| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pyruvate Kinase Deficiency |
| Deficiencia de piruvato cinasa |
|
| E.1.1.1 | Medical condition in easily understood language |
| Lack of Pyruvate Kinase enzyme |
| Carencia de la enzima de piruvato cinasa |
|
| 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 | 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 |
| The primary objective of the study is to evaluate the efficacy of treatment with AG-348, as assessed by the reduction in transfusion burden. |
| El objetivo principal del estudio es evaluar la eficacia del tratamiento con AG 348, determinada mediante la reducción en el número de transfusiones. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objective of this study is to evaluate the safety of treatment with AG-348.
Exploratory objectives are:
• To determine the effect of AG-348 on liver iron status, as measured by:
− Liver iron concentration (LIC)
− Use of iron chelation therapy
• To evaluate health-related quality of life (HRQoL), as determined using patient-reported outcomes
• To evaluate the pharmacokinetics of AG-348 following oral administration
• To evaluate the change in the levels of red blood cell-specific form of pyruvate kinase (PKR) protein in whole blood |
el objetivo secundario de este estudio es evaluar la seguridad del tratamiento con AG 348.
Exploratorios:
• Determinar el efecto de AG 348 en el estado del hierro en el hígado mediante:
La concentración de hierro en el hígado (CHH)
La utilización de terapia quelante del hierro
• Evaluar la calidad de vida relacionada con la salud (CVRS), determinada mediante los resultados comunicados por los pacientes
• Evaluar la farmacocinética de AG 348 tras la administración oral
• Evaluar el cambio en los niveles de una forma de la proteína piruvato cinasa específica de los glóbulos rojos (PKR) en sangre completa |
|
| 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 male or female, aged 18 years and older.
3. Have 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 a history of a minimum of 6 transfusion episodes in the 52-week period prior to date of informed consent as documented in the transfusion history of the subject.
5. Have complete records of transfusion history, defined as having the following available for the 52 weeks prior to the date of informed consent: (1) all the transfusion dates, (2) the number of blood units transfused for all the transfusions, and (3) Hb levels within 1 week prior to transfusion for at least 80% of the transfusions.
6. Received at least 0.8 mg of oral folic acid daily for at least 21 days prior to the first dose of study drug, to be continued daily during study participation.
7. Have adequate organ function, as defined by:
a. Serum AST ≤2.5 × ULN (unless the increased AST is assessed by the Investigator as due to hemolysis and/or hepatic iron deposition) and 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 hepatocellular or biliary disease.
c. Serum creatinine ≤1.25 × ULN. If serum creatinine is >1.25 × ULN, then 24-hour measured or calculated (Cockcroft-Gault) glomerular filtration rate (GFR) must be ≥60 mL/min.
d. Absolute neutrophil count (ANC) ≥1.0 × 109/L
e. Platelet count ≥100 × 109/L
f. Activated partial thromboplastin time (aPTT) and international normalized ratio (INR) ≤1.25 × ULN, unless the subject is receiving therapeutic anticoagulants
8. For women of reproductive potential— defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy, or tubal occlusion; or who have not been naturally postmenopausal (ie, who have not menstruated at all for at least the preceding 12 months and have an elevated follicle-stimulating hormone (FSH) level indicative of menopause at screening):
a. Have a negative serum pregnancy test during Screening.
b. For women of reproductive potential as well as fertile men and their partners who are women of reproductive potential:
− Be abstinent as part of their usual life style, or agree to use 2 effective forms of contraception from the time of giving informed consent, during the study, and for 30 days (both men and women) following the last dose of AG-348. An effective form of contraception is defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, double-barrier method (eg, synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), or male partner sterilization.
9. Be willing to comply with all study procedures, in particular the Individual TT (calculated based on 52 weeks of transfusion history), for the duration of the study. |
1. Haber firmado el consentimiento informado por escrito antes de realizar algún procedimiento del estudio, incluidos los procedimientos de selección.
2. Hombres o mujeres de 18 años o mayores.
3. Haber documentado la presencia de al menos 2 alelos mutantes en el gen PKLR, de los cuales al menos uno es una mutación de cambio de sentido, determinada mediante la prueba de genotipificación realizada por el laboratorio de genotipificación central del estudio.
4. Tener una historia de al menos 6 episodios de transfusiones en el periodo de 52 semanas previo a la fecha de la firma del consentimiento informado como se documenta en la historia de transfusiones del sujeto.
5. Tener datos completos de la historia de transfusiones, que se define como tener los siguientes datos disponibles de las 52 semanas anteriores a la fecha de la firma del consentimiento informado: (1) todas las fechas de las transfusiones, (2) el número de unidades de sangre transfundidas en cada una de las transfusiones y (3) niveles de hemoglobina (Hb) en la semana anterior a la transfusión para al menos el 80 % de las transfusiones.
6. Haber recibido al menos 0,8 mg de ácido fólico al día por vía oral durante al menos 21 días antes de la primera dosis del medicamento del estudio, y continuar así durante la participación en el estudio.
7. Tener una función orgánica adecuada, definida mediante:
a. Aspartato aminotransferasa (AST) en suero ≤2,5 × límite superior de la normalidad (LSN) (a menos que el aumento en AST se deba a hemólisis y/o deposición de hierro en el hígado según la evaluación del investigador) y alanina aminotransferasa (ALT) en suero ≤2,5 × LSN (a menos que el aumento en ALT se deba a deposición de hierro en el hígado según la evaluación del investigador);
b. Niveles normales o elevados de bilirrubina sérica. En los sujetos con la bilirrubina sérica >LSN, el aumento se debe atribuir a hemólisis con o sin síndrome de Gilbert y no se debe asociar a enfermedad hepatocelular o biliar;
c. Creatinina sérica ≤1,25 × LSN. Si la creatinina sérica es >1,25 × LSN, entonces el filtrado glomerular en 24 horas medido o calculado (Cockcroft-Gault) debe ser ≥60 ml/min;
d. Recuento absoluto de neutrófilos ≥1,0 × 109/l;
e. Recuento de plaquetas ≥100 × 109/l;
f. Tiempo de tromboplastina parcial activado y razón internacional normalizada ≤1,25 × LSN, a menos que el sujeto esté tomando anticoagulantes terapéuticos.
8. Las mujeres con capacidad reproductiva —es decir, mujeres sexualmente maduras que no se han sometido a histerectomía, ooforectomía bilateral o ligadura de trompas, o que no son posmenopáusicas de forma natural (se define mujer posmenopáusica como aquella que no ha tenido la menstruación en los últimos 12 meses y que tiene los niveles de la hormona estimuladora de folículos elevados, lo que indica menopausia en la selección):
a. Tienen un resultado negativo en una prueba de embarazo en suero durante la selección
b. Las mujeres con capacidad reproductiva así como los hombres fértiles y sus parejas que son mujeres con capacidad reproductiva:
no deben mantener relaciones sexuales como parte de su estilo de vida habitual o deben aceptar el uso de 2 anticonceptivos efectivos desde el momento de otorgar el consentimiento informado, durante el estudio y durante 30 días (tanto hombres como mujeres) tras la última dosis de AG 348. Los anticonceptivos efectivos son los anticonceptivos hormonales orales, inyectables, parches, dispositivos intrauterinos, método de doble barrera (p. ej., preservativo, diafragma o capuchón cervical con espuma, crema o gel espermicida), o esterilización de la pareja masculina.
9. Estar dispuesto a cumplir con todos los procedimientos del estudio, especialmente el desencadenante de la transfusión individual (calculado según la historia de transfusiones de 52 semanas), durante todo el estudio. |
|
| E.4 | Principal exclusion criteria |
1. Be homozygous for the R479H mutation or have 2 non-missense mutations 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 participate 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 mm Hg or diastolic BP >90 mm Hg) refractory to medical management.
b. History of recent (within 6 months prior to providing 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 (QTcF) >450 msec 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 hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibody (Ab) 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 re-screened after receiving appropriate hepatitis C treatment.
j. Positive test for human immunodeficiency virus (HIV)-1 or -2 Ab.
k. Active infection requiring the use of parenteral antimicrobial agents or ≥Grade 3 in severity (per NCI CTCAE) within 2 months prior to first dose of study drug.
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 the Medical Monitor, could compromise the ability of the subject to cooperate with study visits and procedures.
3. Have a history of transfusions occurring on average more frequently than once every 3 weeks during the 52 weeks prior to signing the ICF.
4. Have a splenectomy scheduled during the study treatment period or have undergone splenectomy within 60 days prior to the Screening Visit.
5. Be currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo. Prior participation in the PK Deficiency NHS (NCT02053480) or PK Deficiency Registry is permitted; subjects enrolling in this current study will be expected to temporarily suspend participation in the NHS or Registry.
6. Have exposure to any investigational drug, device, or procedure within 3 months prior to the first dose of study drug.
7. Have a prior bone marrow or stem cell transplant.
8. Be currently pregnant or breastfeeding.
9. Have a history of major surgery within 6 months of providing informed consent. Note that procedures such as laparoscopic gallbladder surgery are not considered major in this context.
10. Is currently receiving medications that are strong inhibitors of CYP3A4, 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 times their half-life prior to start of study drug dosing (Day 1 of Part 1).
11. Have a history of allergy to sulfonamides if characterized by acute hemolytic anemia, anaphylaxis, or rash of erythema multiforme type or Stevens-Johnson syndrome, or other serious clinical manifestations.
12. Have a history of hypersensitivity to AG-348 or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, and mannitol) |
1. Ser homocigotos para la mutación R479H o tener 2 mutaciones que no son de cambio de sentido en el gen PKLR, determinado mediante la prueba de genotipificación realizada por el laboratorio de genotipificación central del estudio.
2.Tener una afección médica significativa que conlleve un riesgo inaceptable para participar en el estudio y/o que pueda confundir la interpretación de los datos del estudio: a. hipertensión con control deficiente (definida como tensión arterial sistólica >150 mmHg o tensión arterial diastólica >90 mmHg) que no responde al manejo médico// b. antecedentes recientes (6 meses anteriores) de insuficiencia cardiaca congestiva, infarto de miocardio , angina de pecho inestable; ictus hemorrágico, embólico o trombótico; trombosis venosa profunda; o embolia pulmonar o arterial// c. disritmias cardiacas que se consideren clínicamente significativas// d. intervalo QT corregido para la frecuencia cardiaca según el método de Fridericia >450 ms con la excepción de los sujetos con bloqueo de la rama derecha o izquierda// e. colelitiasis o colecistitis clínicamente sintomáticas. //f. antecedentes de hepatitis colestásica inducida por medicamentos// g. sobrecarga de hierro con un diagnóstico clínico de insuficiencia cardiaca (p. ej., deterioro clínicamente significativo de la fracción de eyección del ventrículo izquierdo), insuficiencia hepática (p. ej., fibrosis, cirrosis) o insuficiencia pancreática (p.ej.diabetes)//h.tener un diagnóstico de otro trastorno de la sangre congénito o adquirido, o cualquier otro proceso hemolítico, excepto aloimunización leve, como consecuencia del tratamiento transfusional//i. dar positivo en la prueba del antígeno de superficie de la hepatitis B o de anticuerpos (Ac) contra el virus de la hepatitis C (VHC) con signos de infección activa por el virus de la hepatitis B o C. //j .dar positivo en la prueba de Ac contra el virus de la inmunodeficiencia humana de tipo 1 o de tipo 2//k. tener una infección activa que requiera el uso de antimicrobianos parenterales o cuya gravedad sea de grado ≥3 en los 2 meses anteriores a la primera dosis del medicamento del estudio// l.diabetes mellitus que el investigador considere que está bajo control deficiente o que requiera >3 antidiabéticos, incluida insulina // m. antecedentes de un cáncer primario, a excepción de: cáncer de piel no melanomatoso; cáncer de mama o de cuello uterino; u otro tipo de tumor primario tratado con intención de curar, sin presencia de enfermedad activa conocida y para el que no se ha administrado ningún tratamiento en los últimos 3 años// n.hematopoyesis extramedular inestable que conlleve un riesgo de compromiso neurológico inminente// o .antecedentes recientes o presencia actual de un trastorno psiquiátrico que pueda comprometer la capacidad del sujeto de cooperar en las visitas y los procedimientos del estudio.
3.Tener una historia de transfusiones que como media ocurren con más frecuencia que 1 vez cada 3 semanas durante las 52 semanas previas a la firma del consentimiento informado.
4.Tener programada una esplenectomía durante el periodo de tratamiento del estudio o haberse sometido a una esplenectomía en los 60 días anteriores a la visita de selección.
5.Estar participando actualmente en otro ensayo clínico terapéutico que implique un tratamiento actual con medicamento en investigación o comercializado o un placebo. Está permitido haber participado previamente en el estudio de historia natural (NHS) de la deficiencia de PK (NCT02053480) o en el registro de deficiencia de PK; se espera que los sujetos que participen en este estudio suspendan temporalmente su participación en el estudio NHS o en el registro.
6.Haberse expuesto a algún medicamento, dispositivo o procedimiento en investigación en los 3 meses anteriores a la primera dosis del medicamento del estudio.
7.Tener un trasplante previo de médula ósea o de células madre.
8.Estar embarazada o en periodo de lactancia materna.
9.Tener antecedentes de cirugía mayor en los 6 meses anteriores a la firma del consentimiento informado. Los procedimientos como cirugía de vesícula por laparoscopia no se consideran cirugía mayor en este contexto.
10.Estar actualmente recibiendo medicamentos que sean inhibidores potentes del citocromo P450 (CYP) 3A4, inductores potentes de CYP3A4, inhibidores potentes de la glucoproteína P (P-gp) o digoxina (un sustrato sensible a la P-gp) o que no se hayan dejado de tomar durante un tiempo de al menos 5 veces la semivida de cada uno de ellos antes de comenzar la administración del medicamento del estudio (día 1 de la parte 1).
11. Tener antecedentes de alergia a las sulfonamidas si se caracteriza por anemia hemolítica aguda, anafilaxia o exantema de tipo eritema multiforme o síndrome de Stevens-Johnson, u otras manifestaciones clínicas graves.
12. Tener antecedentes de hipersensibilidad a AG-348 o a sus excipientes (celulosa microcristalina, croscarmelosa sódica, fumarato sódico de estearilo y manitol). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of this study is the proportion of subjects who achieve a reduction in transfusion burden, defined as a ≥33% reduction in the number of RBC units transfused during the 24 weeks of Part 2 compared with the historical transfusion burden standardized to 24 weeks (Standardized Control Period). |
| La variable principal de este estudio es la proporción de sujetos que alcanzan una reducción en el número de transfusiones, definida como una reducción ≥33 % en el número de unidades de hematíes transfundidas durante las 24 semanas de la parte 2 en comparación con el número histórico de transfusiones estandarizado a 24 semanas (periodo de control estandarizado). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| All through the study: for each transfusion administered at any time during the study, the date of transfusion, number of RBC units transfused, HCT, and volume of RBC units will be recorded. |
| Durante todo el estudio: para cada transfusión administrada en cualquier momento durante el estudio, se registrarán la fecha de la transfusión, el número de unidades de hematíes transfundidas, el HCT y el volumen de unidades de hematíes. |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints
The secondary endpoints of the study are the following:
• Annualized total number of RBC units transfused during the study (both Part 1 and Part 2) compared with the historical transfusion burden
• Number of transfusion episodes during Part 2 compared to the Standardized Control Period
• Proportion of subjects who become transfusion-free, defined as 0 transfusions administered during Part 2
• Proportion of subjects who achieve Hb levels in the normal range at least once, 8 weeks or more after a transfusion in Part 2
• The type, incidence, severity, and relationship to treatment of adverse events (AEs) and serious adverse events (SAEs); AEs leading to treatment dose reduction, treatment interruption, and treatment discontinuation
• Clinical laboratory tests over time (serum chemistry/liver function tests/lactate dehydrogenase, hematology, coagulation, lipids, sex steroids, urinalysis), physical examination findings, dual energy x-ray absorptiometry (DXA) scans (hip and lumbar spine), vital signs, and 12-lead electrocardiograms (ECGs)
Exploratory Endpoints
The exploratory endpoints of the study are the following:
• Change from baseline over time in LIC as assessed by magnetic resonance imaging
• Change from baseline over time in usage of iron chelation therapy
• Changes from baseline over time in HRQoL scores (eg, Pyruvate Kinase Deficiency Impact Assessment, Pyruvate Kinase Deficiency Diary, EuroQol-5D-5L, Patient Global Impression of Severity)
• Characterization of pharmacokinetic profile (drug concentrations over time) and determination of pharmacokinetic parameters of AG-348 (eg, area under the plasma concentration × time curve, maximum (peak) concentration, and others as applicable) in Part 2
• Changes in total PKR protein levels. Changes in pyruvate kinase muscle isozyme protein levels and levels of intermediates in the metabolic pathways affected by PKR may also be assessed to further elucidate the mechanism and effects of PKR activation by AG-348 (only in subjects who have agreed to have this optional test performed). |
Las variables secundarias del estudio son las siguientes:
•Número total anualizado de unidades de hematíes transfundidas durante el estudio (parte 1 y parte 2) en comparación con el número histórico de transfusiones.
•Número de episodios de transfusiones durante la parte 2 en comparación con el periodo de control estandarizado.
•Proporción de sujetos que dejan de necesitar transfusiones, es decir, 0 transfusiones administradas durante la parte 2.
•Proporción de sujetos que alcanzan niveles de Hb dentro de los valores normales al menos una vez, 8 semanas o más después de una transfusión en la parte 2.
•El tipo, la incidencia, la gravedad y la relación con el tratamiento de los acontecimientos adversos (AA) y de los acontecimientos adversos graves (AAG); los AA que den lugar a una reducción de la dosis del tratamiento, a la interrupción del tratamiento y a la suspensión del tratamiento.
•Analíticas clínicas a lo largo del tiempo (bioquímica sérica/pruebas de la función hepática/lactato deshidrogenasa, hematología, coagulación, lípidos, hormonas esteroides, análisis de orina), resultados de la exploración física, absorciometría con rayos X de doble energía (DXA) (cadera y espina lumbar), constantes vitales y electrocardiogramas de 12 derivaciones (ECG). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary:
Transfusion & AE: all through the study
Physical exa: Scr, part 1 d1, wk12, part 2 d1, wk12, 24 + FU (ED)
Vital sign, Hematology, Liver function: all visits
ECG: Scr, part 1 d1, part 2 d1, FU
DXA scan: Scr, part 2 d1, wk24, FU (ED)
Serum chem.: Scr, part 1 d1, wk12, part 2 d1, wk12, 24, FU
Coagulation & Urinalysis: Scr, part 1 d1, wk12, part 2 d1, wk12, 24, FU
Lipid: part 1 d1, wk6, 12, 18, part 2 d1, wk4, 8, 12, 18, 24, FU
Sex steroids: part 1 d1, wk4, 8, 12, 16, 20, 24, part 2 d1, wk4, 8, 12, 18, 24, FU
Exploratory:
MRI: Scr, part 2 d1, wk24, FU (ED)
Iron panel: Scr, part 1 d1, wk12, part 2 d1, wk24, FU (ED)
HRQoL assess.: Scr, part 1 d1, wk4, 8, 12, 16, 20, 24, part 2 d1, wk 4, 8, 12, 18, 24, FU
PK profile: part 2 wk 24
PKR prot.: Scr, part 1 d1, part 2 wk 24 |
Secund.Transf y EA: Durante todo el estudio/ Examen físico: Selec, part 1 D1, S12, part 2 D1, S12, 24 + Seguim/ Signos vitales, hemat., funcion hepatica: Todas las visitas/ ECG: Selec, part 1 D1, part 2 D1, Seguim/ DXA Scan: Selec, part 2 D1, S21, Seguim/ Q. sérica: Selec, part 1 D1, S12, part 2 D1, S12, 24 + Seguim/ Coag. y análisis orina: Selec, part 1 D1, S12, part 2 D1, S12, 24 + Seguim/ Lidipos: Part 1 D1, S6, 12, 18, part 2 D1, S4,8,12,18, 24, Seguim/ Ester. Sex.: part 1 D1, S 4,8,12,16,20,24, part 2 D1, S 4,8,12,18,24, Seguim.
Explor.:RMI: Selec, part 2 D1, S24, Seguim/ Panel hierro: Selec, part 1 D1, S12, part 2 D1, S24, Seguim/ Cuest. Calidad Vida: Selec, part 1 D1, S4,8,12,16,20,24, part 2 D1, S4,8,12,18,24, Seguim./ Perfil FC: part 2 S24/ Prot. PKR: Selec, part 1 D1, part 2 S24 |
|
| 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| 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 | No |
| 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 |
| Denmark |
| France |
| Ireland |
| Italy |
| Japan |
| Netherlands |
| Spain |
| United Kingdom |
| 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
|
| LVLS |
| Última Visita del Último Paciente |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 27 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 21 |
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