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 |
|
E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 13.1 |
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 | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Evaluate the safety of 6.0 mg/kg and 12 mg/kg SM101 per week in SLE patients with or without a history of lupus nephritis. |
|
E.2.2 | Secondary objectives of the trial |
Evaluate the efficacy and pharmacokinetics (PK) of 6.0 mg/kg and 12 mg/kg SM101 per week in SLE patients with or without a history of lupus nephritis. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patient has provided written informed consent prior to any study-related procedure
2. Male or female adult patients aged 18 years or older
3. Patients with a body weight equal to or greater than 40 kg and less than or equal to 100 kg
4. Diagnosis of SLE meeting at least four revised main classification criteria of the ACR
5. Clinically active patients with a Safety of Estrogen in Lupus Erythematosus National
Assessment version of the Systemic Lupus Erythematosus Disease Activity Index
(SELENA-SLEDAI) score of equal to or greater than 6 within 8 weeks preceding the first dose of investigational product. A subpopulation will fulfil the additional criterion of lupus nephritis:
• History of class III, IV, V or a combination, excluding pure class V
glomerulonephritis confirmed by renal biopsy according to the International
Society of Nephrology (ISN)/Renal Pathology Society (RPS) classification within
36 months preceding the first dose of investigational product.
6. Patients with a current serological active status defined as an increased serum anti-dsDNA > 25% by Farr assay or above the upper limit of normal (ULN) [SELENA-SLEDAI score = 2] and/or a decrease in C3 and below lower limit of normal (LLN) [SELENA-SLEDAI score = 2]. Abnormality will be confirmed by a central laboratory from a serum sample taken within 3 weeks preceeding the first dose of investigational product
7. Patient has completed immunosuppressant SLE treatment (if any) for active
glomerulonephritis or major organ involvement with cyclophosphamide, MMF, AZA,
methotrexate, cyclosporine, etc., other than listed in inclusion criterion No. 8, within
8 weeks preceding the first dose of investigational product administration
8. Concurrent maintenance immunosuppressant SLE treatment (if any) with less than or equal to 20 mg/day prednisone (or equivalent) alone or in combination with either less than or equal to 2 mg/kg/day AZA or less than or equal to 2 g/day MMF has been stable for 4 weeks preceding the first dose of investigational product and is intended to remain stable within 4 weeks after first dose of investigational
product
9. Concurrent adjuvant maintenance SLE treatment (if any) such as antimalarials,
angiotesnin-converting enzyme (ACE) inhibitors, NSAIDs, cyclooxygenase inhibitors,
anticoagulation- and antiplatelet agents, hormone replacement therapy, etc., has been stable for 4 weeks preceding the first dose of investigational product and is intended to remain stable within 4 weeks after first dose of investigational product
10. Women of childbearing potential must have a negative serum pregnancy test within 3 weeks preceding the first dose of investigational product and a negative urine pregnancy test on study Day 1
11. Both women of childbearing potential and men must use a medically acceptable method of contraception prior to inclusion, throughout the study, and within
4 weeks after investigational product discontinuation
12. Adequate liver function expressed as:
a) Aspartate aminotransferase (AST) less than or equal to 3 times ULN and
b) Alanine aminotransferase (ALT) less than or equal to 3 times ULN and
c) Serum bilirubin less than or equal to 3 times ULN
13. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2, with a life expectancy of at least 9 months |
|
E.4 | Principal exclusion criteria |
1. Female patients who are nursing or pregnant, who may be pregnant, or who contemplate pregnancy during the study period
2. Patient is intended to receive immunosuppressive SLE treatment other than listed in inclusion criterion No. 8 within 4 weeks after first dose of investigational product
3. Patients with proteinuria > 3.5 g/day at baseline or glomerular filtration rate (GFR)
< 60 mL/min/1.73 m2
4. Patients with active SLE neurological disorders as described in Section 8 of the revised ACR SLE criteria within 12 weeks preceding the first dose of investigational product
5. Patients with a BILAG score defined as equal to or greater than 1 BILAG A score or equal to or greater than 2 BILAG B scores within 8 weeks preceding the first dose of investigational product
6. History of class VI glomerulonephritis
7. Patients with non-lupus related renal disease such as microthrombotic disease associated with antiphospholipid syndrome
8. Patients with known retroviral infection such as human immunodeficiency virus (HIV), hepatitis B or C
9. Patients with other acute infections within 4 weeks preceding the first dose of
investigational product
10. Patient received intravenous immunoglobulins (IVIGs) treatment within 12 weeks
preceding the first dose of investigational product
11. Patient received any B cell depleting therapy (e.g. Rituximab) within 48 weeks preceding the first dose of investigational product
12. Any kind of disorder that compromises the ability of the patient to give written informed consent and/or to comply with all study procedures
13. Known hypersensitivity to any recombinant E. coli-derived product or investigational product excipients (Polysorbat 20, Mannitol, Sucrose)
14. Patients participating in a concurrent clinical trial or treated with another investigational product within 4 weeks or five terminal half-lives (whichever is longer) preceding the first dose of investigational product
15. History of alcohol or drug abuse within the previous 5 years
16. Any condition which in the judgment of the Investigator would place the patient at undue risk or interfere with the results of the study
17. Patients with an active malignancy
18. Patients with active, serious, life-threatening disease with a life expectancy of less than 9 months |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Incidence of adverse events (AEs) during the study period according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4 |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Efficacy
Kidney parameters
• Change in proportion of patients with proteinuria (urine protein > 0.2, > 0.5, > 1.0 and > 2.0 g/day)
• Percent change of urine protein
• Percent change of glomerular filtration rate (GFR)
• Change in proportion of patients with active urine sediment defined as equal to or greater than 5 white blood cell (WBC) count/high power field (HPF) or equal to or greater than 5 red blood cell (RBC) count/HPF or equal to or greater than 1 cellular
cast
• Percent change of urinary neutrophil gelatinase-associated lipocalin (uNGAL)
• Proportion of patients with a complete or partial renal SLE response according to the kidney response criteria defined by the Systemic Lupus International Collaborating
Clinics (SLICC) group
• Incidence of end-stage renal disease (ESRD) requiring dialysis or renal transplantation
Serology parameters
• Percent change of anti-double-stranded DNA-antibodies (antidsDNA),
anti-complement-component C1q-antibodies (anti- C1q), C3 and C4 concentration
• Proportion of patients with a serological SLE response (defined as: a) 25% increase of C3 level and b) 4-fold decrease in anti-dsDNA concentration from baseline)
Numerical scoring parameters
• Renal activity score according to SLICC criteria • Percent change of the Safety of Estrogen in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index (SELENASLEDAI) score
• Percent change of British Isles Lupus Assessment Group BILAG score
• Percent change of the Physician Global Assessment (PGA) score
• Proportion of patients with a clinical SLE response (defined as reduction of at least 4, 5, 6 or 7 points in the SELENASLEDAI score from baseline)
• Proportion of patients with flares defined as 1 new BILAG A score or 2 new BILAG B scores
• Time to flare defined as 1 new BILAG A score or 2 new BILAG B scores
• Proportion of patients with no worsening (< 0.3 point increase from baseline) in the PGA score
Treatment parameters
• Proportion of patients requiring rescue medication, defined as increase in concomitant immunosuppression or new immunosuppressant therapy including corticosteroids
• Total number of rescue medication intake
• Cumulative dose of overall immunosuppressive SLE treatment including corticosteroids
• Proportion of patients with dose reduction of overall immunosuppressive SLE treatment including corticosteroids
Other
• Number of unscheduled hospital days • Investigational product PK parameters |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
From baseline to end of week 4, 12 and 24 except;
Incidence of end-stage renal disease (ESRD) requiring dialysis or renal transplantation from baseline to end of week 24
Proportion of patients with flares defined as 1 new BILAG A score or 2 new BILAG B scores from baseline to end of week 24
Time to flare defined as 1 new BILAG A score or 2 new BILAG B scores from baseline to end of week 24
Proportion of patients with no worsening (< 0.3 point increase from baseline) in the PGA score to end of week 24
Treatment parameters from baseline to end of week 24
Number of unscheduled hospital days from baseline to end of week 24
Investigational product PK parameters at end of week 1 and 4
|
|
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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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 | 3 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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 |
Belgium |
France |
Germany |
Italy |
Poland |
Spain |
United Kingdom |
|
E.8.7 | Trial has a data monitoring committee | Yes |
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
|
Last visit of the last subject |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |