Study of Efficacy and Safety of Twice Daily Oral LNP023 in Adult PNH Patients With Residual Anemia Despite Anti-C5 Antibody Treatment (APPLY-PNH)
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| ClinicalTrials.gov Identifier: NCT04558918 |
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Recruitment Status :
Completed
First Posted : September 22, 2020
Results First Posted : November 28, 2023
Last Update Posted : April 2, 2024
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Paroxysmal Nocturnal Hemoglobinuria (PNH) | Drug: LNP023 Drug: Eculizumab Drug: Ravulizumab | Phase 3 |
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 Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 97 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | 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. |
| Actual Study Start Date : | January 25, 2021 |
| Actual Primary Completion Date : | September 26, 2022 |
| Actual Study Completion Date : | March 6, 2023 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: LNP023 200mg b.i.d.
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.
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Drug: LNP023
Taken Orally b.i.d. Dosage Supplied: 200 mg Dosage form: Hard gelatin capsule Route of Administration: Oral
Other Name: iptacopan |
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Active Comparator: Anti-C5 antibody
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.
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Drug: Eculizumab
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 Drug: Ravulizumab 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 |
- 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.
- Marginal Proportion (Expressed as Percentages) of Participants Who Remain Free From Transfusions [ Time Frame: Between Day 14 and Day 168 ]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.
- 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 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.
- Change From Baseline in FACIT-Fatigue Questionnaire in the Randomized Treatment Period [ Time Frame: Baseline, mean of visits between Day 126 and Day 168 ]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.
- Change From Baseline in Absolute Reticulocyte Count in the Randomized Treatment Period [ Time Frame: Baseline and mean of visits between Day 126 and 168 ]Change from baseline in absolute reticulocyte count as mean of visits between Day 126 and Day 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 ]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).
- Adjusted Annualized Clinical BTH Rate in the Randomized Treatment Period [ Time Frame: Between Day 1 and Day 168 ]
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 in the Randomized Treatment Period [ Time Frame: Between Day 1 and Day 168 ]
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.
- Change From Baseline in Absolute Reticulocyte Count at Day 336 [ Time Frame: Baseline and Day 336 ]Change from baseline in absolute reticulocyte count at visit Day 336. Patients randomized to anti-C5 antibody were switched to LNP023 (iptacopan) on Day 169 and were treated until Day 336 (treatment extension period).
- Ratio to Baseline in Log-transformed LDH at Visit Day 336 [ Time Frame: Baseline and Day 336 ]
Average of the Lactate dehydrogenase (LDH) log transformed ratio to baseline at visit Day 336.The log transformation used refers to the natural log (base of e).
Patients randomized to anti-C5 treatment switched to LNP023 (iptacopan) on Day 169 and were treated until Day 336 (treatment extension period).
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04558918
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| Study Director: | Novartis Pharmaceuticals | Novartis Pharmaceuticals |
Documents provided by Novartis ( Novartis Pharmaceuticals ):
| Responsible Party: | Novartis Pharmaceuticals |
| ClinicalTrials.gov Identifier: | NCT04558918 |
| Other Study ID Numbers: |
CLNP023C12302 2019-004665-40 ( EudraCT Number ) |
| First Posted: | September 22, 2020 Key Record Dates |
| Results First Posted: | November 28, 2023 |
| Last Update Posted: | April 2, 2024 |
| Last Verified: | February 2024 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| 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. |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Paroxysmal nocturnal hemoglobinuria Hemoglobin Anemia |
LNP023 eculizumab ravulizumab |
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Hemoglobinuria Anemia Hemoglobinuria, Paroxysmal Hematologic Diseases Proteinuria Urination Disorders Urologic Diseases Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Urogenital Diseases Male Urogenital Diseases |
Urological Manifestations Anemia, Hemolytic Myelodysplastic Syndromes Bone Marrow Diseases Eculizumab Ravulizumab Complement Inactivating Agents Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs |