A Novel Combination Therapeutic Strategy Aiming to Functional Cure for Chronic Hepatitis B Virus Infection (A)
Hepatitis B virus (HBV) infection is a major public health threat in China. At present, a functional cure, also known as clinical cure or sustained Hepatitis B surface antigen (HBsAg) loss, is recommended as the ideal endpoint of HBV treatment. However, HBsAg loss can be achieved in less than 10% of chronic hepatitis B (CHB) patients treated with current available antiviral drug interferonα (IFNα) or nucleos(t)ide analogues (NAs) monotherapy. With the support of the national major special funding for infectious diseases from "11th Five-Year Plan" to "13th Five-Year Plan", we have implemented a pioneer clinical study of sequential combination of IFNα therapy on NAs to treat NAs-treated CHB patients (ie. New Switch Study). This is the world's first clinical trial aiming to functional cure, which increased the rate of HBsAg loss to 15% in the overall population in our study, and to 30-50% among those with lower baseline HBsAg levels. How to further improve the HBsAg loss rate is an urgent issue for us. The key point of achieving functional cure is to reverse the HBV-specific T cell exhaustion and establish the long-term immune control against HBV infection. Programmed death-1(PD-1)/programmed death-ligand 1 (PD-L1) axis blockade has been demonstrated to reinvigorate exhausted CD8+ T cells, and would be a potential strategy to treat chronic HBV infection. In this study, a large multicenter prospective study will be performed to explore the safety and efficacy of a novel combination strategy involving immune checkpoint inhibitor (anti-PD-1/anti-PD-L1 antibody) and IFNα in CHB patients, observe the HBsAg loss rate in NA-treated CHB patients receiving this combination strategy, evaluate the potential of breaking immune tolerance by this strategy, and further assess its efficacy to further improve the clinical cure rate on the basis of New Switch Study. Based on New Switch Study, this study further attempts to reverse T cell exhaustion in CHB patients, explore a novel platform of combination therapy development for clinical cure, and ultimately increase the HBsAg loss rate to higher than 50% in overall patients. The implementation of the project is expected to reduce the burden of HBV infection in China and contribute to the goal of global elimination of hepatitis B and C by 2030 (WHO 2030).
Tutkimuksen yleiskatsaus
Tila
Tila
Ehdot
Ehdot
Interventio / Hoito
Interventio / Hoito
Opintotyyppi
Opintotyyppi
Ilmoittautuminen (Arvioitu)
Ilmoittautuminen
Vaihe
Vaihe
- Vaihe 2
Yhteystiedot ja paikat
Opiskeluyhteys
Opiskeluyhteys
- Nimi: Dachuan Cai, MD
- Puhelinnumero: +86 18323409779
- Sähköposti: cqmucdc@cqmu.edu.cn
Tutki yhteystietojen varmuuskopiointi
- Nimi: Min Chen, PhD
- Puhelinnumero: +86 17338600343
- Sähköposti: mchen@hospital.cqmu.edu.cn
Opiskelupaikat
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Chongqing Municipality
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Chongqing, Chongqing Municipality, Kiina, 400010
- Rekrytointi
- The 2nd affiliated Hospital of Chongqing Medical University
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Päätutkija:
- HONG REN, Professor
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Ottaa yhteyttä:
- DACHUAN CAI
- Puhelinnumero: +8618323409779
- Sähköposti: cqmucdc@cqmu.edu.cn
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Ottaa yhteyttä:
- HONG REN
- Puhelinnumero: +8613983888786
- Sähköposti: renhong0531@vip.sina.com
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Osallistumiskriteerit
Kelpoisuusvaatimukset
Kelpoisuusvaatimukset
Opintokelpoiset iät
Hyväksyy terveitä vapaaehtoisia
Sukupuolet, jotka voivat opiskella
Kuvaus
Inclusion Criteria:
- Sign the informed consent form before inclusion and be able to complete the study according to the study requirements;
- 18-60 years old.
- NAs-naive/NAs-experienced CHB patients.
Exclusion Criteria:
- A history of allergy, or who are suspected by the researcher to be allergic to the active ingredient of the drug under study or its excipients;
- Use of inhibitors, inducers or substrates of CYP3A4 within 28 days before enrollment;
- Systematical use of immunosuppressants, immunomodulators (thymosin) and cytotoxic drugs within 6 months before enrollment, or vaccination of live attenuated vaccine within 1 month before enrollment;
- Acute infection within 2 weeks before enrollment which requires intravenous antibiotic treatment, or existing infection which requires anti-infection treatment when enrollment;
- Clinically significant acute and chronic liver disease not caused by HBV infection (judged by reseachers);
- Confirmed or suspected decompensated cirrhosis, including but not limited to: hepatic encephalopathy, hepatorenal syndrome, bleeding from esophageal varices, splenomegaly, ascites, etc, or evidence of progressive liver fibrosis;
- Primary liver cancer, or alpha-fetoprotein (AFP) is greater than 50 ug/L or imaging suggests the possibility of malignant liver lesions, or other malignant tumors or a history of other malignant tumors within 5 years before enrollment (except that the malignant tumors have been completely relieved after treatment and patients have not received additional medical or surgical intervention within 3 years before screening);
- A history of pathological fracture or osteoporosis;
- Gastrointestinal dysfunction or gastrointestinal diseases that might affect the absorption of oral drugs, such as severe gastric ulcer, erosive gastritis, partial gastrectomy, and persistent gastrointestinal symptoms (such as nausea, vomiting, or diarrhea) >2 grades;
- Serious diseases of circulatory, respiratory, urinary, blood, metabolic, immune, mental, neurological, renal and other systems;
- Major trauma or major surgery within 3 months before enrollment, or planned surgery during the study period;
- Blood donation/loss ≥ 400 mL within 3 months before enrollment, or given a blood transfusion within 3 months before enrollment, or blood donation/loss ≥ 200 mL within 1 month before enrollment;
- Platelet count<90 × 10^9/L, white blood cell count<3.0 × 10^9/L, neutrophil count<1.3 × 10^9/L, total serum bilirubin>2 × upper limit of normal (ULN), albumin<30 g/L, creatinine clearance ≤ 60 mL/min (calculated by CKD-EPI formula), or international normalized ratio of prothrombin time (INR)>1.5 (unless receiving stable anticoagulant therapy);
- Hepatitis C virus (HCV) antibody (+), HIV antigen/antibody (+), or treponema pallidum antibody (+) and rapid plasma regain (RPR) test (+);
- A history of continuous alcohol abuse within 3 years before enrollment (average daily alcohol consumption exceeds 20 gram);
- A history of drug dependence or drug abuse within 1 year before enrollment;
- Those who have participated in clinical trials of other investigational drugs or medical devices and taken investigational drugs or used medical devices within 3 months before enrollment;
- Female in suckling period or pregnancy test (+) during screening;
- Subjects who are considered by the researcher to have other factors that are not suitable for the study
Opintosuunnitelma
Miten tutkimus on suunniteltu?
Suunnittelun yksityiskohdat
- Ensisijainen käyttötarkoitus: Hoito
- Jako: Ei satunnaistettu
- Inventiomalli: Rinnakkaistehtävä
- Naamiointi: Ei mitään (avoin tarra)
Aseiden lukumäärä
Aseet ja interventiot
Osallistujaryhmä / ArmOsallistujaryhmä / Arm |
Interventio / HoitoInterventio / Hoito |
|---|---|
|
Kokeellinen: NAs combined with Sintilimab/Envafolimab
NAs (Once/day, 1 capsule/time, oral)combined with Sintilimab(anti-PD-1 antibody, once/three weeks, dose lower than the dose used in cancer patients, intravenous injection) /Envafolimab(anti-PD-L1 antibody, once/two weeks, dose lower than the dose used in cancer patients, subcutaneous injection), followed by NAs monotherapy |
Sintilimab(anti-PD-1 antibody),once/three weeks, dose lower than the dose used in cancer patients, intravenous injection; Envafolimab(anti-PD-L1 antibody),once/two weeks, dose lower than the dose used in cancer patients, subcutaneous injection
Muut nimet:
NAs(ETV/TDF/TAF), Once/day, 1 capsule/time, oral |
|
Active Comparator: NAs
NAs(Once/day, 1 capsule/time, oral) |
NAs(ETV/TDF/TAF), Once/day, 1 capsule/time, oral |
Mitä tutkimuksessa mitataan?
Ensisijaiset tulostoimenpiteet
Ensisijaiset tulostoimenpiteet
Tulosmittaus |
Toimenpiteen kuvaus |
Aikaikkuna |
|---|---|---|
|
Serum HBsAg
Aikaikkuna: Baseline
|
Serum HBsAg level |
Baseline
|
|
Serum HBsAg
Aikaikkuna: 24 weeks after the treatment
|
Serum HBsAg level |
24 weeks after the treatment
|
|
Serum HBsAg
Aikaikkuna: 48 weeks after the treatment
|
Serum HBsAg level |
48 weeks after the treatment
|
|
Serum HBsAg
Aikaikkuna: 24 weeks after the end of treatment
|
Serum HBsAg level |
24 weeks after the end of treatment
|
|
Serum HBV DNA
Aikaikkuna: Baseline
|
Serum HBV DNA level |
Baseline
|
|
Serum HBV DNA
Aikaikkuna: 24 weeks after the treatment
|
Serum HBV DNA level |
24 weeks after the treatment
|
|
Serum HBV DNA
Aikaikkuna: 48 weeks after the treatment
|
Serum HBV DNA level |
48 weeks after the treatment
|
|
Serum HBV DNA
Aikaikkuna: 24 weeks after the end of treatment
|
Serum HBV DNA level |
24 weeks after the end of treatment
|
|
Serum alanine aminotransferase (ALT)
Aikaikkuna: Baseline
|
Serum ALT level |
Baseline
|
|
Serum alanine aminotransferase (ALT)
Aikaikkuna: 24 weeks after the treatment
|
Serum ALT level |
24 weeks after the treatment
|
|
Serum alanine aminotransferase (ALT)
Aikaikkuna: 48 weeks after the treatment
|
Serum ALT level |
48 weeks after the treatment
|
|
Serum alanine aminotransferase (ALT)
Aikaikkuna: 24 weeks after the end of treatment
|
Serum ALT level |
24 weeks after the end of treatment
|
Muut tulostoimenpiteet
Muut tulostoimenpiteet
Tulosmittaus |
Toimenpiteen kuvaus |
Aikaikkuna |
|---|---|---|
|
Other HBV markers (HBsAb, HBeAg, HBeAb, and HBcAb)
Aikaikkuna: Baseline
|
Levels of other HBV markers (HBsAb, HBeAg, HBeAb, and HBcAb) |
Baseline
|
|
Other HBV markers (HBsAb, HBeAg, HBeAb, and HBcAb)
Aikaikkuna: 24 weeks after the treatment
|
Levels of other HBV markers (HBsAb, HBeAg, HBeAb, and HBcAb) |
24 weeks after the treatment
|
|
Other HBV markers (HBsAb, HBeAg, HBeAb, and HBcAb)
Aikaikkuna: 48 weeks after the treatment
|
Levels of other HBV markers (HBsAb, HBeAg, HBeAb, and HBcAb) |
48 weeks after the treatment
|
|
Other HBV markers (HBsAb, HBeAg, HBeAb, and HBcAb)
Aikaikkuna: 24 weeks after the end of treatment
|
Levels of other HBV markers (HBsAb, HBeAg, HBeAb, and HBcAb) |
24 weeks after the end of treatment
|
|
Immune response of T and B cells
Aikaikkuna: Baseline
|
Frequencies and functions of T and B cells (tested by flowcytometry/FluoroSpot/ELISPOT) |
Baseline
|
|
Immune response of T and B cells
Aikaikkuna: 24 weeks after the treatment
|
Frequencies and functions of T and B cells (tested by flowcytometry/FluoroSpot/ELISPOT) |
24 weeks after the treatment
|
|
Immune response of T and B cells
Aikaikkuna: 48 weeks after the treatment
|
Frequencies and functions of T and B cells (tested by flowcytometry/FluoroSpot/ELISPOT) |
48 weeks after the treatment
|
|
Immune response of T and B cells
Aikaikkuna: 24 weeks after the end of treatment
|
Frequencies and functions of T and B cells (tested by flowcytometry/FluoroSpot/ELISPOT) |
24 weeks after the end of treatment
|
|
Virus and host genome
Aikaikkuna: Baseline
|
Detect virus and host genome using peripheral blood and liver tissue by sequencing |
Baseline
|
|
Virus and host genome
Aikaikkuna: 24 weeks after the treatment
|
Detect virus and host genome using peripheral blood and liver tissue by sequencing |
24 weeks after the treatment
|
|
Virus and host genome
Aikaikkuna: 48 weeks after the treatment
|
Detect virus and host genome using peripheral blood and liver tissue by sequencing |
48 weeks after the treatment
|
|
Virus and host genome
Aikaikkuna: 24 weeks after the end of treatment
|
Detect virus and host genome using peripheral blood and liver tissue by sequencing |
24 weeks after the end of treatment
|
Yhteistyökumppanit ja tutkijat
Sponsori
Sponsori
Yhteistyökumppanit
Yhteistyökumppanit
Tutkijat
Tutkijat
- Opintojohtaja: Hong Ren, MM, The Second Affiliated Hospital of Chongqing Medical University
Opintojen ennätyspäivät
Opi tärkeimmät päivämäärät
Opiskelun aloitus (Todellinen)
Opiskelun aloitus
Ensisijainen valmistuminen (Arvioitu)
Ensisijainen valmistuminen
Opintojen valmistuminen (Arvioitu)
Opintojen valmistuminen
Opintoihin ilmoittautumispäivät
Ensimmäinen lähetetty
Ensimmäinen lähetetty
Ensimmäinen toimitettu, joka täytti QC-kriteerit
Ensimmäinen toimitettu, joka täytti QC-kriteerit
Ensimmäinen Lähetetty (Todellinen)
Ensimmäinen Lähetetty
Tutkimustietojen päivitykset
Viimeisin päivitys julkaistu (Todellinen)
Viimeisin päivitys julkaistu
Viimeisin lähetetty päivitys, joka täytti QC-kriteerit
Viimeisin lähetetty päivitys, joka täytti QC-kriteerit
Viimeksi vahvistettu
Viimeksi vahvistettu
Lisää tietoa
Tähän tutkimukseen liittyvät termit
Muita asiaankuuluvia MeSH-ehtoja
- Veren välityksellä leviävät infektiot
- Patologiset prosessit
- Krooninen sairaus
- Sairauden ominaisuudet
- Infektiot
- Virussairaudet
- Ruoansulatuskanavan sairaudet
- Maksasairaudet
- Hepatiitti, virus, ihminen
- Tartuntataudit
- DNA-virusinfektiot
- Hepadnaviridae-infektiot
- Hepatiitti, krooninen
- Hepatiitti
- Patologiset tilat, merkit ja oireet
- B-hepatiitti
- Hepatiitti B, krooninen
- Envafolimab
- sintilimabi
Muut tutkimustunnusnumerot
Muut tutkimustunnusnumerot
- 2025-0215
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Aiotko jakaa yksittäisten osallistujien tietoja (IPD)?
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