Systemic Lupus Erythematosus
Conditions
Keywords
Systemic Lupus, Mycophenolate Mofetil, Voclosporin
Brief summary
The primary purpose of this study is to evaluate the potential effectiveness of 24 weeks of MMF within previously discovered immunologically defined subsets of SLE patients. Treatment effects will be evaluated within the individual immunologically-homogenous subsets defined at screening. This study will also explore and compare pre-randomization gene expression patterns among responders and non-responders to MMF and MMF plus voclosporin, use comprehensive immunophenotyping to study the immunologic changes that accompany treatment- induced disease improvement and to better understand immunologic changes associated with the loss of clinical response.
Detailed description
The study was conducted in 3 stages with a maximum participant follow-up time of 56 weeks. Stage 1 was a treatment withdrawal period lasting up to 4 weeks where consenting participants receive up to 3 intramuscular injections of a long-acting corticosteroid to achieve amelioration of symptoms. In addition, participants withdraw from all other treatments for lupus with the following exceptions: (i) as needed (PRN) nonsteroidal anti-inflammatory treatments may be started or continued, (ii) PRN topicals may be continued, (iii) hydroxychloroquine, chloroquine, or quinacrine may be continued at any stable dose, and (iv) prednisone, if\<= 10 mg/day, may be continued at stable doses but not started. Qualifying participants from Stage 1 were randomized (1:1) into Stage 2 to receive either MMF or placebo for MMF for up to 48 weeks. Participants who experienced a Stage 2 treatment failure at or before the Week 24 visit and a corticosteroid injection was deemed sufficient for treatment without new or increased lupus medication were eligible to re-randomize (1:1) into Stage 3 to receive either MMF + Voclosporin or MMF + Placebo for Voclosporin for up to 24 Weeks. Participants who did not experience a Stage 2 treatment failure at or before the Stage 2 Week 48 visit were to return for an End of Study/Safety Follow-up visit 4 weeks after the final dose of study-provided medication. Similarly, participants who did not experience a Stage 3 treatment failure at or before the Stage 3 Week 24 visits were asked to return for an End of Study/Safety Follow-up visit 4 weeks after the final dose of study provided medication.
Interventions
DRUGMycophenolate Mofetil
Stage 2 Dosing: Week 1: Participants will receive 500mg MMF/Placebo twice daily Week 2: Participants will receive 500mg/Placebo in the morning and 1,000mg MMF/Placebo in the evening Weeks 3-48: Participants will receive 1000mg MMF/Placebo twice daily
DRUGPlacebo for Mycophenolate Mofetil
Stage 2 Dosing: Week 1: Participants will receive 500mg MMF/Placebo twice daily Week 2: Participants will receive 500mg/Placebo in the morning and 1,000mg MMF/Placebo in the evening Weeks 3-48: Participants will receive 1000mg MMF/Placebo twice daily
DRUGVoclosporin
Weeks 1-24: 23.7 mg Voclosporin (3 x 7.9 capsules) twice daily
DRUGPlacebo for Voclosporin
Weeks 1-24: 23.7 mg Placebo for Voclosporin (3 x 7.9 capsules) twice daily
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
Participants must meet all of the following criteria to be eligible for randomization as study participants. 1. Aged ≥ 18 and ≤ 60 years at the time of informed consent. 2. Meets EULAR/ACR 2019 criteria for SLE. 3. Moderately severe, active, but non-organ threatening disease. Specifically, signs or symptoms meeting criteria for a minimum of: 1. 1 BILAG A (severe) score in the constitutional, musculoskeletal or mucocutaneous system at the time of screening. See
Exclusion criteria
number 2 for additional detail. 2. 2 BILAG B (moderate) activity scores in any organ systems; or 3. 1 BILAG B (moderate) activity score in any organ systems and a SELENA-SLEDAI score of ≥ 6. * If there is only 1 BILAG B score: * If a musculoskeletal BILAG B is scored due to moderate arthritis, where some loss off functional range of movements was present on several days over the last 4 weeks, there must also be a minimum of at least 3 joints that are both tender and swollen due to lupus disease activity in wrists, MCPs or PIPs for the participant to qualify. * If a mucocutaneous BILAG B is scored due to acute or subacute cutaneous skin eruption, the rash must cover at least 4% of the body surface area for the participant to qualify. Any active discoid lesion or other form of chronic cutaneous lupus would be qualifying. 4. Approval, by an adjudication committee of a brief entry packet describing the type, severity and duration of symptoms meeting the minimal criteria for entry. The participant will meet this criterion if the committee is confident of all of the following: 1. Convincing diagnosis of SLE, 2. Active disease, due to SLE, warranting the potential of dual therapy with potent immune modulators, 3. No medical or other condition to contraindicate participation in a placebo-controlled, outpatient study of this design. 5. Women of childbearing potential must have a negative serum pregnancy test at screening. 6. Able or willing to use reliable methods of contraception, as outlined in the Mycophenolate REMS brochure for health care providers, from 4 weeks prior to first randomization to 6 weeks after completion of the study. This criterion applies to females of reproductive potential. Inclusion Criteria Required Prior to Randomization Participants who meet the following criterion at the Stage 2 Randomization Visit may proceed to randomization in Stage 2: 7. After completion of corticosteroid injection(s) and prior to randomization in Stage 2, the participant and his/her physician must agree that disease activity has improved sufficiently from screening such that randomization is acceptable. 1. The physician must score the CGI-C as moderately better or much better prior to randomization. • The reference value for the CGI-C should be the investigator's determination of the participant's condition at the Screening Visit. 2. The participant must agree that his/her symptoms have improved (yes/no).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Participants Who Experience a Stage 2 Treatment Failure at or Before the Stage 2 Week 24 Visit. | From Baseline to Stage 2 Week 24 | Treatment failure is defined as the first occurrence after randomization (Stage 2) of any of the following events: 1. Methylprednisolone acetate injection or treatment with a new or increased lupus medication, except the occasional use of corticosteroids for reasons not associated with Systemic Lupus Erythematosus (SLE) flare 2. British Isles Lupus Assessment Group (BILAG) flare, defined as any item marked new or worse that could support a BILAG A (severe flare) or 2 organs with items marked new or worse that could support a BILAG B (moderate flare), and if the participant's condition is deemed by the investigator to be moderately worse or much worse compared to the day of randomization, as assessed by the Clinician Global Impression of Change (CGI-C) 3. Premature permanent discontinuation of study-assigned treatment for any reason |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Response in Stage 2, Defined by the BILAG-based Combined Lupus Assessment (BICLA) at Stage 2 Week 24. | Stage 2 Week 24 | The BILAG-based Composite Lupus Assessment (BICLA) is a composite index used to assess disease activity in SLE. A BICLA response is defined as meeting all of the following criteria: * Improvement of all Screening BILAG A scores to B, C or D * Improvement of all Screening BILAG B scores to C or D * No new BILAG A score among organs scored as B, C, D, or E at Screening * \<= 1 new BILAG B score among organs scored as C, D, or E at Screening * No worsening of the Hybrid Systemic Lupus Erythematosus Disease Activity Index (H-SLEDAI) * Less than a 10% increase (worsening) in the Physician's Global Assessment (PGA) Participants who experience treatment failure prior to Stage 2 Week 24 visit are imputed as BICLA Non-responders at Stage 2 Week 24. Participants who do not have evaluable data at Stage 2 Week 24 for reasons other than a treatment failure are not imputed. |
| The Proportion of Participants Who Experience a Stage 3 Treatment Failure, After Stage 3 Re-randomization at or Before Completing Stage 3 Week 24. | From re-randomization to Stage 3 Week 24 | Treatment failure is defined as the first occurrence after re-randomization (Stage 3) of any of the following events: 1. Methylprednisolone acetate injection or treatment with a new or increased lupus medication, except the occasional use of corticosteroids for reasons not associated with Systemic Lupus Erythematosus (SLE) flare 2. British Isles Lupus Assessment Group (BILAG) flare, defined as any item marked new or worse that could support a BILAG A (severe flare) or 2 organs with items marked new or worse that could support a BILAG B (moderate flare), and if the participant's condition is deemed by the investigator to be moderately worse or much worse compared to the day of randomization, as assessed by the Clinician Global Impression of Change (CGI-C) 3. Premature permanent discontinuation of study-assigned treatment for any reason |
| The Incidence of Grade 3 or Higher Hypertension in Stage 1 | Day -28 to Day -1 | Defined as a systolic blood pressure \>= 160 mm Hg or a diastolic blood pressure of \>= 100 mm Hg |
| The Incidence of Grade 3 or Higher Hypertension in Stage 2 | Stage 2 Day 0 up to Stage 2 Week 48 | Defined as a systolic blood pressure \>= 160 mm Hg or a diastolic blood pressure of \>= 100 mm Hg |
| Time to Treatment Failure in Stage 3, Defined as the Interval From the Day of Stage 3 Randomization Until the Day of Treatment Failure. | Start of Stage 3 up to the day of treatment failure | Treatment failure is defined as the first occurrence after re-randomization (Stage 3) of any of the following events: 1. Methylprednisolone acetate injection or treatment with a new or increased lupus medication, except the occasional use of corticosteroids for reasons not associated with Systemic Lupus Erythematosus (SLE) flare 2. British Isles Lupus Assessment Group (BILAG) flare, defined as any item marked new or worse that could support a BILAG A (severe flare) or 2 organs with items marked new or worse that could support a BILAG B (moderate flare), and if the participant's condition is deemed by the investigator to be moderately worse or much worse compared to the day of randomization, as assessed by the Clinician Global Impression of Change (CGI-C) 3. Premature permanent discontinuation of study-assigned treatment for any reason |
| Clinical Response in Stage 3, Defined by the BILAG-based Combined Lupus Assessment (BICLA) at Stage 3 Week 24. | Stage 3 Week 24 | The BILAG-based Composite Lupus Assessment (BICLA) is a composite index used to assess disease activity in SLE. A BICLA response is defined as meeting all of the following criteria: * Improvement of all Screening BILAG A scores to B, C or D * Improvement of all Screening BILAG B scores to C or D * No new BILAG A score among organs scored as B, C, D, or E at Screening * \<= 1 new BILAG B score among organs scored as C, D, or E at Screening * No worsening of the Hybrid Systemic Lupus Erythematosus Disease Activity Index (H-SLEDAI) * Less than a 10% increase (worsening) in the Physician's Global Assessment (PGA) Participants who experience treatment failure prior to Stage 3 Week 24 visit are imputed as BICLA Non-responders at Stage 2 Week 24. Participants who do not have evaluable data at Stage 3 Week 24 for reasons other than a treatment failure are not imputed. |
| The Incidence of Grade 3 or Higher Related Adverse Events (AEs) in Stage 2 | Stage 2 Day 0 up to Stage 2 Week 48 | Defined as adverse events that emerged during Stage 2 that are of Grade 3 or higher with a relationship to Stage 2 study drug of Possible or Definite. |
| The Incidence of Grade 3 or Higher Related Adverse Events (AEs) in Stage 3 | After Stage 3 re-randomization Day 0 to Stage 3 Week 24 | Defined as adverse events that emerged during Stage 3 that are of Grade 3 or higher with a relationship to Stage 3 study drug of Possible or Definite. |
| The Incidence of Grade 3 or Higher Infections in Stage 1 | Day -28 to Day -1 | Defined as infection adverse events that emerged during Stage 1 and are of Grade 3 or higher. |
| The Incidence of Grade 3 or Higher Infections in Stage 2 | Stage 2 Day 0 up to Stage 2 Week 48 | Defined as infection adverse events that emerged during Stage 2 and are of Grade 3 or higher. |
| The Incidence of Grade 3 or Higher Infections in Stage 3 | After Stage 3 re-randomization Day 0 to Stage 3 Week 24 | Defined as infection adverse events that emerged during Stage 3 and are of Grade 3 or higher. |
| The Incidence of Renal Dysfunction in Stage 1 | Day -28 to Day -1 | Defined as Grade 3 or higher chronic kidney disease with eGFR \< 30 ml/min per 1.73 m\^2 |
| The Incidence of Renal Dysfunction in Stage 2 | Stage 2 Day 0 up to Stage 2 Week 48 | Defined as Grade 3 or higher chronic kidney disease with eGFR \< 30 ml/min per 1.73 m\^2 |
| The Incidence of Renal Dysfunction in Stage 3 | After Stage 3 re-randomization Day 0 to Stage 3 Week 24 | Defined as Grade 3 or higher chronic kidney disease with eGFR \< 30 ml/min per 1.73 m\^2 |
| The Incidence of Grade 3 or Higher Hypertension in Stage 3 | After Stage 3 re-randomization Day 0 to Stage 3 Week 24 | Defined as a systolic blood pressure \>= 160 mm Hg or a diastolic blood pressure of \>= 100 mm Hg |
Countries
United States
Participant flow
Recruitment details
10 sites were activated in the United States, beginning in October 2022. In Stage 1, 12 consenting participants received an intramuscular injection of a long-acting corticosteroid injection and withdrew from all other treatments for lupus. In Stage 2, 8 eligible participants were randomized to receive either MMF or placebo. In Stage 3, 3 eligible participants from Stage 2 were re-randomized to receive either MMF + Voclosporin or MMF + Placebo.
