Safety, Pharmacokinetics, and Preliminary Efficacy Study of CDZ173 in Patients With Primary Sjögren's Syndrome

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02775916
• Collaborator: (none)
• Enrollment: 30
• Locations: 2
• Arms: 2
• Actual Duration (Months): 11.5
• Patients Per Site: 15
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

This Study is designed to evaluate the safety, tolerability, pharmacokinetics and preliminary therapeutic efficacy of oral administrations of CDZ173 in patients with primary Sjögren's syndrome.

Condition or Disease	Intervention/Treatment	Phase
Primary Sjögren's Syndrome	Drug: CDZ173; Drug: Placebo	Phase 2

Detailed Description

This study is designed to evaluate the safety, tolerability, pharmacokinetics and preliminary therapeutic efficacy of oral administrations of CDZ173, a selective PI3K delta inhibitor, for 12 weeks, in patients with primary Sjögren's syndrome. Data from this study will provide the basis for further development of the compound for the treatment of primary Sjögren's syndrome.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of CDZ173 in Patients With Primary Sjögren's Syndrome
• Actual Study Start Date: Jun 1, 2016
• Actual Primary Completion Date: May 17, 2017
• Actual Study Completion Date: May 17, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CDZ173 Capsule	Drug: CDZ173
Placebo Comparator: Placebo Capsule matching Placebo	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Primary Sjögren's Syndrome With Adverse Events and Death up to Day 85 [up to Day 85]

   Safety and tolerability of CDZ173 in patients with primary Sjögren's syndrome up to End of Treatment Day 85

2. Change From Baseline in the EULAR Sjögren's Syndrome Patient Reported Intensity (ESSPRI) After 12 Weeks of Treatment Day 85 [Baseline and 12 weeks (Day 85)]

   The ESSPRI is an established disease outcome measure for Sjögren's syndrome. The ESSPRI is a patient-reported, subjective symptom index for primary Sjögren's syndrome developed by the EULAR consortium. It consists of three questions covering the cardinal symptoms of Sjögren's syndrome: dryness, fatigue and pain (articular and/or muscular). Each domain scored on scale of 0-10 (0 =no symptom at all and 10 = worst symptom imaginable), and an overall score is calculated as the mean of the three individual domains where all domains carry the same weight. Minimum score can be 0 and maximum score can be 10.

Secondary Outcome Measures

1. Change From Baseline in the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) After 12 Weeks of Treatment Day 85 [Baseline and 12 weeks (Day 85)]

   The ESSDAI is an established disease outcome measure for Sjögren's syndrome. 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. A reduction from baseline (i.e., a negative change from baseline) in the ESSDAI score is indicative of improvement in a patient.). Each domain is assessed for activity level (i.e., no, low, moderate, high) and assigned a numerical score based on pre-determined weighting of each individual domain. An overall score is then calculated as the sum of all individual weighted domain scores. Overall score is calculated as sum of all individual weighted domain scores (ranges from 0 (best) to 123 (worst activity).

2. Change From Baseline in the Short Form (36) Health Survey (SF-36) After 12 Weeks of Treatment Day 85 [Baseline and 12 weeks (Day 85)]

   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 Baseline in Multidimensional Fatigue Inventory (MFI) After 12 Weeks of Treatment (Day 85) [Baseline and 12 weeks (Day 85)]

   The Multidimensional Fatigue Inventory (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 possible range from 4-20. The reported total score has a range from 20-100. The reported total score has a range from 20-100, higher scores are associated with greater fatigue.

4. Change From Baseline in Physician Global Assessment of the Patient's Overall Disease Activity (Physician VAS) After 12 Weeks of Treatment Day 85 [Baseline and 12 weeks (Day 85)]

   A reduction from baseline (i.e., a negative change from baseline) in physician global VAS assessment score indicates improvement in patients. The visual analogue scale used is a 100 mm VAS ranging from "no disease" (0 mm) to "maximal disease activity" (100 mm).

