Lupus Nephritis
Conditions
Keywords
lupus nephritis, calcineurin inhibitors, voclosporin
Brief summary
The purpose of this study is to assess the efficacy of voclosporin compared with placebo in achieving renal response after 52 weeks of therapy in subjects with active lupus nephritis.
Detailed description
The aim of the current study is to investigate whether voclosporin, added to the standard of care treatment in active lupus nephritis (LN), is able to reduce disease activity over a treatment period of 52 weeks. The background therapy will be mycophenolate mofetil (MMF) and initial treatment with IV methylprednisolone, followed by a reducing course of oral corticosteroids. Subjects with active, flaring LN will be eligible to enter the study. They are required to have a diagnosis of LN according to established diagnostic criteria and clinical and biopsy features suggestive of active nephritis. Efficacy will be assessed by the ability of the drug combination to reduce the level of proteinuria (as measured by Urine Protein Creatinine Ratio (UPCR)) while demonstrating an acceptable safety profile.
Interventions
DRUGVoclosporin
calcineurin inhibitor
DRUGPlacebo Oral Capsule
matching placebo capsule
Sponsors
Aurinia Pharmaceuticals Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: \- Subjects with evidence of active nephritis, defined as follows: * Kidney biopsy result within 2 years prior to screening indicating Class III, IV-S, IV-G (alone or in combination with Class V), or Class V LN with a doubling or greater increase of UPCR within the last 6 months to a minimum of ≥1.5 mg/mg for Class III/IV or to a minimum of ≥2 mg/mg for Class V at screening. Biopsy results over 6 months prior to screening must be reviewed with a medical monitor to confirm eligibility. OR * Kidney biopsy result within 6 months prior to screening indicating Class III, IV-S or IV-G (alone or in combination with Class V) LN with a UPCR of ≥1.5 mg/mg at screening. OR * Kidney biopsy result within 6 months prior to screening indicating Class V LN and a UPCR of ≥2 mg/mg at screening. * Women of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test at baseline.
Exclusion criteria
* Estimated glomerular filtration rate (eGFR) of ≤45 mL/minute at screening. * Current or medical history of: * Congenital or acquired immunodeficiency. * In the opinion of the Investigator, clinically significant drug or alcohol abuse within 2 years prior to screening. * Malignancy within 5 years of screening, with the exception of basal and squamous cell carcinomas treated by complete excision. * Lymphoproliferative disease or previous total lymphoid irradiation. * Severe viral infection or known HIV infection. * Active tuberculosis (TB), or known history of TB/evidence of old TB if not taking prophylaxis with isoniazid. * Other known clinically significant active medical conditions, such as: * Severe cardiovascular disease, liver dysfunction or chronic obstructive pulmonary disease or asthma requiring oral steroids or any other overlapping autoimmune condition for which the condition or the treatment of the condition may affect the study assessments or outcomes.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adjudicated Renal Response at Week 52 | 52 Weeks | The primary efficacy endpoint was the number of subjects showing renal response at Week 52. Renal response was adjudicated based on blinded data by an independent Clinical Endpoints Committee based on meeting the following criteria * UPCR of ≤0.5 mg/mg & * eGFR ≥60 mL/min/1.73 m2 or no confirmed decrease from baseline in eGFR of \>20% & * Received no rescue medication for LN & * Did not receive more than 10 mg prednisone for ≥3 consecutive days or for ≥7 days in total during Weeks 44 through 52, prior to assessment Note:To be disqualified from renal response, the subject had to fail both eGFR measures (i.e., confirmed eGFR \<60 mL/min/1.73 m2 & confirmed \>20% drop from baseline) & have an associated treatment-related or disease-related AE that impacted eGFR Withdrawals prior to Week 52 with insufficient Week 52 data to determine response were defined non responders. Subjects who discontinued study drug but continued to attend study visits had their data assessed for response |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Urine Protein Creatinine Ratio of ≤0.5 mg/mg (Number of Days) | 52 Weeks | Time in days to reduction in Urine Protein Creatinine Ratio to decrease to 0.5 mg/mg or less. |
| Number of Participants With Renal Response at Week 24 | Week 24 | Number of subjects showing renal response at Week 24. Renal response was adjudicated based on blinded data by an Independent Clinical Endpoints Committee based on the following criteria: UPCR of ≤0.5 mg/mg, & eGFR ≥60 mL/min/1.73 m2 or no confirmed decrease from baseline in eGFR of \>20%, and Received no rescue medication for LN & Did not receive more than 10 mg prednisone for ≥3 consecutive days or for ≥7 days in total during Weeks 16 through 24, just prior to the renal response assessment. Note:To be disqualified from renal response, the subject had to fail both eGFR measures (i.e., confirmed eGFR \<60 mL/min/1.73 m2 AND confirmed \>20% drop from BL) & have an associated treatment-related or disease-related AE that impacted eGFR. Subjects who withdrew prior to the Week 24 assessment and provided insufficient Week 24 data to determine response were defined as non-responders. Subjects who discontinued study drug but continued to attend study visits had their data assessed for response. |
| Number of Subjects With Partial Renal Response at Weeks 24 & 52 | Weeks 24 and 52 | Number of subjects with partial Renal Response (defined as a 50% reduction in UPCR from baseline) at Week 24 and at Week 52. Baseline UPCR is the average of 2 pre-randomisation values. |
| Number of Subjects Achieving, and Remaining in, Renal Response (Urine Protein Creatinine Ratio ≤0.5 mg/mg) | Week 52 | Number of subjects achieving, and remaining in, renal response (Urine Protein Creatinine ratio ≤0.5 mg/mg) |
| Duration of Renal Response (Number of Days) | Week 52 | Duration in days until second occurrence of UPCR \>0.5 mg/mg in those subjects who achieve a reduction in UPCR to below 0.5 mg/mg |
| Number of Subjects Achieving 50% Reduction in Urine Protein Creatinine Ratio | 52 Weeks | Number of subjects achieving 50% reduction in Urine Protein Creatinine ratio |
| Number of Participants With Reduction in Urine Protein Creatinine Ratio to 0.5 mg/mg or Less | 52 Weeks | Number of Participants With Reduction in Urine Protein Creatinine Ratio to 0.5 mg/mg or Less |
| Change From Baseline in eGFR | Baseline and Weeks 2, 4, 8, 12, 16, 16, 20, 24, 30, 36, 42, 48 and 52. | Change from baseline by visit in estimated Glomerular Filtration rate. eGFR is corrected to a maximum value of 90 mL/min/1.73 m2 |
| Change From Baseline in UPCR | Baseline and Weeks 2, 4, 8, 12, 16, 16, 20, 24, 30, 36, 42, 48 and 52. | Change from baseline by visit in Urine Protein Creatinine Ratio. Baseline is the average of two pre-randomisation values. |
| Number of Subjects With Renal Response With Low Dose Steroids | Week 24 and Week 52 | Programmed Renal Response whilst on low dose steroids (\<2.5 mg/day) for the preceding 8 Weeks at Weeks 24 and 52 |
| Change From Baseline in Safety of Estrogens in Systemic Lupus Erythematosus National Assessment Systemic Lupus Erythematosus Disease Activity Index (SELENA - SLEDAI) | Week 24 and Week 52 | Change from baseline in Safety of Estrogens in Systemic Lupus Erythematosus National Assessment Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score at Week 24 and 52. The SELENA-SLEDAI tool is a cumulative and weighted index used to assess disease activity across 24 different disease descriptors in patients with lupus. A patient's SELENA-SLEDAI total score is the sum of all marked lupus related descriptors (seizure, psychosis, organic brain syndrome, visual disturbance, cranial nerve disorder, lupus headache, cerebrovascular accident, vasculitis, arthritis, myositis, urinary casts, hematuria, proteinuria, pyuria, new rash, alopecia, mucosal ulcers, pleurisy, pericarditis, low complement, increased DNA binding, fever, thrombocytopenia, leukopenia). A total score can fall between 0 and 105, with a higher score representing a more significant degree of disease activity. |
| Change From Baseline in Patient Reported Outcomes | Week 24 and Week 52 | Health-related quality of life (HRQoL) information was collected using the Short Form Health Survey (SF-36) HRQoL assessment and the LupusPRO (v1.7) assessment. The SF-36 is a participant self-rated questionnaire that is a general measure of perceived health status comprising 36 questions, which yields an 8-scale health profile. Scoring ranges from 0 to 100 with higher scores reflecting better health. LupusPro assessment is a patient-reported questionnaire regarding the effect of lupus or its treatment on the patient's health, quality of life, and the medical care received related to lupus. The questionnaire consists of 43 questions within 8 HRQOL domains and 4 Non-HRQoL domains. Scores range from 0 to 100 with higher scores reflecting better quality of life. |
| Time to 50% Reduction in UPCR (Number of Days) | 52 weeks | Time in days to reduction in Urine Protein Creatinine Ratio to decrease by 50% compared to baseline. Baseline is the average of two pre-randomisation values. |
Countries
Argentina, Belarus, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Croatia, Dominican Republic, Guatemala, Japan, Malaysia, Mexico, Netherlands, North Macedonia, Peru, Philippines, Poland, Puerto Rico, Russia, Serbia, South Africa, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United States, Vietnam
Participant flow
Recruitment details
Eligible subjects were randomized in a ratio of 1:1 to receive either voclosporin 23.7 mg twice daily (BID) or matching placebo for 52 weeks. All subjects were also to receive 2 g/day mycophenolate mofetil (MMF). In addition, all subjects were to receive 0.5 g/day intravenous (IV) methylprednisolone on Days 1 and 2 before changing to a reducing course of oral corticosteroid therapy on Day 3.
Participants by arm
| Arm | Count |
|---|---|
| Voclosporin oral, 23.7 mg BID
Voclosporin: calcineurin inhibitor | 179 |
| Placebo Voclosporin placebo, oral, 3 capsules BID
Placebo: matching placebo capsule | 178 |
| Total | 357 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Adverse Event (AE) Prior to First Dose | 1 | 0 |
| Overall Study | Death | 1 | 5 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 3 |
| Overall Study | None of the above | 0 | 4 |
| Overall Study | Physician Decision | 2 | 3 |
| Overall Study | Pregnancy | 1 | 0 |
| Overall Study | Prohibited medication required | 1 | 0 |
| Overall Study | Protocol non-compliance | 1 | 1 |
| Overall Study | Withdrawal by Subject | 7 | 14 |
Baseline characteristics
| Characteristic | Voclosporin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 32.8 years STANDARD_DEVIATION 10.93 | 33.6 years STANDARD_DEVIATION 11 | 33.2 years STANDARD_DEVIATION 10.96 |
| Baseline estimated glomerular filtration rate (eGFR) | 92.1 mL/min/1.73 m2 STANDARD_DEVIATION 30.06 | 90.4 mL/min/1.73 m2 STANDARD_DEVIATION 28.97 | 91.2 mL/min/1.73 m2 STANDARD_DEVIATION 29.51 |
| Baseline Urine Protein Creatinine Ratio (UPCR) | 4.14 mg/mg STANDARD_DEVIATION 2.711 | 3.87 mg/mg STANDARD_DEVIATION 2.363 | 4.00 mg/mg STANDARD_DEVIATION 2.537 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 57 Participants | 59 Participants | 116 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 122 Participants | 118 Participants | 240 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Lupus Nephritis (LN) history Years since diagnosis of LN | 4.6 years STANDARD_DEVIATION 5.07 | 4.7 years STANDARD_DEVIATION 4.89 | 4.6 years STANDARD_DEVIATION 4.97 |
| Lupus Nephritis (LN) history Years since diagnosis of systemic lupus erythematosus (SLE) | 6.6 years STANDARD_DEVIATION 6.41 | 6.9 years STANDARD_DEVIATION 6.07 | 6.7 years STANDARD_DEVIATION 6.23 |
| Lupus Nephritis (LN) history Years since first Proteinuria | 4.8 years STANDARD_DEVIATION 5.2 | 4.6 years STANDARD_DEVIATION 4.51 | 4.7 years STANDARD_DEVIATION 4.86 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) Asian | 53 Participants | 56 Participants | 109 Participants |
| Race (NIH/OMB) Black or African American | 21 Participants | 13 Participants | 34 Participants |
| Race (NIH/OMB) More than one race | 37 Participants | 44 Participants | 81 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 68 Participants | 61 Participants | 129 Participants |
| Region of Enrollment Europe | 52 participants | 52 participants | 104 participants |
| Region of Enrollment South America | 49 participants | 48 participants | 97 participants |
| Region of Enrollment Southeast Asia | 52 participants | 52 participants | 104 participants |
| Region of Enrollment United States | 26 participants | 26 participants | 52 participants |
| Sex: Female, Male Female | 161 Participants | 152 Participants | 313 Participants |
| Sex: Female, Male Male | 18 Participants | 26 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 178 | 5 / 178 |
| other Total, other adverse events | 161 / 178 | 156 / 178 |
| serious Total, serious adverse events | 37 / 178 | 38 / 178 |
Outcome results
Primary
Number of Participants With Adjudicated Renal Response at Week 52
The primary efficacy endpoint was the number of subjects showing renal response at Week 52. Renal response was adjudicated based on blinded data by an independent Clinical Endpoints Committee based on meeting the following criteria * UPCR of ≤0.5 mg/mg & * eGFR ≥60 mL/min/1.73 m2 or no confirmed decrease from baseline in eGFR of \>20% & * Received no rescue medication for LN & * Did not receive more than 10 mg prednisone for ≥3 consecutive days or for ≥7 days in total during Weeks 44 through 52, prior to assessment Note:To be disqualified from renal response, the subject had to fail both eGFR measures (i.e., confirmed eGFR \<60 mL/min/1.73 m2 & confirmed \>20% drop from baseline) & have an associated treatment-related or disease-related AE that impacted eGFR Withdrawals prior to Week 52 with insufficient Week 52 data to determine response were defined non responders. Subjects who discontinued study drug but continued to attend study visits had their data assessed for response
Time frame: 52 Weeks
Population: Intent to Treat
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Voclosporin | Number of Participants With Adjudicated Renal Response at Week 52 | Number of renal responders | 73 Participants |
| Voclosporin | Number of Participants With Adjudicated Renal Response at Week 52 | Number of renal non-responders | 106 Participants |
| Placebo Oral Capsule | Number of Participants With Adjudicated Renal Response at Week 52 | Number of renal responders | 40 Participants |
| Placebo Oral Capsule | Number of Participants With Adjudicated Renal Response at Week 52 | Number of renal non-responders | 138 Participants |
Comparison: The primary endpoint was the proportion of subjects showing renal response at Week 52 as adjudicated by the Clinical Endpoints Committee.p-value: <0.00195% CI: [1.64, 4.27]Regression, Logistic
Secondary
Change From Baseline in eGFR
Change from baseline by visit in estimated Glomerular Filtration rate. eGFR is corrected to a maximum value of 90 mL/min/1.73 m2
Time frame: Baseline and Weeks 2, 4, 8, 12, 16, 16, 20, 24, 30, 36, 42, 48 and 52.
Population: Intent to Treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Voclosporin | Change From Baseline in eGFR | Week 2 change from baseline | -1.5 ml/min/1.73 square metres | Standard Deviation 9.44 |
| Voclosporin | Change From Baseline in eGFR | Week 24 change from baseline | -0.3 ml/min/1.73 square metres | Standard Deviation 13.8 |
| Voclosporin | Change From Baseline in eGFR | Week 8 change from baseline | -0.9 ml/min/1.73 square metres | Standard Deviation 13.1 |
| Voclosporin | Change From Baseline in eGFR | Week 30 change from baseline | -0.8 ml/min/1.73 square metres | Standard Deviation 14.2 |
| Voclosporin | Change From Baseline in eGFR | Week 12 change from baseline | -0.3 ml/min/1.73 square metres | Standard Deviation 11.74 |
| Voclosporin | Change From Baseline in eGFR | Week 36 change from baseline | -1.9 ml/min/1.73 square metres | Standard Deviation 14.89 |
| Voclosporin | Change From Baseline in eGFR | Baseline | 78.3 ml/min/1.73 square metres | Standard Deviation 15.83 |
| Voclosporin | Change From Baseline in eGFR | Week 42 change from baseline | -2.8 ml/min/1.73 square metres | Standard Deviation 16.7 |
| Voclosporin | Change From Baseline in eGFR | Week 16 change from baseline | -0.1 ml/min/1.73 square metres | Standard Deviation 12.27 |
| Voclosporin | Change From Baseline in eGFR | Week 48 change from baseline | -3.6 ml/min/1.73 square metres | Standard Deviation 17.2 |
| Voclosporin | Change From Baseline in eGFR | Week 4 change from baseline | -0.4 ml/min/1.73 square metres | Standard Deviation 10.39 |
| Voclosporin | Change From Baseline in eGFR | Week 52 change from baseline | -1.5 ml/min/1.73 square metres | Standard Deviation 16.16 |
| Voclosporin | Change From Baseline in eGFR | Week 20 change from baseline | -0.7 ml/min/1.73 square metres | Standard Deviation 12.09 |
| Placebo Oral Capsule | Change From Baseline in eGFR | Week 52 change from baseline | 1.5 ml/min/1.73 square metres | Standard Deviation 15 |
| Placebo Oral Capsule | Change From Baseline in eGFR | Baseline | 77.4 ml/min/1.73 square metres | Standard Deviation 16.98 |
| Placebo Oral Capsule | Change From Baseline in eGFR | Week 2 change from baseline | 3.3 ml/min/1.73 square metres | Standard Deviation 10.12 |
| Placebo Oral Capsule | Change From Baseline in eGFR | Week 4 change from baseline | 3.2 ml/min/1.73 square metres | Standard Deviation 9.86 |
| Placebo Oral Capsule | Change From Baseline in eGFR | Week 12 change from baseline | 3.3 ml/min/1.73 square metres | Standard Deviation 12.85 |
| Placebo Oral Capsule | Change From Baseline in eGFR | Week 16 change from baseline | 2.8 ml/min/1.73 square metres | Standard Deviation 13.25 |
| Placebo Oral Capsule | Change From Baseline in eGFR | Week 20 change from baseline | 3.2 ml/min/1.73 square metres | Standard Deviation 13.04 |
| Placebo Oral Capsule | Change From Baseline in eGFR | Week 24 change from baseline | 2.8 ml/min/1.73 square metres | Standard Deviation 13.84 |
| Placebo Oral Capsule | Change From Baseline in eGFR | Week 30 change from baseline | 1.8 ml/min/1.73 square metres | Standard Deviation 14.4 |
| Placebo Oral Capsule | Change From Baseline in eGFR | Week 36 change from baseline | 1.5 ml/min/1.73 square metres | Standard Deviation 14.84 |
| Placebo Oral Capsule | Change From Baseline in eGFR | Week 42 change from baseline | 1.5 ml/min/1.73 square metres | Standard Deviation 15.53 |
| Placebo Oral Capsule | Change From Baseline in eGFR | Week 48 change from baseline | 1.1 ml/min/1.73 square metres | Standard Deviation 15.71 |
| Placebo Oral Capsule | Change From Baseline in eGFR | Week 8 change from baseline | 3.8 ml/min/1.73 square metres | Standard Deviation 11.27 |
Comparison: Week 2p-value: <0.00195% CI: [-7.3, -1.9]Mixed Models Analysis
Comparison: Week 4p-value: 0.01495% CI: [-6.1, -0.7]Mixed Models Analysis
Comparison: Week 8p-value: <0.00195% CI: [-7.3, -1.9]Mixed Models Analysis
Comparison: Week 12p-value: 0.01795% CI: [-6, -0.6]Mixed Models Analysis
Comparison: Week 16p-value: 0.08595% CI: [-5.1, 0.3]Mixed Models Analysis
Comparison: Week 20p-value: 0.03595% CI: [-5.7, -0.2]Mixed Models Analysis
Comparison: Week 24p-value: 0.12195% CI: [-5, 0.6]Mixed Models Analysis
Comparison: Week 30p-value: 0.1295% CI: [-5, 0.6]Mixed Models Analysis
Comparison: Week 36p-value: 0.10295% CI: [-5.1, 0.5]Mixed Models Analysis
Comparison: Week 42p-value: 0.02295% CI: [-6.1, 0.5]Mixed Models Analysis
Comparison: Week 48p-value: 0.00495% CI: [-7, -1.3]Mixed Models Analysis
Comparison: Week 52p-value: 0.05595% CI: [-5.7, 0.1]Mixed Models Analysis
Secondary
Change From Baseline in Patient Reported Outcomes
Health-related quality of life (HRQoL) information was collected using the Short Form Health Survey (SF-36) HRQoL assessment and the LupusPRO (v1.7) assessment. The SF-36 is a participant self-rated questionnaire that is a general measure of perceived health status comprising 36 questions, which yields an 8-scale health profile. Scoring ranges from 0 to 100 with higher scores reflecting better health. LupusPro assessment is a patient-reported questionnaire regarding the effect of lupus or its treatment on the patient's health, quality of life, and the medical care received related to lupus. The questionnaire consists of 43 questions within 8 HRQOL domains and 4 Non-HRQoL domains. Scores range from 0 to 100 with higher scores reflecting better quality of life.
Time frame: Week 24 and Week 52
Population: Intent to Treat
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Voclosporin | Change From Baseline in Patient Reported Outcomes | LupusPRO non-HRQOL change from baseline at Week 24 | 1.06 score on a scale |
| Voclosporin | Change From Baseline in Patient Reported Outcomes | LupusPRO non-HRQOL change from baseline at Week 52 | 4.08 score on a scale |
| Voclosporin | Change From Baseline in Patient Reported Outcomes | SF-36 change from baseline at Week 24 | 6.64 score on a scale |
| Voclosporin | Change From Baseline in Patient Reported Outcomes | SF-36 change from baseline at Week 52 | 10.44 score on a scale |
| Voclosporin | Change From Baseline in Patient Reported Outcomes | LupusPRO HRQOL change from baseline at Week 24 | 7.7 score on a scale |
| Voclosporin | Change From Baseline in Patient Reported Outcomes | LupusPRO HRQOL change from baseline at Week 52 | 9.24 score on a scale |
| Placebo Oral Capsule | Change From Baseline in Patient Reported Outcomes | LupusPRO non-HRQOL change from baseline at Week 24 | 2.94 score on a scale |
| Placebo Oral Capsule | Change From Baseline in Patient Reported Outcomes | LupusPRO HRQOL change from baseline at Week 24 | 6.06 score on a scale |
| Placebo Oral Capsule | Change From Baseline in Patient Reported Outcomes | LupusPRO non-HRQOL change from baseline at Week 52 | 3.74 score on a scale |
| Placebo Oral Capsule | Change From Baseline in Patient Reported Outcomes | SF-36 change from baseline at Week 24 | 7.11 score on a scale |
| Placebo Oral Capsule | Change From Baseline in Patient Reported Outcomes | LupusPRO HRQOL change from baseline at Week 52 | 9.84 score on a scale |
| Placebo Oral Capsule | Change From Baseline in Patient Reported Outcomes | SF-36 change from baseline at Week 52 | 10.81 score on a scale |
Comparison: SF-36 Change from Baseline Week 24p-value: 0.73395% CI: [-3.21, 2.26]Mixed Models Analysis
Comparison: SF-36 Change from Baseline at Week 52p-value: 0.80195% CI: [-3.29, 2.54]Mixed Models Analysis
Comparison: LupusPRO HRQOL Change from Baseline at Week 24p-value: 0.23995% CI: [-1.14, 4.54]Mixed Models Analysis
Comparison: LupusPRO HRQOL Change from Baseline at Week 52p-value: 0.69595% CI: [-3.62, 2.42]Mixed Models Analysis
Comparison: LupusPRO non-HRQOL Change from Baseline at Week 24p-value: 0.1995% CI: [-4.72, 0.94]Mixed Models Analysis
Comparison: LupusPRO non-HRQOL Change from Baseline at Week 52p-value: 0.82695% CI: [-2.67, 3.35]Mixed Models Analysis
Secondary
Change From Baseline in Safety of Estrogens in Systemic Lupus Erythematosus National Assessment Systemic Lupus Erythematosus Disease Activity Index (SELENA - SLEDAI)
Change from baseline in Safety of Estrogens in Systemic Lupus Erythematosus National Assessment Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score at Week 24 and 52. The SELENA-SLEDAI tool is a cumulative and weighted index used to assess disease activity across 24 different disease descriptors in patients with lupus. A patient's SELENA-SLEDAI total score is the sum of all marked lupus related descriptors (seizure, psychosis, organic brain syndrome, visual disturbance, cranial nerve disorder, lupus headache, cerebrovascular accident, vasculitis, arthritis, myositis, urinary casts, hematuria, proteinuria, pyuria, new rash, alopecia, mucosal ulcers, pleurisy, pericarditis, low complement, increased DNA binding, fever, thrombocytopenia, leukopenia). A total score can fall between 0 and 105, with a higher score representing a more significant degree of disease activity.
Time frame: Week 24 and Week 52
Population: Intent to Treat
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Voclosporin | Change From Baseline in Safety of Estrogens in Systemic Lupus Erythematosus National Assessment Systemic Lupus Erythematosus Disease Activity Index (SELENA - SLEDAI) | Change from baseline at Week 24 | -4.5 scores on a scale |
| Voclosporin | Change From Baseline in Safety of Estrogens in Systemic Lupus Erythematosus National Assessment Systemic Lupus Erythematosus Disease Activity Index (SELENA - SLEDAI) | Change from baseline at Week 52 | -6 scores on a scale |
| Placebo Oral Capsule | Change From Baseline in Safety of Estrogens in Systemic Lupus Erythematosus National Assessment Systemic Lupus Erythematosus Disease Activity Index (SELENA - SLEDAI) | Change from baseline at Week 24 | -4.1 scores on a scale |
| Placebo Oral Capsule | Change From Baseline in Safety of Estrogens in Systemic Lupus Erythematosus National Assessment Systemic Lupus Erythematosus Disease Activity Index (SELENA - SLEDAI) | Change from baseline at Week 52 | -5.5 scores on a scale |
Comparison: Week 24p-value: 0.37395% CI: [-1.6, 0.6]Mixed Models Analysis
Comparison: Week 52p-value: 0.27795% CI: [-1.4, 0.4]Mixed Models Analysis
Secondary
Change From Baseline in UPCR
Change from baseline by visit in Urine Protein Creatinine Ratio. Baseline is the average of two pre-randomisation values.
Time frame: Baseline and Weeks 2, 4, 8, 12, 16, 16, 20, 24, 30, 36, 42, 48 and 52.
Population: Intent to Treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Voclosporin | Change From Baseline in UPCR | Week 52 change from baseline | -2.65 mg/mg | Standard Deviation 2.872 |
| Voclosporin | Change From Baseline in UPCR | Week 12 change from baseline | -2.56 mg/mg | Standard Deviation 2.293 |
| Voclosporin | Change From Baseline in UPCR | Baseline | 4.14 mg/mg | Standard Deviation 2.711 |
| Voclosporin | Change From Baseline in UPCR | Week 2 change from baseline | -1.46 mg/mg | Standard Deviation 1.991 |
| Voclosporin | Change From Baseline in UPCR | Week 4 change from baseline | -1.98 mg/mg | Standard Deviation 2.29 |
| Voclosporin | Change From Baseline in UPCR | Week 8 change from baseline | -2.23 mg/mg | Standard Deviation 2.213 |
| Voclosporin | Change From Baseline in UPCR | Week 16 change from baseline | -2.75 mg/mg | Standard Deviation 2.462 |
| Voclosporin | Change From Baseline in UPCR | Week 20 change from baseline | -2.74 mg/mg | Standard Deviation 2.968 |
| Voclosporin | Change From Baseline in UPCR | Week 24 change from baseline | -2.74 mg/mg | Standard Deviation 2.567 |
| Voclosporin | Change From Baseline in UPCR | Week 30 change from baseline | -2.66 mg/mg | Standard Deviation 3.336 |
| Voclosporin | Change From Baseline in UPCR | Week 36 change from baseline | -2.74 mg/mg | Standard Deviation 2.871 |
| Voclosporin | Change From Baseline in UPCR | Week 42 change from baseline | -2.91 mg/mg | Standard Deviation 2.522 |
| Voclosporin | Change From Baseline in UPCR | Week 48 change from baseline | -2.71 mg/mg | Standard Deviation 2.807 |
| Placebo Oral Capsule | Change From Baseline in UPCR | Week 36 change from baseline | -1.63 mg/mg | Standard Deviation 3.188 |
| Placebo Oral Capsule | Change From Baseline in UPCR | Week 12 change from baseline | -1.48 mg/mg | Standard Deviation 2.688 |
| Placebo Oral Capsule | Change From Baseline in UPCR | Week 20 change from baseline | -1.54 mg/mg | Standard Deviation 2.82 |
| Placebo Oral Capsule | Change From Baseline in UPCR | Week 48 change from baseline | -1.8 mg/mg | Standard Deviation 3.004 |
| Placebo Oral Capsule | Change From Baseline in UPCR | Baseline | 3.87 mg/mg | Standard Deviation 2.363 |
| Placebo Oral Capsule | Change From Baseline in UPCR | Week 24 change from baseline | -1.59 mg/mg | Standard Deviation 2.899 |
| Placebo Oral Capsule | Change From Baseline in UPCR | Week 2 change from baseline | -0.7 mg/mg | Standard Deviation 2.312 |
| Placebo Oral Capsule | Change From Baseline in UPCR | Week 42 change from baseline | -1.78 mg/mg | Standard Deviation 3.39 |
| Placebo Oral Capsule | Change From Baseline in UPCR | Week 4 change from baseline | -1.07 mg/mg | Standard Deviation 2.155 |
| Placebo Oral Capsule | Change From Baseline in UPCR | Week 30 change from baseline | -1.7 mg/mg | Standard Deviation 3.112 |
| Placebo Oral Capsule | Change From Baseline in UPCR | Week 8 change from baseline | -1.43 mg/mg | Standard Deviation 2.448 |
| Placebo Oral Capsule | Change From Baseline in UPCR | Week 52 change from baseline | -1.88 mg/mg | Standard Deviation 3.05 |
| Placebo Oral Capsule | Change From Baseline in UPCR | Week 16 change from baseline | -1.58 mg/mg | Standard Deviation 2.81 |
Comparison: Week 2p-value: 0.01195% CI: [-1, -0.13]Mixed Models Analysis
Comparison: Week 4p-value: <0.00195% CI: [-1.13, -0.4]Mixed Models Analysis
Comparison: Week 8p-value: <0.00195% CI: [-1.05, -0.34]Mixed Models Analysis
Comparison: Week 12p-value: <0.00195% CI: [-1.33, -0.55]Mixed Models Analysis
Comparison: Week 16p-value: <0.00195% CI: [-1.6, -0.76]Mixed Models Analysis
Comparison: Week 20p-value: <0.00195% CI: [-1.63, -0.68]Mixed Models Analysis
Comparison: Week 24p-value: <0.00195% CI: [-1.59, -0.72]Mixed Models Analysis
Comparison: Week 30p-value: <0.00195% CI: [-1.58, -0.46]Mixed Models Analysis
Comparison: Week 36p-value: <0.00195% CI: [-1.73, -0.69]Mixed Models Analysis
Comparison: Week 42p-value: <0.00195% CI: [-1.87, -0.86]Mixed Models Analysis
Comparison: Week 48p-value: <0.00195% CI: [-1.56, -0.55]Mixed Models Analysis
Comparison: Week 52p-value: <0.00195% CI: [-1.52, -0.46]Mixed Models Analysis
Secondary
Duration of Renal Response (Number of Days)
Duration in days until second occurrence of UPCR \>0.5 mg/mg in those subjects who achieve a reduction in UPCR to below 0.5 mg/mg
Time frame: Week 52
Population: Intent to Treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Voclosporin | Duration of Renal Response (Number of Days) | 216 days |
| Placebo Oral Capsule | Duration of Renal Response (Number of Days) | 198 days |
Secondary
Number of Participants With Reduction in Urine Protein Creatinine Ratio to 0.5 mg/mg or Less
Number of Participants With Reduction in Urine Protein Creatinine Ratio to 0.5 mg/mg or Less
Time frame: 52 Weeks
Population: Intent to Treat
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Voclosporin | Number of Participants With Reduction in Urine Protein Creatinine Ratio to 0.5 mg/mg or Less | Subjects with UPCR ≤ 0.5 | 116 Participants |
| Voclosporin | Number of Participants With Reduction in Urine Protein Creatinine Ratio to 0.5 mg/mg or Less | Subjects without UPCR ≤ 0.5 | 63 Participants |
| Placebo Oral Capsule | Number of Participants With Reduction in Urine Protein Creatinine Ratio to 0.5 mg/mg or Less | Subjects with UPCR ≤ 0.5 | 78 Participants |
| Placebo Oral Capsule | Number of Participants With Reduction in Urine Protein Creatinine Ratio to 0.5 mg/mg or Less | Subjects without UPCR ≤ 0.5 | 100 Participants |
p-value: <0.00195% CI: [1.51, 2.7]Log Rank
Secondary
Number of Participants With Renal Response at Week 24
Number of subjects showing renal response at Week 24. Renal response was adjudicated based on blinded data by an Independent Clinical Endpoints Committee based on the following criteria: UPCR of ≤0.5 mg/mg, & eGFR ≥60 mL/min/1.73 m2 or no confirmed decrease from baseline in eGFR of \>20%, and Received no rescue medication for LN & Did not receive more than 10 mg prednisone for ≥3 consecutive days or for ≥7 days in total during Weeks 16 through 24, just prior to the renal response assessment. Note:To be disqualified from renal response, the subject had to fail both eGFR measures (i.e., confirmed eGFR \<60 mL/min/1.73 m2 AND confirmed \>20% drop from BL) & have an associated treatment-related or disease-related AE that impacted eGFR. Subjects who withdrew prior to the Week 24 assessment and provided insufficient Week 24 data to determine response were defined as non-responders. Subjects who discontinued study drug but continued to attend study visits had their data assessed for response.
Time frame: Week 24
Population: intent to Treat
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Voclosporin | Number of Participants With Renal Response at Week 24 | Number of renal responders | 58 Participants |
| Voclosporin | Number of Participants With Renal Response at Week 24 | Number of renal non-responders | 121 Participants |
| Placebo Oral Capsule | Number of Participants With Renal Response at Week 24 | Number of renal responders | 35 Participants |
| Placebo Oral Capsule | Number of Participants With Renal Response at Week 24 | Number of renal non-responders | 143 Participants |
p-value: 0.00295% CI: [1.34, 3.72]Regression, Cox
Secondary
Number of Subjects Achieving 50% Reduction in Urine Protein Creatinine Ratio
Number of subjects achieving 50% reduction in Urine Protein Creatinine ratio
Time frame: 52 Weeks
Population: Intent-to-Treat
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Voclosporin | Number of Subjects Achieving 50% Reduction in Urine Protein Creatinine Ratio | Subjects with 50% UPCR reduction | 173 Participants |
| Voclosporin | Number of Subjects Achieving 50% Reduction in Urine Protein Creatinine Ratio | Subjects without 50% UPCR reduction | 6 Participants |
| Placebo Oral Capsule | Number of Subjects Achieving 50% Reduction in Urine Protein Creatinine Ratio | Subjects with 50% UPCR reduction | 135 Participants |
| Placebo Oral Capsule | Number of Subjects Achieving 50% Reduction in Urine Protein Creatinine Ratio | Subjects without 50% UPCR reduction | 43 Participants |
Secondary
Number of Subjects Achieving, and Remaining in, Renal Response (Urine Protein Creatinine Ratio ≤0.5 mg/mg)
Number of subjects achieving, and remaining in, renal response (Urine Protein Creatinine ratio ≤0.5 mg/mg)
Time frame: Week 52
Population: Intent to Treat population achieving UPCR \<0.5 mg/mg
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Voclosporin | Number of Subjects Achieving, and Remaining in, Renal Response (Urine Protein Creatinine Ratio ≤0.5 mg/mg) | Subjects achieving UPCR ≤ 0.5 mg/mg | 116 Participants |
| Voclosporin | Number of Subjects Achieving, and Remaining in, Renal Response (Urine Protein Creatinine Ratio ≤0.5 mg/mg) | number with 2nd occurrence of UPCR > 0.5 mg/mg | 53 Participants |
| Voclosporin | Number of Subjects Achieving, and Remaining in, Renal Response (Urine Protein Creatinine Ratio ≤0.5 mg/mg) | number without 2nd occurrence of UPCR > 0.5 mg/mg | 63 Participants |
| Placebo Oral Capsule | Number of Subjects Achieving, and Remaining in, Renal Response (Urine Protein Creatinine Ratio ≤0.5 mg/mg) | Subjects achieving UPCR ≤ 0.5 mg/mg | 78 Participants |
| Placebo Oral Capsule | Number of Subjects Achieving, and Remaining in, Renal Response (Urine Protein Creatinine Ratio ≤0.5 mg/mg) | number with 2nd occurrence of UPCR > 0.5 mg/mg | 37 Participants |
| Placebo Oral Capsule | Number of Subjects Achieving, and Remaining in, Renal Response (Urine Protein Creatinine Ratio ≤0.5 mg/mg) | number without 2nd occurrence of UPCR > 0.5 mg/mg | 41 Participants |
p-value: 0.34995% CI: [0.53, 1.25]Regression, Cox
p-value: 0.646Log Rank
Secondary
Number of Subjects With Partial Renal Response at Weeks 24 & 52
Number of subjects with partial Renal Response (defined as a 50% reduction in UPCR from baseline) at Week 24 and at Week 52. Baseline UPCR is the average of 2 pre-randomisation values.
Time frame: Weeks 24 and 52
Population: Intent to Treat
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Voclosporin | Number of Subjects With Partial Renal Response at Weeks 24 & 52 | Week 24 | 126 Participants |
| Voclosporin | Number of Subjects With Partial Renal Response at Weeks 24 & 52 | Week 52 | 125 Participants |
| Placebo Oral Capsule | Number of Subjects With Partial Renal Response at Weeks 24 & 52 | Week 24 | 89 Participants |
| Placebo Oral Capsule | Number of Subjects With Partial Renal Response at Weeks 24 & 52 | Week 52 | 92 Participants |
Comparison: Week 24p-value: <0.00195% CI: [1.56, 3.79]Regression, Logistic
Comparison: Week 52p-value: <0.00195% CI: [1.45, 3.51]Regression, Logistic
Secondary
Number of Subjects With Renal Response With Low Dose Steroids
Programmed Renal Response whilst on low dose steroids (\<2.5 mg/day) for the preceding 8 Weeks at Weeks 24 and 52
Time frame: Week 24 and Week 52
Population: Intent to Treat
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Voclosporin | Number of Subjects With Renal Response With Low Dose Steroids | Renal Response at Week 24 | 32 Participants |
| Voclosporin | Number of Subjects With Renal Response With Low Dose Steroids | Renal Response at Week 52 | 64 Participants |
| Placebo Oral Capsule | Number of Subjects With Renal Response With Low Dose Steroids | Renal Response at Week 24 | 16 Participants |
| Placebo Oral Capsule | Number of Subjects With Renal Response With Low Dose Steroids | Renal Response at Week 52 | 36 Participants |
Comparison: Week 24p-value: 0.00895% CI: [1.26, 4.71]Regression, Logistic
Comparison: Week 52p-value: <0.00195% CI: [1.48, 4]Regression, Logistic
Secondary
Time to 50% Reduction in UPCR (Number of Days)
Time in days to reduction in Urine Protein Creatinine Ratio to decrease by 50% compared to baseline. Baseline is the average of two pre-randomisation values.
Time frame: 52 weeks
Population: Intent to Treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Voclosporin | Time to 50% Reduction in UPCR (Number of Days) | 29 days |
| Placebo Oral Capsule | Time to 50% Reduction in UPCR (Number of Days) | 63 days |
p-value: <0.00195% CI: [1.62, 2.6]Log Rank
Secondary
Time to Urine Protein Creatinine Ratio of ≤0.5 mg/mg (Number of Days)
Time in days to reduction in Urine Protein Creatinine Ratio to decrease to 0.5 mg/mg or less.
Time frame: 52 Weeks
Population: Intent to Treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Voclosporin | Time to Urine Protein Creatinine Ratio of ≤0.5 mg/mg (Number of Days) | 169 days |
| Placebo Oral Capsule | Time to Urine Protein Creatinine Ratio of ≤0.5 mg/mg (Number of Days) | 372 days |