An adaptive seamless randomized, double-blind, placebo-controlled, dose ranging study to investigate the efficacy and safety of LNP023 in primary IgA nephropathy patients
- Conditions
- IgA kidney diseaseIgAN10029149
- Registration Number
- NL-OMON50202
- Lead Sponsor
- ovartis
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 4
* Female and male patients * 18 years of age with a biopsy-verified 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 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
* 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.
* 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 2 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 metho
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>To evaluate the dose response relationship of LNP023 on the reduction in<br /><br>proteinuria versus placebo after 90 days of treatment in patients with IgA<br /><br>nephropathy.</p><br>
- Secondary Outcome Measures
Name Time Method <p>- To evaluate the safety and tolerability of LNP023<br /><br>- To assess the effect of LNP023 on renal function up to 90 days of treatment<br /><br>(combining Part 1 and Part 2 of the study)<br /><br>- To assess the pharmacokinetics of LNP023<br /><br>- To assess the effect of LNP023 on alternative complement pathway<br /><br>- To estimate the lowest dose that provides maximal reduction of proteinuria<br /><br>- To assess the effect of LNP023 on renal function up to Day 180 (Part 2 of the<br /><br>study)</p><br>