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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04889430

Collaborator

(none)

Enrollment

Locations

Arm

35.9

Anticipated Duration (Months)

2.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Atypical Hemolytic Uremic Syndrome	Drug: Iptacopan	Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

50 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Masking Description:

Open label single arm study

Primary Purpose:

Treatment

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

Actual Study Start Date :

Jan 17, 2022

Anticipated Primary Completion Date :

Dec 17, 2024

Anticipated Study Completion Date :

Jan 14, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Iptacopan 200 mg b.i.d Single arm open-label with 50 adult patients receiving 200mg oral twice daily doses of iptacopan	Drug: Iptacopan Iptacopan 200mg twice daily oral Other Names: LNP023

Arm

Intervention/Treatment

Experimental: Iptacopan 200 mg b.i.d

Single arm open-label with 50 adult patients receiving 200mg oral twice daily doses of iptacopan

Drug: Iptacopan

Iptacopan 200mg twice daily oral

Other Names:

LNP023

Outcome Measures

Primary Outcome Measures

Percentage of participants with complete TMA response without the use of PE/PI and anti-C5 antibody [26 weeks of study treatment]
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
Long term safety and efficacy evaluations [52 weeks of study treatment]
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

Secondary Outcome Measures

Time to achieve complete TMA response [26 weeks of study treatment]
Effect of study treatment iptacopan on time to complete TMA response during the first 26 weeks of study treatment
Percentage of participants with increase from baseline in hemoglobin levels ≥ 2 g/dL [26 weeks of study treatment]
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
Change from baseline on hematologic parameters [At week 26]
Change from baseline in hematologic parameters (platelets, LDH, hemoglobin) at Week 26
Percentage of participants on dialysis [26 weeks of study treatment]
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
Change from baseline on estimated glomerular filtration rate [At week 26]
Change from baseline in eGFR after 26 weeks of study treatment.
Change from baseline in chronic kidney disease (CKD) stage [At week 26]
Change from baseline in CKD stage (1-5) based on eGFR categories at Week 26
Change from baseline in patient-reported outcomes score as measured by the Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue Questionnaire [At week 26]
Change from baseline in patient-reported outcomes scores for FACIT-Fatigue Questionnaire 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 [At Week 26]
Change from baseline in patient-reported outcomes scores for the EuroQol 5-level EQ-5D version (EQ-5D-5L) Questionnaire at Week 26
Change from baseline in patient-reported outcomes score as measured by the Patient Global Impression of Severity (PGIS) questionnaire [At Week 26]
Change from baseline in patient-reported outcomes scores for Patient Global Impression of Severity (PGIS) 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) [At Week 26]
Change from baseline in patient-reported outcomes scores for Short-form 36 health survey questionnaire version 2 (SF-36 v2) at Week 26

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Main Inclusion Criteria:

Adult patients with evidence of 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 (<5% activity), 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 28 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, severe systemic infection, COVID-19 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Torrance	California	United States	90502
2	Novartis Investigative Site	Albuquerque	New Mexico	United States	87131
3	Novartis Investigative Site	Innsbruck	Tyrol	Austria	6020
4	Novartis Investigative Site	Wien		Austria	1090
5	Novartis Investigative Site	Sao Paulo	SP	Brazil	05403 000
6	Novartis Investigative Site	São Paulo	SP	Brazil	04038-002
7	Novartis Investigative Site	Ostrava Poruba	Czech Republic	Czechia	708 52
8	Novartis Investigative Site	Praha 4		Czechia	140 00
9	Novartis Investigative Site	Praha		Czechia	12808
10	Novartis Investigative Site	Thessaloniki	GR	Greece	570 10
11	Novartis Investigative Site	Vellore	Tamil Nadu	India	632004
12	Novartis Investigative Site	Lucknow	Uttar Pradesh	India	226014
13	Novartis Investigative Site	Iruma-gun	Saitama	Japan	350-0495
14	Novartis Investigative Site	Izumo-city	Shimane	Japan	693 8501
15	Novartis Investigative Site	Seoul		Korea, Republic of	03080
16	Novartis Investigative Site	Seoul		Korea, Republic of	03722
17	Novartis Investigative Site	Ljubljana		Slovenia	1000
18	Novartis Investigative Site	Taichung		Taiwan	40447
19	Novartis Investigative Site	Taoyuan		Taiwan	33305
20	Novartis Investigative Site	Newcastle Upon Tyne		United Kingdom	NE7 7DN