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

• ClinicalTrials.gov Identifier: NCT03656562
• Recruitment Status: Active, not recruiting
• First Posted: September 4, 2018
• Last Update Posted: April 4, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

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 (Clinical Trial)
• 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.
• 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: December 19, 2018
• Estimated Primary Completion Date: August 16, 2024
• Estimated Study Completion Date: August 16, 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 :

1. SRI-4 response status [ Time Frame: 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 :

1. PhGA VAS - overall disease activity [ Time Frame: 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
2. PGA VAS - global disease activity [ Time Frame: 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
3. Flare rate and time to first flare [ Time Frame: 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
4. Time to first flare [ Time Frame: 18 months ]
   Time to first flare, with flare defined as one new 'A' score or two or more 'B' score using BILAG -2004
5. PK Cohort 1 - Cmax,ss [ Time Frame: 18+ months ]
   PK Cohort 1 (VAY736): free VAY736 serum concentration (Cmax at steady state)
6. PK Cohort 1 - Ctrough,ss [ Time Frame: 18+ months ]
   PK Cohort 1 (VAY736): free VAY736 serum concentration (Ctrough at steady state)
7. PK Cohort 2 - Cmax,ss [ Time Frame: 18 months ]
   PK Cohort 2 (CFZ533): free CFZ533 concentration in plasma (Cmax at steady state).
8. PK Cohort 2 - Ctrough,ss [ Time Frame: 18 months ]
   PK Cohort 2 (CFZ533): free CFZ533 concentration in plasma (Ctrough at steady state).
9. PD Cohort 2 (CFZ533): total soluble CD40 [ Time Frame: 18 months ]
   PD Cohort 2 (CFZ533): total soluble CD40 in plasma.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Argentina

Novartis Investigative Site

Ciudad Autonoma de Bs As, Buenos Aires, Argentina, C1015ABO

Australia, Victoria

Novartis Investigative Site

Clayton, Victoria, Australia, 3168

China, Guangdong

Novartis Investigative Site

Guangzhou, Guangdong, China, 510000

China, Jiangsu

Novartis Investigative Site

Nanjing, Jiangsu, China, 210008

China

Novartis Investigative Site

Shanghai, China, 200127

Czechia

Novartis Investigative Site

Praha 2, Czechia, 128 50

France

Novartis Investigative Site

Pessac Cedex, France, 33604

Germany

Novartis Investigative Site

Berlin, Germany, 10117

Novartis Investigative Site

Freiburg, Germany, 79106

Hungary

Novartis Investigative Site

Budapest, Hungary, 1023

Novartis Investigative Site

Debrecen, Hungary, 4032

Israel

Novartis Investigative Site

Ramat Gan, Israel, 52621

Japan

Novartis Investigative Site

Nagoya, Aichi, Japan, 457 8510

Novartis Investigative Site

Nagoya, Aichi, Japan, 460-0001

Novartis Investigative Site

Chuo ku, Tokyo, Japan, 104-8560

Novartis Investigative Site

Shinjuku ku, Tokyo, Japan, 162 8655

Novartis Investigative Site

Shinjuku-ku, Tokyo, Japan, 160 8582

Korea, Republic of

Novartis Investigative Site

Gwangju, Korea, Republic of, 61469

Poland

Novartis Investigative Site

Bydgoszcz, Poland, 85 168

Novartis Investigative Site

Poznan, Poland, 60-218

Novartis Investigative Site

Warszawa, Poland, 00-874

Russian Federation

Novartis Investigative Site

Saint Petersburg, Moscow Region, Russian Federation, 194044

Novartis Investigative Site

St Petersburg, Russian Federation, 190068

Novartis Investigative Site

Yekaterinburg, Russian Federation, 620109

Spain

Novartis Investigative Site

Barcelona, Catalunya, Spain, 08035

Novartis Investigative Site

Barcelona, Spain, 08041

Taiwan

Novartis Investigative Site

Taichung, Taiwan ROC, Taiwan, 40201

Novartis Investigative Site

Taichung, Taiwan, 40447

Novartis Investigative Site

Taichung, Taiwan, 40705

Thailand

Novartis Investigative Site

Bangkok, Thailand, 10400

Novartis Investigative Site

Bangkok, Thailand, 10700

Sponsors and Collaborators

Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03656562
• Other Study ID Numbers: CVAY736X2208
• First Posted: September 4, 2018
• Last Update Posted: April 4, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Plan Description

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

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Systemic Lupus Erythematosus (SLE); Anti-CD40; anti-BAFF-receptor; B-cell depletion; BAFF-receptor blockade; ianalumab; VAY736; iscalimab; CFZ533

Additional relevant MeSH terms:

Lupus Erythematosus, Systemic; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Antibodies, Monoclonal; Immunologic Factors; Physiological Effects of Drugs