An adaptive seamless randomized, double-blind, placebo-controlled, dose ranging study to investigate the efficacy and safety of LNP023 in primary IgA nephropathy patientsShort title
LNP023 & IgANPEudraCT-No.
09.06.2020General Short Description
An adaptive seamless randomized, double-blind, placebo-controlled, dose ranging study to investigate the efficacy and safety of LNP023 in primary IgA nephropathy patientsScientific Short Description
An adaptive seamless randomized, double-blind, placebo-controlled, dose ranging study to investigate the efficacy and safety of LNP023 in primary IgA nephropathy patients
Investigated Disease, Health IssueICD-Code
- N02.8 - Rezidivierende und persistierende Hämaturie; Sonstige morphologische Veränderungen
18 - 99Gender
AllAdditional Inclusion Criteria
IgA nephropathy patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Female and male patients >18 years of age with a biopsy-verified IgA nephropathy and where the biopsy was performed within the prior three years.
3. Able to communicate well with the investigator, to understand and comply with the requirements of the study.
4. 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
5. Measured 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
Urine protein to creatinine ratio (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.
7. Vaccination against Neisseria meningitidis types A, C, Y and W-135 is required at least 30 days prior to first dosing with LNP023. Vaccination against N. meningitidis type B should be conducted if available and acceptable by local regulations, at least 29 days prior to first dosing
8. Vaccination for the prevention of S. pneumoniae and H. influenza, if available and acceptable by local regulations, at least 30 days prior to first dosing
9. 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.
10. Laboratory values must meet the following criteria:
hemoglobin ≥ 9.0 g/dL
platelet count ≥ 100,000/mm3
11. Vital signs should be within the following ranges
body temperature between 35.0-37.5 °C
systolic blood pressure, 90-160 mm Hg
diastolic blood pressure, 50-90 mm Hg
pulse rate, 40-90bpm, below 50bpm if no other clinically significant ECG abnormalities as per Investigator decision. For subjects with heart rates less than 50 bpm, evidence should be provided that they have no history of (i) moderate or severe valvular disease; (ii) history of coronary artery disease, myocardial infarction, hypertension or diabetes mellitus; (iii) history of cardiomyopathy, congenital heart defect, open heart surgery, or ongoing arrhythmia; (iv) family history of sudden death in a first degree relative.
IgA nephropathy patients fulfilling any of the following criteria are not eligible for inclusion in this study:
1. Presence of crescent formation in ≥50% of glomeruli assessed on renal biopsy
2. Patients previously treated with immunosuppressive agents such as cyclophosphamide or mycophenolate mofetil (MMF) or mycophenolate sodium, or cyclosporine, tacrolimus, sirolimus or systemic corticosteroids exposure within 90 days prior to start of LNP023/Placebo dosing
3. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of enrollment, or within 30 days, whichever is longer; or longer if required by local regulations
4. All transplanted patients (any organ, including bone marrow)
5. History of immunodeficiency diseases, or a positive 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
6. 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
Inflammatory bowel disease, peptic ulcers, severe gastrointestinal disorder includingrectal 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 2 x upper limit of normal (ULN)
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 IgNA that is associated with hematuria at screening and before dosing; [If necessary, laboratory testing may be repeated on one occasion (as soon as possible) prior to randomization, to rule out any laboratory error]
7. 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 hCG laboratory test.
8. A history of clinically significant 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 permanentlydiscontinued for the duration of the study
9. History of severe allergic reactions as per Investigator decision
10. Plasma donation (> 200mL) within 30 days prior to first dosing.
11. Donation or loss of 400 mL or more of blood within eight (8) weeks prior to initial dosing, or longer if required by local regulation
12. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception from first dosing until EOS. Highly effective contraception methods include:
Total abstinence from heterosexual intercourse (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
Female sterilization (have had surgical bilatera