Study of Efficacy and Safety of LNP023 in Primary IgA Nephropathy Patients (APPLAUSE-IgAN)

• ClinicalTrials.gov Identifier: NCT04578834
• Recruitment Status: Active, not recruiting
• First Posted: October 8, 2020
• Last Update Posted: May 3, 2024
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: September 9, 2020
• First Posted Date: October 8, 2020
• Last Update Posted Date: May 3, 2024
• Actual Study Start Date: January 25, 2021
• Estimated Primary Completion Date: October 15, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 30, 2021)

• Ratio to baseline in Urine Protein to Creatinine Ratio (sampled from 24h urine collection) at 9 months [ Time Frame: Baseline and 9 months ]
  Evaluated at interim analysis - To demonstrate superiority of LNP023 vs. placebo in the change of proteinuria at 9 months by measuring Urine Protein to Creatinine Ratio sampled from a 24h urine collection.
• Annualized total estimated Glomerular Filtration Rate (eGFR) slope over 24 months). [ Time Frame: Baseline and 24 months ]
  Evaluated at the final analysis - to demonstrate superiority of LNP023 vs. placebo in slowing IgAN progression measured by the annualized total slope of Estimated Glomerular Filtration Rate (eGFR) change over 24 months.

Original Primary Outcome Measures (submitted: October 1, 2020)

• Ratio to baseline in Urine Protein to Creatinine Ratio (sampled from 24h urine collection) at 9 months [ Time Frame: Baseline and 9 months ]
  Evaluated at interim analysis - To demonstrate superiority of LNP023 vs. placebo in the change of proteinuria at 9 months by measuring Urine Protein to Creatinine Ratio sampled from a 24h urine collection.
• Annualized total Estimated Glomerular Filtration Rate (eGFR) slope estimated over 24 months). [ Time Frame: Baseline and 24 months ]
  Evaluated at the final analysis - to demonstrate superiority of LNP023 vs. placebo in slowing renal disease progression measured by the annualized total slope of Estimated Glomerular Filtration Rate (eGFR) change over 24 months.

Current Secondary Outcome Measures (submitted: April 28, 2023)

• Change from baseline in estimated glomerular filtration rate at 9 months [ Time Frame: Baseline and 9 months ]
  Evaluated at interim analysis - To evaluate the effect of LNP023 vs. placebo on slowing estimated glomerular filtration rate decrease as measured by the change from baseline in eGFR
• Proportion of participants reaching Urine Protein To Creatinine Ratio <1g/g without receiving Corticosteroids/Immunosuppressant or other newly approved drugs or initiating new background therapy for treatment of IgAN or Kidney Replacement Therapy (KRT) [ Time Frame: Baseline and 9 months ]
  Evaluated at interim analysis - To assess the effect of LNP023 vs. placebo on the proportion of study participants reaching proteinuria below 1g/g of Urine Protein To Creatinine Ratio (sampled from 24h urine collection) at 9 months.
• Annualized total Estimated Glomerular Filtration Rate slope estimated over 12 months [ Time Frame: Baseline and 12 months ]
  Evaluated at interim analysis - To evaluate the effect of LNP023 vs. placebo on slowing IgAN progression measured by the annualized total slope of Estimated Glomerular Filtration Rate change over 1 year.
• Change from baseline to 9 months in the fatigue scale measured by the Functional Assessment Of Chronic Illness Therapy-Fatigue questionnaire [ Time Frame: Baseline and 9 months ]
  Evaluated at interim analysis - To assess the effect of LNP023 vs. placebo on the change from baseline to 9 months in fatigue scale measured by the Functional Assessment Of Chronic Illness Therapy-Fatigue questionnaire.
• Time from randomization to first occurrence of composite kidney failure endpoint event [ Time Frame: Up to 24 months ]
  Evaluated at final analysis - demonstrate the superiority of LNP023 vs. placebo on delaying the time to first occurrence of a composite kidney failure endpoint, defined as reaching either sustained ≥30% decline in Estimated Glomerular Filtration Rate (eGFR) relative to baseline or sustained eGFR <15 mL/min/1.73m2 or maintenance dialysis or receipt of kidney transplant or death from kidney failure.
• Ratio to baseline in Urine Protein-To-Creatinine Ratio (sampled from 24h urine collection) at 9 months [ Time Frame: Baseline and 9 months ]
  Evaluated at final analysis - To demonstrate superiority of LNP023 vs. placebo in the change of proteinuria at 9 months by measuring Urine Protein To Creatinine Ratio sampled from a 24h urine collection.
• Proportion of participants reaching Urine Protein-To-Creatinine Ratio <1g/g without receiving Corticosteroids/Immunosuppressant Therapy or other newly approved drugs or initiating new background therapy for treatment of IgAN or initiating KRT [ Time Frame: Baseline and 9 months ]
  Evaluated at final analysis - To demonstrate the superiority of LNP023 vs. placebo on the proportion of study participants reaching proteinuria below 1g/g of Urine Protein To Creatinine Ratio (sampled from 24h urine collection) at 9 months.
• Change from baseline to 9 months in the fatigue scale measured by the Functional Assessment Of Chronic Illness Therapy-Fatigue questionnaire. [ Time Frame: Baseline and 9 months ]
  Evaluated at final analysis - To demonstrate the superiority of LNP023 vs. placebo on the change from baseline to 9 months in the fatigue scale measured by Functional Assessment Of Chronic Illness Therapy-Fatigue questionnaire.

Original Secondary Outcome Measures (submitted: October 1, 2020)

• Proportion of participants reaching Urine Protein To Creatinine Ratio <1g/g at 9 months, without receiving Corticosteroids/Immunosuppressant or other newly approved drugs for treatment of IgAN or initiating Renal Replacement Therapy. [ Time Frame: Baseline and 9 months ]
  Evaluated at interim analysis - To assess the effect of LNP023 vs. placebo on the proportion of study participants reaching proteinuria below 1g/g of Urine Protein To Creatinine Ratio (sampled from 24h urine collection) at 9 months.
• Annualized total Estimated Glomerular Filtration Rate slope estimated over 12 months [ Time Frame: Baseline and 12 months ]
  Evaluated at interim analysis - To evaluate the effect of LNP023 vs. placebo on slowing renal disease progression measured by the annualized total slope of Estimated Glomerular Filtration Rate change over 1 year.
• Change from baseline to 9 months in the fatigue scale measured by the Functional Assessment Of Chronic Illness Therapy-Fatigue questionnaire [ Time Frame: Baseline and 9 months ]
  Evaluated at interim analysis - To assess the effect of LNP023 vs. placebo on the change from baseline to 9 months in fatigue scale measured by the Functional Assessment Of Chronic Illness Therapy-Fatigue questionnaire.
• Time from randomization to first occurrence of composite renal endpoint event, defined as reaching either ≥30% decline in Estimated Glomerular Filtration Rate (eGFR) relative to baseline, or End Stage Renal Disease (ESRD), or renal death [ Time Frame: Up to 24 months ]
  Evaluated at final analysis - To demonstrate the superiority of LNP023 vs. placebo on delaying the time to first occurrence of a composite renal endpoint of reaching either at least 30% change in Estimated Glomerular Filtration Rate, End-Stage Renal Disease or renal death.
• Ratio to baseline in Urine Protein-To-Creatinine Ratio (sampled from 24h urine collection) at 9 months [ Time Frame: Baseline and 9 months ]
  Evaluated at final analysis - To demonstrate superiority of LNP023 vs. placebo in the change of proteinuria at 9 months by measuring Urine Protein To Creatinine Ratio sampled from a 24h urine collection.
• Proportion of participants reaching Urine Protein-To-Creatinine Ratio <1g/g at 9 months without receiving Corticosteroids/Immunosuppressant Therapy or other newly approved drugs for treatment of IgAN or initiating renal replacement therapy [ Time Frame: Baseline and 9 months ]
  Evaluated at final analysis - To demonstrate the superiority of LNP023 vs. placebo on the proportion of study participants reaching proteinuria below 1g/g of Urine Protein To Creatinine Ratio (sampled from 24h urine collection) at 9 months.
• Change from baseline to 9 months in the fatigue scale measured by the Functional Assessment Of Chronic Illness Therapy-Fatigue questionnaire. [ Time Frame: Baseline and 9 months ]
  Evaluated at final analysis - To demonstrate the superiority of LNP023 vs. placebo on the change from baseline to 9 months in the fatigue scale measured by Functional Assessment Of Chronic Illness Therapy-Fatigue questionnaire.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Efficacy and Safety of LNP023 in Primary IgA Nephropathy Patients
• Official Title: A Multi-center, Randomized, Double-blind, Placebo-controlled, Parallel Group, Phase III Study to Evaluate the Efficacy and Safety of LNP023 in Primary IgA Nephropathy Patients
• Brief Summary: The study is designed as a multicenter, randomized, double-blind, placebo controlled study to demonstrate the superiority of iptacopan (LNP023) at a dose of 200 mg b.i.d. compared to placebo on top of maximally tolerated ACEi or ARB on reduction of proteinuria and slowing renal disease progression in primary IgA Nephropathy patients.
• Detailed Description: The purpose of the study is to evaluate the efficacy and safety of iptacopan (LNP023) compared to placebo on proteinuria reduction and slowing disease progression in primary IgAN patients. The study will be the pivotal trial for registration of LNP023 in IgA Nephropathy patients with the aim to demonstrate a clinically meaningful reduction in proteinuria by LNP023 vs. placebo as assessed by reduction in urine protein to creatinine ratio (UPCR) sampled from a 24 hour urine collection at an IA at 9 months. The trial will continue in a blinded fashion to confirm long-term efficacy based on annualized total slope of eGFR decline over 24 months to provide confirmatory evidence of LNP023 efficacy and safety in treating patients with IgAN. The trial will enroll approximately 470 participants; 430 biopsy-proven IgAN participants with eGFR ≥30 mL /min/1.73m2 (main study population) and up to approximately 40 participants with eGFR 20 to <30 mL/min/1.73m2 (severe renal impairment (SRI) population).
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: IgA Nephropathy

Intervention

• Drug: Placebo
  Placebo to LNP023 200mg b.i.d
• Drug: LNP023
  LNP023 200mg b.i.d
  Other Name: iptacopan

Study Arms

• Experimental: LNP023 200mg b.i.d
  Intervention: Drug: LNP023
• Placebo Comparator: Placebo to LNP023 200mg b.i.d
  Intervention: Drug: Placebo

• Publications *: Reich HN, Floege J. How I Treat IgA Nephropathy. Clin J Am Soc Nephrol. 2022 Aug;17(8):1243-1246. doi: 10.2215/CJN.02710322. Epub 2022 Jun 8. No abstract available.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: May 2, 2024): 519
• Original Estimated Enrollment (submitted: October 1, 2020): 450
• Estimated Study Completion Date: October 15, 2025
• Estimated Primary Completion Date: October 15, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Male and female patients ≥ 18 years of age with an eGFR level and biopsy-confirmed IgA nephropathy as follows:
• For patients eGFR* ≥ 45ml/min/1.73m2, a qualifying biopsy performed within the last 5 years is required.
• For patients with eGFR* 30 to <45ml/min/1.73m2, a qualifying biopsy performed within 2 years with < 50% tubulointerstitial fibrosis is required.
• For patients with eGFR* 20 to <30ml/min/1.73m2, a qualifying biopsy performed at any time.

In all cases, if a historical biopsy is not available, one may be performed during screening. *eGFR calculated using the CKD-EPI formula (or modified MDRD formula according to specific ethnic groups and local practice guidelines)

• Proteinuria due to primary diagnosis of IgA nephropathy as assessed at screening by UPCR ≥1 g/g (113 mg/mmol) sampled from FMV or 24h urine collection, as well as at the completion of the run-in period by UPCR ≥1 g/g (113 mg/mmol) calculated as the (geometric) mean of two 24h urine collections obtained within 14 days of each other at baseline.
• Vaccination against Neisseria meningitidis and Streptococcus pneumoniae infection is required prior to the start of study treatment. If the patient has not been previously vaccinated, or if a booster is required, vaccine should be given according to local regulations at least 2 weeks prior to first study drug administration. If study treatment has to start earlier than 2 weeks post vaccination, prophylactic antibiotic treatment should be initiated.
• If not previously vaccinated, vaccination against Haemophilus influenzae infections should be given, if available and according to local regulations, at least 2 weeks prior to first study drug administration.
• All patients must have been on supportive care including stable dose regimen of ACEi or ARB at either the locally approved maximal daily dose or the maximally tolerated dose (per investigators' judgment) for approximately 90 days before first study drug administration. In addition, if patients are taking diuretics, other antihypertensive medication, or other background medication for IgAN, the doses should also be stabilized for approximately 90 days prior to the first dosing of study treatment.

Exclusion Criteria:

• Any secondary IgAN as defined by the investigator; secondary IgAN can be associated with cirrhosis, celiac disease, Human Immunodeficiency Virus (HIV) infection, dermatitis herpetiformis, seronegative arthritis, small-cell carcinoma, lymphoma, disseminated tuberculosis, bronchiolitis obliterans, and inflammatory bowel disease, familial mediterranean fever, etc.
• Sitting office SBP >140 mmHg or DBP >90 mmHg at the randomization visit
• Patients previously treated with immunosuppressive or other immunomodulatory agents such as but not limited to cyclophosphamide, rituximab, infliximab, eculizumab, canakinumab, mycophenolate mofetil (MMF) or mycophenolate sodium (MPS), cyclosporine, tacrolimus, sirolimus, everolimus, or systemic corticosteroids exposure (>7.5 mg/d prednisone/prednisolone equivalent) within 90 days (or 180 days for rituximab) prior to first study drug administration. Participants previously or currently treated with oral budesonide. Participants treated with endothelin (receptor) antagonists within 90 days prior to first study drug administration.
• Prior use of iptacopan (LNP023) or prior enrollment in any other LNP023 clinical trial where study drug was taken, including matching placebo
• History of recurrent invasive infections caused by encapsulated organisms, such as meningococcus and pneumococcus.
• Active systemic bacterial, viral (including COVID-19) or fungal infection within 14 days prior to study drug administration.

Other protocol-defined inclusion/exclusion criteria may apply.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Belgium, Brazil, Canada, Chile, China, Colombia, Czechia, Denmark, France, Germany, Hungary, India, Israel, Italy, Japan, Korea, Republic of, Malaysia, Mexico, Netherlands, Norway, Russian Federation, Singapore, Slovakia, Slovenia, South Africa, Spain, Sweden, Taiwan, Thailand, Turkey, United Kingdom, United States, Vietnam
• Removed Location Countries: Finland, Puerto Rico

Administrative Information

• NCT Number: NCT04578834
• Other Study ID Numbers: CLNP023A2301
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

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

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: May 2024