Clinical Trials Register

Summary
EudraCT Number:	2021-003567-10
Sponsor's Protocol Code Number:	217023
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-11-19
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2021-003567-10

A.3

Full title of the trial

A phase 2, single-blinded, randomised, controlled multi-country study to evaluate the safety, reactogenicity, efficacy and immune response following sequential treatment with an anti-sense oligonucleotide (ASO) against chronic Hepatitis B (CHB) followed by chronic Hepatitis B targeted immunotherapy (CHB-TI) in CHB patients receiving nucleos(t)ide analogue (NA) therapy.

Estudio Fase II, simple ciego, aleatorizado, controlado e internacional para evaluar la seguridad, reactogenicidad, eficacia y respuesta inmune tras el tratamiento secuencial con un oligonucleótido antisentido (ASO) para la hepatitis B crónica (HBC) seguido de inmunoterapia dirigida contra la hepatitis B crónica (HBC-IT) en pacientes con HBC en tratamiento con análogos de nucleós(t)idos (AN).

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A study on the safety, efficacy and immune response following sequential treatment with an anti-sense oligonucleotide against chronic Hepatitis B (CHB) and chronic Hepatitis B targeted immunotherapy (CHB-TI) in CHB patients receiving nucleos(t)ide analogue (NA) therapy.

Estudio para evaluar la seguridad, eficacia y respuesta inmune tras el tratamiento secuencial con un oligonucleótido antisentido (ASO) para la hepatitis B crónica (HBC) e inmunoterapia dirigida contra la hepatitis B crónica (HBC-IT) en pacientes con HBC en tratamiento con análogos de nucleós(t)idos (AN).

A.3.2

Name or abbreviated title of the trial where available

TH HBV ASO-001

A.4.1

Sponsor's protocol code number

217023

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	GlaxoSmithKline SA
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	GlaxoSmithKline Biologicals
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	GlaxoSmithKline S.A.
B.5.2	Functional name of contact point	Centro de Información
B.5.3	Address:
B.5.3.1	Street Address	c/ Severo Ochoa, 2
B.5.3.2	Town/ city	Tres Cantos (Madrid)
B.5.3.3	Post code	28760
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34902202700
B.5.5	Fax number	+3491 8070479
B.5.6	E-mail	es-ci@gsk.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	GSK3228836
D.3.2	Product code	GSK3228836
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Bepirovirsen
D.3.9.1	CAS number	1403787-62-1
D.3.9.3	Other descriptive name	GSK3228836A
D.3.9.4	EV Substance Code	SUB208554
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	TH HBV adjuvanted recombinant proteins vaccine (80-80)
D.3.2	Product code	HBc-HBs/AS01B-4 80-80 vaccine component
D.3.4	Pharmaceutical form	Powder and suspension for suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NA
D.3.9.2	Current sponsor code	HBc
D.3.9.3	Other descriptive name	Recombinant HBV proteins HBc
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	80
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NA
D.3.9.2	Current sponsor code	HBs
D.3.9.3	Other descriptive name	Recombinant HBV proteins HBs
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	80
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	TH HBV MVA-HBV 2x10e8 pfu vaccine component
D.3.2	Product code	MVA-HBV 2x10e8 pfu
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NA
D.3.9.2	Current sponsor code	MVA-HBV
D.3.9.3	Other descriptive name	Modified Vaccinia Ankara HBV vaccine
D.3.10	Strength
D.3.10.1	Concentration unit	PFU plaque forming unit
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200000000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	Yes
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 4
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	TH HBV ChAd155-hli-HBV 5x10e10 vp vaccine component
D.3.2	Product code	ChAd155-hli-HBV 5x10e10 vp
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NA
D.3.9.2	Current sponsor code	ChAd155-hIi-HBV
D.3.9.3	Other descriptive name	Chimpanzee adenovirus HBV vaccine
D.3.10	Strength
D.3.10.1	Concentration unit	Vector genome
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50000000000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	Yes
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Intramuscular use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Hepatitis B virus (HBV) infection

Infección de virus de la hepatitis B (VHB)

E.1.1.1

Medical condition in easily understood language

HBV infection, especially chronic infection, is a significant worldwide medical problem that affects the liver.

La infección por el VHB, especialmente la crónica, es un importante problema médico mundial que afecta al hígado.

