| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Paroxysmal Nocturnal Hemoglobinuria (PNH) |
| Emoglobinuria Parossistica Notturna (PNH) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Blood disorder |
| Emoglobinuria Parossistica Notturna (PNH) |
|
| 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). |
Valutare l¿effetto di LNP023 sulla riduzione dell¿emolisi cronica in pazienti affetti da PNH quando
aggiunto alla SoC (anticorpo monoclonale anti-C5) |
|
| 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
|
Valutare la sicurezza e la tollerabilit¿ di LNP023 in pazienti affetti da PNH quando aggiunto alla SoC
(anticorpo monoclonale anti-C5). |
|
| 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 18-75 (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).
•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).
•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.
•Previous vaccination for the prevention of S. pneumoniae and H. influenzae at least 4 weeks prior to first dosing with LNP023.
•Able to communicate well with the investigator, to understand and comply with the requirements of the study.
Other protocol defined inclusion criteria may apply. |
Prima di qualsiasi valutazione si deve acquisire il consenso informato firmato.
Uomini e donne con età compresa tra i 18 e i 75 anni (inclusi) che al basale abbiano una diagnosi di PNH basata dalla documentazione del numeri di cloni
= 10% di RBCs e/o granulociti con deficit di GPI, misurati mediante citometria a flusso.
Valori di LDH =1.5 volte il limite superiore di normalità ottenuti per almeno 3 volte prima della somministrazione della SoC misurate in 3 differenti giorni in un periodo massimo di 10 settimane prima del Giorno 1 ( sono accettabili i valori ottenuti durante lo screening, al basale o lo storico clinico). Tutti gli altri valori di LDH pre-SoC ottenuti nel periodo di screening devono essere >1 volta il limite superiore di normalità (per campioni pre-SoC raccolti lo stesso giorno della somministrazione della SoC)
Pazienti con PNH in trattamento stabile con la terapia standard per il blocco del complemento (anticorpo monoclonale anti-C5) da almeno 3 mesi prima del primo trattamento con LNP023.
Vaccinazione precedente contro Neisseria Meningitidis tipi A,C, Y e W-135 ottenuto almeno 4 settimane prima della prima dose di
LNP023. Se disponibile e accettata dalle regole locali deve essere fatta la vaccinazione contro Neisseria Meningitidis tipo B, almeno 4 settimane prima della prima somministrazione di LNP023.
Vaccinazione precedente per la prevenzione di S. Pneumoniae e H. Influenzae almeno 4 settimane prima della prima dose di LNP023.
Capacità di comunicare bene con il medico dello studio, per capire ed essere compliante con le procedure dello studio. |
|
| 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, platelets <30x10E9/l neutrophils <1x10E9/l) as verified both at screening and at baseline (unless baseline was skipped)
•A positive HIV 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 |
Partecipazione ad altri studi clinici o uso di altri farmaci sperimentali al momento dell’arruolamento, o entro 5 emivite
dall’arruolamento, o entro 30, a seconda di quale dei due periodi di tempo è più lungo.
Deficit ereditario del complemento conosciuto o sospetto al momento dello screening.
Storia di trapianto di cellule staminali ematopoietiche verificata sia allo screening che al basale (a meno che il basale sia evitato).
Pazienti con comprovata evidenza di insufficienza midollare (reticolociti < 60x10E9/I, piastrine < 30x10E9/I, neutrofili < 1x10E9/I)
sia allo screening che al basale (a meno che il basale sia evitato).
Test positivo per HIV allo screening.
Presenza o sospetto (in base al giudizio del clinico) di infezione attiva nelle 2 settimane precedenti la prima dose di LNP023, o
storia di infezioni batteriche gravi ricorrenti.
Storia di meningite ricorrente, storia di infezioni da meningococco nonostante la vaccinazione come appurato sia allo screening
che al basale (a meno che il basale sia evitato).
Pazienti in trattamento con immunosoppressori come ma non limitati a ciclosporina, MMF, tacrolimus, ciclofosfamide, metotrexato
da meno 8 settimane precedenti il primo trattamento con LNP023 a meno che non siano a dosaggio stabile da almeno 3 mesi
prima della prima dose di LNP023.
Corticosteroidi sistemici somministrati alla dose di = 10 mg al giorno di prednisone equivalente entro meno di 4 settimane prima
del primo trattamento con LNP023
Pazienti con comorbidità gravi, es. pazienti con malattia renale grave (dialisi), patologie cardiache avanzate (NYHA classe IV),
ipertensione arteriale polmonare grave (WHO classe IV), evento trombotico instabile come giudicato dal medico dello studio sia
allo screening che al basale (a meno che il basale sia evitato).
Qualsiasi condizione medica che possa interferire con la partecipazione del paziente allo studio, o che possa causare eventi
avversi gravi durante lo studio.
Donne in gravidanza o allattamento, o che abbiano intenzione di concepire durante il periodo dello studio.
Donne in età fertile, definite come tutte le donne fisiologicamente in grado di rimanere gravide, a meno che non utilizzino un
metodo contraccettivo altamente efficace dalla prima dose di LNP023 fino alla EoS. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| LDH level at study week 13 |
| Livello Di LDH alla settimana 13 dello studio |
|
| 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,
¿Total and free hemoglobin, reticulocytes, C3 fragment deposition, haptoglobin, bilirubin, red blood cell count, freedom from
transfusion
¿Total drug LNP023 non-compartmental PK parameters, including but not limited to Cmax and AUC and trough evaluation |
Tutti i parametri di sicurezza, inclusi: chimica ematologica, ematologia, esame urine, ECG,
segni vitali, eventi avversi, trasfusioni,
¿ Emoglobina libera e totale, reticulociti, De4posizione del frammento C3, aptoglobina, bilirubina, conta globuli rossi, incidenza
trasfusioni
¿ parametri di farmacoconetica, compresa valutazione Cmax e AUC |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Entire study duration |
| Intera durata dello studio |
|
| 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 | No |
| 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 |
| Tollerabilit¿: effetto di LPN023 sui marcatori di emolisi intra ed extravascolare quando somministrato in aggiunta alle cure standard (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 | No |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| 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 | Information not present in EudraCT |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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