This study is NOT currently recruiting participants.
Number
20-DK-0067
Sponsoring Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Recruitment Detail
Type: No longer recruiting/follow-up only Gender: Male & Female Min Age: 18 Years Max Age: N/A
Referral Letter Required
No
Population Exclusion(s)
Children
Keywords
Digestive System Diseases; Liver Diseases; RNA Virus Infections; Antiviral Agents; Physiological Effects of Drugs
Recruitment Keyword(s)
None
Condition(s)
Hepatitis Delta Virus
Investigational Drug(s)
Lonafarnib
Investigational Device(s)
Intervention(s)
Drug: Lonafarnib Other: Placebo
Supporting Site
National Institute of Diabetes and Digestive and Kidney Diseases
There is no vaccine or approved treatment for hepatitis D virus (HDV). Researchers want to study new treatments for this disease, to improve quality of life for people with HDV.
Objective:
To learn if lonafarnib and ritonavir, taken with or without PEG IFN-alfa-2a, will reduce the amount of HDV in the blood.
Eligibility:
People age 18 and older who have had chronic HDV for at least 6 months.
Design:
Participants will be screened with:
-Medical history
-Physical exam
-Blood and urine samples
-Chronic liver disease questionnaire
-Eye exam
-Electrocardiogram
-Liver blood vessel pressure measurements and biopsy. For this, a catheter is guided along a neck vein to the liver. Pressure measurements are taken. Then a biopsy is taken. If needed, the biopsy can be taken through the chest.
-Liver scan to measure scar tissue
-Liver ultrasound and MRI (Magnetic Resonance Imaging). For MRI, participants lie on a table that slides in and out of the scanner. They will get a contrast dye through an intravenous catheter.
Participants will either take lonafarnib capsules and ritonavir tablets twice daily by mouth, or they will take placebos.
Some participants will also take PEG IFN-alfa-2a once weekly. It is injected by the participant under the skin.
Participants will take entecavir or tenofovir.
Participants will repeat the screening tests during the study. They will give stool samples.
Participation lasts up to 2 years.
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INCLUISON CRITERIA: Patients must meet all of the following inclusion criteria before study entry to be eligible for enrollment into the study. 1. Chronic HDV infection for at least 6 months in duration, documented by a positive HDV antibody (Ab) test and HDV RNA >= 500 IU/mL by quantitative polymerase chain reaction (qPCR) assay prior to initiation of study treatment. a. Note: Non-genotype 1 HDV will be capped at 15% of total enrollment. 2. Demonstrable suppression of HBV DNA (< 20 IU/mL) following at least 12 weeks of anti-HBV nucleos(t)ide treatment with entecavir or tenofovir prior to initiating therapy. 3. Serum ALT > 1.3 x upper limit of the normal range (ULN) and < 10 x ULN. 4. Willing and able to comply with study procedures and provide written informed consent. 5. Able to read and understand a language in which an informed consent form and other patient study documents are available. 6. Able to self-administer medication orally and via subcutaneous (SC) injection. 7. Male and female participants who are 18 years of age or above. 8. Body mass index (BMI) of >= 18 kg/m^2 and weight >= 45 kg. 9. Liver biopsy within 45 days of Day 1 demonstrating evidence of chronic hepatitis. If no liver biopsy is available, the patient must be willing to consent to and have no contraindication to liver biopsy. 10. ECGs demonstrating no acute ischemia or clinically significant (CS) abnormality and a corrected QT interval by Fridericia correction formula (QTcF) < 450 ms. 11. Normal dilated retinal examination. 12. Sexually active female patients of childbearing potential and sexually active male patients with partners of childbearing potential must agree to use adequate methods of contraception during the study. Females of childbearing potential are all those except women who are surgically sterile, who have medically documented ovarian failure, or who are at least 1 year postmenopausal. For female patients: - Progestogen injection (eg, Depo-Provera(R)) for >= 3 months before screening AND a barrier method (use of condom [male partner] or diaphragm with spermicide or cervical cap with spermicide) from screening, or - Intrauterine device (IUD) or intrauterine system (IUS) in place >= 3 months before screening AND a barrier method (use of condom [male partner] or diaphragm with spermicide or cervical cap with spermicide) from screening, or - Surgical sterilization of the partner (vasectomy >= 1 month before screening) AND a barrier method (use of condom [male partner] or diaphragm with spermicide or cervical cap with spermicide) from screening, or - Double-barrier methods (use of condom [male partner] with either diaphragm with spermicide or cervical cap with spermicide) from screening. For male patients: - Surgical sterilization (vasectomy >= 1 month before screening) AND a barrier method (use of condom or diaphragm with spermicide or cervical cap with spermicide) from screening, or - Consistently and correctly use a condom from screening AND female partner must agree to use a hormonal contraceptive, a nonhormonal nonbarrier method (eg, copper IUD), or a nonhormonal barrier method (eg, diaphragm with spermicide or cervical cap with spermicide). EXCLUSION CRITERIA: General Exclusions 1. Participation in a clinical trial with, or use of, any investigational agent within 30 days or 5 half-lives, whichever is longer, before screening. 2. Previous use of LNF within 12 months before pre-screening/screening or during the study. 3. Female patients who are pregnant or breastfeeding. Female patients must have a negative serum test at screening and a negative urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [hCG]) at baseline, within 24 hours prior to the start of any investigational agent). Male patients with female sexual partners who are pregnant. Exclusions Based on Disease 4. Current or previous history of decompensated liver disease (Child-Pugh Class B or C) based on documented Child-Pugh score. a. A formal Child-Pugh score assessment is conducted and documented at screening. For patients categorized as Child- Pugh A (with a score of 5) with well compensated liver disease, enrollment will be allowed. 5. Co-infected with human immunodeficiency virus (HIV) or hepatitis C virus (HCV) by detectable HIV RNA and HCV RNA, respectively. 6. Positive results for HIV or HCV Ab at screening. Patients with a positive HCV Ab at screening are allowed if they have completed a curative antiviral regimen and have documented undetectable HCV RNA for at least 3 months before screening and at screening. 7. History or current evidence of significant portal hypertension such as hepatic venous pressure gradient (HVPG) >= 10 mmHg; current presence or history of esophageal or abdominal varices, variceal bleeding, or splenomegaly > 12 cm length on imaging. In a case when the spleen measures larger than 12 cm and the Principal Investigator believes the subject meets all other non-cirrhotic criteria, a discussion with the Medical Monitor is warranted for patient inclusion. 8. Current evidence or history of ascites requiring diuretics or paracentesis, or hepatic encephalopathy. 9. Any of the following abnormal laboratory test results at screening: -Platelet count < 90,000 cells/mm^3 -White blood cell (WBC) count < 3,000 cells/mm^3 -Absolute neutrophil count (ANC) < 1,500 cells/mm^3 -Hemoglobin -- < 11 g/dL for women -- < 12 g/dL for men -Confirmed creatinine clearance (< 30 mL/min by Cockroft-Gault) -Alpha-fetoprotein >= 100 ng/mL -Abnormal thyroid-stimulating hormone (TSH) or total thyroxine (T4) levels -- Patients with well-controlled thyroid function may be enrolled following discussion with the Medical Monitor. -Bilirubin (Bullet) 2 mg/dL, regardless of cirrhosis status. -- Following discussion with the Medical Monitor and case review, patients may be appropriate to enroll. 10. Evidence of another form of viral hepatitis or another form of liver disease (eg, autoimmune liver disease, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson's disease, alcoholic liver disease, nonalcoholic steatohepatitis, hemochromatosis, alpha-1-anti-trypsin deficiency). 11. History of hepatocellular carcinoma. 12. Patients with any of the following: - Current eating disorder (as defined by Diagnostic and Statistical Manual of Mental Disorders [DSM]-5) - Evidence of alcohol substance use disorder, as defined by DSM-5, or excessive intake, defined as follows: -- > 20 g/day for females (1.5 standard alcohol drinks) or -- > 30 g/day for males (2.0 standard alcohol drinks). Note: A standard drink contains 14 g of alcohol: 355 mL/12 oz of beer, 148 mL/5 oz of wine, or 44 mL/1.5 oz of spirits. - Blood alcohol concentration > 0.08% - Drug abuse within the previous 6 months before screening, with the exception of cannabinoids and their derivatives. 13. Prior history or current evidence of any of the following: - Immunologically mediated disease (eg, rheumatoid arthritis, inflammatory bowel disease, severe psoriasis, systemic lupus erythematosus) that requires more than intermittent nonsteroidal anti-inflammatory medications for management or that requires chronic use of systemic corticosteroids in the 6 months before pre-screening/screening (periodic use of oral steroid taper and inhaled asthma medications are allowed), - Retinal disorder or clinically relevant ophthalmic disorder, - Any malignancy within 5 years before screening. Exceptions are malignancies surgically excised with curative intent and/or evidence of being disease free for at least 5 years (eg, breast ductal carcinoma in situ [DCIS] or squamous/basal cell skin cancer treated with curative intent), or successfully treated in-situ carcinoma of the cervix, - Cardiomyopathy or significant ischemic cardiac or cerebrovascular disease (including history of angina, myocardial infarction, or interventional procedure for coronary artery disease), - Chronic pulmonary disease (eg, chronic obstructive pulmonary disease) associated with functional impairment, as defined by a forced expiratory volume in 1 second/forced vital capacity (FEV(1)/ FVC) ratio < 0.7, - Pancreatitis or colitis, - Severe or uncontrolled psychiatric disorder (eg, depression, manic condition, psychosis, acute and/or chronic cognitive dysfunction, suicidal behavior, history of suicide attempt, and relapse of substance abuse), - Bone marrow or solid organ transplantation, - For patients who are stable for 1 year post-transplantation and do not require immunosuppressive therapy(ies), following a case review, enrollment may be considered. 14. Other significant medical condition that may require intervention during the study. Patients with any serious condition that, in the opinion of the Medical Monitor, would preclude evaluation of response or make it unlikely that the contemplated course of therapy and follow-up could be completed. Patients for whom participation in the study would increase their risk. 15. Any condition that may impact proper absorption (eg, short bowel syndrome, inflammatory bowel disease, atrophic gastritis, partial gastrectomy) should be discussed with the Medical Monitor. Exclusions Based on Concurrent Medication Use 16. Any prescription, over-the-counter (OTC) product, or herbal product that is not approved by the Medical Monitor (refer to the Concomitant Medication Manual for guidance), 17. Consumption of grapefruit, Seville oranges, or product that contains grapefruit or Seville oranges within 14 days of Baseline (Day 1). 18. Therapy with an immunomodulatory agent, IFN-a (eg, IFN-alfa-2a or IFN-alfa-2b, or pegylated IFN-alfa-2a or alfa-2b), cytotoxic agent, or chronic systemic corticosteroids within 12 months of screening and during the study. a. Periodic use of oral steroids or inhaled steroids to manage asthma is acceptable. 19. Use of heparin or warfarin during the study. 20. Systemic antibiotics, antifungals, or antivirals for treatment of active infection other than HBV within 14 days before study randomization or have a chronic condition that would likely require such therapy during the study. 21. Long-term treatment (> 2 weeks) before or during the study with agents that have a high risk for nephrotoxicity or hepatotoxicity unless it is approved by the Medical Monitor. 22. Receipt of systemic immunosuppressive therapy within 3 months before screening or during the study. 23. History or evidence for any intolerance or hypersensitivity to LNF, RTV, PEG IFN-alfa-2a, tenofovir or entecavir, or other substances that are part of study treatment. 24. Concomitant use (within 2 weeks of Day 1 and throughout study conduct) of any medications (prescription, OTC, herbal products) or foods as follows: - Known potent inhibitors of CYP3A, including statins (with the exception of pravastatin and fluvastatin); - Known potent inducers of CYP3A or CYP3A sensitive substrates; - Known CYP2C19 and P-gp sensitive substrates with a narrow therapeutic index - refer to the Concomitant Medication Manual for additional instructions; - Known sensitive substrates of OCT1 with a narrow therapeutic index; and - Drugs known to prolong the PR or QT interval unless otherwise described in this protocol. 25. Concomitant use of medications contraindicated in the prescribing information for RTV, PEG IFN-alfa-2a, tenofovir, or entecavir. Screening ECGs or clinical laboratory tests may be repeated once without discussing with the Medical Monitor. All other requests for rescreening following a screening failure need to be discussed with the Principal Investigator and the Medical Monitor. All results from the repeated tests will need to meet the protocol defined eligibility criteria.
Patients must meet all of the following inclusion criteria before study entry to be eligible for enrollment into the study.
1. Chronic HDV infection for at least 6 months in duration, documented by a positive HDV antibody (Ab) test and HDV RNA >= 500 IU/mL by quantitative polymerase chain reaction (qPCR) assay prior to initiation of study treatment.
a. Note: Non-genotype 1 HDV will be capped at 15% of total enrollment.
2. Demonstrable suppression of HBV DNA (< 20 IU/mL) following at least 12 weeks of anti-HBV nucleos(t)ide treatment with entecavir or tenofovir prior to initiating therapy.
3. Serum ALT > 1.3 x upper limit of the normal range (ULN) and < 10 x ULN.
4. Willing and able to comply with study procedures and provide written informed consent.
5. Able to read and understand a language in which an informed consent form and other patient study documents are available.
6. Able to self-administer medication orally and via subcutaneous (SC) injection.
7. Male and female participants who are 18 years of age or above.
8. Body mass index (BMI) of >= 18 kg/m^2 and weight >= 45 kg.
9. Liver biopsy within 45 days of Day 1 demonstrating evidence of chronic hepatitis. If no liver biopsy is available, the patient must be willing to consent to and have no contraindication to liver biopsy.
10. ECGs demonstrating no acute ischemia or clinically significant (CS) abnormality and a corrected QT interval by Fridericia correction formula (QTcF) < 450 ms.
11. Normal dilated retinal examination.
12. Sexually active female patients of childbearing potential and sexually active male patients with partners of childbearing potential must agree to use adequate methods of contraception during the study. Females of childbearing potential are all those except women who are surgically sterile, who have medically documented ovarian failure, or who are at least 1 year postmenopausal.
For female patients:
- Progestogen injection (eg, Depo-Provera(R)) for >= 3 months before screening AND a barrier method (use of condom [male partner] or diaphragm with spermicide or cervical cap with spermicide) from screening, or
- Intrauterine device (IUD) or intrauterine system (IUS) in place >= 3 months before screening AND a barrier method (use of condom [male partner] or diaphragm with spermicide or cervical cap with spermicide) from screening, or
- Surgical sterilization of the partner (vasectomy >= 1 month before screening) AND a barrier method (use of condom [male partner] or diaphragm with spermicide or cervical cap with spermicide) from screening, or
- Double-barrier methods (use of condom [male partner] with either diaphragm with spermicide or cervical cap with spermicide) from screening.
For male patients:
- Surgical sterilization (vasectomy >= 1 month before screening) AND a barrier method (use of condom or diaphragm with spermicide or cervical cap with spermicide) from screening, or
- Consistently and correctly use a condom from screening AND female partner must agree to use a hormonal contraceptive, a nonhormonal nonbarrier method (eg, copper IUD), or a nonhormonal barrier method (eg, diaphragm with spermicide or cervical cap with spermicide).
EXCLUSION CRITERIA:
General Exclusions
1. Participation in a clinical trial with, or use of, any investigational agent within 30 days or 5 half-lives, whichever is longer, before screening.
2. Previous use of LNF within 12 months before pre-screening/screening or during the study.
3. Female patients who are pregnant or breastfeeding. Female patients must have a negative serum test at screening and a negative urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [hCG]) at baseline, within 24 hours prior to the start of any investigational agent). Male patients with female sexual partners who are pregnant.
Exclusions Based on Disease
4. Current or previous history of decompensated liver disease (Child-Pugh Class B or C) based on documented Child-Pugh score.
a. A formal Child-Pugh score assessment is conducted and documented at screening. For patients categorized as Child- Pugh A (with a score of 5) with well compensated liver disease, enrollment will be allowed.
5. Co-infected with human immunodeficiency virus (HIV) or hepatitis C virus (HCV) by detectable HIV RNA and HCV RNA, respectively.
6. Positive results for HIV or HCV Ab at screening. Patients with a positive HCV Ab at screening are allowed if they have completed a curative antiviral regimen and have documented undetectable HCV RNA for at least 3 months before screening and at screening.
7. History or current evidence of significant portal hypertension such as hepatic venous pressure gradient (HVPG) >= 10 mmHg; current presence or history of esophageal or abdominal varices, variceal bleeding, or splenomegaly > 12 cm length on imaging. In a case when the spleen measures larger than 12 cm and the Principal Investigator believes the subject meets all other non-cirrhotic criteria, a discussion with the Medical Monitor is warranted for patient inclusion.
8. Current evidence or history of ascites requiring diuretics or paracentesis, or hepatic encephalopathy.
9. Any of the following abnormal laboratory test results at screening:
-Platelet count < 90,000 cells/mm^3
-White blood cell (WBC) count < 3,000 cells/mm^3
-Absolute neutrophil count (ANC) < 1,500 cells/mm^3
-Hemoglobin
-- < 11 g/dL for women
-- < 12 g/dL for men
-Confirmed creatinine clearance (< 30 mL/min by Cockroft-Gault)
-Alpha-fetoprotein >= 100 ng/mL
-Abnormal thyroid-stimulating hormone (TSH) or total thyroxine (T4) levels
-- Patients with well-controlled thyroid function may be enrolled following discussion with the Medical Monitor.
-Bilirubin (Bullet) 2 mg/dL, regardless of cirrhosis status.
-- Following discussion with the Medical Monitor and case review, patients may be appropriate to enroll.
10. Evidence of another form of viral hepatitis or another form of liver disease (eg, autoimmune liver disease, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson's disease, alcoholic liver disease, nonalcoholic steatohepatitis, hemochromatosis, alpha-1-anti-trypsin deficiency).
11. History of hepatocellular carcinoma.
12. Patients with any of the following:
- Current eating disorder (as defined by Diagnostic and Statistical Manual of Mental Disorders [DSM]-5)
- Evidence of alcohol substance use disorder, as defined by DSM-5, or excessive intake, defined as follows:
-- > 20 g/day for females (1.5 standard alcohol drinks) or
-- > 30 g/day for males (2.0 standard alcohol drinks).
Note: A standard drink contains 14 g of alcohol: 355 mL/12 oz of beer, 148 mL/5 oz of wine, or 44 mL/1.5 oz of spirits.
- Blood alcohol concentration > 0.08%
- Drug abuse within the previous 6 months before screening, with the exception of cannabinoids and their derivatives.
13. Prior history or current evidence of any of the following:
- Immunologically mediated disease (eg, rheumatoid arthritis, inflammatory bowel disease, severe psoriasis, systemic lupus erythematosus) that requires more than intermittent nonsteroidal anti-inflammatory medications for management or that requires chronic use of systemic corticosteroids in the 6 months before pre-screening/screening (periodic use of oral steroid taper and inhaled asthma medications are allowed),
- Retinal disorder or clinically relevant ophthalmic disorder,
- Any malignancy within 5 years before screening. Exceptions are malignancies surgically excised with curative intent and/or evidence of being disease free for at least 5 years (eg, breast ductal carcinoma in situ [DCIS] or squamous/basal cell skin cancer treated with curative intent), or successfully treated in-situ carcinoma of the cervix,
- Cardiomyopathy or significant ischemic cardiac or cerebrovascular disease (including history of angina, myocardial infarction, or interventional procedure for coronary artery disease),
- Chronic pulmonary disease (eg, chronic obstructive pulmonary disease) associated with functional impairment, as defined by a forced expiratory volume in
1 second/forced vital capacity (FEV(1)/ FVC) ratio < 0.7,
- Pancreatitis or colitis,
- Severe or uncontrolled psychiatric disorder (eg, depression, manic condition, psychosis, acute and/or chronic cognitive dysfunction, suicidal behavior, history of suicide attempt, and relapse of substance abuse),
- Bone marrow or solid organ transplantation,
- For patients who are stable for 1 year post-transplantation and do not require immunosuppressive therapy(ies), following a case review, enrollment may be considered.
14. Other significant medical condition that may require intervention during the study. Patients with any serious condition that, in the opinion of the Medical Monitor, would preclude evaluation of response or make it unlikely that the contemplated course of therapy and follow-up could be completed. Patients for whom participation in the study would increase their risk.
15. Any condition that may impact proper absorption (eg, short bowel syndrome, inflammatory bowel disease, atrophic gastritis, partial gastrectomy) should be discussed with the Medical Monitor.
Exclusions Based on Concurrent Medication Use
16. Any prescription, over-the-counter (OTC) product, or herbal product that is not approved by the Medical Monitor (refer to the Concomitant Medication Manual for guidance),
17. Consumption of grapefruit, Seville oranges, or product that contains grapefruit or Seville oranges within 14 days of Baseline (Day 1).
18. Therapy with an immunomodulatory agent, IFN-a (eg, IFN-alfa-2a or IFN-alfa-2b, or pegylated IFN-alfa-2a or alfa-2b), cytotoxic agent, or chronic systemic corticosteroids within 12 months of screening and during the study.
a. Periodic use of oral steroids or inhaled steroids to manage asthma is acceptable.
19. Use of heparin or warfarin during the study.
20. Systemic antibiotics, antifungals, or antivirals for treatment of active infection other than HBV within 14 days before study randomization or have a chronic condition that would likely require such therapy during the study.
21. Long-term treatment (> 2 weeks) before or during the study with agents that have a high risk for nephrotoxicity or hepatotoxicity unless it is approved by the Medical Monitor.
22. Receipt of systemic immunosuppressive therapy within 3 months before screening or during the study.
23. History or evidence for any intolerance or hypersensitivity to LNF, RTV, PEG IFN-alfa-2a, tenofovir or entecavir, or other substances that are part of study treatment.
24. Concomitant use (within 2 weeks of Day 1 and throughout study conduct) of any medications (prescription, OTC, herbal products) or foods as follows:
- Known potent inhibitors of CYP3A, including statins (with the exception of pravastatin and fluvastatin);
- Known potent inducers of CYP3A or CYP3A sensitive substrates;
- Known CYP2C19 and P-gp sensitive substrates with a narrow therapeutic index - refer to the Concomitant Medication Manual for additional instructions;
- Known sensitive substrates of OCT1 with a narrow therapeutic index; and
- Drugs known to prolong the PR or QT interval unless otherwise described in this protocol.
25. Concomitant use of medications contraindicated in the prescribing information for RTV, PEG IFN-alfa-2a, tenofovir, or entecavir.
Screening ECGs or clinical laboratory tests may be repeated once without discussing with the Medical Monitor. All other requests for
rescreening following a screening failure need to be discussed with the Principal Investigator and the Medical Monitor. All results from the repeated tests will need to meet the protocol defined eligibility criteria.
Principal Investigator
Referral Contact
For more information: