Hepatitis D, Liver Disease
Conditions
Keywords
Hepatitis D, Hepatitis D Virus, Cirrhosis
Brief summary
Background: Infection with hepatitis D virus leads to a chronic liver disease with no effective treatment. Lonafarnib has improved hepatitis D virus levels in blood, but the medication still needs more research. Ritonavir makes other drugs more effective and is used with lonafarnib to make it more effective. Lambda interferon stimulates the body s response to viruses. Researchers want to see if combining these drugs fights hepatitis D and helps the liver. Objectives: To see if combining lonafarnib, ritonavir, and lambda interferon is safe and effective to treat chronic hepatitis D infection. Eligibility: Adults at least 18 years old with chronic hepatitis D infection Design: Participants will be screened with a physical exam, medical history, and blood and urine tests. Throughout the study, all participants will: * Follow rules for medicine, food, and contraception * Take hepatitis B medicine * Have weight checked * Have routine blood and urine tests * Give stool samples * Female participants will have pregnancy tests. Participants will have 3 visits before treatment. They will repeat screening tests and have a heart test and liver scan. Participants will have a 5-day inpatient stay. They will: * Baseline blood and urine tests * Have eye tests * Answer health questions * Have a liver sample taken and liver blood pressure measured. Participants will be sedated. * Have reproductive tests * Start the study drugs and have blood draws Over 24 weeks of treatment, participants will: -Take 2 study drugs by mouth every day and 1 as a weekly injection
Detailed description
Chronic delta hepatitis is a serious form of chronic liver disease caused by infection with the hepatitis D virus (HDV), a small RNA virus that requires farnesylation of its major structural protein (HDV antigen) for replication. Based on previous and ongoing clinical trials demonstrating effectiveness against HDV, we propose to treat 26 adult patients with chronic delta hepatitis using the combination of the farnesyltransferase inhibitor (FTI) lonafarnib (LNF), the protease inhibitor ritonavir (RTV) and peginterferon lambda-1a(lambda). In this phase 2a open label study, the safety and antiviral effects of triple therapy with LNF, RTV and lambda for a period of 6 months. After dosing, all patients will be monitored for 24 weeks off therapy. Nucleos(t)ide analogue therapy will be instituted/continued during this study to prevent the possibility of hepatitis B virus (HBV) reactivation/flare for the duration of participation in this clinical trial. Patients with quantifiable HDV RNA in serum will be enrolled. At each clinic visit, patients will be questioned about side effects, symptoms and quality of life, undergo focused physical examination, and have blood drawn for complete blood counts, HDV RNA, and routine liver tests (including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, direct and total bilirubin, and albumin). At the end of the treatment, patients will be admitted to the clinical center and will undergo repeat liver biopsy and hepatic venous pressure gradient (HVPG) measurements, repeat physical examination, assessment of symptoms (using a symptom scale questionnaire), complete blood counts, routine liver tests, and hepatitis B and D viral markers. The primary therapeutic endpoint will be a decline of HDV RNA viral titer of 2 logs at the end of therapy. The primary safety endpoint will be the ability to tolerate the drugs at the prescribed dose for the full course of therapy. This clinical trial is designed as a phase 2a study assessing the antiviral activity, safety and tolerance of fixed doses of lonafarnib, ritonavir and peginterferon lambda.
Interventions
DRUGPeg-interferon lambda
Peg-interferon Lambda is a covalent conjugate of human recombinant non- pegylated interferon (IFN) lambda and a 20-kDa linear pegylated (PEG) chain.
DRUGLonafarnib
Oral prenylation inhibitor
DRUGRitonavir
Booster of lonafarnib action
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age 18 years or above, male or female. * Presence of anti-HDV in serum. * Presence of quantifiable HDV RNA in serum at three time pre-treatment points with a mean HDV RNA level \>2 log10 above the lower limit of quantification (LLOQ) of the HDV RNA assay. * Demonstration of chronicity as evidenced by the presence of HDV RNA in serum for \>/= 6 months, or presence of Anti-HDV antibody \>/= 6months.
Exclusion criteria
* Decompensated liver disease, defined by bilirubin \>4mg/dL, albumin \<3.0 gm/dL, prothrombin time \>2 sec prolonged, or history of bleeding esophageal varices, ascites or hepatic encephalopathy. Laboratory abnormalities that are not thought to be due to liver disease may not necessarily require exclusion. Patients with ALT levels greater than 1000 U/L (\>25 times ULN) will not be enrolled but may be followed until three determinations are below this level. Patients with an absolute neutrophil count \<1000/dL and platelets \<75,000/dL will be excluded from the study as well. * Pregnancy, active breast-feeding, or inability to practice adequate contraception, in women of childbearing potential or in partners of such women. Adequate contraception is defined as vasectomy in male sexual partners of female participants, tubal ligation in women, or use of two contraceptive methods such as condoms and spermicide combination with an intrauterine device or Depo-Provera, or Norplant. * Significant systemic or major illnesses other than liver disease, including, but not limited to, congestive heart failure, renal failure (eGFR \<50 ml/min), organ transplantation, serious psychiatric disease or depression (only if felt to be at high risk by the NIH psychiatric consultation service), or active coronary artery disease. * Systemic immunosuppressive therapy within the previous 2 months before enrollment. * Evidence of another form of liver disease in addition to viral hepatitis (for example autoimmune liver disease, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson disease, alcoholic liver disease, ongoing drug induced liver disease, nonalcoholic steatohepatitis (but not steatosis), hemochromatosis, or alpha-1-antitrypsin deficiency). * Active substance abuse, such as alcohol, inhaled or injection drugs within the previous year. * Evidence of hepatocellular carcinoma. This will be determined on the basis of imaging with ultrasound/ CT scan or MRI performed a maximum of 6 months prior to enrollment. Elevated alpha fetoprotein (AFP) levels will be evaluated clinically and further imaging may be performed if felt necessary. * Evidence of concurrent hepatitis C infection with positive serum hepatitis C virus (HCV) RNA. * Any experimental therapy or pegylated interferon therapy within 6 months prior to enrollment. * Active, serious autoimmune disease such as systemic lupus erythematosus, ulcerative colitis, Crohn s disease or rheumatoid arthritis, that is in the opinion of the investigators might be exacerbated by therapy with lambda interferon. This will be evaluated at baseline and during follow-up laboratory testing (including blood and urine studies) in addition to described symptoms at each outpatient visit. * Diagnosis of malignancy in the five years prior to the enrollment with exception granted to superficial dermatologic malignancies. * Evidence of HIV co-infection; HIV 1/2 antibody positivity on serum testing. * Concurrent usage of statins as these drugs inhibits mevalonate synthesis, which reduces protein prenylation. * Concurrent usage of moderate and strong CYTOCHROME P-450 CYP3A (CYP3A) inhibitors and inducers. * Concurrent usage of alpha 1 adrenoreceptor antagonist, antiarrhythmic, pimozide, sildenafil, sedative and hypnotics, ergot and St. John s Wort due to possible effect of ritonavir on hepatic metabolism of these drugs resulting in potentially life-threatening side effects. * Clinically significant baseline EKG abnormalities such as corrected QT (QTc) interval \>450 ms and/or prolonged PR interval. * Uncontrolled elevated triglycerides (\>500 mg/dL). Patients on lipid lowering therapy other than statins will be eligible for this study. * History of pancreatitis from causes other than gallstone pancreatitis. Subjects with a baseline amylase and/or lipase level \>3 ULN will be excluded from the study. * Inability to understand or sign informed consent. * Any other condition, which in the opinion of the investigators would impede the patient s participation or compliance in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Decline of Hepatitis D Virus (HDV) RNA Viral Titer of >2 Logs | Baseline and 24 weeks | Decline of HDV RNA viral titer of \>2 logs from baseline at 24 weeks of therapy |
| Number of Participants Who Discontinue Medication | 24 weeks | Discontinuation of the medication before 24 weeks by the clinical team or patient will be considered a failure to tolerate the medicine. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Normalization of Serum ALT | End of therapy, and 12 and 24 weeks after completing therapy | Normalization of serum ALT (ALT \<20 in females and ALT \<31 in males) at the end of therapy, at week 12 of posttherapy follow-up and at week 24 of post-therapy follow-up, OR reduction in serum ALT by \>50% of baseline at week 12 of post therapy follow up and week 24 of post therapy follow up. |
| Number of Participants With Reduction of Hepatic Venous Pressure Gradient (HVPG) | Baseline and 24 weeks after completing therapy | Reduction in hepatic venous pressure gradient (HVPG) measurements by \>25% of baseline OR normalization of HVPG (\<5 mm Hg) at 24 weeks after completing therapy |
| Number of Participants With Reduction in Fibroscan Transient Elastography Values | Baseline and 24 weeks | Reduction in Fibroscan transient elastography values by \>25% of baseline at end of therapy. |
| Number of Participants With Loss of HBsAg at Week 24 | Week 24 | Loss of HBsAg from the serum at week 24 |
| Number of Participants With Sustained Virologic Response | 12 and 24 weeks after completing therapy | Undetectable HDV RNA at both 12 and 24 weeks post treatment follow-up visits |
| Number of Participants With Loss of HBsAg at 24 Weeks After Completing Therapy | 24 weeks after completing therapy | Loss of HBsAg from the serum at 24 weeks after completing therapy |
| Change in Quantitative Log HBsAg Levels From Baseline to Week 24 | Baseline and week 24 | Change in quantitative log HBsAg levels at from baseline to week 24 |
| Change in Quantitative Log HBsAg Levels From Baseline 24 Weeks After Completing Therapy | Baseline and 24 weeks after completing therapy | Change in quantitative log HBsAg levels at from baseline to 24 weeks after completing therapy |
| Number of Participants With Loss of HBsAg at Week 12 Weeks After Completing Therapy | 12 weeks after completing therapy | Loss of HBsAg from the serum at 12 weeks after completing therapy |
| Number of Participants With Reduction in Histologic Inflammatory Scores (Modified HAI) | End of treatment and 24 weeks after completing therapy. | Reduction in histologic inflammatory scores (modified HAI) by at least two points with no progression in histologic fibrosis (Ishak) at week 24 post-treatment follow-up. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment Treatment with Lonafarnib, Ritonavir, and Peginterferon lambda | 26 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Out of country and could not return for post-treatment visits | 1 |
Baseline characteristics
| Characteristic | Treatment |
|---|---|
| Age, Continuous | 42 years STANDARD_DEVIATION 10 |
| Body mass index | 27.3 kg/m^2 STANDARD_DEVIATION 8.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 14 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 8 Participants |
| Region of Enrollment United States | 26 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 26 |
| other Total, other adverse events | 24 / 26 |
| serious Total, serious adverse events | 0 / 26 |
Outcome results
Primary
Number of Participants Who Discontinue Medication
Discontinuation of the medication before 24 weeks by the clinical team or patient will be considered a failure to tolerate the medicine.
Time frame: 24 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Number of Participants Who Discontinue Medication | 3 Participants |
Primary
Number of Participants With Decline of Hepatitis D Virus (HDV) RNA Viral Titer of >2 Logs
Decline of HDV RNA viral titer of \>2 logs from baseline at 24 weeks of therapy
Time frame: Baseline and 24 weeks
Population: Three participants who discontinued treatment before 24 weeks did not have HDV RNA measured at 24 weeks. They were seen at post-treatment visits
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Number of Participants With Decline of Hepatitis D Virus (HDV) RNA Viral Titer of >2 Logs | 18 Participants |
Secondary
Change in Quantitative Log HBsAg Levels From Baseline 24 Weeks After Completing Therapy
Change in quantitative log HBsAg levels at from baseline to 24 weeks after completing therapy
Time frame: Baseline and 24 weeks after completing therapy
Population: 24 participants had HBsAg measurements at 24 weeks after the end of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment | Change in Quantitative Log HBsAg Levels From Baseline 24 Weeks After Completing Therapy | 0.16 log IU/mL | Standard Deviation 0.19 |
Secondary
Change in Quantitative Log HBsAg Levels From Baseline to Week 24
Change in quantitative log HBsAg levels at from baseline to week 24
Time frame: Baseline and week 24
Population: 22 participants had HBsAg values at week 24
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment | Change in Quantitative Log HBsAg Levels From Baseline to Week 24 | 0.15 log IU/mL | Standard Deviation 0.22 |
Secondary
Number of Participants With Loss of HBsAg at 24 Weeks After Completing Therapy
Loss of HBsAg from the serum at 24 weeks after completing therapy
Time frame: 24 weeks after completing therapy
Population: 24 participants had HBsAg measurements at 24 weeks after the end of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Number of Participants With Loss of HBsAg at 24 Weeks After Completing Therapy | 0 Participants |
Secondary
Number of Participants With Loss of HBsAg at Week 12 Weeks After Completing Therapy
Loss of HBsAg from the serum at 12 weeks after completing therapy
Time frame: 12 weeks after completing therapy
Population: 24 participants had HBsAg measurements at 12 weeks after the end of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Number of Participants With Loss of HBsAg at Week 12 Weeks After Completing Therapy | 0 Participants |
Secondary
Number of Participants With Loss of HBsAg at Week 24
Loss of HBsAg from the serum at week 24
Time frame: Week 24
Population: 22 participants had HBsAg values at week 24
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Number of Participants With Loss of HBsAg at Week 24 | 0 Participants |
Secondary
Number of Participants With Normalization of Serum ALT
Normalization of serum ALT (ALT \<20 in females and ALT \<31 in males) at the end of therapy, at week 12 of posttherapy follow-up and at week 24 of post-therapy follow-up, OR reduction in serum ALT by \>50% of baseline at week 12 of post therapy follow up and week 24 of post therapy follow up.
Time frame: End of therapy, and 12 and 24 weeks after completing therapy
Population: Two participants did not have ALT measures at 12 weeks post treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Number of Participants With Normalization of Serum ALT | 2 Participants |
Secondary
Number of Participants With Reduction in Fibroscan Transient Elastography Values
Reduction in Fibroscan transient elastography values by \>25% of baseline at end of therapy.
Time frame: Baseline and 24 weeks
Population: Only 13 participants had Fibroscans at baseline and 24 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Number of Participants With Reduction in Fibroscan Transient Elastography Values | 4 Participants |
Secondary
Number of Participants With Reduction in Histologic Inflammatory Scores (Modified HAI)
Reduction in histologic inflammatory scores (modified HAI) by at least two points with no progression in histologic fibrosis (Ishak) at week 24 post-treatment follow-up.
Time frame: End of treatment and 24 weeks after completing therapy.
Population: 21 participants had liver biopsies at 24 weeks post treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Number of Participants With Reduction in Histologic Inflammatory Scores (Modified HAI) | 6 Participants |
Secondary
Number of Participants With Reduction of Hepatic Venous Pressure Gradient (HVPG)
Reduction in hepatic venous pressure gradient (HVPG) measurements by \>25% of baseline OR normalization of HVPG (\<5 mm Hg) at 24 weeks after completing therapy
Time frame: Baseline and 24 weeks after completing therapy
Population: Five participant did not have HVPG measured at 24 weeks post treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Number of Participants With Reduction of Hepatic Venous Pressure Gradient (HVPG) | 10 Participants |
Secondary
Number of Participants With Sustained Virologic Response
Undetectable HDV RNA at both 12 and 24 weeks post treatment follow-up visits
Time frame: 12 and 24 weeks after completing therapy
Population: 25 participants had data at 24 weeks post treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Number of Participants With Sustained Virologic Response | 3 Participants |