Recruiting
Phase 1
Safety and Antiviral Activity of a Monoclonal Hepatitis B Antibody (The SAMBA Study)
Condition(s) studied
Hepatitis B
Investigational drug(s) / intervention(s)
HepB mAb19: The study has two parts:
Part A will involve administering a single ascending dose of HepB mAb19 or placebo using a randomized, double-blind method in Groups 1-3 at dose levels of 3, 10, and 30 mg/kg. Participants enrolled in Groups 1-3 will be randomized at a 3:1 ratio to receive HepB mAb19 or placebo. Part B will assess the maximum tolerated dose (MTD) in Group 4 in an openlabel fashion. Participants will receive HepB mAb19 at MTD.
Study summary
Hepatitis B virus (HBV) remains a major global health problem with an estimated 257 million people living with the infection worldwide. Chronic HBV (CHB) is a major cause of liver cirrhosis and hepatocellular carcinoma. While antiviral therapies are available and suppress viral levels, treatment is long-term, does not clear the infection and rarely leads to long-term control once discontinued. Moreover, treatment access is not ideal on a global level with less than 10% of people in need receiving treatment. Although a strategy that eliminates all viral particles from the body represents the "holy grail" of HBV therapy, a strategy that leads to HBsAg loss and allows patients to stop treatment is highly desirable. New strategies to achieve either complete viral clearance or a state of viral control without the need for long-term treatment are being developed, including approaches to restore immune responses. Antibodies are key modulators of immune responses because of their dual functionality. In addition to directly targeting a viral antigen, antibodies differ from direct antivirals in that they can recruit other immune cells to eliminate infected cells and accelerate viral clearance.
This study will evaluate the safety and pharmacokinetics of a monoclonal antibody that was isolated from an HBV-vaccinated individual, HepB mAb19, as well as its potential effects on viral levels and antiviral immune responses in individuals living with CHB.
Eligibility
Inclusion Criteria:
* Age ≥ 18 to ≤ 70;
* HBV infection confirmed by positive HBsAg for ≥6 months;
* On HBV-active nucleos(t)ide therapy for ≥6 months without change in NRTI in the previous 3 months;
* The following laboratory values 49 days prior to study entry (day 0):
* HBV DNA below lower limit of quantification;
* HBs antibody negative;
* HBeAg negative;
* Ability and willingness to provide informed consent.
* For participants who can become pregnant (i.e., participants who have not been post-menopausal for at least 24 consecutive months, who have had menses within the preceding 24 months, or who have not undergone surgical sterilization, specifically hysterectomy and/or bilateral oophorectomy or bilateral salpingectomy), negative serum or urine pregnancy test at screening and on day 0 (study entry).
* Participants who can become pregnant must agree to use two methods of contraception, one of which must be from the highly effective methods for contraception listed below. Barrier methods of contraception are permitted for the second method of contraception. Contraception must be used from 10 days prior to study entry and during study follow up. Acceptable methods of contraception include:
* Contraceptive subdermal implant;
* Intrauterine device or intrauterine system;
* Combined estrogen and progestogen oral contraceptive;
* Injectable progestogen;
* Contraceptive vaginal ring;
* Percutaneous contraceptive patches;
* Partner sterilization with documentation of azoospermia prior to the participant\'s entry into the study, and this partner is the sole partner for that participant. The documentation of partner sterility can come from the site personnel\'s review of medical records or medical history interview provided by the participant or the partner. Self-reported documentation of reproductive potential should be entered in the source documents.
* Participants who can impregnate a partner and who are engaging in sexual activity that could lead to pregnancy must agree to use condoms from 10 days prior to study entry and during study follow up to avoid impregnating a partner who can get pregnant.
Exclusion Criteria:
* Clinical symptoms, imaging studies or liver histology suggestive of advanced fibrosis (exclude fibrosis grade 3 and 4 by FibroScan) (Fibroscan®\< 9 kpa) 12 months prior to entry or done at the pre-infusion visit. Note: If FibroScan results are not available, imaging will be performed at the preinfusion visit.
* Presence of a LI-RADS4 or 5 liver lesion on imaging 12 months prior to entry or done at pre-infusion visit, if prior results not available.
* Alpha fetoprotein \>20 ng/ml. Note: Alpha-fetoprotein (AFP) above normal but \< 20 is acceptable for entry if earlier AFP levels (older than 6 months) are within normal range and imaging is negative in last 3 months).
* HIV-1, HCV or hepatitis delta virus infection 12 months prior to entry or done at screen, if prior results not available;
* History of hematopoietic stem cell transplant or solid organ transplant;
* Any confirmed significant allergic reactions (urticaria or anaphylaxis) against any drug, monoclonal antibody or vaccine, or multiple drug allergies (non-active hay fever is acceptable);
* History of cardiovascular disease (e.g., cardiac insufficiency, coronary artery disease, cardiomyopathy, congestive heart failure, family history of congenital long QT syndrome, family history of sudden death);
* History or presence of clinically significant Electrocardiogram (ECG) abnormalities based on the average of the triplicate ECG recordings (e.g., PR interval \>210 ms, QT corrected for heart rate using the Fridericia's correction factor \[QTcF\] \> 450 ms for males and QTcF \>470 ms for females);
* History of systemic corticosteroids, immunosuppressive anti-cancer, systemic interferons or interleukins 6 months prior to entry;
* History of chronic liver disease from another cause, ICD, or autoimmune diseases that in the opinion of the investigator would preclude participation;
* Any significant acute infection (e.g. influenza, COVID-19) or any other clinically significant illness 2 weeks prior to entry.
* Laboratory abnormalities in the parameters listed below:
* Absolute neutrophil count \<1,000 /mm3
* Hemoglobin \<10 gm/dL (6.21 mmol/L)
* Platelet count \<150,000 /mm3
* ALT \>2.0 x Upper normal limit (ULN)
* AST \>2.0 x ULN
* Total bilirubin \>1.5 ULN (except individuals with known Gilbert\'s)
* Albumin \<3.5 gm/dL
* Estimated glomerular filtration rate (eGFR) \<70 mL/min
* INR ≥1.2
* Pregnancy or lactation;
* Any vaccination 2 weeks prior to entry;
* Receipt of anti-HBV mAb therapy of any kind in the past (including HBIG);
* Participation in another clinical study of an investigational product currently or 12 weeks prior to, or expected participation during this study
Primary outcome measure(s)
- Safety and tolerability — From enrollment to the end of follow up at 48 weeks
Safety and tolerability evaluation will be done by recording of adverse events. The DAIDS AE Grading Table Corrected version 2.1 (July 2017) will be used to grade adverse events. In addition, the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grading scale will be used for reporting and grading adverse events related to infusion reactions and cytokine release syndromes within 24 hours of the start of IP or placebo administration that are considered administration reactions or cytokine release syndromes.
- Pharmacokinetic profile — From enrollment to the end of follow up at 48 weeks
HepB mAb19 levels in serum will be measured by a validated sandwich ELISA method developed and performed by Celldex Therapeutics. HepB mAb19 levels will be measured before and at the end of the administration, at 3 and 6 hours, 1, 3, 7 days and on weeks 2, 3, 4 weeks after administration, and at later time points during follow up.
- Pharmacokinetic profile — From enrollment to follow up at 48 weeks
Assesment of HepB mAb19 elimination half-life (t1/2)
- Pharmacokinetic profile — From enrollment to follow up at 48 weeks
Assesment of clearance (CL/F) of HepB mAb19
- Pharmacokinetic profile — From enrollment to follow up at 48 weeks
Calculation of volume of distribution (Vz/F)
- Pharmacokinetic profile — From enrollment to follow up at 48 weeks
Calculation of area under the curve (AUC) for HepB mAb19
- Pharmacokinetic profile — From enrollment to follow up at 48 weeks
Calculation of HepB mAb19 decay curve
- Maximum tolerated dose — From enrollment to follow up at 48 weeks
To establish the maximum tolerated dose (MDT)
Trial sites (1)
| Facility | City | Region | Status |
|---|
| Department of Infectious Diseases, Aarhus University Hospital |
Aarhus N |
Denmark |
Recruiting |
More Aarhus University Hospital trials in Denmark
Other trials for the same condition
