Paroxysmal Nocturnal Hemoglobinuria (PNH)Phase 3APPLY-PNHNCT04558918
Study of Efficacy and Safety of Twice Daily Oral LNP023 in Adult PNH Patients With Residual Anemia Despite Anti-C5 Antibody Treatment
A Phase 3 study testing LNP023, Eculizumab and Ravulizumab in people with Paroxysmal Nocturnal Hemoglobinuria (PNH), run by Novartis Pharmaceuticals at 39 sites in 12 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Paroxysmal Nocturnal Hemoglobinuria (PNH)
- What is being tested?
- LNP023, Eculizumab and Ravulizumab
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 97 participants
- Where
- 39 sitesin 12 countries
- Study dates
- 25 Jan 2021to 6 Mar 2023
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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.
Trial locations and contacts
39 sites in 12 countries.
39 sites in 12 countries
Italy7 sites
Novartis Investigative Site
Ascoli Piceno, AP, 63100
Novartis Investigative Site
Avellino, AV, 83100
Novartis Investigative Site
Bassano del Grappa, VI, 36061
Novartis Investigative Site
Florence, FI, 50139
Novartis Investigative Site
Milan, MI, 20122
Novartis Investigative Site
Roma, RM, 00161
Novartis Investigative Site
Torino, TO, 10126
Japan7 sites
Novartis Investigative Site
Fukushima, Fukushima, 960 1295
Novartis Investigative Site
Kanazawa, Ishikawa-ken, 920-8641
Novartis Investigative Site
Kyoto, 606 8507
Novartis Investigative Site
Nagoya, Aichi-ken, 453-8511
Novartis Investigative Site
Shinjuku-ku, Tokyo, 160-0023
Novartis Investigative Site
Suita, Osaka, 565 0871
Novartis Investigative Site
Suwa, Nagano, 392-8510
United States5 sites
Augusta University Georgia Patient Treatment
Augusta, Georgia, 30912
Levine Cancer Insitute Carolinas Healthcare System
Charlotte, North Carolina, 28204
Cleveland Clinic Foundation Dept.ofTaussigCancer Center
Cleveland, Ohio, 44195
City Of Hope National Med Center City of Hope Medical Center
Duarte, California, 91010
Univ Cali Irvine ALS Neuromuscular
Orange, California, 92868
Germany5 sites
Novartis Investigative Site
Aachen, 52074
Novartis Investigative Site
Essen, 45147
Novartis Investigative Site
Hamburg, 20246
Novartis Investigative Site
Riesa, 01589
Novartis Investigative Site
Ulm, 89081
France3 sites
Novartis Investigative Site
Lille, 59037
Novartis Investigative Site
Paris, 75475
Novartis Investigative Site
Toulouse, 31059
Spain3 sites
Novartis Investigative Site
Barcelona, Catalonia, 08036
Novartis Investigative Site
Donostia / San Sebastian, Basque Country, 20080
Novartis Investigative Site
Santiago de Compostela, Galicia, 15706
Brazil2 sites
Novartis Investigative Site
Santo André, São Paulo, 09090-790
Novartis Investigative Site
São Paulo, São Paulo, 01323-900
Taiwan2 sites
Novartis Investigative Site
Hualien City, 970
Novartis Investigative Site
Taipei, 10002
United Kingdom2 sites
Novartis Investigative Site
Leeds, LS9 7TF
Novartis Investigative Site
London, SE5 9RS
About this study
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.
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.
Read the 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
- Being tested
- LNP023, Eculizumab, Ravulizumab
- Keywords
- Paroxysmal nocturnal hemoglobinuria, Hemoglobin, Anemia, LNP023, eculizumab, ravulizumab
- Medical subject headings
- Hemoglobinuria, Paroxysmal, Anemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LNP023Drug
Also called iptacopan
Taken Orally b.i.d. Dosage Supplied: 200 mg Dosage form: Hard gelatin capsule Route of Administration: Oral
EculizumabDrug
Administered as intravenous infusion every 2 weeks as per the stable regimen, the maintenance dose is a fixed dose.
Dosage Supplied: 300 mg/30mL Dosage form: Concentrate solution for infusion
RavulizumabDrug
Administered as intravenous infusion every 8 weeks, the maintenance dose is based on body weight.
Dosage Supplied: 300 mg/30mL Dosage form: Concentrate solution for infusion
| Study group | Role | What they receive |
|---|---|---|
| LNP023 200mg b.i.d. | Experimental | Iptacopan 200mg b.i.d. hard gelatin capsule. After 24 weeks of LNP023 200mg b.i.d. treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive an additional 24 weeks of LNP023 200mg b.i.d. Receives: Drug: LNP023 |
| Anti-C5 antibody | Active comparator | In the Randomized Treatment Period patients randomized to receive Anti-C5 antibody continued with the same stable regimen of Anti-C5 antibody therapy as they had received prior to randomization. For eculizumab (administered as intravenous infusion every 2 weeks), the maintenance dose was a fixed dose, whereas for ravulizumab (administered as intravenous infusion every 8 weeks), the maintenance dose was based on body weight. After 24 weeks of Anti-C5 antibody treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive 24 weeks of LNP023 200mg b.i.d. Receives: Drug: Eculizumab; Drug: Ravulizumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Sustained increase in hemoglobin levels (responder) is defined as an increase from baseline in hemoglobin levels ≥ 2 g/dL on three out of four measurements taken at the visits occurring in last six weeks (between Day 126 and 168) of the randomized treatment period, without requiring red blood cell (RBC) transfusions between Day 14 and Day 168. Requiring RBC transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level ≤ 9 g/dL with signs /and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤ 7 g/dL, regardless of presence of clinical signs and/or symptoms).
The term 'marginal proportion' can be interpreted as the population average probability of being a responder for each treatment group. These values include adjustment for baseline covariates and missing data has also been taken into account.
Measured: Baseline, hemoglobin between Day 126 and Day 168 and absence of transfusions between Day 14 and Day 168
Marginal Proportion (Expressed as Percentages) of Participants With Sustained Hemoglobin Levels of ≥ 12 g/dL in the Absence of Red Blood Cell Transfusions
Sustained hemoglobin levels (responder) is defined as hemoglobin levels ≥ 12 g/dL on three out of four measurements taken at the visits occurring in last six weeks (between Day 126 and 168) of the randomized treatment period, without requiring red blood cell (RBC) transfusions between Day 14 and Day 168. Requiring RBC transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level ≤ 9 g/dL with signs /and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤ 7 g/dL, regardless of presence of clinical signs and/or symptoms).
The term 'marginal proportion' can be interpreted as the population average probability of being a responder for each treatment group. These values include adjustment for baseline covariates and missing data has also been taken into account.
Measured: Hemoglobin between Day 126 and Day 168 and absence of transfusions between Day 14 and Day 168
Percentage of Patients Meeting Hematological Response Criterion After the Start of LNP023 Treatment
Patients with hematological response are those with ≥ 2g/dL increase in hemoglobin from baseline regardless of transfusions and patients with Hb ≥ 12g/dL regardless of transfusions.
Patients in the LNP023-LNP023 group received iptacopan from Day 1 to Day 336 (48 weeks) while patients in the anti-C5 antibody-LNP023 group received iptacopan from Day 169 to Day 336 (treatment extension period - 24 weeks).
Measured: Up to 48 weeks
Number of Patients Not Requiring RBC Transfusions After the Start of LNP023 Treatment
Requiring RBC transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level ≤ 9 g/dL with signs /and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤ 7 g/dL, regardless of presence of clinical signs and/or symptoms).
Patients randomized to anti-C5 treatment switched to LNP023 (iptacopan) on Day 169 and were treated until Day 336 (treatment extension period).
Measured: Up to 48 weeks
Change From Baseline in Hemoglobin at Visit Day 336
Patients randomized to anti-C5 treatment switched to LNP023 (iptacopan) on Day 169 and were treated until Day 336 (treatment extension period).
Measured: Baseline, Day 336
Change From Baseline in FACIT-Fatigue Questionnaire at Day 336
The FACIT-Fatigue is a 13-item questionnaire with support for its validity and reliability in PNH that assesses patient self-reported fatigue and its impact on daily activities and function. All FACIT scales are scored so that a high score is better. As each of the 13 items of the FACIT-F Scale ranges from 0-4, the range of possible scores is 0-52, with 0 being the worst possible score and 52 the best.
Patients randomized to anti-C5 treatment switched to LNP023 (iptacopan) on Day 169 and were treated until Day 336 (treatment extension period).
Measured: Baseline, Day 336
Adjusted Annualized Clinical BTH Rate After the Start of LNP023 Treatment
This endpoint is considering clinical BTH events after the start of LNP023 treatment. Therefore, results are presented in a single arm on LNP023 since it includes all patients in the Combined Full analysis set.
Adjusted annualized rate of clinical breakthrough hemolysis (BTH) events are from negative binomial model. A patient with multiple occurrences of an event under one treatment is counted only once for that treatment.The breakthrough is defined clinical if either there is a decrease in hemoglobin levels equal to or more than 2 g/dL (compared to the latest assessment, or within 15 days) or if patients present signs or symptoms of gross hemoglobinuria, painful crisis, dysphagia or any other significant clinical PNH-related signs \& symptoms, in presence of laboratory evidence of intravascular hemolysis.
Measured: Up to 336 Days
Adjusted Annualized Major Adverse Vascular Events Rate After the Start of LNP023 Treatment
This endpoint is considering clinical BTH events after the start of LNP023 treatment. Therefore, results are presented in a single arm on LNP023 since it includes all patients in the Combined Full analysis set.
Adjusted annualized Major Adverse Vascular Events (MAVEs incl. thrombosis) rate. A MAVE is defined as: acute peripheral vascular occlusion, amputation (non-traumatic; nondiabetic), cerebral arterial occlusion/cerebrovascular accident, cerebral venous occlusion, dermal thrombosis, gangrene (non-traumatic; nondiabetic), hepatic/portal vein thrombosis (Budd-Chiari syndrome), mesenteric/visceral arterial, thrombosis or infarction, mesenteric/visceral vein thrombosis or infarction, myocardial infarction, pulmonary embolus, renal arterial thrombosis, renal vein thrombosis, thrombophlebitis / deep vein thrombosis, transient ischemic attack, unstable angina or other.
A patient with multiple occurrences of an event under one treatment is counted only once for that treatment.
Measured: Up to 336 Days
Secondary outcomes (7)
Marginal Proportion (Expressed as Percentages) of Participants Who Remain Free From Transfusions
Marginal proportion (expressed as percentages) of participants who did not require transfusions between Day 14 and Day 168. Requiring red blood cell transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level ≤ 9 g/dL with signs /and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤ 7 g/dL, regardless of presence of clinical signs and/or symptoms). The term 'marginal proportion' can be interpreted as the population average probability of being a responder for each treatment group. These values include adjustment for baseline covariates and missing data has also been taken into account.
Measured: Between Day 14 and Day 168
Change From Baseline in Hemoglobin Between Day 126 and 168
Change from baseline in hemoglobin levels as mean of visits between Day 126 and Day 168.
For this analysis, in order to factor out the effect of transfusions, if a patient had a transfusion during the randomized treatment period, then the hemoglobin values 30 days following the transfusion were excluded and hemoglobin data were imputed.
Measured: Baseline and mean of visits between Day 126 and 168
Change From Baseline in FACIT-Fatigue Questionnaire in the Randomized Treatment Period
The FACIT-Fatigue is a 13-item questionnaire with support for its validity and reliability in PNH that assesses patient self-reported fatigue and its impact on daily activities and function. All FACIT scales are scored so that a high score is better. As each of the 13 items of the FACIT-F Scale ranges from 0-4, the range of possible scores is 0-52, with 0 being the worst possible score and 52 the best.
Measured: Baseline, mean of visits between Day 126 and Day 168
Change From Baseline in Absolute Reticulocyte Count in the Randomized Treatment Period
Change from baseline in absolute reticulocyte count as mean of visits between Day 126 and Day 168
Measured: Baseline and mean of visits between Day 126 and 168
Ratio to Baseline in Log-transformed LDH in the Randomized Treatment Period
Average of the Lactate dehydrogenase (LDH) log transformed ratio to baseline in each treatment estimated between Day 126 and Day 168.The log transformation used refers to the natural log (base of e).
Measured: Baseline and mean of visits between Day 126 and 168
Adjusted Annualized Clinical BTH Rate in the Randomized Treatment Period
Adjusted annualized rate of clinical breakthrough hemolysis (BTH) events are from negative binomial model.
A patient with multiple occurrences of an event under one treatment is counted only once for that treatment.
The breakthrough is defined clinical if either there is a decrease in hemoglobin levels equal to or more than 2 g/dL (compared to the latest assessment, or within 15 days) or if patients present signs or symptoms of gross hemoglobinuria, painful crisis, dysphagia or any other significant clinical PNH-related signs \& symptoms, in presence of laboratory evidence of intravascular hemolysis.
Measured: Between Day 1 and Day 168
Adjusted Annualized Major Adverse Vascular Events Rate in the Randomized Treatment Period
Adjusted annualized Major Adverse Vascular Events (MAVEs incl. thrombosis) rate. A MAVE is defined as: acute peripheral vascular occlusion, amputation (non-traumatic; nondiabetic), cerebral arterial occlusion/cerebrovascular accident, cerebral venous occlusion, dermal thrombosis, gangrene (non-traumatic; nondiabetic), hepatic/portal vein thrombosis (Budd-Chiari syndrome), mesenteric/visceral arterial, thrombosis or infarction, mesenteric/visceral vein thrombosis or infarction, myocardial infarction, pulmonary embolus, renal arterial thrombosis, renal vein thrombosis, thrombophlebitis / deep vein thrombosis, transient ischemic attack, unstable angina or other.
A patient with multiple occurrences of an event under one treatment is counted only once for that treatment.
Measured: Between Day 1 and Day 168
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Sep 2020
- Study start25 Jan 2021
- Primary completion26 Sep 2022
- Study completion6 Mar 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Paroxysmal Nocturnal Hemoglobinuria (PNH)Studies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 97 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04558918
- Sponsor's protocol ID
- CLNP023C12302
- Other IDs
- 2019-004665-40, 2019
- Acronym
- APPLY-PNH
- Status last verified
- Oct 2024
- First submitted
- 27 Aug 2020
- Last updated
- 9 Oct 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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.
Publications
DeCastro C, Sheinberg P, Han B, Vallow S, Bermann G, Dhalke M, Kumar R, Dickie G, Galipeau N, Lamoureux R, Rupinski K, Lowe C, Nieves A, de Fontbrune FS, de Latour RP. Patient-Reported Meaningful Change in Symptoms and Impacts of Paroxysmal Nocturnal Hemoglobinuria (PNH) in Three Phase III Clinical Trials of Iptacopan. Patient. 2025 Nov;18(6):699-712. doi: 10.1007/s40271-025-00755-5. Epub 2025 Jul 22.
PubMed 40694294Risitano AM, Kulasekararaj AG, Scheinberg P, Roth A, Han B, Maciejewski JP, Ueda Y, de Castro CM, Di Bona E, Fu R, Zhang L, Griffin M, Langemeijer SMC, Panse J, Schrezenmeier H, Barcellini W, Mauad VAQ, Schafhausen P, Tavitian S, Beggiato E, Chew LP, Gaya A, Huang WH, Jang JH, Kitawaki T, Kutlar A, Notaro R, Pullarkat V, Schubert J, Terriou L, Uchiyama M, Lee LWL, Yap ES, Frieri C, Marano L, de Fontbrune FS, Gandhi S, Trikha R, Alashkar F, Yang C, Liu H, Kelly RJ, Hochsmann B, Lawniczek T, Mahajan N, Solar-Yohay S, Kerloeguen C, Ferber P, Kumar R, Wang Z, Thorburn C, Maitra S, Li S, Verles A, Dahlke M, de Latour RP. Oral iptacopan monotherapy in paroxysmal nocturnal haemoglobinuria: final 48-week results from the open-label, randomised, phase 3 APPLY-PNH trial in anti-C5-treated patients and the open-label, single-arm, phase 3 APPOINT-PNH trial in patients previously untreated with complement inhibitors. Lancet Haematol. 2025 Jun;12(6):e414-e430. doi: 10.1016/S2352-3026(25)00081-X.
PubMed 40447351Peffault de Latour R, Roth A, Kulasekararaj AG, Han B, Scheinberg P, Maciejewski JP, Ueda Y, de Castro CM, Di Bona E, Fu R, Zhang L, Griffin M, Langemeijer SMC, Panse J, Schrezenmeier H, Barcellini W, Mauad VAQ, Schafhausen P, Tavitian S, Beggiato E, Chew LP, Gaya A, Huang WH, Jang JH, Kitawaki T, Kutlar A, Notaro R, Pullarkat V, Schubert J, Terriou L, Uchiyama M, Wong Lee Lee L, Yap ES, Sicre de Fontbrune F, Marano L, Alashkar F, Gandhi S, Trikha R, Yang C, Liu H, Kelly RJ, Hochsmann B, Kerloeguen C, Banerjee P, Levitch R, Kumar R, Wang Z, Thorburn C, Maitra S, Li S, Verles A, Dahlke M, Risitano AM. Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med. 2024 Mar 14;390(11):994-1008. doi: 10.1056/NEJMoa2308695.
PubMed 38477987
Study at a glance
From the registry record, last updated by the sponsor on 9 Oct 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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.
- ClinicalTrials.gov ID
- NCT04558918
- Acronym / sponsor ID
- APPLY-PNH / CLNP023C12302
- Keywords
- Paroxysmal nocturnal hemoglobinuria, Hemoglobin, Anemia, LNP023, eculizumab, ravulizumab
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 97 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- 25 Jan 2021 (actual)
- Primary completion
- 26 Sep 2022 (actual)
- Study completion
- 6 Mar 2023 (actual)
- First posted
- 22 Sep 2020 (actual)
- Results
- Posted 28 Nov 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| LNP023 200mg b.i.d. | Experimental | Drug: LNP023Iptacopan 200mg b.i.d. hard gelatin capsule. After 24 weeks of LNP023 200mg b.i.d. treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive an additional 24 weeks of LNP023 200mg b.i.d. |
| Anti-C5 antibody | Active comparator | Drug: Eculizumab, Drug: RavulizumabIn the Randomized Treatment Period patients randomized to receive Anti-C5 antibody continued with the same stable regimen of Anti-C5 antibody therapy as they had received prior to randomization. For eculizumab (administered as intravenous infusion every 2 weeks), the maintenance dose was a fixed dose, whereas for ravulizumab (administered as intravenous infusion every 8 weeks), the maintenance dose was based on body weight. After 24 weeks of Anti-C5 antibody treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive 24 weeks of LNP023 200mg b.i.d. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (7 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LNP023Also: iptacopanTaken Orally b.i.d. Dosage Supplied: 200 mg Dosage form: Hard gelatin capsule Route of Administration: Oral | Drug | LNP023 200mg b.i.d. |
| EculizumabAdministered as intravenous infusion every 2 weeks as per the stable regimen, the maintenance dose is a fixed dose. Dosage Supplied: 300 mg/30mL Dosage form: Concentrate solution for infusion | Drug | Anti-C5 antibody |
| RavulizumabAdministered as intravenous infusion every 8 weeks, the maintenance dose is based on body weight. Dosage Supplied: 300 mg/30mL Dosage form: Concentrate solution for infusion | Drug | Anti-C5 antibody |
Primary outcome
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
Time frame: Baseline, hemoglobin between Day 126 and Day 168 and absence of transfusions between Day 14 and Day 168
Sustained increase in hemoglobin levels (responder) is defined as an increase from baseline in hemoglobin levels ≥ 2 g/dL on three out of four measurements taken at the visits occurring in last six weeks (between Day 126 and 168) of the randomized treatment period, without requiring red blood cell (RBC) transfusions between Day 14 and Day 168. Requiring RBC transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level ≤ 9 g/dL with signs /and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤ 7 g/dL, regardless of presence of clinical signs and/or symptoms). The term 'marginal proportion' can be interpreted as the population average probability of being a responder for each treatment group. These values include adjustment for baseline covariates and missing data has also been taken into account.
Marginal Proportion (Expressed as Percentages) of Participants With Sustained Hemoglobin Levels of ≥ 12 g/dL in the Absence of Red Blood Cell Transfusions
Time frame: Hemoglobin between Day 126 and Day 168 and absence of transfusions between Day 14 and Day 168
Sustained hemoglobin levels (responder) is defined as hemoglobin levels ≥ 12 g/dL on three out of four measurements taken at the visits occurring in last six weeks (between Day 126 and 168) of the randomized treatment period, without requiring red blood cell (RBC) transfusions between Day 14 and Day 168. Requiring RBC transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level ≤ 9 g/dL with signs /and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤ 7 g/dL, regardless of presence of clinical signs and/or symptoms). The term 'marginal proportion' can be interpreted as the population average probability of being a responder for each treatment group. These values include adjustment for baseline covariates and missing data has also been taken into account.
Percentage of Patients Meeting Hematological Response Criterion After the Start of LNP023 Treatment
Time frame: Up to 48 weeks
Patients with hematological response are those with ≥ 2g/dL increase in hemoglobin from baseline regardless of transfusions and patients with Hb ≥ 12g/dL regardless of transfusions. Patients in the LNP023-LNP023 group received iptacopan from Day 1 to Day 336 (48 weeks) while patients in the anti-C5 antibody-LNP023 group received iptacopan from Day 169 to Day 336 (treatment extension period - 24 weeks).
Number of Patients Not Requiring RBC Transfusions After the Start of LNP023 Treatment
Time frame: Up to 48 weeks
Requiring RBC transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level ≤ 9 g/dL with signs /and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤ 7 g/dL, regardless of presence of clinical signs and/or symptoms). Patients randomized to anti-C5 treatment switched to LNP023 (iptacopan) on Day 169 and were treated until Day 336 (treatment extension period).
Change From Baseline in Hemoglobin at Visit Day 336
Time frame: Baseline, Day 336
Patients randomized to anti-C5 treatment switched to LNP023 (iptacopan) on Day 169 and were treated until Day 336 (treatment extension period).
Change From Baseline in FACIT-Fatigue Questionnaire at Day 336
Time frame: Baseline, Day 336
The FACIT-Fatigue is a 13-item questionnaire with support for its validity and reliability in PNH that assesses patient self-reported fatigue and its impact on daily activities and function. All FACIT scales are scored so that a high score is better. As each of the 13 items of the FACIT-F Scale ranges from 0-4, the range of possible scores is 0-52, with 0 being the worst possible score and 52 the best. Patients randomized to anti-C5 treatment switched to LNP023 (iptacopan) on Day 169 and were treated until Day 336 (treatment extension period).
Adjusted Annualized Clinical BTH Rate After the Start of LNP023 Treatment
Time frame: Up to 336 Days
This endpoint is considering clinical BTH events after the start of LNP023 treatment. Therefore, results are presented in a single arm on LNP023 since it includes all patients in the Combined Full analysis set. Adjusted annualized rate of clinical breakthrough hemolysis (BTH) events are from negative binomial model. A patient with multiple occurrences of an event under one treatment is counted only once for that treatment.The breakthrough is defined clinical if either there is a decrease in hemoglobin levels equal to or more than 2 g/dL (compared to the latest assessment, or within 15 days) or if patients present signs or symptoms of gross hemoglobinuria, painful crisis, dysphagia or any other significant clinical PNH-related signs \& symptoms, in presence of laboratory evidence of intravascular hemolysis.
Adjusted Annualized Major Adverse Vascular Events Rate After the Start of LNP023 Treatment
Time frame: Up to 336 Days
This endpoint is considering clinical BTH events after the start of LNP023 treatment. Therefore, results are presented in a single arm on LNP023 since it includes all patients in the Combined Full analysis set. Adjusted annualized Major Adverse Vascular Events (MAVEs incl. thrombosis) rate. A MAVE is defined as: acute peripheral vascular occlusion, amputation (non-traumatic; nondiabetic), cerebral arterial occlusion/cerebrovascular accident, cerebral venous occlusion, dermal thrombosis, gangrene (non-traumatic; nondiabetic), hepatic/portal vein thrombosis (Budd-Chiari syndrome), mesenteric/visceral arterial, thrombosis or infarction, mesenteric/visceral vein thrombosis or infarction, myocardial infarction, pulmonary embolus, renal arterial thrombosis, renal vein thrombosis, thrombophlebitis / deep vein thrombosis, transient ischemic attack, unstable angina or other. A patient with multiple occurrences of an event under one treatment is counted only once for that treatment.
7 secondary outcomes
Marginal Proportion (Expressed as Percentages) of Participants Who Remain Free From Transfusions
Time frame: Between Day 14 and Day 168
Change From Baseline in Hemoglobin Between Day 126 and 168
Time frame: Baseline and mean of visits between Day 126 and 168
Change From Baseline in FACIT-Fatigue Questionnaire in the Randomized Treatment Period
Time frame: Baseline, mean of visits between Day 126 and Day 168
Change From Baseline in Absolute Reticulocyte Count in the Randomized Treatment Period
Time frame: Baseline and mean of visits between Day 126 and 168
Ratio to Baseline in Log-transformed LDH in the Randomized Treatment Period
Time frame: Baseline and mean of visits between Day 126 and 168
Adjusted Annualized Clinical BTH Rate in the Randomized Treatment Period
Time frame: Between Day 1 and Day 168
Adjusted Annualized Major Adverse Vascular Events Rate in the Randomized Treatment Period
Time frame: Between Day 1 and Day 168
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Oct 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 40694294DeCastro C, Sheinberg P, Han B, Vallow S, Bermann G, Dhalke M, Kumar R, Dickie G, Galipeau N, Lamoureux R, Rupinski K, Lowe C, Nieves A, de Fontbrune FS, de Latour RP. Patient-Reported Meaningful Change in Symptoms and Impacts of Paroxysmal Nocturnal Hemoglobinuria (PNH) in Three Phase III Clinical Trials of Iptacopan. Patient. 2025 Nov;18(6):699-712. doi: 10.1007/s40271-025-00755-5. Epub 2025 Jul 22.
- Derived from this study: PubMed 40447351Risitano AM, Kulasekararaj AG, Scheinberg P, Roth A, Han B, Maciejewski JP, Ueda Y, de Castro CM, Di Bona E, Fu R, Zhang L, Griffin M, Langemeijer SMC, Panse J, Schrezenmeier H, Barcellini W, Mauad VAQ, Schafhausen P, Tavitian S, Beggiato E, Chew LP, Gaya A, Huang WH, Jang JH, Kitawaki T, Kutlar A, Notaro R, Pullarkat V, Schubert J, Terriou L, Uchiyama M, Lee LWL, Yap ES, Frieri C, Marano L, de Fontbrune FS, Gandhi S, Trikha R, Alashkar F, Yang C, Liu H, Kelly RJ, Hochsmann B, Lawniczek T, Mahajan N, Solar-Yohay S, Kerloeguen C, Ferber P, Kumar R, Wang Z, Thorburn C, Maitra S, Li S, Verles A, Dahlke M, de Latour RP. Oral iptacopan monotherapy in paroxysmal nocturnal haemoglobinuria: final 48-week results from the open-label, randomised, phase 3 APPLY-PNH trial in anti-C5-treated patients and the open-label, single-arm, phase 3 APPOINT-PNH trial in patients previously untreated with complement inhibitors. Lancet Haematol. 2025 Jun;12(6):e414-e430. doi: 10.1016/S2352-3026(25)00081-X.
- Derived from this study: PubMed 38477987Peffault de Latour R, Roth A, Kulasekararaj AG, Han B, Scheinberg P, Maciejewski JP, Ueda Y, de Castro CM, Di Bona E, Fu R, Zhang L, Griffin M, Langemeijer SMC, Panse J, Schrezenmeier H, Barcellini W, Mauad VAQ, Schafhausen P, Tavitian S, Beggiato E, Chew LP, Gaya A, Huang WH, Jang JH, Kitawaki T, Kutlar A, Notaro R, Pullarkat V, Schubert J, Terriou L, Uchiyama M, Wong Lee Lee L, Yap ES, Sicre de Fontbrune F, Marano L, Alashkar F, Gandhi S, Trikha R, Yang C, Liu H, Kelly RJ, Hochsmann B, Kerloeguen C, Banerjee P, Levitch R, Kumar R, Wang Z, Thorburn C, Maitra S, Li S, Verles A, Dahlke M, Risitano AM. Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med. 2024 Mar 14;390(11):994-1008. doi: 10.1056/NEJMoa2308695.
- A Plain Language Trial Summary is available on novctrd.comLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
39 sites in 12 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing LNP023, Eculizumab and Ravulizumab in people with Paroxysmal Nocturnal Hemoglobinuria (PNH), run by Novartis Pharmaceuticals at 39 sites in 12 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 9 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 39 sites in Italy, Japan, United States, Germany, France and 7 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 28 Nov 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome 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 (time frame: Baseline, hemoglobin between Day 126 and Day 168 and absence of transfusions between Day 14 and Day 168). The study lists 8 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04558918, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Oct 2024.