E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Proven PBC, as demonstrated by the presence of at least 2 of the following 3 diagnostic factors: - History of increased ALP levels for at least 6 months - Positive serum AMA titer (>1:40) - Liver biopsy consistent with PBC Patient should be on incomplete response to UDCA |
Diagnosi di Cirrosi Biliare Primitiva (PBC), confermata dalla presenza di almeno 2 dei seguenti 3 criteri diagnostici: - Storia di aumento del livello delle ALP per almeno 6 mesi - Positività sierica per AMA (>1:40) - Biopsia epatica diagnostica per la diagnosi di PBC I pazienti devono presentare una risposta incompleta al trattamneto standar Acido Ursodesossicolico |
|
E.1.1.1 | Medical condition in easily understood language |
Patients with a diagnosis of Primary Biliary Cirrhosis (PBC) that do not respond to UDCA |
Pazienti con diagnosi di Cirrosi Biliare Primitiva (PBC) che non rispondono in modo soddisfacente al farmaco Acido Ursodesossicolico |
|
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 | 14.1 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10021428 |
E.1.2 | Term | Immune system disorders |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10019805 |
E.1.2 | Term | Hepatobiliary disorders |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
•To investigate the efficacy of multiple doses of NI 0801 on hepatic function |
•Valutare l’efficacia di dosi multiple di NI 0801 sulle funzioni epatiche |
|
E.2.2 | Secondary objectives of the trial |
•To evaluate the safety and tolerability of multiple doses of NI-0801 in PBC patients •To characterize the pharmacokinetic and pharmacodynamic profile of multiple doses of NI 0801 |
•Valutare la sicurezza e tollerabilità di dosi multiple di NI-0801 in pazienti affetti da PBC •Caratterizzare il profilo farmacocinetico e farmacodinamico di dosi multiple di NI 0801 |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female, 18 years or older 2. Proven PBC, as demonstrated by the presence of at least 2 of the following 3 diagnostic factors: - History of increased ALP levels for at least 6 months - Positive serum AMA titer (>1:40) - Liver biopsy consistent with PBC 3. Incomplete response to UDCA defined as failure to normalise ALP levels or to reduce ALP levels by more than 40% after 1 year of therapy with UDCA according to the local recommended dose. 4. Stable dose of UDCA for at least 6 months prior to screening 5. Screening ALP > 1.5 ULN 6. Screening ALT or AST > 1.5 ULN 7. Female patients must be postmenopausal, surgically sterile, or willing to use 2 methods of effective contraception with all sexual partners until 3 months after having received the last dose of study medication 8. Male patients who agree to take the appropriate precautions to avoid fathering a child until 3 months after having received the last dose of study medication 9. Have given written informed consent 10. Patients must be able to adhere to the study visits and protocol requirements |
1. Uomini o donne, dai 18 anni in su 2. Diagnosi di Cirrosi Biliare Primitiva (PBC), confermata dalla presenza di almeno 2 dei seguenti 3 criteri diagnostici: - Storia di aumento del livello delle ALP per almeno 6 mesi - Positività sierica per AMA (>1:40) - Biopsia epatica diagnostica per la diagnosi di PBC 3. Risposta incompleta all'UDCA definita come definita come il fallimento nella normalizzazione dei livelli di ALP o nella riduzione dei livelli di ALP di almeno il 40% dopo 1 anno di terapia con UDCA, secondo le linee guida locali. 4. Dose stabile di UDCA per almeno sei mesi rpiam dello screening 5. Allo screening ALP > 1.5 ULN 6. Allo screening ALT or AST > 1.5 ULN 7. Patienti donne devono essere in postmenopausa, sterili o devono accettare di fare uso di 2 metodi contraccettivi con tutti i partner fino a 3 mesi dopo aver ricevuto l'ultima dose di farmaco 8. Pazienti uomini che acconsentono a prendere adeguate precauzioni contraccettive fino a 3 mnesi dopo aver ricevuto l'ultima dose di farmaco 9. Firma del Consenso Informato 10. I pazienti devono essere in grado di seguire le procedure dello studio |
|
E.4 | Principal exclusion criteria |
• Screening bilirubin > 2.9 mg/dL (50 μmol/L) • Screening creatinine clearance < 80 ml/min • History or presence of hepatic decompensation (e.g., esophageal variceal bleeding, hepatic encephalopathy, or ascites) • Positive serology result for Human Immunodeficiency Virus (HIV), Hepatitis B or C • Known or previous diagnosis of malignancy • Presence of any active infection • Previous history of active TB within 12 months of screening |
• Allo screening bilirubina > 2.9 mg/dL (50 μmol/L) • Allo screening clearance della creatinina < 80 ml/min • Presenza o storia di disfunzione epatica (e.g., sanguinamento delle varici-esofagee, encefalopatia epatica, o ascite) • Positività al Virus da Immunodeficiencenza Acquisita (HIV), Epatite B o C • Precedente diagnosi di un tumore • Presenza di qualsiasi infezione attiva • Storia di TB attiva nei 12 mesi precedenti lo screening |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Change in liver enzyme measurements from baseline to Week 12 (SD85) |
Cambiamento dei valori degli enzimi epatici dalla visita di baseline (screening) alla settimana 12 (giorno di studio 85) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Week 12 (SD85) |
settimana 12 (giorno di studio 85) |
|
E.5.2 | Secondary end point(s) |
PBC-related exploratory assessments • Biochemical markers of liver function • Mayo risk score (MRS) • Liver stiffness measurement (LSM) with Transient Elastography (Fibroscan™) • Enhanced Liver Fibrosis (ELF) test • Quality-of-Life assessment: PBC-40 Pharmacokinetic characterisation Pharmacodynamic measurements • The evolution over time of total circulating CXCL10 levels will be measured Extent of the NI 0801 inhibition on CXCL10 chemotactic activity by in vitro chemotaxis • Serum cytokines and chemokines • FACS analysis for the quantification of leukocytes and subsets and CXCR3 expression on these subsets Safety and tolerability • All emerging AEs • The number of subjects withdrawing from the study for safety relatedreasons • Vital signs and any changes revealed by medical examination. • Laboratory abnormalities in Safety Hematology parameters, Safety Blood Chemistry parameters and Urinalysis parameters Immunogenicity • The presence of anti-drug antibodies |
Indagini esploratorie correlate con la PBC: • Marcatori biochimici delle funzioni epatiche • Valore di rischio Mayo (MRS) • Misura dell'inspessimento epatico (LMS) con l'uso dell'Elastografia Transiente (Fibroscan) • test dell'Aumento della fibrosi epatica (ELF) • Questionario sulla qualità di vita: PBC-40 Caratterizzazione Farmacicinetica Misurazioni Farmacodinamiche • Valutazione nel tempo dei livelli totali circolanti di CXCL10 Inibizione di NI 0801 sull'attività chemotattica di CXCL10 atrtaverso la chemotassi in vitro • Citochine e chemochine sieriche • Analisi FACS per la quantizzazione dei leucociti e sottopopolazioni, espressione di CXCR3 su quetsa sottopopolazione Sicurezza e tollerabilità • tutti gli EA segnalati • Il numero dei soggetti che interrompono lo studio per motivi di sicurezza • Segni vitali e qualsiasi cambiamneto rilevato dall'esame medico • Valori di laboratorio anomali nei parametri ematologici, chimici e nei parametri urinari di immunogenicità • Presenza di anticorpi anti-farmaco |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
ELF, Fibroscan, PBC-40: SD1, SD85, W18 PK, blood samples: SD1, SD5, SD15, SD29, SD43, SD57, SD71, SD75, SD85, W18, W24 Chemokines/cytokines: SD1, SD5, SD15, SD29, SD43, SD57, SD71, SD75, SD85, W18, W24 FACS: SD1, SD85 Immunogenicity: SD1, SD15, SD29, SD43, SD57, SD71, W24 Vital signs, hematology and biochemistry blood samples, AEs recording & concomittant medications: SD1, SD5, SD15, SD29, SD43, SD57, SD71, SD75, SD85, W18, W24 |
ELF, Fibroscan, PBC-40: SD1, SD85, W18 PK, campioni di sangue: SD1, SD5, SD15, SD29, SD43, SD57, SD71, SD75, SD85, W18, W24 Chemochine/citochine: SD1, SD5, SD15, SD29, SD43, SD57, SD71, SD75,SD85,W18, W24 FACS: SD1, SD85 Immunogenicità: SD1, SD15, SD29, SD43, SD57, SD71, W24 Segni vitali, campioni di sangue per ematologia e biochimica, segnalazione AEs e farmaci concomitanti: SD1, SD5, SD15, SD29, SD43, SD57, SD71, SD75, SD85, W18, W24 |
|
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 | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 10 |
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 | No |
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
|
The end of the study is defined as the last patient completes the last follow-up visit at the week 24 post-dose. |
La fine dello studio è definita quando l'ultimo paziente completa l'ultima visita di follow-up 24 settimane dopo l'ultima infusione. |
|
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 | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 12 |
E.8.9.2 | In all countries concerned by the trial days | 0 |