"Safety, efficacy, immunogenicity study of GSK Biologicals’ HBV viral vector and adjuvanted proteins vaccine (GSK3528869A) in adult patients with chronic Hepatitis B infection. "

Overview

Sponsor-declared trial summary

Key facts

Sponsor

GlaxoSmithKline Biologicals

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Virus Diseases [C02]

Trial duration

18 Mar 2019 → 11 Oct 2024

Decision date (initial)

2024-04-11

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2023-510020-68-00

EudraCT number

2017-001452-55

ClinicalTrials.gov

NCT03866187

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety

To assess the safety of escalating doses of the HBV viral vector vaccines (prime-boost) and/or adjuvanted proteins vaccines in patients with chronic HBV infection who are virally suppressed on NA therapy

Secondary objectives 3

1. To assess the immunogenicity of the HBV viral vector vaccines (prime-boost) and/or adjuvanted proteins vaccines in patients with chronic HBV infection who are virally suppressed on NA therapy
2. "To assess the efficacy of the HBV viral vector vaccines (prime-boost) and/or adjuvanted proteins vaccines in patients with chronic HBV infection who are virally suppressed on NA therapy. Proof-of-principle (PoP) will be achieved if  At least 15% of patients (i.e. a lower limit of the 80% CI of at least 15%) in one vaccine group show at least 10-fold decrease (i.e. 1-log difference) in qHBsAg or show HBsAg loss at Day 337 versus Day 1, or  If there is at least a 10-fold difference in mean HBsAg concentration between a vaccine group at Day 337 and the respective control group (i.e. the criterion is to observe a point estimate of at least 10-fold decrease between the groups with statistical significance, i.e., 80% CI on the ratio not including 1). "
3. To assess the long-term safety of escalating doses of the HBV viral vector vaccines (prime-boost) and/or adjuvanted proteins vaccines in patients with chronic HBV infection who are virally suppressed on NA therapy.

Conditions and MedDRA coding

Hepatitis B, Chronic

Study design 1 period

Regulatory references

Scientific advice from competent authorities

Medicines And Healthcare Products Regulatory Agency, Federal Agency For Medicines And Health Products, Paul-Ehrlich-Institut

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. "• Patients who, in the opinion of the investigator, can and will comply with the requirements of the protocol (e.g. completion of the diary cards, return for follow-up visits). • 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. Please, refer to the glossary of terms for the definition of 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. Please refer to the glossary of terms for the definition of adequate contraception. • 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. • CHB patient, under and adherent to treatment with a nucleos(t)ide analogue with high barrier to resistance (e.g. ETV, TDF, TAF) given as per approved label/dosage for at least 24 months. • Documented medical history of 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 lower limit of quantification (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 ≤ 48 U/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 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 2

1. "• Use of any investigational or non-registered product (drug or vaccine) other than the study vaccines during the period starting 30 days before the first dose of study vaccines (Day -29 to Day 1), or planned use during the study period. • Any medical condition that in the judgment of the investigator would make intramuscular (IM) injection unsafe. • Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs (including but not limited to IFN) 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 (HSV) 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 (e.g. aminoglycosides, amphotericin B, vancomycin, cidofovir, foscarnet, cis-platinum, pentamidine, etc.) or competitors of renal excretion (e.g. probenecid) 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 (pharmaceutical product or device). • Medical history of cirrhosis. • Medical history of hepatic decompensation (e.g. ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, variceal bleeding, or hepatic encephalopathy). • 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 HCV and hepatitis D Virus (HDV) infection. History of acute hepatitis A and acute hepatitis E is not an exclusion criterion. • Suspicion of or confirmed HCC or any other liver cancer in medical history or at Screening: • Suspicious foci at liver imaging exam. • Elevated α-fetoprotein > 50 ng/ml. "
2. "• Documented evidence of other currently active cause of hepatitis (e.g. auto-immune hepatitis, primary biliary cirrhosis; primary sclerosing cholangitis, hemochromatosis, alpha-1 antitrypsin deficiency, Wilson's disease). • Hematology and biochemistry parameters outside normal clinical range at Screening: Biochemistry:  Glomerular filtration rate (GFR) < 60 mL/min  Bilirubin > 27.5 µmol/L unless it is considered as clinically not significant by the Investigator or the diagnosis of Gilbert Syndrome has been established and confirmed by the Investigator  GGT > 65 U/L for males or GGT > 45 U/L for females unless it is considered as clinically not significant by the Investigator  ALT > 48 U/L  AST > 42 U/L unless it is considered as clinically not significant by the Investigator  ALP > 125 U/L unless it is considered as clinically not significant by the Investigator Hematology:  Hemoglobin < 12.0 g/dl (for females) or < 13.5 g/dl (for males) unless it is considered as clinically not significant by the Investigator  Red blood cell (RBC) count < 3.9 x 106 cells/mm3 (females) or < 4.4 x 106 cells/mm3 (males) unless it is considered as clinically not significant by the Investigator  White blood cell count (WBC) < 3,500 cells/mm3 or > 12,000 cells/mm3 unless it is considered as clinically not significant by the Investigator  Platelets < 140,000 cells/mm3  International Normalized Ratio (INR) > 1.32 (i.e. 1.1 x ULN) • Known diabetes Type I. • Body Mass Index (BMI) > 35 kg/m² 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. This would include any uncontrolled clinically significant renal, cardiac, pulmonary, vascular, neurogenic, digestive, metabolic (diabetes, thyroid disorders, adrenal disease), immunodeficiency disorders or cancer. • 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 (such as mild diarrhea, mild upper respiratory infection) may, be enrolled for Screening at the discretion of the investigator, provided that the condition is resolved at the time of vaccination. "

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. "• Occurrence of AEs from vaccination up to Day 337:  Occurrence of each solicited local and general symptoms within 7 days after each vaccination (from day of vaccination to six days after vaccination).  Occurrence of unsolicited AEs within 30 days after each vaccination (from day of vaccination to 29 days after vaccination).  Occurrence of hematological, biochemical or urinalysis laboratory abnormalities within 30 days after each vaccination . "
2. " Occurrence of SAEs up to six months after the last dose (Day 337, Visit 22).  Occurrence of pIMDs up to six months after the last dose (Day 337, Visit 22).  Occurrence of liver-disease related AEs up to six months after the last dose (Day 337, Visit 22).  Occurrence of hematological AESIs up to six months after the last dose (Day 337, Visit 22).  Occurrence of medically attended events (MAEs) up to six months after the last dose (Day 337, Visit 22). "

Secondary endpoints 4

1. "Immunogenicity Immunogenicity with respect to HBV components of the viral vectored vaccines and adjuvanted proteins vaccines, at predefined time points (see Table 4 and Table 5). • Anti-HBc antibodies: seropositivity and concentration. • Anti-HBs antibodies: seroconversion and concentration; anti-HBs ≥10 mIU/ml and ≥100 mIU/ml. • Frequency of HBc- and HBs- specific CD4+ T-cells and CD8+ T-cells; CD4+ T-cells responder, CD8+ T-cells responder."
2. "Efficacy • qHBsAg: number of patients with ≥ 0.5 log decrease, ≥ 1-log decrease, HBsAg loss and log-changes since pre-vaccination. • Number of patients with HBsAg loss and anti-HBs seroconversion. • Mean qHBsAg in each group. "
3. "Safety • Occurrence of AEs from vaccination up to Day 841:  Occurrence of any SAEs throughout the study period,  Occurrence of SAEs causally related to an investigational vaccine throughout the study period,  Occurrence of MAEs throughout the study period,  "
4. " Occurrence of pIMDs throughout the study period,  Occurrence of liver disease-related AEs throughout the study period,  Occurrence of spontaneous local or general bleeding with thrombocytopenia (< 50,000 platelets/mm3),  Occurrence of anemia with Hb < 9.5 g/dl,  Occurrence of AEs and SAEs leading to study withdrawal. • Pregnancy and pregnancy outcome throughout the study period. "

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 6

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

GlaxoSmithKline Biologicals

Sponsor organisation

GlaxoSmithKline Biologicals

Address

Rue De L'Institut 89

City

Rixensart

Postcode

1330

Country

Belgium

Scientific contact point

Organisation

GlaxoSmithKline Biologicals

Contact name

EU GSK Clinical Trials Call Center

Public contact point

Organisation

GlaxoSmithKline Biologicals

Contact name

EU GSK Clinical Trials Call Center

Third parties 12

Locations

3 EU/EEA countries · 15 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 23 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications