| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Idiopathic Pulmonary Fibrosis |
| fibrosi polmonare idiopatica |
|
| E.1.1.1 | Medical condition in easily understood language |
| Idiopathic Pulmonary Fibrosis |
| fibrosi polmonare idiopatica |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10021240 |
| E.1.2 | Term | Idiopathic pulmonary fibrosis |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal 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 |
The main objective of the trial will be to assess safety and tolerability of
combined treatment with nintedanib and pirfenidone |
| Valutare la sicurezza e la tollerabilità del trattamento combinato con nintedanib e pirfenidone. |
|
| E.2.2 | Secondary objectives of the trial |
| A secondary objective is to assess the exposure, based on pharmacokinetic trough concentration values, to nintedanib either given alone or in combination with pirfenidone and to assess the assess the exposure of pirfenidone when combined with nintedanib |
| Un obiettivo secondario è valutare - sulla base dei valori concentrazione della PK trough - il grado di esposizione a nintedanib, sia somministrato in mono-terapia sia in combinazione con pirfenidone e valutare grado di esposizione a pirfenidone in combinazione con nintedanib |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
-Written informed consent consistent with ICH-GCP and local laws,
signed prior to any study procedures being performed (including any
required washout)
-Male or female patients aged greater than or equal to 40 years at visit 1
-Idiopathic Pulmonary Fibrosis (IPF) diagnosis, based upon the
ATS/ERS/JRS/ALAT 2011 guideline and confirmed by the investigator
based on chest high resolution computed tomography (HRCT) scan
performed within 12 months of visit 1
-FVC greater than or equal to 50% of predicted normal at visit 1 |
1. Firma del modulo di consenso informato in coerenza con le ICH-GCP prima di qualunque procedura di studio (inclusi i washout).
2. Paziente uomo o donna >= 40 anni di età alla visita 1.
3. Diagnosi di IPF sulla base della linea guida ATS/ERS/JRS/ALAT 20112011 e confermata dallo sperimentatore sulla base di scansione tomografica computerizzata del petto ad alta risoluzione (HRCT) effettuata entro 12 mesi dalla visita 1.
4. FVC >= 50% del valore normale predetto alla visita 1.
|
|
| E.4 | Principal exclusion criteria |
-ALT, AST > 1.5 fold upper limit of normal (ULN) at visit 1
-Total bilirubin > 1.5 fold ULN at visit 1
-Relevant airways obstruction (i.e. pre-bronchodilator FEV1/FVC <0.7)
at visit 1
-History of myocardial infarction within 6 months of visit 1 or unstable
angina within 1 month of visit 1
-Bleeding Risk: Known genetic predisposition to bleeding, Patients who
require fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K
antagonists, dabigatran, heparin, hirudin etc) or high dose antiplatelet
therapy, History of haemorrhagic central nervous system event within 12
months prior to visit 1, History of haemoptysis or haematuria, active
gastro-intestinal bleeding or ulcers and/or major injury or surgery
within 3 months prior to visit 1, International normalised ratio (INR) > 2
at visit 1, Prothrombin time and partial thromboplastin time (PTT) >
150% of
institutional ULN at visit 1
-Planned major surgery during the trial participation, including lung
transplantation,major abdominal or major intestinal surgery.
-History of thrombotic event (including stroke and transient ischemic
attack) within 12
months of visit 1
-Severe renal impairment (Creatinine clearance < 30 mL/min calculated by Cockcroft-Gault formula) or end-stage renal disease requiring dialisys.
-Treatment with NAC, prednisone >15 mg daily or >30 mg every 2 days
OR equivalent
dose of other oral corticosteroids and/or fluvoxamine within 2 weeks of
visit 2
-Treatment with azathioprine, cyclophosphamide, cyclosporine as well as
any other
investigational drug within 8 weeks of visit 2
-Previous treatment with pirfenidone
-Permanent discontinuation of nintedanib in the past due to AEs
considered drug-related
-Known hypersensitivity to nintedanib, pirfenidone, peanut or soya or to
any of the
excipients
-A disease or condition which in the opinion of the investigator may
interfere with testing procedures or put the patient at risk when
participating in this trial
-Alcohol or drug abuse which in the opinion of the treating physician
would interfere with treatment
-Women who are pregnant, nursing, or who plan to become pregnant
while in the trial.
-Women of childbearing potential not willing or able to use highly
effective methods of
birth control per ICH M3 (R2) that result in a low failure rate of less than
1% per year
when used consistently and correctly5 for 28 days prior to and 3 months
after nintedanib administration
-Patients not able to understand and follow study procedures including
completion of selfadministered questionnaires without help
-Patients who require dose reduction and/or temporary interruption
during the run-in period with nintedanib 150 mg bid
|
1. ALT, AST > 1.5 volte superiori al limite di normalità (ULN) alla visita 11.
2. bilirubina totale > 1.5 volte superiore all’ ULN alla visita 11.
3. Ostruzione rilevante alle vie aeree (i.e. FEV1/FVC <0.7 pre-broncodilatatore) alla visita 1.
4. Anamnesi di infarto del miocardio entro 6 mesi dalla visita 1 o angina instabile entro 1 mese dalla visita 1.
5. Rischio di sanguinamento:
-Nota predisposizione genetica al sanguinamento
-Pazienti che richiedono fibrinolisi, dose piena di terapia anticoagulante (e.g.
Antagonisti della vitamina K, dabigatran, eparina, irudina etc) o alti dosaggi di terapia anti-piastrinica.
-Anamnesi di eventi emorragici correlati al sistema nervoso centrale entro 12 mesi prima della visita 1.
-Anamnesi di emottisi o ematuria, sanguinamenti gastro intestinali attivi, o ulcere e/o danno grave o chirurgia maggiore entro 3 mesi prima della visita 1.
-Tempo di protrombina e tromboplastina parziale (PTT) > 150% dell’ULN istituzionale alla visita 1.
6. Chirurgia maggiore pianificata durante la partecipazione allo studio, incluso trapianto del polmone, chirurgia rilevante all’addome o all’intestino.
7. Anamnesi di evento trombotico (incluso ictus e attacco ischemico transiente) entro 12
mesi dalla visita 1.
8. Anamnesi di patologia renale di stadio terminale che richiede dialisi Disfunzione renale di grado severo ( con .Creatinine clearance <30 mL/min calcolata con la formula di Cockcroft–Gault) oppure patologia renale di ultimo stadio che richieda dialisi.
9. Trattamento con NAC, prednisone >15 mg al dì o >30 mg ogni 2 giorni O equivalente
dose di altri corticosteroidi orali e/o fluvoxamina entro le 2 settimane dalla visita 2.
10. Trattamento con azatrioprina, ciclofosfamide, ciclosporine e qualunque altro farmaco sperimentale entro le 8 settimane dalla visita 2.
11. Trattamento pregresso con pirfenidone.
12. Pregressa interruzione permanente di nintedanib per AEs considerati farmaco-correlati.
13. Nota ipersensibilità a nintedanib, pirfenidone, arachidi o soia o qualunque altro eccipiente elencato nella section 4.1.1 del protocollo di studio.
14. Patologia o condizione che a giudizio dello sperimentatore può interferire con le procedure dello studio o mettere a rischio il paziente qualora partecipi allo studio.
15. Abuso di alcol o droghe che a giudizio del medico curante interferirebbero con il trattamento.
16. Donne incinta, in allattamento o che pianifichino una gravidanza durante lo studio.
17. Donne in età fertile non disposte o non in grado di utilizzare metodi efficaci di contraccezione in accordo alle ICH M3 (R2) che comportino un basso tasso di fallimento, inferiore all’ 1% per anno se utilizzati con consistenza e correttezza per 28 giorni prima e 3 mesi dopo l’assunzione di nintedanib.
18. Pazienti non in grado di comprendere e seguire le procedure dello studio inclusi i questionari autosomministrati senza aiuto.
19. Pazienti che richiedono riduzione del dosaggio e/o interruzione temporanea del nintedanib 150 mg bid durante il run-in. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1: The primary endpoint is the percentage of patients with on-treatment
gastrointestinal (GI) AEs (SOC GI disorders) from baseline to week 12 |
L’Endpoint Primario è la percentuale di pazienti in trattamento che hanno eventi avversi (AEs) gastrointestinali (SOC GI disorders) dal baseline alla settimana 12.
Eventi avversi durante il trattamento sono definiti come AEs con insorgenza fin dal primo dosaggio del trattamento randomizzato e fino all’ultima dose (inclusa).
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1: Pre-dose plasma concentrations at steady state (Cpre,ss) of
nintedanib at baseline, weeks
2 and 4
2: Pre-dose plasma concentrations at steady state (Cpre,ss) of
pirfenidone at weeks 2 and 4. |
1) Concentrazioni plasmatiche pre-dose allo steady state (Cpre,ss) di nintedanib al baseline, alla settimana 2 e 4.
2) Concentrazioni plasmatiche pre-dose allo steady state (Cpre,ss) di pirfenidone alle settimane 2 e 4.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1: baseline, week 2 and week 4
2: week 2 and week 4
|
1) basale, settimana 2 e settimana 4
2) basale, settimana 2 e settimana 4 |
|
| 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 | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| France |
| Germany |
| Italy |
| Netherlands |
| United States |
|
| 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
|
|
| 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 | 2 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 21 |
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