Idiopathic Membranous Nephropathy
Conditions
Keywords
Idiopathic membranous nephropathy, MN
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.
Interventions
DRUGLNP023
Investigation of LNP023
DRUGRituximab
Comparison of rituximab dose
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open label study for treatment (LNP023 or rituximab).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ratio Between Baseline Urine Protein Creatinine Ratio (UPCR) and Urine Protein Creatinine Ratio at 24 Weeks of Treatment (From 24h Urine Collection) | Baseline, Day 113, Day 169 | The primary endpoint of this study is the ratio between UPCR at 24 weeks of treatment measured in 24h urine and baseline UPCR . To assess the primary objective, the log-transformed ratio to baseline in UPCR was analyzed using a mixed model for repeated measures (MMRM). The results were back transformed and presented on the original scale. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Plasma Levels of sC5b-9 | Baseline, Day 15, Day 29, Day 57, Day 113, Day 169 | Soluble C5b-9 (sC5b-9) is a biomarker of the complement pathway activity that correlate with disease progression. Baseline is defined as the last non-missing measurement prior to randomization. Measurements for LNP023 group were done pre-dose. |
| Ratio to Baseline of Urine Protein Creatinine Ratio (UPCR) Measured in First Morning Void | Baseline, Day 15, Day 29, Day 57, Day 85, Day 113, Day 141, Day 169, Day 266 and Day 378 | Adjusted geometric mean ratio to baseline of Urine Protein Creatinine Ratio (UPCR) measured in first morning void. First morning void urine sample was collected in the morning of the day before the visit and kept in the fridge. |
| Number of Participants by Treatment Response at 24 Weeks of Treatment | Baseline, Day 169 | Participants were considered complete responders if at 24 weeks of treatment, they showed complete remission of proteinuria (i.e., Urine Protein (UP) ≤ 0.3 g/24h), partial responders if they showed partial remission (i.e., UP \> 0.3g/24h and ≤ 3.5 g/24h and a reduction of UP by \>50% from baseline), and non-responders if UP \>3.5g/24h and/or reduction of UP from baseline \<50%. |
| Change From Baseline in (eGFR) Estimated Glomerular Filtration Rate Over Time | Baseline, Day 15, Day 29, Day 57, Day 85, Day 113, Day 141, Day 169 | Changes in renal function were assessed via estimated glomerular filtration rate (eGFR). Change in eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. |
| Change From Baseline in Plasma Levels of Circulating Fragment of Factor B (Bb) | Baseline, Day 15, Day 29, Day 57, Day 113 and Day 169 | The drug (LNP023) is expected to block the complement alternative pathway dysregulation and thereby should normalize complement biomarker levels in serum. Bb is a biomarker that accurately reflects the level of complement Alternative Pathway activation. Baseline is defined as the last non-missing measurement prior to randomization. Measurements for LNP023 group were done pre-dose. |
| Pharmacokinetic Parameter Cmax in Plasma | 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: Cmax is the maximum (peak) observed plasma drug concentration after dose administration (mass x volume-1) |
| Pharmacokinetic Parameter AUClast in Plasma | 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: AUClast is the AUC from time zero to the last measurable concentration sampling time (tlast) (mass x time x volume-1) |
| Pharmacokinetic Parameter AUCtau in Plasma | 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 : AUCtau is the AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-1) |
| Pharmacokinetics in Urine: Renal Plasma Clearance Derived From 24 Hour Urine Sample | Day 113 | Pharmacokinetics of LNP023 in urine: Renal plasma clearance derived from 24 hour urine sample |
| Pharmacokinetic Parameter Tmax in Plasma | 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 : Tmax is the time to reach maximum (peak) plasma drug concentration after dose administration (time). Actual sampling time points were considered for the calculation of PK parameters. |
Countries
Argentina, China, Czechia, Germany, India, Netherlands, Spain, Taiwan, United Kingdom
Participant flow
Recruitment details
Participants took part in 18 investigative sites in 9 countries/regions: Argentina (3), Czech Republic (1), Germany (4), India (2), Netherlands (1), Spain (2), United Kingdom (3), China (1) and Taiwan (1)
Participants by arm
| Arm | Count |
|---|---|
| LNP023 10/50 mg b.i.d. As per protocol V00, participants took LNP023 10 mg orally b.i.d. for 4 weeks followed by LNP023 50 mg orally b.i.d. for 20 weeks | 3 |
| LNP023 200 mg b.i.d. Combination of the LNP023 25/200 mg b.i.d. and 50/200 mg b.i.d. groups. Under protocol V00, participants took LNP023 25 mg orally b.i.d. for 4 weeks followed by LNP023 200 mg orally b.i.d. for 20 weeks.
Under protocol v01, participants took LNP023 50 mg orally b.i.d. for 4 weeks followed by LNP023 200 mg orally b.i.d. for 20 weeks. | 19 |
| Rituximab Rituximab 1 g i.v. at Day 1 and Day 15 | 15 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 |
| Overall Study | Patient Requires Other Treatment | 0 | 1 | 0 |
| Overall Study | Study Terminated By Sponsor | 0 | 6 | 1 |
| Overall Study | Subject Decision | 0 | 1 | 0 |
| Overall Study | Suspected Lack Of Efficacy | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | LNP023 10/50 mg b.i.d. | LNP023 200 mg b.i.d. | Rituximab |
|---|---|---|---|---|
| Age, Continuous | 48.5 years STANDARD_DEVIATION 12.43 | 55.0 years STANDARD_DEVIATION 18.52 | 48.9 years STANDARD_DEVIATION 8.84 | 46.7 years STANDARD_DEVIATION 15.33 |
| Race/Ethnicity, Customized Asian | 10 Participants | 1 Participants | 5 Participants | 4 Participants |
| Race/Ethnicity, Customized Black Or African American | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 25 Participants | 2 Participants | 14 Participants | 9 Participants |
| Sex: Female, Male Female | 6 Participants | 1 Participants | 4 Participants | 1 Participants |
| Sex: Female, Male Male | 31 Participants | 2 Participants | 15 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 19 | 0 / 22 | 0 / 15 | 0 / 37 |
| other Total, other adverse events | 2 / 3 | 13 / 19 | 15 / 22 | 7 / 15 | 22 / 37 |
| serious Total, serious adverse events | 0 / 3 | 3 / 19 | 3 / 22 | 4 / 15 | 7 / 37 |
Outcome results
Primary
Ratio Between Baseline Urine Protein Creatinine Ratio (UPCR) and Urine Protein Creatinine Ratio at 24 Weeks of Treatment (From 24h Urine Collection)
The primary endpoint of this study is the ratio between UPCR at 24 weeks of treatment measured in 24h urine and baseline UPCR . To assess the primary objective, the log-transformed ratio to baseline in UPCR was analyzed using a mixed model for repeated measures (MMRM). The results were back transformed and presented on the original scale.
Time frame: Baseline, Day 113, Day 169
Population: PD set: In line with the protocol, PD (pharmacodynamics) analyses were performed for all participants who received LNP023 200 mg or rituximab and experienced no protocol deviations with relevant impact on PD/efficacy data. Only participants with a value for UPCR at both Baseline and Day 113 or Day 169 were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| LNP023 200 mg b.i.d. | Ratio Between Baseline Urine Protein Creatinine Ratio (UPCR) and Urine Protein Creatinine Ratio at 24 Weeks of Treatment (From 24h Urine Collection) | Day 113 | 0.94 ratio to baseline |
| LNP023 200 mg b.i.d. | Ratio Between Baseline Urine Protein Creatinine Ratio (UPCR) and Urine Protein Creatinine Ratio at 24 Weeks of Treatment (From 24h Urine Collection) | Day 169 | 0.88 ratio to baseline |
| Rituximab | Ratio Between Baseline Urine Protein Creatinine Ratio (UPCR) and Urine Protein Creatinine Ratio at 24 Weeks of Treatment (From 24h Urine Collection) | Day 113 | 0.89 ratio to baseline |
| Rituximab | Ratio Between Baseline Urine Protein Creatinine Ratio (UPCR) and Urine Protein Creatinine Ratio at 24 Weeks of Treatment (From 24h Urine Collection) | Day 169 | 0.64 ratio to baseline |
p-value: 0.26795% CI: [0.9, 2.08]Mixed Models Analysis
Secondary
Change From Baseline in (eGFR) Estimated Glomerular Filtration Rate Over Time
Changes in renal function were assessed via estimated glomerular filtration rate (eGFR). Change in eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
Time frame: Baseline, Day 15, Day 29, Day 57, Day 85, Day 113, Day 141, Day 169
Population: PD set: In line with the protocol, PD (pharmacodynamics) analyses were performed for all participants who received LNP023 200 mg or rituximab and experienced no protocol deviations with relevant impact on PD/efficacy data. Only participants with a eGFR value at both Baseline and the different time points were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNP023 200 mg b.i.d. | Change From Baseline in (eGFR) Estimated Glomerular Filtration Rate Over Time | Day 57 | 2.0 mL/min/1.73 m^2 | Standard Deviation 11.1 |
| LNP023 200 mg b.i.d. | Change From Baseline in (eGFR) Estimated Glomerular Filtration Rate Over Time | Day 29 | -0.5 mL/min/1.73 m^2 | Standard Deviation 8.53 |
| LNP023 200 mg b.i.d. | Change From Baseline in (eGFR) Estimated Glomerular Filtration Rate Over Time | Day 85 | -1.6 mL/min/1.73 m^2 | Standard Deviation 11.53 |
| LNP023 200 mg b.i.d. | Change From Baseline in (eGFR) Estimated Glomerular Filtration Rate Over Time | Day 113 | 1.2 mL/min/1.73 m^2 | Standard Deviation 8.64 |
| LNP023 200 mg b.i.d. | Change From Baseline in (eGFR) Estimated Glomerular Filtration Rate Over Time | Day 141 | -1.8 mL/min/1.73 m^2 | Standard Deviation 9.1 |
| LNP023 200 mg b.i.d. | Change From Baseline in (eGFR) Estimated Glomerular Filtration Rate Over Time | Day 169 | -1.3 mL/min/1.73 m^2 | Standard Deviation 7.36 |
| LNP023 200 mg b.i.d. | Change From Baseline in (eGFR) Estimated Glomerular Filtration Rate Over Time | Day 15 | 2.3 mL/min/1.73 m^2 | Standard Deviation 12.07 |
| Rituximab | Change From Baseline in (eGFR) Estimated Glomerular Filtration Rate Over Time | Day 141 | 7.1 mL/min/1.73 m^2 | Standard Deviation 9.29 |
| Rituximab | Change From Baseline in (eGFR) Estimated Glomerular Filtration Rate Over Time | Day 15 | 0.3 mL/min/1.73 m^2 | Standard Deviation 8.33 |
| Rituximab | Change From Baseline in (eGFR) Estimated Glomerular Filtration Rate Over Time | Day 113 | 10.8 mL/min/1.73 m^2 | Standard Deviation 15.41 |
| Rituximab | Change From Baseline in (eGFR) Estimated Glomerular Filtration Rate Over Time | Day 29 | 6.1 mL/min/1.73 m^2 | Standard Deviation 10.44 |
| Rituximab | Change From Baseline in (eGFR) Estimated Glomerular Filtration Rate Over Time | Day 57 | 9.2 mL/min/1.73 m^2 | Standard Deviation 21.05 |
| Rituximab | Change From Baseline in (eGFR) Estimated Glomerular Filtration Rate Over Time | Day 169 | 3.1 mL/min/1.73 m^2 | Standard Deviation 13.21 |
| Rituximab | Change From Baseline in (eGFR) Estimated Glomerular Filtration Rate Over Time | Day 85 | 10.2 mL/min/1.73 m^2 | Standard Deviation 16.4 |
Secondary
Change From Baseline in Plasma Levels of Circulating Fragment of Factor B (Bb)
The drug (LNP023) is expected to block the complement alternative pathway dysregulation and thereby should normalize complement biomarker levels in serum. Bb is a biomarker that accurately reflects the level of complement Alternative Pathway activation. Baseline is defined as the last non-missing measurement prior to randomization. Measurements for LNP023 group were done pre-dose.
Time frame: Baseline, Day 15, Day 29, Day 57, Day 113 and Day 169
Population: PD set: In line with the protocol, PD (pharmacodynamics) analyses were performed for all participants who received LNP023 200 mg or rituximab and experienced no protocol deviations with relevant impact on PD/efficacy data. Only participants with values of plasma levels of circulating fragment of factor B at both Baseline and the different time points were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNP023 200 mg b.i.d. | Change From Baseline in Plasma Levels of Circulating Fragment of Factor B (Bb) | Day 15 | 1520.59 ng/mL | Standard Deviation 9370.086 |
| LNP023 200 mg b.i.d. | Change From Baseline in Plasma Levels of Circulating Fragment of Factor B (Bb) | Day 113 | -877.27 ng/mL | Standard Deviation 1562.716 |
| LNP023 200 mg b.i.d. | Change From Baseline in Plasma Levels of Circulating Fragment of Factor B (Bb) | Day 29 | -732.00 ng/mL | Standard Deviation 1412.633 |
| LNP023 200 mg b.i.d. | Change From Baseline in Plasma Levels of Circulating Fragment of Factor B (Bb) | Day 169 | -984.00 ng/mL | Standard Deviation 1794.419 |
| LNP023 200 mg b.i.d. | Change From Baseline in Plasma Levels of Circulating Fragment of Factor B (Bb) | Day 57 | -545.00 ng/mL | Standard Deviation 1379.201 |
| Rituximab | Change From Baseline in Plasma Levels of Circulating Fragment of Factor B (Bb) | Day 169 | -570.00 ng/mL | Standard Deviation 611.167 |
| Rituximab | Change From Baseline in Plasma Levels of Circulating Fragment of Factor B (Bb) | Day 29 | -318.46 ng/mL | Standard Deviation 604.44 |
| Rituximab | Change From Baseline in Plasma Levels of Circulating Fragment of Factor B (Bb) | Day 57 | -75.38 ng/mL | Standard Deviation 787.545 |
| Rituximab | Change From Baseline in Plasma Levels of Circulating Fragment of Factor B (Bb) | Day 113 | -219.17 ng/mL | Standard Deviation 703.568 |
| Rituximab | Change From Baseline in Plasma Levels of Circulating Fragment of Factor B (Bb) | Day 15 | -417.69 ng/mL | Standard Deviation 701.667 |
Secondary
Change From Baseline in Plasma Levels of sC5b-9
Soluble C5b-9 (sC5b-9) is a biomarker of the complement pathway activity that correlate with disease progression. Baseline is defined as the last non-missing measurement prior to randomization. Measurements for LNP023 group were done pre-dose.
Time frame: Baseline, Day 15, Day 29, Day 57, Day 113, Day 169
Population: PD set: In line with the protocol, PD (pharmacodynamics) analyses were performed for all participants who received LNP023 200 mg or rituximab and experienced no protocol deviations with relevant impact on PD/efficacy data. Only participants with a value of plasma levels of sC5b-9 at both Baseline and the different time points were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNP023 200 mg b.i.d. | Change From Baseline in Plasma Levels of sC5b-9 | Day 113 | -113.32 ng/mL | Standard Deviation 108.118 |
| LNP023 200 mg b.i.d. | Change From Baseline in Plasma Levels of sC5b-9 | Day 57 | -90.62 ng/mL | Standard Deviation 108.483 |
| LNP023 200 mg b.i.d. | Change From Baseline in Plasma Levels of sC5b-9 | Day 15 | -80.40 ng/mL | Standard Deviation 98.229 |
| LNP023 200 mg b.i.d. | Change From Baseline in Plasma Levels of sC5b-9 | Day 169 | -84.07 ng/mL | Standard Deviation 96.045 |
| LNP023 200 mg b.i.d. | Change From Baseline in Plasma Levels of sC5b-9 | Day 29 | -82.80 ng/mL | Standard Deviation 118.338 |
| Rituximab | Change From Baseline in Plasma Levels of sC5b-9 | Day 15 | -38.49 ng/mL | Standard Deviation 52.258 |
| Rituximab | Change From Baseline in Plasma Levels of sC5b-9 | Day 29 | -24.51 ng/mL | Standard Deviation 94.826 |
| Rituximab | Change From Baseline in Plasma Levels of sC5b-9 | Day 113 | -24.95 ng/mL | Standard Deviation 128.721 |
| Rituximab | Change From Baseline in Plasma Levels of sC5b-9 | Day 57 | -14.02 ng/mL | Standard Deviation 107.651 |
| Rituximab | Change From Baseline in Plasma Levels of sC5b-9 | Day 169 | -21.76 ng/mL | Standard Deviation 122.654 |
Secondary
Number of Participants by Treatment Response at 24 Weeks of Treatment
Participants were considered complete responders if at 24 weeks of treatment, they showed complete remission of proteinuria (i.e., Urine Protein (UP) ≤ 0.3 g/24h), partial responders if they showed partial remission (i.e., UP \> 0.3g/24h and ≤ 3.5 g/24h and a reduction of UP by \>50% from baseline), and non-responders if UP \>3.5g/24h and/or reduction of UP from baseline \<50%.
Time frame: Baseline, Day 169
Population: PD set: In line with the protocol, PD (pharmacodynamics) analyses were performed for all participants who received LNP023 200 mg or rituximab and experienced no protocol deviations with relevant impact on PD/efficacy data. Only participants with UP values at both baseline and Day 169 were included in the analysis.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LNP023 200 mg b.i.d. | Number of Participants by Treatment Response at 24 Weeks of Treatment | Complete | 0 Participants |
| LNP023 200 mg b.i.d. | Number of Participants by Treatment Response at 24 Weeks of Treatment | Partial | 2 Participants |
| LNP023 200 mg b.i.d. | Number of Participants by Treatment Response at 24 Weeks of Treatment | No response | 7 Participants |
| Rituximab | Number of Participants by Treatment Response at 24 Weeks of Treatment | Complete | 0 Participants |
| Rituximab | Number of Participants by Treatment Response at 24 Weeks of Treatment | Partial | 2 Participants |
| Rituximab | Number of Participants by Treatment Response at 24 Weeks of Treatment | No response | 7 Participants |
Secondary
Pharmacokinetic Parameter AUClast in Plasma
Pharmacokinetics of LNP023: AUClast is the AUC from time zero to the last measurable concentration sampling time (tlast) (mass x time x volume-1)
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)
Population: PK set: PK (pharmacokinetic) analysis set included all participants with at least one available valid PK concentration measurement, who received any LNP023 and experienced no protocol deviations with relevant impact on PK data. Only participants with PK values at the different time points were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNP023 200 mg b.i.d. | Pharmacokinetic Parameter AUClast in Plasma | Day 29 | 5970 hr*ng/mL | Standard Deviation 4150 |
| Rituximab | Pharmacokinetic Parameter AUClast in Plasma | Day 29 | 8140 hr*ng/mL | Standard Deviation 3080 |
| LNP023 50 mg b.i.d. (4-week Administration) | Pharmacokinetic Parameter AUClast in Plasma | Day 29 | 9920 hr*ng/mL | Standard Deviation 3960 |
| LNP023 50 mg b.i.d. (20-week Administration) | Pharmacokinetic Parameter AUClast in Plasma | Day 113 | 5940 hr*ng/mL | Standard Deviation 989 |
| LNP023 200 mg b.i.d. | Pharmacokinetic Parameter AUClast in Plasma | Day 113 | 22200 hr*ng/mL | Standard Deviation 15600 |
Secondary
Pharmacokinetic Parameter AUCtau in Plasma
Pharmacokinetics of LNP023 : AUCtau is the AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-1)
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)
Population: PK set: PK (pharmacokinetic) analysis set included all participants with at least one available valid PK concentration measurement, who received any LNP023 and experienced no protocol deviations with relevant impact on PK data. Only participants with PK values at the different time points were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNP023 200 mg b.i.d. | Pharmacokinetic Parameter AUCtau in Plasma | Day 29 | 9850 hr*ng/mL | Standard Deviation 5790 |
| Rituximab | Pharmacokinetic Parameter AUCtau in Plasma | Day 29 | 12800 hr*ng/mL | Standard Deviation 3490 |
| LNP023 50 mg b.i.d. (4-week Administration) | Pharmacokinetic Parameter AUCtau in Plasma | Day 29 | 16500 hr*ng/mL | Standard Deviation 5920 |
| LNP023 50 mg b.i.d. (20-week Administration) | Pharmacokinetic Parameter AUCtau in Plasma | Day 113 | 10700 hr*ng/mL | Standard Deviation 1640 |
| LNP023 200 mg b.i.d. | Pharmacokinetic Parameter AUCtau in Plasma | Day 113 | 36800 hr*ng/mL | Standard Deviation 26100 |
Secondary
Pharmacokinetic Parameter Cmax in Plasma
Pharmacokinetics of LNP023: Cmax is the maximum (peak) observed plasma drug concentration after dose administration (mass x volume-1)
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)
Population: PK set: PK (pharmacokinetic) analysis set included all participants with at least one available valid PK concentration measurement, who received any LNP023 and experienced no protocol deviations with relevant impact on PK data. Only participants with PK values at the different time points were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNP023 200 mg b.i.d. | Pharmacokinetic Parameter Cmax in Plasma | Day 29 | 1200 ng/mL | Standard Deviation 799 |
| Rituximab | Pharmacokinetic Parameter Cmax in Plasma | Day 29 | 2070 ng/mL | Standard Deviation 938 |
| LNP023 50 mg b.i.d. (4-week Administration) | Pharmacokinetic Parameter Cmax in Plasma | Day 29 | 2140 ng/mL | Standard Deviation 917 |
| LNP023 50 mg b.i.d. (20-week Administration) | Pharmacokinetic Parameter Cmax in Plasma | Day 113 | 1220 ng/mL | Standard Deviation 304 |
| LNP023 200 mg b.i.d. | Pharmacokinetic Parameter Cmax in Plasma | Day 113 | 4810 ng/mL | Standard Deviation 2850 |
Secondary
Pharmacokinetic Parameter Tmax in Plasma
Pharmacokinetics of LNP023 : Tmax is the time to reach maximum (peak) plasma drug concentration after dose administration (time). Actual sampling time points were considered for the calculation of PK parameters.
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)
Population: PK set: PK (pharmacokinetic) analysis set included all participants with at least one available valid PK concentration measurement, who received any LNP023 and experienced no protocol deviations with relevant impact on PK data. Only participants with PK values at the different time points were included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| LNP023 200 mg b.i.d. | Pharmacokinetic Parameter Tmax in Plasma | Day 29 | 2.04 hours |
| Rituximab | Pharmacokinetic Parameter Tmax in Plasma | Day 29 | 2.00 hours |
| LNP023 50 mg b.i.d. (4-week Administration) | Pharmacokinetic Parameter Tmax in Plasma | Day 29 | 2.03 hours |
| LNP023 50 mg b.i.d. (20-week Administration) | Pharmacokinetic Parameter Tmax in Plasma | Day 113 | 2.05 hours |
| LNP023 200 mg b.i.d. | Pharmacokinetic Parameter Tmax in Plasma | Day 113 | 1.00 hours |
Secondary
Pharmacokinetics in Urine: Renal Plasma Clearance Derived From 24 Hour Urine Sample
Pharmacokinetics of LNP023 in urine: Renal plasma clearance derived from 24 hour urine sample
Time frame: Day 113
Population: PK set: PK (pharmacokinetic) analysis set included all participants with at least one available valid PK concentration measurement, who received any LNP023 and experienced no protocol deviations with relevant impact on PK data. Only participants with PK values at Day 113 were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LNP023 200 mg b.i.d. | Pharmacokinetics in Urine: Renal Plasma Clearance Derived From 24 Hour Urine Sample | 0.602 L/hr | — |
| Rituximab | Pharmacokinetics in Urine: Renal Plasma Clearance Derived From 24 Hour Urine Sample | 1.19 L/hr | Standard Deviation 0.668 |
Secondary
Ratio to Baseline of Urine Protein Creatinine Ratio (UPCR) Measured in First Morning Void
Adjusted geometric mean ratio to baseline of Urine Protein Creatinine Ratio (UPCR) measured in first morning void. First morning void urine sample was collected in the morning of the day before the visit and kept in the fridge.
Time frame: Baseline, Day 15, Day 29, Day 57, Day 85, Day 113, Day 141, Day 169, Day 266 and Day 378
Population: PD set: In line with the protocol, PD (pharmacodynamics) analyses were performed for all participants who received LNP023 200 mg or rituximab and experienced no protocol deviations with relevant impact on PD/efficacy data. Only participants with a value of UPCR measured in first morning void at the different time points were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| LNP023 200 mg b.i.d. | Ratio to Baseline of Urine Protein Creatinine Ratio (UPCR) Measured in First Morning Void | Day 29 | 0.98 ratio to baseline |
| LNP023 200 mg b.i.d. | Ratio to Baseline of Urine Protein Creatinine Ratio (UPCR) Measured in First Morning Void | Day 141 | 0.75 ratio to baseline |
| LNP023 200 mg b.i.d. | Ratio to Baseline of Urine Protein Creatinine Ratio (UPCR) Measured in First Morning Void | Day 85 | 1.03 ratio to baseline |
| LNP023 200 mg b.i.d. | Ratio to Baseline of Urine Protein Creatinine Ratio (UPCR) Measured in First Morning Void | Day 169 | 0.72 ratio to baseline |
| LNP023 200 mg b.i.d. | Ratio to Baseline of Urine Protein Creatinine Ratio (UPCR) Measured in First Morning Void | Day 57 | 1.02 ratio to baseline |
| LNP023 200 mg b.i.d. | Ratio to Baseline of Urine Protein Creatinine Ratio (UPCR) Measured in First Morning Void | Day 266 | 0.57 ratio to baseline |
| LNP023 200 mg b.i.d. | Ratio to Baseline of Urine Protein Creatinine Ratio (UPCR) Measured in First Morning Void | Day 113 | 1.05 ratio to baseline |
| LNP023 200 mg b.i.d. | Ratio to Baseline of Urine Protein Creatinine Ratio (UPCR) Measured in First Morning Void | Day 378 (End Of Study) | 0.37 ratio to baseline |
| LNP023 200 mg b.i.d. | Ratio to Baseline of Urine Protein Creatinine Ratio (UPCR) Measured in First Morning Void | Day 15 | 0.94 ratio to baseline |
| Rituximab | Ratio to Baseline of Urine Protein Creatinine Ratio (UPCR) Measured in First Morning Void | Day 378 (End Of Study) | 0.46 ratio to baseline |
| Rituximab | Ratio to Baseline of Urine Protein Creatinine Ratio (UPCR) Measured in First Morning Void | Day 15 | 1.15 ratio to baseline |
| Rituximab | Ratio to Baseline of Urine Protein Creatinine Ratio (UPCR) Measured in First Morning Void | Day 29 | 0.90 ratio to baseline |
| Rituximab | Ratio to Baseline of Urine Protein Creatinine Ratio (UPCR) Measured in First Morning Void | Day 57 | 0.77 ratio to baseline |
| Rituximab | Ratio to Baseline of Urine Protein Creatinine Ratio (UPCR) Measured in First Morning Void | Day 85 | 0.75 ratio to baseline |
| Rituximab | Ratio to Baseline of Urine Protein Creatinine Ratio (UPCR) Measured in First Morning Void | Day 113 | 0.92 ratio to baseline |
| Rituximab | Ratio to Baseline of Urine Protein Creatinine Ratio (UPCR) Measured in First Morning Void | Day 141 | 0.77 ratio to baseline |
| Rituximab | Ratio to Baseline of Urine Protein Creatinine Ratio (UPCR) Measured in First Morning Void | Day 169 | 0.55 ratio to baseline |
| Rituximab | Ratio to Baseline of Urine Protein Creatinine Ratio (UPCR) Measured in First Morning Void | Day 266 | 0.34 ratio to baseline |
Comparison: Day 15p-value: 0.459895% CI: [0.47, 1.42]Mixed Model for Repeated Measures
Comparison: Day 169p-value: 0.452895% CI: [0.65, 2.61]Mixed Model for Repeated Measures