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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Atypical Hemolytic Uremic Syndrome
• Intervention / Treatment: Drug: Iptacopan

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 Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Novartis Pharmaceuticals; Phone Number: 1-888-669-6682; Email: novartis.email@novartis.com
• Study Contact Backup: Name: Novartis Pharmaceuticals; Phone Number: +41613241111

Study Locations

• Austria
  • Wien, Austria, 1090
    • Recruiting
    • Novartis Investigative Site
  • Tyrol
    • Innsbruck, Tyrol, Austria, 6020
      • Recruiting
      • Novartis Investigative Site
• Brazil
  • Salvador, Brazil, 40301-155
    • Recruiting
    • Novartis Investigative Site
  • CE
    • Fortaleza, CE, Brazil, 60430 370
      • Recruiting
      • Novartis Investigative Site
  • DF
    • Brasilia, DF, Brazil, 71635-580
      • Recruiting
      • Novartis Investigative Site
  • MG
    • Belo Horizonte, MG, Brazil, 30150-221
      • Recruiting
      • Novartis Investigative Site
  • RS
    • Porto Alegre, RS, Brazil, 90020-090
      • Recruiting
      • Novartis Investigative Site
  • SP
    • Sao Paulo, SP, Brazil, 05403 000
      • Recruiting
      • Novartis Investigative Site
    • São Paulo, SP, Brazil, 04038-002
      • Recruiting
      • Novartis Investigative Site
• China
  • Beijing, China, 100730
    • Recruiting
    • Novartis Investigative Site
  • Beijing, China, 100191
    • Recruiting
    • Novartis Investigative Site
  • Beijing, China, 100034
    • Recruiting
    • Novartis Investigative Site
  • Shanghai, China, 200025
    • Recruiting
    • Novartis Investigative Site
  • Shanxi, China, 710063
    • Recruiting
    • Novartis Investigative Site
  • Jiangsu
    • Nanjing, Jiangsu, China, 210009
      • Recruiting
      • Novartis Investigative Site
• Czechia
  • Praha, Czechia, 12808
    • Recruiting
    • Novartis Investigative Site
  • Praha 4, Czechia, 140 00
    • Recruiting
    • Novartis Investigative Site
  • Poruba
    • Ostrava, Poruba, Czechia, 708 52
      • Recruiting
      • Novartis Investigative Site
• Greece
  • Athens, Greece, 115 27
    • Recruiting
    • Novartis Investigative Site
  • Heraklion Crete, Greece, 711 10
    • Recruiting
    • Novartis Investigative Site
  • GR
    • Thessaloniki, GR, Greece, 570 10
      • Recruiting
      • Novartis Investigative Site
• India
  • Andhra Pradesh
    • Hyderabad, Andhra Pradesh, India, 500012
      • Recruiting
      • Novartis Investigative Site
  • Kerala
    • Thiruvananthapuram, Kerala, India, 695011
      • Recruiting
      • Novartis Investigative Site
  • Maharashtra
    • Nagpur, Maharashtra, India, 440015
      • Recruiting
      • Novartis Investigative Site
    • Pune, Maharashtra, India, 411011
      • Recruiting
      • Novartis Investigative Site
  • Punjab
    • Chandigarh, Punjab, India, 160012
      • Recruiting
      • Novartis Investigative Site
  • Tamil Nadu
    • Chennai, Tamil Nadu, India, 600 006
      • Recruiting
      • Novartis Investigative Site
    • Vellore, Tamil Nadu, India, 632517
      • Recruiting
      • Novartis Investigative Site
  • Uttar Pradesh
    • Lucknow, Uttar Pradesh, India, 226014
      • Recruiting
      • Novartis Investigative Site
• Japan
  • Saitama
    • Iruma-gun, Saitama, Japan, 350-0495
      • Recruiting
      • Novartis Investigative Site
  • Shimane
    • Izumo-city, Shimane, Japan, 693 8501
      • Recruiting
      • Novartis Investigative Site
  • Tokyo
    • Bunkyo ku, Tokyo, Japan, 113 8655
      • Recruiting
      • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Recruiting
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 03722
    • Recruiting
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 06591
    • Recruiting
    • Novartis Investigative Site
• Slovakia
  • Bratislava, Slovakia, 833 05
    • Recruiting
    • Novartis Investigative Site
• Slovenia
  • Ljubljana, Slovenia, 1000
    • Recruiting
    • Novartis Investigative Site
• Taiwan
  • Taichung, Taiwan, 40447
    • Recruiting
    • Novartis Investigative Site
  • Taoyuan, Taiwan, 33305
    • Recruiting
    • Novartis Investigative Site
• United Kingdom
  • London, United Kingdom, NW1 2BU
    • Recruiting
    • Novartis Investigative Site
  • Newcastle Upon Tyne, United Kingdom, NE7 7DN
    • Recruiting
    • Novartis Investigative Site
• United States
  • California
    • Los Angeles, California, United States, 90033
      • Recruiting
      • Novartis Investigative Site
    • Torrance, California, United States, 90502
      • Recruiting
      • Novartis Investigative Site
  • District of Columbia
    • Washington, District of Columbia, United States, 20007 2197
      • Recruiting
      • Novartis Investigative Site
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131-0001
      • Recruiting
      • Novartis Investigative Site
  • New York
    • Bronx, New York, United States, 10461
      • Recruiting
      • Novartis Investigative Site
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Recruiting
      • Novartis Investigative Site
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Recruiting
      • Novartis Investigative Site
  • Texas
    • Temple, Texas, United States, 76502
      • Recruiting
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): January 17, 2022
• Primary Completion (Estimated): December 23, 2025
• Study Completion (Estimated): January 6, 2026

Study Registration Dates

• First Submitted: May 7, 2021
• First Submitted That Met QC Criteria: May 13, 2021
• First Posted (Actual): May 17, 2021

Study Record Updates

• Last Update Posted (Actual): December 26, 2023
• Last Update Submitted That Met QC Criteria: December 22, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: LNP023; iptacopan; aHUS; atypical hemolytic uremic syndrome; thrombotic microangiopathy
• Additional Relevant MeSH Terms: Pathologic Processes; Kidney Diseases; Urologic Diseases; Disease; Hematologic Diseases; Anemia; Thrombocytopenia; Blood Platelet Disorders; Anemia, Hemolytic; Thrombotic Microangiopathies; Uremia; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Syndrome; Azotemia; Hemolysis; Hemolytic-Uremic Syndrome; Atypical Hemolytic Uremic Syndrome
• Other Study ID Numbers: CLNP023F12301; 2020-005186-13 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No