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

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)

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.

Study Overview

• Status: Recruiting
• Conditions: IC-MPGN
• Intervention / Treatment: Drug: iptacopan; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 68
• Phase: Phase 3

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

• Study Contact: Name: Novartis Pharmaceuticals; Phone Number: 1-888-669-6682; Email: Novartis.email@novartis.com
• Study Contact Backup: Name: Novartis Pharmaceuticals; Phone Number: +41613241111

Study Locations

• Brazil
  • Salvador, Brazil, 40301-155
    • Recruiting
    • Novartis Investigative Site
  • DF
    • Brasilia, DF, Brazil, 71635-580
      • Recruiting
      • Novartis Investigative Site
  • MG
    • Belo Horizonte, MG, Brazil, 30150-221
      • Recruiting
      • Novartis Investigative Site
  • RJ
    • Niteroi, RJ, Brazil, 24020 096
      • Recruiting
      • Novartis Investigative Site
    • Rio de Janeiro, RJ, Brazil, 22211 230
      • Recruiting
      • Novartis Investigative Site
  • RS
    • Porto Alegre, RS, Brazil, 90020-090
      • Recruiting
      • Novartis Investigative Site
  • Recife
    • Pernambuco, Recife, Brazil, 50740-900
      • Recruiting
      • Novartis Investigative Site
  • SP
    • Botucatu, SP, Brazil, 18618-970
      • Recruiting
      • Novartis Investigative Site
    • Santo Andre, SP, Brazil, 09090-790
      • Recruiting
      • Novartis Investigative Site
    • Sao Paulo, SP, Brazil, 05403 000
      • Recruiting
      • Novartis Investigative Site
    • São Paulo, SP, Brazil, 04038-002
      • Recruiting
      • Novartis Investigative Site
• Czechia
  • Prague 2, Czechia, 128 08
    • Recruiting
    • Novartis Investigative Site
• France
  • Montpellier, France, 34295
    • Recruiting
    • Novartis Investigative Site
  • Paris, France, 75015
    • Recruiting
    • Novartis Investigative Site
  • Paris 15, France, 75015
    • Recruiting
    • Novartis Investigative Site
  • Toulouse 4, France, 31054
    • Recruiting
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 13353
    • Recruiting
    • Novartis Investigative Site
  • Dresden, Germany, 01307
    • Recruiting
    • Novartis Investigative Site
  • Essen, Germany, 45147
    • Recruiting
    • Novartis Investigative Site
  • Mainz, Germany, 55131
    • Recruiting
    • Novartis Investigative Site
• Israel
  • Haifa, Israel, 310 9601
    • Recruiting
    • Novartis Investigative Site
  • Jerusalem, Israel, 91031
    • Recruiting
    • Novartis Investigative Site
  • Petach-Tikva, Israel, 49202
    • Recruiting
    • Novartis Investigative Site
• Italy
  • Napoli, Italy, 80100
    • Recruiting
    • Novartis Investigative Site
  • BG
    • Ranica, BG, Italy, 24020
      • Recruiting
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20122
      • Recruiting
      • Novartis Investigative Site
• Japan
  • Okayama
    • Okayama-city, Okayama, Japan, 700-8558
      • Recruiting
      • Novartis Investigative Site
  • Tokyo
    • Hachioji-city, Tokyo, Japan, 193-0944
      • Recruiting
      • Novartis Investigative Site
• Poland
  • Olsztyn, Poland, 10-561
    • Recruiting
    • Novartis Investigative Site
  • Wroclaw, Poland, 50-417
    • Recruiting
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28040
    • Recruiting
    • Novartis Investigative Site
  • Castilla Y Leon
    • Salamanca, Castilla Y Leon, Spain, 37007
      • Recruiting
      • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08036
      • Recruiting
      • Novartis Investigative Site
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Recruiting
      • Novartis Investigative Site
• Switzerland
  • Bern, Switzerland, 3010
    • Recruiting
    • Novartis Investigative Site
• Turkey
  • Ankara, Turkey, 06500
    • Recruiting
    • Novartis Investigative Site
  • Izmir, Turkey, 35575
    • Recruiting
    • Novartis Investigative Site
  • Kocaeli, Turkey, 41380
    • Recruiting
    • Novartis Investigative Site
• United Kingdom
  • Cardiff, United Kingdom, CF14 4XW
    • Recruiting
    • Novartis Investigative Site
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital Nephrology Department
      • Contact: Sherley Mejia; Email: smejia4@mgh.harvard.edu
      • Principal Investigator: Meghan Sise
  • New York
    • New York, New York, United States, 10032
      • Recruiting
      • Col Uni Med Center New York Presby
      • Contact: Phone Number: 212-304-5684
      • Principal Investigator: Andrew S Bomback

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 60 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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 screening in adults and within 3 years of screening 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 renin angiotensin system inhibitors (RASi), e.g 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.
• Body mass index (BMI) >38 kg/m2 at screening and randomization. Body weight <35 kg at screening and randomization

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo to iptacopan 200mg b.i.d.	Drug: Placebo; Placebo to iptacopan 200mg b.i.d. (Adults 200mg b.i.d; Adolescents 2x 100mg b.i.d)
Experimental: iptacopan 200mg b.i.d	Drug: iptacopan; iptacopan 200 mg b.i.d. (Adults 200mg b.i.d; Adolescents 2x 100mg b.i.d)

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): October 2, 2023
• Primary Completion (Estimated): October 23, 2026
• Study Completion (Estimated): November 26, 2026

Study Registration Dates

• First Submitted: February 23, 2023
• First Submitted That Met QC Criteria: February 23, 2023
• First Posted (Actual): March 6, 2023

Study Record Updates

• Last Update Posted (Actual): April 12, 2024
• Last Update Submitted That Met QC Criteria: April 10, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: proteinuria; eGFR; UPCR; LNP023; iptacopan; IC-MPGN
• Additional Relevant MeSH Terms: Immune System Diseases; Kidney Diseases; Urologic Diseases; Nephritis; Glomerulonephritis; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Glomerulonephritis, Membranoproliferative
• Other Study ID Numbers: CLNP023B12302; 2022-002328-11 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No