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

NCT ID: NCT03373461

Last Updated: 2023-01-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 112 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-02-07
• Study Completion Date: 2021-06-22

Brief Summary

Efficacy and safety of LNP023 in IgAN patients

Detailed Description

This was a multicenter, randomized, double-blind, dose-ranging, parallel-group study with an adaptive design (Part 1 informed the design adaptations for Part 2). In Part 1, three doses of LNP023 (10 mg, 50 mg, and 200 mg) vs. placebo control were compared; In Part 2, four doses of LNP023 (10 mg, 50 mg, 100 mg, and 200 mg) vs. placebo control were compared. The study comprised a run-in phase in order that patients were on stable and maximally tolerated dose of Angiotensin-converting-enzyme inhibitor (ACEi) or Angiotensin II Receptor Blockers (ARB) for at least 90 days, a 90 days treatment phase in Part 1; a 180 days treatment phase in Part 2 and a 90 days follow-up phase in both Parts 1 and 2.

Conditions

IgA Nephropathy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Placebo

Placebo identical to LNP023 twice a day

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Matching placebo to LNP023

LNP023 10 mg BID

10 mg taken twice a day.

Group Type: EXPERIMENTAL

LNP023

Intervention Type: DRUG

LNP023 5, 25, 100 mg capsles

LNP023 50 mg BID

50 mg taken twice a day.

Group Type: EXPERIMENTAL

LNP023

Intervention Type: DRUG

LNP023 5, 25, 100 mg capsles

LNP023 100 mg BID - Part 2

100 mg taken twice a day.

Group Type: EXPERIMENTAL

LNP023

Intervention Type: DRUG

LNP023 5, 25, 100 mg capsles

LNP023 200 mg BID

200 mg taken twice a day.

Group Type: EXPERIMENTAL

LNP023

Intervention Type: DRUG

LNP023 5, 25, 100 mg capsles

Interventions

LNP023

LNP023 5, 25, 100 mg capsles

Intervention Type: DRUG

Placebo

Matching placebo to LNP023

Intervention Type: OTHER

Eligibility Criteria

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

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 cyclosporine, 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
• 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]

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 permanently discontinued 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 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.

13. 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

14. History of any porphyria metabolic disorder

15. 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.

16. History of hypersensitivity to any of the study treatments or excipients or to drugs of similar chemical classes

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Novartis Investigative Site

Caba, Buenos Aires, Argentina

Novartis Investigative Site

Ciudad Autonoma de Bs As, Buenos Aires, Argentina

Novartis Investigative Site

Westmead, New South Wales, Australia

Novartis Investigative Site

Parkville, Victoria, Australia

Novartis Investigative Site

Edegem, Antwerpen, Belgium

Novartis Investigative Site

Leuven, , Belgium

Novartis Investigative Site

Roeselare, , Belgium

Novartis Investigative Site

Curitiba, Paraná, Brazil

Novartis Investigative Site

Porto Alegre, Rio Grande do Sul, Brazil

Novartis Investigative Site

Guangzhou, Guangdong, China

Novartis Investigative Site

Beijing, , China

Novartis Investigative Site

Guangzhou, , China

Novartis Investigative Site

Shanghai, , China

Novartis Investigative Site

Barranquilla, , Colombia

Novartis Investigative Site

Prague, , Czechia

Novartis Investigative Site

Aalborg, , Denmark

Novartis Investigative Site

Arhus N, , Denmark

Novartis Investigative Site

HUS, Finland, Finland

Novartis Investigative Site

Montpellier, , France

Novartis Investigative Site

Berlin, , Germany

Novartis Investigative Site

Heidelberg, , Germany

Novartis Investigative Site

Hong Kong SAR, , Hong Kong

Novartis Investigative Site

New Delhi, National Capital Territory of Delhi, India

Novartis Investigative Site

New Delhi, , India

Novartis Investigative Site

Ashkelon, , Israel

Novartis Investigative Site

Jerusalem, , Israel

Novartis Investigative Site

Petah Tikva, , Israel

Novartis Investigative Site

Toyoake, Aichi-ken, Japan

Novartis Investigative Site

Sapporo, Hokkaido, Japan

Novartis Investigative Site

Sendai, Miyagi, Japan

Novartis Investigative Site

Okayama, Okayama-ken, Japan

Novartis Investigative Site

Osaka, Osaka, Japan

Novartis Investigative Site

Kuala Lumpur, , Malaysia

Novartis Investigative Site

Groningen, , Netherlands

Novartis Investigative Site

Bergen, , Norway

Novartis Investigative Site

Loerenskog, , Norway

Novartis Investigative Site

Oslo, , Norway

Novartis Investigative Site

Singapore, , Singapore

Novartis Investigative Site

Singapore, , Singapore

Novartis Investigative Site

Seoul, , South Korea

Novartis Investigative Site

Lund, , Sweden

Novartis Investigative Site

Stockholm, , Sweden

Novartis Investigative Site

New Taipei City, , Taiwan

Novartis Investigative Site

Taichung, , Taiwan

Novartis Investigative Site

Taipei, , Taiwan

Novartis Investigative Site

Bangkok, , Thailand

Novartis Investigative Site

Bangkok, , Thailand

Novartis Investigative Site

Istanbul, TUR, Turkey (Türkiye)

Novartis Investigative Site

Ankara, , Turkey (Türkiye)

Novartis Investigative Site

Kocaeli, , Turkey (Türkiye)

Novartis Investigative Site

Talas / Kayseri, , Turkey (Türkiye)

Novartis Investigative Site

Cambridge, Cambrigdeshire, United Kingdom

Novartis Investigative Site

Salford, Manchester, United Kingdom

Novartis Investigative Site

Leicester, , United Kingdom

Novartis Investigative Site

London, , United Kingdom

Novartis Investigative Site

Newcastle upon Tyne, , United Kingdom

Countries

Argentina; Australia; Belgium; Brazil; China; Colombia; Czechia; Denmark; Finland; France; Germany; Hong Kong; India; Israel; Japan; Malaysia; Netherlands; Norway; Singapore; South Korea; Sweden; Taiwan; Thailand; Turkey (Türkiye); United Kingdom

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://www.novctrd.com/ctrdweb/patientsummary/patientsummaries?patientSummaryId=1215

A Plain Language Trial Summary is available on novctrd.com

Other Identifiers

2017-000891-27

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CLNP023X2203

Identifier Type: -

Identifier Source: org_study_id