Study of efficacy and safety of LNP023 in participants with active lupus nephritis Class III-IV, +/- V

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

16 Feb 2023 → ongoing

Decision date (initial)

2024-08-13

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Novartis Pharma AG

External identifiers

EU CT number

2023-509332-26-00

EudraCT number

2021-002046-33

ClinicalTrials.gov

NCT05268289

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Therapy, Pharmacodynamic, Efficacy, Pharmacogenetic, Others, Dose response

The primary objectives are to evaluate the proportion of patients achieving complete renal response (CRR) at week 24 in the absence of renalflares with the iptacopan treatment regimens
• Iptacopan 200 mg b.i.d + corticosteroid taper + MMF/MPS
• Iptacopan 50 mg b.i.d + corticosteroid taper + MMF/MPS
• Iptacopan 200 mg b.i.d + no corticosteroid taper + MMF/MPS
compared to SoC (corticosteroid taper + MMF/MPS).The primary clinical question of interest is: What is the difference in the proportion of patients achieving CRR at week 24 (based on the Urine Protein-To-Creatinine Ratio (UPCR) value from 24 hour urine samples) in the absence of renal flares for treatment in patients with LN demonstrating active renal disease, regardless of treatment discontinuations and as if rescue corticosteroids for other reasons than renal flares had not been administered

Secondary objectives 3

1. To evaluate the superiority of the three iptacopan treatment regimens described above compared to SoC in:  achieving CRR or PRR at Week 24  achieving CRR at week 52  achieving early CRR (time-to-CRR)  achieving CRR or PRR rate at week 52  in achieving at least 25% improvement in 24h UPCR at week 24  in reducing the frequency of courses of corticosteroids for renal and non-renal indications at a dose exceeding an average of 20 mg/day (of prednisolone or equivalent) for more than 10 days at week 24 and week 52  in change from baseline in FACIT-Fatigue score at week 24 and week 52  in change from baseline in SLEDAI-2K score at week 24 and week 52  in change from baseline in BILAG-2004 score at weeks 24 and 52
2. To evaluate the safety and tolerability of 52 weeks of treatment
3. To assess the dose-exposure response of iptacopan on top of SoC for reduction in proteinuria at week 24The secondary clinical questions of interest are to explore the dose-exposure response of iptacopan on top of SoC, to evaluate the safety and tolerability of the three iptacopan regimens described above and to investigate their effect on complete or partial renal response, proteinuria, occurrence of renal flares, use of high-dose corticosteroids and quality of life

Conditions and MedDRA coding

Lupus Nephritis Class III-IV, +/- V

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD 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.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Male and female patients ≥ 18 years of age or older at the time of screening
2. All patients should have been on supportive care including stable dose regimen of anti-malarials (e.g. hydroxychloroquine) unless contraindicated
3. 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
4. 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
5. Participants should have a negative COVID-19 test result at screening (performed as per local SoC). Vaccination against COVID-19 should follow local SoC.
6. 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
7. 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
8. 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
9. 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)
10. Vaccination against Haemophilus influenzae is recommended, according to local guidelines, at least 2 weeks before treatment with iptacopan is initiated
11. 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 9

1. Participants who in the opinion of the investigator have previously failed to respond to therapy with MMF/MPS will not be included
2. 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.
3. Presence of rapidly progressive glomerulonephritis (RPGN) as defined by 50% decline in eGFR within 3 months prior to screening
4. 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
5. 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
6. 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
7. 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
8. 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
9. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Part 1 and 2: Proportion of patients achieving Complete Renal Response (CRR) at week 24 in the absence of renal flares

Secondary endpoints 9

1. Parts 1 and 2: Proportion of patients achieving CRR or PRR in the absence of renal flares at weeks 24 and 52
2. Time-to-Complete Renal Response (CRR) based on first morning void (FMV) urine samples
3. Proportion of patients achieving ≥25% UPCR reduction in the absence of renal flares compared to baseline at week 24
4. Frequency of courses of corticosteroids for renal and non-renal indications at a dose exceeding an average of 20mg/day (of prednisolone or equivalent) for more than 10 days between weeks 24 and 52
5. Change from baseline FACIT-Fatigue Score at weeks 24 and 52
6. Change from baseline in SLEDAI-2K score at weeks 24 and 52
7. Change from baseline in BILAG-2004 score at weeks 24 and 52
8. Safety endpoints up to week 52 for Part 1 and 2
9. Log-transformed ratio to baseline of 24h UPCR at week 24

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 3

Placebo 2

Auxiliary 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel

Postcode

4056

Country

Switzerland

Scientific contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Public contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Third parties 11

Locations

5 EU/EEA countries · 23 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 51 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications