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Study of Safety, Efficacy, Tolerability, Pharmacokinetics and Pharmacodynamics of LNP023 in in Patients With Paroxysmal Nocturnal Hemoglobinuria (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: NCT03439839
Recruitment Status : Active, not recruiting
First Posted : February 20, 2018
Last Update Posted : May 19, 2020
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE February 14, 2018
First Posted Date  ICMJE February 20, 2018
Last Update Posted Date May 19, 2020
Actual Study Start Date  ICMJE April 9, 2018
Actual Primary Completion Date April 22, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 14, 2018)
Reduction of chronic hemolysis [ Time Frame: 13 weeks ]
Reduction of chronic hemolysis based on LDH level
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 27, 2019)
  • 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
  • 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)
  • 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
  • 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)
  • 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
  • Incidence of blood transfusion [ Time Frame: anytime during the study (day -70 to day 1261) ]
    Incidence of blood transfusion
Original Secondary Outcome Measures  ICMJE
 (submitted: February 14, 2018)
  • C3 deposition [ Time Frame: Baseline; day 1, 8, 22, 29,57,92 ]
    Level of C3 deposition on red blood cells
  • Profile of Pharmacokinetics: Maximum plasma concentration (Cmax) [ Time Frame: day 1,2, 8,15,29,57,92 ]
    Profile of Pharmacokinetics: Maximum plasma concentration (Cmax)
  • Measurement of total and free hemoglobin [ Time Frame: Screening, Baseline; day 1, 2, 8, 15 22, 29, 36,43, 57,71, 85, 92, 106 ]
    total and free hemoglobin in blood
  • Profile of Pharmacokinetics (PK): Area Under the Curve (AUC) [ Time Frame: day 1,2, 8,15,29,57,92 ]
    Profile of Pharmacokinetics (PK): Area Under the Curve (AUC)
  • Measurement of bilirubin [ Time Frame: Screening, Baseline; day 1, 2, 8, 15 22, 29, 36,43, 57,71, 85, 92, 106 ]
    Blood bilirubin
  • Incidence of blood transfusion [ Time Frame: anytime during the study (day -28 to day 106) ]
    Incidence of blood transfusion
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Safety, Efficacy, Tolerability, Pharmacokinetics and Pharmacodynamics of LNP023 in in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)
Official Title  ICMJE 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
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).
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).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE 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
Condition  ICMJE Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)
Intervention  ICMJE Drug: LNP023
LNP023 bid
Study Arms  ICMJE
  • Experimental: Arm 1
    10 patients receiving LNP023 high dose daily over up to approximately 3 years
    Intervention: Drug: LNP023
  • Experimental: Arm 2
    5 patients receiving LNP023 low dose daily over up to approximately 3 years
    Intervention: Drug: LNP023
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: February 11, 2020)
16
Original Estimated Enrollment  ICMJE
 (submitted: February 14, 2018)
10
Estimated Study Completion Date  ICMJE June 7, 2023
Actual Primary Completion Date April 22, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France,   Germany,   Italy
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03439839
Other Study ID Numbers  ICMJE CLNP023X2201
2017-000888-33 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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

Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Novartis
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP