Efficacy and safety of iptacopan (LNP023) in adult patients with atypical hemolytic uremic syndrome naïve to complement inhibitor therapy

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] - Hemic and Lymphatic Diseases [C15]

Trial duration

27 Jun 2022 → 11 Apr 2026

Decision date (initial)

2024-07-03

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Novartis Pharma AG

External identifiers

EU CT number

2023-508840-22-00

EudraCT number

2020-005186-13

ClinicalTrials.gov

NCT04889430

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Pharmacokinetic, Efficacy, Others

To assess the proportion of participants treated with iptacopan achieving complete thrombotic microangiopathy (TMA) response during 26 weeks of study treatment.

Secondary objectives 8

1. To assess the effect of iptacopan on time to complete TMA response.
2. To assess the proportion of participants achieving an increase from baseline in hemoglobin levels of ≥ 2 g/dL.
3. To assess the effect of iptacopan on hematologic parameters (platelets, lactate dehydrogenase (LDH), hemoglobin).
4. To assess the effect of iptacopan on dialysis requirement status.
5. To assess the effect of iptacopan on estimated glomerular filtration rate (eGFR).
6. To assess the effect of iptacopan on chronic kidney disease (CKD) stage.
7. To assess the effect of iptacopan on patient-reported overall fatigue severity and health-related quality of life.
8. To assess safety and tolerability of iptacopan.

Conditions and MedDRA coding

Atypical hemolytic uremic syndrome

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.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. Male and female patients ≥ 18 years of age with evidence of active thrombotic microangiopathy (TMA), including thrombocytopenia, evidence of hemolysis, and kidney injury, based on the following laboratory findings: • Platelet count <150x109/L during the Screening Period, and • LDH ≥1.5 x upper limit of normal (ULN) during the Screening Period and hemoglobin ≤ lower limit of normal (LLN) for age and gender during the Screening Period, and • Serum creatinine ≥ULN during the Screening Period with acute worsening of kidney function. (Patients requiring dialysis for acute kidney injury are eligible).
2. 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 regulations, at least 2 weeks prior to first study drug administration. If study treatment has to start earlier than 2 weeks post vaccination or before vaccination is given, prophylactic antibiotic treatment must be administered at the start of study treatment and for at least 2 weeks after vaccination.
3. If not received previously, vaccination against Haemophilus influenzae infection should be given if available and according to local regulations. The vaccine should be given at least 2 weeks prior to first study drug administration.
4. Among patients with a kidney transplant, (a) known history of aHUS prior to current kidney transplantation, or (b) If no history of aHUS prior to the current transplantation is available, patients may be eligible without changes of immunosuppressive regimen if investigator excludes other causes of TMA not attributable to aHUS, especially transplant rejection. If immunosuppressive regimens (e.g., calcineurin inhibitor [CNI] or mammalian target of rapamycin inhibitor [mTORi] need to be modified after transplantation, evidence that TMA has persisted for at least 4 days after modification needs to be available.

Exclusion criteria 12

1. Previous or ongoing treatment with complement inhibitors, including anti-C5 antibody.
2. A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency, and/or Shiga toxin-related hemolytic uremic syndrome (STX-HUS), and/or positive direct Coombs test.
3. Identified drug exposure-related HUS or HUS related to known genetic defects of cobalamin C metabolism or known diacylglycerol kinase ε (DGKE) mediated aHUS.
4. Started receiving PE/PI 14 days or longer before the start of screening visit for the current TMA.
5. Bone marrow transplantation (BMT)/hematopoietic stem cell transplantation (HSCT), heart, lung, small bowel, pancreas, or liver transplantation.
6. In patients with a kidney transplant, acute kidney dysfunction consistent with the diagnosis of transplantation failure due to acute/chronic active T-Cell mediated rejection (TCMR) and/or active/chronic active antibody-mediated rejection (ABMR) according to Banff 2017 criteria.
7. Among patients with native kidney, history or presence of any kidney disease other than aHUS, such as: • Known kidney biopsy finding suggestive of underlying disease other than aHUS • Kidney ultrasound finding demonstrating small kidneys suggestive of chronic kidney failure • Known family history and/or genetic diagnosis of non-complement mediated genetic kidney disease (e.g., focal segmental glomerulosclerosis) • Laboratory tests indicative of a kidney disease other than aHUS (eg, Anti-glomerular Basement Membrane (anti-GBM) antibodies, Anti-Neutrophil Cytoplasmic Antibodies (ANCA), Anti-Phospholipase A2 Receptor (anti-PLA2R) antibodies, anti-double stranded DNA (anti-dsDNA) antibodies) • Liver disease or liver injury at screening • Patients with sepsis or active severe systemic bacterial, viral (including COVID-19) or fungal infection.
8. Presence of systemic infections (bacterial, viral, fungal or parasitic) that, in the opinion of the Investigator, confounds an accurate diagnosis of aHUS or impedes the ability to manage the aHUS disease.
9. Active infection, or history of recurrent invasive infections, caused by encapsulated bacteria (i.e., meningococcus, pneumococcus), or H. influenzae.
10. Systemic sclerosis (scleroderma), systemic lupus erythematosus (SLE), or antiphospholipid antibody positivity or syndrome.
11. Chronic hemo- or peritoneal dialysis.
12. Any adenoviral COVID-19 vaccine within 28 days prior to screening visit.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Complete TMA response without the use of PE/PI and anti-C5 antibody during 26 weeks of study treatment. Complete TMA Response is defined as (1) hematological normalization in platelet count (platelet count ≥150 x 109/L) and LDH (below ULN), and (2) improvement in kidney function (≥ 25% serum creatinine reduction from baseline), maintained for two measurements obtained at least four weeks apart, and any measurement in between.

Secondary endpoints 8

1. Time to achieve TMA response during 26 weeks of study treatment.
2. Response is defined as an increase in hemoglobin of ≥ 2 g/dL from baseline, observed at two measurements obtained at least 4 weeks apart and any measurement in between during 26 weeks of study treatment.
3. Change from baseline in hematologic parameters (platelets, LDH, hemoglobin) at Week 26.
4. Proportion of participants on dialysis (done for this TMA event) who no longer require dialysis through 26 weeks of study treatment.
5. Change from baseline in eGFR values at Week 26.
6. Change from baseline in CKD stage (1-5) based on eGFR categories at Week 26.
7. Change from baseline in patient-reported outcomes score for FACIT-Fatigue, Patient Global Impression of Severity (PGIS), EuroQol 5-level EQ-5D version (EQ-5D-5L) and Short-form 36 health survey questionnaire version 2 (SF-36 v2) at Week 26.
8. Safety evaluations (including adverse events/serious adverse events (SAE), safety laboratory parameters and vital signs).

Investigational products

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

Test 1

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 20

Locations

5 EU/EEA countries · 11 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 53 files

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

Application history

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