Study of Efficacy and Safety of LNP023 in Primary IgA Nephropathy Patients

IgA Nephropathy Clinical Trial

— APPLAUSE-IgAN  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04578834
• Other study ID #: CLNP023A2301
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: January 25, 2021
• Est. completion date: October 15, 2025

Study information

• Verified date: May 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 519
• Est. completion date: October 15, 2025
• Est. primary completion date: October 15, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Glomerulonephritis, IGA
• IgA Nephropathy
• Kidney Diseases

Intervention

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

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	Ciudad Autonoma de Buenos Aire
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	Santa Fe
Australia	Novartis Investigative Site	Adelaide	South Australia
Australia	Novartis Investigative Site	Parkville	Victoria
Australia	Novartis Investigative Site	St Albans	Victoria
Australia	Novartis Investigative Site	Westmead	New South Wales
Australia	Novartis Investigative Site	Woolloongabba	Queensland
Belgium	Novartis Investigative Site	Edegem	Antwerpen
Belgium	Novartis Investigative Site	Leuven
Belgium	Novartis Investigative Site	Roeselare
Brazil	Novartis Investigative Site	Belo Horizonte	MG
Brazil	Novartis Investigative Site	Curitiba	PR
Brazil	Novartis Investigative Site	Porto Alegre	RS
Brazil	Novartis Investigative Site	Sao Jose do Rio Preto
Brazil	Novartis Investigative Site	Sao Paulo	SP
Brazil	Novartis Investigative Site	São Paulo	SP
Canada	Novartis Investigative Site	Oshawa	Ontario
Chile	Novartis Investigative Site	Temuco
China	Novartis Investigative Site	Beijing	Beijing
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Changchun	Jilin
China	Novartis Investigative Site	Changsha	Hunan
China	Novartis Investigative Site	Guang Zhou
China	Novartis Investigative Site	Guangzhou	Guangdong
China	Novartis Investigative Site	Guangzhou	Guangdong
China	Novartis Investigative Site	Hangzhou	Zhejiang
China	Novartis Investigative Site	Luoyang	Henan
China	Novartis Investigative Site	Ningbo
China	Novartis Investigative Site	Qingdao
China	Novartis Investigative Site	Shanghai
China	Novartis Investigative Site	Shanghai
China	Novartis Investigative Site	Shanxi
China	Novartis Investigative Site	Shenzhen
China	Novartis Investigative Site	Shenzhen	Guangdong
China	Novartis Investigative Site	Taiyuan	Shanxi
China	Novartis Investigative Site	Urumqi	Xinjiang
China	Novartis Investigative Site	Wenzhou	Zhejiang
China	Novartis Investigative Site	Yinchuan	Ningxia
China	Novartis Investigative Site	Zhejiang
China	Novartis Investigative Site	Zhengzhou	Henan
Colombia	Novartis Investigative Site	Barranquilla
Colombia	Novartis Investigative Site	Medellin	Antioquia
Czechia	Novartis Investigative Site	Praha
Denmark	Novartis Investigative Site	Aalborg
Denmark	Novartis Investigative Site	Arhus N
Denmark	Novartis Investigative Site	Copenhagen
Denmark	Novartis Investigative Site	Odense
France	Novartis Investigative Site	Marseille
France	Novartis Investigative Site	Montpellier
France	Novartis Investigative Site	Paris
Germany	Novartis Investigative Site	Aachen
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Dresden
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Freiburg
Germany	Novartis Investigative Site	Gottingen
Germany	Novartis Investigative Site	Hannover
Germany	Novartis Investigative Site	Kiel
Germany	Novartis Investigative Site	Magdeburg
Germany	Novartis Investigative Site	Mainz
Germany	Novartis Investigative Site	Stuttgart
Germany	Novartis Investigative Site	Tuebingen
Germany	Novartis Investigative Site	Ulm
Hungary	Novartis Investigative Site	Debrecen
Hungary	Novartis Investigative Site	Pecs
Hungary	Novartis Investigative Site	Szeged
India	Novartis Investigative Site	Bangalore	Karnataka
India	Novartis Investigative Site	Hyderabad	Telangana
India	Novartis Investigative Site	New Delhi
India	Novartis Investigative Site	New Delhi	Delhi
Israel	Novartis Investigative Site	Ashkelon
Israel	Novartis Investigative Site	Jerusalem
Israel	Novartis Investigative Site	Petach Tikva
Italy	Novartis Investigative Site	Bologna	BO
Italy	Novartis Investigative Site	Napoli
Japan	Novartis Investigative Site	Chiba-city	Chiba
Japan	Novartis Investigative Site	Kasugai	Aichi
Japan	Novartis Investigative Site	Kawasaki	Kanagawa
Japan	Novartis Investigative Site	Kyoto
Japan	Novartis Investigative Site	Matsumoto	Nagano
Japan	Novartis Investigative Site	Niigata
Japan	Novartis Investigative Site	Okayama-city	Okayama
Japan	Novartis Investigative Site	Omihachiman	Shiga
Japan	Novartis Investigative Site	Osaka
Japan	Novartis Investigative Site	Osaka-city	Osaka
Japan	Novartis Investigative Site	Sapporo	Hokkaido
Japan	Novartis Investigative Site	Sapporo-city	Hokkaido
Japan	Novartis Investigative Site	Toyoake city	Aichi
Japan	Novartis Investigative Site	Toyota	Aichi
Japan	Novartis Investigative Site	Yokohama	Kanagawa
Japan	Novartis Investigative Site	Yokohama-city	Kanagawa
Korea, Republic of	Novartis Investigative Site	Bundang Gu	Gyeonggi Do
Korea, Republic of	Novartis Investigative Site	Busan
Korea, Republic of	Novartis Investigative Site	Cheongju si	Chungcheongbuk Do
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul	Seocho Gu
Korea, Republic of	Novartis Investigative Site	Taegu
Malaysia	Novartis Investigative Site	Kuala Lumpur
Malaysia	Novartis Investigative Site	Kuala Lumpur
Mexico	Novartis Investigative Site	Cdmx
Mexico	Novartis Investigative Site	Mexicali	Baja California Norte
Mexico	Novartis Investigative Site	Queretaro
Netherlands	Novartis Investigative Site	Groningen
Norway	Novartis Investigative Site	Bergen
Norway	Novartis Investigative Site	Nordbyhagen	Oslo
Russian Federation	Novartis Investigative Site	Omsk
Russian Federation	Novartis Investigative Site	Rostov On Don
Russian Federation	Novartis Investigative Site	St. Petersburg
Singapore	Novartis Investigative Site	Singapore
Singapore	Novartis Investigative Site	Singapore
Slovakia	Novartis Investigative Site	Kosice
Slovenia	Novartis Investigative Site	Ljubljana
Slovenia	Novartis Investigative Site	Maribor
South Africa	Novartis Investigative Site	Bloemfontein	Free State
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Pamplona	Navarra
Spain	Novartis Investigative Site	Salamanca	Castilla Y Leon
Spain	Novartis Investigative Site	Sevilla	Andalucia
Sweden	Novartis Investigative Site	Danderyd
Sweden	Novartis Investigative Site	Stockholm
Taiwan	Novartis Investigative Site	Kaohsiung
Taiwan	Novartis Investigative Site	New Taipei
Taiwan	Novartis Investigative Site	New Taipei City
Taiwan	Novartis Investigative Site	Taichung
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taoyuan
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Bangkok
Turkey	Novartis Investigative Site	Ankara
Turkey	Novartis Investigative Site	Antalya
Turkey	Novartis Investigative Site	Istanbul
Turkey	Novartis Investigative Site	Istanbul
Turkey	Novartis Investigative Site	Istanbul	Sultangazi
Turkey	Novartis Investigative Site	Istanbul	TUR
Turkey	Novartis Investigative Site	Kocaeli
Turkey	Novartis Investigative Site	Mersin
Turkey	Novartis Investigative Site	Talas / Kayseri
United Kingdom	Novartis Investigative Site	Leicester
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Newcastle Upon Tyne
United Kingdom	Novartis Investigative Site	Salford	Manchester
United States	University of Michigan	Ann Arbor	Michigan
United States	University of Colorado Anschutz	Aurora	Colorado
United States	Johns Hopkins Hospital J Hopkins Medical Institution	Baltimore	Maryland
United States	Renal Associates of Baton Rouge	Baton Rouge	Louisiana
United States	Novartis Investigative Site	Boise	Idaho
United States	Brigham and Womens Hosp Harvard Med School .	Boston	Massachusetts
United States	CaRe Research Nephrology Research	Chubbuck	Idaho
United States	Dallas Renal Group Liberty Res Center	Dallas	Texas
United States	AZ Kidney Dise and Hypertension Ctr .	Glendale	Arizona
United States	Nep Assoc of Northern Illinois	Hinsdale	Illinois
United States	Prolato Clinical Research Center .	Houston	Texas
United States	New Jersey Kidney Care	Jersey City	New Jersey
United States	Clinical Research Consultants LLC .	Kansas City	Missouri
United States	DaVita Clinical Research Cardiology Renal Metabolic	Las Vegas	Nevada
United States	UCLA Medical Center	Los Angeles	California
United States	Columbia University Irving Medical Nephrology	New York	New York
United States	Nephrology Associates PA	Newark	Delaware
United States	AKDHC Medical Research ServicesLLC	Phoenix	Arizona
United States	Mayo Clinic Rochester .	Rochester	Minnesota
United States	Kaiser Permanente Dpt of Research and Evaluation	San Diego	California
United States	North America Research Institute	San Dimas	California
United States	University of Washington Medical Center .	Seattle	Washington
Vietnam	Novartis Investigative Site	Ho Chi Minh	VNM
Vietnam	Novartis Investigative Site	Ho Chi Minh

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Vietnam,  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, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Ratio to baseline in Urine Protein to Creatinine Ratio (sampled from 24h urine collection) at 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.	Baseline and 9 months
Primary	Annualized total estimated Glomerular Filtration Rate (eGFR) slope over 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.	Baseline and 24 months
Secondary	Change from baseline in estimated glomerular filtration rate at 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	Baseline and 9 months
Secondary	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)	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.	Baseline and 9 months
Secondary	Annualized total Estimated Glomerular Filtration Rate slope estimated over 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.	Baseline and 12 months
Secondary	Change from baseline to 9 months in the fatigue scale measured by the Functional Assessment Of Chronic Illness Therapy-Fatigue questionnaire	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.	Baseline and 9 months
Secondary	Time from randomization to first occurrence of composite kidney failure endpoint event	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.	Up to 24 months
Secondary	Ratio to baseline in Urine Protein-To-Creatinine Ratio (sampled from 24h urine collection) at 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.	Baseline and 9 months
Secondary	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	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.	Baseline and 9 months
Secondary	Change from baseline to 9 months in the fatigue scale measured by the Functional Assessment Of Chronic Illness Therapy-Fatigue questionnaire.	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.	Baseline and 9 months