| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pyruvate Kinase Deficiency |
| Deficit di Piruvato Chinasi |
|
| E.1.1.1 | Medical condition in easily understood language |
| Lack of Pyruvate Kinase enzyme |
| carenza dell'Enzima Piruvato |
|
| 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 efficacy of treatment with AG-348 compared with placebo in increasing hemoglobin (Hb) concentrations |
| Valutare l'efficacia del trattamento con AG 348 nell'aumentare le concentrazioni di emoglobina (Hb) rispetto al placebo |
|
| E.2.2 | Secondary objectives of the trial |
Secondary:
• To evaluate the safety of AG-348
• To determine the effect of the study treatment regimens on markers of hemolysis, hematopoietic activity, and other indicators of clinical activity
• To determine the effect of the study treatment regimens on health-related quality of life (HRQoL), as determined using patient-reported outcomes (PROs)
• To evaluate the pharmacokinetics of AG-348 after oral administration
• To evaluate the relationship between AG-348 pharmacokinetics and safety parameters
Exploratory:
• To evaluate the relationship of AG-348 pharmacokinetics to indicators of clinical activity
• To evaluate the pharmacodynamic markers of pyruvate kinase deficiency (PK deficiency) and how they are affected by study treatment
• To determine the effect of the study treatment regimens on:
o Number of transfusion events and number of red blood cell (RBC) units transfused
o Use and amount used of iron chelation therapy
o Liver iron concentration (LIC) |
•Valutare la sicurezza di AG 348
•Determinare l'effetto dei regimi terapeutici in studio sui marker di emolisi, attività emopoietica e altri indicatori di attività clinica
•Determinare l'effetto dei regimi terapeutici in studio 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
•Valutare il rapporto tra la farmacocinetica di AG 348 e i parametri di sicurezza
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have provided signed written informed consent prior to performing any study procedure, including screening procedures
2. Be aged 18 years or older
3. Have documented clinical laboratory confirmation of PK deficiency, defined as documented presence of at least 2 mutant alleles in the PKLR gene, of which at least 1 is a missense mutation, as determined per the genotyping performed by the study central genotyping laboratory
4. Have an Hb concentration less than or equal to 10.0 g/dL regardless of gender (average of at least 2 Hb measurements [separated by a minimum of 7 days] during the Screening Period)
5. Be considered not regularly transfused, defined as having had no more than 4 transfusion episodes in the 12-month period up to the first day of study treatment and no transfusions in the 3 months prior to the first day of study treatment
6. Have received at least 0.8 mg oral folic acid daily for at least 21 days prior to the first dose of study treatment, to be continued daily during study participation
7. Have adequate organ function, as defined by:
a. Serum aspartate aminotransferase (AST) <=2.5 × ULN (unless the increased AST is assessed by the Investigator as due to hemolysis and/or hepatic iron deposition) and alanine aminotransferase (ALT) <=2.5 × ULN (unless the increased ALT is assessed by the Investigator as due to hepatic iron deposition)
b. Normal or elevated levels of serum bilirubin. In subjects with serum bilirubin > ULN, the elevation must be attributed to hemolysis with or without Gilbert’s syndrome and must not be associated with choledocholithiasis, cholecystitis, biliary obstruction, or hepatocellular disease
c. Estimated glomerular filtration rate (GFR) >=60 mL/min/1.73 m2, measured GFR >=60 mL/min, or calculated creatinine clearance (CrCL; Cockcroft-Gault) >=60 mL/min;
d. Absolute neutrophil count >=1.0 × 109/L
e. Platelet count >=100 × 109/L in the absence of a spleen, or platelet count =50 × 109/L in the presence of a spleen and in the absence of any other cause of thrombocytopenia (based on an average of at least 2
measurements [separated by a minimum of 7 days] during the Screening Period).
f. Activated partial thromboplastin time and international normalized ratio <=1.25 × ULN, unless the subject is receiving therapeutic anticoagulants
For the full list please refer to the Protocol V4.0 dated 14Aug2019. |
1.Accordo del consenso informato scritto prima dell'esecuzione di una qualsiasi indagine dello studio, compresi gli accertamenti di screening.
2.Età pari o superiore ai 18 anni.
3.Conferma documentata dal laboratorio clinico di deficit di PK, definito dalla presenza documentata di almeno 2 alleli mutanti nel gene PKLR, di cui almeno 1 è una mutazione missense, come determinato dalla genotipizzazione effettuata dal laboratorio centrale di genotipizzazione.
4.Presenza di concentrazione di Hb pari o inferiore a 10,0 g/dL a prescindere dal sesso [media di almeno 2 misurazioni di Hb (separate da almeno 7 giorni) durante il periodo di screening].
5.Determinazione dello stato non regolarmente trasfuso, definito come un numero non superiore a 4 eventi trasfusionali ricevuti in un periodo di 12 mesi fino al primo giorno di somministrazione del trattamento in studio e nessuna trasfusione nei 3 mesi precedenti al primo giorno di somministrazione del trattamento in studio.
6.Assunzione di almeno 0,8 mg al giorno di acido folico orale come minimo nei 21 giorni precedenti alla somministrazione della prima dose del trattamento in studio; tale dose sarà continuata giornalmente per l'intera durata della partecipazione allo studio.
7.Adeguata funzionalità degli organi, definita da:
a.aspartato aminotransferasi (AST) <= 2,5 volte l'ULN (a meno che lo sperimentatore non abbia determinato che l'aumento dell'AST sia dovuto a emolisi e/o deposizione epatica di ferro) e alanina aminotransferasi (ALT) <= 2,5 volte l'ULN (a meno che lo sperimentatore non abbia determinato che l'aumento dell'ALT sia dovuto a deposizione epatica di ferro) nel siero;
b.livelli normali o innalzati di bilirubina sierica; nei soggetti con bilirubina sierica > l'ULN, l'aumento deve essere attribuito a emolisi con o senza sindrome di Gilbert e non deve essere associata a coledocolitiasi, colecistite, occlusione biliare o malattia epatocellulare;
c.velocità di filtrazione glomerulare (GFR) stimata >= 60 mL/min/1,73 m2, GFR misurata >= 60 mL/min o clearance della creatinina calcolata (CrCL; Cockcroft-Gault) >= 60 mL/min;
d.conta assoluta dei neutrofili >= 1,0 × 109/L;
e.conta piastrinica >= 100 × 109/L in assenza della milza, oppure conta piastrinica >= 50 x 109/L in presenza della milza e in assenza di altre cause di trombocitopenia [sulla base di una media di almeno 2 misurazioni (separate da almeno 7 giorni) durante il periodo di screening;
f.tempo di tromboplastina parziale attivata e rapporto internazionale normalizzato <= 1,25 volte l'ULN, a meno che il soggetto no riceva anticoagulanti terapeutici.
Per la lista completa riferirsi al Protocol V4.0 datato14Aug2019. |
|
| E.4 | Principal exclusion criteria |
1. Are homozygous for the R479H mutation or have 2 non-missense mutations, without the presence of another missense mutation, in the PKLR gene as determined per the genotyping performed by the study central genotyping laboratory
2. Have a significant medical condition that confers an unacceptable risk to participating in the study, and/or that could confound the interpretation of the study data. Such significant medical conditions include, but are not limited to the following:
a. Poorly controlled hypertension (defined as systolic blood pressure [BP] >150 mmHg or diastolic BP >90 mmHg) refractory to medical management
b. History of recent (within 6 months prior to signing informed consent) congestive heart failure; myocardial infarction or unstable angina pectoris; hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism
c. Cardiac dysrhythmias judged as clinically significant by the Investigator
d. Heart-rate corrected QT interval-Fridericia's method >450 msec (average of triplicate ECGs) with the exception of subjects with right or left bundle branch block
e. Clinically symptomatic cholelithiasis or cholecystitis. Prior cholecystectomy is not exclusionary. Subjects with symptomatic cholelithiasis or cholecystitis may be rescreened once the disorder has been treated and clinical symptoms have resolved
f. History of drug-induced cholestatic hepatitis
g. Iron overload sufficiently severe to result in a clinical diagnosis by the Investigator of cardiac (eg, clinically significant impaired left ventricular ejection fraction), hepatic (eg, fibrosis, cirrhosis), or pancreatic (eg, diabetes) dysfunction
h. Have a diagnosis of any other congenital or acquired blood disorder or any other hemolytic process, except mild allo-immunization, as a consequence of transfusion therapy
i. Positive test for HBsAg or HCVAb with signs of active hepatitis B or C virus infection. If the subject is positive for HCVAb, a reverse transcriptase-polymerase chain reaction test will be conducted. Subjects with hepatitis C may be rescreened after receiving appropriate hepatitis C treatment
j. Positive test for HIV-1 or -2 Ab
k. Active infection requiring the use of parenteral antimicrobial agents or Grade =3 in severity within 2 months prior to the first dose of study treatment
l. Diabetes mellitus judged to be under poor control by the Investigator or requiring >3 antidiabetic agents, including insulin (all insulins are considered 1 agent); use of insulin per se is not exclusionary
m. History of any primary malignancy, with the exception of: curatively treated nonmelanomatous skin cancer; curatively treated cervical or breast carcinoma in situ; or other primary tumor treated with curative intent, no known active disease present, and no treatment administered during the last 3 years
n. Unstable extramedullary hematopoiesis that could pose a risk of imminent neurologic compromise
o. Current or recent history of psychiatric disorder that, in the opinion of the Investigator or Medical Monitor, or designee could compromise the ability of the subject to cooperate with study visits and procedures
3. Have a splenectomy scheduled during the study treatment period or have undergone splenectomy within 60 days prior to signing informed consent
For the full list please refer to the Protocol V4.0 dated 14Aug2019. |
1.Presenza omoz mut R479H o di 2 mut non missense, senza la presenza di un'altra mutaz missense, nel gene PKLR, come determinato dalla genotipizzaz effettuata dal lab centrale di genotipizzazione.
2.Presenza di importante patologia che rappresenti un rischio inaccettabile per la partecipazione allo studio e/o che potrebbe confondere l'interpretaz dei dati dello studio. Tali patologie importanti comprendono a mero titolo esemplificativo:
a.ipertensione scarsamente controllata, definita come pressione sistolica > 150 mmHg o pressione diastolica > 90 mmHg, refrattaria alla gestione medica;
b.anamnesi recente (nei 6 mesi precedenti alla firma del consenso informato) di insuff cardiaca congestizia, infarto miocardico o angina instabile; ictus emorragico, embolico o trombotico; trombosi venosa profonda o embolia polmonare o arteriosa;
c.disritmia cardiaca considerata clinicamente signif dallo sperimentatore;
d.intervallo QT corretto per la freq cardiaca mediante il metodo di Fridericia (QTcF) > 450 msec (in media elettrocardiogrammi eseguiti in triplicato [ECG]) con l'eccezi di soggetti con blocco di branca dx o sx;
e.colelitiasi o colecistite clinicam sintomatica; una pregressa colecistectomia non è un fattore esclusivo; una volta trattata la malattia e risolti i sintomi clinici, i soggetti con colelitiasi o colecistite sintomatica possono ripetere lo screening;
f.anamnesi di epatite colestatica farmaco-indotta;
g.sovraccarico marziale suff severo che induce lo sperimentatore a formulare una diagnosi clinica di insufficienza cardiaca (ad es., compromissione clinicamente significativa della frazione di eiezione ventricolare sinistra), epatica (ad es., fibrosi, cirrosi) o pancreatica (ad es., diabete);
h.diagnosi di qualsiasi altra patologia ematica congenita o acquisita o di qualsiasi altro processo emolitico, con l'eccezione di lieve immunizzazione allogenica, quale conseguenza della terapia trasfusionale;
i.test positivo per l'antigene di superficie dell'epatite B o l'anticorpo (Ab) verso il virus dell’epatite C (HCV) con segni di infezione attiva da virus dell'epatite B o C. Se il soggetto è positivo per HCVAb, verrà effettuato il test di reazione a catena della polimerasi dopo retrotrascrizione. I soggetti con epatite C potranno ripetere lo screening dopo aver ricevuto idoneo trattamento per l'epatite C;
j.test positivo per l'Ab verso il virus dell'immunodeficienza umana 1 o 2;
k.infezione attiva necessitante della somministrazione parenterale di agenti antimicrobici o di severità di grado = 3 (secondo la classificazione del National Cancer Institute Common Terminology Criteria for Adverse Events) nei 2 mesi precedenti alla somministrazione della prima dose del trattamento in studio;
l.diabete mellito che lo sperimentatore considera essere scarsamente controllato o necessitante della somministrazione di più di 3 agenti antidiabetici, compresa insulina (tutte le insuline sono considerate 1 agente); l'uso di insulina per sé non è un fattore esclusivo;
m.anamnesi di qualsiasi neoplasia maligna primitiva, con l'eccezione di: tumore cutaneo non melanomatoso trattato in modo curativo, carcinoma della cervice o della mammella in situ trattato in modo curativo o altro tumore primitivo trattato con intento curativo, assenza di nota malattia attiva e nessun trattamento somministrato negli ultimi 3 anni;
n.emopoiesi extramidollare instabile che potrebbe rappresentare un rischio di imminente compromissione neurologica;
o.anamnesi attuale o prossima di disturbo psichiatrico che, secondo l'opinione dello sperimentatore o del responsabile del monitoraggio clinico o suo collaboratore designato, potrebbe compromettere la capacità del soggetto di collaborare alle visite e alle indagini dello studio.
3.Splenectomia programmata durante il periodo di trattamento in studio o splenectomia effettuata nei 60 giorni precedenti alla firma del consenso informato.
Per la lista completa riferirsi al Protocol V4.0 datato14Aug2019. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is the hemoglobin response, defined as a =1.5 g/dL increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments at Weeks 16, 20, and 24 during the Fixed Dose Period.
The individual subject’s baseline Hb concentration is defined as the average of all available Hb concentrations collected from the central laboratory for that subject during the Screening Period up to the first dose of study treatment. |
The primary endpoint is the hemoglobin response, defined as a =1.5 g/dL increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments at Weeks 16, 20, and 24 during the Fixed Dose Period.
The individual subject’s baseline Hb concentration is defined as the average of all available Hb concentrations collected from the central laboratory for that subject during the Screening Period up to the first dose of study treatment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Weeks 16, 20 & 24 during the fixed dose period |
| Weeks 16, 20 & 24 during the fixed dose period |
|
| E.5.2 | Secondary end point(s) |
Key secondary endpoint:
· Average change from baseline in Hb concentration at Weeks 16, 20, and 24
Other secondary endpoint:
· Maximal Hb concentration increase from baseline
· Time to first achieve an increase in Hb concentration of 1.5 g/dL or more from baseline
· Average change from baseline at Weeks 16, 20, and 24 in markers of hemolysis: bilirubin, LDH, and haptoglobin levels
· Average change from baseline at Weeks 16, 20, and 24 in markers of hematopoietic activity: reticulocyte percentages
· Change from baseline in HRQoL PRO scores: Pyruvate Kinase Deficiency Diary (PKDD) and Pyruvate Kinase Deficiency Impact Assessment (PKDIA)
· Change from baseline at Week 24 in other indicators of clinical activity: iron biomarkers
· Safety endpoints, including: the type, incidence, severity, and relationship to study treatment of AEs and SAEs; number of discontinuations due to AEs; results of clinical laboratory tests over time (eg, serum chemistry, LFT, hematology, lipids, sex steroids, urinalysis, coagulation); physical examination (PE) findings; dual-energy x-ray absorption (DXA) scans; vital signs; 12-lead electrocardiogram (ECG) data
· Pharmacokinetic endpoints, including plasma concentrations over time and pharmacokinetic parameters of AG-348 (eg, AUC, Cmax, others as applicable)
Exploratory endpoint:
· Exposure-response (or pharmacokinetic-pharmacodynamic) relationship between relevant pharmacokinetic parameters and endpoints that are indicators of clinical activity
· Change from baseline in additional markers of hematopoietic activity: soluble transferrin receptor
· Change from baseline in PKR protein level
· Relationship between baseline PKR protein level and Hb response status
· Change from baseline in HRQoL PRO scores: European quality of life five-dimensional descriptive system (EQ-5D-5L)
· Change from baseline in PKR flux assay results
· Proportion of subjects requiring transfusions and the total number of RBC units transfused
· Use of iron chelation therapy over time
· Change from baseline over time in LIC as assessed by magnetic resonance imaging
|
| - |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
· Hematology: Scrn, D1, W2, 3, 4, 6, 7, 8, 10, 12, 16, 20, 24 & FUV
· Markers of erythopoietic activity: Scrn, D1, W12 & 24
· Circulating heme: Scrn, D1, W12 & 24
· PKDD: daily thourought Scrn, part 1 & 2
· PKDIA: Scrn, W4, 8, 12, 16, 20, 24,
· Iron panel & markers: Scrn, D1, W12 & 24
· PE: Scrn, D12, W12 & 24
· DXA: Scrn, W24
· ECG: Scrn, D12, W12 & 24, FUV
· Serum chemistry: Scrn, D1, W12, 24 & FUB
· Coag studies & urinalysis: Scrn, D1, W12 & 24
· LFT & LDH: Scrn, D1, W2, 4, 6, 8, 10, 12, 16, 20, 24 & FUV
· AEs: allthrough the study
· PK assessments: D1, W2, 6, 12 & 16 Exploratory:
· Soluble transferrin receptor: D1, W12 & 24
· EQ-5D-5L: Scrn, W12 & 24
· PKR prot: D1; W16
· PKR flux assay: D1, W12
· Liver MRI: Scrn, 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 | 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
Part 1 individualized dose optimization followed by a part 2 fixed-dose
period
|
| Part 1 individualized dose optimization followed by a part 2 fixed-dose period |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 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 |
| Brazil |
| Canada |
| Japan |
| Korea, Republic of |
| Thailand |
| Turkey |
| United States |
| Czechia |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| Portugal |
| Spain |
| Switzerland |
| United Kingdom |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 15 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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