Clinical trial NCT04578834: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: IgA Nephropathy
Keywords: LNP023
IgA nephropathy
IgAN, proteinuria
UPCR
eGFR
eGFR slope
kidney function decline
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2020-10-08
Enrollment: 519
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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.

Primary outcomes:
measure: Ratio to baseline in Urine Protein to Creatinine Ratio (sampled from 24h urine collection) at 9 months
timeFrame: Baseline and 9 months
measure: Annualized total estimated Glomerular Filtration Rate (eGFR) slope over 24 months).
timeFrame: Baseline and 24 months
Secondary outcomes:
measure: Change from baseline in estimated glomerular filtration rate at 9 months
timeFrame: Baseline and 9 months
measure: 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)
timeFrame: Baseline and 9 months
measure: Annualized total Estimated Glomerular Filtration Rate slope estimated over 12 months
timeFrame: Baseline and 12 months
measure: Change from baseline to 9 months in the fatigue scale measured by the Functional Assessment Of Chronic Illness Therapy-Fatigue questionnaire
timeFrame: Baseline and 9 months
measure: Time from randomization to first occurrence of composite kidney failure endpoint event
timeFrame: Up to 24 months
measure: Ratio to baseline in Urine Protein-To-Creatinine Ratio (sampled from 24h urine collection) at 9 months
timeFrame: Baseline and 9 months
measure: 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
timeFrame: Baseline and 9 months
measure: Change from baseline to 9 months in the fatigue scale measured by the Functional Assessment Of Chronic Illness Therapy-Fatigue questionnaire.
timeFrame: Baseline and 9 months
Other outcomes:
Locations:
city: Glendale
country: United States
facility: AZ Kidney Dise and Hypertension Ctr
state: Arizona
city: Phoenix
country: United States
facility: AKDHC Medical Research ServicesLLC
state: Arizona
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: San Diego
country: United States
facility: Kaiser Permanente
state: California
city: San Dimas
country: United States
facility: North America Research Institute
state: California
city: Aurora
country: United States
facility: University of Colorado Anschutz
state: Colorado
city: Newark
country: United States
facility: Nephrology Associates PA
state: Delaware
city: Boise
country: United States
facility: Boise Kidney and Hypertension
state: Idaho
city: Chubbuck
country: United States
facility: CaRe Research
state: Idaho
city: Hinsdale
country: United States
facility: Nep Assoc of Northern Illinois
state: Illinois
city: Baton Rouge
country: United States
facility: Renal Associates of Baton Rouge
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Brigham and Womens Hosp Harvard Med School
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: Kansas City
country: United States
facility: Clinical Research Consultants LLC
state: Missouri
city: Las Vegas
country: United States
facility: DaVita Clinical Research
state: Nevada
city: Jersey City
country: United States
facility: New Jersey Kidney Care
state: New Jersey
city: New York
country: United States
facility: Columbia University Irving Medical
state: New York
city: Dallas
country: United States
facility: Dallas Renal Group
state: Texas
city: Houston
country: United States
facility: Prolato Clinical Research Center
state: Texas
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Ciudad Autonoma de Buenos Aire
country: Argentina
facility: Novartis Investigative Site
city: Cordoba
country: Argentina
facility: Novartis Investigative Site
city: Cordoba
country: Argentina
facility: Novartis Investigative Site
city: Santa Fe
country: Argentina
facility: Novartis Investigative Site
city: Westmead
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Woolloongabba
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: Adelaide
country: Australia
facility: Novartis Investigative Site
state: South Australia
city: Parkville
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: St Albans
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Edegem
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Roeselare
country: Belgium
facility: Novartis Investigative Site
city: Belo Horizonte
country: Brazil
facility: Novartis Investigative Site
state: MG
city: Curitiba
country: Brazil
facility: Novartis Investigative Site
state: PR
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
state: RS
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Jose do Rio Preto
country: Brazil
facility: Novartis Investigative Site
city: Oshawa
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Temuco
country: Chile
facility: Novartis Investigative Site
city: Beijing
country: China
facility: Novartis Investigative Site
state: Beijing
city: Guangzhou
country: China
facility: Novartis Investigative Site
state: Guangdong
city: Guangzhou
country: China
facility: Novartis Investigative Site
state: Guangdong
city: Shenzhen
country: China
facility: Novartis Investigative Site
state: Guangdong
city: Luoyang
country: China
facility: Novartis Investigative Site
state: Henan
city: Zhengzhou
country: China
facility: Novartis Investigative Site
state: Henan
city: Changsha
country: China
facility: Novartis Investigative Site
state: Hunan
city: Changchun
country: China
facility: Novartis Investigative Site
state: Jilin
city: Yinchuan
country: China
facility: Novartis Investigative Site
state: Ningxia
city: Taiyuan
country: China
facility: Novartis Investigative Site
state: Shanxi
city: Urumqi
country: China
facility: Novartis Investigative Site
state: Xinjiang
city: Hangzhou
country: China
facility: Novartis Investigative Site
state: Zhejiang
city: Wenzhou
country: China
facility: Novartis Investigative Site
state: Zhejiang
city: Beijing
country: China
facility: Novartis Investigative Site
city: Beijing
country: China
facility: Novartis Investigative Site
city: Guang Zhou
country: China
facility: Novartis Investigative Site
city: Ningbo
country: China
facility: Novartis Investigative Site
city: Qingdao
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Shanxi
country: China
facility: Novartis Investigative Site
city: Shenzhen
country: China
facility: Novartis Investigative Site
city: Zhejiang
country: China
facility: Novartis Investigative Site
city: Medellin
country: Colombia
