Clinical trial NCT03866187: Safety, Efficacy, Immunogenicity Study of GSK Biologicals' HBV Viral Vector and Adjuvanted Proteins Vaccine (GSK3528869A) in Adult Patients With Chronic Hepatitis B Infection
Official title: A first-time-in Human (FTIH), Phase I/II, Randomized, Multi-centric, Single-blind, Controlled Dose-escalation Study to Evaluate the Reactogenicity, Safety, Immunogenicity and Efficacy of GSK Biologicals' HBV Viral Vector Vaccines Given in a Prime-boost Schedule With Sequential or Co-administration of Adjuvanted Proteins Therapeutic Vaccine (GSK3528869A) in Chronic Hepatitis B Patients (18-65 Years Old) Well Controlled Under Nucleo(s)Tide Analogue (NA) Therapy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Hepatitis B, Chronic
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2019-03-07
Enrollment: 135
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Study will be conducted following a staggered design overseen by Internal Safety Review Committee (iSCR):

* Step A (low dose of each vaccine): Approximately 15 patients will be randomized (1:1:1). Fourteen days after the 2nd vaccination, iSRC will review all available safety data (of at least 12 patients if approved by local authorities). If considered appropriate to continue, Step B will start.
* Step B (prime-boost with ChAd155-hIi-HBV and Modified Vaccinia Ankara HBV vaccine (MVA-HBV) and sequential administration with HBc-HBs/AS01B-4): Approximately 40 patients will first be randomized (2:1:1) for vaccination. Fourteen days after the 2nd vaccination, iSRC will review all available safety data. If considered appropriate to continue, approximately 36 additional patients will be randomized for vaccination.
* Step C (prime-boost with ChAd155-hIi-HBV and MVA-HBV and co-administration with HBc-HBs/AS01B-4): Step C randomization (2:1) will start post completion of Step B enrolment.
Primary purpose: TREATMENT

Brief summary: A First-Time-In-Human study on GSK's therapeutic vaccines to evaluate the reactogenicity, safety, immunogenicity and efficacy on reduction of serum HBV surface antigen in HBV suppressed subjects under nucleo(s)tide treatment.


Eligibility criteria: Inclusion Criteria:

* Patients who, in the opinion of the investigator, can and will comply with the requirements of the protocol.
* Written informed consent obtained from the patient prior to performing any study specific procedure.
* A male or female between, and including, 18 and 65 years of age at the time of the first vaccination.
* Female patients of non-childbearing potential may be enrolled in the study. Non-childbearing potential is defined as hysterectomy, bilateral ovariectomy or post-menopause.
* Female patients of childbearing potential may be enrolled in the study if the patient:

  * has practiced adequate contraception for 30 days prior to vaccination, and
  * has a negative pregnancy test at Screening, and
  * has agreed to continue adequate contraception from Screening until 12 weeks after completion of the vaccination series
* Male patients:

  * with documented bilateral vasectomy and resultant azoospermia, bilateral orchiectomy or azoospermia, or
  * who agree to practice abstinence from penile-vaginal intercourse (when this is their preferred and usual lifestyle) or use condoms from Screening until 12 weeks after completion of the vaccination series.
* Chronic Hepatitis B (CHB) patient, under and adherent to treatment with a nucleo(s)tide analogue with high barrier to resistance given as per approved label/dosage for at least 24 months.
* Documented medical history of Hepatitis B Virus e Antigen (HBeAg)-negative CHB prior to onset of NA therapy (applicable to all patients in Step A and Step B and to some patients in Step C) or documented medical history of HBeAg-negative CHB over a period of at least 24 months prior screening (applicable to some patients in Step C only).
* Documented HBV viral suppression as per local clinical diagnosis within the previous 24 months AND at Screening test HBV DNA \< 10 IU/mL. If no results are available, two Screening tests need to be performed at least 2 weeks apart. Small fluctuations of HBV DNA (≤ 10 x LLOQ; LLOQ defined by laboratory that performed testing) are allowed provided HBV DNA is \< 10 IU/mL at Screening and was clearly not rising during the previous 24 months.
* Documented normal level of ALT as per local clinical diagnosis within the previous 24 months AND at Screening test ALT \< 48U/L. Small fluctuations of ALT (≤ 1.5 X ULN) are allowed provided ALT\< 48 U/L at Screening. If no results are available, two Screening tests need to be performed at least 2 weeks apart. ULN are to be defined according to local laboratory reference range.
* No clinical diagnosis of cirrhosis (e.g. F4 by METAVIR scoring system or ≥ 6 by Ishak scoring system or FibroScan TE score \> 12.5 kPa) within the previous 24 months.
* FibroScan Transient Elastography (TE) score \< 9.6 kPa and FibroTest score \< 0.59 at Screening. A patient with one of these parameters out of range, but having the liver biopsy within 12 months before screening that showed F0-2 by METAVIR scoring system or stage 0-4 by Ishak scoring system, can be included.
* HBsAg concentration \> 50 IU/mL and anti-HBs negative at Screening.
* Anti-HBc positive at Screening.
* HBeAg-negative at Screening.

Exclusion Criteria:

* Use of any investigational or non-registered product other than the study vaccines during the period starting 30 days before the first dose of study vaccines, or planned use during the study period.
* Any medical condition that in the judgment of the investigator would make intramuscular injection unsafe.
* Chronic administration of immunosuppressants or other immune-modifying drugs during the period starting six months prior to the first vaccine dose. For corticosteroids, this will mean prednisone ≥ 10 mg/day or equivalent. Inhaled and topical steroids are allowed.
* Administration of immunoglobulins and/or any blood products during the period starting 3 months before the first dose of study vaccines or planned administration during the study period.
* Use of systemic cytotoxic agents, chronic antiviral agents or Chinese herbal medicines which, in the opinion of the investigator, may have activity against HBV within the previous 6 months prior to randomization into this study. Antiviral treatment/prevention for influenza or herpes simplex virus is allowed.
* Administration of adenovirus/adenovector-based or MVA-based vaccine within the last 12 months except for adenovirus/adenovector-based COVID-19 vaccines that could be administered up to 30 days prior to the first study vaccine dose (applicable for all patients except for the patients in France) OR Administration of adenovirus/adenovector-based or MVA-based vaccine within the last 12 months (applicable for the patients in France only).
* Planned administration/administration of a vaccine not foreseen by the study protocol in the period starting 14 days before each dose and ending 30 days after each dose of vaccines, with the exception of influenza vaccine that may be given at any time except within a 7-day period before or after each vaccine 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. Note: If the type of COVID-19 vaccine is unknown, the allowed interval of 30 days before or after each study vaccine dose should be followed.
* Treatment with nephrotoxic drugs or competitors of renal excretion within 2 months prior to Screening or the expectation that patient will receive any of these during the course of the study. TAF/TDF given as NA therapy is allowed.
* Concurrently participating in another clinical study, at any time during the study period, in which the patient has been or will be exposed to an investigational or a non-investigational vaccine/product.
* Medical history of cirrhosis or hepatic decompensation.
* Planned for liver transplantation or previous liver transplantation.
* Personal or family (first degree) history of autoimmune disease.
* Family history of congenital or hereditary immunodeficiency.
* History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccines.
* Evidence of Hepatitis C Virus and hepatitis D Virus infection.
* Suspicion of or confirmed Hepatocellular Carcinoma or any other liver cancer in medical history or at Screening:

  * Suspicious foci at liver imaging exam
  * Elevated α-fetoprotein \> 50 ng/mL.
* Documented evidence of other currently active cause of hepatitis.
* Hematology and biochemistry parameters outside normal clinical range at Screening:

Biochemistry:

* Glomerular filtration rate \< 60 mL/min
* Bilirubin \> 27.5 µmol/L unless \*or the diagnosis of Gilbert Syndrome has been established and confirmed by the Investigator
* GGT \> 65 U/L (males) or \> 45 U/L (females)\*
* ALT \> 48 U/L
* AST \> 42 U/L\*
* ALP \> 125 U/L\*

Hematology:

* Hemoglobin \< 12.0 g/dL (females) or \< 13.5 g/dL (males)\*
* Red blood cell count \< 3.9 x 10\^6 cells/mm\^3 (females) or \< 4.4 x 10\^6 cells/mm\^3 (males)\*
* White blood cell count \< 3,500 cells/mm\^3 or \> 12,000 cells/mm\^3\*
* Platelets \< 140,000 cells/mm\^3
* INR \> 1.32 (i.e. 1.1 x ULN) \*unless it is considered as clinically not significant by the Investigator

  * Known diabetes Type I.
  * Body Mass Index \> 35 kg/m\^2 at Screening.
  * Any serious or active medical or psychiatric illnesses other than chronic hepatitis B which, in the opinion of the investigator, would interfere with patient treatment, assessment or compliance with the protocol.
  * History of or current drug abuse and/or excess of alcohol consumption as defined per local guidelines.
  * HIV-positive patient.
  * Pregnant or lactating female.
  * Female planning to become pregnant or planning to discontinue contraceptive precautions in the period starting from the Screening Visit up to 12 weeks post-last vaccination visit.
  * Fever and or acute minor illness may be enrolled for Screening at the discretion of the investigator, provided that the condition is resolved at the time of vaccination.

Primary outcomes:
measure: Number of subjects reporting solicited local adverse events (AEs)
timeFrame: Within 7 days after each vaccination (from day of vaccination to 6 days after vaccination)
measure: Number of subjects reporting solicited general AEs
timeFrame: Within 7 days after each vaccination (from day of vaccination to 6 days after vaccination)
measure: Number of subjects reporting unsolicited AEs
timeFrame: Within 30 days after each vaccination (from day of vaccination to 29 days after vaccination)
measure: Number of subjects with hematological, biochemical or urinalysis laboratory abnormalities
timeFrame: Within 30 days after each vaccination (from day of vaccination to 29 days after vaccination)
measure: Number of subjects reporting serious adverse events (SAEs)
timeFrame: From Day 1 up to Day 337 (6 months after last dose)
measure: Number of subjects reporting potential immune-mediated diseases (pIMDs)
timeFrame: From Day 1 up to Day 337 (six months after the last dose)
measure: Number of subjects reporting liver-disease-related (LDR) AEs
timeFrame: From Day 1 up to Day 337 (six months after the last dose)
measure: Number of subjects reporting any hematological adverse events of specific interest (AESIs)
timeFrame: From Day 1 up to Day 337 (six months after last dose)
measure: Number of subjects reporting medically-attended adverse events (MAEs)
timeFrame: From Day 1 up to Day 337 (six months after the last dose)
Secondary outcomes:
measure: Number of seropositive subjects for anti-hepatitis B core antibody (anti-HBc)
timeFrame: At Days 1,15, 71, 113, 127, 183, 337, 505 and 841
measure: Evaluation of immunogenicity in terms of Anti-HBc antibody concentration
timeFrame: At Days 1,15, 71, 113, 127, 183, 337, 505 and 841
measure: Number of subjects with anti-hepatitis B surface antigen (anti-HBs) seroconversion
timeFrame: At Days 1,15, 71, 113, 127, 183, 337, 505 and 841
measure: Evaluation of immunogenicity in terms of anti-HBs antibody concentration
timeFrame: At Days 1,15, 71, 113, 127, 183, 337, 505 and 841
measure: Number of subjects with anti-HBs antibody concentration equal to or above 10 mIU/mL
timeFrame: At Days 1,15, 71, 113, 127, 183, 337, 505 and 841
measure: Number of subjects with anti-HBs antibody concentration equal to or above 100 mIU/mL
timeFrame: At Days 1,15, 71, 113, 127, 183, 337, 505 and 841
measure: Frequency of HBs-specific CD4+ T-cells
timeFrame: At Days 1,15, 57, 64, 71, 113, 127, 169, 183, 337, 505 and 841
measure: Frequency of HBs-specific CD8+ T-cells
timeFrame: At Days 1,15, 57, 64, 71, 113, 127, 169, 183, 337, 505 and 841
measure: Frequency of HBc-specific CD4+ T-cells
timeFrame: At Days 1,15, 57, 64, 71, 113, 127, 169, 183, 337, 505 and 841
measure: Frequency of HBc-specific CD8+ T-cells
timeFrame: At Days 1,15, 57, 64, 71, 113, 127, 169, 183, 337, 505 and 841
measure: Frequency of HBs-specific CD4+ T-cells responders
timeFrame: At Days 1,15, 57, 64, 71, 113, 127, 169, 183, 337, 505 and 841
measure: Frequency of HBc-specific CD4+ T-cells responders
timeFrame: At Days 1,15, 57, 64, 71, 113, 127, 169, 183, 337, 505 and 841
measure: Frequency of HBs-specific CD8+ T-cells responders
timeFrame: At Days 1,15, 57, 64, 71, 113, 127, 169, 183, 337, 505 and 841
measure: Frequency of HBc-specific CD8+ T-cells responders
timeFrame: At Days 1,15, 57, 64, 71, 113, 127, 169, 183, 337, 505 and 841
measure: Number of subjects with ≥ 0.5 log decrease of qHBsAg since pre-vaccination
timeFrame: At Days 1, 31, 57, 87, 113, 143, 169, 199, 225, 281, 337, 421, 505, 673, 841
measure: Number of subjects with ≥ 1 log decrease of qHBsAg since pre-vaccination
timeFrame: At Days 1, 31, 57, 87, 113, 143, 169, 199, 225, 281, 337, 421, 505, 673, 841
measure: Number of subjects with qHBsAg loss
timeFrame: At Days 1, 31, 57, 87, 113, 143, 169, 199, 225, 281, 337, 421, 505, 673, 841
measure: Changes in qHBsAg since pre-vaccination
timeFrame: At Days 1, 31, 57, 87, 113, 143, 169, 199, 225, 281, 337, 421, 505, 673, 841
measure: Number of subjects with HBsAg loss and anti-HBs seroconversion
timeFrame: At Days 1, 337, 505 and 841
measure: Evaluation of qHBsAg geometric mean concentrations
timeFrame: At Day 1, 31, 57, 87, 113, 143, 169, 199, 225, 281, 337, 421, 505, 673, 841
measure: Number of subjects reporting any SAEs and SAEs causally related to an investigational vaccine
timeFrame: Throughout the study period (from Day 1 up to Day 841)
measure: Number of subjects reporting MAEs
timeFrame: Throughout the study period (from Day 1 up to Day 841)
measure: Number of subjects reporting pIMDs
timeFrame: Throughout the study period (from Day 1 up to Day 841)
measure: Number of subjects reporting liver-disease-related AEs
timeFrame: Throughout the study period (from Day 1 up to Day 841)
measure: Number of subjects reporting spontaneous local or general bleeding with thrombocytopenia
timeFrame: Throughout the study period (from Day 1 up to Day 841)
measure: Number of subjects reporting anemia
timeFrame: Throughout the study period (from Day 1 up to Day 841)
measure: Number of subjects reporting AEs and SAEs leading to study withdrawal
timeFrame: Throughout the study period (from Day 1 up to Day 841)
measure: Number of subjects reporting pregnancy and outcomes of reported pregnancy
timeFrame: Throughout the study period (from Day 1 up to Day 841)
Other outcomes:
Locations:
city: Antwerpen
country: Belgium
facility: GSK Investigational Site
city: Bruxelles
country: Belgium
facility: GSK Investigational Site
city: Edegem
country: Belgium
facility: GSK Investigational Site
city: Gent
country: Belgium
facility: GSK Investigational Site
city: Clichy Cedex
country: France
facility: GSK Investigational Site
city: CrEteil Cedex
country: France
facility: GSK Investigational Site
city: Lyon
country: France
facility: GSK Investigational Site
city: Strasbourg
country: France
facility: GSK Investigational Site
city: Aachen
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Bonn
country: Germany
facility: GSK Investigational Site
city: Essen
country: Germany
facility: GSK Investigational Site
city: Frankfurt
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Mainz
country: Germany
facility: GSK Investigational Site
city: Tuebingen
country: Germany
facility: GSK Investigational Site
city: Pokfulam
country: Hong Kong
facility: GSK Investigational Site
city: Krakow
country: Poland
facility: GSK Investigational Site
city: Lancut
country: Poland
facility: GSK Investigational Site
city: Myslowice
country: Poland
facility: GSK Investigational Site
city: Poznan
country: Poland
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: COrdoba
country: Spain
facility: GSK Investigational Site
city: Granada
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Palma de Mallorca
country: Spain
facility: GSK Investigational Site
city: Santander
country: Spain
facility: GSK Investigational Site
city: Sevilla
country: Spain
facility: GSK Investigational Site
city: TorrejOn Ardoz Madrid
country: Spain
facility: GSK Investigational Site
city: Taichung
country: Taiwan
facility: GSK Investigational Site
city: Taichung
country: Taiwan
facility: GSK Investigational Site
city: Tainan
country: Taiwan
facility: GSK Investigational Site
city: Taipei
country: Taiwan
facility: GSK Investigational Site
city: Taoyuan
country: Taiwan
facility: GSK Investigational Site
city: Bangkok
country: Thailand
facility: GSK Investigational Site
city: Chiangmai
country: Thailand
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Nottingham
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: