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Study of Safety, Efficacy, Tolerability, Pharmacokinetics and Pharmacodynamics of LNP023 in in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)

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ClinicalTrials.gov Identifier: NCT03439839
Recruitment Status : Recruiting
First Posted : February 20, 2018
Last Update Posted : March 1, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
The main purpose of this study is to evaluate the efficacy of LNP023 in patients with PNH, showing signs of active hemolysis despite treatment with SoC (defined as an antibody with anti C5 activity).

Condition or disease Intervention/treatment Phase
Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) Drug: LNP023 Phase 2

Detailed Description:

LNP023 is a novel oral small molecular weight compound, that inhibits alternative complement pathway (AP). Blockade of the AP with oral LNP023 has the potential to prevent both intra - and extravascular hemolysis.

This study includes a screening period of up to 68 days, a baseline visit, up to approximately 3 years of treatment with LNP023 administered in addition to SoC, and an End of Study (EoS) visit 2 weeks after last LNP023 administration.

The main purpose of this study is to evaluate the efficacy of LNP023 in patients with PNH, showing signs of active hemolysis despite treatment with SoC (defined as an antibody with anti C5 activity).


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Open label, non-randomized study
Masking: None (Open Label)
Masking Description: No masking used in the study
Primary Purpose: Treatment
Official Title: An Open Label, Single Arm, Multiple Dose Study to Assess Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of LNP023 When Administered in Addition to Standard of Care (SoC) in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) With Signs of Active Hemolysis
Actual Study Start Date : April 9, 2018
Estimated Primary Completion Date : July 11, 2019
Estimated Study Completion Date : April 13, 2023


Arm Intervention/treatment
Experimental: Arm 1
10 patients receiving LNP023 high dose daily over up to approximately 3 years
Drug: LNP023
LNP023 bid

Experimental: Arm 2
5 patients receiving LNP023 low dose daily over up to approximately 3 years
Drug: LNP023
LNP023 bid




Primary Outcome Measures :
  1. Reduction of chronic hemolysis [ Time Frame: 13 weeks ]
    Reduction of chronic hemolysis based on LDH level


Secondary Outcome Measures :
  1. C3 deposition [ Time Frame: Baseline; day 1, 8, 22, 29, 57, 92, 106, 113, 141, 169, 253, 337, 505, 673, 785, 953, 1121, 1233, 1240, 1247, 1261 ]
    Level of C3 deposition on red blood cells

  2. Profile of Pharmacokinetics: Maximum plasma concentration (Cmax) [ Time Frame: day 1,2, 8,15,29,57,92, 169, 337, 505, 673, 785, 953, 1121, 1233, 1240, 1247, 1261 ]
    Profile of Pharmacokinetics: Maximum plasma concentration (Cmax)

  3. Measurement of total and free hemoglobin [ Time Frame: Screening, Baseline; day 1, 2, 8, 15 22, 29, 36,43, 57,71, 85, 92, 106, 113, 127, 141, 155, 169, 197, 225, 253, 281, 309, 337, 393, 449, 505, 561, 617, 673, 729, 785, 841, 897, 953, 1009, 1065, 1021, 1171, 1233, 1240, 1247, 1261 ]
    total and free hemoglobin in blood

  4. Profile of Pharmacokinetics (PK): Area Under the Curve (AUC) [ Time Frame: day 1,2, 8,15,29,57,92, 169, 337, 505, 673, 785, 953, 1121, 1233, 1240, 1247, 1261 ]
    Profile of Pharmacokinetics (PK): Area Under the Curve (AUC)

  5. Measurement of bilirubin [ Time Frame: Screening, Baseline; day 1, 2, 8, 15 22, 29, 36,43, 57,71, 85, 92, 106, 113, 127, 141, 155, 169, 197, 225, 253, 281, 309, 337, 393, 449, 505, 561, 617, 673, 729, 785, 841, 897, 953, 1009, 1065, 1021, 1171, 1233, 1240, 1247, 1261 ]
    Blood bilirubin

  6. Incidence of blood transfusion [ Time Frame: anytime during the study (day -70 to day 1261) ]
    Incidence of blood transfusion



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Written informed consent must be obtained before any assessment is performed.
  2. Male and female patients between the age of 18-80 (inclusive) at baseline with a diagnosis of PNH based on documented clone size of ≥10% by RBCs and/or granulocytes, measured by GPI-deficiency on flow cytometry (screening or medical history data acceptable).
  3. For Cohort 1 only: LDH values ≥1.5x upper limit of the normal range for at least 3 pre-SoC dosing measurements taken in relation to 3 different SoC dosing dates over a maximum of 10 weeks prior to Day 1 (screening, baseline or medical history data acceptable). All other screening pre-SoC LDH values have to be > 1x upper limit of normal range (for pre-SoC samples collected at the same day as SoC administration).
  4. For Cohort 2: LDH values ≥1.25x upper limit of the normal range for at least 3 pre-SoC dosing measurements taken in relation to 3 different SoC dosing dates over a maximum of 10 weeks prior to Day 1 (screening, baseline or medical history data acceptable). All other screening pre-SoC LDH values have to be > 1x upper limit of normal range (for pre-SoC samples collected at the same day as SoC administration).
  5. For Cohort 2 only: Hemoglobin level <10.5 g/dL at Baseline.
  6. PNH patients on stable regimen of standard of care complement blockade (monoclonal antibody with anti C5 activity) for at least 3 months prior to first treatment with LNP023.
  7. Previous vaccination against Neisseria meningitidis types A, C, Y and W-135 is required at least 4 weeks prior to first dosing with LNP023.Vaccination against N. meningitidis type B should be conducted if available and acceptable by local regulations, at least 4 weeks prior to first dosing with LNP023. If LNP023 treatment has to start earlier than 4 weeks post vaccination, prophylactic antibiotic treatment must be initiated.
  8. Previous vaccination for the prevention of S. pneumoniae and H. influenzae at least 4 weeks prior to first dosing with LNP023. If LNP023 treatment has to start earlier than 4 weeks post vaccination, prophylactic antibiotic treatment must be initiated.
  9. Able to communicate well with the investigator, to understand and comply with the requirements of the study.
  10. For Part 2 of the study patients who as per judgment of Investigator benefit from LNP023 treatment based on reduced hemolytic parameters as compared to Screening and Baseline. -

Exclusion Criteria:

  1. Participation in any other investigational drug trial or use of other investigational drugs at the time of enrollment, or within 5 elimination half-lives of enrollment, or within 30 days, whichever is longer; or longer if required by local regulations
  2. Known or suspected hereditary complement deficiency at screening
  3. History of hematopoietic stem cell transplantation as verified both at screening and at baseline (unless baseline was skipped)
  4. Patients with laboratory evidence of bone marrow failure (reticulocytes <60x109/l, or platelets <30x109/l, or neutrophils <1x109/l) as verified both at screening and at baseline (unless baseline was skipped)
  5. A positive HIV, Hepatitis B (HBV) or Hepatitis C (HCV) test result at screening
  6. Presence or suspicion (based on judgment of the investigator) of active infection within 2 weeks prior to first dose of LNP023, or history of severe recurrent bacterial infections
  7. History of recurrent meningitis, history of meningococcal infections despite vaccination as verified both at screening and at baseline (unless baseline was skipped)
  8. Patients on the immunosuppressive agents such as but not limited to cyclosporine, MMF, tacrolimus, cyclophosphamide, methotrexate less than 8 weeks prior to first treatment with LNP023 unless on a stable regimen for at least 3 months prior to first LNP023 dose.
  9. Systemic corticosteroids administered at the dose of ≥ 10 mg per day prednisone equivalent within less than 4 weeks prior to first treatment with LNP023
  10. Severe concurrent co-morbidities, e.g. patients with severe kidney disease (dialysis), advanced cardiac disease (NYHA class IV), severe pulmonary arterial hypertension (WHO class IV), unstable thrombotic event not amenable to active treatment as judged by the investigator both at screening and at baseline (unless baseline was skipped)
  11. Any medical condition deemed likely to interfere with the patient's participation in the study, or likely to cause serious adverse events during the study
  12. Female patients who are pregnant or breastfeeding, or intending to conceive during the course of the study
  13. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception from first dosing with LNP023 until EOS.

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): NCT03439839


Contacts
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Contact: Novartis Pharmaceuticals +41613241111 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals

Locations
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France
Novartis Investigative Site Recruiting
Paris, France, 75010
Germany
Novartis Investigative Site Recruiting
Essen, Germany, 45147
Italy
Novartis Investigative Site Recruiting
Napoli, Italy, 80131
Sponsors and Collaborators
Novartis Pharmaceuticals

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03439839     History of Changes
Other Study ID Numbers: CLNP023X2201
2017-000888-33 ( EudraCT Number )
First Posted: February 20, 2018    Key Record Dates
Last Update Posted: March 1, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
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: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Complement, alternative pathway, paroxysmal nocturnal hemoglobinuria,
hemolysis

Additional relevant MeSH terms:
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Hemoglobinuria
Hemoglobinuria, Paroxysmal
Proteinuria
Urination Disorders
Urologic Diseases
Urological Manifestations
Signs and Symptoms
Anemia, Hemolytic
Anemia
Hematologic Diseases
Myelodysplastic Syndromes
Bone Marrow Diseases