5. Change From Baseline in Patient's Global Assessment of Their Disease Activity (VAS) After 12 Weeks of Treatment Day 85 [Baseline and 12 weeks]

   A reduction from baseline (or, a negative change from baseline) in patient global VAS assessment score indicates improvement in patients. The visual analogue scale used is a 100 mm VAS ranging from "no disease" (0 mm) to "maximal disease activity" (100 mm).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Diagnosis of primary Sjögren's syndrome (pSS)

• ESSDAI score ≥ 6 at screening visit

Exclusion Criteria:

• Secondary Sjögren's syndrome

Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Berlin		Germany	10117
2	Novartis Investigative Site	Debrecen		Hungary	4032

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Statistical Analysis Plan - Jun 30, 2017
• Study Protocol - Sep 15, 2016

More Information

Additional Information:

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

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02775916
• Other Study ID Numbers: CCDZ173X2203; 2014-004616-12
• First Posted: May 18, 2016
• Last Update Posted: Jan 5, 2021
• Last Verified: Sep 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Sjogren's Syndrome; Syndrome

Study Results

Participant Flow

Arm/Group Title	CDZ173	Placebo
Arm/Group Description	Capsule BID	Capsule matching Placebo BID
Period Title: Overall Study
STARTED	20	10
COMPLETED	17	10
NOT COMPLETED	3	0

Baseline Characteristics

Arm/Group Title	CDZ173	Placebo	Total
Arm/Group Description	Capsule BID	Capsule matching Placebo BID	Total of all reporting groups
Overall Participants	20	10	30
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.7 (13.85)	44.7 (11.58)	47.3 (13.07)
Sex: Female, Male (Count of Participants)
Female	17 85%	9 90%	26 86.7%
Male	3 15%	1 10%	4 13.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	20 100%	10 100%	30 100%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Primary Sjögren's Syndrome With Adverse Events and Death up to Day 85
Description	Safety and tolerability of CDZ173 in patients with primary Sjögren's syndrome up to End of Treatment Day 85
Time Frame	up to Day 85

Outcome Measure Data

Analysis Population Description

Safety Analysis Set - All randomized patients in the CDZ173 group (20 patients) and placebo group (10 patients) were included in the safety analysis set

Arm/Group Title	CDZ173	Placebo
Arm/Group Description	Capsule BID	Capsule matching Placebo BID
Measure Participants	20	10
Participants with at least one AE	20 100%	8 80%
Participants with at least one SAE	1 5%	0 0%
Death	0 0%	0 0%

2. Primary Outcome

Title	Change From Baseline in the EULAR Sjögren's Syndrome Patient Reported Intensity (ESSPRI) After 12 Weeks of Treatment Day 85
Description	The ESSPRI is an established disease outcome measure for Sjögren's syndrome. The ESSPRI is a patient-reported, subjective symptom index for primary Sjögren's syndrome developed by the EULAR consortium. It consists of three questions covering the cardinal symptoms of Sjögren's syndrome: dryness, fatigue and pain (articular and/or muscular). Each domain scored on scale of 0-10 (0 =no symptom at all and 10 = worst symptom imaginable), and an overall score is calculated as the mean of the three individual domains where all domains carry the same weight. Minimum score can be 0 and maximum score can be 10.
Time Frame	Baseline and 12 weeks (Day 85)

Outcome Measure Data

Analysis Population Description

PD analysis set - All randomized patients in the CDZ173 group (20 patients) and placebo group (10 patients) were included in the PD analysis set

