Study of Efficacy and Safety of Iptacopan in Participants With IC-MPGN

Study Overview
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Brief Summary
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This study is designed as a multicenter, randomized, double-blind, parallel group, placebo-controlled study to evaluate the efficacy and safety of iptacopan (LNP023) in idiopathic immune complex mediated membranoproliferative glomerulonephritis.

Detailed Description
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The purpose of this Phase III study is to evaluate the efficacy and safety of iptacopan compared to placebo (both administered in combination with standard of care) in participants (adults and adolescents aged 12-17 years) with idiopathic IC-MPGN. The study aims to demonstrate a reduction in proteinuria and improvement in estimated glomerular filtration rate (eGFR) in participants treated with iptacopan compared to placebo. Change in patient-reported fatigue will also be evaluated. Alternative complement pathway (AP) dysregulation is believed to underlie the clinical manifestations and progression of IC-MPGN. Upon completion of study treatment, participants will have the option to discontinue iptacopan treatment and enter a 30 day safety follow-up or continue iptacopan treatment by transitioning to an open label extension study (CLNP023B12001B; NCT03955445) and continue iptacopan treatment.

Official Title
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A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled Study to Evaluate the Efficacy and Safety of Iptacopan (LNP023) in Idiopathic Immune Complex Mediated Membranoproliferative Glomerulonephritis (IC-MPGN)

Conditions
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IC-MPGN

Intervention / Treatment
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* Drug: Placebo
* Drug: iptacopan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female participants age ≥ 12 and ≤ 60 years at screening. Diagnosis of idiopathic IC-MPGN as confirmed by kidney biopsy within 12 months prior to enrollment in adults and within 3 years of enrollment in adolescents (a biopsy report, review and confirmation by the Investigator is required). If such a biopsy is not available in an adult participant, this must be obtained at screening (performed and assessed locally for adults only). Prior to randomization, all participants must have been on a maximally recommended or tolerated dose of an ACEI or ARB for at least 90 days (or as according to local guidelines). The doses of other drugs administered to reduce proteinuria and control the disease including mycophenolic acids (MPAs - mycophenolate mofetil or mycophenolate sodium), corticosteroids, SGLT2 inhibitors and mineralocorticoid receptor antagonists should be stable for at least 90 days prior to randomization UPCR ≥ 1.0 g/g (≥ 113 mg/mmol) sampled from the first morning void urine sample at Day -75 and Day -15 Estimated GFR (using the chronic kidney disease [CKD]-EPI formula for adult participants and modified Schwartz formula for adolescents aged 12 to 17 years) or measured GFR ≥ 30 ml/min/1.73m2 at screening and Day -15. Mandatory vaccination against Neisseria meningitidis and Streptococcus pneumoniae infection prior to the start of study treatment. If the participant has not been previously vaccinated, or if a booster is required, the vaccine should be given according to local regulations at least 2 weeks prior to the first administration of study treatment. If the study treatment has to start earlier than 2 weeks post vaccination, prophylactic antibiotic treatment should be initiated in accordance with local standard of care. If not previously vaccinated, or if a booster is required, vaccination against Haemophilus influenzae infections should be given, if available and according to local regulations, at least 2 weeks prior to the first study treatment administration. If the study treatment has to start earlier than 2 weeks post vaccination, prophylactic antibiotic treatment should be initiated in accordance with local standard of care. Exclusion Criteria: Participants who have undergone cell or solid organ transplantation, including kidney transplantation. Participants diagnosed with secondary IC-MPGN including but not limited to any of the following conditions: Deposition of antigen-antibody immune complexes as a result of any chronic infections, including Hepatitis C virus (HCV) including HCV-associated mixed cryoglobulinemia, hepatitis B virus (HBV); Bacterial-endocarditis, infected ventriculo-atrial shunt, visceral abscesses, leprosy, meningococcal meningitis; chronic bacterial infections Protozoa/other infections- malaria, schistosomiasis, mycoplasma, leishmaniasis, filariasis, histroplasmosis Renal deposition of immune complexes as a result of a systemic autoimmune disease: Systemic lupus erythematosus (SLE) Sjögren syndrome Rheumatoid arthritis Mixed connective tissue disease Deposition of monoclonal immunoglobulins because of a monoclonal gammopathy due to plasma cell or B cell disorders. Monoclonal gammopathy of undetermined significance (MGUS) confirmed by the measurement of serum free light chains or other investigation as per local standard of care. Fibrillary glomerulonephritis Rapidly progressive crescentic glomerulonephritis defined as a 50% decline in the eGFR within 3 months with kidney biopsy findings of glomerular crescent formation seen in at least 50% of glomeruli on the most recent biopsy. Kidney biopsy showing interstitial fibrosis/tubular atrophy (IF/TA) of more than 50%. Participants with an active systemic bacterial, viral or fungal infection within 14 days prior to study treatment administration or the presence of fever ≥ 38°C (100.4°F) within 7 days prior to study treatment administration. A history of recurrent invasive infections caused by encapsulated organisms, e.g., Neisseria meningitidis and Streptococcus pneumoniae. The use of inhibitors of complement factors (e.g., Factor B, Factor D, complement 3 (C3) inhibitors, anti-Complement 5 (C5) antibodies, C5a receptor antagonists) within 6 months prior to the Screening visit. The use of immunosuppressants (except MPAs), cyclophosphamide or systemic corticosteroids at a dose >7.5 mg/day (or equivalent for a similar corticosteroid medication) within 90 days of study drug administration. The use of MPAs is not permitted within 90 days prior to randomization in India, as per the local health authority requirement. Acute post-infectious glomerulonephritis at screening, based upon the opinion of the investigator.

Ages Eligible for Study
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Minimum Age: 12 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: iptacopan 200mg b.i.d<br>iptacopan 200mg b.i.d | Drug: iptacopan<br>* iptacopan 200 mg b.i.d. (Adults 200mg b.i.d; Adolescents 2x 100mg b.i.d)<br>|
| Placebo Comparator: Placebo to iptacopan 200mg b.i.d.<br>Placebo to iptacopan 200mg b.i.d. | Drug: Placebo<br>* Placebo to iptacopan 200mg b.i.d. (Adults 200mg b.i.d; Adolescents 2x 100mg b.i.d)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Log-transformed ratio to baseline in UPCR (sampled from a 24-hour urine collection) at 6 months. | To demonstrate the superiority of iptacopan compared to placebo in reducing proteinuria at 6 months. | 6 months (double-blind) | 
| Log-transformed ratio to baseline in UPCR at the 12-month visit (both study treatment arms) | To evaluate the effect of iptacopan on proteinuria at 12 months. | 12 months | 
| Log-transformed ratio to 6-month visit in UPCR at the 12-month visit in the placebo arm. | To evaluate the effect of iptacopan on proteinuria at 12 months. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in eGFR | To demonstrate the superiority of iptacopan vs. placebo in improving estimated glomerular filtration rate (eGFR). | 6 months of double-blind & 6 months of open label (up to 12 months) | 
| Change in eGFR from the 6-month visit to the 12- month visit of the placebo arm | To evaluate the effect at 12 months of iptacopan in improving eGFR | month 6 and month 12 | 
| Proportion of patients achieved a composite renal endpoint | To demonstrate the superiority of iptacopan vs. placebo in the proportion of participant who achieved a composite renal endpoint at 6 and 12 months (both study arms). | 6 months of double-blind & 6 months of open label (up to 12 months) | 
| Proportion of patients achieving a composite renal endpoint from the 6-month visit to the 12-month visit of the placebo arm | To evaluate the effect at 12 months of iptacopan on a composite renal endpoint in placebo arm | month 6, month 12 | 
| Change from baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) score. | To demonstrate the superiority of iptacopan compared to placebo in improvement of patient-reported fatigue at 6 months and 12 months (both study arms). | 6 months of double-blind & 6 months of open label (up to 12 months) | 
| Change in the FACIT-Fatigue score from the 6-month visit to the 12-month visit at the placebo arm | To evaluate the effect at 12 months of iptacopan in improvement of participant-reported fatigue in placebo arm | month 6, month 12 | 
| Number of participants with abnormal vital signs, ECGs and safety laboratory measurements | To evaluate the safety and tolerability of iptacopan compared to placebo, number of participants with abnormal vital signs (msDBP/msSBP/heart rate), ECGs and safety laboratory measurements will be collected. msDBP: mean sitting diastolic blood pressure msSBP: mean sitting systolic blood pressure | 6 months of double-blind & 6 months of open label (up to 12 months) | 
| Number of participants with study drug discontinuation due to an AE | To evaluate the safety and tolerability of iptacopan compared to placebo, number of participants with study drug discontinuation due to an AE (or any safety issue) will be collected | 6 months of double-blind & 6 months of open label (up to 12 months) | 
| Number of participants with clinically significant changes in heart rate, blood pressure, echocardiography parameters and NT-proBPN in adolescent patients | To evaluate the effect of iptacopan compared to placebo, number of participants with clinically significant changes in heart rate, blood pressure (msDBP/ msSBP), echocardiography parameters and NT-proBPN in adolescent patients will be collected | 6 months of double-blind & 6 months of open label (up to 12 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LNP023, IC-MPGN, iptacopan, UPCR, eGFR, proteinuria