| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Paroxysmal Nocturnal Hemoglobinuria (PNH) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10018911 |
| E.1.2 | Term | Haemolyses and related conditions |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the effect of LNP023 on the reduction of chronic hemolysis in PNH patients when administered in addition to SoC (monoclonal antibody with anti C5 activity). |
|
| E.2.2 | Secondary objectives of the trial |
To assess the safety and tolerability of LNP023 in patients with PNH when administered in addition to SoC (monoclonal antibody with anti C5 activity).
To assess the effect of LNP023 on markers of intra and extravascular hemolysis when administered in addition to SoC (monoclonal antibody with anti C5 activity)
To assess the plasma PK of LNP023 in PNH patients
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•Written informed consent must be obtained before any assessment is performed.
•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).
•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 the screening pre-SoC LDH values > 1x upper limit of normal range (for pre-SoC samples collected at the same day as SoC administration).
For Cohort 2 only: 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).
• For Cohort 2 only: Hemoglobin level <10.5 g/dL at baseline.
•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.
•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.
•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.
•Able to communicate well with the investigator, to understand and comply with the requirements of the study.
•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.
Other protocol defined inclusion criteria may apply. |
|
| E.4 | Principal exclusion criteria |
•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
•Known or suspected hereditary complement deficiency at screening
•History of hematopoietic stem cell transplantation as verified both at screening and at baseline (unless baseline was skipped)
•Patients with laboratory evidence of bone marrow failure (reticulocytes <60x10E9/l or, platelets <30x10E9/l or neutrophils <1x10E9/l) as verified both at screening and at baseline (unless baseline was skipped)
•A positive HIV, Hepatitis B (HBV) or Hepatitis C (HCV) test result at screening
•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
•History of recurrent meningitis, history of meningococcal infections despite vaccination as verified both at screening and at baseline (unless baseline was skipped)
•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 6 3 months prior to first LNP023 dose.
•Systemic corticosteroids administered at the dose of ≥ 10 mg per day prednisone equivalent within less than 4 weeks prior to first treatment with LNP023
•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)
•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
•Female patients who are pregnant or breastfeeding, or intending to conceive during the course of the study
•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.
Other protocol defined exclusion criteria may apply |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| •LDH level at study week 13 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
•All safety parameters including: blood chemistry, hematology, urinalysis, ECG evaluation, vital signs, adverse events, transfusions, PROs
•Total and free hemoglobin, reticulocytes, LDH, C3 fragment deposition, PNH-type red blood cells, haptoglobin, bilirubin, red blood cell count, freedom from transfusion
•Non-compartmental PK parameters or LNP023 in plasma, including but not limited to Cmax, Tmax and AUC and Ctrough |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
-Tolerability
-effect of LNP023 on markers of intra and extravascular hemolysis when administered in addition to SoC |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 6 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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