Clinical trial NCT04558918: Study of Efficacy and Safety of Twice Daily Oral LNP023 in Adult PNH Patients With Residual Anemia Despite Anti-C5 Antibody Treatment
Official title: A Randomized, Multicenter, Active-comparator Controlled, Open-label Trial to Evaluate Efficacy and Safety of Oral, Twice Daily LNP023 in Adult Patients With PNH and Residual Anemia, Despite Treatment With an Intravenous Anti-C5 Antibody.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Paroxysmal Nocturnal Hemoglobinuria (PNH)
Keywords: Paroxysmal nocturnal hemoglobinuria
Hemoglobin
Anemia
LNP023
eculizumab
ravulizumab
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2020-09-22
Enrollment: 97
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study was a multi-center, randomized, open-label, active comparator-controlled, parallel group study.

The purpose of this Phase 3 study in PNH patients presenting with residual anemia despite treatment with anti-C5 antibody, was to determine whether iptacopan is efficacious and safe for the treatment of PNH through demonstration of superiority of iptacopan compared to anti-C5 antibody treatment.

Detailed description: The study comprised three periods:

* A screening period lasting up to 8 weeks (unless there was a need to extend it for vaccinations required for inclusion, vaccinations were started as early as possible to avoid extension of the screening period)
* A 24-week randomized, open-label, active controlled, treatment period for the primary efficacy and safety analyses. Patients who met the eligibility criteria at screening were stratified based on the type of prior anti-C5 antibody treatment (eculizumab or ravulizumab) and based on the transfusion history as reported during the last 6 months prior to randomization (i.e. transfusion received/not received). Patients were randomized to one of the two treatment groups in an 8:5 ratio to either iptacopan monotherapy at a dose of 200 mg orally b.i.d. or i.v. anti-C5 antibody treatment (patients continued with the same regimen during the randomized treatment period as they were prior to randomization), respectively.
* A 24-week open-label, iptacopan treatment extension period. The patients randomized to the active comparator group were offered to switch to iptacopan on Day 168 (Week 24 visit) and entered the treatment extension period, after receiving a last dose of anti-C5 antibody treatment (eculizumab or ravulizumab). For patients in the comparator group not agreeing to switch treatment, Week 24 visit was the End of Study visit for the trial with no participation in the treatment extension period. For patients agreeing to switch to oral iptacopan, the Extension treatment started on the day after completion of the Week 24 visit. The patients in the iptacopan group who, in the opinion of investigator, benefitted from treatment and were taking iptacopan at Week 24 visit (i.e. did not permanently discontinue study medication), were offered the opportunity to continue oral iptacopan treatment during the treatment extension period.
* Data cut-off date used for the primary results submission was 26- Sep-2022

Eligibility criteria: Inclusion Criteria:

* Male and female participants ≥ 18 years of age with a diagnosis of PNH confirmed by high-sensitivity flow cytometry with clone size ≥ 10%
* Stable regimen of anti-C5 antibody treatment (either eculizumab or ravulizumab) for at least 6 months prior to randomization
* Mean hemoglobin level \<10 g/dL
* Vaccination against Neisseria meningitidis infection is required prior to the start of treatment.
* If not received previously, vaccination against Streptococcus pneumoniae and Haemophilus influenzae infections should be given

Exclusion Criteria:

* Participants on a stable eculizumab dose but with a dosing interval of 11 days or less or patients on stable ravulizumab dose but with a dosing interval of less than 8 weeks.
* Known or suspected hereditary complement deficiency at screening
* History of hematopoietic stem cell transplantation
* Patients with laboratory evidence of bone marrow failure (reticulocytes \<100x10E9/L; platelets \<30x10E9/L; neutrophils \<500x10E6/L).
* Active systemic bacterial, viral (incl. COVID-19), or fungal infection within 14 days prior to study drug administration
* A history of recurrent invasive infections caused by encapsulated organisms, e.g. meningococcus or pneumococcus.
* Major concurrent comorbidities including but not limited to severe kidney disease (e.g., eGFR \< 30 mL/min/1.73 m2, dialysis), advanced cardiac disease (e.g., NYHA class IV), severe pulmonary disease (e.g., severe pulmonary hypertension (WHO class IV)), or hepatic disease (e.g., active hepatitis) that in the opinion of the investigator precludes participant's participation in the study.

Primary outcomes:
measure: Marginal Proportion (Expressed as Percentages) of Participants With Sustained Increase in Hemoglobin Levels From Baseline of ≥ 2 g/dL in the Absence of Red Blood Cell Transfusions
timeFrame: Baseline, hemoglobin between Day 126 and Day 168 and absence of transfusions between Day 14 and Day 168
measure: Marginal Proportion (Expressed as Percentages) of Participants With Sustained Hemoglobin Levels of ≥ 12 g/dL in the Absence of Red Blood Cell Transfusions
timeFrame: Hemoglobin between Day 126 and Day 168 and absence of transfusions between Day 14 and Day 168
measure: Percentage of Patients Meeting Hematological Response Criterion After the Start of LNP023 Treatment
timeFrame: Up to 48 weeks
measure: Number of Patients Not Requiring RBC Transfusions After the Start of LNP023 Treatment
timeFrame: Up to 48 weeks
measure: Change From Baseline in Hemoglobin at Visit Day 336
timeFrame: Baseline, Day 336
measure: Change From Baseline in FACIT-Fatigue Questionnaire at Day 336
timeFrame: Baseline, Day 336
measure: Adjusted Annualized Clinical BTH Rate After the Start of LNP023 Treatment
timeFrame: Up to 336 Days
measure: Adjusted Annualized Major Adverse Vascular Events Rate After the Start of LNP023 Treatment
timeFrame: Up to 336 Days
Secondary outcomes:
measure: Marginal Proportion (Expressed as Percentages) of Participants Who Remain Free From Transfusions
timeFrame: Between Day 14 and Day 168
measure: Change From Baseline in Hemoglobin Between Day 126 and 168
timeFrame: Baseline and mean of visits between Day 126 and 168
measure: Change From Baseline in FACIT-Fatigue Questionnaire in the Randomized Treatment Period
timeFrame: Baseline, mean of visits between Day 126 and Day 168
measure: Change From Baseline in Absolute Reticulocyte Count in the Randomized Treatment Period
timeFrame: Baseline and mean of visits between Day 126 and 168
measure: Ratio to Baseline in Log-transformed LDH in the Randomized Treatment Period
timeFrame: Baseline and mean of visits between Day 126 and 168
measure: Adjusted Annualized Clinical BTH Rate in the Randomized Treatment Period
timeFrame: Between Day 1 and Day 168
measure: Adjusted Annualized Major Adverse Vascular Events Rate in the Randomized Treatment Period
timeFrame: Between Day 1 and Day 168
Other outcomes:
measure: Change From Baseline in Absolute Reticulocyte Count at Day 336
timeFrame: Baseline and Day 336
measure: Ratio to Baseline in Log-transformed LDH at Visit Day 336
timeFrame: Baseline and Day 336
Locations:
city: Duarte
country: United States
facility: City Of Hope National Med Center City of Hope Medical Center
state: California
city: Orange
country: United States
facility: Univ Cali Irvine ALS Neuromuscular
state: California
city: Augusta
country: United States
facility: Augusta University Georgia Patient Treatment
state: Georgia
city: Charlotte
country: United States
facility: Levine Cancer Insitute Carolinas Healthcare System
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation Dept.ofTaussigCancer Center
state: Ohio
city: Santo Andre
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Ostrava
country: Czechia
facility: Novartis Investigative Site
state: Poruba
city: Lille
country: France
facility: Novartis Investigative Site
city: Paris 10
country: France
facility: Novartis Investigative Site
city: Toulouse
country: France
facility: Novartis Investigative Site
city: Aachen
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Riesa
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Ascoli Piceno
country: Italy
facility: Novartis Investigative Site
state: AP
city: Avellino
country: Italy
facility: Novartis Investigative Site
state: AV
city: Firenze
country: Italy
facility: Novartis Investigative Site
state: FI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Torino
country: Italy
facility: Novartis Investigative Site
state: TO
city: Bassano Del Grappa
country: Italy
facility: Novartis Investigative Site
state: VI
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Fukushima city
country: Japan
facility: Novartis Investigative Site
state: Fukushima
city: Kanazawa-city
country: Japan
facility: Novartis Investigative Site
state: Ishikawa
city: Suwa
country: Japan
facility: Novartis Investigative Site
state: Nagano
city: Suita
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Shinjuku-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Kyoto
country: Japan
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Nijmegen
country: Netherlands
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Santiago De Compostela
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: San Sebastian
country: Spain
facility: Novartis Investigative Site
state: Pais Vasco
city: Hualien
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Leeds
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: