A study evaluating the of safety and efficacy of LNP023 in patients with a kidney disorder called IgAN nephropathy

• Register: EUCTR
• Last refreshed on: 18 January 2021
• Main ID: EUCTR2017-000891-27-SE
• Date of registration: 17/10/2017
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma AG
• Public title: A study evaluating the of safety and efficacy of LNP023 in patients with a kidney disorder called IgAN nephropathy
• Scientific title: An adaptive seamless randomized, double-blind, placebo-controlled, dose ranging study to investigate the efficacy and safety of LNP023 in primary IgA nephropathy patients
• Date of first enrolment: 19/02/2018
• Target sample size: 96
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-000891-27
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: yes; Other trial design description: adaptive; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 5
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Belgium, Brazil, Canada, China, Colombia, Czech Republic, Denmark, Finland, France, Germany, Hong Kong, Hungary, India, Israel, Italy, Japan, Jordan, Korea, Republic of, Lebanon, Malaysia, Netherlands, Norway, Philippines, Singapore, Spain, Sweden, Taiwan, Thailand, Turkey, United Kingdom, United States

Contacts

• Name: Medical information
• Affiliation: Novartis Sverige AB

• Name: Medical information
• Affiliation: Novartis Sverige AB

Key inclusion & exclusion criteria

Inclusion criteria:
•Female and male patients = 18 years of age with a biopsyverified IgA nephropathy and where the biopsy was performed within the previous three years. If the most recent renal biopsy was performed
more than three years ago, a new biopsy should be performed.
•Patients must weigh at least 35 kg to participate in the study, and must have a body mass index (BMI) within the range of 15 - 38 kg/m2. BMI =Body weight (kg) / [Height (m)]2
•Measured Glomerular Filtration Rate (GFR) or estimated GFR calculated using the CKD-EPI formula (or modified MDRD formula according to specific ethnic groups and local practice guidelines [Imai, et
al, 2011]) =30 mL/min per 1.73 m2
•UPCR =0.8 g/g (=90 mg/mmol) sampled from first morning void (FMV) or urine protein =0.75 g/24hr from a 24h urine collection at screening and urine protein =0.75 g / 24h from a 24h urine collection at
the completion of the run- in period
•Vaccination against Neisseria meningitidis types A, C, Y and W-135 is required at least 4 weeks prior to first dosing with LNP023. Vaccination against N. meningitidis type B, S. pneumoniae and H. influenzae should be conducted if available and acceptable by local regulations, at least 4 weeks prior to first dosing with LNP023
•All patients must have been on supportive care including a maximally tolerated dose of ACEi or ARB therapy for the individual, antihypertensive therapy or diuretics for at least 90 days before dosing.

Other protocol defined inclusion criteria may apply.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 92
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 4

Exclusion criteria:
• Presence of crescent formation in =50% of glomeruli assessed on renal biopsy
• Patients previously treated with immunosuppressive agents such as cyclophosphamide, mycophenolate mofetil (MMF) or mycophenolate sodium, cyclosporine, tacrolimus, sirolimus, or systemic corticosteroids within 90 days prior to start of LNP023/Placebo dosing
• All transplanted patients (any organ, including bone marrow)
• History of immunodeficiency diseases, or a positive Human Immunodeficiency Virus (HIV; ELISA and Western blot) test result.
• Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV). A positive HBV surface antigen (HBsAg) test, or if standard local practice, a positive HBV core antigen test, excludes a patient. Patients with a positive HCV antibody test should have HCV RNA levels measured. Subjects with positive (detectable) HCV RNA should be excluded
• Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the subject in case of participation in the study. The Investigator should make this determination in consideration of the subject's medical history and/or clinical or laboratory evidence of any of the following:
• A history of invasive infections caused by encapsulated organisms e.g. meningococcus or pneumococcus
•Splenectomy
•Inflammatory bowel disease, peptic ulcers, severe gastrointestinal disorder including rectal bleeding;
• Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection;
•Pancreatic injury or pancreatitis;
•Liver disease or liver injury as indicated by abnormal liver function tests. ALT (SGPT), AST (SGOT), GGT, alkaline phosphatase and serum bilirubin will be tested.
•Any single parameter of ALT, AST, GGT, alkaline phosphatase or serum bilirubin must not exceed 3 x upper limit of normal (ULN)
•Prothrombin Time / International normalized ration (PT/INR) must be within the reference range of normal individuals. Evidence of urinary obstruction or difficulty in voiding any urinary tract disorder other than IgAN that is associated with hematuria at screening; [If necessary, laboratory testing may be repeated on one occasion (as soon as possible) prior to randomization, to rule out any laboratory error]
• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test.
• A history of clinically significant electrocardiogram (ECG)abnormalities, or any of the following ECG abnormalities at screening or baseline:
• PR > 200 msec
• QRS complex > 120 msec
• QTcF > 450 msec (males)
• QTcF > 460 msec (females)
• History of familial long QT syndrome or known family history of Torsades de Pointes
• Use of agents known to prolong the QT interval unless they can be permanently discontinued for the duration of the study
• History of severe allergic reactions as per Investigator decision
• Female patients who are pregnant or breastfeeding, or intending to conceive during the course of the study
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception from first dosing with LNP023 until an additional one week following cessation of study drug. History of malignancy of any organ system (other than localized

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Primary IgA Nephropathy
MedDRA version: 20.0 Level: HLGT Classification code 10029149 Term: Nephropathies System Organ Class: 10038359 - Renal and urinary disorders

Therapeutic area: Diseases [C] - Immune System Diseases [C20]

Intervention(s)

Product Name: Iptacopan
Product Code: LNP023
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Iptacopan
Other descriptive name:  LNP023 HYDROCHLORIDE SALT
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Product Name: Iptacopan
Product Code: LNP023
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Iptacopan
Other descriptive name:  LNP023 HYDROCHLORIDE SALT
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Product Name: Iptacopan
Product Code: LNP023
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Iptacopan
Other descriptive name:  LNP023 HYDROCHLORIDE SALT
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: -To evaluate the safety and tolerability of LNP023
-To assess the effect of LNP023 on renal function
-To assess the pharmacokinetics of LNP023
-To assess the effect of LNP023 on alternative complement pathway
-To estimate the lowest dose that provides maximal reduction of proteinuria

Main Objective: To evaluate the dose response relationship of LNP023 on the reduction in proteinuria versus placebo after 90 days of treatment in patients with IgA nephropathy.

Timepoint(s) of evaluation of this end point: Baseline and day 90

Primary end point(s): The primary variable for the statistical analysis is the ratio to baseline of urine protein to creatinine concentration ratio (UPCR based on 24h urine
collection) at 90 days.

Secondary Outcome(s)

Secondary end point(s): Assessment of safety based on vital signs, physical examination, ECGs, laboratory assessments, laboratory assessments, and collection of AEs assessed from baseline until the end of the study visit
- Estimated glomerular filtration rate (eGFR; estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation); Serum creatinine; Hematuria (number of erythrocytes/high-power-field (hpf) measured through microscopic examination); 24h-UP, 24h-UA, UACR (urine albumin to creatinine concentration ratio); UPCR (urine protein to creatinine concentration ratio) from first morning void.
- Plasma: Non-compartmental parameters related to total parent drug, including but not limited to Tmax, Cmax, AUClast and AUCtau will be
calculated for each dose level; Urine: Non-compartmental parameters, including but not limited to total cumulative urinary excretion (Ae) and renal plasma clearance (CLr)
- Plasma levels of alternative pathway biomarkers including Bb and sC5b-9
- Ratio to baseline of UPCR
- Estimated glomerular filtration rate (eGFR; estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation) UPCR from 24 hour sample and first morning void Hematuria (number of erythrocytes/high-power-field (hpf) measured through microscopic examination) UACR (urine albumin to creatinine concentration ratio).

Timepoint(s) of evaluation of this end point: - Baseline, Day 1, 8, 15, 30, 90, 120
- Baseline, Day 1, 8, 15, 30, 90, 120
- Baseline, Day 1, 8, 15, 30, 60, 90, 120, 180
- Baseline, Day 1, 30, 60, 90, 120, 180
- Baseline, Day 1, 8, 15, 30, 60, 90
- Baseline, Day 1, 8, 15, 30, 60, 90
- Baseline, Day 1, 8, 15, 30, 60, 90
- Baseline, Day 1, 8, 15, 30, 60, 90
- Baseline, Day 1, 8, 15, 30, 60, 90

Secondary ID(s)

2017-000891-27-GB

CLNP023X2203

Source(s) of Monetary Support

Novartis Pharma AG

Ethics review

Status: Approved
Approval date: 19/02/2018
Contact: