Study of Efficacy and Safety of LNP023 in Participants With Active Lupus Nephritis Class III-IV, +/- V

Study Overview
=================
Brief Summary
-----------------
The overall purpose of this two-part study is to evaluate the efficacy, safety and tolerability of iptacopan (LNP023) in addition to standard of care treatment.

Detailed Description
-----------------
The overall purpose of this two-part study is to evaluate the efficacy, safety and tolerability of iptacopan (LNP023) in addition to standard of care treatment.

Official Title
-----------------
An Adaptive, Randomized, Double-blind, Dose Exploration, Parallel Group, Placebo Controlled, Multicenter Phase 2 Trial to Evaluate the Efficacy, Safety and Tolerability of LNP023 in Combination With Standard-of-care With and Without Oral Corticosteroids in Patients With Active Lupus Nephritis Class III-IV, +/- V

Conditions
-----------------
Lupus Nephritis

Intervention / Treatment
-----------------
* Drug: Iptacopan (part 1)
* Drug: Iptacopan (part 2)
* Drug: Placebo + standard of care
* Drug: Iptacopan + placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Unequivocally positive ANA test result and/or a positive anti dsDNA at screening Active biopsy-proven lupus nephritis within 3 months of screening demonstrating Class III or IV lupus nephritis with or without co-existing features of Class V lupus nephritis. Documentation of active renal disease at the time of screening necessitating the commencement of therapy with corticosteroids in combination with MMF/MPS. eGFR ≥ 30 ml/min/1.73 m2 Vaccination against Neisseria meningitidis and Streptococcus pneumoniae infections Vaccination against Haemophilus influenzae infection Supportive care including stable dose regimen of anti-malarials (e.g. hydroxychloroquine) unless contraindicated, ACEi or ARB at either locally approved maximal daily dose or the maximally tolerated dose (per investigators' judgement) at screening, as per the local clinical practice. Doses should remain stable throughout the study. First presentation or flare of lupus nephritis. Exclusion Criteria: Induction treatment with cyclophosphamide within 3 months of planned treatment for this study; treatment with calcineurin inhibitors within the previous 3 months prior to screening Presence of rapidly progressive glomerulonephritis (RPGN) as defined by 50% decline in eGFR within 3 months prior to screening. Renal biopsy presenting with interstitial fibrosis/tubular atrophy (IF/TA) or glomerulosclerosis of more than 50%, or which in the opinion of the investigator is such that it precludes likely response to immunosuppressive therapy. Participants being treated with systemic corticosteroids (>5 mg/day prednisone or equivalent) for indications other than SLE or LN e.g. acute asthma, inflammatory bowel disease. Participants being treated with systemic corticosteroids for SLE or LN will be excluded if they have taken more than an average of 10 mg/day prednisone (or equivalent) in the previous 4 weeks and more than an average of 20 mg/day in the previous 1 week Receipt of more than a total dose of 1000 mg equivalent i.v. pulse methylprednisolone (cumulative dose) within 2 weeks prior to enrollment (and at enrollment) Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Iptacopan + standard of care (part 1)<br>Iptacopan + standard of care | Drug: Iptacopan (part 1)<br>* Taken for 52 Weeks<br>* Other names: LNP023;|
| Placebo Comparator: Placebo matching iptacopan + standard of care (part 1)<br>Placebo matching iptacopan standard of care | Drug: Placebo + standard of care<br>* Taken for 52 Weeks<br>|
| Active Comparator: Iptacopan + standard of care (part 2)<br>Iptacopan + standard of care | Drug: Iptacopan (part 2)<br>* Taken for 52 Weeks<br>* Other names: LNP023;|
| Active Comparator: Iptacopan + placebo (part 2)<br>Iptacopan + placebo standard of care | Drug: Iptacopan + placebo<br>* Taken for 52 Weeks<br>* Other names: LNP023 and placebo;|
| Active Comparator: Placebo matching iptacopan + standard of care (part 2)<br>Placebo matching iptacopan + standard of care | Drug: Placebo + standard of care<br>* Taken for 52 Weeks<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and 2: Proportion of patients achieving Complete Renal Response (CRR) at week 24 in the absence of renal flares | Part 1: To evaluate the proportion of patients achieving complete renal response with iptacopan treatment A plus standard of care, compared to treatment alone Part 2: To evaluate the proportion of patients achieving complete renal response with Iptacopan treatment B plus standard of care, compared to treatment D alone Part 2: To evaluate the proportion of patients achieving complete renal response with Iptacopan treatment C plus standard of care, compared to treatment D alone Complete Renal Response is defined as meeting the following criteria: estimated glomerular filtration rate (eGFR) ≥ 90 mL/min/1.73 m2 or no less than 85% of baseline value, and 24h urine protein-to-creatinine ratio (UPCR) ≤ 0.5 g/g. | Baseline and week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts 1 and 2: Proportion of patients achieving CRR or PRR in the absence of renal flares | Proportion of patients achieving complete renal response or partial renal response | Baseline, week 24, week 52 | 
| Proportion of patients achieving ≥25% UPCR reduction in the absence of renal flares compared to baseline at week 24 | Frequency of renal flares between weeks 24 and 52 | Baseline, week 24 week 52 | 
| Log-transformed ratio to baseline of 24h UPCR at week 24 | Dose exposure response for reduction in proteinurea. (each 24h urine protein-to-creatinine ratio value will based on two 24 urine collections sampled within 10 days before the respective study visit) | Baseline week 24 | 
| Change from baseline FACIT-Fatigue Score | Measure fatigue in patients | Weeks 24 and 52 | 
| Change from baseline in SLEDAI-2K score at weeks 24 and 52 | Measure disease activity in SLE | Weeks 24 and 52 | 
| Change from baseline in BILAG-2004 score at weeks 24 and 52 | Measure disease activity | Weeks 24 and 52 | 
| Time-to-Complete Renal Response (CRR) based on first morning void(FMV) urine samples | Measurement of time to complete renal response based on urine samples | Week 24 and Week 52 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
LNP023, Iptacopan, Lupus Nephritis, proteinuria, Urine Protein-to-Creatinine Ratio, complete renal response, estimated glomerular filtration rate, renal flares, Systemic Lupus Erythematosus