| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pyruvate Kinase Deficiency Haemolytic anaemia |
| Carenza di piruvato chinasi Anemia emolitica |
|
| E.1.1.1 | Medical condition in easily understood language |
Lack of Pyruvate Kinase enzyme
Lack of red blood cells following their destruction and removal from the bloodstream |
Mancanza di enzima piruvato chinasi
Mancanza di globuli rossi dopo la loro distruzione e rimozione dal flusso sanguigno |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10037682 |
| E.1.2 | Term | Pyruvate kinase deficiency anaemia |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic 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 evaluate the long-term safety and tolerability of AG-348 |
| Valutare la sicurezza e tollerabilità a lungo termine di AG-348 |
|
| E.2.2 | Secondary objectives of the trial |
•To evaluate the long-term efficacy of AG-348
•To evaluate the efficacy of AG-348 in increasing hemoglobin (Hb) concentrations in subjects who previously received placebo in Study AG348-C-006 (ie, Cohort 1)
•To determine the effect of AG-348 on health-related quality of life (HRQoL) using patient reported outcomes (PROs)
•To evaluate the pharmacokinetics of AG-348 after oral administration (Cohort 1 only)
•To evaluate the relationship between AG-348 pharmacokinetics and safety parameters (Cohort 1 only) |
•Valutare l'efficacia a lungo termine di AG-348
•Valutare l'efficacia di AG-348 nell'aumentare le concentrazioni di emoglobina (Hb) nei soggetti che avevano precedentemente ricevuto il placebo nello studio AG348-C-006 (ossia la Coorte 1)
•Determinare l'effetto di AG-348 sulla qualità della vita correlata alla salute (HRQoL), determinata utilizzando gli esiti segnalati dal paziente (PRO)
•Valutare la farmacocinetica di AG-348 dopo la somministrazione orale (solo Coorte 1)
•Valutare il rapporto tra la farmacocinetica di AG-348 e i parametri di sicurezza (solo Coorte 1) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Have signed written informed consent prior to participating in this extension study;
2.Have completed either antecedent study AG348-C-006 or AG348-C-007 through the Part 2 Week 24 Visit;
3.Cohorts 2 and 3: Have demonstrated clinical benefit from AG-348 treatment in the antecedent study, in the opinion of the Investigator;
4.For women of reproductive potential, have a negative pregnancy test at the Screening/Day 1 Visit;
5.For women of reproductive potential as well as men with partners who are women of reproductive potential, be abstinent as part of their usual lifestyle, or agree to use 2 forms of contraception, 1 of which must be considered highly effective, from the time of giving informed consent, during the study, and for 28 days (both men and women) following the last dose of study drug. |
1.Accordo e firma del consenso informato scritto prima della partecipazione a questo studio di estensione;
2.Aver completato lo studio antecedente di AG-348 (ossia, fino alla visita della Settimana 24 della Parte 2 dello studio AG348-C-006 o AG348-C-007);
3.Coorti 2 e 3: aver dimostrato di aver tratto, a giudizio dello sperimentatore, un beneficio clinico dal trattamento con AG-348 nello studio antecedente;
4.Donne potenzialmente fertili: test di gravidanza negativo allo screening/visita Giorno 1;
5.Le donne potenzialmente fertili nonché gli uomini le cui partner sono in età fertile devono praticare l'astinenza quale parte del loro stile di vita abituale oppure accettare di far uso di 2 metodi anticoncezionali, uno dei quali deve essere considerato altamente efficace, dal momento in cui accordano il consenso informato, durante lo svolgimento dello studio e nei28 giorni (uomini e donne) successivi alla somministrazione dell'ultima dose del farmaco sperimentale. |
|
| E.4 | Principal exclusion criteria |
1.Have a significant medical condition (including clinically significant laboratory abnormality) that developed during his/her antecedent AG-348 study that confers an unacceptable risk to participating in this extension study, that could confound the interpretation of the study data, and/or that compromises the ability of the subject to complete study visits and procedures;
