Efficacy and Safety of LNP023 Compared With Rituximab in Subjects With Idiopathic Membranous Nephropathy

• ClinicalTrials.gov Identifier: NCT04154787
• Recruitment Status: Active, not recruiting
• First Posted: November 6, 2019
• Last Update Posted: January 18, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: October 8, 2019
• First Posted Date: November 6, 2019
• Last Update Posted Date: January 18, 2023
• Actual Study Start Date: November 23, 2019
• Estimated Primary Completion Date: January 17, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 16, 2023)

Ratio between baseline Urine Protein Creatinine Ratio and Urine Protein Creatinine Ratio at 24 weeks of treatment (from 24h urine collection) [ Time Frame: Baseline, Week 24 ]

To assess the efficacy of LNP023 compared with rituximab

Original Primary Outcome Measures (submitted: November 4, 2019)

Ratio between baseline Urine Protein Creatinine Ratio and Urine Protein Creatinine Ratio at 24 weeks of treatment (from 24h urine collection) [ Time Frame: Baseline, Week 24 ]

To assess the efficacy of high dose LNP023 (regimen B) compared with rituximab

Current Secondary Outcome Measures (submitted: January 16, 2023)

• Meausrement of Plasma levels of Bb and sC5b-9 [ Time Frame: Week 24 ]
  Measurement of LNP023 systemic drug exposure and pharmacodynamics, mode-of-action markers and clinical efficacy
• Urine Protein Creatinine Ratio measured in first morning void [ Time Frame: Week 24 ]
  Urine Protein Creatinine Ratio (UPCR) measured in first morning void
• Proportion of subjects with a complete remission [ Time Frame: Week 24 ]
  LNP023 compared with rituximab on proteinuria remission and renal function, defined as level of proteinuria at 24 weeks, derived from 24 hour urine
• Proportion of subjects with a partial remission [ Time Frame: Week 24 ]
  LNP023 compared with rituximab on proteinuria remission and renal function defined as reduction of proteinuria from baseline at 24 weeks of treatment, derived from 24 hour urine collection
• Change in (eGFR) estimated Glomerular Filtration Rate from baseline to 24 weeks of treatment [ Time Frame: Baseline, Week 24 ]
  LNP023 compared with rituximab on proteinuria remission and renal function by applying the Chronic Kidney Disease Epidemiology Collaboration (CKDEPI) equation from baseline to 24 weeks of treatment
• Pharmacokinetic parameter Tmax in plasma [ Time Frame: Day 29 and Day 113 (pre-dose and 0.25 hours, 0.5 hours, 1 hour 2 hours, 4 hours and 6 hours post dose) ]
  Pharmacokinetics of LNP023 : Plasma concentration measured for time to maximum total concentration (Tmax)
• Pharmakinetic parameter Cmax in plasma [ Time Frame: Day 29 and Day 113 (pre-dose and 0.25 hours, 0.5 hours, 1 hour 2 hours, 4 hours and 6 hours post dose) ]
  Pharmacokinetics of LNP023: Plasma concentration measured for (Cmax) maximum or peak concentration of the drug observed after its administration
• Pharmacokinetic parameter AUClast in plasma [ Time Frame: Day 29 and Day 113 (pre-dose and 0.25 hours, 0.5 hours, 1 hour 2 hours, 4 hours and 6 hours post dose) ]
  Pharmacokinetics of LNP023: Plasma concentration measured for (AUClast) Area under the curve concentration calculation of AUC from time 0 to the last point
• Pharmacokinetic parameter AUCtau in plasma [ Time Frame: Day 29 and Day 113 (pre-dose and 0.25 hours, 0.5 hours, 1 hour 2 hours, 4 hours and 6 hours post dose) ]
  Pharmacokinetics of LNP023 : Plasma concentration for (AUCtau) Area Under the Curve (plasma concentration-time curve for a dosing interval)
• Pharmacokinetics in urine: renal plasma clearance derived from 24 hour urine sample [ Time Frame: Week 16 ]
  Pharmacokinetics of LNP023: Urine: renal plasma clearance derived from 24 hour urine sample

Original Secondary Outcome Measures (submitted: November 4, 2019)

• Meausrement of Plasma levels of Bb and sC5b-9 [ Time Frame: Week 24 ]
  Measurement of LNP023 systemic drug exposure and pharmacodynamics, mode-of-action markers and clinical efficacy
• Ratio between baseline (UPCR) Urine Proetin Creatinine Ratio and (UPCR) Urine Protein Creatinine Ratio at 24 weeks of treatment (from 24h urine collection) [ Time Frame: Week 24 ]
  Measurement in the difference in response between the low (regimen A) and high (regimen B) dose of LNP023
• Proportion of subjects with a complete remission [ Time Frame: Week 24 ]
  LNP023 compared with rituximab on proteinuria remission and renal function, defined as level of proteinuria at 24 weeks, derived from 24 hour urine
• Proportion of subjects with a partial remission [ Time Frame: Week 24 ]
  LNP023 compared with rituximab on proteinuria remission and renal function defined as reduction of proteinuria from baseline at 24 weeks of treatment, derived from 24 hour urine collection
• Change in (eGFR) estimated Glomerular Filtration Rate from baseline to 24 weeks of treatment [ Time Frame: Baseline, Week 24 ]
  LNP023 compared with rituximab on proteinuria remission and renal function by applying the Chronic Kidney Disease Epidemiology Collaboration (CKDEPI) equation from baseline to 24 weeks of treatment
• Pharmacokinetic parameter Tmax in plasma [ Time Frame: Day 29 and Day 113 (pre-dose and 0.25 hours, 0.5 hours, 1 hour 2 hours, 4 hours and 6 hours post dose) ]
  Pharmacokinetics of LNP023 : Plasma concentration measured for time to maximum total concentration (Tmax)
• Pharmakinetic parameter Cmax in plasma [ Time Frame: Day 29 and Day 113 (pre-dose and 0.25 hours, 0.5 hours, 1 hour 2 hours, 4 hours and 6 hours post dose) ]
  Pharmacokinetics of LNP023: Plasma concentration measured for (Cmax) maximum or peak concentration of the drug observed after its administration
• Pharmacokinetic parameter AUClast in plasma [ Time Frame: Day 29 and Day 113 (pre-dose and 0.25 hours, 0.5 hours, 1 hour 2 hours, 4 hours and 6 hours post dose) ]
  Pharmacokinetics of LNP023: Plasma concentration measured for (AUClast) Area under the curve concentration calculation of AUC from time 0 to the last point
• Pharmacokinetic parameter AUCtau in plasma [ Time Frame: Day 29 and Day 113 (pre-dose and 0.25 hours, 0.5 hours, 1 hour 2 hours, 4 hours and 6 hours post dose) ]
  Pharmacokinetics of LNP023 : Plasma concentration for (AUCtau) Area Under the Curve (plasma concentration-time curve for a dosing interval)
• Pharmacokinetics in urine: renal plasma clearance derived from 24 hour urine sample [ Time Frame: Week 16 ]
  Pharmacokinetics of LNP023: Urine: renal plasma clearance derived from 24 hour urine sample

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy and Safety of LNP023 Compared With Rituximab in Subjects With Idiopathic Membranous Nephropathy
• Official Title: A Randomized, Open-label, Two Arm, Parallel Group, Proof-of-concept Clinical Trial to Investigate the Efficacy and Safety of LNP023 Compared With Rituximab in the Treatment of Subjects With Idiopathic Membranous Nephropathy
• Brief Summary: This is a randomized, open-label, two arm, parallel group, proof-of-concept, non-confirmatory study evaluating the efficacy and safety of LNP023 compared with rituximab in subjects with membranous nephropathy (MN) who are at high risk of disease progression defined on the basis of antibody anti-PLA2R titre and proteinuria.
• Detailed Description: This is a randomized, open-label, two arm, parallel group, proof-of-concept, non-confirmatory study evaluating the efficacy and safety of LNP023 compared with rituximab in subjects with membranous nephropathy (MN) who are at high risk of disease progression defined on the basis of antibody anti-PLA2R titre and proteinuria. The screening period will last up to 12 weeks and the whole study will last up to 65 weeks. Approximately 52 subjects will be randomized to one of the two arms. Treatment with LNP023 or rituximab is open label. LNP023 arm have a 4-week period of initial dose treatment, followed by a 20-week period of full dose treatment to evaluate the effect of the different LNP023 doses on complement biomarkers. Efficacy will be evaluated at the end of the 24-week treatment period. The randomization ratio is 1:1; LNP023 : rituximab.
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

A randomized, open-label, two arm, parallel group, proof-of-concept, non-confirmatory study evaluating the efficacy and safety of LNP023 compared with rituximab in subjects with MN who are at high risk of disease progression defined on the basis of antibody anti-PLA2R titre and proteinuria. The screening period will last up to 12 weeks and the whole study will last up to 65 weeks. Approximately 52 subjects will be randomized to one of the two arms. Treatment with LNP023 or rituximab is open label. LNP023 arm have a 4-week period of initial dose treatment, followed by a 20-week period of full dose treatment to evaluate the effect of the different LNP023 doses on complement biomarkers. Efficacy will be evaluated at the end of the 24-week treatment period. The randomization ratio is 1:1; LNP023:rituximab

Masking: None (Open Label)
Masking Description:

Open label study for treatment (LNP023 or rituximab).

Primary Purpose: Treatment

• Condition: Glomerulonephritis, Membranous

Intervention

• Drug: LNP023
  Investigation of LNP023
• Drug: Rituximab
  Comparison of rituximab dose

Study Arms

• Experimental: LNP023
  LNP023
  Intervention: Drug: LNP023
• Active Comparator: Rituximab
  Rituximab
  Intervention: Drug: Rituximab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 16, 2023): 37
• Original Estimated Enrollment (submitted: November 4, 2019): 72
• Estimated Study Completion Date: January 17, 2023
• Estimated Primary Completion Date: January 17, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Female or male adult (≥18 years) subjects at screening visit with a diagnosis of idiopathic (primary) MN confirmed by renal biopsy within 36 months prior to screening. A renal biopsy may be taken at any time during the run-in period to confirm the diagnosis of MN and facilitate subject eligibility, if the most recent biopsy was performed greater than 36 months prior to the screening visit.
• Anti-PLA2R antibody titer of ≥ 60 RU/mL at screening visit. If sites opt to use a local laboratory, with prior agreement with sponsor, an anti-PLA2R titer performed within 4 weeks prior to screening visit can be used.
• Urine protein ≥ 3.5 g/24h at screening and baseline visits
• ≤50% reduction in both anti-PLA2R level and 24h urine protein between screening and baseline
• Estimated GFR (using the CKD-EPI formula) ≥ 30 mL/min per 1.73 m2 at screening
• Receiving stable dose at the maximum recommended dose according to local guidelines or maximum tolerated dose of ACEi and/or ARB and/or statins and/or diuretics for at least 8 weeks prior to Day 1
• Vaccination against Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae (in accordance with local guidelines) at least 28 days prior to Day 1 and no longer than 5 years prior to Day 1.

Exclusion Criteria:

• Secondary causes of MN, e.g. systemic autoimmune diseases, solid or haematological malignancies, infections or chronic intake of drugs (e.g. gold salts, NSAIDs, penicillamines)
• Diagnostic renal biopsy showing evidence of crescent formation in glomeruli, suggestive of an alternative or additional diagnosis to primary idiopathic MN.
• Previous treatment with B-cell depleting or B-cell modifying agents such as, but not limited to rituximab, belimumab, daratumomab or bortezomib.
• Previous treatment with immunosuppressive agents such as cyclophosphamide, chlorambucil, mycophenolate mofetil (or equivalent), cyclosporine, tacrolimus or azathioprine within 90 days prior to Day 1. Low dose systemic corticosteroid therapy is permitted, though the subject should have been on stable dose equivalent to ≤10 mg prednisolone for at least 90 days prior to Day 1.
• Previous treatment with gemfibrozil or strong CYP2C8 inhibitors such as clopidogrel within 7 days prior to Day 1
• Presence or suspicion (based on judgment of the investigator) of active infection within 30 days prior to Day 1, or history of severe recurrent bacterial infections
• Known contra-indications for the use of rituximab, including hypersensitivity to the active substance or to murine proteins, or to any of the excipients (sodium citrate, polysorbate 80, sodium chloride, sodium hydroxide, hydrochloric acid, water for injections). Other contra-indications for the use of rituximab, including active, severe infection, patients in a severely immunocompromised state, severe heart failure (NYHA Class IV) or severe, uncontrolled cardiac disease.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, China, Czechia, France, Germany, India, Netherlands, Singapore, Spain, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT04154787
• Other Study ID Numbers: CLNP023D12201
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: January 2023