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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
Recruitment Status : Recruiting
First Posted : September 22, 2020
Last Update Posted : May 10, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
The purpose of this Phase 3 study 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

Condition or disease Intervention/treatment Phase
Paroxysmal Nocturnal Hemoglobinuria (PNH) Drug: LNP023 Drug: Eculizumab Drug: Ravulizumab Phase 3

Detailed Description:

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.

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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
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.
Drug: LNP023
Taken Orally b.i.d. Dosage Supplied: 200 mg Dosage form: Hard gelatin capsule Route of Administration: Oral

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.
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





Primary Outcome Measures :
  1. 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.

  2. 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


Secondary Outcome Measures :
  1. Percentage of participants who remain free from transfusions [ Time Frame: Day 14 and Day 168 ]
    Percentage of participants who remain free from transfusions

  2. 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

  3. 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

  4. 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

  5. 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

  6. Rate of breakthrough hemolysis (BTH) [ Time Frame: Day 1 and Day 168 ]
    Rate of breakthrough hemolysis (BTH)

  7. 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
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
  • 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


Information from the National Library of Medicine

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


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Locations
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France
Novartis Investigative Site Recruiting
Lille, France, 59037
Novartis Investigative Site Recruiting
Paris Cedex 10, France, 75475
Novartis Investigative Site Recruiting
Pierre Benite Cedex, France, 69495
Novartis Investigative Site Recruiting
Toulouse, France, 31059
Novartis Investigative Site Recruiting
Vandoeuvre les Nancy, France, 54511
Germany
Novartis Investigative Site Recruiting
Aachen, Germany, 52074
Novartis Investigative Site Recruiting
Essen, Germany, 45147
Novartis Investigative Site Recruiting
Ulm, Germany, 89081
Hungary
Novartis Investigative Site Recruiting
Budapest, Hungary, 1085
Italy
Novartis Investigative Site Recruiting
Avellino, AV, Italy, 83100
Novartis Investigative Site Recruiting
Milano, MI, Italy, 20122
Japan
Novartis Investigative Site Recruiting
Nagoya, Aichi, Japan, 453-8511
Novartis Investigative Site Recruiting
Kanazawa-city, Ishikawa, Japan, 920-8641
Novartis Investigative Site Recruiting
Isehara, Kanagawa, Japan, 259-1193
Novartis Investigative Site Recruiting
Suwa, Nagano, Japan, 392-8510
Novartis Investigative Site Recruiting
Osaka Sayama, Osaka, Japan, 589 8511
Novartis Investigative Site Recruiting
Suita city, Osaka, Japan, 565 0871
Novartis Investigative Site Recruiting
Shinagawa ku, Tokyo, Japan, 141 8625
Novartis Investigative Site Recruiting
Shinjuku-ku, Tokyo, Japan, 160-0023
Korea, Republic of
Novartis Investigative Site Recruiting
Seoul, Korea, Republic of, 03080
Novartis Investigative Site Recruiting
Seoul, Korea, Republic of, 06351
Netherlands
Novartis Investigative Site Recruiting
Nijmegen, Netherlands, 6500 MB
Spain
Novartis Investigative Site Recruiting
Sevilla, Andalucia, Spain, 41013
Novartis Investigative Site Recruiting
Barcelona, Catalunya, Spain, 08036
Novartis Investigative Site Recruiting
San Sebastian, Pais Vasco, Spain, 20080
Novartis Investigative Site Recruiting
Madrid, Spain, 28040
Taiwan
Novartis Investigative Site Recruiting
Hualien, Taiwan, 970
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
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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: May 10, 2021
Last Verified: May 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.


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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Paroxysmal nocturnal hemoglobinuria
Hemoglobin
Anemia
LNP023
eculizumab
ravulizumab
Additional relevant MeSH terms:
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Hemoglobinuria
Anemia
Hemoglobinuria, Paroxysmal
Hematologic Diseases
Proteinuria
Urination Disorders
Urologic Diseases
Urological Manifestations
Anemia, Hemolytic
Myelodysplastic Syndromes
Bone Marrow Diseases
Ravulizumab
Complement Inactivating Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs