Examining Distinct Immunophenotypes to Validate and Enhance Rational Treatment in Systemic Lupus

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 2, Double-Blind, Placebo-Controlled Trial of Mycophenolate Mofetil Alone or With Voclosporin for Systemic Lupus: Examining Distinct Immunophenotypes to Validate and Enhance Rational Treatment (DIVERT) (ALE10)

Conditions
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Systemic Lupus Erythematosus

Intervention / Treatment
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* Drug: Mycophenolate Mofetil
* Drug: Placebo for Mycophenolate Mofetil
* Drug: Voclosporin
* Drug: Placebo for Voclosporin
* Drug: Mycophenolate Mofetil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Participants must meet all of the following criteria to be eligible for randomization as study participants. Aged ≥ 18 and ≤ 60 years at the time of informed consent. Meets EULAR/ACR 2019 criteria for SLE. Moderately severe, active, but non-organ threatening disease. Specifically, signs or symptoms meeting criteria for a minimum of: 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 BILAG B (moderate) activity scores in any organ systems; or 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. 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: Convincing diagnosis of SLE, Active disease, due to SLE, warranting the potential of dual therapy with potent immune modulators, No medical or other condition to contraindicate participation in a placebo-controlled, outpatient study of this design. Women of childbearing potential must have a negative serum pregnancy test at screening. 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: 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. 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. The participant must agree that his/her symptoms have improved (yes/no). Exclusion Criteria Participants who meet any of the following criteria are not eligible for randomization as study participants: Inability or unwillingness of a participant to understand and provide written informed consent or comply with the study protocol. BILAG A (severe) disease in the Cardiorespiratory, Neuropsychiatric, Gastrointestinal, Ophthalmic, Renal, or Hematological Systems. Severe or unstable nephritis defined as any of the following: History of confirmed Class 3-5 nephritis within the last 2 years, History of confirmed Class 3-5 nephritis > 2 years ago in the absence of documented treatment including both induction and maintenance therapy, UPCR > 1 g/g at screening, • If UPCR is > 0.5 g/g and ≤ 1 g/g at screening, then a second assessment must be completed with at least 1 week between assessments. If the second assessment is > 1 g/g or has increased by ≥ 0.3 g/g, then the participant is excluded. Evidence of chronic kidney disease defined as eGFR < 45 mL/min per 1.73 m2 at screening, where 175 x (Creatinine/88.4)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if of African descent). History of cirrhosis or chronic liver disease unrelated to SLE other than fatty liver disease. History, within 1 year of the Screening Visit, of uncontrolled SLE that would have warranted a BILAG A (except mucocutaneous, constitutional, musculoskeletal) including, but not limited to, hemolytic anemia, neuropsychiatric lupus, or interstitial lung disease. Uncontrolled HTN at the Screening or Randomization Visits defined as a blood pressure > 150/100 with or without treatment, not to exceed 3 complementary antihypertensive treatments. Any of the following laboratory values during screening: Hemoglobin (Hg) < 8.0 g/dL, WBC < 2.0 x 10^9 cells/L, ANC < 1.0 x 10^9 cells/L, Platelets < 60 x 10^9 cells/L at screening, • If platelets < 70 x 10^9 cells/L at screening, platelet count should be retested 2 weeks later. If platelets are < 60 x 10^9 cells/L at retest, participant will be excluded AST or ALT > 2.5 times the ULN, Serum IgG levels < 5 g/L Use of ≥ 40 mg/day of prednisone within 4 weeks prior to the Screening Visit or use of > 20 mg/day of prednisone at screening. Unwilling or unable to taper to ≤ 10 mg/day of prednisone or equivalent by the day of randomization. Use of hydroxychloroquine, chloroquine, or quinacrine, if taking, at a prescribed dose that has not been stable for at least 2 months prior to randomization. Use of MMF within 1 year of randomization. Use of CNIs within 3 months of randomization. Topical formulations applied stably for at least one month are allowed. Use of rituximab, obinutuzumab, ocrelizumab, or long-acting B cell depletion agents within 1 year of randomization. Use of agents ≥ 6 months and within 1 year of randomization is permitted if there is evidence of B cell reconstitution as defined as CD19+ counts of ≥ 50 cells/µL. History of intolerance or allergy to MMF, voclosporin, or long-acting corticosteroid preparations. Individuals with known hypersensitivity to Polysorbate 80 (Tween). A woman who is pregnant, breastfeeding, or planning pregnancy from the time of consent until 6 weeks after completion of the study. Any participant with plans for major surgery during the time of the trial. Active infections requiring hospitalization or intravenous antibiotics within 1 month prior to the Screening Visit. Any grade 2 infection or higher from 14 days prior to the Screening Visit and through the screening period that has not resolved by randomization. Acute herpes zoster within 4 months of the Screening Visit. Positive results from a SARS-CoV-2 antigen test administered 2 days prior to and on the day of first randomization. Positive Quantiferon Gold (or equivalent) assay. Indeterminate Quantiferon Gold (or equivalent) assays must be repeated (with same or other interferon gamma release assay per local policy) and shown to be negative. Alternatively, if the Quantiferon Gold (or equivalent) assay remains indeterminate, a participant must have a negative PPD. Finally, if the participant has had the BCG vaccine or has some other condition complicating the interpretation of TB testing, consultation with infection disease specialist must be obtained. • Participants diagnosed with latent TB are eligible but must have received appropriate prophylaxis for 30 days prior to initiation of Stage 2 treatment. Serologic evidence at screening of chronic infections including: HIV infection. Hepatitis B as indicated by surface antigen or hepatitis B core antibody positivity; if a participant has an isolated positive hepatitis B core antibody, they will be eligible to participate in the study if they are negative for reflex viral load at Screening. Hepatitis C as indicated by anti-hepatitis C antibody positivity; if a participant is Hepatitis C antibody positive, they will be eligible to participate in the study if they are negative for viral load at Screening. Current, diagnosed, or self-reported drug or alcohol abuse within the last 6 months that, in the opinion of the investigator, would interfere with the ability to comply with study protocol. Recipient of live attenuated vaccine(s) within 8 weeks of the Screening Visit. Use of investigational drugs (excluding SARS-CoV-2 vaccinations or SARS-CoV2 therapeutics) within 8 weeks of the Screening Visit or 5 half-lives, whichever is longer. Past or current mental or physical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements, or may impact the quality or interpretation of the data obtained from the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MMF<br>Participants will receive 500 mg mycophenolate mofetil (MMF) bid for 7 days, followed by 500mg and 1,000mg MMF in divided doses for 7 days. They will then continue at a stable dose of 1,000mg MMF bid. Visits to evaluate AEs, vital signs, hematology and chemistry, study medication compliance, medication use, disease status, participant reported outcomes, and to obtain biomarker samples will occur every 4 weeks after randomization | Drug: Mycophenolate Mofetil<br>* 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<br>* Other names: MMF;|
| Placebo Comparator: Placebo for MMF<br>Participants will receive 500 mg corresponding mycophenolate mofetil (MMF) placebo bid for 7 days, followed by 500mg and 1,000mg corresponding MMF placebo in divided doses for 7 days. They will then continue at a stable dose of 1,000mg corresponding MMF placebo bid. Visits to evaluate AEs, vital signs, hematology and chemistry, study medication compliance, medication use, disease status, participant reported outcomes, and to obtain biomarker samples will occur every 4 weeks after randomization | Drug: Placebo for Mycophenolate Mofetil<br>* 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<br>* Other names: MMF;|
| Experimental: MMF+ Placebo for Voclosporin<br>Participants randomized in this arm will receive up to 24 weeks of mycophenolate mofetil (MMF) plus placebo for voclosporin, also during the first 2 weeks of treatment, a single intramuscular injection of 80 mg methylprednisolone acetate may be administered if needed to achieve amelioration of symptoms without meeting the definition of treatment failure in Stage 3 and without a requirement to stop Stage 3 study-provided medication | Drug: Placebo for Voclosporin<br>* Weeks 1-24: 23.7 mg Placebo for Voclosporin (3 x 7.9 capsules) twice daily<br>Drug: Mycophenolate Mofetil<br>* Stage 3 Dosing: Participants who received placebo MMF in Stage 2: Week 1: Participants will receive 500mg MMF plus matching placebo for MMF (to appear like a 1000mg dose) twice daily Week 2: Participants will receive 500mg plus matching placebo for MMF (to appear like a 1000mg dose) and 1000mg in divided doses Weeks 3-24: 1000mg MMF twice daily Participants who received MMF in Stage 2 • Week 1-24: 1000mg MMF twice daily<br>* Other names: MMF;|
| Experimental: MMF+ Voclosporin<br>Participants randomized in this arm will receive up to 24 weeks of mycophenolate mofetil (MMF) plus voclosporin, also during the first 2 weeks of treatment, a single intramuscular injection of 80 mg methylprednisolone acetate may be administered if needed to achieve amelioration of symptoms without meeting the definition of treatment failure in Stage 3 and without a requirement to stop Stage 3 study-provided medication | Drug: Voclosporin<br>* Weeks 1-24: 23.7 mg Voclosporin (3 x 7.9 capsules) twice daily<br>* Other names: Lupkynis(TM);Drug: Mycophenolate Mofetil<br>* Stage 3 Dosing: Participants who received placebo MMF in Stage 2: Week 1: Participants will receive 500mg MMF plus matching placebo for MMF (to appear like a 1000mg dose) twice daily Week 2: Participants will receive 500mg plus matching placebo for MMF (to appear like a 1000mg dose) and 1000mg in divided doses Weeks 3-24: 1000mg MMF twice daily Participants who received MMF in Stage 2 • Week 1-24: 1000mg MMF twice daily<br>* Other names: MMF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The cumulative incidence of participants who experience a Stage 2 treatment failure | Treatment failure is defined as the first occurrence after randomization (Stage 2) of any of the following events: 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 or 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); or Premature permanent discontinuation of study-assigned treatment for any reason | At or before the Stage 2 Week 24 visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical response in Stage 2 defined by the BILAG-based Combined Lupus Assessment (BICLA) at Stage 2 Week 24 | Clinical response at Week 24 is defined by the BICLA as follows: All BILAG A scores must improve to B, C, or D, and All BILAG B scores must improve to C or D, and No new BILAG A scores among organs scored as B, C, D, or E, and ≤ 1 new BILAG B scores among organs scored as C, D, or E , and No worsening of H-SLEDAI total score, and Less than a 10% increase (worsening) in the Physician's Global Assessment (visual analogue scale). The reference values for BILAG, H-SLEDAI total score and PGA are the assessments obtained at the Screening Visit. | At Stage 2 Week 24 | 
| The cumulative incidence of participants who experience a Stage 3 treatment failure | Treatment failure is defined as the first occurrence after re-randomization (Stage 3) of any of the following events: Methylprednisolone acetate injection or treatment with a new or increased lupus medication, except the occasional use of corticosteroids for reasons not associated with SLE flare (see Section 7.1.2.2, Prednisone (or equivalent) for additional information); or 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); or Premature permanent discontinuation of study-assigned treatment for any reason. | At or before the Stage 3 Week 24 visit | 
| Time to treatment failure in Stage 3 | defined as the interval from the day of Stage 3 randomization until the day of treatment failure. | From the day of Stage 3 randomization until the date of Stage 3 clinical response, assessed up to the Week 24 visit | 
| Clinical response in Stage 3 | Defined by the Based Combined Lupus Assessment (BICLA) | At Stage 3 Week 24 | 
| The incidence of Grade 3 or higher related Adverse Events (AEs) in Stage 1 | Adverse Events (AEs) will be evaluated separately for each stage of the study | Day -28 to Day -1 | 
| The incidence of Grade 3 or higher related Adverse Events (AEs) in Stage 2 | Adverse Events (AEs) will be evaluated separately for each stage of the study | Day 0 up to Week 48 | 
| The incidence of Grade 3 or higher related Adverse Events (AEs) in Stage 3 | Adverse Events (AEs) will be evaluated separately for each stage of the study | After re-randomization Day 0 to Week 24 | 
| The incidence of Grade 3 or higher infections in Stage 1 |  | Day -28 to Day -1 | 
| The incidence of Grade 3 or higher infections in Stage 2 |  | Day 0 up to week 48 | 
| The incidence of Grade 3 or higher infections in Stage 3 |  | After re-randomization Day 0 to Week 24 | 
| 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 | Day -28 to Day -1 | 
| 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 | Day 0 up to Week 48 | 
| 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 | After re-randomization Day 0 to Week 24 | 
| The incidence of Grade 3 or higher hypertension in Stage 1 | The incidence of Grade 3 or higher hypertension, defined as a systolic blood pressure >=160 mm Hg or a diastolic blood pressure of >= 100 mm Hg | Day -28 to Day -1 | 
| The incidence of Grade 3 or higher hypertension in stage 2 | The incidence of Grade 3 or higher hypertension, defined as a systolic blood pressure >=160 mm Hg or a diastolic blood pressure of >= 100 mm Hg | Day 0 up to Week 48 | 
| 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 | After re-randomization Day 0 to Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Systemic Lupus, Mycophenolate Mofetil, Voclosporin