| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Hepatitis B virus (HBV) infection |
| Infección por hepatitis crónica B |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Hepatitis B virus (HBV) infection |
| Infección por hepatitis crónica B |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10008910 |
| E.1.2 | Term | Chronic hepatitis B |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 is to study the virological efficacy of both stopping NUC and stopping NUC after SLGN treatment compared to a control arm (NUC taken continuously for 76 weeks) which is defined as the standard of care for CHB treatment in HBeAg negative patients. |
| Evaluar si suspender los NUC o suspender los NUC después de la administración de SLGN puede aumentar la tasa de disminución de AgHBs en comparación con el tratamiento de referencia de la HBC en pacientes con HBC sin cirrosis con supresión vírica que son negativos para AgHBe. Los análisis exploratorios ayudarán a dilucidar si las modificaciones en el entorno inmunitario del hígado son responsables de la disminución de AgHBs. |
|
| E.2.2 | Secondary objectives of the trial |
In terms of efficacy :
o To assess and compare virological responses at each time point (HBsAg decline, reduction in HBsAg levels, loss of HBsAg)
o To evaluate changes in serum HBsAg, HBcrAg, HBV RNA and HBV DNA from baseline and at each timepoint.
o To assess the time to HBsAg loss.
o To assess rates and time to HBsAb seroconversion
In terms of safety/tolerance:
o To describe ALT flares at each time point.
o To assess all grade AEs
o To assess the re-treatment rate (NUC therapy)
In terms of quality of life :
o To assess and compare health-related quality of life, evaluated using the EuroQol five-dimensions questionnaire (EQ-5D-5L), at baseline, W28 and W76 (WP7, see appendices 5 & 6).
Exploratory objectives, to evaluate:
o The modulation of innate immune responses
o The reconstitution of HBV-specific adaptive responses
o The evolution of HBV intra-hepatic markers
o Evolution of viral genome integration burden in selected patients by capture-sequencing. |
En términos de eficacia:
o Evaluar y comparar las respuestas virológicas en cada momento.
o Evaluar los cambios en el HBsAg, el HBcrAg, el ARN del VHB y el ADN del VHB en suero desde el inicio y en cada punto de tiempo.
o Evaluar el tiempo de pérdida de HBsAg.
o Evaluar las tasas y el tiempo de seroconversión de HBsAb
En términos de seguridad / tolerancia:
o Describir los destellos ALT en cada momento.
o Evaluar todos los EA.
o Evaluar la tasa de retratamiento.
En términos de calidad de vida:
o Evaluar y comparar la calidad de vida relacionada con la salud, evaluada mediante el cuestionario de cinco dimensiones EQ-5D-5L, al inicio, W28 y W76.
Objetivos exploratorios, para evaluar:
o La modulación de las respuestas inmunitarias innatas
o La reconstitución de respuestas adaptativas específicas del VHB
o La evolución de los marcadores intrahepáticos del VHB
o Evolución de la carga de integración del genoma viral en pacientes seleccionados. |
|
| 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 |
| A cost-effectiveness study will be performed from data collected as part of the protocol. For the cost-effectiveness study, a quality of life questionnaire will be filled out at W0, W28 and W76. |
| Se realizará un estudio de rentabilidad a partir de los datos recopilados como parte del protocolo. Para el estudio de coste-efectividad, se completará un cuestionario de calidad de vida en W0, W28 y W76. |
|
| E.3 | Principal inclusion criteria |
1) Patients with HBeAg negative CHB on documented NUC for ≥ 3 years with HBV DNA LLOQ by local assay by polymerase chain reaction (PCR) documented at least annually over the last 3 years. NUC can include only tenofovir/TDF, tenofovir/TAF or entecavir,
2) HBsAg > 100 IU/mL but < 1,000 IU/mL at screening,
3) Male and female subjects aged 18 to 70 years (inclusive) at the day of screening,
4) Ultrasound, computed tomography (CT) scan, or magnetic resonance imaging (MRI) within 6 months of screening date with no evidence of hepatocellular carcinoma (HCC),
5) No evidence of advanced fibrosis or cirrhosis at screening: Elastography (Fibroscan) value ≤ 9 kPa and ultrasonography without any sign of cirrhosis and platelets ≥ 150x109/L,
6) No evidence of advanced fibrosis or cirrhosis before the onset of NUC therapy,
7) HBV DNA < 20 IU/mL at screening,
8) ALT levels within the normal range of the local lab (< ULN) at screening,
9) Negative urine or serum pregnancy test (for women of childbearing potential) documented within the 24-hour period prior to the first dose of IMP. If the urine pregnancy test is positive, a follow-up serum test is required for confirmation,
10) Women of childbearing potential must agree to use a highly effective method of contraception from screening throughout the study period and for 7 days after the last dose of study drug. Men with female partners who are of childbearing potential must agree that they or their partners will use a highly effective method of contraception from screening throughout the study period and for 7 days after the last dose of study drug.
a) Women of childbearing potential are sexually mature women who have not undergone bilateral oophorectomy or hysterectomy; or who have not been postmenopausal (ie, who have not menstruated at all) for at least 1 year.
b) Highly effective methods of contraception not using hormonal contraceptives will be intrauterine device, tubal sterilization, Essure microinsert system; male partner sterilization; or total abstinence from heterosexual intercourse, when this is the preferred and usual lifestyle of the subject. Note: The double-barrier method (eg, synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), periodic abstinence (such as calendar, symptothermal, post-ovulation), withdrawal (coitus interruptus), lactational amenorrhea method, and spermicide only are not acceptable as highly effective methods of contraception.
11) Screening Electrocardiogram (ECG) without clinically significant abnormalities and with QTcF interval (QT corrected using Fridericia’s formula) ≤ 450 msec for males and ≤ 470 msec for females,
12) Must be willing and able to comply with all study requirements,
13) Must have the ability to understand and sign a written informed consent form (ICF),
14) Participant covered by Health Insurance (for French participants) |
1) Pacientes con HBC negativos para AgHBe con registro de NUC durante ≥ 3 años con el LLOQ del ADN del VHB por ensayo local mediante la reacción en cadena de la polimerasa (RCP) registrada al menos una vez al año durante los últimos 3 años. Entre los NUC se pueden incluir solo tenofovir/TDF, tenofovir/TAF o entecavir,
2) AgHBs > 100 UI/mi pero < 3000 UI/ml en la selección,
3) Sujetos hombres y mujeres con edades comprendidas entre los 18 y 70 años (ambos incluidos) el día de la selección,
4) Ecografía, tomografía axial computarizada (TAC) o resonancia magnética (RM) en los 6 meses anteriores a la fecha de selección sin indicios de carcinoma hepatocelular (CHC),
5) Sin indicios de fibrosis avanzada ni cirrosis en la selección: Valores de la elastografía (FibroScan) ≤ 9 kPa y ecografía sin indicios de cirrosis y plaquetas ≥ 150 x109/l,
6) Sin indicios de fibrosis avanzada ni cirrosis antes del inicio del tratamiento con NUC,
7) ADN del VHB < 20 UI/ml en la selección,
8) Niveles de ALAT dentro del rango normal del laboratorio local (< LSN) en la selección,
9) Prueba de embarazo en orina o suero negativa (para mujeres fértiles) registrada en un plazo de 24 horas antes de la primera dosis del MI. Si la prueba de embarazo en orina da positivo, será necesario confirmación mediante una prueba complementaria en suero,
10) Las mujeres fértiles deben acceder a utilizar un método anticonceptivo de alta eficacia.
11) Electrocardiograma (ECG) en la selección sin anomalías significativas desde un punto de vista clínico y con intervalo QTcF (QT corregido por la fórmula de Fridericia) ≤ 450 ms para hombres y ≤ 470 ms para mujeres,
12) Deben poder y querer cumplir todos los requisitos del estudio,
13) Deben poder entender y firmar un formulario de consentimiento informado (FCI),
14) Participante cubierto por un seguro médico (para los participantes franceses) |
|
| E.4 | Principal exclusion criteria |
1) Any history of decompensation of liver disease including history of ascites, encephalopathy and gastrointestinal bleeding,
2) Any sign of oesophageal and/or gastric varices,
3) Laboratory parameters not within defined thresholds:
a) White blood cells < 4,000 cells/μL (< 4.0×109/L);
b) Hemoglobin < 11 g/dL (< 110 g/L) for females, < 13 g/dL (< 130 g/L) for males;
c) Platelets < 130,000 per μL (< 130×109/L);
d) Albumin < 3.5 g/dL (< 35 g/L);
e) International normalized ratio (INR) > 1.5;
f) Total bilirubin > 1.2 mg/dL (> 20.52 μmol/L).
Note: subjects with an elevated indirect bilirubin and known Gilbert’s disease can be included if direct bilirubin is within normal limits.
g) Alpha-fetoprotein (AFP) > 20 ng/mL;
h) Creatinine clearance (using the Cockcroft-Gault method) < 60 mL/min;
4) Co-infection with hepatitis C virus (HCV) (antibodies anti-HCV positive), human immunodeficiency virus type 1 (HIV-1) (antibodies anti-HIV positive) or hepatitis D virus (HDV) (antibodies anti-HDV positive),
5) Evidence or history or suspicion of HCC,
6) Malignancy within 5 years prior to screening, with the exception of specific cancers that are cured by surgical resection (basal cell skin cancer, etc). Note: subjects under evaluation for possible malignancy are not eligible.
7) Significant cardiovascular, pulmonary, or neurological disease,
8) Received solid organ or bone marrow transplant,
9) Received within 3 months of screening or expected to receive prolonged therapy with immunomodulators (eg, corticosteroids, anti-TNF) or biologics (eg, monoclonal antibody, IFN),
10) Subjects currently taking medication(s) that are transported through organic anion transporting polypeptide 1 (OATP1) including, but not limited to: atazanavir, rifampin, cyclosporine, eltrombopag, gemfibrozil, lopinavir/ritonavir, and saquinavir,
11) Concomitant treatment with the following medications (if taken within 21 days prior the baseline visit through the end of treatment plus 7 days)/diet:
a) Hematologic stimulating agents (eg, erythropoiesis-stimulating agents; granulocyte colony stimulating factor [GCSF]; and thrombopoietin [TPO] mimetics),
b) Potent CYP3A4 inhibitors or inducers, including but not limited to antifungals (fluconazole, ketoconazole…), antibiotics (telithromycin, rifabutin, rifampicin…), St. John's Wort, grapefruit juice, anticonvulsants (carbamazepine, phenobarbital, phenytoin…) etc,
c) Immunosuppressant (except short term use of prednisone as a steroid burst [≤ 1 week of use]) and cytotoxic medications,
12) Known hypersensitivity or resistance to study drugs or formulation excipients,
13) Diagnosis of autoimmune disease (e.g., systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, autoimmune hepatitis, sarcoidosis, psoriasis of greater than mild severity, autoimmune uveitis), poorly controlled diabetes mellitus, significant psychiatric illness, severe chronic obstructive pulmonary disease, hemoglobinopathy, retinal disease, or immunosuppressed patients,
14) Use of another investigational agent within 6 months of screening and during the whole duration of the trial,
15) Current alcohol or substance abuse judged by the Investigator to potentially interfere with compliance,
16) Females who are breastfeeding, pregnant or may wish to become pregnant during the study,
17) Female subjects unwilling to refrain from egg donation and in vitro fertilization during and until at least 7 days after the last study drug dose. Male subjects unwilling to refrain from sperm donation during and until at least 7 days after the last study drug,
18) Any medical condition that, in the opinion of the investigator, could interfere with evaluation of the study objectives or safety of the subjects. |
1) Cualquier antecedente de descompensación de enfermedad hepática, como antecedentes de ascitis, encefalopatía y hemorragia gastrointestinal,
2) Cualquier signo de varices esofágicas o gástricas,
3) Valores analíticos fuera de los umbrales definidos:
a) Leucocitos < 4000 células/μl (< 4,0 × 109/l);
b) Hemoglobina < 11 g/dl (< 110 g/l) para las mujeres, < 13 g/dl (< 130 g/l) para los hombres;
c) Plaquetas < 130 000 por μl (< 130 × 109/l);
d) Albúmina < 3,5 g/dl (< 35 g/l);
e) Índice internacional normalizado (IIN) > 1,5;
f) Bilirrubina total > 1,2 mg/dl (> 20,52 μmol/l).
Nota: se podrá incluir a sujetos con una bilirrubina indirecta elevada y enfermedad de Gilbert conocida si la bilirrubina directa se encuentra dentro de los límites normales.
g) Alfafetoproteína (AFP) > 20 ng/ml;
h) Aclaramiento de creatinina (mediante el método de Cockcroft-Gault) < 60 ml/min;
4) Infección simultánea con el virus de la hepatitis C (VHC) (positivo por anticuerpos anti-VHC), virus de la inmunodeficiencia humana de tipo 1 (VIH-1) (positivo por anticuerpos anti-VIH) o virus de la hepatitis D (VHD) (positivo por anticuerpos anti-VHD),
5) Indicios, antecedentes o sospecha de carcinoma hepatocelular,
6) Neoplasia maligna en los 5 años anteriores a la selección, con la excepción de cánceres concretos que se curan mediante resección quirúrgica (cáncer de piel basocelular, etc.). Nota: los sujetos evaluados por posible neoplasia maligna quedarán excluidos.
7) Enfermedad cardiovascular, pulmonar o neurológica significativa,
8) Haber recibido un trasplante de órgano sólido o de médula ósea,
9) Haber recibido en los 3 meses anteriores a la selección o que se prevea recibir tratamiento prolongado con inmunomoduladores (p. ej., corticoesteroides, anti-FNT) o biofármacos (p. ej., anticuerpos monoclonales, interferones),
10) Sujetos que toman actualmente medicamentos que se transportan a través de polipéptidos transportadores de aniones orgánicos (OATP1) como, entre otros, atazanavir, rifampina, ciclosporina, eltrombopag, gemfibrozilo, lopinavir/ritonavir y saquinavir,
11) Tratamiento concomitante con los siguientes medicamentos (si se toman en los 21 días anteriores a la visita inicial hasta el final del tratamiento más 7 días)/dieta:
a) Agentes estimulantes hemáticos (p. ej., agentes estimulantes de la eritrocitopoyesis; factor estimulante de las colonias de granulocitos [FEC-G] y miméticos de la trombopoyetina [TPO]),
b) Inhibidores o inductores potentes del CYP3A4, como, entre otros, antifúngicos (fluconazol, ketoconazol...), antibióticos (telitromicina, rifabutina, rifampicina...), hierba de san Juan, zumo de pomelo, anticonvulsivos (carbamazepina, fenobarbital, fenitoína...), etc.,
c) Inmunodepresores (excepto el uso de corta duración de prednisona como tratamiento de choque con corticoides [≤ 1 semana de uso]) y medicamentos citotóxicos,
12) Hipersensibilidad conocida o resistencia a los medicamentos del estudio o a los excipientes de la fórmula,
13) Diagnóstico de enfermedad autoinmunitaria (p. ej., lupus eritematoso diseminado, artritis reumatoide, enfermedad intestinal inflamatoria, hepatitis autoinmunitaria, sarcoidosis, psoriasis de gravedad superior a leve, uveítis autoinmunitaria), diabetes mellitus mal controlada, enfermedad psiquiátrica significativa, enfermedad pulmonar obstructiva crónica grave, hemoglobinopatía, enfermedad retiniana o pacientes inmunodeprimidos,
14) Uso de otro medicamento en investigación en los 6 meses anteriores a la selección y durante todo el ensayo,
15) Consumo excesivo actual de alcohol o sustancias que, a juicio del investigador, podrían interferir con el cumplimiento,
16) Mujeres en periodo de lactancia, embarazadas o que deseen quedarse embarazadas durante el estudio,
17) Mujeres que no deseen abstenerse de donar óvulos y de realizarse una fecundación in vitro durante el estudio y en los 7 días posteriores a la última dosis del medicamento del estudio. Varones que no deseen abstenerse de donar esperma durante el estudio y en los 7 días posteriores a la última dosis del medicamento del estudio,
18) Cualquier enfermedad médica que, a juicio del investigador, pudiera interferir con la evaluación de los objetivos del estudio o la seguridad de los sujetos. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint for efficacy is the percentage of subjects with ≥ 1.0 log10 IU/mL decline of HBsAg |
| El criterio de valoración principal para la eficacia es el porcentaje de sujetos con una disminución de AgHBs ≥ 1,0 log10 UI/ml en la semana 76 en comparación con el inicio del estudio. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Week 76 compared to baseline |
| A la semana 76 |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints in terms of efficacy are:
o Percentage of subjects with HBsAg ≥ 0.3 log10 IU/mL decline at weeks 12, 24, 28, 36, 48, 76 compared to baseline
o Percentage of subjects with HBsAg ≥ 0.5 log10 IU/mL decline at weeks 12, 24, 28, 36, 48, 76 compared to baseline
o Percentage of subjects with HBsAg ≥ 1.0 log10 IU/mL decline at weeks 12, 24, 28, 36, 48 compared to baseline
o Percentage of subjects with HBsAg < 100 IU/mL at weeks 12, 24, 28, 36, 48, 76
o Percentage of subjects with HBsAg < 10 IU/mL at weeks 12, 24, 28, 36, 48, 76
o Percentage of subjects with HBsAg loss at weeks 12, 24, 28, 36, 48, 76 and time to HBsAg loss since baseline
o Percentage of subjects with HBsAb seroconversion at weeks 12, 24, 28, 36, 48, 76 and time to HBsAb seroconversion
o Changes in serum HBsAg, HBcrAg, HBV RNA and HBV DNA levels in log10 IU/mL from baseline to weeks 12, 24, 28, 36, 48, 76.
Secondary endpoints in terms of safety/tolerance are:
o Percentage of subjects reporting a grade 3 or 4 AE
o Percentage of all grade AEs
o Percentage of subjects with ALT flares at each time point (ALT flares defined as ≥ 10 x ULN)
o Percentage of subjects in whom NUC treatment has been re-initiated.
Secondary endpoints in terms of quality of life are:
o To assess and compare health-related quality of life, measured using EQ-5D-5L utility score (collected with a self-completed questionnaire, see appendix 5) at baseline, weeks 28 and 76 (WP7, see appendix 6).
Exploratory endpoints
o Evolution of serum cytokine/chemokine profiling and in phenotypic expression of innate cell surface markers between W0 and W76
o Evolution of gene expression profiling of innate immune genes between W0 and W76
o Evolution of memory- and exhaustion-related phenotypic parameters on intrahepatic and peripheral CD8 and CD4 T cells between W0 and W76
o Evolution of CD8- and CD4-mediated anti-viral activity expressed as cytokine production, cytotoxicity and capacity of expansion between W0 and W76
o Evolution of HBV-specific T cell metabolism, mitochondrial, proteasomal, DNA repair functions and epigenetic regulation between W0 and W76
o Evolution of deregulated transcriptional profiles of HBV-specific T cells between W0 and W76
o Evolution of intrahepatic levels of cccDNA and pgRNA by droplet digital PCR (ddPCR) between W20 and W32
o Description of cccDNA epigenenetic status by micro-ChIP and, in selected cases by cccDNA ChIP-Seq and/or cccDNA ATAC-Seq at W20 and W32
o Evolution of viral genome sequences obtained by NGS between W20 and W32.
o Frequency of viral genome integration in selected patients by capture-sequencing between W20 and W32. |
Los criterios de valoración secundarios en términos de eficacia son:
o Porcentaje de sujetos con disminución de AgHBs ≥ 0,3 log10 UI/ml en las semanas 12, 24, 28, 36, 48, 76 en comparación con el inicio del estudio
o Porcentaje de sujetos con disminución de AgHBs ≥ 0,5 log10 UI/ml en las semanas 12, 24, 28, 36, 48, 76 en comparación con el inicio del estudio
o Porcentaje de sujetos con disminución de AgHBs ≥ 1,0 log10 UI/ml en las semanas 12, 24, 28, 36, 48 en comparación con el inicio del estudio
o Porcentaje de sujetos con AgHBs < 100 UI/ml en las semanas 12, 24, 28, 36, 48, 76
o Porcentaje de sujetos con AgHBs < 10 UI/ml en las semanas 12, 24, 28, 36, 48, 76
o Porcentaje de sujetos con pérdida de AgHBs en las semanas 12, 24, 28, 36, 48, 76 y tiempo hasta la pérdida de AgHBs desde el inicio del estudio
o Porcentaje de sujetos con seroconversión de HBsAb en las semanas 12, 24, 28, 36, 48, 76 y tiempo hasta la seroconversión de HBsAb
o Cambios en niveles séricos de AgHBs, HBcrAg, ARN del VHB y el ADN del VHB en log10 UI/ml desde el inicio del estudio hasta las semanas 12, 24, 28, 36, 48, 76.
Los criterios de valoración secundarios en términos de seguridad/tolerancia son:
o Porcentaje de sujetos que notifican un AA de grado 3 o 4
o Porcentaje de AA de todos los grados
o Porcentaje de sujetos con empeoramientos de ALAT en cada momento temporal (los empeoramientos de ALAT se definen como ≥ 10 veces el LSN)
o Porcentaje de sujetos a los que se les ha reiniciado el tratamiento con NUC.
Los criterios de valoración secundarios en términos de calidad de vida son:
o Evaluar y comparar la calidad de vida relacionada con la salud, a través de la medición de la puntuación de utilidad del EQ-5D-5L (recogida con un cuestionario a cumplimentar por el paciente, ver apéndice 5) en el inicio del estudio, las semanas 28 y 76 (PT7, ver apéndice 6). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
For secondary endpoints in terms of efficacy : Weeks 12, 24, 28, 36, 48, 76 compared to baseline
For secondary endpoints in terms of safety/tolerance : End of the trial
For secondary endpoints in terms of quality of life are: at baseline, weeks 28 and 76
For Exploratory endpoints : between W0 and W76 or between W20 and W32. |
Para criterios de valoración secundarios en términos de eficacia: semanas 12, 24, 28, 36, 48, 76 en comparación con el valor inicial
Para criterios de valoración secundarios en términos de seguridad / tolerancia: Fin de la prueba
Los criterios de valoración secundarios en términos de calidad de vida son: al inicio, semanas 28 y 76
Para puntos finales exploratorios: entre W0 y W76 o entre W20 y W32. |
|
| 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 | No |
| 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 | 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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
| 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 | 6 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 the trial is defined as 12 months after the W76 visit of the last participant (LVLS), in order to complete all analyses |
| El final del ensayo se define como 12 meses después de la visita S76 del último participante (LVLS), para completar todos los análisis. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 33 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 33 |
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