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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)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04558918
Recruitment Status : Active, not recruiting
First Posted : September 22, 2020
Last Update Posted : September 30, 2022
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)
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
Estimated Study Completion Date : March 9, 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)



Information from the National Library of Medicine

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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


Locations
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United States, California
Novartis Investigative Site
Duarte, California, United States, 91010
Novartis Investigative Site
Orange, California, United States, 92868
United States, Georgia
Novartis Investigative Site
Augusta, Georgia, United States, 30912
United States, North Carolina
Novartis Investigative Site
Charlotte, North Carolina, United States, 28204
United States, Ohio
Novartis Investigative Site
Cleveland, Ohio, United States, 44195
Brazil
Novartis Investigative Site
Santo Andre, SP, Brazil, 09090-790
Novartis Investigative Site
Sao Paulo, SP, Brazil, 01323-900
Czechia
Novartis Investigative Site
Ostrava, Poruba, Czechia, 708 52
France
Novartis Investigative Site
Lille, France, 59037
Novartis Investigative Site
Paris Cedex 10, France, 75475
Novartis Investigative Site
Toulouse, France, 31059
Germany
Novartis Investigative Site
Aachen, Germany, 52074
Novartis Investigative Site
Essen, Germany, 45147
Novartis Investigative Site
Hamburg, Germany, 20246
Novartis Investigative Site
Riesa, Germany, 01589
Novartis Investigative Site
Ulm, Germany, 89081
Italy
Novartis Investigative Site
Ascoli Piceno, AP, Italy, 63100
Novartis Investigative Site
Avellino, AV, Italy, 83100
Novartis Investigative Site
Firenze, FI, Italy, 50139
Novartis Investigative Site
Milano, MI, Italy, 20122
Novartis Investigative Site
Roma, RM, Italy, 00161
Novartis Investigative Site
Torino, TO, Italy, 10126
Novartis Investigative Site
Bassano Del Grappa, VI, Italy, 36061
Japan
Novartis Investigative Site
Nagoya, Aichi, Japan, 453-8511
Novartis Investigative Site
Fukushima city, Fukushima, Japan, 960 1295
Novartis Investigative Site
Kanazawa-city, Ishikawa, Japan, 920-8641
Novartis Investigative Site
Suwa, Nagano, Japan, 392-8510
Novartis Investigative Site
Osaka Sayama, Osaka, Japan, 589 8511
Novartis Investigative Site
Suita city, Osaka, Japan, 565 0871
Novartis Investigative Site
Shinjuku-ku, Tokyo, Japan, 160-0023
Novartis Investigative Site
Kyoto, Japan, 606 8507
Korea, Republic of
Novartis Investigative Site
Seoul, Korea, Republic of, 06351
Netherlands
Novartis Investigative Site
Nijmegen, Netherlands, 6500 MB
Spain
Novartis Investigative Site
Barcelona, Catalunya, Spain, 08036
Novartis Investigative Site
Santiago de Compostela, Galicia, Spain, 15706
Novartis Investigative Site
San Sebastian, Pais Vasco, Spain, 20080
Taiwan
Novartis Investigative Site
Hualien, Taiwan, 970
Novartis Investigative Site
Taipei, Taiwan, 10002
United Kingdom
Novartis Investigative Site
Leeds, United Kingdom, LS9 7TF
Novartis Investigative Site
London, United Kingdom, SE5 9RS
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: September 30, 2022
Last Verified: September 2022
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
Eculizumab
Ravulizumab
Complement Inactivating Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs