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

Primary Purpose

Atypical Hemolytic Uremic Syndrome

Status
Recruiting
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Iptacopan
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Atypical Hemolytic Uremic Syndrome focused on measuring LNP023, iptacopan, aHUS, atypical hemolytic uremic syndrome, thrombotic microangiopathy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
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  • Novartis Investigative SiteRecruiting
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  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Iptacopan 200 mg b.i.d

Arm Description

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

Outcomes

Primary Outcome Measures

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
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

Secondary Outcome Measures

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
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
Change from baseline on hematologic parameters
Change from baseline in hematologic parameters (platelets, LDH, hemoglobin) 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
Change from baseline on estimated glomerular filtration rate
Change from baseline in eGFR after 26 weeks of study treatment.
Change from baseline in chronic kidney disease (CKD) stage
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
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
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
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)
Change from baseline in patient-reported outcomes scores for Short-form 36 health survey questionnaire version 2 (SF-36 v2) at Week 26

Full Information

First Posted
May 7, 2021
Last Updated
September 18, 2023
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT04889430
Brief Title
Efficacy and Safety of Iptacopan (LNP023) in Adult Patients With Atypical Hemolytic Uremic Syndrome Naive to Complement Inhibitor Therapy
Acronym
APPELHUS
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
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 17, 2022 (Actual)
Primary Completion Date
December 23, 2025 (Anticipated)
Study Completion Date
January 6, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Atypical Hemolytic Uremic Syndrome
Keywords
LNP023, iptacopan, aHUS, atypical hemolytic uremic syndrome, thrombotic microangiopathy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Masking Description
Open label single arm study
Allocation
N/A
Enrollment
50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Iptacopan 200 mg b.i.d
Arm Type
Experimental
Arm Description
Single arm open-label with 50 adult patients receiving 200mg oral twice daily doses of iptacopan
Intervention Type
Drug
Intervention Name(s)
Iptacopan
Other Intervention Name(s)
LNP023
Intervention Description
Iptacopan 200mg twice daily oral
Primary Outcome Measure Information:
Title
Percentage of participants with complete TMA response without the use of PE/PI and anti-C5 antibody
Description
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
Time Frame
26 weeks of study treatment
Title
Long term safety and efficacy evaluations
Description
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
Time Frame
52 weeks of study treatment
Secondary Outcome Measure Information:
Title
Time to achieve complete TMA response
Description
Effect of study treatment iptacopan on time to complete TMA response during the first 26 weeks of study treatment
Time Frame
26 weeks of study treatment
Title
Percentage of participants with increase from baseline in hemoglobin levels ≥ 2 g/dL
Description
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
Time Frame
26 weeks of study treatment
Title
Change from baseline on hematologic parameters
Description
Change from baseline in hematologic parameters (platelets, LDH, hemoglobin) at Week 26
Time Frame
At week 26
Title
Percentage of participants on dialysis
Description
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
Time Frame
26 weeks of study treatment
Title
Change from baseline on estimated glomerular filtration rate
Description
Change from baseline in eGFR after 26 weeks of study treatment.
Time Frame
At week 26
Title
Change from baseline in chronic kidney disease (CKD) stage
Description
Change from baseline in CKD stage (1-5) based on eGFR categories at Week 26
Time Frame
At week 26
Title
Change from baseline in patient-reported outcomes score as measured by the Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue Questionnaire
Description
Change from baseline in patient-reported outcomes scores for FACIT-Fatigue Questionnaire at Week 26
Time Frame
At week 26
Title
Change from baseline in patient-reported outcomes score as measured by the EuroQol 5-level EQ-5D version (EQ-5D-5L) Questionnaire
Description
Change from baseline in patient-reported outcomes scores for the EuroQol 5-level EQ-5D version (EQ-5D-5L) Questionnaire at Week 26
Time Frame
At Week 26
Title
Change from baseline in patient-reported outcomes score as measured by the Patient Global Impression of Severity (PGIS) questionnaire
Description
Change from baseline in patient-reported outcomes scores for Patient Global Impression of Severity (PGIS) at Week 26
Time Frame
At Week 26
Title
Change from baseline in patient-reported outcomes score as measured by the Short-form 36 health survey questionnaire version 2 (SF-36 v2)
Description
Change from baseline in patient-reported outcomes scores for Short-form 36 health survey questionnaire version 2 (SF-36 v2) at Week 26
Time Frame
At Week 26

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Novartis Pharmaceuticals
Phone
1-888-669-6682
Email
novartis.email@novartis.com
First Name & Middle Initial & Last Name or Official Title & Degree
Novartis Pharmaceuticals
Phone
+41613241111
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Novartis Investigative Site
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Torrance
State/Province
California
ZIP/Postal Code
90502
Country
United States
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20007 2197
Country
United States
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Albuquerque
State/Province
New Mexico
ZIP/Postal Code
87131-0001
Country
United States
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Bronx
State/Province
New York
ZIP/Postal Code
10461
Country
United States
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Temple
State/Province
Texas
ZIP/Postal Code
76502
Country
United States
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Innsbruck
State/Province
Tyrol
ZIP/Postal Code
6020
Country
Austria
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Wien
ZIP/Postal Code
1090
Country
Austria
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Sao Paulo
State/Province
SP
ZIP/Postal Code
05403 000
Country
Brazil
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
São Paulo
State/Province
SP
ZIP/Postal Code
04038-002
Country
Brazil
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Beijing
ZIP/Postal Code
100034
Country
China
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Beijing
ZIP/Postal Code
100191
Country
China
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Beijing
ZIP/Postal Code
100730
Country
China
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Shanghai
ZIP/Postal Code
200025
Country
China
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Ostrava
State/Province
Poruba
ZIP/Postal Code
708 52
Country
Czechia
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Praha 4
ZIP/Postal Code
140 00
Country
Czechia
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Praha
ZIP/Postal Code
12808
Country
Czechia
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Thessaloniki
State/Province
GR
ZIP/Postal Code
570 10
Country
Greece
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Heraklion Crete
ZIP/Postal Code
711 10
Country
Greece
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Thiruvananthapuram
State/Province
Kerala
ZIP/Postal Code
695011
Country
India
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Nagpur
State/Province
Maharashtra
ZIP/Postal Code
440015
Country
India
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Pune
State/Province
Maharashtra
ZIP/Postal Code
411011
Country
India
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Chandigarh
State/Province
Punjab
ZIP/Postal Code
160012
Country
India
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Chennai
State/Province
Tamil Nadu
ZIP/Postal Code
600 006
Country
India
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Vellore
State/Province
Tamil Nadu
ZIP/Postal Code
632517
Country
India
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Lucknow
State/Province
Uttar Pradesh
ZIP/Postal Code
226014
Country
India
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Iruma-gun
State/Province
Saitama
ZIP/Postal Code
350-0495
Country
Japan
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Izumo-city
State/Province
Shimane
ZIP/Postal Code
693 8501
Country
Japan
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Bunkyo ku
State/Province
Tokyo
ZIP/Postal Code
113 8655
Country
Japan
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Seoul
ZIP/Postal Code
03080
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Seoul
ZIP/Postal Code
03722
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Bratislava
ZIP/Postal Code
833 05
Country
Slovakia
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Ljubljana
ZIP/Postal Code
1000
Country
Slovenia
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Taichung
ZIP/Postal Code
40447
Country
Taiwan
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Taoyuan
ZIP/Postal Code
33305
Country
Taiwan
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Newcastle Upon Tyne
ZIP/Postal Code
NE7 7DN
Country
United Kingdom
Individual Site Status
Recruiting

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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.

Learn more about this trial

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

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