Pre-assignment details
A total of 12 participants consented from November 2022 to April 2024 at 7 sites.
Participants by arm
| Arm | Count |
|---|---|
| Stage 2 MMF Participants receive up to 48 weeks of MMF. A scheduled ramp-up takes place for the first two weeks. Participants receive 500 mg of MMF twice a day for 7 days, followed by 500 mg and 1000 mg of MMF in divided doses for 7 days, followed by a continued stable dose of 1000 mg of MMF twice a day. | 4 |
| Stage 2 Placebo for MMF Participants receive up to 48 weeks of placebo for MMF. A scheduled ramp-up takes place for the first two weeks. Participants receive 500 mg of placebo twice a day for 7 days, followed by 500 mg and 1000 mg of placebo in divided doses for 7 days, followed by a continued stable dose of 1000 mg of placebo twice a day. | 4 |
| Stage 3 MMF + Voclosporin Participants receive up to 24 weeks of MMF plus 23.7 mg voclosporin (3 x 7.9 mg capsules) twice daily. Participants who previously received placebo in Stage 2 receive a scheduled ramp-up of MMF for the first two weeks.
Participants who received placebo in Stage 2:
* Week 1: participants receive 500 mg MMF plus matching MMF placebo (to appear like a 1000mg dose) twice daily
* Week 2: participants receive 500 mg plus matching placebo for MMF (to appear like a 1000 mg dose) and 1000 mg MMF in divided doses
* Weeks 3-24: 1000 mg MMF twice daily
Participants who receive MMF in Stage 2:
• Weeks 1-24: 1000 mg MMF twice daily | 2 |
| Stage 3 MMF + Placebo for Voclosporin Participants receive up to 24 weeks of MMF plus 23.7 mg volvlosporin placebo (3 x 7.9 mg capsules) twice daily. Participants who previously received MMF placebo in Stage 2 receive a scheduled ramp-up of MMF for the first two weeks.
Participants who received placebo in Stage 2:
* Week 1: participants receive 500 mg MMF plus matching placebo (to appear like a 1000mg dose) twice daily
* Week 2: participants receive 500 mg plus matching placebo for MMF (to appear like a 1000 mg dose) and 1000 mg MMF in divided doses
* Weeks 3-24: 1000 mg MMF twice daily
Participants who received MMF in Stage 2:
• Weeks 1-24: 1000 mg MMF twice daily | 1 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Stage 2 | Logistical issues due to participant moving | 1 | 0 | 0 | 0 |
| Stage 2 | Stage 2 Treatment Failure | 2 | 3 | 0 | 0 |
| Stage 2 | Study stopped | 1 | 1 | 0 | 0 |
| Stage 3 | Stage 3 Treatment Failure | 0 | 0 | 0 | 1 |
| Stage 3 | Study Stopped | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Stage 2 MMF | Total | Stage 2 Placebo for MMF | Stage 3 MMF + Voclosporin | Stage 3 MMF + Placebo for Voclosporin |
|---|---|---|---|---|---|
| Age, Continuous Stage 2 | 40.5 years STANDARD_DEVIATION 15.89 | 39.4 years STANDARD_DEVIATION 11.16 | 42.5 years STANDARD_DEVIATION 12.77 | — | — |
| Age, Continuous Stage 3 | — | 44.0 years STANDARD_DEVIATION 12.29 | — | 39.5 years STANDARD_DEVIATION 13.44 | 53.0 years |
| Ethnicity (NIH/OMB) Stage 2 Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants | — | — |
| Ethnicity (NIH/OMB) Stage 2 Not Hispanic or Latino | 4 Participants | 7 Participants | 3 Participants | — | — |
| Ethnicity (NIH/OMB) Stage 2 Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | — | — |
| Ethnicity (NIH/OMB) Stage 3 Hispanic or Latino | — | 0 Participants | — | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Stage 3 Not Hispanic or Latino | — | 3 Participants | — | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Stage 3 Unknown or Not Reported | — | 0 Participants | — | 0 Participants | 0 Participants |
| Race (NIH/OMB) Stage 2 American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Stage 2 Asian | 0 Participants | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Stage 2 Black or African American | 1 Participants | 2 Participants | 1 Participants | — | — |
| Race (NIH/OMB) Stage 2 More than one race | 0 Participants | 1 Participants | 1 Participants | — | — |
| Race (NIH/OMB) Stage 2 Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Stage 2 Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Stage 2 White | 3 Participants | 5 Participants | 2 Participants | — | — |
| Race (NIH/OMB) Stage 3 American Indian or Alaska Native | — | 0 Participants | — | 0 Participants | 0 Participants |
| Race (NIH/OMB) Stage 3 Asian | — | 0 Participants | — | 0 Participants | 0 Participants |
| Race (NIH/OMB) Stage 3 Black or African American | — | 0 Participants | — | 0 Participants | 0 Participants |
| Race (NIH/OMB) Stage 3 More than one race | — | 1 Participants | — | 1 Participants | 0 Participants |
| Race (NIH/OMB) Stage 3 Native Hawaiian or Other Pacific Islander | — | 0 Participants | — | 0 Participants | 0 Participants |
| Race (NIH/OMB) Stage 3 Unknown or Not Reported | — | 0 Participants | — | 0 Participants | 0 Participants |
| Race (NIH/OMB) Stage 3 White | — | 2 Participants | — | 1 Participants | 1 Participants |
| Region of Enrollment United States | 4 participants | 8 participants | 4 participants | 2 participants | 1 participants |
| Sex: Female, Male Stage 2 Female | 4 Participants | 8 Participants | 4 Participants | — | — |
| Sex: Female, Male Stage 2 Male | 0 Participants | 0 Participants | 0 Participants | — | — |
| Sex: Female, Male Stage 3 Female | — | 3 Participants | — | 2 Participants | 1 Participants |
| Sex: Female, Male Stage 3 Male | — | 0 Participants | — | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 4 | 0 / 4 | 0 / 2 | 0 / 1 |
| other Total, other adverse events | 2 / 12 | 3 / 4 | 3 / 4 | 1 / 2 | 0 / 1 |
| serious Total, serious adverse events | 0 / 12 | 0 / 4 | 1 / 4 | 0 / 2 | 0 / 1 |
Outcome results
Primary
The Percentage of Participants Who Experience a Stage 2 Treatment Failure at or Before the Stage 2 Week 24 Visit.
Treatment failure is defined as the first occurrence after randomization (Stage 2) of any of the following events: 1. Methylprednisolone acetate injection or treatment with a new or increased lupus medication, except the occasional use of corticosteroids for reasons not associated with Systemic Lupus Erythematosus (SLE) flare 2. British Isles Lupus Assessment Group (BILAG) flare, defined as any item marked new or worse that could support a BILAG A (severe flare) or 2 organs with items marked new or worse that could support a BILAG B (moderate flare), and if the participant's condition is deemed by the investigator to be moderately worse or much worse compared to the day of randomization, as assessed by the Clinician Global Impression of Change (CGI-C) 3. Premature permanent discontinuation of study-assigned treatment for any reason
Time frame: From Baseline to Stage 2 Week 24
Population: The modified Intent-to-Treat population includes all Stage 2 randomized participants who received at least one dose of Stage 2 study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 2 MMF | The Percentage of Participants Who Experience a Stage 2 Treatment Failure at or Before the Stage 2 Week 24 Visit. | 2 Participants |
| Stage 2 Placebo for MMF | The Percentage of Participants Who Experience a Stage 2 Treatment Failure at or Before the Stage 2 Week 24 Visit. | 2 Participants |
Secondary
Clinical Response in Stage 2, Defined by the BILAG-based Combined Lupus Assessment (BICLA) at Stage 2 Week 24.
