Photosensitivity reaction	1/9 (11.1%)		0/6 (0%)		0/12 (0%)		0/5 (0%)
Rash	1/9 (11.1%)		0/6 (0%)		1/12 (8.3%)		0/5 (0%)
Vascular disorders
Hypotension	0/9 (0%)		0/6 (0%)		0/12 (0%)		1/5 (20%)

Limitations/Caveats

[Not Specified]

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Principal Investigators are NOT employed by the organization sponsoring the study.

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.