facility: Novartis Investigative Site
state: Antioquia
city: Barranquilla
country: Colombia
facility: Novartis Investigative Site
city: Praha
country: Czechia
facility: Novartis Investigative Site
city: Aalborg
country: Denmark
facility: Novartis Investigative Site
city: Arhus N
country: Denmark
facility: Novartis Investigative Site
city: Copenhagen
country: Denmark
facility: Novartis Investigative Site
city: Odense C
country: Denmark
facility: Novartis Investigative Site
city: Turku
country: Finland
facility: Novartis Investigative Site
city: Marseille
country: France
facility: Novartis Investigative Site
city: Montpellier 5
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Goettingen
country: Germany
facility: Novartis Investigative Site
state: Niedersachsen
city: Aachen
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Dresden
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Freiburg
country: Germany
facility: Novartis Investigative Site
city: Hannover
country: Germany
facility: Novartis Investigative Site
city: Kiel
country: Germany
facility: Novartis Investigative Site
city: Magdeburg
country: Germany
facility: Novartis Investigative Site
city: Mainz
country: Germany
facility: Novartis Investigative Site
city: Stuttgart
country: Germany
facility: Novartis Investigative Site
city: Tuebingen
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Debrecen
country: Hungary
facility: Novartis Investigative Site
city: Pecs
country: Hungary
facility: Novartis Investigative Site
city: Szeged
country: Hungary
facility: Novartis Investigative Site
city: New Delhi
country: India
facility: Novartis Investigative Site
state: Delhi
city: Bangalore
country: India
facility: Novartis Investigative Site
state: Karnataka
city: Hyderabad
country: India
facility: Novartis Investigative Site
state: Telangana
city: New Delhi
country: India
facility: Novartis Investigative Site
city: Ashkelon
country: Israel
facility: Novartis Investigative Site
city: Jerusalem
country: Israel
facility: Novartis Investigative Site
city: Petach Tikva
country: Israel
facility: Novartis Investigative Site
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Kasugai
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Toyoake city
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Toyota
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Sapporo-city
country: Japan
facility: Novartis Investigative Site
state: Hokkaido
city: Sapporo
country: Japan
facility: Novartis Investigative Site
state: Hokkaido
city: Kawasaki
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Yokohama-city
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Yokohama
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Matsumoto
country: Japan
facility: Novartis Investigative Site
state: Nagano
city: Okayama-city
country: Japan
facility: Novartis Investigative Site
state: Okayama
city: Omihachiman
country: Japan
facility: Novartis Investigative Site
state: Shiga
city: Chiba
country: Japan
facility: Novartis Investigative Site
city: Kyoto
country: Japan
facility: Novartis Investigative Site
city: Niigata
country: Japan
facility: Novartis Investigative Site
city: Osaka
country: Japan
facility: Novartis Investigative Site
city: Osaka
country: Japan
facility: Novartis Investigative Site
city: Cheongju si
country: Korea, Republic of
facility: Novartis Investigative Site
state: Chungcheongbuk Do
city: Bundang Gu
country: Korea, Republic of
facility: Novartis Investigative Site
state: Gyeonggi Do
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Seocho Gu
city: Busan
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Taegu
country: Korea, Republic of
facility: Novartis Investigative Site
city: Kuala Lumpur
country: Malaysia
facility: Novartis Investigative Site
state: Wilayah Persekutuan
city: Kuala Lumpur
country: Malaysia
facility: Novartis Investigative Site
city: Mexicali
country: Mexico
facility: Novartis Investigative Site
state: Baja California Norte
city: Cdmx
country: Mexico
facility: Novartis Investigative Site
city: Queretaro
country: Mexico
facility: Novartis Investigative Site
city: Groningen
country: Netherlands
facility: Novartis Investigative Site
city: Nordbyhagen
country: Norway
facility: Novartis Investigative Site
state: Oslo
city: Bergen
country: Norway
facility: Novartis Investigative Site
city: Omsk
country: Russian Federation
facility: Novartis Investigative Site
city: Rostov On Don
country: Russian Federation
facility: Novartis Investigative Site
city: St Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Kosice
country: Slovakia
facility: Novartis Investigative Site
city: Ljubljana
country: Slovenia
facility: Novartis Investigative Site
city: Maribor
country: Slovenia
facility: Novartis Investigative Site
city: Bloemfontein
country: South Africa
facility: Novartis Investigative Site
state: Free State
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Salamanca
country: Spain
facility: Novartis Investigative Site
state: Castilla Y Leon
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Pamplona
country: Spain
facility: Novartis Investigative Site
state: Navarra
city: Danderyd
country: Sweden
facility: Novartis Investigative Site
city: Stockholm
country: Sweden
facility: Novartis Investigative Site
city: Kaohsiung
country: Taiwan
facility: Novartis Investigative Site
city: New Taipei City
country: Taiwan
facility: Novartis Investigative Site
city: New Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taoyuan
country: Taiwan
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
state: Sultangazi
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
state: TUR
city: Ankara
country: Turkey
facility: Novartis Investigative Site
city: Antalya
country: Turkey
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Kocaeli
country: Turkey
facility: Novartis Investigative Site
city: Mersin
country: Turkey
facility: Novartis Investigative Site
city: Talas Kayseri
country: Turkey
facility: Novartis Investigative Site
city: Leicester
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Newcastle upon Tyne
country: United Kingdom
facility: Novartis Investigative Site
city: Salford
country: United Kingdom
facility: Novartis Investigative Site
city: Ho Chi Minh
country: Vietnam
facility: Novartis Investigative Site
state: VNM
city: Ho Chi Minh
country: Vietnam
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.