The BILAG-based Composite Lupus Assessment (BICLA) is a composite index used to assess disease activity in SLE. A BICLA response is defined as meeting all of the following criteria: * Improvement of all Screening BILAG A scores to B, C or D * Improvement of all Screening BILAG B scores to C or D * No new BILAG A score among organs scored as B, C, D, or E at Screening * \<= 1 new BILAG B score among organs scored as C, D, or E at Screening * No worsening of the Hybrid Systemic Lupus Erythematosus Disease Activity Index (H-SLEDAI) * Less than a 10% increase (worsening) in the Physician's Global Assessment (PGA) Participants who experience treatment failure prior to Stage 2 Week 24 visit are imputed as BICLA Non-responders at Stage 2 Week 24. Participants who do not have evaluable data at Stage 2 Week 24 for reasons other than a treatment failure are not imputed.
Time frame: Stage 2 Week 24
Population: Includes all Stage 2 randomized participants who received at least one dose of Stage 2 study drug and had evaluable data at the Stage 2 Week 24 visit. Participants who experience treatment failure prior to Stage 2 Week 24 visit are considered BICLA Non-responders at Stage 2 Week 24.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Stage 2 MMF | Clinical Response in Stage 2, Defined by the BILAG-based Combined Lupus Assessment (BICLA) at Stage 2 Week 24. | BICLA Responder | 1 Participants |
| Stage 2 MMF | Clinical Response in Stage 2, Defined by the BILAG-based Combined Lupus Assessment (BICLA) at Stage 2 Week 24. | BICLA Non-responder | 2 Participants |
| Stage 2 Placebo for MMF | Clinical Response in Stage 2, Defined by the BILAG-based Combined Lupus Assessment (BICLA) at Stage 2 Week 24. | BICLA Responder | 0 Participants |
| Stage 2 Placebo for MMF | Clinical Response in Stage 2, Defined by the BILAG-based Combined Lupus Assessment (BICLA) at Stage 2 Week 24. | BICLA Non-responder | 3 Participants |
Secondary
Clinical Response in Stage 3, Defined by the BILAG-based Combined Lupus Assessment (BICLA) at Stage 3 Week 24.
The BILAG-based Composite Lupus Assessment (BICLA) is a composite index used to assess disease activity in SLE. A BICLA response is defined as meeting all of the following criteria: * Improvement of all Screening BILAG A scores to B, C or D * Improvement of all Screening BILAG B scores to C or D * No new BILAG A score among organs scored as B, C, D, or E at Screening * \<= 1 new BILAG B score among organs scored as C, D, or E at Screening * No worsening of the Hybrid Systemic Lupus Erythematosus Disease Activity Index (H-SLEDAI) * Less than a 10% increase (worsening) in the Physician's Global Assessment (PGA) Participants who experience treatment failure prior to Stage 3 Week 24 visit are imputed as BICLA Non-responders at Stage 2 Week 24. Participants who do not have evaluable data at Stage 3 Week 24 for reasons other than a treatment failure are not imputed.
Time frame: Stage 3 Week 24
Population: Includes all Stage 3 re-randomized participants who received at least one dose Stage 3 study drug and had evaluable data at the Stage 3 Week 24 visit. Participants who experience treatment failure prior to Stage 3 Week 24 visit are considered BICLA Non-responders at Stage 3 Week 24.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Stage 2 MMF | Clinical Response in Stage 3, Defined by the BILAG-based Combined Lupus Assessment (BICLA) at Stage 3 Week 24. | BICLA Responder | 0 Participants |
| Stage 2 MMF | Clinical Response in Stage 3, Defined by the BILAG-based Combined Lupus Assessment (BICLA) at Stage 3 Week 24. | BICLA Non-responder | 1 Participants |
| Stage 2 Placebo for MMF | Clinical Response in Stage 3, Defined by the BILAG-based Combined Lupus Assessment (BICLA) at Stage 3 Week 24. | BICLA Responder | 0 Participants |
| Stage 2 Placebo for MMF | Clinical Response in Stage 3, Defined by the BILAG-based Combined Lupus Assessment (BICLA) at Stage 3 Week 24. | BICLA Non-responder | 1 Participants |
Secondary
The Incidence of Grade 3 or Higher Hypertension in Stage 1
Defined as a systolic blood pressure \>= 160 mm Hg or a diastolic blood pressure of \>= 100 mm Hg
Time frame: Day -28 to Day -1
Population: Includes all participants who receive at least one IM injection of a long-acting corticosteroid or who initiate withdrawal of lupus medications in Stage 1.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 2 MMF | The Incidence of Grade 3 or Higher Hypertension in Stage 1 | 0 Participants |
Secondary
The Incidence of Grade 3 or Higher Hypertension in Stage 2
Defined as a systolic blood pressure \>= 160 mm Hg or a diastolic blood pressure of \>= 100 mm Hg
Time frame: Stage 2 Day 0 up to Stage 2 Week 48
Population: Includes participants who received at least one dose of Stage 2 study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 2 MMF | The Incidence of Grade 3 or Higher Hypertension in Stage 2 | 0 Participants |
| Stage 2 Placebo for MMF | The Incidence of Grade 3 or Higher Hypertension in Stage 2 | 0 Participants |
Secondary
The Incidence of Grade 3 or Higher Hypertension in Stage 3
Defined as a systolic blood pressure \>= 160 mm Hg or a diastolic blood pressure of \>= 100 mm Hg
Time frame: After Stage 3 re-randomization Day 0 to Stage 3 Week 24
Population: Includes participants who received at least one dose Stage 3 study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 2 MMF | The Incidence of Grade 3 or Higher Hypertension in Stage 3 | 0 Participants |
| Stage 2 Placebo for MMF | The Incidence of Grade 3 or Higher Hypertension in Stage 3 | 0 Participants |
Secondary
The Incidence of Grade 3 or Higher Infections in Stage 1
Defined as infection adverse events that emerged during Stage 1 and are of Grade 3 or higher.
Time frame: Day -28 to Day -1
Population: Includes all participants who receive at least one IM injection of a long-acting corticosteroid or who initiate withdrawal of lupus medications in Stage 1.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 2 MMF | The Incidence of Grade 3 or Higher Infections in Stage 1 | 0 Participants |
Secondary
The Incidence of Grade 3 or Higher Infections in Stage 2
Defined as infection adverse events that emerged during Stage 2 and are of Grade 3 or higher.
Time frame: Stage 2 Day 0 up to Stage 2 Week 48
Population: Includes participants who received at least one dose of Stage 2 study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 2 MMF | The Incidence of Grade 3 or Higher Infections in Stage 2 | 0 Participants |
| Stage 2 Placebo for MMF | The Incidence of Grade 3 or Higher Infections in Stage 2 | 1 Participants |
Secondary
The Incidence of Grade 3 or Higher Infections in Stage 3
Defined as infection adverse events that emerged during Stage 3 and are of Grade 3 or higher.
Time frame: After Stage 3 re-randomization Day 0 to Stage 3 Week 24
Population: Includes participants who received at least one dose of Stage 3 study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 2 MMF | The Incidence of Grade 3 or Higher Infections in Stage 3 | 0 Participants |
| Stage 2 Placebo for MMF | The Incidence of Grade 3 or Higher Infections in Stage 3 | 0 Participants |
Secondary
The Incidence of Grade 3 or Higher Related Adverse Events (AEs) in Stage 2
Defined as adverse events that emerged during Stage 2 that are of Grade 3 or higher with a relationship to Stage 2 study drug of Possible or Definite.
Time frame: Stage 2 Day 0 up to Stage 2 Week 48
Population: Includes all participants who received at least one dose of Stage 2 study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 2 MMF | The Incidence of Grade 3 or Higher Related Adverse Events (AEs) in Stage 2 | 0 Participants |
| Stage 2 Placebo for MMF | The Incidence of Grade 3 or Higher Related Adverse Events (AEs) in Stage 2 | 0 Participants |
Secondary
The Incidence of Grade 3 or Higher Related Adverse Events (AEs) in Stage 3
Defined as adverse events that emerged during Stage 3 that are of Grade 3 or higher with a relationship to Stage 3 study drug of Possible or Definite.
Time frame: After Stage 3 re-randomization Day 0 to Stage 3 Week 24
Population: Includes all participants who received at least one dose of Stage 3 study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 2 MMF | The Incidence of Grade 3 or Higher Related Adverse Events (AEs) in Stage 3 | 0 Participants |
| Stage 2 Placebo for MMF | The Incidence of Grade 3 or Higher Related Adverse Events (AEs) in Stage 3 | 0 Participants |
Secondary
The Incidence of Renal Dysfunction in Stage 1
Defined as Grade 3 or higher chronic kidney disease with eGFR \< 30 ml/min per 1.73 m\^2
Time frame: Day -28 to Day -1
Population: Includes all participants who receive at least one IM injection of a long-acting corticosteroid or who initiate withdrawal of lupus medications in Stage 1.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 2 MMF | The Incidence of Renal Dysfunction in Stage 1 | 0 Participants |
Secondary
The Incidence of Renal Dysfunction in Stage 2
Defined as Grade 3 or higher chronic kidney disease with eGFR \< 30 ml/min per 1.73 m\^2
Time frame: Stage 2 Day 0 up to Stage 2 Week 48
Population: Includes participants who received at least one dose of Stage 2 study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 2 MMF | The Incidence of Renal Dysfunction in Stage 2 | 0 Participants |
| Stage 2 Placebo for MMF | The Incidence of Renal Dysfunction in Stage 2 | 0 Participants |
Secondary
The Incidence of Renal Dysfunction in Stage 3
Defined as Grade 3 or higher chronic kidney disease with eGFR \< 30 ml/min per 1.73 m\^2
Time frame: After Stage 3 re-randomization Day 0 to Stage 3 Week 24
Population: Includes participants who received at least one dose Stage 3 study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 2 MMF | The Incidence of Renal Dysfunction in Stage 3 | 0 Participants |
| Stage 2 Placebo for MMF | The Incidence of Renal Dysfunction in Stage 3 | 0 Participants |
Secondary
The Proportion of Participants Who Experience a Stage 3 Treatment Failure, After Stage 3 Re-randomization at or Before Completing Stage 3 Week 24.
Treatment failure is defined as the first occurrence after re-randomization (Stage 3) of any of the following events: 1. Methylprednisolone acetate injection or treatment with a new or increased lupus medication, except the occasional use of corticosteroids for reasons not associated with Systemic Lupus Erythematosus (SLE) flare 2. British Isles Lupus Assessment Group (BILAG) flare, defined as any item marked new or worse that could support a BILAG A (severe flare) or 2 organs with items marked new or worse that could support a BILAG B (moderate flare), and if the participant's condition is deemed by the investigator to be moderately worse or much worse compared to the day of randomization, as assessed by the Clinician Global Impression of Change (CGI-C) 3. Premature permanent discontinuation of study-assigned treatment for any reason
Time frame: From re-randomization to Stage 3 Week 24
Population: The Stage 3 modified Intent-to-Treat population consists of all Stage 3 re-randomized participants who received at least one dose of Stage 3 study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 2 MMF | The Proportion of Participants Who Experience a Stage 3 Treatment Failure, After Stage 3 Re-randomization at or Before Completing Stage 3 Week 24. | 0 Participants |
| Stage 2 Placebo for MMF | The Proportion of Participants Who Experience a Stage 3 Treatment Failure, After Stage 3 Re-randomization at or Before Completing Stage 3 Week 24. | 1 Participants |
Secondary
Time to Treatment Failure in Stage 3, Defined as the Interval From the Day of Stage 3 Randomization Until the Day of Treatment Failure.
Treatment failure is defined as the first occurrence after re-randomization (Stage 3) of any of the following events: 1. Methylprednisolone acetate injection or treatment with a new or increased lupus medication, except the occasional use of corticosteroids for reasons not associated with Systemic Lupus Erythematosus (SLE) flare 2. British Isles Lupus Assessment Group (BILAG) flare, defined as any item marked new or worse that could support a BILAG A (severe flare) or 2 organs with items marked new or worse that could support a BILAG B (moderate flare), and if the participant's condition is deemed by the investigator to be moderately worse or much worse compared to the day of randomization, as assessed by the Clinician Global Impression of Change (CGI-C) 3. Premature permanent discontinuation of study-assigned treatment for any reason
Time frame: Start of Stage 3 up to the day of treatment failure
Population: All Stage 3 re-randomized participants who received at least one dose of Stage 3 study drug and experienced a Stage 3 treatment failure.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Stage 2 Placebo for MMF | Time to Treatment Failure in Stage 3, Defined as the Interval From the Day of Stage 3 Randomization Until the Day of Treatment Failure. | 69 Days |