Clinical trial NCT04154787: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Idiopathic Membranous Nephropathy
Keywords: Idiopathic membranous nephropathy
MN
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2019-11-06
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This was a randomized, open-label, two arm, parallel group, proof-of-concept, nonconfirmatory study evaluating the efficacy and safety of LNP023 compared with rituximab in subjects with Idiopathic (primary) membranous nephropathy (iMN) who are at high risk of disease progression defined on the basis of anti- Phospholipase A2 Receptor (PLA2R) antibody titer ≥ 60 RU/mL and proteinuria with urine protein (UP) ≥ 3.5 g/24h.

Detailed description: The overall study was planned for a total of 65 weeks and included:

* A screening phase of up to 12 weeks
* A treatment phase of up to 24 weeks
* A post-treatment follow-up period of 29 weeks

As per protocol amendment V01, subjects were randomized 1:1 to LNP023 (investigational drug) or Rituximab (comparator) and followed the below dosing schedule:

* LNP023 50mg orally b.i.d. for 4 weeks followed by 200mg orally b.i.d. for 20 weeks
* Rituximab 1g i.v. infusions on Day 1 and Day 15

Initially, per protocol V00, subjects were planned to be randomized in a 1:1:1 ratio to 3 treatment arms:

* Low dose LNP023: LNP023 10mg orally b.i.d. for 4 weeks followed by 50mg orally b.i.d. for 20 weeks
* High dose LNP023: 25mg orally b.i.d. for 4 weeks followed by 200mg orally b.i.d. for 20 weeks
* Rituximab 1g i.v. infusions on Day 1 and Day 15

Following protocol amendment 1 implementation, ongoing subjects were switched to 200mg b.i.d. dose after their initial 4 weeks of treatment.

3 subjects completed treatment under protocol V00. PK/PD data from the 3 completing subjects under protocol V00 are not included in the study results.

The main reason for protocol amendment V01 was to align with the clinical study results obtained from the interim analysis of ongoing phase 2 trials with LNP023 which had shown a dose dependent inhibition of the complement alternative pathway and support best efficacy results with LNP023 at a dose level of 200mg.

The study was early terminated as LNP023 after interim analysis of 12 LNP023 and 14 rituximab subjects because it could already be predicted at that point that the primary goal of superiority of LNP023 vs rituximab in the reduction of UPCR at 24 weeks was not possible to achieve if the study continued to completion.

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.

Primary outcomes:
measure: Ratio Between Baseline Urine Protein Creatinine Ratio (UPCR) and Urine Protein Creatinine Ratio at 24 Weeks of Treatment (From 24h Urine Collection)
timeFrame: Baseline, Day 113, Day 169
Secondary outcomes:
measure: Change From Baseline in Plasma Levels of Circulating Fragment of Factor B (Bb)
timeFrame: Baseline, Day 15, Day 29, Day 57, Day 113 and Day 169
measure: Change From Baseline in Plasma Levels of sC5b-9
timeFrame: Baseline, Day 15, Day 29, Day 57, Day 113, Day 169
measure: Ratio to Baseline of Urine Protein Creatinine Ratio (UPCR) Measured in First Morning Void
timeFrame: Baseline, Day 15, Day 29, Day 57, Day 85, Day 113, Day 141, Day 169, Day 266 and Day 378
measure: Number of Participants by Treatment Response at 24 Weeks of Treatment
timeFrame: Baseline, Day 169
measure: Change From Baseline in (eGFR) Estimated Glomerular Filtration Rate Over Time
timeFrame: Baseline, Day 15, Day 29, Day 57, Day 85, Day 113, Day 141, Day 169
measure: Pharmacokinetic Parameter Tmax in Plasma
timeFrame: 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)
measure: Pharmacokinetic Parameter Cmax in Plasma
timeFrame: 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)
measure: Pharmacokinetic Parameter AUClast in Plasma
timeFrame: 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)
measure: Pharmacokinetic Parameter AUCtau in Plasma
timeFrame: 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)
measure: Pharmacokinetics in Urine: Renal Plasma Clearance Derived From 24 Hour Urine Sample
timeFrame: Day 113
Other outcomes:
Locations:
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Cordoba
country: Argentina
facility: Novartis Investigative Site
city: Beijing
country: China
facility: Novartis Investigative Site
city: Praha
country: Czechia
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Dresden
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Jena
country: Germany
facility: Novartis Investigative Site
city: DehraDun
country: India
facility: Novartis Investigative Site
state: Uttarakhand
city: New Delhi
country: India
facility: Novartis Investigative Site
city: Nijmegen
country: Netherlands
facility: Novartis Investigative Site
state: Netherland
city: Hospitalet de Llobregat
country: Spain
facility: Novartis Investigative Site
state: Barcelona
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Leicester
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: