Clinical trial NCT03656562: Study the Efficacy and Safety of VAY736 and CFZ533 in SLE Patients
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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Systemic Lupus Erythematosus (SLE)
Keywords: Systemic Lupus Erythematosus
SLE
Anti-CD40
anti-BAFF-receptor
B-cell depletion
BAFF-receptor blockade
ianalumab
VAY736
iscalimab
CFZ533
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2018-09-04
Enrollment: 107
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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

Detailed 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.

Eligibility 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.

Primary outcomes:
measure: Percentage of Participants With SLE Responder Index (SRI)-4 Response Status at Week 29 With Reduced Steroid Dose Maintained Between Weeks 17 and 29
timeFrame: Baseline, Week 17 to Week 29
Secondary outcomes:
measure: Changes Between Baseline and Week 29 in the Physicians' Global Assessment (PhGA) Visual Analog Scale (VAS) Assessing Patient's Overall Disease Activity
timeFrame: Baseline, Week 5, Week 9, Week 13, Week 17, Week 21, Week 25, Week 29
measure: Changes Between Baseline and Week 29 in the Patient's Global Assessment (PGA) Visual Analog Scale (VAS) Assessing Patient's Global Disease Activity
timeFrame: Baseline, Week 5, Week 9, Week 13, Week 17, Week 21, Week 25, Week 29
measure: Flare Rate and Time to First Flare
timeFrame: 18 months
measure: Time to First Flare
timeFrame: 18 months
measure: PK Cohort 1 - Cmax,ss
timeFrame: 18+ months
measure: PK Cohort 1 - Ctrough,ss
timeFrame: 18+ months
measure: PK Cohort 2 - Cmax,ss
timeFrame: 18 months
measure: PK Cohort 2 - Ctrough,ss
timeFrame: 18 months
measure: PD Cohort 2 (CFZ533): Total Soluble CD40
timeFrame: 18 months
Other outcomes:
Locations:
city: Ciudad Autonoma de Bs As
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Clayton
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Guangzhou
country: China
facility: Novartis Investigative Site
state: Guangdong
city: Nanjing
country: China
facility: Novartis Investigative Site
state: Jiangsu
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Praha 2
country: Czechia
facility: Novartis Investigative Site
city: Pessac Cedex
country: France
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Freiburg
country: Germany
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Debrecen
country: Hungary
facility: Novartis Investigative Site
city: Ramat Gan
country: Israel
facility: Novartis Investigative Site
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Chuo ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Shinjuku ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Shinjuku-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Gwangju
country: Korea, Republic of
facility: Novartis Investigative Site
city: Bydgoszcz
country: Poland
facility: Novartis Investigative Site
city: Poznan
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Ekaterinburg
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
state: Taiwan ROC
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: