Study of Safety and Efficacy of LNP023 in Patients With Kidney Disease Caused by Inflammation

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Completed

CT.gov ID

NCT03373461

Collaborator

(none)

112

Enrollment

Locations

Arms

40.4

Actual Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Efficacy and safety of LNP023 in IgAN patients

Condition or Disease	Intervention/Treatment	Phase
IgA Nephropathy	Drug: LNP023 Drug: Placebo	Phase 2

Detailed Description

The purpose of this Phase IIa/IIb dose ranging study is to generate human data in the intended patient population with IgAN to establish clinical proof-of-concept and to evaluate dose responses to support dose selection for subsequent clinical development of LNP023 for IgAN and potentially other indications

Study Design

Study Type:

Interventional

Actual Enrollment :

112 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

The primary variable is the change from baseline of log transformed UPCR derived from the 24h urine collections at baseline and day 90. An interim analysis will be performed once the last patient has completed treatment in Part 1. The intention of this analysis is to provide preliminary evidence of dose-response relationship for proteinuria, to determine the sample size for Part 2, and to determine the treatment arms to be studied in Part 2.The primary variable is the change from baseline of log transformed UPCR derived from the 24h urine collections at baseline and day 90. An interim analysis will be performed once the last patient has completed treatment in Part 1. The intention of this analysis is to provide preliminary evidence of dose-response relationship for proteinuria, to determine the sample size for Part 2, and to determine the treatment arms to be studied in Part 2.

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official 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

Actual Study Start Date :

Feb 7, 2018

Actual Primary Completion Date :

Dec 29, 2020

Actual Study Completion Date :

Jun 22, 2021

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo to LNP023	Drug: Placebo Placebo to LPN023 b.i.d
Experimental: LNP023 dose 1 Dose 1 of LNP023	Drug: LNP023 LNP023 b.i.d. Dose 1, Dose 2 and Dose 3
Experimental: LNP023 dose 2 Dose 2 of LNP023	Drug: LNP023 LNP023 b.i.d. Dose 1, Dose 2 and Dose 3
Experimental: LNP023 dose 3 Dose 3 of LNP023	Drug: LNP023 LNP023 b.i.d. Dose 1, Dose 2 and Dose 3

Outcome Measures

Primary Outcome Measures

change from baseline of urine protein to creatinine concentration [Baseline and Day 90]
baseline of urine protein to creatinine concentration ratio (UPCR based on 24h urine collection) at 90 days

Secondary Outcome Measures

The effect of LNP023 on renal function - Estimated Glomerular Filtration Rate eGFR [Baseline, Day 1, 8, 15, 30, 90, 120]
eGFR; estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
The effect of LNP023 on renal function - Serum creatinine [Baseline, Day 1, 8, 15, 30, 90, 120]
Serum creatinine
The effect of LNP023 on renal function - Hematuria [Baseline, Day 1, 8, 15, 30, 60, 90, 120, 180]
Hematuria (number of erythrocytes/high-power-field (hpf) measured through microscopic examination)
The effect of LNP023 on renal function - 24h-UP, 24h-UA, UACR (urine albumin to creatinine concentration ratio) [Baseline, Day 1, 30, 60, 90, 120, 180]
24h-UP, 24h-UA, UACR (urine albumin to creatinine concentration ratio)
Plasma Pharmacokinetics (PK) of LNP023: Area Under the Plasma Concentration-time Curve (AUC) [Baseline, Day 1, 8, 15, 30, 60, 90]
AUCtau: Area under the plasma concentration-time curve from time zero to the end of the dosing interval AUClast: Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration. AUClast was calculated as the sum of linear trapezoids using non-compartmental analysis.
Observed Maximum Concentration (Cmax) after Drug Administration [Baseline, Day 1, 8, 15, 30, 60, 90]
Blood samples for pharmacokinetic (PK) evaluation were drawn pre-dose and at 3, 6, and 12 hours on Day 1; at 0 and 12 hours on Day 2; and on Days 3, 4, 6, 8, 10, 14, 18, 22, and 26 following administration of iloperidone. PK parameters were calculated from plasma concentration-time data using non-compartmental methods.
The effect of LNP023 on alternative complement pathway [Baseline, Day 1, 8, 15, 30, 60, 90]
Bb and sC5b-9
To estimate the lowest dose that provides maximal reduction of proteinuria [Baseline, Day 1, 8, 15, 30, 60, 90]
Ratio to baseline of UPCR urinary prt at the lowest dose that provide
Time to Reach the Maximum Plasma Concentration (Tmax) [Baseline, Day 1, 8, 15, 30, 60, 90]
Blood samples for pharmacokinetic (PK) evaluation were drawn pre-dose and at 3, 6, and 12 hours on Day 1; at 0 and 12 hours on Day 2; and on Days 3, 4, 6, 8, 10, 14, 18, 22, and 26 following administration of iloperidone. PK parameters were calculated from plasma concentration-time data using non-compartmental methods.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Female and male patients above 18 years of age with a biopsy-verified IgA nephropathy and where the biopsy was performed within the prior three years.
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 (using the CKD-EPI formula) ≥30 mL/min per 1.73 m2
Urine protein ≥1 g/24hr at screening and ≥0.75 g / 24h after the run- in period
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, S. pneumoniae and H. influenzae should be conducted if available and acceptable by local regulations, at least 30 days 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 or mycophenolate mofetil (MMF), or cyclosporine, systemic corticosteroids exposure within 90 days prior to start of LNP023/Placebo dosing
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
All transplanted patients (any organ, including bone marrow)
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

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)
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]

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.
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 permanently discontinued for the duration of the study

History of severe allergic reactions as per Investigator decision
Plasma donation (> 200mL) within 30 days prior to first dosing.
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
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 1 week after stopping of investigational drug. 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 bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking investigational drug. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
Male sterilization (at least 6 months prior to screening). For female subjects on the study the vasectomized male partner should be the sole partner for that subject.
Use of oral (estrogen and progesterone), injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception that have comparable efficacy (failure <1%), for example hormone vaginal ring or transdermal hormone contraception In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking investigational drug.

If local regulations deviate from the contraception methods listed above and require more extensive measures to prevent pregnancy, local regulations apply and will be described in the ICF.

Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.

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
History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during screening and baseline.
History of hypersensitivity to any of the study treatments or excipients or to drugs of similar chemical classes

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1280AEB
2	Novartis Investigative Site	Ciudad Autonoma de Bs As		Argentina	C1015ABO
3	Novartis Investigative Site	Westmead	New South Wales	Australia	2145
4	Novartis Investigative Site	Parkville	Victoria	Australia	3050
5	Novartis Investigative Site	Edegem	Antwerpen	Belgium	2650
6	Novartis Investigative Site	Leuven		Belgium	3000
7	Novartis Investigative Site	Roeselare		Belgium	8800
8	Novartis Investigative Site	Curitiba	PR	Brazil	80440-020
9	Novartis Investigative Site	Porto Alegre	RS	Brazil	90020-090
10	Novartis Investigative Site	Guangzhou	Guangdong	China	510080
11	Novartis Investigative Site	Beijing		China	100034
12	Novartis Investigative Site	Guang Zhou		China	510080
13	Novartis Investigative Site	Shanghai		China	200040
14	Novartis Investigative Site	Barranquilla		Colombia
15	Novartis Investigative Site	Praha		Czechia	12808
16	Novartis Investigative Site	Aalborg		Denmark	9000
17	Novartis Investigative Site	Arhus N		Denmark	DK-8200
18	Novartis Investigative Site	HUS		Finland	00029
19	Novartis Investigative Site	Montpellier		France	34295
20	Novartis Investigative Site	Berlin		Germany	13353
21	Novartis Investigative Site	Heidelberg		Germany	69120
22	Novartis Investigative Site	Hong Kong SAR		Hong Kong
23	Novartis Investigative Site	New Delhi	Delhi	India	110 017
24	Novartis Investigative Site	New Delhi		India	110029
25	Novartis Investigative Site	Ashkelon		Israel	78278
26	Novartis Investigative Site	Jerusalem		Israel	91120
27	Novartis Investigative Site	Petach Tikva		Israel	49100
28	Novartis Investigative Site	Toyoake city	Aichi	Japan	470 1192
29	Novartis Investigative Site	Sapporo-city	Hokkaido	Japan	006-8555
30	Novartis Investigative Site	Sendai	Miyagi	Japan	981-3205
31	Novartis Investigative Site	Okayama-city	Okayama	Japan	700-8558
32	Novartis Investigative Site	Osaka-city	Osaka	Japan	530-8480
33	Novartis Investigative Site	Seoul		Korea, Republic of	03080
34	Novartis Investigative Site	Kuala Lumpur		Malaysia	50589
35	Novartis Investigative Site	Groningen		Netherlands	9713 GZ
36	Novartis Investigative Site	Bergen		Norway	5021
37	Novartis Investigative Site	Loerenskog		Norway	NO 1478
38	Novartis Investigative Site	Oslo		Norway	NO 0450
39	Novartis Investigative Site	Singapore		Singapore	119228
40	Novartis Investigative Site	Singapore		Singapore	169608
41	Novartis Investigative Site	Lund		Sweden	221 85
42	Novartis Investigative Site	Stockholm		Sweden	141 86
43	Novartis Investigative Site	New Taipei City		Taiwan	23561
44	Novartis Investigative Site	Taichung		Taiwan	40705
45	Novartis Investigative Site	Taipei		Taiwan	10048
46	Novartis Investigative Site	Bangkok		Thailand	10330
47	Novartis Investigative Site	Bangkok		Thailand	10400
48	Novartis Investigative Site	Istanbul	TUR	Turkey	34098
49	Novartis Investigative Site	Ankara		Turkey	06100
50	Novartis Investigative Site	Kocaeli		Turkey	41380
51	Novartis Investigative Site	Talas / Kayseri		Turkey	38039
52	Novartis Investigative Site	Cambridge	Cambrigdeshire	United Kingdom	CB2 0QQ
53	Novartis Investigative Site	Salford	Manchester	United Kingdom	M6 8HD
54	Novartis Investigative Site	Leicester		United Kingdom	LE5 4PW
55	Novartis Investigative Site	London		United Kingdom	SE5 9RS
56	Novartis Investigative Site	Newcastle Upon Tyne		United Kingdom	NE7 7DN

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Novartis Pharmaceuticals

ClinicalTrials.gov Identifier:

NCT03373461

Other Study ID Numbers:

CLNP023X2203
2017-000891-27

First Posted:

Dec 14, 2017

Last Update Posted:

Jul 9, 2021

Last Verified:

Jul 1, 2021

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Novartis Pharmaceuticals

glomerunephritis, complement driven, chronic kidney disease

Additional relevant MeSH terms:

Kidney Diseases

Glomerulonephritis, IGA

Study Results

No Results Posted as of Jul 9, 2021