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Efficacy, Safety, Pharmacokinetics and Pharmacodynamics Study, Assessing Multiple LNP023 Doses in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria

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ClinicalTrials.gov Identifier: NCT03896152
Recruitment Status : Recruiting
First Posted : March 29, 2019
Last Update Posted : October 30, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE March 28, 2019
First Posted Date  ICMJE March 29, 2019
Last Update Posted Date October 30, 2019
Actual Study Start Date  ICMJE April 5, 2019
Estimated Primary Completion Date February 20, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 28, 2019)
Percentage of patients with reduction of Paroxysmal nocturnal hemoglobinuria (PNH) associated hemolysis. [ Time Frame: 12 weeks ]
Percentage of patients with 60% reduction in lactate dehydrogenase (LDH) or LDH below upper limit of normal (ULN) at any time up to week 12
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03896152 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 28, 2019)
  • Change in total and free hemoglobin [ Time Frame: 12 weeks ]
    To assess the effect of LNP023 on markers of intravascular and extravascular hemolysis.
  • Profile of Pharmacokinetics (PK): Area Under the Curve (AUC) [ Time Frame: days: 2,15,16,22,29,36,43,57,71,85,88,92,99 ]
    Profile of Pharmacokinetics (PK): Area Under the Curve (AUC)
  • Prothrombin time (PT) [ Time Frame: 12 weeks ]
    Effect of LNP023 on markers associated with risk of thrombosis.
  • Change in total carboxyhemoglobin [ Time Frame: 12 weeks ]
    To assess the effect of LNP023 on markers of intravascular and extravascular hemolysis.
  • Change in reticulocytes [ Time Frame: 12 weeks ]
    To assess the effect of LNP023 on markers of intravascular and extravascular hemolysis.
  • Change in C3 fragment deposition [ Time Frame: 12 weeks ]
    To assess the effect of LNP023 on markers of intravascular and extravascular hemolysis.
  • Change in haptoglobin [ Time Frame: 12 weeks ]
    To assess the effect of LNP023 on markers of intravascular and extravascular hemolysis.
  • Change in bilirubin [ Time Frame: 12 weeks ]
    To assess the effect of LNP023 on markers of intravascular and extravascular hemolysis.
  • Change in red blood cell count [ Time Frame: 12 weeks ]
    To assess the effect of LNP023 on markers of intravascular and extravascular hemolysis.
  • Change in platelet counts [ Time Frame: 12 weeks ]
    To assess the effect of LNP023 on markers of intravascular and extravascular hemolysis.
  • Change in ferritin [ Time Frame: 12 weeks ]
    To assess the effect of LNP023 on markers of intravascular and extravascular hemolysis.
  • Change in PNH cells [ Time Frame: 12 weeks ]
    To assess the effect of LNP023 on markers of intravascular and extravascular hemolysis.
  • Profile of Pharmacokinetics: Maximum plasma concentration (Cmax) [ Time Frame: days: 2,15,16,22,29,36,43,57,71,85,88,92,99 ]
    Profile of Pharmacokinetics: Maximum plasma concentration (Cmax)
  • Activated partial thromboplastin time (aPTT) [ Time Frame: 12 weeks ]
    Effect of LNP023 on markers associated with risk of thrombosis.
  • D-dimer [ Time Frame: 12 weeks ]
    Effect of LNP023 on markers associated with risk of thrombosis.
  • fibrinogen [ Time Frame: 12 weeks ]
    Effect of LNP023 on markers associated with risk of thrombosis.
  • thrombin clotting time [ Time Frame: 12 weeks ]
    Effect of LNP023 on markers associated with risk of thrombosis.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy, Safety, Pharmacokinetics and Pharmacodynamics Study, Assessing Multiple LNP023 Doses in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria
Official Title  ICMJE A Multi-center, Randomized, Open-label, Efficacy, Safety, Pharmacokinetics and Pharmacodynamics Study, Assessing Multiple LNP023 Doses in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria and 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
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 three-period study includes: a screening phase of up to 8 weeks, a baseline visit, Day 1 (first day that the investigational drug is given), a 4-week treatment period of LNP023 at the first dose in the assigned sequence (Period 1), an 8-week treatment period at the second dose in the assigned sequence (Period 2), an approximately 2 year extension Period 3, followed by a taper down period of 2 weeks and end of study visit and a safety follow up call performed 30 days post end of treatment.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Randomized, open label study
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Paroxysmal Nocturnal Hemoglobinuria
Intervention  ICMJE Drug: LNP023
approximately 2 year of Treatment with LNP023
Study Arms  ICMJE
  • Experimental: Arm 1
    approximately 2 year Treatment with low LNP023 dose
    Intervention: Drug: LNP023
  • Experimental: Arm 2
    approximately 2 year Treatment with higher LNP023 dose
    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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 28, 2019)
10
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 13, 2022
Estimated Primary Completion Date February 20, 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 at least 18 years old at baseline.
  3. Diagnosis of active 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).
  4. LDH values > 1.5 x upper limit of the normal range (ULN) for at least 3 measurements over a maximum of 8 weeks prior to Day 1 (Screening, baseline or medical history data acceptable).
  5. Hemoglobin level < 10.5 g/dL at Baseline.
  6. For Period 3 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.
  7. Vaccinations against N. meningitidis, S. pneumoniae and H. influenzae is required at least 4 weeks prior to first dosing with LNP023 (existing vaccinations should provide effective titers at time of LNP023 treatment start). If LNP023 treatment has to start earlier than 4 weeks post vaccination, prophylactic antibiotic treatment must be initiated.
  8. Able to communicate well with the investigator, to understand and comply with the requirements of the study. -

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. Patients treated with eculizumab or any other complement inhibitor less than 3 months prior to study Day 1
  3. Known or suspected hereditary or acquired complement deficiency.
  4. History of currently active primary or secondary immunodeficiency.
  5. History of splenectomy.
  6. History of bone marrow/ hematopoietic stem cell or solid organ transplants (e.g. heart, lung, kidney, liver).
  7. Evidence of malignant disease, or malignancies diagnosed within the previous 5 years.
  8. Patients with laboratory evidence of bone marrow failure (reticulocytes < 60x10E9/L, or platelets < 50x10E9/L or neutrophils < 1x10E9/L) verified both at screening and baseline.
  9. History of recurrent meningitis, history of meningococcal infections despite vaccination, as verified at both screening and baseline.
  10. 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.
  11. A positive HIV, Hepatitis B (HBV) or Hepatitis C (HCV) test result at screening.
  12. Patients on immunosuppressive agents such, as but not limited to, cyclosporine, tacrolimus, mycophenolate or mycophenolic acid, cyclophosphamide, methotrexate or IV immunoglobulins, 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.
  13. Systemic corticosteroids unless on a stable dose for at least 4 weeks before randomization.
  14. Severe concurrent co-morbidities not amenable to active treatment; e.g., patients with severe kidney disease (CKD stage 4, dialysis), advanced cardiac disease (NYHA class IV), severe pulmonary arterial hypertension (WHO class IV), or unstable thrombotic event, as judged by the investigator, both at screening and baseline (unless baseline was skipped).
  15. 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.
  16. History of hypersensitivity to the study treatment or its excipients or to drugs of similar chemical classes.
  17. Female patients who are pregnant or breastfeeding, or intending to conceive during the course of the study.
  18. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 1 week after stopping of investigational drug -
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Novartis Pharmaceuticals +41613241111 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals
Listed Location Countries  ICMJE Korea, Republic of,   Malaysia,   Russian Federation,   Singapore,   Taiwan
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03896152
Other Study ID Numbers  ICMJE CLNP023X2204
Has Data Monitoring Committee No
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 Not Provided
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Novartis
Verification Date October 2019

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