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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04154787
Recruitment Status : Recruiting
First Posted : November 6, 2019
Last Update Posted : October 28, 2020
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
This is a randomized, treatment open-label, dose-blinded parallel group, three arm, 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 72 subjects will be randomized to one of three arms. Treatment with LNP023 or rituximab is open label, although dose of LNP023 will be blinded for subjects, investigators and sponsor. Both of the low and high-dose LNP023 arms 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 1:1:1; low-dose (regimen A) LNP023: high dose (regimen B) LNP023: rituximab.

Condition or disease Intervention/treatment Phase
Glomerulonephritis, Membranous Drug: LNP023 Drug: Rituximab Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: A randomized, treatment open-label, dose-blinded parallel group, three arm, 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 72 subjects will be randomized to one of three arms. Treatment with LNP023 or rituximab is open label, although dose of LNP023 will be blinded for subjects, investigators and sponsor. Both of the low and high-dose LNP023 arms 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 1:1:1; low-dose (regimen A) LNP023: high dose (regimen B) LNP023:rituximab
Masking: None (Open Label)
Masking Description: Open label study for treatment (LNP023 or rituximab), but double-blind for the LNP023 treatment regimen.
Primary Purpose: Treatment
Official Title: A Randomized, Treatment Open-label, Dose-blinded Parallel Group, Three Arm, 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
Actual Study Start Date : November 23, 2019
Estimated Primary Completion Date : October 12, 2022
Estimated Study Completion Date : October 12, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Diseases
Drug Information available for: Rituximab

Arm Intervention/treatment
Experimental: LNP023 Regimen A
LNP023 low dose
Drug: LNP023
Investigation of low and high LNP023 dose regimens

Experimental: LNP023 Regimen B
LNP023 high dose
Drug: LNP023
Investigation of low and high LNP023 dose regimens

Active Comparator: Rituximab
Rituximab
Drug: Rituximab
Comparison of rituximab dose




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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)

  7. 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

  8. 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

  9. 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)

  10. 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



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 24 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 24 months prior to the screening visit.
  • Anti-PLA2R antibody titer of ≥ 100 RU/mL at screening visit
  • 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) ≥ 45 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04154787


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 andrea.biondani@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Locations
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Argentina
Novartis Investigative Site Recruiting
Caba, Buenos Aires, Argentina, C1280AEB
Novartis Investigative Site Recruiting
Ciudad Autonoma de Bs As, Argentina, C1015ABO
Czechia
Novartis Investigative Site Recruiting
Plzen-Bory, Czechia, 305 99
Novartis Investigative Site Recruiting
Praha, Czechia, 12808
France
Novartis Investigative Site Recruiting
Montpellier, France, 34295
Novartis Investigative Site Recruiting
Paris cedex 15, France, 75015
Novartis Investigative Site Recruiting
Paris, France, 75020
Germany
Novartis Investigative Site Recruiting
Berlin, Germany, 13353
Novartis Investigative Site Recruiting
Dresden, Germany, 01307
Novartis Investigative Site Recruiting
Essen, Germany, 45147
Novartis Investigative Site Recruiting
Hamburg, Germany, 20246
India
Novartis Investigative Site Recruiting
New Delhi, Delhi, India, 110 017
Novartis Investigative Site Recruiting
New Delhi, Delhi, India, 110 060
Novartis Investigative Site Recruiting
Hyderabad, Telangana, India, 500034
Novartis Investigative Site Recruiting
DehraDun, Uttarakhand, India, 248001
Novartis Investigative Site Recruiting
New Delhi, India, 110029
Netherlands
Novartis Investigative Site Recruiting
Nijmegen, Netherland, Netherlands, 6525 GA
Singapore
Novartis Investigative Site Recruiting
Singapore, Singapore, 119228
Novartis Investigative Site Recruiting
Singapore, Singapore, 169608
Novartis Investigative Site Recruiting
Singapore, Singapore, 308433
Spain
Novartis Investigative Site Recruiting
L Hospitalet De Llobregat, Barcelona, Spain, 08907
Novartis Investigative Site Recruiting
Valencia, Comunidad Valenciana, Spain, 46017
Novartis Investigative Site Recruiting
Madrid, Spain, 28041
United Kingdom
Novartis Investigative Site Recruiting
Salford, Manchester, United Kingdom, M6 8HD
Novartis Investigative Site Recruiting
Cardiff, United Kingdom, CF14 4XW
Novartis Investigative Site Recruiting
Leicester, United Kingdom, LE5 4PW
Novartis Investigative Site Recruiting
London, United Kingdom, NW3 2QG
Novartis Investigative Site Recruiting
Manchester, United Kingdom, M13 9WL
Sponsors and Collaborators
Novartis Pharmaceuticals
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04154787    
Other Study ID Numbers: CLNP023D12201
First Posted: November 6, 2019    Key Record Dates
Last Update Posted: October 28, 2020
Last Verified: October 2020
Individual Participant Data (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


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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Idiopathic membranous nephropathy, MN.
Additional relevant MeSH terms:
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Kidney Diseases
Glomerulonephritis
Glomerulonephritis, Membranous
Urologic Diseases
Nephritis
Autoimmune Diseases
Immune System Diseases
Rituximab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents