| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Anemia of Chronic kidney disease (CKD) |
| Anemia da malattia renale cronica |
|
| E.1.1.1 | Medical condition in easily understood language |
| Decrease of hemoglobin in the blood of patients suffering from kidney disease who require dialysis |
| Diminuzione dell' emoglobina nel sangue di pazienti affetti da patologia renale che necessitano di dialisi |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10002272 |
| E.1.2 | Term | Anemia |
| E.1.2 | System Organ Class | 100000004851 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10076412 |
| E.1.2 | Term | Chronic kidney disease stage 5 |
| E.1.2 | System Organ Class | 100000004857 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10076411 |
| E.1.2 | Term | Chronic kidney disease stage 4 |
| E.1.2 | System Organ Class | 100000004857 |
|
| 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 |
| The primary objective of the trial is to demonstrate the efficacy and safety of vadadustat compared to darbepoetin alfa for the maintenance treatment of anemia in hemodialysis subjects after conversion from current ESA therapy |
| L’obiettivo primario dello studio è dimostrare l’efficacia e la sicurezza di vadadustat rispetto a darbepoetina alfa per il trattamento di mantenimento dell’anemia in soggetti sottoposti a emodialisi dopo la conversione dall’attuale terapia con ESA |
|
| E.2.2 | Secondary objectives of the trial |
| Not applicable |
| Non applicabile |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacogenomics
Version: Originale
Date: 17/01/2020
Title: Optional pharmacogenomics (PGx) sub study “Human Biological Samples and Data Collected and Stored for Future Use”
Objectives: please refer to study protocol
|
Farmacogenomica
Versione: Originale
Data: 17/01/2020
Titolo: Sottostudio opzionale di farmacogenomica "Campioni biologici umani e dati raccolti e conservati per uso futuro"
Obiettivi: si riferisca per favore al protocollo di studio
|
|
| E.3 | Principal inclusion criteria |
1) = 18 years of age.
2) Receiving chronic, outpatient TIW in-center hemodialysis for endstage renal disease for at least 12 weeks prior to Screening.
3) Hemodialysis adequacy as indicated by single-pool Kt/Vurea = 1.2 using the most recent historical measurement within 8 weeks prior to or during Screening.
4) Use of any approved ESA for at least the 8 weeks prior to Screening Visit 2.
5) Two Hb values, at least 4 days apart, measured by the central laboratory during Screening within the following prespecified ranges:
a) Hb values between 8.0 and 11.0 g/dL (inclusive) in the US.
b) Hb values between 9.0 and 12.0 g/dL (inclusive) in Europe.
6) Serum ferritin = 100 ng/mL and TSAT = 20% during Screening.
7) Folate and vitamin B12 measurements = lower limit of normal during Screening. |
1) Età =18 anni.
2) Ricezione di emodialisi cronica in regime ambulatoriale TIW per malattia renale allo stadio terminale da almeno 12 settimane prima dello screening.
3) Emodialisi adeguata come indicato da un rapporto Kt/Vurea single-pool =1,2 utilizzando la misurazione storica più recente nelle 8 settimane precedenti o durante lo screening.
4) Uso di qualsiasi ESA approvato per almeno 8 settimane prima della visita di screening 2.
5) Due valori di Hb misurati dal laboratorio centrale a distanza di almeno 4 giorni durante lo screening entro i seguenti intervalli prespecificati:
a) valori di Hb tra 8,0 e 11,0 g/dl (estremi inclusi) negli USA;
b) valori di Hb tra 9,0 e 12,0 g/dl (estremi inclusi) in Europa.
6) Ferritina sierica =100 ng/ml e saturazione della transferrina (TSAT) =20% durante lo screening.
7) Valori di folato e vitamina B12 = limite inferiore della norma durante lo screening. |
|
| E.4 | Principal exclusion criteria |
| 1) Women of childbearing potential who do not agree to practice 2 different methods of birth control or remain abstinent during the trial and for 30 days after the last dose of investigational medicinal product IMP. If employing birth control, 2 of the following precautions must be used:vasectomy of partner, tubal ligation,vaginal diaphragm, intrauterine device, or birth control. 2)Male subjects who have not had a vasectomy and do not agree to the following: use of an acceptable form of contraception during the study and for 30 days after the last dose of the study drug; to not donate semen during the study and for at least 30 days after the last dose of vadadustat. 3)Women who are breast feeding and/or who have a positive pregnancy test result prior to receiving IMP. 4)Subjects with contraindication to required trial assessment. 5)Subjects who have a medical history or medical findings inconsistent with safety or trial compliance. 6) Anemia due to a cause other than CKD. 7)Subjects meeting cut-off of the following equivalent mean weekly doses calculated over 8 weeks prior to Screening Visit 2: a) Methoxy polyethylene glycol-epoetin beta > 50 µg/week. b) Darbepoetin alfa > 100 µg/week. c) Epoetin analogues > 23000 IU/week.8) Active bleeding or recent blood loss within 8 weeks prior to randomization.9) Red blood cell transfusion within 8 weeks prior to randomization.10) Anticipated to discontinue hemodialysis during the trial. 11) The subject is likely to need rescue therapy immediately after enrollment in the trial. 12) History of chronic liver disease. 13) Aspartate aminotransferase /serum glutamic oxaloacetic transaminase, alanine aminotransferase /serum glutamic pyruvic transaminase, or total bilirubin > 1.5 x upper limit of normal during Screening. The Gilbert's syndrome is not excluded. 14)Current uncontrolled hypertension that would contraindicate the use of an ESA. 15)Acute coronary syndrome, surgical or percutaneous intervention for coronary, cerebrovascular or peripheral artery disease, surgical or percutaneous valvular replacement or repair, sustained ventricular tachycardia, hospitalization for HF or Class IV HF, or stroke within 12 weeks prior to or during Screening. 16) History of new or recurrent malignancy within 2 years prior to and during Screening or currently receiving treatment or suppressive therapy for cancer. Subjects with treated basal cell carcinoma of skin, curatively resected squamous cell carcinoma of skin, or cervical carcinoma in situ are not excluded. 17) History of a new or recurrent episode of deep vein thrombosis or pulmonary embolism within 12 weeks prior to or during Screening. 18) History of hemosiderosis or hemochromatosis. 19) History of prior organ transplantation (failed kidney transplant or corneal transplants are not excluded). 20)Scheduled organ transplant from a living donor and subjects on the kidney transplant wait-list who are expected to receive a transplant within 6 months. 21) History of a prior hematopoietic stem cell or bone marrow transplant (stem cell therapy for knee arthritis is not excluded). 22)Known hypersensitivity to vadadustat, darbepoetin alfa, or any of their excipients. 23) Use of an investigational medication within 30 days or 5 half-lives of the investigational medication, prior to screening or during screening and any prior use of a hypoxia-inducible factor prolyl hydroxylase inhibitor. Subjects may participate in another concurrent trial only if that trial is a non-interventional, observational investigation. 24) Subjects with bilateral native nephrectomy. 25) Treated with probenecid within the 28-day Screening Period prior to randomization or during the study treatment duration. 26)Any other reason would make the subject not suitable for participation in the trial. |
| 1)Donne in età fertile che non accettano di adottare 2 diversi metodi contraccettivi o praticare l’astinenza durante lo studio e per 30 giorni dopo l’ultima dose del prodotto medicinale sperimentale (IMP).Se si utilizza un metodo contraccettivo, è necessario adottare 2 delle seguenti precauzioni:vasectomia del partner, legatura delle tube,diaframma vaginale,dispositivo intrauterino o anticoncezionale. 2)Soggetti di sesso maschile che non si sono sottoposti a vasectomia e non acconsentono a quanto segue:uso di un metodo contraccettivo accettabile durante lo studio e per 30 giorni dopo l’ultima dose del farmaco in studio;astensione dalla donazione di sperma durante lo studio e per almeno 30 giorni dopo l’ultima dose di vadadustat. 3)Donne che allattano al seno e/o che risultano positive al test di gravidanza prima di ricevere l’IMP. 4)Soggetti con controindicazioni alla valutazione dello studio richiesta. 5)Soggetti che presentano un’anamnesi medica o risultati medici incompatibili con la sicurezza o la conformità allo studio.6)Anemia dovuta a una causa diversa dalla malattia renale cronica.7)Soggetti che soddisfano il cut-off delle seguenti dosi settimanali medie equivalenti calcolate nelle 8 settimane precedenti la visita di screening 2: a)metossipolietilenglicole-epoetina beta >50 µg/settimana; b)darbepoetina alfa >100 µg/settimana; c)Analoghi della epoetina >23.000 UI/settimana. 8)Sanguinamento attivo o perdita di sangue recente nelle 8 settimane precedenti la randomizzazione. 9)Trasfusione di globuli rossi nelle 8 settimane precedenti la randomizzazione.10)Interruzione dell’emodialisi prevista durante lo studio. 11)Il soggetto debba ricorrere a una terapia di soccorso subito dopo l’arruolamento nello studio.12)Anamnesi di malattia epatica cronica.13)Livelli di AST/SGOT, ALT/SGPT o bilirubina totale >1,5 x ULN durante lo screening. La sindrome di Gilbert non è esclusa.14) Ipertensione non controllata in corso che controindica l’uso di un ESA. 5)Sindrome coronarica acuta, intervento chirurgico o percutaneo per coronaropatia, arteriopatia cerebrovascolare o periferica,sostituzione o riparazione valvolare chirurgica o percutanea, tachicardia ventricolare sostenuta,ricovero ospedaliero per insufficienza cardiaca (HF) o HF di Classe IV o ictus entro 12 settimane prima o durante lo screening.16)Anamnesi di neoplasia maligna nuova o ricorrente nei 2 anni precedenti e durante lo screening o attuale somministrazione di un trattamento o una terapia soppressiva per il tumore. I soggetti con carcinoma cutaneo basocellulare trattato, carcinoma cutaneo a cellule squamose sottoposto a resezione con intento curativo o carcinoma cervicale insitu non sono esclusi.17)Anamnesi di un episodio nuovo o ricorrente di trombosi venosa profonda o embolia polmonare nelle 12 settimane precedenti o durante lo screening.18)Anamnesi di emosiderosi o emocromatosi. 19)Anamnesi di precedente trapianto d’organo (trapianto renale non riuscito o trapianti corneali non sono esclusi). 20)Trapianto d’organo programmato da donatore vivente e soggetti in lista d’attesa per un trapianto renale che si prevede riceveranno un trapianto entro 6 mesi. 21)Anamnesi di un precedente trapianto di cellule staminali ematopoietiche o di midollo osseo (la terapia con cellule staminali per l’artrite del ginocchio non è esclusa). 22)Ipersensibilità nota a vadadustat,darbepoetina alfa o a uno degli eccipienti. 23)Uso di un farmaco sperimentale entro 30 giorni o 5 emivite del farmaco sperimentale prima dello screening o durante lo screening e qualsiasi precedente uso di un inibitore prolil-idrossilasi del fattore inducibile dall’ipossia.I soggetti possono partecipare a altro studio concomitante osservazionale non interventistico. 24)Soggetti con nefrectomia nativa bilaterale. 25)Trattamento con probenecid entro il periodo di screening di 28 giorni prima della randomizzazione o durante il trattamento dello studio.26) Qualsiasi altro motivo che rende il soggetto non idoneo allo studio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Efficacy endpoints: change in hemoglobin (Hb) between Baseline (average pretreatment Hb) and the primary evaluation period (average Hb from Weeks 20 to 26, inclusive). |
| Endpoint di efficacia primari : variazione dell’emoglobina (Hb) tra il basale (Hb media pretrattamento) e il periodo di valutazione primario (Hb media dalla Settimana 20 alla 26, incluse). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| weeks 20 to 26 inclusive |
| dalla Settimana 20 alla 26, incluse |
|
| E.5.2 | Secondary end point(s) |
| efficacy endpoints: change in Hb value between Baseline and the secondary evaluation period (average Hb from Weeks 46 to 52). |
| endpoint di efficacia secondari: variazione nel valore Hb tra il basale e il periodo di valutazione secondario (Hb media dalla Settimana 46 alla 52). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Weeks 46 to 52 inclusive |
| dalla Settimana 46 alla 52 incluse |
|
| 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 | 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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 | 3 |
| 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 | 32 |
| 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 |
| Belgium |
| Czech Republic |
| Hungary |
| Italy |
| Poland |
| Spain |
| United States |
|
| 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
|
The end of trial date is defined as the last date of contact or the date of final contact attempt from the safety follow-up electronic case report form (eCRF) page for the last subject completing or withdrawing from the trial.
The trial will be considered completed (end of trial) after all randomized subjects have completed their final trial visit (ET, Week 52/EOT, or Safety Follow-Up.) |
La data di fine studio è definita come la data dell' ultimo contatto o la data dell' ultimo tentativo di contatto dalla pagina del follow-up di safety nella CRF riguardante l'ultimo paziente che ha completato o si è ritirato dallo studio.
Lo studio sarà considerato completato (fine dello studio) dopo che tutti i soggetti randomizzati avranno completato la loro visita finale dello studio ( ET, settimana 52/EOT o Safety Follow-up). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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