E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Systemic lupus erythematosus (SLE) |
|
E.1.1.1 | Medical condition in easily understood language |
Systemic lupus erythematosus (SLE) |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10042945 |
E.1.2 | Term | Systemic lupus erythematosus |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to determine the effect of VAY736 and of CFZ533 versus their respective placebo on disease activity in SLE patients using the SRI-4 index. |
|
E.2.2 | Secondary objectives of the trial |
- To assess safety and tolerability in patients with SLE by recording all adverse events
- To determine the change from baseline in the Physicians’ Global Assessment (PhGA) at Week 29 by using a visual analogue scale (VAS)
- To determine the change from baseline in the Patient's Global Assessment (PGA) at Week 29 by using a patients VAS
- To determine the pharmacokinetics (PK) of multiple doses of VAY736
(s.c.) and CFZ533 (i.v.) in SLE patients by analyzing PK concentrations in blood
- To assess the effect of VAY736 and of CFZ533 versus their respective
placebo to prevent disease flares in SLE patient’s using BILAG-2004
- To evaluate the immunogenicity of multiple doses of VAY736 (s.c.) or
CFZ533 (i.v.) in SLE patients by analyzing anti-drug antibodies in blood
- To evaluate the pharmacodynamics (PD; rate, extent and duration of
target engagement) of multiple doses of CFZ533 in SLE patients by analyzing total soluble CD40 in plasma |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Written informed consent must be obtained before any assessment is performed
- Male and female patients 18 to 75 years of age
- 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 antimalarial 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 at screening of:
-- at least one "A" in either the mucocutaneous domain or in the
musculoskeletal domain,
OR
-- one "B" in either the mucocutaneous or musculoskeletal domain
AND at least one "A" or "B" in a second domain
- Weigh at least 40 kg at screening
- Other protocol-defined inclusion criteria may apply |
|
E.4 | Principal 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
- Severe organ dysfunction or life threatening 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 2month 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.
- Other protocol-defined exclusion criteria may apply |
|
E.5 End points |
E.5.1 | Primary end point(s) |
SRI-4 response status at Week 29 with reduced steroid dose maintained between Weeks 17 and 29 |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
- Changes between baseline and Week 29 in the PhGA visual analog scale (VAS) assessing patient’s overall disease activity
- Changes between baseline and Week 29 in the PGA visual analog scale (VAS) assessing patient’s global disease activity
- 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, with flare defined as one new ‘A’ score or two or more ‘B’ score using BILAG -2004
- PK Cohort 1 (VAY736): free VAY736 serum concentration (Cmax at steady state)
- PK Cohort 1 (VAY736): free VAY736 serum concentration (Ctrough at steady state)
- PK Cohort 2 (CFZ533): free CFZ533 concentration in plasma (Cmax at steady state).
- PK Cohort 2 (CFZ533): free CFZ533 concentration in plasma (Ctrough at steady state).
- PD Cohort 2 (CFZ533): total soluble CD40 in plasma. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
29 Weeks
29 Weeks
18 months
18 months
End of Study
End of Study
18 months
18 months
18 months |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Immunogenicity
Tolerability |
|
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Thailand |
Argentina |
China |
Czechia |
Germany |
Hungary |
Israel |
Japan |
Korea, Republic of |
Poland |
Russian Federation |
Spain |
Taiwan |
United States |
France |
|
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |