Chronic Hepatitis BLVLNCT00973219
Hepatitis B Surface Antigen(HBsAg) Loss in Chronic Hepatitis B Patients With Low Viral Load
A study testing Peg-Interferon alfa 2a + Adefovir dipivoxil, Peg-Interferon alfa 2a + Tenofovir disoproxil fumarate in people with Chronic Hepatitis B, run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) at 1 site in Netherlands.
Trial summary
Rationale: Worldwide, approximately 400 million people are chronically infected with hepatitis B virus (HBV). Chronic HBV infection increases the risk of developing cirrhosis, hepatic decompensation and hepatocellular carcinoma (HCC). Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Chronic Hepatitis B
- What is being tested?
- Peg-Interferon alfa 2a + Adefovir dipivoxil, Peg-Interferon alfa 2a + Tenofovir disoproxil fumarate
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 151 participants
- Where
- 1 siteNetherlands
- Study dates
- Sep 2009to Oct 2019
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Male and female patients > 18 and ≤ 70 years of age
- Positive HBsAg for more than 6 months.
- Negative for HBeAg for more than 6 months.
- HBV DNA < 2.0 E04 IU/mL
- Serum ALT < 5 * ULN as determined by two values taken >14 days apart during the six months before the first dose of study drug with at least one of the determinations obtained during the screening period.
- Negative urine or serum pregnancy test (for women of childbearing potential) documented within the 24-hour period prior to the first dose of test drug.
Who cannot join
- Patients co-infected with HCV, HIV or who have decompensated liver disease, hepato-cellular carcinoma, significant cardiac disease, significant renal disease, seizure disorders or severe retinopathy.
- Patients who have received nucleos(t)ide analogues for their chronic hepatitis B within 6 weeks before enrollment or have received Peg-IFN within 3 months before enrollment.
- Patients must not have received any other systemic anti-viral, anti-neoplastic or immuno-modulatory treatment (including supraphysiologic doses of steroids or radiation) <3 months prior to the first dose of study drug or the expectation that such treatment will be needed at any time during the study.
- Positive test at screening for anti-HAV IgM, anti-HIV, HCV RNA. (Patients that have cleared the hepatitis C virus can be included in the study)
- Patients who are expected to need systemic antiviral therapy other than that provided by the study at any time during their participation in the study are also excluded. Exception: patients who have had a limited (<7 day) course of acyclovir for herpetic lesions more than 1 month prior to the first administration of test drug are not excluded.
- Evidence of decompensated liver disease (Child pugh B-C)
Show all 26Show fewer
- Serum total bilirubin > twice the upper limit of normal at screening
- History or other evidence of bleeding from esophageal varices or other conditions consistent with decompensated liver disease.
- History or other evidence of a medical condition associated with chronic liver disease other than HBV (e.g., hemochromatosis, autoimmune hepatitis, metabolic liver diseases including Wilson's disease and alfa1-antitrypsin deficiency, alcoholic liver disease, toxin exposures, thalassemia).
- Women with ongoing pregnancy or who are breast feeding.
- Neutrophil count <1500 cells/mm3 or platelet count <80,000 cells/mm3 at screening.
- Hemoglobin < 7.1 mmol/L (< 11.5 g/dL) for females and < 7.8 mmol/L (< 12.5 g/dL) for men at screening.
- Serum creatinine level >1.5 times the upper limit of normal at screening.
- Unstable ongoing severe psychiatric disease, especially depression (stable patients can be included).
- History of immunologically mediated disease (e.g., inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia, scleroderma, severe psoriasis, rheumatoid arthritis).
- History or other evidence of chronic pulmonary and cardiac disease associated with functional limitation. Severe cardiac disease (e.g., NYHA Functional Class III or IV, myocardial infarction within 6 months, ventricular tachyarrhythmias requiring ongoing treatment, unstable angina or other significant cardiovascular diseases).
- History of a severe seizure disorder or current anticonvulsant use and clinically unstable disease.
- Evidence of an active or suspected cancer or a history of malignancy where the risk of recurrence is >20% within 5 years. Patients with a lesion suspicious of hepatic malignancy on a screening imaging study will only be eligible if the likelihood of carcinoma is <10% following an appropriate evaluation.
- Major organ transplantation. (patients with skin, cornea or bone transplantation are allowed to be included into the study)
- Thyroid disease with thyroid function poorly controlled on prescribed medications. Patients with elevated thyroid stimulating hormone or T4 concentrations, with elevation of antibodies to thyroid peroxidase and any clinical manifestations of thyroid disease that are not stable on prescribed medication are excluded. Stable patients can be included.
- History or other evidence of severe retinopathy (e.g. CMV retinitis, macula degeneration) or clinically relevant ophthalmological disorder due to diabetes mellitus or hypertension.
- Inability or unwillingness to provide informed consent or abide by the requirements of the study.
- History or other evidence of severe illness or any other conditions which would make the patient, in the opinion of the investigator, unsuitable for the study.
- Patients with a value of alfa-fetoprotein >100 ng/mL are excluded, unless stability (less than 10% increase) has been documented over at least the previous 3 months.
- Evidence of current hard drug(s) (i.e. cannabis products are allowed) and/or alcohol abuse (20g/day for women and 30g/day for men).
- Patients included in another trial or having been given investigational drugs within 12 weeks prior to screening.
Trial locations and contacts
1 site in 1 country.
Netherlands1 site
Academic Medical Center
Amsterdam, North Holland, 1100 AZ
About this study
Official title: A Randomized Prospective Open-label Trial for Comparing Combination Therapy Peg-Interferon Alfa-2a/Adefovir Dipivoxil and Peg-Interferon Alfa-2a/Tenofovir Disoproxil Fumarate Versus no Treatment in HBeAg Negative Chronic Hepatitis B Patients With Low Viral Load.
Rationale:
Worldwide, approximately 400 million people are chronically infected with hepatitis B virus (HBV). Chronic HBV infection increases the risk of developing cirrhosis, hepatic decompensation and hepatocellular carcinoma (HCC). The risk of developing hepatocellular carcinoma is highest in HBeAg positive patients with high HBV DNA levels, but still the relative risk remains 10 for HBeAg negative patients. Furthermore it has been shown that when HBsAg is cleared before cirrhosis has developed, the prognosis is excellent. Recently the investigators have shown that HBeAg negative patients with high HBV-DNA load and low baseline HBsAg levels had a significantly higher HBsAg clearance (positive predictive value of 85%) after combination therapy with peginterferon alfa2a (Peg-IFN) and adefovir.
Read more
Based on these results, a trial was designed to investigate whether combination of a nucleos(t)ide analogue combined with PegIFN, could also provoke a high rate of HBsAg clearance in chronic hepatitis B patients with low (HBV DNA <20,000 IU/mL) viral load.
Study design:
This is a three arm open-label prospective randomized controlled trial. 150 patients will be enrolled into the study after assessment of eligibility. All patients must have documented HBsAg positivity for longer than 6 months, HBeAg negativity, anti-HBe positivity, HBV DNA < 20,000 IU/mL and ALT < 5 * upper limit of normal. Patients with a Child Pugh class B or C will be excluded. Group 1 will consist of patients treated with Peg-IFN and adefovir, group 2 will consist of patients treated with Peg-IFN and tenofovir and group 3 will consist of untreated controls. Patients in group 1 and 2 will receive medication for the period of one year. For enrolment into the study a liverbiopsy at time of enrolment is compulsory and is advisable at end of treatment (week 48).
Study population: The study population will consist of 150 patients chronically infected with hepatitis B virus with low viral load and HBeAg negativity.
Main study parameters/endpoints:
The aim of this study is to investigate what proportion of HBeAg negative, inactive carriers of the hepatitis B virus with low (< 20,000 IU/mL) load will lose HBsAg when treated with nucleot(s)ide analogue/Peg-IFN combination therapy.
In this study the investigators hypothesize that both treatment with peg-interferon and ADF or Peg-IFN and TDF in HBeAg negative chronic hepatitis B patients with low HBV DNA viral load will induce a high rate of HBsAg loss, comparable to that in patients with high viral load after treatment with ADF and Peg-IFN.
- Conditions
- Chronic Hepatitis B
- Being tested
- Peg-Interferon alfa 2a + Adefovir dipivoxil, Peg-Interferon alfa 2a + Tenofovir disoproxil fumarate
- Keywords
- HBsAg loss, HBsAg seroconversion, chronic hepatitis B, low viral load, inactive carrier hepatitis B
- Medical subject headings
- Hepatitis B, Chronic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Peg-Interferon alfa 2a + Adefovir dipivoxil, Peg-Interferon alfa 2a + Tenofovir disoproxil fumarateDrug
Also called Pegsys®, Hepsera®, Viread®
Peg-Interferon alfa 2a 180ug/week + Adefovir dipivoxil 10mg/day, Peg-Interferon alfa 2a 180ug/week + Tenofovir disoproxil fumarate 245mg/day
| Study group | Role | What they receive |
|---|---|---|
| Peg-Interferon alfa 2a + Adefovir | Active comparator | 50 HBeAg negative chronic hepatitis B patients with low viral load will receive Peg-Interferon alfa 2a + Adefovir for a period of 48 weeks. Receives: Drug: Peg-Interferon alfa 2a + Adefovir dipivoxil, Peg-Interferon alfa 2a + Tenofovir disoproxil fumarate |
| Peg-Interferon alfa 2a + Tenofovir | Active comparator | 50 HBeAg negative chronic hepatitis B patients with low viral load will receive Peg-Interferon alfa 2a + Tenofovir for a period of 48 weeks. Receives: Drug: Peg-Interferon alfa 2a + Adefovir dipivoxil, Peg-Interferon alfa 2a + Tenofovir disoproxil fumarate |
| no treatment | No intervention | 50 HBeAg negative chronic hepatitis B patients with low viral load will not receive treatment during a period of 48 weeks |
What is being measured
The primary outcome is the main question the study is designed to answer.
The primary objective is to demonstrate the efficacy of combination therapy (Peg-IFN and adefovir or Peg-IFN and tenofovir) for inducing loss of HBsAg compared to no-treatment in HBeAg negative chronic hepatitis B patients with low viral load.
Measured: 6.5 years including long term follow up
Secondary outcomes (1)
The secondary objectives are to evaluate: a. the rate of HBsAg loss and anti-HBs seroconversion, b. To establish predictive markers at baseline and during the first 12 weeks of treatment for response of primary and secondary endpoints.
Measured: 6.5 years including long term follow up.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Sep 2009 (estimated)
- Study startSep 2009
- Primary completionOct 2019
- Study completionOct 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Chronic Hepatitis BStudies of the same condition, open and under way.
- More trials run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 151 participants (actual)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, H.W.Reesink, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
- Investigators
- H.R. Reesink, MD PhD, Principal investigator, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00973219
- Sponsor's protocol ID
- TTM16002
- Other IDs
- EudraCT number: 2009-013117-94, ABR number: 28338
- Acronym
- LVL
- Status last verified
- Mar 2021
- First submitted
- 8 Sep 2009
- Last updated
- 29 Mar 2021
- Results posted
- No
- Data monitoring committee
- Yes
Publications
de Niet A, Jansen L, Stelma F, Willemse SB, Kuiken SD, Weijer S, van Nieuwkerk CMJ, Zaaijer HL, Molenkamp R, Takkenberg RB, Koot M, Verheij J, Beuers U, Reesink HW. Peg-interferon plus nucleotide analogue treatment versus no treatment in patients with chronic hepatitis B with a low viral load: a randomised controlled, open-label trial. Lancet Gastroenterol Hepatol. 2017 Aug;2(8):576-584. doi: 10.1016/S2468-1253(17)30083-3. Epub 2017 May 15.
PubMed 28522204
Study at a glance
From the registry record, last updated by the sponsor on 29 Mar 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized Prospective Open-label Trial for Comparing Combination Therapy Peg-Interferon Alfa-2a/Adefovir Dipivoxil and Peg-Interferon Alfa-2a/Tenofovir Disoproxil Fumarate Versus no Treatment in HBeAg Negative Chronic Hepatitis B Patients With Low Viral Load.
- ClinicalTrials.gov ID
- NCT00973219
- Acronym / sponsor ID
- LVL / TTM16002
- Conditions
- Chronic Hepatitis B
- Keywords
- HBsAg loss, HBsAg seroconversion, chronic hepatitis B, low viral load, inactive carrier hepatitis B
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 151 participants (actual)
- Lead sponsor
- Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)University, hospital or other
- Study start
- Sep 2009 (actual)
- Primary completion
- Oct 2019 (actual)
- Study completion
- Oct 2019 (actual)
- First posted
- 9 Sep 2009 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Rationale:
Worldwide, approximately 400 million people are chronically infected with hepatitis B virus (HBV). Chronic HBV infection increases the risk of developing cirrhosis, hepatic decompensation and hepatocellular carcinoma (HCC). The risk of developing hepatocellular carcinoma is highest in HBeAg positive patients with high HBV DNA levels, but still the relative risk remains 10 for HBeAg negative patients. Furthermore it has been shown that when HBsAg is cleared before cirrhosis has developed, the prognosis is excellent. Recently the investigators have shown that HBeAg negative patients with high HBV-DNA load and low baseline HBsAg levels had a significantly higher HBsAg clearance (positive predictive value of 85%) after combination therapy with peginterferon alfa2a (Peg-IFN) and adefovir.
Based on these results, a trial was designed to investigate whether combination of a nucleos(t)ide analogue combined with PegIFN, could also provoke a high rate of HBsAg clearance in chronic hepatitis B patients with low (HBV DNA <20,000 IU/mL) viral load.
Study design:
This is a three arm open-label prospective randomized controlled trial. 150 patients will be enrolled into the study after assessment of eligibility. All patients must have documented HBsAg positivity for longer than 6 months, HBeAg negativity, anti-HBe positivity, HBV DNA < 20,000 IU/mL and ALT < 5 * upper limit of normal. Patients with a Child Pugh class B or C will be excluded. Group 1 will consist of patients treated with Peg-IFN and adefovir, group 2 will consist of patients treated with Peg-IFN and tenofovir and group 3 will consist of untreated controls. Patients in group 1 and 2 will receive medication for the period of one year. For enrolment into the study a liverbiopsy at time of enrolment is compulsory and is advisable at end of treatment (week 48).
Study population: The study population will consist of 150 patients chronically infected with hepatitis B virus with low viral load and HBeAg negativity.
Main study parameters/endpoints:
The aim of this study is to investigate what proportion of HBeAg negative, inactive carriers of the hepatitis B virus with low (< 20,000 IU/mL) load will lose HBsAg when treated with nucleot(s)ide analogue/Peg-IFN combination therapy.
In this study the investigators hypothesize that both treatment with peg-interferon and ADF or Peg-IFN and TDF in HBeAg negative chronic hepatitis B patients with low HBV DNA viral load will induce a high rate of HBsAg loss, comparable to that in patients with high viral load after treatment with ADF and Peg-IFN.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Peg-Interferon alfa 2a + Adefovir | Active comparator | Drug: Peg-Interferon alfa 2a + Adefovir dipivoxil, Peg-Interferon alfa 2a + Tenofovir disoproxil fumarate50 HBeAg negative chronic hepatitis B patients with low viral load will receive Peg-Interferon alfa 2a + Adefovir for a period of 48 weeks. |
| Peg-Interferon alfa 2a + Tenofovir | Active comparator | Drug: Peg-Interferon alfa 2a + Adefovir dipivoxil, Peg-Interferon alfa 2a + Tenofovir disoproxil fumarate50 HBeAg negative chronic hepatitis B patients with low viral load will receive Peg-Interferon alfa 2a + Tenofovir for a period of 48 weeks. |
| no treatment | No intervention | –50 HBeAg negative chronic hepatitis B patients with low viral load will not receive treatment during a period of 48 weeks |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Male and female patients > 18 and ≤ 70 years of age
- Positive HBsAg for more than 6 months.
- Negative for HBeAg for more than 6 months.
- HBV DNA < 2.0 E04 IU/mL
- Serum ALT < 5 * ULN as determined by two values taken >14 days apart during the six months before the first dose of study drug with at least one of the determinations obtained during the screening period.
Key exclusion criteria (26 listed)
- Patients co-infected with HCV, HIV or who have decompensated liver disease, hepato-cellular carcinoma, significant cardiac disease, significant renal disease, seizure disorders or severe retinopathy.
- Patients who have received nucleos(t)ide analogues for their chronic hepatitis B within 6 weeks before enrollment or have received Peg-IFN within 3 months before enrollment.
- Patients must not have received any other systemic anti-viral, anti-neoplastic or immuno-modulatory treatment (including supraphysiologic doses of steroids or radiation) <3 months prior to the first dose of study drug or the expectation that such treatment will be needed at any time during the study.
- Positive test at screening for anti-HAV IgM, anti-HIV, HCV RNA. (Patients that have cleared the hepatitis C virus can be included in the study)
- Patients who are expected to need systemic antiviral therapy other than that provided by the study at any time during their participation in the study are also excluded. Exception: patients who have had a limited (<7 day) course of acyclovir for herpetic lesions more than 1 month prior to the first administration of test drug are not excluded.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Peg-Interferon alfa 2a + Adefovir dipivoxil, Peg-Interferon alfa 2a + Tenofovir disoproxil fumarateAlso: Pegsys®, Hepsera®, Viread®Peg-Interferon alfa 2a 180ug/week + Adefovir dipivoxil 10mg/day, Peg-Interferon alfa 2a 180ug/week + Tenofovir disoproxil fumarate 245mg/day | Drug | Peg-Interferon alfa 2a + Adefovir, Peg-Interferon alfa 2a + Tenofovir |
Primary outcome
The primary objective is to demonstrate the efficacy of combination therapy (Peg-IFN and adefovir or Peg-IFN and tenofovir) for inducing loss of HBsAg compared to no-treatment in HBeAg negative chronic hepatitis B patients with low viral load.
Time frame: 6.5 years including long term follow up
1 secondary outcome
The secondary objectives are to evaluate: a. the rate of HBsAg loss and anti-HBs seroconversion, b. To establish predictive markers at baseline and during the first 12 weeks of treatment for response of primary and secondary endpoints.
Time frame: 6.5 years including long term follow up.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Mar 2021.
- Background: PubMed 28522204de Niet A, Jansen L, Stelma F, Willemse SB, Kuiken SD, Weijer S, van Nieuwkerk CMJ, Zaaijer HL, Molenkamp R, Takkenberg RB, Koot M, Verheij J, Beuers U, Reesink HW. Peg-interferon plus nucleotide analogue treatment versus no treatment in patients with chronic hepatitis B with a low viral load: a randomised controlled, open-label trial. Lancet Gastroenterol Hepatol. 2017 Aug;2(8):576-584. doi: 10.1016/S2468-1253(17)30083-3. Epub 2017 May 15.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
H.R. Reesink, MD PhD principal investigator
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Peg-Interferon alfa 2a + Adefovir dipivoxil, Peg-Interferon alfa 2a + Tenofovir disoproxil fumarate in people with Chronic Hepatitis B, run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Mar 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The primary objective is to demonstrate the efficacy of combination therapy (Peg-IFN and adefovir or Peg-IFN and tenofovir) for inducing loss of HBsAg compared to no-treatment in HBeAg negative chronic hepatitis B patients with low viral load. (time frame: 6.5 years including long term follow up). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00973219, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Mar 2021.