2.Are currently pregnant or breastfeeding;
3.Have a splenectomy scheduled during the study treatment period;
4.Meet the withdrawal criteria of his/her antecedent AG-348 study during screening of this extension study. Withdrawal criteria of the antecedent AG-348 studies are as follows:
- Withdrawal of consent
- Development of an intercurrent medical condition that precludes further participation in the study
- Subject requires use of a prohibited concomitant medication
- Investigator decision
- Persistent nonadherence to protocol requirements
- Pregnancy
- Lost to follow-up
5.Are currently receiving medications that are strong inhibitors of cytochrome P450 (CYP)3A4, strong inducers of CYP3A4, strong inhibitors of P-glycoprotein (P-gp), or digoxin (a P-gp sensitive substrate medication) that have not been stopped for a duration of at least 5 days or a timeframe equivalent to 5 half-lives (whichever is longer) prior to start of study drug on this extension study;
6.Have received anabolic steroids, including testosterone preparations, within 28 days prior to Screening/Day 1 of this extension study;
7.Have received hematopoietic stimulating agents (eg, erythropoietins, granulocyte colony stimulating factors, thrombopoietins) within 28 days start of study drug on this extension study;
8.Have exposure to any investigational drug other than AG-348, device, or procedure within 3 months prior to Screening/Day 1 of this extension study. |
1.Presenza di importante patologia (compresa la presenza di anomalie clinicamente significative nelle analisi di laboratorio), sviluppata durante la partecipazione allo studio antecedente di AG-348 che rappresenti un rischio inaccettabile per la partecipazione a questo studio di estensione, che possa confondere l'interpretazione dei dati dello studio e/o che comprometta la capacità del soggetto di completare le visite e le procedure dello studio;
2.Gravidanza o allattamento con latte materno in corso;
3.Splenectomia programmata durante il periodo di trattamento dello studio;
4.Soddisfazione dei criteri di ritiro dal rispettivo studio antecedente di AG-348 durante lo screening di questo studio di estensione. I criteri per il ritiro dai precedenti studi con AG-348 sono i seguenti:
• revoca del consenso
• insorgenza di malattia intercorrente che esclude l’ulteriore partecipazione allo studio
• il soggetto necessita l’assunzione di un farmaco concomitante non ammesso
• decisione dello sperimentatore
• continua mancata aderenza ai requisiti del protocollo
• gravidanza
• perdita al follow-up
5.Terapia in corso con medicinali che sono forti inibitori del citocromo P450 (CYP)3A4, forti induttori di CYP3A4, forti inibitori della P-glicoproteina (P-gp) o della digossina (un medicinale che è un substrato sensibile alla P-gp), la cui somministrazione non è stata interrotta durante un periodo di alemeno 5 giorni o di un periodo pari a 5 volte le emivite (a seconda di quale periodo sia il più lungo) prima di iniziare il
trattamento con il farmaco sperimentale in questo studio di estensione;
6.Terapia con steroidi anabolici, compresi preparati a base di testosterone, somministrata nei 28 giorni precedenti allo screening/Giorno 1 di questo studio di estensione;
7.Terapia con agenti stimolanti l'emopoiesi (ad es., eritropoietine, fattori stimolanti le colonie granulocitiche, trombopoietine, ecc.) somministrata nei 28 giorni precedenti all’inizio del trattamento con il farmaco sperimentale in questo studio di estensione;
8.Esposizione a qualsiasi farmaco sperimentale diverso da AG-348, dispositivo o procedura sperimentale nei 3 mesi precedenti allo screening/Giorno 1 di questo studio di estensione. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1)Number of Subjects with Adverse Events (AEs) and Adverse Events of Special Interest (AESIs)
2)Number of Subjects with AEs Leading to Dose Reduction, Treatment Interruption and Treatment Discontinuation |
1)Numero di soggetti con eventi avversi (AE) e eventi avversi di particolare interesse (AESI)
2)Numero di soggetti con AE che portano alla riduzione della dose, all'interruzione o alla sospensione del trattamento |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From baseline to end of study (Week 197) |
| Dalla baseline alla fine dello studio (settimana 197) |
|
| E.5.2 | Secondary end point(s) |
Cohort 1 only:
- Proportion of subjects achieving a hemoglobin response, defined as a = 1.5 g/dL (0.93 mmol/L) increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments at Weeks 16, 20, and 24
- Average change from baseline in Hb concentration at Weeks 16, 20, and 24
- Pharmacokinetic endpoints, including plasma concentrations over time and pharmacokinetic parameters of AG-348 (eg, AUC, Cmax, others as applicable)
- Exposure-response relationship between safety parameters and AG-348 concentration and relevant AG-348 pharmacokinetic parameters
All cohorts:
- Change from baseline in Hb concentration
- Change from baseline in markers of hemolysis: bilirubin, lactate dehydrogenase (LDH), and haptoglobin levels
- Change from baseline in markers of erythropoietic activity: reticulocyte percentages
- Change from baseline in the number of transfusion events
- Change from baseline in the number of RBC units transfused
- Change from baseline in HRQoL PRO scores: Pyruvate Kinase Deficiency Diary (PKDD) and Pyruvate Kinase Deficiency Impact Assessment (PKDIA) |
Cohort 1 only:
- Proportion of subjects achieving a hemoglobin response, defined as a = 1.5 g/dL (0.93 mmol/L) increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments at Weeks 16, 20, and 24
- Average change from baseline in Hb concentration at Weeks 16, 20, and 24
- Pharmacokinetic endpoints, including plasma concentrations over time and pharmacokinetic parameters of AG-348 (eg, AUC, Cmax, others as applicable)
- Exposure-response relationship between safety parameters and AG-348 concentration and relevant AG-348 pharmacokinetic parameters
All cohorts:
- Change from baseline in Hb concentration
- Change from baseline in markers of hemolysis: bilirubin, lactate dehydrogenase (LDH), and haptoglobin levels
- Change from baseline in markers of erythropoietic activity: reticulocyte percentages
- Change from baseline in the number of transfusion events
- Change from baseline in the number of RBC units transfused
- Change from baseline in HRQoL PRO scores: Pyruvate Kinase Deficiency Diary (PKDD) and Pyruvate Kinase Deficiency Impact Assessment (PKDIA) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1)Weeks 16, 20, 24
2)Week 12: pre-dose, post-dose at 30 minutes, 1 hour (h), 2 h, 4 h, 8 h
3)Week 12: pre-dose, post-dose at 30 minutes, 1 h, 2 h, 4 h, 8 h
4)From baseline up to Week 197
5)From baseline up to Week 197
6)From baseline up to Week 197
7)From baseline up to Week 197
8)From baseline up to Week 197
9)From baseline up to Week 197
10)From baseline up to Week 197
11)From baseline up to Week 193
12)From baseline up to Week 193 |
1)Weeks 16, 20, 24
2)Week 12: pre-dose, post-dose at 30 minutes, 1 hour (h), 2 h, 4 h, 8 h
3)Week 12: pre-dose, post-dose at 30 minutes, 1 h, 2 h, 4 h, 8 h
4)From baseline up to Week 197
5)From baseline up to Week 197
6)From baseline up to Week 197
7)From baseline up to Week 197
8)From baseline up to Week 197
9)From baseline up to Week 197
10)From baseline up to Week 197
11)From baseline up to Week 193
12)From baseline up to Week 193 |
|
| 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 | 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 | 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 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| 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 |
| Korea, Republic of |
| Thailand |
| United States |
| Denmark |
| France |
| Germany |
| Ireland |
| Italy |
| Netherlands |
| Portugal |
| Spain |
| Switzerland |
| United Kingdom |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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