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 :
Recruiting
First Posted : September 22, 2020
Last Update Posted : December 15, 2021
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Paroxysmal Nocturnal Hemoglobinuria (PNH) | Drug: LNP023 Drug: Eculizumab Drug: Ravulizumab | Phase 3 |
The purpose of this Phase 3 randomized, multicenter, active-comparator controlled, open-label trial is to determine whether LNP023 is efficacious and safe for the treatment in PNH through demonstration of superiority of LNP023 compared to anti-C5 antibody treatment in adult PNH patients presenting with residual anemia despite treatment with anti-C5 therapy.
The study is planned to randomize approx. 91 patients in various countries.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 91 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 |
| Estimated Primary Completion Date : | July 26, 2022 |
| Estimated Study Completion Date : | January 31, 2023 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: LNP023 monotherapy
Participants will be randomized to one of the two treatment arms in a 8:5 ratio to either LNP023 monotherapy at a dose of 200 mg orally b.i.d. (approximately 56 participants), or i.v. anti-C5 antibody treatment (approximately 35 participants continuing with the same regimen during the randomized treatment period as they were on prior to randomization), respectively.
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Drug: LNP023
Taken Orally b.i.d. Dosage Supplied: 200 mg Dosage form: Hard gelatin capsule Route of Administration: Oral |
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Active Comparator: anti-C5 antibody treatment
Participants will be randomized to one of the two treatment arms in a 8:5 ratio to either LNP023 monotherapy at a dose of 200 mg orally b.i.d. (approximately 56 participants), or i.v. anti-C5 antibody treatment (approximately 35 participants continuing with the same regimen during the randomized treatment period as they were on prior to randomization), respectively.
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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 |
- Percentage of participants achieving a sustained increase in hemoglobin levels of ≥ 2 g/dL in the absence of red blood cell transfusions [ Time Frame: Day 168 ]Percentage of participants achieving a sustained increase in hemoglobin levels from baseline of ≥ 2 g/dL in the absence of red blood cell transfusions.
- Percentage of participants achieving sustained hemoglobin levels ≥ 12 g/dL in the absence of red blood cell transfusions [ Time Frame: Day 168 ]Percentage of participants achieving sustained hemoglobin levels ≥ 12 g/dL in the absence of red blood cell transfusions
- Percentage of participants who remain free from transfusions [ Time Frame: Day 14 and Day 168 ]Percentage of participants who remain free from transfusions
- Average change in hemoglobin [ Time Frame: Baseline and as mean of visit Day 126, 140, 154 and 168 ]Change from baseline in hemoglobin (g/dL) as mean of visits between Day 126 and Day 168
- Change in fatigue score, using the FACIT-Fatigue questionnaire [ Time Frame: Baseline and as mean of visits Day 126, 140, 154 and Day 168 ]Change from baseline in FACIT-Fatigue scores as mean of visits between Day 126 and Day 168
- Average change in reticulocyte counts [ Time Frame: Baseline and as mean of visit Day 126, 140, 154 and 168 ]Change from baseline in reticulocyte count as mean of visits between Day 126 and Day 168
- Average percent change in LDH [ Time Frame: Baseline and as mean of visit Day 126, 140, 154 and 168 ]Percent change from baseline in LDH levels (U/L) as mean of visits between Day 126 and Day 168
- Rate of breakthrough hemolysis (BTH) [ Time Frame: Day 1 and Day 168 ]Rate of breakthrough hemolysis (BTH)
- Rates of Major Adverse Vascular Events (MAVEs incl. thrombosis) [ Time Frame: Day 1 and Day 168 ]Rates of Major Adverse Vascular Events (MAVEs incl. thrombosis)
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| 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
- 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 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., 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.
Other protocol-defined inclusion/exclusion criteria may apply
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
| Contact: Novartis Pharmaceuticals | 1-888-669-6682 | novartis.email@novartis.com | |
| Contact: Novartis Pharmaceuticals | +41613241111 |
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| Study Director: | Novartis Pharmaceuticals | 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 |
| Last Update Posted: | December 15, 2021 |
| Last Verified: | December 2021 |
| 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 Urological Manifestations Anemia, Hemolytic |
Myelodysplastic Syndromes Bone Marrow Diseases Eculizumab Ravulizumab Complement Inactivating Agents Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs |