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Treatment of Chronic Delta Hepatitis With Lonafarnib, Ritonavir and Lambda Interferon

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ClinicalTrials.gov Identifier: NCT03600714
Recruitment Status : Completed
First Posted : July 26, 2018
Last Update Posted : June 30, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) )

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


Condition or disease Intervention/treatment Phase
Liver Disease Hepatitis D Drug: Peg-interferon lambda Drug: Lonafarnib Drug: Ritonavir Phase 2

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 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 ALT, 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 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 31 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Treatment of Chronic Delta Hepatitis With Lonafarnib, Ritonavir and Lambda Interferon
Actual Study Start Date : August 1, 2018
Actual Primary Completion Date : November 9, 2020
Actual Study Completion Date : November 9, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment
Treatment with Lonafarnib, Ritonavir, and Peginterferon lambda
Drug: Peg-interferon lambda
Peg-interferon Lambda is a covalent conjugate of human recombinant non- pegylated IFN lambda and a 20-kDa linear PEG chain.

Drug: Lonafarnib
Oral prenylation inhibitor

Drug: Ritonavir
Booster of lonafarnib action




Primary Outcome Measures :
  1. Decline of HDV RNA viral titer of >2 logs [ Time Frame: Baseline and 24 weeks ]
    Decline of HDV RNA viral titer of >2 logs from baseline at 24 weeks of therapy

  2. Number of participants who discontinue medication [ Time Frame: 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 Outcome Measures :
  1. Number of participants with sustained virologic response [ Time Frame: 12 and 24 weeks after completing therapy ]
    Undetectable HDV RNA at both 12 and 24 weeks post treatment follow-up visits

  2. Number of participants with reduction in histologic inflammatory scores (modified HAI) [ Time Frame: 24 weeks after completing therapy. ]
    Reduction in histologic inflammatory scores (modified HAI) by at leasttwo points with no progression in histologic fibrosis (Ishak) at week 24 post-treatment follow-up.

  3. Number of participants with normalization of serum ALT [ Time Frame: 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.

  4. Number of participants with reduction of hepatic venous pressure gradient (HVPG) [ Time Frame: Baseline and 24 weeks ]
    Reduction in hepatic venous pressure gradient (HVPG) measurements by >25% of baseline OR normalization of HVPG (<5 mm Hg) at end of therapy.

  5. Number of participants with reduction in Fibroscan transient elastography values [ Time Frame: Baseline and 24 weeks ]
    Reduction in Fibroscan transient elastography values by >25% of baseline at end of therapy.

  6. Number of participants with loss of HBsAg at week 24 [ Time Frame: Week 24 ]
    Loss of HBsAg from the serum at week 24

  7. Number of participants with loss of HBsAg at week 24 [ Time Frame: 12 weeks after completing therapy ]
    Loss of HBsAg from the serum at 12 weeks after completing therapy

  8. Number of participants with loss of HBsAg at week 24 [ Time Frame: 24 weeks after completing therapy ]
    Loss of HBsAg from the serum at 24 weeks after completing therapy

  9. Change in quantitative HBsAg levels from baseline to week 24 [ Time Frame: Baseline and week 24 ]
    Change in quantitative HBsAg levels at from baseline to week 24

  10. Change in quantitative HBsAg levels from baseline 24 weeks after completing therapy [ Time Frame: Baseline and 24 weeks after completing therapy ]
    Change in quantitative HBsAg levels at from baseline to 24 weeks after completing therapy



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • 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.

INCLUSION 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 AFP levels will be evaluated clinically and further imaging may be performed if felt necessary.
  • Evidence of concurrent hepatitis C infection with positive serum 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 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 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03600714


Locations
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United States, Maryland
National Institutes of Health Clinical Center
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
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Principal Investigator: Christopher Koh, M.D. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Additional Information:
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Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier: NCT03600714    
Other Study ID Numbers: 180123
18-DK-0123
First Posted: July 26, 2018    Key Record Dates
Last Update Posted: June 30, 2021
Last Verified: May 12, 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ):
Hepatitis D
Hepatitis D Virus
Cirrhosis
Additional relevant MeSH terms:
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Hepatitis A
Hepatitis D
Hepatitis D, Chronic
Hepatitis
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Infections
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Hepatitis, Chronic
Interferons
Ritonavir
Lonafarnib
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
HIV Protease Inhibitors
Viral Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors