Evaluation of Iptacopan in Combination with Standard-of-Care for Efficacy and Safety in Adult Patients with Active Lupus Nephritis Class III-IV, +/- V
- Trial ID
- 2023-509332-26-00
- Protocol
- CLNP023K12201
- Sponsor
- Novartis Pharma AG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the proportion of patients with **lupus nephritis** Class III-IV, +/- V achieving complete renal response (CRR) at week 24 without renal flares when treated with various **iptacopan** regimens compared to standard-of-care (SoC). This is clinically relevant as achieving CRR is indicative of effective disease management and can potentially reduce long-term renal damage in patients with active renal disease.
Secondary objectives include evaluating the superiority of three iptacopan treatment regimens compared to SoC in achieving CRR or partial renal response (PRR) at week 24 and week 52, achieving early CRR, and improving 24-hour urine protein-to-creatinine ratio (UPCR) by at least 25% at week 24. Additionally, the study aims to assess the reduction in corticosteroid use, changes in FACIT-Fatigue, SLEDAI-2K, and BILAG-2004 scores at weeks 24 and 52, and the safety and tolerability of 52 weeks of treatment. Furthermore, the dose-exposure response of iptacopan on top of SoC for proteinuria reduction at week 24 will be assessed, along with the impact on renal response, proteinuria, renal flares, high-dose corticosteroid use, and quality of life.
Participants
The clinical trial involves a total of **192 participants** diagnosed with **Lupus Nephritis Class III-IV, +/- V**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific inclusion criteria, including active biopsy-proven lupus nephritis and a requirement for stable supportive care, such as anti-malarials and ACEi or ARB therapy. All participants must have been vaccinated against COVID-19 and other specified infections prior to randomization. The trial population is characterized by active renal disease necessitating treatment with corticosteroids in combination with MMF/MPS. Lifestyle considerations include maintaining stable medication regimens and adhering to vaccination protocols. The study does not specify additional lifestyle factors such as diet or physical activity. The trial includes a vulnerable population, ensuring comprehensive monitoring and adherence to ethical standards.
Plans and Procedures
The clinical trial is designed as an adaptive, **randomized**, **double-blind**, dose exploration, parallel group, placebo-controlled, multicenter phase 2 study. The primary objective is to evaluate the efficacy, safety, and tolerability of LNP023 in combination with standard-of-care with and without oral corticosteroids in adult patients with active **lupus nephritis** Class III-IV, +/- V. The trial is expected to run from August 2022 to September 2028, with the primary endpoint being the proportion of patients achieving Complete Renal Response (CRR) at week 24 in the absence of renal flares.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, vaccination status, and renal biopsy results. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety, with assessments including urine protein-to-creatinine ratio (UPCR) and various clinical scores. The end-of-study visit will occur at week 52, marking the conclusion of the participant's involvement in the trial.
The expected length of participant involvement is approximately 52 weeks. Conditions that may lead to early termination from the study include the development of adverse events, sub-optimally controlled hypertension, or other clinically important indications as determined by the investigator. Participants will receive either LNP023 or a placebo, with additional treatments including corticosteroid taper and mycophenolate mofetil (MMF) or mycophenolate sodium (MPS) as part of the standard-of-care regimen. The trial aims to provide insights into the treatment of lupus nephritis, focusing on achieving CRR and reducing renal flares.
Treatment
The clinical trial involves the administration of several treatments, including **IPTACOPAN**, **MYCOPHENOLATE SODIUM**, **PREDNISONE**, and **METHYLPREDNISOLONE**, as well as placebo controls. **IPTACOPAN** is administered in the form of hard gelatin capsules, with a maximum daily dose of 400 mg and a total dose of 145,600 mg over a 52-week period. The route of administration is oral. **IPTACOPAN** is a chemical compound known as IPTACOPAN HYDROCHLORIDE, and it is provided by Novartis Pharma AG. The dosing schedule involves twice-daily administration (b.i.d.).
**MYCOPHENOLATE SODIUM** is provided as a gastro-resistant tablet with a maximum daily dose of 2160 mg and a total dose of 786,240 mg over 52 weeks. The administration route is oral. This chemical compound is used in combination with other treatments to evaluate its efficacy in the trial.
**PREDNISONE** is administered in tablet form, with a maximum daily dose of 40 mg and a total dose of 40 mg over a 52-week period. The route of administration is oral. **PREDNISONE** is a chemical compound used as part of the standard-of-care therapy in the trial.
**METHYLPREDNISOLONE** is administered intravenously, with a maximum daily dose of 500 mg and a total dose of 1000 mg over a 3-week period. This chemical compound is used in combination with other treatments to assess its impact on the trial outcomes.
The trial also includes placebo controls, such as a placebo to **LNP023** in the form of hard gelatin capsules and a placebo to **PREDNISONE**. These placebos are used to maintain the double-blind nature of the study and to provide a comparator for evaluating the efficacy of the experimental treatments.
Participant compliance is monitored throughout the trial to ensure adherence to the dosing schedules and to assess the safety and tolerability of the treatments. The trial aims to evaluate the efficacy of these treatments in achieving complete renal response in patients with active lupus nephritis.
Efficacy
The efficacy of the clinical trial will be assessed primarily by evaluating the proportion of patients achieving **Complete Renal Response (CRR)** at week 24 in the absence of renal flares. This assessment will be based on the Urine Protein-To-Creatinine Ratio (UPCR) value obtained from 24-hour urine samples. The primary objective is to determine the difference in the proportion of patients achieving CRR with various iptacopan treatment regimens compared to the standard of care (SoC), which includes a corticosteroid taper and MMF/MPS.
Secondary efficacy endpoints include the proportion of patients achieving CRR or Partial Renal Response (PRR) in the absence of renal flares at weeks 24 and 52, time-to-CRR based on first morning void urine samples, and the proportion of patients achieving a ≥25% reduction in UPCR compared to baseline at week 24. Additional secondary endpoints involve the frequency of corticosteroid courses for renal and non-renal indications, changes from baseline in FACIT-Fatigue Score, SLEDAI-2K score, and BILAG-2004 score at weeks 24 and 52, as well as safety endpoints up to week 52. The log-transformed ratio to baseline of 24-hour UPCR at week 24 will also be analyzed.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male and female patients ≥ 18 years of age or older at the time of screening
- All patients should have been on supportive care including stable dose regimen of anti-malarials (e.g. hydroxychloroquine) unless contraindicated
- Patients should be receiving stable optimized ACEi or ARB therapy at either locally approved maximal daily dose or the maximally tolerated dose (per investigators' judgement) at randomization as per the local clinical practice. The dose of ACEi / ARB therapy should remain stable throughout the study unless there is a clinically important indication to change this e.g. the development of adverse events or sub-optimally controlled hypertension
- Patients with first presentation or flare of lupus nephritis can be included. All participants with a LN flare, following prior treatment with cyclophosphamide can be included. Participants who have developed a LN flare following treatment with MMF may be included if the treating physician is of the opinion that participation in the study is of potential benefit to the patient, considering the doses of MMF with or without corticosteroids being used in the study protocol
- Participants should have a negative COVID-19 test result at screening (performed as per local SoC). Vaccination against COVID-19 should follow local SoC.
- Unequivocally positive anti-nucleosome antibodies (ANA) test result defined as an ANA titre ≥1:80 (based on HEp-2 immunofluorescence assay or an equivalent positive enzyme immunoassay) and/or a positive anti dsDNA at screening
- Active biopsy-proven lupus nephritis within 3 months prior to screening demonstrating Class III or IV lupus nephritis with or without co-existing features of Class V lupus nephritis. If a biopsy was not performed within 3 months of screening, a repeat biopsy is needed to verify LN as a main cause of flare. This renal biopsy will need to be performed during the screening period and after confirmation that the patient has met all other inclusion/exclusion criteria at screening
- Documentation of active renal disease at the time of screening necessitating the commencement of therapy with corticosteroids in combination with MMF/MPS. Active renal disease will be defined by the following: ● Positive dipstick for hematuria (not associated with menstruation or UTI) ● Proteinuria (to be confirmed at screening and prior to randomization) At screening: UPCR of ≥ 1.5 g/g sampled from a first morning void or 24 hour urine collection Prior to randomization: Confirmation of UPCR ≥ 1.5 g/g sampled from a 24 hour urine collection on two separate days, within a window of 10 days prior to randomization. The calculation of the (arithmetic) mean of the UPCR values obtained from the two 24h urine collections will be used to confirm eligibility
- eGFR ≥ 30 ml/min/1.73 m2 (eGFR calculated using the CKD-EPI formula or modified MDRD formula according to specific ethnic groups and local practice guidelines)
- Vaccination against Haemophilus influenzae is recommended, according to local guidelines, at least 2 weeks before treatment with iptacopan is initiated
- Vaccination against Neisseria meningitidis and Streptococcus pneumoniae infections is required prior to the start of study treatment. If the patient has not been previously vaccinated, or if a booster is required, vaccine should be given according to local guidelines at least 2 weeks prior to first study drug administration. If study treatment is expected to start earlier than 2 weeks post vaccination, prophylactic antibiotic treatment should be initiated.
Exclusion Criteria
- Participants who in the opinion of the investigator have previously failed to respond to therapy with MMF/MPS will not be included
- Induction treatment with cyclophosphamide within 3 months of planned treatment for this study; treatment with calcineurin inhibitors within the previous 3 months prior to randomization.
- Presence of rapidly progressive glomerulonephritis (RPGN) as defined by 50% decline in eGFR within 3 months prior to screening
- Renal biopsy presenting with interstitial fibrosis/tubular atrophy (IF/TA) or glomerulosclerosis of more than 50% based on chronicity index score (Bajema et. al s 2018), or which in the opinion of the investigator is such that it precludes likely response to immunosuppressive therapy. Patients previously treated with immunosuppressive or other immunomodulatory agents which are not considered standard of care for treatment of lupus nephritis within the previous 1 year
- Participants being treated with systemic corticosteroids (>5 mg/day prednisone or equivalent) for indications other than SLE or LN e.g. acute asthma, inflammatory bowel disease
- Participants being treated with systemic corticosteroids for SLE or LN will be excluded if they have taken more than an average of 15 mg/day prednisone (or equivalent) in the previous 4 weeks and more than an average of 30 mg/day in the 1 week prior to randomization
- For participants with renal biopsy confirming Class III or IV lupus nephritis (+/- class V) more than 2 months prior to screening: receipt of more than a total dose of 1000 mg equivalent IV pulse methylprednisolone (cumulative dose) within 2 weeks prior to randomization
- Prior treatment with any of the following within 1 year prior to screening: • Nitrogen mustard, chlorambucil, vincristine, procarbazine, etoposide, abatacept • Treatment with any B-cell targeted therapy • Treatment with biological investigational agent • Treatment with interleukin-6 targeted therapy
- Participants with current clinical, radiographic, or laboratory evidence of active or latent TB; history of active TB within 2 years of screening (even if treated); in the opinion of the investigator and based on appropriate evaluation, have a risk of reactivation of TB that precludes the use of conventional immunosuppression
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 10 Aug 2022 | 7 |
 Germany | Recruiting | 10 Aug 2022 | 12 |
 Hungary | Recruiting | 10 Aug 2022 | 12 |
 Portugal | Recruiting | 10 Aug 2022 | 10 |
 Spain | Recruiting | 10 Aug 2022 | 7 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
MYCOPHENOLIC ACID | Other | PHF00170MIG | ORAL | 3 | 52 | SCP139856 |
PREDNISONE | Other | — | ORAL | 40 | 52 | SUB10020MIG |
MYCOPHENOLATE SODIUM | Other | — | ORAL | 2160 | 52 | SUB16447MIG |
PREDNISONE | Comparator | — | ORAL | 40 | 52 | SUB10020MIG |
MYCOPHENOLATE SODIUM | Other | — | ORAL | 2160 | 52 | SUB16447MIG |
Placebo 0 mg hard gelatin capsule size 0 and size 2,placebo to LNP023 | Placebo | N/A | — | — | — | N/A |
METHYLPREDNISOLONE | Other | PHF00243MIG | INTRAVENOUS | 500 | 3 | SCP101878658 |
IPTACOPAN | Test | HARD GELATIN CAPSULES | ORAL | 400 | 52 | PRD10338043 |
PREDNISONE | Other | — | ORAL | 40 | 52 | SUB10020MIG |
PREDNISONE | Other | — | ORAL | 40 | 52 | SUB10020MIG |