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

Systemic Lupus Erythematosus (SLE) Clinical Trial

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03656562
• Other study ID #: CVAY736X2208
• Secondary ID: 2018-001508-12
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: December 19, 2018
• Est. completion date: April 24, 2026

Study information

• Verified date: June 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

The study consists of a 28-day screening period, a blinded treatment period of 28 weeks where randomized patients received treatment with investigational drug (ianalumab or iscalimab) or placebo. At the end of Week 29 visit, the patients enter the open label treatment phase where patients in active treatment group continued to receive active treatment and patients in placebo group started active treatment with ianalumab/iscalimab until Week 49. After completion of the open-label treatment period, all patients enter a Follow-Up period in order to monitor safety and efficacy up to Week 69. The Week 69 visit is the End of Study (EoS) visit for patients in Cohort 2 (CFZ533). Study duration for patients in Cohort 2 will be approximately 18 months. For Cohort 1 (VAY736). Patients who do not achieve B-cell recovery by Week 69 Visit will enter into a Secondary Follow-Up period until achieving B cell recovery criteria (B-cell count is at >= 50 cells/µl or at least 80% of baseline levels). Safety follow-up visits will be scheduled as deemed appropriate until the patient achieves the B cell recovery criteria, followed by an EoS 4 weeks later.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 107
• Est. completion date: April 24, 2026
• Est. primary completion date: July 27, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Lupus Erythematosus, Systemic
• Systemic Lupus Erythematosus (SLE)

Intervention

Drug:
• VAY736
150 mg powder in vial for solution for injection; after reconstitution to 150 mg/mL per vial, a dose of 300 mg
• VAY736 Placebo
solution for injection; 0 mg/mL administered as 2 mL s.c. injection
• CFZ533
150 mg/mL as concentrate in vial for infusion, administered at a dose of 10 mg/kg as i.v. infusion
• CFZ533 Placebo
Placebo as concentrate in vial for infusion, administered at a dose of 10 mg/kg as i.v. infusion

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Ciudad Autonoma de Bs As	Buenos Aires
Australia	Novartis Investigative Site	Clayton	Victoria
China	Novartis Investigative Site	Guangzhou	Guangdong
China	Novartis Investigative Site	Nanjing	Jiangsu
China	Novartis Investigative Site	Shanghai
Czechia	Novartis Investigative Site	Praha 2
France	Novartis Investigative Site	Pessac Cedex
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Freiburg
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Debrecen
Israel	Novartis Investigative Site	Ramat Gan
Japan	Novartis Investigative Site	Chuo ku	Tokyo
Japan	Novartis Investigative Site	Nagoya	Aichi
Japan	Novartis Investigative Site	Nagoya	Aichi
Japan	Novartis Investigative Site	Shinjuku ku	Tokyo
Japan	Novartis Investigative Site	Shinjuku-ku	Tokyo
Korea, Republic of	Novartis Investigative Site	Gwangju
Poland	Novartis Investigative Site	Bydgoszcz
Poland	Novartis Investigative Site	Poznan
Poland	Novartis Investigative Site	Warszawa
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Saint Petersburg
Russian Federation	Novartis Investigative Site	Yekaterinburg
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona
Taiwan	Novartis Investigative Site	Taichung	Taiwan ROC
Taiwan	Novartis Investigative Site	Taichung
Taiwan	Novartis Investigative Site	Taichung
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Bangkok

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

Argentina,  Australia,  China,  Czechia,  France,  Germany,  Hungary,  Israel,  Japan,  Korea, Republic of,  Poland,  Russian Federation,  Spain,  Taiwan,  Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With SLE Responder Index (SRI)-4 Response Status at Week 29 With Reduced Steroid Dose Maintained Between Weeks 17 and 29	The primary endpoint is a composite of SRI-4 response at Week 29 with sustained reduction in oral corticosteroid from Week 17 through Week 29. Patients taking other rescue medication or prohibited medication or drop out before Week 29 were considered non-responders.; SRI-4 response is defined as below: having >= 4 points reduction from baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score (score is 0 to 105; a higher score indicating more severe disease) AND; no new British Isles Lupus Activity Group (BILAG)-2004 A organ domain score and no more than one new BILAG-2004 B organ domain scores compared with baseline AND; <10 mm point increase from baseline with scale 0 to 100 mm in the physician's global assessment from baseline; Sustained reduction in oral corticosteroid is defined as below: =< 5 mg/day or less than or equal to baseline dose, whichever was lower at Week 17 AND; no increase of that dose from Week 17 through Week 29	Baseline, Week 17 to Week 29
Secondary	Changes Between Baseline and Week 29 in the Physicians' Global Assessment (PhGA) Visual Analog Scale (VAS) Assessing Patient's Overall Disease Activity	The Physician's global assessment (PhGA-VAS) of disease activity was performed using 100 mm VAS ranging from "no disease activity" (score 0) to "maximal disease activity" (score 100), after the question on how well the patient was doing with the disease considering all aspects affected by the disease. The investigator was then measuring the distance in mm from the left edge of the scale and entering the value.	Baseline, Week 5, Week 9, Week 13, Week 17, Week 21, Week 25, Week 29
Secondary	Changes Between Baseline and Week 29 in the Patient's Global Assessment (PGA) Visual Analog Scale (VAS) Assessing Patient's Global Disease Activity	The patient's global assessment of disease activity was performed using a Visual Analogue Scale (VAS) of 100 mm ranging from "no disease activity" (score 0) to "severe disease activity" (score 100), after the question on how well the patient was doing with the disease considering all aspects affected by the disease. The investigator was then measuring the distance in mm from the left edge of the scale and entering the value.	Baseline, Week 5, Week 9, Week 13, Week 17, Week 21, Week 25, Week 29
Secondary	Flare Rate and Time to First Flare	Flare rate and time to first flare, with flare defined as one new 'A' score or two or more 'B' score using BILAG -2004	18 months
Secondary	Time to First Flare	Time to first flare, with flare defined as one new 'A' score or two or more 'B' score using BILAG -2004	18 months
Secondary	PK Cohort 1 - Cmax,ss	PK Cohort 1 (VAY736): free VAY736 serum concentration (Cmax at steady state)	18+ months
Secondary	PK Cohort 1 - Ctrough,ss	PK Cohort 1 (VAY736): free VAY736 serum concentration (Ctrough at steady state)	18+ months
Secondary	PK Cohort 2 - Cmax,ss	PK Cohort 2 (CFZ533): free CFZ533 concentration in plasma (Cmax at steady state).	18 months
Secondary	PK Cohort 2 - Ctrough,ss	PK Cohort 2 (CFZ533): free CFZ533 concentration in plasma (Ctrough at steady state).	18 months
Secondary	PD Cohort 2 (CFZ533): Total Soluble CD40	PD Cohort 2 (CFZ533): total soluble CD40 in plasma.	18 months