Arm/Group Title	CDZ173	Placebo
Arm/Group Description	Capsule BID	Capsule matching Placebo BID
Measure Participants	20	10
Mean (Standard Deviation) [total score on scale]	-1.778 (2.4509)	-0.741 (1.3517)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CDZ173, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.69
	Confidence Interval	(2-Sided) 95%; -3.343 to 1.937
	Parameter Dispersion	Type: Standard Deviation; Value: 1.332
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) After 12 Weeks of Treatment Day 85
Description	The ESSDAI is an established disease outcome measure for Sjögren's syndrome. 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. A reduction from baseline (i.e., a negative change from baseline) in the ESSDAI score is indicative of improvement in a patient.). Each domain is assessed for activity level (i.e., no, low, moderate, high) and assigned a numerical score based on pre-determined weighting of each individual domain. An overall score is then calculated as the sum of all individual weighted domain scores. Overall score is calculated as sum of all individual weighted domain scores (ranges from 0 (best) to 123 (worst activity).
Time Frame	Baseline and 12 weeks (Day 85)

Outcome Measure Data

Analysis Population Description

PD analysis set - All randomized patients in the CDZ173 group (20 patients) and placebo group (10 patients) were included in the PD analysis set

Arm/Group Title	CDZ173	Placebo
Arm/Group Description	Capsule BID	Capsule matching Placebo BID
Measure Participants	20	10
Least Squares Mean (Standard Error) [total score on scale]	-2.82 (1.165)	-3.34 (1.168)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CDZ173, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.51
	Confidence Interval	(2-Sided) 95%; -2.52 to 3.55
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.466
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in the Short Form (36) Health Survey (SF-36) After 12 Weeks of Treatment Day 85
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 and 12 weeks (Day 85)

Outcome Measure Data

Analysis Population Description

PD analysis set - All randomized patients in the CDZ173 group (20 patients) and placebo group (10 patients) were included in the PD analysis set

Arm/Group Title	CDZ173	Placebo
Arm/Group Description	Capsule BID	Capsule matching Placebo BID
Measure Participants	20	10
Physical Component Summary Score	4.82 (2.235)	4.42 (2.425)
Mental Component Summary Score	5.43 (3.415)	1.10 (3.792)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CDZ173, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.40
	Confidence Interval	(2-Sided) 95%; -6.08 to 6.89
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.119
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CDZ173, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	4.33
	Confidence Interval	(2-Sided) 95%; -5.27 to 13.93
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.615
	Estimation Comments

5. Secondary Outcome

Title	Change in Baseline in Multidimensional Fatigue Inventory (MFI) After 12 Weeks of Treatment (Day 85)
Description	The Multidimensional Fatigue Inventory (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 possible range from 4-20. The reported total score has a range from 20-100. The reported total score has a range from 20-100, higher scores are associated with greater fatigue.
Time Frame	Baseline and 12 weeks (Day 85)

Outcome Measure Data

Analysis Population Description

PD analysis set - All randomized patients in the CDZ173 group (20 patients) and placebo group (10 patients) were included in the PD analysis set

Arm/Group Title	CDZ173	Placebo
Arm/Group Description	Capsule BID	Capsule matching Placebo BID
Measure Participants	20	10
Least Squares Mean (Standard Error) [total score on scale]	-8.80 (5.557)	-2.25 (5.774)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CDZ173, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-6.55
	Confidence Interval	(2-Sided) 95%; -21.76 to 8.66
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.270
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in Physician Global Assessment of the Patient's Overall Disease Activity (Physician VAS) After 12 Weeks of Treatment Day 85
Description	A reduction from baseline (i.e., a negative change from baseline) in physician global VAS assessment score indicates improvement in patients. 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 and 12 weeks (Day 85)

Outcome Measure Data

Analysis Population Description

PD analysis set - All randomized patients in the CDZ173 group (20 patients) and placebo group (10 patients) were included in the PD analysis set

Arm/Group Title	CDZ173	Placebo
Arm/Group Description	Capsule BID	Capsule matching Placebo BID
Measure Participants	20	10
Least Squares Mean (Standard Error) [total score on a scale]	-10.06 (6.584)	0.91 (7.699)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CDZ173, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-10.97
	Confidence Interval	(2-Sided) 95%; -30.94 to 9.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.626
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in Patient's Global Assessment of Their Disease Activity (VAS) After 12 Weeks of Treatment Day 85
Description	A reduction from baseline (or, a negative change from baseline) in patient global VAS assessment score indicates improvement in patients. 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 and 12 weeks

Outcome Measure Data

Analysis Population Description

PD analysis set - All randomized patients in the CDZ173 group (20 patients) and placebo group (10 patients) were included in the PD analysis set

Arm/Group Title	CDZ173	Placebo
Arm/Group Description	Capsule BID	Capsule matching Placebo BID
Measure Participants	20	10
Least Squares Mean (Standard Error) [total score on a scale]	-4.83 (7.268)	2.87 (8.412)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CDZ173, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-7.69
	Confidence Interval	(2-Sided) 95%; -29.75 to 14.37
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10.595
	Estimation Comments

Adverse Events

Time Frame	Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit (Day 113)
Arm/Group Title	CDZ173		Placebo
Arm/Group Description	Capsule BID		Capsule matching Placebo BID
All Cause Mortality
	CDZ173		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/10 (0%)
Serious Adverse Events
	CDZ173		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/20 (5%)		0/10 (0%)
Skin and subcutaneous tissue disorders
Rash	1/20 (5%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	CDZ173		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/20 (95%)		8/10 (80%)
Eye disorders
Dry Eye	1/20 (5%)		1/10 (10%)
Gastrointestinal disorders
Abdominal Pain	2/20 (10%)		0/10 (0%)
Abdominal Pain Upper	1/20 (5%)		1/10 (10%)
Diarrhoea	5/20 (25%)		1/10 (10%)
Flatulence	1/20 (5%)		3/10 (30%)
Nausea	2/20 (10%)		0/10 (0%)
Toothache	2/20 (10%)		0/10 (0%)
General disorders
Chest Discomfort	1/20 (5%)		1/10 (10%)
Chills	0/20 (0%)		1/10 (10%)
Fatigue	2/20 (10%)		1/10 (10%)
Feeling Cold	2/20 (10%)		0/10 (0%)
Pyrexia	2/20 (10%)		1/10 (10%)
Infections and infestations
Infected Bite	0/20 (0%)		1/10 (10%)
Tooth Infection	0/20 (0%)		1/10 (10%)
Upper Respiratory Tract Infection	3/20 (15%)		0/10 (0%)
Vaginal Infection	0/20 (0%)		1/10 (10%)
Viral Upper Respiratory Tract Infection	7/20 (35%)		4/10 (40%)
Metabolism and nutrition disorders
Decreased Appetite	2/20 (10%)		0/10 (0%)
Musculoskeletal and connective tissue disorders
Arthritis	0/20 (0%)		1/10 (10%)
Back Pain	2/20 (10%)		0/10 (0%)
Sjogren's Syndrome	2/20 (10%)		0/10 (0%)
Nervous system disorders
Dizziness	2/20 (10%)		0/10 (0%)
Headache	7/20 (35%)		1/10 (10%)
Paraesthesia	1/20 (5%)		1/10 (10%)
Psychiatric disorders
Depression	0/20 (0%)		1/10 (10%)
Reproductive system and breast disorders
Dysmenorrhoea	1/20 (5%)		1/10 (10%)
Respiratory, thoracic and mediastinal disorders
Cough	0/20 (0%)		1/10 (10%)
Dyspnoea	3/20 (15%)		0/10 (0%)
Nasal Congestion	0/20 (0%)		1/10 (10%)
Oropharyngeal Pain	3/20 (15%)		0/10 (0%)
Skin and subcutaneous tissue disorders
Dry Skin	2/20 (10%)		0/10 (0%)
Eczema	1/20 (5%)		1/10 (10%)
Hyperhidrosis	1/20 (5%)		1/10 (10%)
Rash	10/20 (50%)		1/10 (10%)
Vascular disorders
Phlebitis	0/20 (0%)		1/10 (10%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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 (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.