Efficacy and Safety of Iptacopan (LNP023) in Adult Patients With Atypical Hemolytic Uremic Syndrome Naive to Complement Inhibitor Therapy

Study Overview
=================
Brief Summary
-----------------
The purpose of this Phase 3 study is to determine whether iptacopan (LNP023) is efficacious and safe for the treatment of aHUS in adult patients who are treatment naive to complement inhibitor therapy.

Detailed Description
-----------------
The study is designed as a multicenter, single-arm, open label study to demonstrate the efficacy and safety of LNP023 (iptacopan) at a dose of 200 mg b.i.d. in adult patients with aHUS who are treatment naive to complement inhibitor therapy (including anti-C5 antibody). The study will enroll approximately 50 participants and assess the effects of iptacopan on a range of efficacy assessments relevant to aHUS including hematological and kidney parameters, dialysis requirement, changes in chronic kidney disease (CKD) stage, as well as patient reported outcomes (PRO) for fatigue and quality of life.

Official Title
-----------------
A Multicenter, Single-arm, Open Label Trial to Evaluate Efficacy and Safety of Oral, Twice Daily LNP023 in Adult aHUS Patients Who Are Naive to Complement Inhibitor Therapy

Conditions
-----------------
Atypical Hemolytic Uremic Syndrome

Intervention / Treatment
-----------------
* Drug: Iptacopan


Participation Criteria
=================
Eligibility Criteria
-----------------
Main Inclusion Criteria: Adult patients with evidence of active thrombotic microangiopathy (TMA), including thrombocytopenia, evidence of hemolysis, and acute kidney injury Vaccinations against Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae infections are 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 Main Exclusion Criteria: Treatment with complement inhibitors, including anti-C5 antibody ADAMTS13 deficiency (<10% activity or <0.1U/ml), and/or Shiga toxin-related hemolytic uremic syndrome (STx-HUS), and/or Positive direct Coombs test Identified drug exposure-related HUS or HUS related to known genetic defects of cobalamin C metabolism or known diacylglycerol kinase ε (DGKE) mediated aHUS Receiving PE/PI, for 14 days or longer, prior to the start of screening for the current TMA Bone marrow transplantation (BMT)/hematopoietic stem cell transplantation (HSCT), heart, lung, small bowel, pancreas, or liver transplantation Patients with sepsis or active severe systemic bacterial, viral (including COVID-19) or fungal infection, systemic infection which confounds an accurate diagnosis of aHUS or impedes the ability to manage the aHUS disease, active infection (or history of recurrent invasive infections) caused by encapsulated bacteria Kidney disease suggestive of other disease than aHUS or of chronic kidney failure or family history of non-complement mediated genetic kidney disease Liver disease or liver injury at screening Systemic sclerosis (scleroderma), systemic lupus erythematosus (SLE), or antiphospholipid antibody positivity or syndrome Chronic hemo- or peritoneal dialysis Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Iptacopan 200 mg b.i.d<br>Single arm open-label with 50 adult patients receiving 200mg oral twice daily doses of iptacopan | Drug: Iptacopan<br>* Iptacopan 200mg twice daily oral<br>* Other names: LNP023;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with complete TMA response without the use of PE/PI and anti-C5 antibody | The number/percentage of participants treated with iptacopan achieving complete thrombotic microangiopathy (TMA) response during 26 weeks of study treatment. Complete TMA Response is defined as (1) hematological normalization in platelet count (platelet count ≥150 x 10^9/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 | 26 weeks of study treatment | 
| Long term safety and efficacy evaluations | Long term (one year) safety, tolerability and efficacy of iptacopan via 1) safety evaluations including adverse events/serious adverse events, safety laboratory parameters, vital signs etc. after 52 weeks of study treatment, and 2) efficacy evaluations including complete TMA response, hematological parameters (platelets, LDH, hemoglobin), eGFR, PROs after 52 weeks of study treatment | 52 weeks of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to achieve complete TMA response | Effect of study treatment iptacopan on time to complete TMA response during the first 26 weeks of study treatment | 26 weeks of study treatment | 
| Percentage of participants with increase from baseline in hemoglobin levels ≥ 2 g/dL | Response is defined as the percentage of participants with 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 | 26 weeks of study treatment | 
| Change from baseline on hematologic parameters | Change from baseline in hematologic parameters (platelets, LDH, hemoglobin) at Week 26 | At week 26 | 
| Percentage of participants on dialysis | For participants requiring dialysis within 5 days prior to iptacopan treatment initiation, the number of participants who no longer require dialysis through 26 weeks of study treatment will be evaluated by means of proportion and corresponding confidence interval | 26 weeks of study treatment | 
| Change from baseline on estimated glomerular filtration rate | Change from baseline in eGFR after 26 weeks of study treatment. | At week 26 | 
| Change from baseline in chronic kidney disease (CKD) stage | Change from baseline in CKD stage (1-5) based on eGFR categories at Week 26 | At week 26 | 
| Change from baseline in patient-reported outcomes score as measured by the Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue Questionnaire | Change from baseline in patient-reported outcomes scores for FACIT-Fatigue Questionnaire at Week 26 | At week 26 | 
| Change from baseline in patient-reported outcomes score as measured by the EuroQol 5-level EQ-5D version (EQ-5D-5L) Questionnaire | Change from baseline in patient-reported outcomes scores for the EuroQol 5-level EQ-5D version (EQ-5D-5L) Questionnaire at Week 26 | At Week 26 | 
| Change from baseline in patient-reported outcomes score as measured by the Patient Global Impression of Severity (PGIS) questionnaire | Change from baseline in patient-reported outcomes scores for Patient Global Impression of Severity (PGIS) at Week 26 | At Week 26 | 
| Change from baseline in patient-reported outcomes score as measured by the Short-form 36 health survey questionnaire version 2 (SF-36 v2) | Change from baseline in patient-reported outcomes scores for Short-form 36 health survey questionnaire version 2 (SF-36 v2) at Week 26 | At Week 26 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
LNP023, iptacopan, aHUS, atypical hemolytic uremic syndrome, thrombotic microangiopathy