This study has been transitioned to CTIS with ID 2024-512203-40-00 check the CTIS register for the current data. The purpose of the study is to evaluate (1) the efficacy of monotherapy and combination VIR-2218 and VIR-3434 therapy in suppressing HDV…
ID
Source
Brief title
Condition
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoints
- Proportion of participants with undetectable HDV RNA (< LOD) or >= 2 log10
decrease in HDV RNA from baseline and alanine aminotransferase (ALT)
normalization (ALT < upper limit of normal [ULN]) at Week 24 (Cohorts 2 and 3
only)
- Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs)
Secondary outcome
Secondary endpoints:
- Proportion of participants with undetectable HDV RNA (< LOD) or >= 2 log10
decrease in HDV RNA from baseline and ALT normalization at Week 12, Week 48,
Week 72, Week 96, Week 144 and Week 192
- Proportion of participants with undetectable HDV RNA (< LOD) or >= 2 log10
decrease in HDV RNA from baseline at Week 12, Week 24, Week 48, Week 72, Week
96, Week 144 and Week 192
- Proportion of participants with undetectable HDV RNA (< LOD) at Week 12, Week
24, Week 48, Week 72, Week 96, Week 144 and Week 192
- Proportion of participants with HDV RNA < lower limit of quantitation (LLOQ)
at Week 12, Week 24, Week 48, Week 72, Week 96, Week 144 and Week 192
- Change from baseline in HDV RNA at Week 12, Week 24, Week 48, Week 72, Week
96, Week 144 and Week 192
- Proportion of participants with ALT normalization at Week 12, Week 24, Week
48, Week 72, Week 96, Week 144 and Week 192
- Incidence of anti-drug antibodies (ADA) and titers of ADA to VIR-3434 at
specified study visits up to Week 192 (for cohorts with VIR-3434)
- Change from baseline in liver fibrosis at Week 48, Week 96, Week 144, and
Week 192
- Change from baseline in Model for End Stage Liver Disease (MELD) score at
Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 96, Week
144, and Week 192
- Change from baseline in Child-Pugh-Turcotte (CPT) score at Week 24, Week 48,
Week 72, Week 96, Week 144, and Week 192
Background summary
Treatment options for HDV infection are limited to pegylated interferon alfa
(PEG-IFNα) and, in some regions of the world, buleviritide (BLV). Limitations
and poor efficacy of current agents highlights an unmet need for patients with
chronic HDV infection in all stages of the disease.
This study aims to evaluate whether the combination of investigational
therapies VIR-2218 and VIR-3434 in comparison to monotherapy treatment of each
can achieve durable suppression of HDV in patients with chronic HBV/HDV
infection. VIR-2218 is a small interfering ribonucleic acid (siRNA) associated
with substantial reductions in HBsAg in patients with chronic HBV infection.
VIR-3434 is a monoclonal antibody (mAb) targeting HBsAg with multiple potential
mechanisms of action, including strong neutralizing activity to HDV and HBV and
enhanced immunologic activity due to Fc domain engineering. Coadministration of
VIR-2218+VIR-3434 has the potential to durably suppress HDV viremia, normalize
liver inflammation, reverse or halt the progression of liver fibrosis and
hepatic impairment, and improve the quality of life of persons with chronic HDV
infection.
Study objective
This study has been transitioned to CTIS with ID 2024-512203-40-00 check the CTIS register for the current data.
The purpose of the study is to evaluate (1) the efficacy of monotherapy and
combination VIR-2218 and VIR-3434 therapy in suppressing HDV viremia and
normalizing ALT in participants with varying degrees of liver fibrosis and
compensated cirrhosis and (2) the safety of VIR-2218 and VIR-3434 in this
population.
Primary objectives
- To evaluate the efficacy of VIR-2218 and VIR-3434 in participants with
chronic HDV infection in Cohorts 2 and 3 only
- To evaluate the safety of VIR-2218 and VIR-3434 in participants with chronic
HDV infection in each cohort
Secondary objectives
- To evaluate the efficacy of VIR-2218 and VIR-3434 in participants with
chronic HDV infection on HDV RNA and ALT normalization in each cohort
- To assess the immunogenicity of VIR-3434 (for cohorts with VIR-3434)
- To assess the effects of VIR-2218 and VIR-3434 on liver fibrosis and hepatic
function in each cohort
Study design
This is a Phase 2, multicenter, randomized, open-label study designed to
evaluate the efficacy, safety and tolerability of VIR-2218 and VIR-3434 in
noncirrhotic and cirrhotic CPT-A adult participants with chronic HDV infection
on NRTI therapy.
The study will consist of cohorts receiving either VIR-2218 or VIR-3434
monotherapy or combination therapy. For Cohorts 1a and 1b, the study
intervention treatment period with VIR-2218 and VIR-3434 is composed of 2
periods: Induction (12 weeks) and Maintenance (up to 84 weeks). For Cohorts 2a,
2b1, 2b2, and 2c, 3, and 5 the intervention period with VIR-2218 and VIR-3434
consists of the study intervention treatment period (up to 192 weeks). The
study also includes two optional sub-studies collecting (1) liver tissue and
(2) blood samples for PK studies.
Intervention
The research study includes 2 groups (or cohorts), and each group will contain
participants with different levels of liver disease and will evaluate different
dosing schedules of the study drugs VIR-2218 and VIR-3434. Please refer to the
protocol for a detailed table with information on Intervention groups and
duration.
Study burden and risks
BURDEN:
Physical examination
ECG
Blood sampling
Urine sampling
Liver scan
Questionnaires
Pregnancy test
Liver biopsy
When participants experience ALT elevation meeting ECI criteria:
- Abdominal ultrasound, including doppler flow if available (CT or MRI is
acceptable in place of ultrasound if clinically indicated)
RISK:
VIR-2218
Possible side effects of VIR-2218 include, but are not limited to:
• Changes in liver function/liver related blood tests: Since VIR-2218 targets
the liver, there is a potential for liver injury. You will be carefully
monitored throughout the research study for any signs of liver injury,
including liver blood tests, and other potential symptoms of liver injury.
Changes in liver related blood tests could be short term or may require
research study discontinuation and possibly additional medical care. In an
ongoing research study, 2 of 5 participants with chronic HDV had an increase in
their liver function blood test results after receiving VIR-2218 as a single
therapy (treatment for their HDV). These liver function blood test results
returned to normal over time and did not result in permanent changes in their
liver function.
• Immunogenicity: Is the creation of antibodies against which may affect
VIR-2218. This means that if antibodies (products of the body's defense)
against VIR-2218 are present, VIR-2218 may not work as well as expected and/or
there may be unknown side effects.
• Injection site reactions: Pain or a local immune reaction (i.e., redness
and/or swelling, at the injection site which can vary in severity) has occurred
in participants with chronic HBV who have received VIR-2218 alone. These
reactions were considered mild to moderate. If you experience a reaction, the
injection site may be photographed to monitor the reaction over time. The
photographs will not identify you and they will not include your face, only the
injection site.
• Allergic reaction, which may or may not occur with any drug. Some symptoms of
allergic reactions are:
• Rash
• Itching
• Wheezing, or difficulty breathing
• Dizziness or fainting
• Swelling around the mouth, tongue, throat or eyes
• A fast pulse and/or a drop in blood pressure
• Sweating
VIR-3434
Possible side effects of VIR-3434 include, but are not limited to:
• Changes in liver function/liver related blood tests: Since VIR-3434 targets a
virus in the liver, there is a potential for liver injury. You will be
carefully monitored throughout the research study for any signs of liver
injury, including liver blood tests, and other potential symptoms of liver
injury. Changes in liver related blood tests could be short term or may require
additional medical care.
• Immune complex disease: Immune complexes are formed when antibodies (which
are proteins that help the body fight infections) combine with antigens (which
are foreign substances in the body). When a large amount of immune complexes
are formed, they can be deposited throughout the body and cause problems with
your organs. This may result in a variety of conditions, including but not
limited to rash, joint pain, kidney injury, and stomach pain.
• Immunogenicity: Is the generation of antibodies against VIR-3434 which may
affect VIR-3434. This means that if antibodies are present the drug may not
work as well as expected and/or there may be unknown side effects.
• Hypersensitivity reactions: injection site reactions (pain, redness, itching
and/or swelling, at the injection site which can vary in severity), and serious
allergic reactions, which may be severe or life-threatening.
o These are potential risks associated with antibody treatments. The risk of
developing such conditions after receiving VIR-3434 is unknown.
o Serious allergic reactions including anaphylaxis, which may or may not occur
with any new experimental study drug. Some symptoms of allergic reactions are:
* Rash
* Itching
* Wheezing, or difficulty breathing
* Dizziness or fainting
* Swelling around the mouth, tongue, throat, or eyes
* A fast pulse and/or a drop in blood pressure
* Sweating
Possible risks of study procedures:
- Blood Draws and Injections: Having a drug injected or blood taken may cause
some discomfort, bruising, minor infection, or bleeding.
- Ultrasound Scan: Gel from this procedure may be sticky but the test should
not cause any pain or discomfort
- Magnetic Resonance Imaging (MRI): During this test, the patient will lie in a
small, closed area inside a large magnetic tube. Some people are scared or
anxious in small places (claustrophobic). The MRI scanner makes loud banging
noises while taking a measurement, so either ear plugs, or specially designed
headphones may be used to reduce the noise. It is possible the that the MRI
will be done with contrast (dye) to help them see the images from the scan more
clearly. Possible risks of contrast can be found below.
- Contrast Dye (with MRI): If contrast (dye) is ordered with the MRI scan, it
is given by injection into a vein (IV). The most commonly used contrast agent
contains a material called gadolinium. About 1 in 100 people may notice
discomfort, tingling or warmth in the lips, metallic taste in the mouth,
tingling in the arm, nausea, or headache. These symptoms go away quickly. There
is a small risk of an allergic reaction to gadolinium. However, a severe
allergic reaction occurs in less than one in 300,000 people. The placement of
the needle to give the contrast may cause minor pain, bruising and/or infection
at the injection site.
- Computerized Tomography (CT) Scan: The cumulative radiation exposure from
these tests is considered small and is not likely to adversely affect the
patient or disease. However, the effects of radiation add up over a lifetime.
It is possible that having several of these tests may add to your risk of
injury or disease. It is possible to have the CT scan with contrast (dye) to
help them see the images from the scan more clearly. Possible risks of contrast
can be found below.
- Contrast Dye (with CT): If contrast (dye) is ordered with the CT scan, it is
given by injection into a vein (IV) or the patient may be asked to drink oral
contrast. Most CT contrast reactions (approximately 95%) are mild to moderate
and most resolve themselves without treatment. There is a chance of developing
an allergic reaction from the contrast material, which may cause symptoms
ranging from mild itching or a rash to severe difficulty breathing, shock or
rarely, death. The contrast material may also cause kidney problems.
For IV contrast: Patient may feel discomfort when the contrast material is
injected. Patient may feel warm, flushed, get a metallic taste in the mouth or,
rarely, may make them vomit or feel sick to the stomach. The placement of the
needle to give you the contrast may cause minor pain, bruising and/or infection
at the injection site.
For oral contrast: Patient may experience vomiting, nausea, cramping,
bloating, constipation, or diarrhea after taking the contrast.
Genetic Testing: There is a risk that information about taking part in a
genetic research study may influence insurance companies or employers regarding
the patient's health. To further safeguard the privacy, genetic information
obtained in this research study will not be placed in the medical record.
Taking part in a research study involving genetic research may also have a
negative impact on family or other relationships.
The genetic testing could show the patient may be at risk for certain diseases.
If others found out, it could lead to discrimination or other problems.
However, it is very unlikely for patient or others to know the test results
from the genetic testing. The results are not part of the research study
records and are not given to patient or study doctor.
HIV and hepatitis testing: The HIV t
1800 Owens St., Suite 900 -
San Francisco, CA 94158
US
1800 Owens St., Suite 900 -
San Francisco, CA 94158
US
Listed location countries
Age
Inclusion criteria
Age 1. Age >= 18 (or age of legal consent, whichever is older) to < 70 years at
the time of screening Type of Participant and Disease Characteristics 2.
Chronic HBV infection defined as a positive serum HBsAg, HBV DNA, or HBeAg on 2
occasions at least 6 months apart based on previous (within the past 12 months)
or current laboratory documentation (any combination of these tests performed 6
months apart is acceptable) 3. On locally approved NRTI therapy for at least 12
weeks prior to Day 1 4. HBsAg > 0.05 IU/mL at screening 5. Positive HDV
antibody for at least 6 months prior to screening and HDV RNA >= 500 IU/mL at
screening 6. Serum alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) > ULN and < 5 x ULN Weight 7. Body Mass Index (BMI) >= 18
kg/m2 to <= 40 kg/m2 Sex and Contraceptive/Barrier Requirements 8. Female
participants must have a negative pregnancy test or confirmation of
postmenopausal status. Postmenopausal status is defined as 12 months with no
menses without an alternative medical cause (see Section 10.7 for additional
details). Women of childbearing potential (WOCBP) must have a negative blood
pregnancy test at screening and a negative urine pregnancy test on Day 1,
cannot be breast feeding, and must be willing to use highly effective methods
of contraception (Section 10.7) 14 days before study intervention
administration through 48 weeks after the last dose of VIR-2218 or VIR-3434.
Female participants must also agree to refrain from egg donation and in vitro
fertilization from the time of study intervention administration through 48
weeks after the last dose of VIR-2218 or VIR-3434. 9. Male participants with
female partners of childbearing potential must agree to meet 1 of the following
contraception requirements from the time of study intervention administration
through 48 weeks after the last dose of VIR-2218 or VIR-3434: documentation of
vasectomy or azoospermia, or male condom use plus partner use of 1 of the
contraceptive options listed for contraception for WOCBP (Section 10.7). Male
participants must also agree to not donate sperm from the time of first study
intervention administration through 48 weeks after the last dose of VIR-2218 or
VIR-3434. Informed Consent 10. Capable of giving signed informed consent as
described in Section 10.1.3, which includes compliance with the requirements
and restrictions listed in the informed consent form (ICF) and in this protocol
Other Inclusion Criteria 11. 12-lead electrocardiogram (ECG) within normal
limits; or, with no clinically significant abnormalities at screening, as
determined by the investigator. 12. Agrees not to donate blood during the
duration of the study and for an additional 3 months after the last dose of
study intervention. Cohort Specific Inclusion Criteria 13. Cohort 1 specific
inclusion criteria • Noncirrhotic * Liver biopsy with METAVIR F0-F3 or Liver
elastography (eg, Fibroscan®) < 12 kilopascal (kPa) within the 12 months prior
to screening * Creatinine clearance (CLcr) >= 30 mL/min as calculated by the
Cockcroft-Gault formula at screening * Platelet count > 150,000 cells/mm3 (/µL)
• Cirrhotic * Liver biopsy with METAVIR F4 or Liver elastography (Fibroscan®) >=
12 kPa (Cohort 2) within the 12 months prior to screening * CLcr >= 60 mL/min as
calculated by the Cockcroft-Gault formula at screening * CPT score of 5 or 6,
inclusive at screening and at start of study 14. Cohorts 2a, 2b1, 2b2, 2c, 3 &
4 specific inclusion criteria • Noncirrhotic -Liver biopsy with METAVIR F0-F3
or Liver elastography (eg, Fibroscan®) < 12 kPa within the 12 months prior to
screening -CLcr >= 30 mL/min as calculated by the Cockcroft-Gault formula at
screening -Platelet count > 150,000 cells/mm3 (/µL) • CPT-A Cirrhotic -Liver
biopsy with METAVIR F4 or Liver elastography (eg, Fibroscan®) >= 12 kPa within
the 12 months prior to screening -CLcr >= 60 mL/min as calculated by the
Cockcroft-Gault formula at screening -Platelet count > 90,000 cells/mm3 (/µL)
-CPT score of 5 or 6, inclusive at screening and at start of study
*Alternatives to Fibroscan, eg, 2D-Shear Wave Elastography, can be allowed
following approval of the sponsor
15. Cohort 5 specific inclusion criteria
• Noncirrhotic
* Liver biopsy with METAVIR F0-F3 or Liver elastography (eg,
Fibroscan®)
< 8 kilopascal (kPa) within the 12 months prior to screening
* Creatinine clearance (CLcr) >= 30 mL/min as calculated by the
Cockcroft-Gault formula at screening
* Platelet count > 150,000 cells/mm3 (/µL)
* HBsAg < 10,000 IU/mL
Exclusion criteria
Medical Conditions 1. History of clinically significant liver disease from
non-HBV and non-HDV etiology as determined by the investigator 2. History of
clinically significant immune complex disease as determined by the investigator
3. History of clinically significant autoimmune disorder as determined by the
investigator 4. History of HBV-related extrahepatic disease, including but not
limited to HBV-related rash, arthritis, or glomerulonephritis 5. History of
allergic reactions, hypersensitivity, or intolerance to study intervention, its
metabolites or excipients 6. Anti-HBs >10 mIU/L at screening 7. Corrected QT
interval (QTc) > 450 milliseconds 8. ALT or AST >= 5x ULN 9. Total bilirubin >
2.0 mg/dL 10. Serum albumin < 30 g/L 11. Absolute neutrophil count < 1,000/mm3
(/µL) 12. International normalized ratio (INR) > 1.5 13. Hemoglobin < 8 g/dL
14. History of anaphylaxis 15. History of malignancy diagnosed or treated
within 5 years (localized treatment of squamous or noninvasive basal cell skin
cancers is permitted; cervical carcinoma in situ is allowed if appropriately
treated prior to screening); participants under evaluation for malignancy are
not eligible 16. History of or listed for bone marrow or solid organ transplant
17. Known active infection other than chronic HBV and HDV infection or any
clinically significant acute condition such as fever (> 38° C) or acute
respiratory illness within 7 days prior to Day 1 18. Coinfection with human
immunodeficiency virus (HIV), hepatitis A virus (HAV), hepatitis C virus (HCV)
or hepatitis E virus (HEV). Participants who are HCV antibody positive and HCV
RNA negative are eligible. Participants who are HAV or HEV immunoglobulin M
antibody (IgM) positive are not eligible. Participants who are asymptomatic and
HAV or HEV immunoglobulin G antibody (IgG) positive are eligible. 19. Any
clinically significant medical or psychiatric condition that may interfere with
study intervention, assessment, or compliance with the protocol or otherwise
makes the participant unsuitable for participation in the study, as determined
by the investigator. Participants with controlled Diabetes Mellitus are
eligible. 20. Acute or worsening chronic hepatitis, fluctuating or rapidly
deteriorating hepatic function or use of any therapy known to exacerbate
hepatic dysfunction in the opinion of the investigator. Prior/Concomitant
Therapy 21. Therapy with an immunomodulatory agent, IFN-α (eg, IFN-alfa-2a or
IFN-alfa-2b, or pegylated IFN-alfa-2a or alfa 2b), immunosuppressants (eg,
disease-modifying antirheumatic drugs), cytotoxic or chemotherapeutic agent, or
chronic systemic corticosteroids within 6 months of screening. 22. Received an
HDV active agent (including lonafarnib and bulevirtide) within 90 days or 5
half-lives (if known), whichever is longer, before study drug administration or
are active in the Follow-Up period of another clinical study involving
interventional treatment. Participants must also agree not to take part in any
other interventional study at any time during their participation in this
study, inclusive of the Follow-Up Period. 23. Receipt of an oligonucleotide
(eg, siRNA, antisense oligonucleotide) with activity against HBV within 48
weeks before study drug administration 24. Receipt of VIR-3434 or any antibody
targeting HBV or HDV within 24 weeks of first study drug administration
Additional Exclusions 25. History or clinical evidence of alcohol or drug abuse
within the 12 months before screening or a positive drug screen at screening
unless it can be explained by a prescribed medication (the diagnosis and
prescription must be approved by the investigator). Cannabis use is permitted.
Additional Exclusions Criteria for Hepatically Impaired Participants 26.
Participants requiring paracentesis > 1 time per month. 27. Participants with
refractory encephalopathy or significant Central Nervous System disease as
judged by the investigator. 28. History of gastric or esophageal variceal
bleeding within the past 6 months. 29. Participants with Transjugular
Intrahepatic Portosystemic Shunt (TIPS) placement. 30. Presence of
hepatopulmonary or hepatorenal syndrome. 31. Presence of primary cholestatic
liver diseases. 32. Inability or unwillingness to comply with dietary
recommendations for liver cirrhosis and hepatic impairment as advised by the
investigator and lifestyle considerations outlined in this protocol.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-512203-40-00 |
| EudraCT | EUCTR2022-001993-78-NL |
| ClinicalTrials.gov | NCT05461170 |
| CCMO | NL82432.000.22 |