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10019731
E.1.2	Term	Hepatitis B
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Safety
• To assess the safety of sequential treatment with GSK3228836 and GSK3528869A in participants with CHB infection stable on NA therapy.
Efficacy
• To assess the efficacy of sequential treatment with GSK3228836 and GSK3528869A.
• To assess the efficacy of sequential treatment with GSK3228836 and GSK3528869A in comparison with GSK3228836 treatment.

Seguridad
• Evaluar la seguridad del tratamiento secuencial con GSK3228836 yGSK3528869A en participantes con una HBC estable en tratamiento con AN.
•Evaluar la eficacia del tratamientosecuencial con GSK3228836 yGSK3528869A.
•Evaluar la eficacia del tratamientosecuencial con GSK3228836 yGSK3528869A en comparación con eltratamiento con GSK3228836.

E.2.2

Secondary objectives of the trial

Safety
• To assess the safety of sequential treatment with GSK3228836 and GSK3528869A in participants with CHB infection stable on NA therapy.
Efficacy
• To assess the efficacy of sequential treatment with GSK3228836 and GSK3528869A in comparison with baseline in participants with CHB infection who are virally suppressed on NA therapy.
• To describe durability of Sustained Virologic Response (SVR)
Immunogenicity
• To assess the humoral and cellular immune responses specific to HBs and HBc antigens of sequential treatment with GSK3228836 and GSK3528869A in participants with CHB infection who are virally suppressed on NA therapy.

Seguridad
•Evaluar la seguridad del tratamientos ecuencial con GSK3228836 yGSK3528869A en participantes con una HBC estable en tratamiento con AN
•Evaluar la eficacia del tratamiento secuencial con GSK3228836 y GSK3528869A en comparación con los valores basales previos a la administración de los compuestos de GSK en estudio en participantes conHBC y supresión viral mediante el tratamiento con AN.
Inmunogenicidad
•Describir la durabilidad de la RVM
•Evaluar las respuestas inmunes humoraly celular específicas de los antígenosHBs y HBc con el tratamiento secuencialcon GSK3228836 y GSK3528869A enparticipantes con HBC y supresión viralmediante el tratamiento con AN.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Participants, who, in the opinion of the investigator, can and will comply with the requirements of the protocol.
• Written or witnessed/thumb printed informed consent obtained from the participant prior to performance of any study-specific procedure.
• A male or female between, and including, 18 and 65 years of age at the time of signing of the informed consent.
• Participants who are Hepatitis B envelop antigen (HBeAg) positive or negative.
• Participants who have documented chronic HBV infection ≥6 months prior to screening and currently receiving stable NA therapy population defined as no changes to their nucleos(t)ide regimen from at least 6 months prior to screening and with no planned changes to the stable regimen over the duration of the study.
• CHB patient, under and adherent to treatment with a NA with high barrier to resistance (e.g. entecavir, tenofovir disoproxil fumarate and tenofovir alafenamide).
• Participants with ALT ≤ 2x upper limit of normal (ULN) documented in last 6 months.
• Participants with plasma or serum HBsAg concentration >100 IU/mL.
• Participants must be adequately suppressed, defined as plasma or serum HBV DNA <90 IU/mL.
• A male participant is eligible to participate if they agree to the following during the intervention period and for at least 90 days after the last dose of study intervention
- Refrain from donating sperm
- AND be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent OR Must agree to use contraception/barrier as detailed below
o Agree to use a male condom [and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak] when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant
• A female participant is eligible to participate:
- If she is not pregnant or breastfeeding
- AND at least one of the following conditions applies:
o Is not a WOCBP
o Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency during the intervention period and for at least 90 days after the last dose of study treatment.
• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention.
- If a urine test cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.

Todos los participantes deberán cumplir TODOS los criterios siguientes en el momento de la incorporación al estudio:
•Participantes que, en opinión del investigador, puedan y vayan a cumplir los requisitos del protocolo (p. ej., cumplimentación de los diarios, asistencia a las visitas de seguimiento).
•Obtención del consentimiento informado por escrito o con la presencia de un testigo/firmado con la huella dactilar del paciente antes de realizar cualquiera de los procedimientos específicos del estudio.
•Pacientes de ambos sexos de 18 a 65 años, ambos inclusive, en el momento de la firma del consentimiento informado.
•Participantes con HBeAg positivo o negativo.
•Participantes con infección crónica documentada por el VHB ≥6 meses antes de la selección que estén recibiendo tratamiento estable con AN, definida como la ausencia de cambios en su pauta de nucleós(t)idos desde al menos 6 meses antes de la selección y sin cambios previstos en la pauta estable durante todo el estudio.
•Paciente con HBC bajo tratamiento (y cumpliéndolo) con un AN con una barrera elevada a la resistencia (p. ej., entecavir, tenofovir disoproxil fumarato y tenofovir alafenamida).
•Participantes con alanina transaminasa (ALT) 2 veces el límite superior de la normalidad (LSN) documentada en los últimos 6 meses.
•Participantes con una concentración plasmática o sérica de HBsAg >100 UI/ml.
•Los participantes deberán presentar una supresión adecuada, definida como una concentración plasmática o sérica de ADN del VHB <90 UI/ml.
•Un participante varón podrá participar si se compromete a lo siguiente durante el período de intervención y, como mínimo, durante los 90 días siguientes a la última dosis de la intervención del estudio:
Abstenerse de donar semen
Y practicar la abstinencia de relaciones heterosexuales como modo de vida preferido y habitual (abstinencia a largo plazo y persistente) y comprometerse a mantenerla O comprometerse a utilizar métodos anticonceptivos/de barrera como se detalla a continuación
o Compromiso de usar preservativo masculino [además de ser advertido de los beneficios de que la pareja utilice un método anticonceptivo muy eficaz, ya que el preservativo puede romperse o se puede producir una fuga] durante las relaciones sexuales con una mujer en edad fértil (MEF) que no esté embarazada.
• Una mujer podrá participar:
Si no está embarazada ni amamantando
Y se aplica al menos una de las condiciones siguientes:
o No es una MEF
o Es una MEF y utiliza un método anticonceptivo muy eficaz (con un índice de fallos <1 % anual), preferiblemente con baja dependencia de la usuaria, durante el período de intervención y, como mínimo, durante 90 días después de la última dosis del tratamiento del estudio.
•Las MEF deberán obtener un resultado negativo en una prueba de gran sensibilidad (orina o suero según exija la normativa local) en las 24 horas previas a la primera dosis de la intervención del estudio.
Cuando una prueba en orina no pueda confirmarse como negativa (p. ej., un resultado ambiguo), se exigirá una prueba de embarazo en suero. En tal caso, la mujer no podrá participar si el resultado de la prueba de embarazo en suero es positivo.

