Lonafarnib With Ritonavir in HDV (LOWR-2)

Sponsor

Eiger BioPharmaceuticals (Industry)

Overall Status

Completed

CT.gov ID

NCT02430194

Collaborator

Ankara University (Other)

Enrollment

Location

Arms

30.5

Actual Duration (Months)

1.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

An Open-label, Dose-ranging Study to Evaluate the Safety and Efficacy of Lonafarnib With Ritonavir Boosting in Patients Chronically Infected With Delta Hepatitis (HDV) (LOWR-2).

Condition or Disease	Intervention/Treatment	Phase
Chronic Hepatitis D Infection	Drug: lonafarnib Drug: Ritonavir Drug: PEG IFN-a	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. Up to forty-five subjects with chronic delta hepatitis will be randomized to receive one of nine different doses of lonafarnib. Dosing will occur over 12-48 weeks, and during that time, evidence of antiviral response will be assessed by frequent measurements of HDV-RNA. The primary therapeutic endpoint will be an improvement in quantitative serum HDV RNA levels after treatment with lonafarnib therapy. The primary safety endpoint will be the ability to tolerate the drug at the prescribed dose for the treatment duration. Several secondary endpoints will be measured, including side effects, ALT levels, and symptoms. Therapy will be stopped for intolerance to lonafarnib. This study is designed as a phase 2a study assessing the safety, tolerance and antiviral activity of nine dosing combinations of lonafarnib with ritonavir boosting with and without PEG IFN-alpha.

Study Design

Study Type:

Interventional

Actual Enrollment :

58 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

An Open-label, Dose-ranging, Proof-of-Concept Study to Evaluate the Safety and Efficacy of Lonafarnib With Ritonavir-Boosting in Patients Chronically Infected With Delta Hepatitis (HDV) (LOWR-2)

Actual Study Start Date :

Dec 1, 2014

Actual Primary Completion Date :

Apr 18, 2017

Actual Study Completion Date :

Jun 15, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: lonafarnib/ritonavir - I lonafarnib 100 mg BID + ritonavir 100 mg QD;	Drug: lonafarnib antiviral farnesyl transferase inhibitor Other Names: Sarasar, EBP994 Drug: Ritonavir CYP 3A4 inhibitor, lonafarnib booster Other Names: Norvir
Experimental: lonafarnib/ritonavir - II lonafarnib 150 mg QD + ritonavir 100 mg QD;	Drug: lonafarnib antiviral farnesyl transferase inhibitor Other Names: Sarasar, EBP994 Drug: Ritonavir CYP 3A4 inhibitor, lonafarnib booster Other Names: Norvir
Experimental: lonafarnib/ritonavir - III lonafarnib 75 mg BID + ritonavir 100 mg BID; + PEG IFN-a 180 ug QW on Week 12	Drug: lonafarnib antiviral farnesyl transferase inhibitor Other Names: Sarasar, EBP994 Drug: Ritonavir CYP 3A4 inhibitor, lonafarnib booster Other Names: Norvir Drug: PEG IFN-a immunomodulator Other Names: Pegasys PEG IFN-alpha Pegylated interferon-alpha-2a
Experimental: lonafarnib/ritonavir - IV lonafarnib 50 mg BID + ritonavir 100 mg BID; + PEG IFN-a 180 ug QW on Week 12	Drug: lonafarnib antiviral farnesyl transferase inhibitor Other Names: Sarasar, EBP994 Drug: Ritonavir CYP 3A4 inhibitor, lonafarnib booster Other Names: Norvir Drug: PEG IFN-a immunomodulator Other Names: Pegasys PEG IFN-alpha Pegylated interferon-alpha-2a
Experimental: lonafarnib/ritonavir - V lonafarnib 100 mg BID + ritonavir 50 mg BID;	Drug: lonafarnib antiviral farnesyl transferase inhibitor Other Names: Sarasar, EBP994 Drug: Ritonavir CYP 3A4 inhibitor, lonafarnib booster Other Names: Norvir
Experimental: lonafarnib/ritonavir - VI lonafarnib 100 mg QD + ritonavir 100 mg QD;	Drug: lonafarnib antiviral farnesyl transferase inhibitor Other Names: Sarasar, EBP994 Drug: Ritonavir CYP 3A4 inhibitor, lonafarnib booster Other Names: Norvir
Experimental: lonafarnib/ritonavir - VII lonafarnib 50 mg BID + ritonavir 100 mg BID; + PEG IFN-a 180 ug QW;	Drug: lonafarnib antiviral farnesyl transferase inhibitor Other Names: Sarasar, EBP994 Drug: Ritonavir CYP 3A4 inhibitor, lonafarnib booster Other Names: Norvir Drug: PEG IFN-a immunomodulator Other Names: Pegasys PEG IFN-alpha Pegylated interferon-alpha-2a
Experimental: lonafarnib/ritonavir/PEG IFN-a - VIII lonafarnib 25 mg BID + ritonavir 100 mg BID + PEG IFN-a 180 ug QW;	Drug: lonafarnib antiviral farnesyl transferase inhibitor Other Names: Sarasar, EBP994 Drug: Ritonavir CYP 3A4 inhibitor, lonafarnib booster Other Names: Norvir Drug: PEG IFN-a immunomodulator Other Names: Pegasys PEG IFN-alpha Pegylated interferon-alpha-2a
Experimental: lonafarnib/ritonavir/PEG IFN-a - IX lonafarnib 50 mg BID + ritonavir 100 mg BID	Drug: lonafarnib antiviral farnesyl transferase inhibitor Other Names: Sarasar, EBP994 Drug: Ritonavir CYP 3A4 inhibitor, lonafarnib booster Other Names: Norvir
Experimental: lonafarnib/ritonavir - X lonafarnib 25 mg BID + ritonavir 100 mg BID	Drug: lonafarnib antiviral farnesyl transferase inhibitor Other Names: Sarasar, EBP994 Drug: Ritonavir CYP 3A4 inhibitor, lonafarnib booster Other Names: Norvir

Outcome Measures

Primary Outcome Measures

Decline of HDV RNA from baseline to end of treatment with lonafarnib and ritonavir [12-48 weeks]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Males or females, 18 to 65 years of age who are diagnosed with HDV by PCR
Chronic hepatitis D infection, genotype 1, documented by a positive anti-HDV Ab test at least of 6 months duration and detectable HDV RNA by PCR within 3 months to study entry
Liver biopsy within the last two years (biopsy can be done at the Screening Visit)
Positive viral load of >100,000 copies/mL as measured by quantitative PCR
Electrocardiogram (ECG) shows no acute ischemia or clinically significant abnormality and a QT/QTc interval <450 milliseconds - using Bazett's correction
Females of childbearing potential (intact uterus and within 1 year since the last menstrual period) should be non-lactating and have a negative serum pregnancy test. In addition, these subjects should agree to use one of the following acceptable birth control methods throughout the study:

abstinence
surgical sterilization (bilateral tubal ligation, hysterectomy, bilateral oophorectomy) six months minimum
IUD in place for at least six months
barrier methods (condom or diaphragm) with spermicide
surgical sterilization of the partner (vasectomy for six months)
hormonal contraceptives for at least three months prior to the first dose of study drug

Willing and able to comply with study procedures and provide written informed consent

Exclusion Criteria:

Participation in a clinical trial with or use of any investigational agent within 30 days of Study Visit 1
Patients co-infected with HIV
Patients with screening tests positive for HCV, or anti-HIV Ab
History of decompensated cirrhosis within the past year
Active jaundice defined by total bilirubin > 2.0 excluding Gilbert's disease
INR ≥ 1.5
Eating disorder or alcohol abuse within the past 2 years, excessive alcohol intake (> 20 g per day for females (1.5 standard alcohol drinks) or > 30 g per day for males (2.0 standard alcohol drinks) (a standard drink contains 14 g of alcohol: 12 oz of beer, 5 oz of wine or 1.5 oz of spirits) (1.0 fluid oz (US) = 29.57 mL)
Drug abuse within the last six months with the exception of cannabinoids and their derivatives
Patients with absolute neutrophil count (ANC) < 1500 cells/mm3; platelet count < 100,000 cells/mm3; hemoglobin < 12 g/dL for women and < 13 g/dL for men; abnormal TSH,T4, or T3 or thyroid function not adequately controlled; or serum creatinine concentration ≥ 1.5 times upper limit of normal (ULN)
History or clinical evidence of any of the following:

variceal bleeding, ascites, hepatic encephalopathy, CTP score > 6, decompensated liver disease or any other form of non-viral hepatitis
immunologically mediated disease (e.g., rheumatoid arthritis, inflammatory bowel disease, severe psoriasis, systemic lupus erythematosus) requiring more than intermittent nonsteroidal anti-inflammatory medications for management or that requires frequent or prolonged use of corticosteroids (inhaled asthma medications are allowed)
any malignancy within 3 years except for basal cell skin cancer
significant or unstable cardiac disease (e.g., angina, congestive heart failure, uncontrolled hypertension, history of arrhythmia)
chronic pulmonary disease (e.g., chronic obstructive pulmonary disease) associated with functional impairment
severe or uncontrolled psychiatric disease, including severe depression, history of suicidal ideation, suicidal attempts or psychosis requiring medication and/or hospitalization 2