Clinical trial NCT05755386: Study of Efficacy and Safety of Iptacopan in Participants With IC-MPGN
Official title: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: IC-MPGN
Keywords: LNP023
IC-MPGN
iptacopan
UPCR
eGFR
proteinuria
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2023-03-06
Enrollment: 106
Sex: ALL
Minimum age (years): 12
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

* Male and female patients including adults (aged at least 18 years to ≤ 60 years) and adolescents (12 -17 years in non-EU countries at screening and 16-17 years in EU countries 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.

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 3 months or 5 half-lives 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

Primary outcomes:
measure: Log-transformed ratio to baseline in UPCR (sampled from a 24-hour urine collection) at 6 months.
timeFrame: 6 months (double-blind)
measure: Log-transformed ratio to baseline in UPCR at the 18-month visit (each study treatment arm)
timeFrame: 18 months
measure: Log-transformed ratio to 12-month visit in UPCR at the 18-month visit in the placebo arm.
timeFrame: 18 months
Secondary outcomes:
measure: Change from baseline in eGFR
timeFrame: 12 months and 18 months
measure: Change in eGFR from the 12-month visit to the 18- month visit of the placebo arm
timeFrame: 18 months
measure: Proportion of patients achieved a composite renal endpoint
timeFrame: 6 and 12 months
measure: Change from baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) score.
timeFrame: 12 months
measure: Number of participants with abnormal vital signs, ECGs and safety laboratory measurements as well as study drug discontinuation due to an AE
timeFrame: up to 18 months
measure: Number of participants with clinically significant changes in heart rate, blood pressure, echocardiography parameters in adolescent patients
timeFrame: up to 18 months
measure: Annualized total eGFR slope estimated over 12 months.
timeFrame: 12 months
measure: Log-transformed ratio to baseline in UPCR (sampled from a 24-hour urine collection) at 12 months.
timeFrame: 12 months
measure: Proportion of participants who achieved the composite renal endpoint at 18 months
timeFrame: 18 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Ronald Reagan UCLA Medical Center
state: California
city: Orange
country: United States
facility: Univ Cali Irvine ALS Neuromuscular
state: California
city: San Francisco
country: United States
facility: UCSF
state: California
city: Aurora
country: United States
facility: Childrens Hospital Colorado
state: Colorado
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: New York
country: United States
facility: Col Uni Med Center New York Presby
state: New York
city: Temple
country: United States
facility: Baylor Scott and White Research
state: Texas
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Buenos Aires
country: Argentina
facility: Novartis Investigative Site
city: Brasilia
country: Brazil
facility: Novartis Investigative Site
state: DF
city: Belo Horizonte
country: Brazil
facility: Novartis Investigative Site
state: MG
city: Pernambuco
country: Brazil
facility: Novartis Investigative Site
state: Recife
city: Niteroi
country: Brazil
facility: Novartis Investigative Site
state: RJ
city: Rio de Janeiro
country: Brazil
facility: Novartis Investigative Site
state: RJ
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
state: RS
city: Botucatu
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Santo Andre
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Salvador
country: Brazil
facility: Novartis Investigative Site
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Praha
country: Czechia
facility: Novartis Investigative Site
city: Montpellier Cedex 5
country: France
facility: Novartis Investigative Site
city: Paris 15
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Toulouse 4
country: France
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: Mainz
country: Germany
facility: Novartis Investigative Site
city: Nagpur
country: India
facility: Novartis Investigative Site
state: Maharashtra
city: New Delhi
country: India
facility: Novartis Investigative Site
city: Haifa
country: Israel
facility: Novartis Investigative Site
city: Jerusalem
country: Israel
facility: Novartis Investigative Site
city: Petach Tikva
country: Israel
facility: Novartis Investigative Site
city: Bari
country: Italy
facility: Novartis Investigative Site
state: BA
city: Ranica
country: Italy
facility: Novartis Investigative Site
state: BG
city: Brescia
country: Italy
facility: Novartis Investigative Site
state: BS
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Torino
country: Italy
facility: Novartis Investigative Site
state: TO
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Okayama-city
country: Japan
facility: Novartis Investigative Site
state: Okayama
city: Hachioji-city
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Osaka
country: Japan
facility: Novartis Investigative Site
city: Olsztyn
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Wroclaw
country: Poland
facility: Novartis Investigative Site
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: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Bern
country: Switzerland
facility: Novartis Investigative Site
city: Lausanne
country: Switzerland
facility: Novartis Investigative Site
city: Ankara
country: Turkey
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Izmir
country: Turkey
facility: Novartis Investigative Site
city: Kocaeli
country: Turkey
facility: Novartis Investigative Site
city: Bangor
country: United Kingdom
facility: Novartis Investigative Site
city: Cardiff
country: United Kingdom
facility: Novartis Investigative Site
city: Ho Chi Minh
country: Vietnam
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: