Study the Efficacy and Safety of VAY736 and CFZ533 in SLE Patients

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03656562

Collaborator

(none)

107

Enrollment

Locations

Arms

65.5

Anticipated Duration (Months)

3.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study is designed to evaluate the safety, tolerability, pharmacokinetics and therapeutic efficacy of treatment with either VAY736 or CFZ533 in patients with SLE to enable further development of these compounds as treatment in this disease population

Condition or Disease	Intervention/Treatment	Phase
Systemic Lupus Erythematosus (SLE)	Drug: VAY736 Drug: VAY736 Placebo Drug: CFZ533 Drug: CFZ533 Placebo	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

107 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

The investigational drug or placebo will be administered on top of SLE background therapy. Patients will be randomized at baseline into one of two treatment cohorts (VAY736 or CFZ533) and to either active or placebo double blind treatment within that cohort. From Week 29 onwards all patients will receive open label active treatment until week 53 in the respective cohort.The investigational drug or placebo will be administered on top of SLE background therapy. Patients will be randomized at baseline into one of two treatment cohorts (VAY736 or CFZ533) and to either active or placebo double blind treatment within that cohort. From Week 29 onwards all patients will receive open label active treatment until week 53 in the respective cohort.

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Masking Description:

Patients, investigator staff, persons performing the assessments, and the clinical trial team (CTT) will remain blind to the identity of the treatment within each cohort from the time of randomization until end of the Week 29 visit

Primary Purpose:

Treatment

Official Title:

A Placebo-controlled, Patient and Investigator Blinded, Randomized Parallel Cohort Study to Assess Pharmacodynamics, Pharmacokinetics, Safety, Tolerability and Preliminary Clinical Efficacy of VAY736 and CFZ533 in Patients With Systemic Lupus Erythematosus (SLE)

Actual Study Start Date :

Dec 19, 2018

Anticipated Primary Completion Date :

Jun 3, 2024

Anticipated Study Completion Date :

Jun 3, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1 VAY736 multiple doses of VAY736, s.c.	Drug: VAY736 Powder for solution for injection
Placebo Comparator: Cohort 1 VAY736 Placebo multiple doses of matching placebo s.c. until week 29. Multiple doses of VAY736, s.c from week 29 until week 53.	Drug: VAY736 Placebo Solution for injection
Experimental: Cohort 2 CFZ533 multiple doses of CFZ533, i.v.	Drug: CFZ533 Concentrate for solution for infusion
Placebo Comparator: Cohort 2 CFZ533 Placebo multiple doses of matching placebo i.v. until week 29. Multiple doses of CFZ533, i.v. from week 29 until week 53.	Drug: CFZ533 Placebo Solution for infusion

Outcome Measures

Primary Outcome Measures

SRI-4 response status [29 Weeks]
SRI-4 response status at Week 29 (reduced steroid dose maintained between Weeks 17 and 29). Clinical efficacy will be measured using the SLE Responder Index (SRI-4), a composite endpoint that incorporates SLEDAI-2K, BILAG 2004, and a visual analog scale (VAS) of physician-rated disease activity to determine patient improvement.

Secondary Outcome Measures

PhGA VAS - overall disease activity [from Baseline to Week 29]
Changes between baseline and Week 29 in the Physicians' Global Assessment (PhGA) visual analog scale (VAS) assessing patient's overall disease activity
PGA VAS - global disease activity [from baseline to Week 29]
Changes between baseline and Week 29 in the Patient's Global Assessment (PGA) visual analog scale (VAS) assessing patient's global disease activity
Flare rate and time to first flare [18 months]
Flare rate and time to first flare, with flare defined as one new 'A' score or two or more 'B' score using BILAG -2004
Time to first flare [18 months]
Time to first flare, with flare defined as one new 'A' score or two or more 'B' score using BILAG -2004
PK Cohort 1 - Cmax,ss [18+ months]
PK Cohort 1 (VAY736): free VAY736 serum concentration (Cmax at steady state)
PK Cohort 1 - Ctrough,ss [18+ months]
PK Cohort 1 (VAY736): free VAY736 serum concentration (Ctrough at steady state)
PK Cohort 2 - Cmax,ss [18 months]
PK Cohort 2 (CFZ533): free CFZ533 concentration in plasma (Cmax at steady state).
PK Cohort 2 - Ctrough,ss [18 months]
PK Cohort 2 (CFZ533): free CFZ533 concentration in plasma (Ctrough at steady state).
PD Cohort 2 (CFZ533): total soluble CD40 [18 months]
PD Cohort 2 (CFZ533): total soluble CD40 in plasma.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Written informed consent must be obtained before any assessment is performed
Fulfill ≥4 of the 11 American College of Rheumatology 1997 classification criteria for SLE
Patient diagnosed with SLE for at least 6 months prior to screening
Elevated serum titers at screening of ANA (≥1:80) of a pattern consistent with an SLE diagnosis, including at a minimum either anti-double stranded DNA (anti-ds DNA) or anti-Ro (SSA) or anti-La (SSB) or anti-nuclear ribonucleoprotein (anti-RNP) or anti-Smith (anti-Sm)
Currently receiving corticosteroids and/or anti-malarial and/or thalidomide treatment and/or another DMARD on a stable dose according to protocol requirements
SLEDAI-2K score of ≥6 at screening
BILAG 2004 score of one "A" score either in the mucocutaneous or in the musculoskeletal domain or one "B" score in either the mucocutaneous or musculoskeletal domain and at least one "A" or "B" score in a second domain at screening
Weigh at least 40 kg at screening

Exclusion Criteria:

Cohort 2 (CFZ533/Placebo) only:

Patients who are at significant risk for thromboembolic events based on the following:
History of either thrombosis or 3 or more spontaneous abortions
Presence of lupus anticoagulant or significantly prolonged activated partial thromboplastin time (aPTT) consistent with co-existent anti-phospholipid syndrome and without concurrent prophylactic treatment with aspirin or anticoagulants as per local standard of care

All Cohorts:

History of receiving prior to screening:
Within 12 weeks: i.v. corticosteroids, calcineurin inhibitors or other oral DMARD
Within 24 weeks: cyclophosphamide or biologics such as intravenous Ig, plasmapheresis, anti-TNF-a mAb, CTLA4-Fc Ig (abatacept) or BAFF targeting agents (e.g., belimumab)
Any B-cell depleting therapies (e.g., anti-CD20 mAb, anti-CD22 mAb, anti-CD52 mAb) or TACI-Ig (atacicept) administered within 52 weeks prior to screening, and a B-cell count <50 cells/μ at the time of screening
Evidence of past exposure to tuberculosis as assessed by Quantiferon testing at screening
Presence of human immunodeficiency virus (HIV) infection at screening
Severe organ dysfunction or life threatening disease; ECOG performance status > 1 at screening
Presence of WHO Class III-IV renal involvement with proliferative disease Presence of severe lupus kidney disease as defined by proteinuria above 6 g/day or equivalent using spot urine protein creatinine ratio, or serum creatinine greater than 2.5 mg/dL (221.05 μmol/L), or requiring immune suppressive induction or maintenance treatment exceeding protocol defined limits
Active viral, bacterial or other infections at the time of screening or enrollment
Receipt of live/attenuated vaccine within a 2-month period before first dosing
Uncontrolled, co-existing serious disease, e.g., uncontrolled hypertension, heart failure, type I diabetes, thyroid disease within 3 months prior to first dosing, or significant, unresolved illness within 2 weeks prior to first dosing
History of hypersensitivity to drugs of similar chemical class
Chronic infection with hepatitis B (HBV) or hepatitis C (HCV). Subjects who are HBsAg negative and HBcAb positive are excluded unless negative for HBV DNA. Once past screening and enrolled into study, requirements for monitoring and antiviral treatment are enacted.

Subjects with a positive HCV antibody test should have HCV RNA levels measured. Subjects with positive (detectable) HCV RNA should be excluded.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Ciudad Autonoma de Bs As	Buenos Aires	Argentina	C1015ABO
2	Novartis Investigative Site	Clayton	Victoria	Australia	3168
3	Novartis Investigative Site	Hefei	Anhui	China	230001
4	Novartis Investigative Site	Guangzhou	Guangdong	China	510000
5	Novartis Investigative Site	Nanjing	Jiangsu	China	210008
6	Novartis Investigative Site	Shanghai		China	200127
7	Novartis Investigative Site	Praha 2		Czechia	128 50
8	Novartis Investigative Site	Pessac Cedex		France	33604
9	Novartis Investigative Site	Berlin		Germany	10117
10	Novartis Investigative Site	Freiburg		Germany	79106
11	Novartis Investigative Site	Budapest		Hungary	1023
12	Novartis Investigative Site	Debrecen		Hungary	4032
13	Novartis Investigative Site	Ramat Gan		Israel	52621
14	Novartis Investigative Site	Nagoya	Aichi	Japan	457 8510
15	Novartis Investigative Site	Nagoya	Aichi	Japan	460-0001
16	Novartis Investigative Site	Chuo ku	Tokyo	Japan	104-8560
17	Novartis Investigative Site	Shinjuku ku	Tokyo	Japan	162 8655
18	Novartis Investigative Site	Shinjuku-ku	Tokyo	Japan	160 8582
19	Novartis Investigative Site	Gwangju		Korea, Republic of	61469
20	Novartis Investigative Site	Bydgoszcz		Poland	85 168
21	Novartis Investigative Site	Poznan		Poland	60-218
22	Novartis Investigative Site	Warszawa		Poland	00-874
23	Novartis Investigative Site	Saint Petersburg	Moscow Region	Russian Federation	194044
24	Novartis Investigative Site	St Petersburg		Russian Federation	190068
25	Novartis Investigative Site	Yekaterinburg		Russian Federation	620109
26	Novartis Investigative Site	Barcelona	Catalunya	Spain	08035
27	Novartis Investigative Site	Barcelona		Spain	08041
28	Novartis Investigative Site	Taichung	Taiwan ROC	Taiwan	40201
29	Novartis Investigative Site	Taichung		Taiwan	40447
30	Novartis Investigative Site	Taichung		Taiwan	40705
31	Novartis Investigative Site	Bangkok		Thailand	10400
32	Novartis Investigative Site	Bangkok		Thailand	10700