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.
ID
Source
Brief title
Condition
- Nephropathies
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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.
Secondary outcome
- To evaluate the safety and tolerability of LNP023
- To assess the effect of LNP023 on renal function up to 90 days of treatment
(combining Part 1 and Part 2 of the study)
- 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
- To assess the effect of LNP023 on renal function up to Day 180 (Part 2 of the
study)
Background summary
Antibodies belong to the body's immune system. The immune system must protect
the body against organisms that can enter the body, such as bacteria, viruses.
If the immune system recognizes a foreign substance (eg a bacterium), it will
form antibodies against this substance. This happens to defend the body.
In IgA kidney disease, IgA (immunoglobulin A) antibodies also end up in the
kidneys. This caused an inflammatory reaction in the kidney filters. This leads
among other things to the loss of protein via the urine.
If an important part of the body's immune system becomes too active, diseases
can arise such IgA nephropathy. LNP023 inhibits the functioning of this part of
the immune system. As a result, the disease can become less active and the
symptoms can become less serious. For example, the amount of protein that
disappears from the body
LNP023 has not yet been approved ("registered") by the Dutch government as a
medicine. Doctors are not yet allowed to prescribe the drug. Registration with
patients is required for registration. So far, approximately 78 healthy
subjects have been treated with LNP023 in a study.
Study 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.
Study design
This is an adaptive seamless randomized, double-blind, placebo-controlled, dose
ranging study evaluating the efficacy and safety LNP023 following 90 - 180 days
of treatment. In Part 1, 4 groups of IgAN patients will be randomized to three
doses (10mg, 50mg and 200mg b.i.d) of LNP023 or Placebo. At the end of Part 1,
a pre-specified interim analysis will be performed to evaluate the initial
response to therapy and to make design choices for Part 2 using predefined
rules. The trial may either be stopped for futility, or continued with some
design adaptations (increase of the sample size and addition of a dose arm of
either 25 mg or 100 mg b.i.d) for the treatment phase of Part 2. Hence,
patients in Part 2 will be randomized to placebo, 10 mg, 50 mg, 200 mg b.i.d
and a 4th active dose of either 25 mg b.i.d or 100 mg b.i.d. 100 mg dose was
chosen by the DMC after the interim analysis Part 1. The treatment phase will
be extended to 180 days in Part 2 compared to Part 1, during which additional
efficacy and safety data will be collected. Data from Part 1 and Part 2 of the
study up to approximately Day 90 will be pooled and used for the interim
analysis Part 2 (IA2).
Intervention
LNP023 is available as 5 mg, 25 mg, 100 mg and matching placebo capsules.
b.i.d. Patients will be randomized to either 0 mg (matching Placebo), 10mg,
50mg, or 200 mg b.i.d. in Part 1. Either the dose of 25 mg or 100 mg b.i.d will
be added in Part 2 based on the interim analysis results in Part 1. 100 mg was
chosen by DMC after interim analysis part 1.
Study burden and risks
Part 1 of the study takes 7 to 9 months. Part 2 takes 10 to 12 months. The
study starts with the screening visit and a start-up phase of 1 to 3 months.
Then there is a treatment period of about 3 months in Part 1 and 6 months in
Part 2 during which you use the study medication. Three months after the last
administration of the study medication, there is a final check for the study.
Based on 10-12 visits, the burden will be as follows:
- Physical examination: 6x in Part 1, 8x in Part 2
- ECG: 10x in Part 1, 11x in Part 2
- Vital signs: 14x
- Blood test: 20x (max 350 ml in total for 9 months in Part 1 and 450ml in
total for 12 months in Part 2)
- Pregnancy test (if applicable): 6x in Part 1, 7x in Part 2
- Urine test: 10x in Part 1, 12 keer in Part 2
- 24 h urine collection: 8x in Part 1, 9x in Part 2
- Complete questionnaires: 6x in Part 1, 8x in Part 2
Vaccination (if applicable): 1x
Optional:
- Pharmacogenicity (1x blood collection)
Side effects of research medication and inconveniences research procedures.
haaksbergweg 16
Amsterdam 1101 BX
NL
haaksbergweg 16
Amsterdam 1101 BX
NL
Listed location countries
Age
Inclusion criteria
* 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.
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 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 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 basal cell
carcinoma of the skin or in-situ cervical cancer), treated or untreated, within
the past 5 years, regardless of whether there is evidence of local recurrence
or metastases
* History of any porphyria metabolic disorder
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-000891-27-NL |
| ClinicalTrials.gov | NCT03373461 |
| CCMO | NL65098.056.18 |