An Adaptive Seamless Randomized, Double-blind, Placebo-controlled, Dose Ranging Study to Investigate the Efficacy and Safety of LNP023 in Primary IgA Nephropathy Patients

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

Sponsors

Lead sponsor: Novartis Pharmaceuticals

Source Novartis
Brief Summary

Efficacy and safety of LNP023 in IgAN patients

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

Overall Status Recruiting
Start Date February 7, 2018
Completion Date June 24, 2021
Primary Completion Date December 25, 2020
Phase Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
change from baseline of urine protein to creatinine concentration Baseline and Day 90
Secondary Outcome
Measure Time Frame
The effect of LNP023 on renal function - Estimated Glomerular Filtration Rate eGFR Baseline, Day 1, 8, 15, 30, 90, 120
The effect of LNP023 on renal function - Serum creatinine Baseline, Day 1, 8, 15, 30, 90, 120
The effect of LNP023 on renal function - Hematuria Baseline, Day 1, 8, 15, 30, 60, 90, 120, 180
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
Plasma Pharmacokinetics (PK) of LNP023: Area Under the Plasma Concentration-time Curve (AUC) Baseline, Day 1, 8, 15, 30, 60, 90
Observed Maximum Concentration (Cmax) after Drug Administration Baseline, Day 1, 8, 15, 30, 60, 90
The effect of LNP023 on alternative complement pathway Baseline, Day 1, 8, 15, 30, 60, 90
To estimate the lowest dose that provides maximal reduction of proteinuria Baseline, Day 1, 8, 15, 30, 60, 90
Time to Reach the Maximum Plasma Concentration (Tmax) Baseline, Day 1, 8, 15, 30, 60, 90
Enrollment 146
Condition
Intervention

Intervention type: Drug

Intervention name: LNP023

Description: LNP023 b.i.d. Dose 1, Dose 2 and Dose 3

Intervention type: Drug

Intervention name: Placebo

Description: Placebo to LPN023 b.i.d

Arm group label: Placebo

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

Gender: All

Minimum age: 18 Years

Maximum age: N/A

Healthy volunteers: No

Overall Contact

Last name: Novartis Pharmaceuticals

Phone: 1-888-669-6682

Email: [email protected]

Location
facility status
Novartis Investigative Site | Florence, Alabama, 35630, United States Recruiting
Novartis Investigative Site | Ann Arbor, Michigan, 48109, United States Recruiting
Novartis Investigative Site | Temple, Texas, 76502, United States Recruiting
Novartis Investigative Site | Caba, Buenos Aires, C1280AEB, Argentina Recruiting
Novartis Investigative Site | Ciudad Autonoma de Bs As, C1015ABO, Argentina Recruiting
Novartis Investigative Site | Westmead, New South Wales, 2145, Australia Recruiting
Novartis Investigative Site | Parkville, Victoria, 3050, Australia Recruiting
Novartis Investigative Site | Edegem, Antwerpen, 2650, Belgium Recruiting
Novartis Investigative Site | Leuven, 3000, Belgium Recruiting
Novartis Investigative Site | Roeselare, 8800, Belgium Recruiting
Novartis Investigative Site | Beijing, Beijing, 100039, China Recruiting
Novartis Investigative Site | Guangzhou, Guangdong, 510080, China Recruiting
Novartis Investigative Site | Beijing, 100034, China Recruiting
Novartis Investigative Site | Guang Zhou, 510080, China Recruiting
Novartis Investigative Site | Shanghai, 200040, China Recruiting
Novartis Investigative Site | Barranquilla, Colombia Recruiting
Novartis Investigative Site | Prague 4, 140 21, Czechia Recruiting
Novartis Investigative Site | Praha, 12808, Czechia Recruiting
Novartis Investigative Site | Aalborg, 9000, Denmark Recruiting
Novartis Investigative Site | Arhus N, DK-8200, Denmark Recruiting
Novartis Investigative Site | HUS, 00029, Finland Recruiting
Novartis Investigative Site | Montpellier, 34295, France Recruiting
Novartis Investigative Site | Berlin, 13353, Germany Recruiting
Novartis Investigative Site | Hamburg, 20246, Germany Recruiting
Novartis Investigative Site | Heidelberg, 69120, Germany Recruiting
Novartis Investigative Site | Hong Kong SAR, Hong Kong Recruiting
Novartis Investigative Site | Pecs, 7632, Hungary Recruiting
Novartis Investigative Site | New Delhi, Delhi, 110 017, India Recruiting
Novartis Investigative Site | Mysore, Karnataka, 570001, India Recruiting
Novartis Investigative Site | New Delhi, 110029, India Recruiting
Novartis Investigative Site | Ashkelon, 78278, Israel Recruiting
Novartis Investigative Site | Jerusalem, 91120, Israel Recruiting
Novartis Investigative Site | Petach Tikva, 49100, Israel Recruiting
Novartis Investigative Site | Ranica, BG, 24020, Italy Recruiting
Novartis Investigative Site | Napoli, 80100, Italy Recruiting
Novartis Investigative Site | Toyoake city, Aichi, 470 1192, Japan Recruiting
Novartis Investigative Site | Sapporo-city, Hokkaido, 006-8555, Japan Recruiting
Novartis Investigative Site | Nishinomiya, Hyogo, 663 8501, Japan Recruiting
Novartis Investigative Site | Kawasaki-city, Kanagawa, 216-8511, Japan Recruiting
Novartis Investigative Site | Yokohama-city, Kanagawa, 236-0004, Japan Recruiting
Novartis Investigative Site | Sendai, Miyagi, 981-8501, Japan Recruiting
Novartis Investigative Site | Okayama-city, Okayama, 700-8558, Japan Recruiting
Novartis Investigative Site | Osaka-city, Osaka, 530-8480, Japan Recruiting
Novartis Investigative Site | Bunkyo ku, Tokyo, 113-8431, Japan Recruiting
Novartis Investigative Site | Bunkyo-ku, Tokyo, 113-8519, Japan Recruiting
Novartis Investigative Site | Seoul, Seocho Gu, 06591, Korea, Republic of Recruiting
Novartis Investigative Site | Seoul, 03080, Korea, Republic of Recruiting
Novartis Investigative Site | Kuala Lumpur, Selangor Darul Ehsan, 43000, Malaysia Recruiting
Novartis Investigative Site | Kuala Lumpur, 50589, Malaysia Recruiting
Novartis Investigative Site | Groningen, 9713 GZ, Netherlands Recruiting
Novartis Investigative Site | Bergen, 5021, Norway Recruiting
Novartis Investigative Site | Loerenskog, NO 1478, Norway Recruiting
Novartis Investigative Site | Oslo, NO 0450, Norway Recruiting
Novartis Investigative Site | Singapore, 119228, Singapore Recruiting
Novartis Investigative Site | Singapore, 169608, Singapore Recruiting
Novartis Investigative Site | Barcelona, Catalunya, 08025, Spain Recruiting
Novartis Investigative Site | Madrid, 28040, Spain Recruiting
Novartis Investigative Site | Madrid, 28041, Spain Recruiting
Novartis Investigative Site | Lund, 221 85, Sweden Recruiting
Novartis Investigative Site | Stockholm, 141 86, Sweden Recruiting
Novartis Investigative Site | New Taipei City, 23561, Taiwan Recruiting
Novartis Investigative Site | Taichung, 40705, Taiwan Recruiting
Novartis Investigative Site | Taipei, 10048, Taiwan Recruiting
Novartis Investigative Site | Taoyuan, 33305, Taiwan Recruiting
Novartis Investigative Site | Bangkok, 10330, Thailand Recruiting
Novartis Investigative Site | Bangkok, 10400, Thailand Recruiting
Novartis Investigative Site | Istanbul, TUR, 34098, Turkey Recruiting
Novartis Investigative Site | Ankara, 06100, Turkey Recruiting
Novartis Investigative Site | Kocaeli, 41380, Turkey Recruiting
Novartis Investigative Site | Talas / Kayseri, 38039, Turkey Recruiting
Novartis Investigative Site | Cambridge, Cambrigdeshire, CB2 0QQ, United Kingdom Recruiting
Novartis Investigative Site | Salford, Manchester, M6 8HD, United Kingdom Recruiting
Novartis Investigative Site | Leicester, LE5 4PW, United Kingdom Recruiting
Novartis Investigative Site | London, SE5 9RS, United Kingdom Completed
Novartis Investigative Site | London, W12 0HS, United Kingdom Recruiting
Novartis Investigative Site | Newcastle Upon Tyne, NE7 7DN, United Kingdom Recruiting
Location Countries

Argentina

Australia

Belgium

China

Colombia

Czechia

Denmark

Finland

France

Germany

Hong Kong

Hungary

India

Israel

Italy

Japan

Korea, Republic of

Malaysia

Netherlands

Norway

Singapore

Spain

Sweden

Taiwan

Thailand

Turkey

United Kingdom

United States

Verification Date

May 2020

Responsible Party

Responsible party type: Sponsor

Keywords
Condition Browse
Number Of Arms 4
Arm Group

Arm group label: Placebo

Arm group type: Placebo Comparator

Description: Placebo to LNP023

Arm group label: LNP023 dose 1

Arm group type: Experimental

Description: Dose 1 of LNP023

Arm group label: LNP023 dose 2

Arm group type: Experimental

Description: Dose 2 of LNP023

Arm group label: LNP023 dose 3

Arm group type: Experimental

Description: Dose 3 of LNP023

Patient Data Yes
Study Design Info

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.

Primary purpose: Treatment

Masking: Double (Participant, Investigator)

Source: ClinicalTrials.gov