E.4

Principal exclusion criteria

Medical conditions
•Clinically significant abnormalities, aside from chronic HBV infection in medical history or physical examination
•Co-infection with: Current or past history of HCV,HIV,HDV
•History of or suspected liver cirrhosis and/or evidence of cirrhosis as determined by
-both AST-Platelet Index (APRI) >2 and FibroSure/FibroTest result >0.7
-Liver biopsy (i.e., METAVIR Score F4) or Liver stiffness >12 kPa
•FibroScan TE score >9.6 kPa and FibroTest score >0.59 at Screening
•Diagnosed or suspected HCC
•History of malignancy within the past 5 years with the exception of specific cancers that are cured by surgical resection
•History of vasculitis or presence of symptoms and signs of potential vasculitis
•History of extrahepatic disorders possibly related to HBV immune conditions
•Positive (or borderline positive) ANCA at screening
•Low C3/C4 at screening AND evidence of past history or current manifestations of vasculitic/inflammatory/autoimmune conditions
•History of alcohol or drug abuse/dependence
•QTcF ≥450 msec
•Laboratory results as follows:
-Serum albumin<3.5 g/dL
-GFR<60 mL/min/1.73m^2
-INR>1.25
-PLT count<140x10^9/L
-HGB<10 g/dl
-T Bil>1.25xULN unless it is considered as clinically not significant by the Investigator
-ACR≥0.03 mg/mg
•Medical history of hepatic decompensation
•Planned for liver transplantation or previous liver transplantation
•Documented evidence of other currently active cause of hepatitis
•Any other clinical condition that might pose additional risk to the participant due to participation in the study
•Major congenital defects
•Recurrent history or uncontrolled neurological disorders or seizures
•History of any reaction or hypersensitivity likely to be exacerbated by any component of the study intervention(s)
Prior/Concomitant therapy
•Use of any investigational or non-registered product other than the study interventions during the period beginning 30 days before the first dose of study interventions, or their planned use during the study
•Use of systemic cytotoxic agents, chronic antiviral agents or Chinese herbal medicines which may have activity against HBV within the previous 6 months (M) prior the study
•Currently taking, or took within 12 M of screening, any interferon-containing therapy
•Administration of adenovirus/adenovector-based or MVA-based vaccine within the last 12 M, except for adenovirus/adenovector-based COVID-19 vaccines that could be administered up to 30 days prior to the first study vaccine dose
•Planned administration/administration of a vaccine not foreseen by the study protocol in the period starting 14 days before the first dose and ending 30 days after the last dose of study intervention administration, with the exception of influenza vaccine that may be given at any time except within a 7-day period before or after each dose and COVID-19 vaccine that may be given at any time except within a 30-day period before or after each vaccine dose apart from COVID-19 mRNA based-vaccines that may be administered any time except for the period of 14 days before and 30 days after each study vaccine dose
•Administration of long-acting immune-modifying drugs at any time during the study
•Administration of immunoglobulins and/or any blood products or plasma derivatives during the period starting 3 M before the first dose of study interventions or planned administration during the study
•Chronic administration of immunosuppressants or other immune-modifying drugs during the period starting 3 M prior to the first study intervention (e.g. prednisone equivalent ≥20 mg/day). Inhaled and topical steroids are allowed
•Participants for whom immunosuppressive treatment is not advised
•Treatment with nephrotoxic drugs or competitors of renal excretion within 2 M prior to Screening or planned during the study
•Participants requiring anti-coagulation therapies
Prior/Concurrent clinical study experience
•Concurrently participating in another clinical study, at any time during the study period, in which the participant has been or will be exposed to an investigational or a non-investigational intervention
•Previous participation in clinical trials with administration of either GSK3228836 or GSK3528869A
•Previous participation in a clinical study in which he/she has received an investigational product within the following time period prior to the first dosing day in the current study: 5 half-lives or twice the duration of the biological effect of the study treatment or 90 days
•Prior treatment with any other oligonucleotide or siRNA within 12 M prior to the first dosing day
Other exclusions
•Pregnant or lactating female
•Female planning to become pregnant or planning to discontinue contraceptive precautions
•Any study personnel or their immediate dependents, family, or household members
•History of/sensitivity to GSK3228836, or components thereof, or a history of drug or other allergy that contraindicates their participation

Enfermedades
•Anomalías clínicamente significativas, aparte de la infección crónica por el VHB en la historia clínica (p. ej., hepatopatía moderada o grave distinta de la infección crónica por el VHB, síndrome coronario agudo en los 6 meses previos a la selección, cirugía mayor en los 3 meses previos a la selección, cardiopatía significativa/inestable, diabetes no controlada, diátesis hemorrágica, enfermedad autoinmunitaria o coagulopatía) o la exploración física.
•Coinfección por:
Presencia o antecedentes de infección por el virus de la hepatitis C (VHC)
Virus de la inmunodeficiencia humana (VIH)
Virus de la hepatitis D (VHD)
•Antecedentes o sospecha de cirrosis hepática y/o signos de cirrosis determinados por
Índice aspartato aminotransferasa (AST)-plaquetas (APRI) >2 y resultado de FibroSure/FibroTest >0,7.
o Si solo se obtiene un resultado positivo en un parámetro (APRI o FibroSure/FibroTest), se tendrá que hablar con un director clínico del estudio o su representante antes de permitir la inclusión en el estudio. (Véase en el Glosario de términos la definición de director clínico del estudio.)
Con independencia de la puntuación APRI de Fibrosure/FibroTest, si el participante cumple uno de los criterios históricos siguientes, será excluido del estudio:
o biopsia hepática (puntuación METAVIR F4)
o rigidez hepática >12 kPa
• Puntuación de ET FibroScan <9,6 kPa y puntuación de FibroTest <0,59 en la selección. Podrá incluirse a un participante con uno de estos parámetros fuera del intervalo, pero debe haberse sometido a una biopsia hepática en los 12 meses previos a la selección con un resultado de F0-2 según el sistema de puntuación METAVIR o estadio 0-4 según el sistema de puntuación de Ishak.
• Diagnóstico o sospecha de CHC, demostrado por lo siguiente:
concentración de alfafetoproteína ≥200 ng/ml si la concentración de alfafetoproteína de selección es ≥50 ng/ml y <200 ng/ml, deberá documentarse la ausencia de masa hepática mediante estudios de imagen en los 6 meses previos a la aleatorización.
•Antecedentes de neoplasia maligna en los últimos 5 años, a excepción de cánceres específicos que se curan mediante resección quirúrgica (por ejemplo, cáncer de piel); no podrán participar los participantes en evaluación por una posible neoplasia maligna.
• Antecedentes de vasculitis o presencia de síntomas y signos de posible vasculitis [p. ej., erupción vasculítica, ulceración de la piel, detección repetida de sangre en la orina sin causa identificada] o antecedentes/presencia de otras enfermedades que puedan estar asociadas con la condición de vasculitis (p. ej., lupus eritematoso sistémico, artritis reumatoide, policondritis recidivante, mononeuritis múltiple)].
• Antecedentes de trastornos extrahepáticos posiblemente relacionados con procesos inmunitarios del VHB (p. ej., síndrome nefrótico, cualquier tipo de glomerulonefritis, poliarteritis nudosa, crioglobulinemia, hipertensión no controlada).
• Anticuerpos anticitoplasma de neutrófilos (ANCA) positivos (o positivos limítrofes) en la V de selección:
Podrá considerarse la inclusión en el estudio de los participantes que cumplan estos criterios tras:
o análisis de MPO ANCA [anticuerpos anticitoplasma perinuclear de neutrófilos (pANCA)] y PR3-ANCA [anticuerpos anticitoplasma de neutrófilos clásicos (cANCA)]; Y
o conversación con un director clínico del estudio o un delegado para repasar los antecedentes médicos completos del participante a fin de garantizar que no haya antecedentes pasados ni manifestaciones actuales de una enfermedad vasculítica/inflamatoria/autoinmunitaria.
• C3/C4 bajo en la selección Y signos de antecedentes o manifestaciones actuales de trastornos vasculíticos/inflamatorios/autoinmunitarios.
Todos los participantes con valores bajos de C3/C4 en la selección deberán consultar sus antecedentes médicos con el director clínico del estudio o con su representante antes del reclutamiento.
• Antecedentes de abuso/dependencia de alcohol o drogas
Consumo actual de alcohol, según el criterio del investigador, que podría afectar al cumplimiento del participante.
Antecedentes o presencia de abuso o dependencia de drogas, según el criterio del investigador, que podría afectar al cumplimiento del participante.
o Esto se refiere a drogas y sustancias ilegales con potencial de abuso. Los medicamentos que utiliza el participante siguiendo las indicaciones, ya sean de venta con o sin receta, son aceptables y no afectan a los criterios de exclusión.
• Fórmula de corrección del QT de Fridericia (QTcF) ≥450 ms (si un solo ECG realizado en la selección muestra un QTcF ≥450 ms, deberá utilizarse la media de tres determinaciones para confirmar que el participante cumple los criterios de exclusión).

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E.5 End points

E.5.1

Primary end point(s)

1. Percentage of participants reporting any grade 3 adverse event (AE) from first dose of GSK3228836 up to study end
2. Percentage of participants reporting any serious adverse event (SAE) from first dose of GSK3228836 up to study end
3. Percentage of participants reporting any grade 3 adverse events of special interest (AESIs) from first dose of GSK3228836 up to study end
4. Percentage of participants who achieve sustained virologic response (SVR) for 24 weeks after end of active treatment in the absence of rescue medication, and difference between treatment arms (corresponding to GSK3228836 regimens)

1. Porcentaje de participantes que notifican algún evento adverso (EA) de grado 3 desde la primera dosis de GSK3228836 hasta el final del estudio
2. Porcentaje de participantes que informan de algún evento adverso grave (EAG) desde la primera dosis de GSK3228836 hasta el final del estudio
3. Porcentaje de participantes que informan de eventos adversos de grado 3 de interés especial (AESI) desde la primera dosis de GSK3228836 hasta el final del estudio
4. Porcentaje de participantes que logran una respuesta virológica sostenida (RVS) durante 24 semanas después de finalizar el tratamiento activo en ausencia de medicación de rescate y diferencia entre los brazos de tratamiento (correspondiente a las pautas de GSK3228836)

E.5.1.1

Timepoint(s) of evaluation of this end point

1. From first dose of GSK3228836 (Treatment 1 [T1]-Day[D]1) up to study end (Treatment 2 [T2]-D841)
2, 3. From first dose of GSK3228836 (T1-D1) up to study end (T2-D841)
4. For up to 24 weeks after end of active treatment (end of active treatment = T1-D78 for ASO12 group, T1-D162 for ASO24 group and T2-D169 for ASO12-TI and ASO24-TI groups)

1. Desde la primera dosis de GSK3228836 (Tratamiento 1 [T1] -Día [D] 1) hasta fin del estudio (Tratamiento 2 [T2] -D841)
2, 3. Desde la primera dosis de GSK3228836 (T1-D1) hasta el final del estudio (T2-D841)
4. Hasta 24 semanas después de la finalización del tratamiento activo (finalización de tratamiento activo = T1-D78 para el grupo ASO12, T1-D162 para el grupo ASO24 y T2-D169 para grupos ASO12-TI y ASO24-TI)

E.5.2

Secondary end point(s)

1 Percentage (%) of participants reporting each solicited administration site event post-GSK3528869A study intervention administration
2 % of participants reporting each solicited systemic event post-GSK3528869A study intervention administration
3 % of participants reporting any unsolicited AE post-GSK3528869A study intervention administration
4 % of participants reporting any AE from first dose of GSK3228836 up to study end
5 % of participants reporting any AESIs from first dose of GSK3228836 up to study end
6 % of participants reporting any pIMDs from first dose of GSK3528869A up to study end
7 % of participants reporting hematological, biochemical or urinalysis laboratory abnormalities at pre-defined time points during T1 period
8 % of participants reporting hematological, biochemical or urinalysis laboratory abnormalities at pre-defined time points during T2 period
9 % of participants reporting hematological, biochemical or urinalysis laboratory abnormalities at pre-defined time points during follow-up period
10 % of participants who achieve quantitative Hepatitis B surface antigen assessment (qHBsAg) decrease & HBsAg loss at pre-defined time points from GSK3228836 baseline (T1-D1) up to end of treatment period
11 % of participants who achieve qHBsAg decrease & HBsAg loss at pre-defined time points from GSK3228836 baseline (T1-D1) up to end of T1 period
12 % of participants who achieve qHBsAg decrease & HBsAg loss at pre-defined time points from GSK3528869A/control baseline (T2-D1) up to end of T2 period
13 Changes in qHBsAg at pre-defined time points from GSK3228836 baseline (T1-D1) up to end of treatment period
14 Changes in qHBsAg at pre-defined time points from GSK3228836 baseline (T1-D1) up to end of T1 period
15 Changes in qHBsAg at pre-defined time points from GSK3528869A/control baseline (T2-D1) up to end of T2 period
16 % of participants in ASO24-TI & ASO24 groups with HBsAg loss & anti-HBs seroconversion
17 % of participants in ASO12-TI & ASO12 groups with HBsAg loss & anti-HBs seroconversion
18 Geometric mean concentrations (GMCs) of qHBsAg for participants in ASO24-TI & ASO24 groups
19 Geometric mean concentrations (GMCs) of qHBsAg for participants in ASO12-TI & ASO12 groups
20 Duration of SVR in terms of time to the first occurrence of HBsAg reversion and/or HBV DNA reversion
21 % of participants in ASO24-TI & ASO24 groups who experienced HBV DNA virologic breakthrough
22 % of participants in ASO12-TI & ASO12 groups who experienced HBV DNA virologic breakthrough
23 % of participants with anti-HBc antibody response
24 Anti-HBc antibody concentrations
25 % of participants who achieved HBsAg seroconversion
26 % of participants with anti-HBs antibody response
27 Anti-HBs antibody concentrations
28 % of participants with anti-HBs antibody concentrations ≥10 mIU/mL
29 % of participants with anti-HBs antibody concentrations ≥100 mIU/mL
30 Frequency of HBc-specific CD4+ T-cells
31 Frequency of HBs-specific CD4+ T-cells
32 Frequency of HBc-specific CD8+ T-cells
33 Frequency of HBs-specific CD8+ T-cells
34 Number of HBc- & HBs-specific CD4+ T cells responders
35 Number of HBc- & HBs-specific CD8+ T cells responders

Timeframes:
1,2 Within 7 days post-administration (day of administration + 6 subsequent days) of each dose of GSK3528869A study intervention
3 Within 30 days post-administration (day of administration + 29 subsequent days) of each dose of GSK3528869A study intervention
4,5 From first dose of GSK3228836 (T1-D1) up to study end (T2-D841)
6 From first dose of GSK3528869A (T2-D1) up to study end (T2-D841)
7,11,14 At T1:1,8,15,22,29,36,43,50,57,64,71,78,85,92,99,106,113,120,127,134,141,148,155,162 (ASO24-TI & ASO24 groups) & T1:1,8,15,22,29,36,43,50,57,64,71,78 (ASO12-TI & ASO12 groups)
8 At T2:1,3,8,15,31,57,64,71,87,113,120,127,143,169,176,183,199
9 At T2:225,281,337,421,505,673,841
10,13 At T1:1,8,15,22,29,36,43,50,57,64,71,78,85,92,99,106,113,120,127,134,141,148,155,162; T2:1,15,31,57,71,87,113,143,169,199 (ASO24-TI & ASO24 groups); T1:1,8,15,22,29,36,43,50,57,64,71,78; T2:1,15,31,57,71,87,113,143,169,199 (ASO12-TI & ASO12 groups)
12,15 At T2:1,15,31,57,71,87,113,143,169,199
16,18,21 At T1:1,8,15,22,29,36,43,50,57,64,71,78,85,92,99,106,113,120,127,134,141,148,155,162 & T2:1,15,31,57,71,87,113,143,169,199,225,281,337,421,505,673,841
17,19,22 At T1:1,8,15,22,29,36,43,50,57,64,71,78 & T2:1,15,31,57,71,87,113,143,169,199,225,281,337,421,505,673,841
20 From T1-D1 up to first occurrence of HBsAg reversion and/or HBV DNA reversion, assessed from T1-D1 up to T2-D841
23,24,25,26,27,28,29 At T1:1,29,57,85,113,141,162 & T2: 1,15,57,71,113,127,169,183,337,505,841 (ASO24-TI & ASO24 groups) & T1: 1,29,57 & T2: 1,15,57,71,113,127,169,183,337,505,841 (ASO12-TI & ASO12 groups)
30,31,32,33,34,35 At T1:1,78 & T2:1,15,71,127,183,337,505,841

1.Porcentaje (%) de participantes que informan cada evento solicitado en el lugar de administración tras la administración de GSK3528869A
2.% de los participantes que informan de cada evento sistémico solicitado después de la administración de GSK3528869A
3.% de los participantes que informan cualquier EA no solicitado después de la administración de GSK3528869A
4.% de los participantes que informan cualquier EA desde la primera dosis de GSK3228836 hasta el final del estudio
5.% de los participantes que informan cualquier AESI desde la primera dosis de GSK3228836 hasta el final del estudio
6.% de los participantes que informan cualquier pIMD esde la primera dosis de GSK3528869A hasta el final del estudio
7.% de los participantes donde se informan valores hematológicos, bioquímicos o de orina alterados en los tiempos predefinidos durante el período T1
8.% de los participantes donde se informan valores hematológicos, bioquímicos o de orina alterados en los tiempos predefinidos durante el período T2
9.% de los participantes donde se informan valores hematológicos, bioquímicos o de orina alterados en los tiempos predefinidos durante el período de seguimiento
10.% de los participantes que logran una disminución de antígeno de superficie de Hepatitis B (qHBsAg) en una detección cuantitativa y pérdida del HBsAg en puntos en los tiempos predefinidos desde la visita de inicio del GSK3228836 (T1-D1) hasta el final del periodo de tratamiento
11.% de los participantes que logran una disminución de qHBsAg y pérdida de HBsAg en los tiempos predefinidos desde el inicio del GSK3228836 (T1-D1) hasta el final de periodo T1
12.% de los participantes que lograron una disminución de qHBsAg y pérdida de HBsAg en los tiempos predefinidos desde el inicio / control de GSK3528869A (T2-D1) hasta el final del periodo T2
13.Cambios en qHBsAg en los tiempos predefinidos de desde el inicio del GSK3228836 (T1-D1) hasta el final del período de tratamiento
14.Cambios en qHBsAg en los tiempos predefinidos desde el inicio del GSK3228836 (T1-D1) hasta el final del período T1
15.Cambios en qHBsAg en los tiempos predefinidos desde el inicio / control del GSK3528869A (T2-D1) hasta el final del período T2
16.de los participantes en los grupos ASO24-TI y ASO24 con pérdida de HBsAg y seroconversión anti-HBs
17.% de los participantes en los grupos ASO12-TI y ASO12 con pérdida de HBsAg y seroconversión anti-HBs
18.Concentraciones medias geométricas (GMC) de qHBsAg para los participantes en los Grupos ASO24-TI y ASO24
19.Concentraciones medias geométricas (GMC) de qHBsAg para participantes en los Grupos ASO12-TI y ASO12
20.Duración de la RVS (Respuesta virológica sostenida) en términos de tiempo hasta la primera aparición de reversión del HBsAg y/o reaparición del ADN del VHB
21.% de los participantes en los grupos ASO24-TI y ASO24 que presentan reaparición del DNA del VHB virológico
22.% de los participantes en los grupos ASO24-TI y ASO24 que presentan reaparición del DNA del VHB virológico
23.% de los participantes con respuesta de anticuerpos anti-HBc
24.Concentraciones de anticuerpos anti-HBc
25.% de los participantes que logran la seroconversión de HBsAg
26.% de los participantes con respuesta de anticuerpos anti-HBs
27.Concentraciones de anticuerpos anti-HBs
28.% de los participantes con concentraciones de anticuerpos anti-HBs ≥10 mUI / ml
29.% de los participantes con concentraciones de anticuerpos anti-HBs ≥100 mUI / mL
30.Frecuencia de linfocitos T CD4 + específicos de HBc
31.Frecuencia de linfocitos T CD4 + específicos de HBs
32.Frecuencia de linfocitos T CD8 + específicos de HBc
33.Frecuencia de linfocitos T CD8 + específicos de HBs
34.Número de linfocitos T CD4 + específicos de HBc y HBs respondedores
35.Número de linfocitos T CD8 + específicos de HBc- y HBs respondedores
Tiempos:
1,2-Dentro de los 7 días posteriores a la administración (día de administración + 6
días posteriores) de cada dosis de intervención del estudio GSK3528869A
3-Dentro de los 30 días posteriores a la administración (día de administración + 29
días posteriores) de cada dosis de intervención del estudio GSK3528869A
4,5-Desde la primera dosis de GSK3228836 (T1-D1) hasta el final del estudio (T2-D841)
6-Desde la primera dosis de GSK3528869A (T2-D1) hasta el final del estudio (T2-D841)
7,11,14- En T1: 1,8,15,22,29,36,43,50,57,64,71,78,85,92,99,106,113,120,127,134,141,148,155,162 (grupos ASO24-TI y ASO24) y T1: 1,8,15,22,29,36,43,50,57,64,71,78 (grupos ASO12-TI y ASO12)
8-En T2: 1,3,8,15,31,57,64,71,87,113,120,127,143,169,176,183,199
9-En T2: 225,281,337,421,505,673,841
10,13-En T1: 1,8,15,22,29,36,43,50,57,64,71,78,85,92,99,106,113,120,127,134,141,148,155,162; T2: 1,15,31,57,71,87,113,143,169,199 (ASO24-TI y Grupos ASO24); T1: 1,8,15,22,29,36,43,50,57,64,71,78; T2: 1,15,31,57,71,87,113,143,169,199 (grupos ASO12-TI y ASO12)
12,15-En T2: 1,15,31,57,71,87,113,143,169,199
16,18,21-

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E.5.2.1

Timepoint(s) of evaluation of this end point

Due to the character limitation, timeframes for secondary endpoints are added in section E.5.2 after endpoints.

Debido a la limitación de caracteres, los plazos para los criterios de valoración secundarios se añaden en la sección E.5.2 después de los criterios de valoración.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Immunogenicity

Inmunoginicidad.

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

Yes

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Scuencial

Sequential

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

Hong Kong

Korea, Republic of

Philippines

Russian Federation

Singapore

Taiwan

Thailand

Turkey

Belgium

Bulgaria

France

Germany

Italy

Poland

Romania

Spain

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

End of Study (EoS): Date of the last testing/reading released of the Human Biological Samples or imaging data, related to primary and secondary endpoints. EoS must be achieved no later than 8 months after Last Subject Last Visit (LSLV).

Fin del estudio (EoS): Fecha de la última prueba/lectura publicada de las Muestras Biológicas Humanas o los datos de imágenes, relacionados con los criterios de valoración primarios. El fin del estudio debe lograrse no más tarde de los 8 meses después de la última visita al sujeto.

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

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

180

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

123

F.4.2.2

In the whole clinical trial

184

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

After the participant has ended the participation in this trial they will continue with standard care.

Una vez que el participante haya finalizado su participación en este ensayo, continuará con la atención estándar.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2022-03-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-02-08

P. End of Trial
P.	End of Trial Status	Ongoing

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Orphan Designation Number:
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