E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Lupus nephritis manifests as diverse patterns of immune complex-mediated renal disease affecting glomerular, tubulointerstitial, and vascular compartments. |
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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 | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10025140 |
E.1.2 | Term | Lupus nephritis |
E.1.2 | System Organ Class | 10038359 - Renal and urinary 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 |
• To assess the efficacy of 2 doses of voclosporin compared to placebo in achieving complete remission after 24 weeks of therapy in subjects with active Lupus Nephritis (LN). |
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E.2.2 | Secondary objectives of the trial |
• To assess the safety and tolerability of 2 doses of voclosporin over 48 weeks
compared to placebo in subjects with active LN.
• To assess the efficacy of 2 doses of voclosporin versus placebo over 48 weeks in
subjects with active LN. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written informed consent (by subject or legally acceptable representative) before any study-specific procedures are performed.
2. Male or female subjects aged 18 to 75 years inclusive at the time of consent.
3. Diagnosis of systemic lupus erythematosus (SLE) according to the American College of Rheumatology criteria (1997; see Appendix 7).
4. Kidney biopsy within 6 months prior to screening (Visit 1) with a histologic
diagnosis of lupus nephritis (International Society of Nephrology/Renal
Pathology Society 2003 classification of lupus nephritis) Classes III, IV-S or
IV-G, (A) or (A/C); or Class V, alone or in combination with Class III or IV;
see Appendix 5. If a subject has not had a recent kidney biopsy, one may be
performed to assess eligibility into the study provided consent is in place and
provided results are received before randomization.
5. Subjects with laboratory evidence of active nephritis at screening, defined as
follows:
• Class III, IV-S or IV-G
Confirmed proteinuria ≥1,500 mg/24 hours when assessed by 24-hour urine
collection, defined by a urine protein/creatinine ratio (UPCR) of
≥1.5 mg/mg assessed in a first morning void urine specimen (2 samples).
• Class V (alone or in combination with Class III or IV)
Confirmed proteinuria ≥2,000 mg/24 hours when assessed by 24-hour urine
collection, defined by a UPCR of ≥2 mg/mg assessed in a first morning
void urine specimen (2 samples)
6. In the opinion of the Investigator, subject requires high dose corticosteroids and immunosuppressive therapy. |
|
E.4 | Principal exclusion criteria |
1. Subjects unable or unwilling to give written informed consent and/or to comply with study procedures.
2. Estimated glomerular filtration rate (eGFR) as calculated by the Chronic Kidney Disease Epidemiology Collaboration equation of ≤45 mL/min/1.73 m2 at screening (Visit 1)
3. Currently taking or known need for any of the medications listed in Section 7.8, Prohibited Therapy and Concomitant Treatment.
4. Serum potassium >5.5 mmol/L at screening confirmed before randomization.
5. Currently requiring renal dialysis (hemodialysis or peritoneal dialysis) or expected to require dialysis during the study period.
6. A previous kidney transplant or planned transplant within study treatment period.
7. In the opinion of the Investigator, subject does not require long-term immunosuppressive treatment (in addition to corticosteroids).
8. Any known hypersensitivity or contraindication to MMF, mycophenolic acid, cyclosporine, corticosteroids or any components of these drug products.
9. Current or medical history of:
• Pancreatitis or gastrointestinal hemorrhage within 6 months prior to screening.
• Active unhealed peptic ulcer within 3 months prior to screening. If an ulcer has healed and the subject is on adequate therapy, the subject may be randomized.
• Congenital or acquired immunodeficiency.
• In the opinion of the Investigator, clinically significant drug or alcohol abuse 2 years prior to screening.
• Malignancy within 5 years of screening, with the exception of basal and squamous cell carcinomas treated by complete excision. Subjects with cervical dysplasia that is cervical intraepithelial neoplasia 1, but have been treated with conization or loop electrosurgical excision procedure, and have had a normal repeat PAP are allowed.
• Lymphoproliferative disease or previous total lymphoid irradiation.
• Severe viral infection (such as CMV, HBV, HCV) within 3 months of screening; or known human immunodeficiency virus infection.
• Active tuberculosis (TB), or known history of TB/evidence of old TB if not taking prophylaxis with isoniazid.
10. Other known clinically significant active medical conditions, such as:
• Severe cardiovascular disease including congestive heart failure, history of cardiac dysrhythmia or congenital long QT syndrome. QTcF (QT interval duration corrected for heart rate using method of Fridericia) exceeding 480 msec in the presence of a normal QRS interval (<110 msec) at time of screening will result in exclusion.
• Liver dysfunction (aspartate aminotransferase, alanine aminotransferase, or bilirubin greater than 2.5 times the upper limit of normal) at screening and confirmed before randomization.
• Chronic obstructive pulmonary disease or asthma requiring oral steroids.
• Bone marrow insufficiency unrelated to active SLE (according to Investigator judgment) with white blood cell count <2,500/mm3; absolute neutrophil count <1.3 × 103/μL; thrombocytopenia (platelet count <50,000/mm3).
• Active bleeding disorders.
• Current infection requiring IV antibiotics.
11. Any overlapping autoimmune condition for which the condition or the treatment of the condition may affect the study assessments or outcomes (e.g., scleroderma with significant pulmonary hypertension; any condition for
which additional immunosuppression is indicated). Overlapping conditions for which the condition or treatment is not expected to affect assessments or outcomes (e.g., Sjogren’s syndrome) are not excluded.
12. Other major physical or psychiatric illness or major traumatic injury within 6 months prior to screening.
13. Any other medical condition which, in the Investigator’s judgment, may be associated
with increased risk to the subject or may interfere with study assessments or
outcomes.
14. Subjects who are pregnant, breast feeding or, if of childbearing potential, not using
adequate contraceptive precautions. Subjects must agree to use adequate
contraception during the study and for 1 month after the last dose of the study
medication.
• Two reliable forms of contraception must be used simultaneously unless
abstinence is the chosen method. Effective contraception must be used before
beginning study medication, during study dosing, and 1 month following
discontinuation of study dosing, even when there has been a history of infertility,
unless due to hysterectomy.
15. Participation in another clinical trial within 4 weeks prior to screening (Visit 1) and/or
receipt of investigational drugs within 4 weeks or 5 half-lives of the drug (whichever
is longer) prior to screening (Visit 1). |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary Endpoint:
Complete remission is defined as:
• Confirmed protein/creatinine ratio of ≤0.5 mg/mg and
• eGFR ≥60 mL/min/1.73 m2 or no confirmed decrease from baseline in eGFR of
≥20%.
Subjects who receive rescue medication for lupus (see Section 7.8, Prohibited
Therapy and Concomitant Treatment) or >10 mg prednisone for >3 consecutive
days or >7 days total from Weeks 16-26 will not be considered as achieving
complete remission. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
• Complete remission as per the primary endpoint analyzed at Week 48
• Complete remission in the presence of low dose steroids at Week 24 (defined as
confirmed complete remission and ≤5 mg prednisone for ≥8 weeks) and Week 48
(defined as confirmed complete remission and ≤5 mg prednisone for ≥12 weeks)
• Time to complete remission
• Time to (and proportion achieving) sustained early complete remission (defined as
complete remission which occurs on or before Week 24 which is sustained through
Week 48)
• Time to sustained complete remission (defined as the first occurrence of complete
remission which is sustained through Week 48)
• Duration of complete remission (in months)
• Partial remission as defined by 50% reduction in UPCR from baseline to Week 24
and baseline to Week 48
• Time to partial remission
• Time to (and proportion achieving) sustained early partial remission (partial
remission which occurs on or before Week 24 which is sustained through Week 48)
• Time to sustained partial remission (defined as the first occurrence of partial
remission which is sustained through Week 48)
• Change from baseline in UPCR at Week 24 and Week 48
• Change from baseline in serum creatinine, urine protein, serum albumin, and eGFR at
each time point
• Proportion of subjects with active urinary sediment (defined by >10 RBC/hpf with
dysmorphic RBC and/or RBC casts on urinalysis of a urine sample which has a
minimum volume of 50 mL) at each visit
• Change from baseline in the SELENA-SLEDAI score at Week 24 and Week 48
• Change from screening in immunology parameters (C3, C4, and anti-dsDNA) and
biomarkers (to be determined) at Weeks 12, 24 ,and 48 |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoints as specified in section E.5.2 |
|
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 | Yes |
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
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 |
Argentina |
Belarus |
Bulgaria |
Georgia |
Guatemala |
Mexico |
Poland |
Russian Federation |
Serbia |
Spain |
Sri Lanka |
Ukraine |
United States |
|
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 | 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 | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |