Background: Hepatitis D virus (HDV) was identified as the infectious agent causing viral hepatitis in the presence of hepatitis B virus (HBV). While HDV can replicate autonomously inside the hepatocyte, the virus requires co-infection with HBV to complete virion assembly and to facilitate transmission. HDV causes the most severe form of viral hepatitis, with rapid progression to cirrhosis and high rates of development of hepatocellular carcinoma. Currently there are no FDA approved therapies for chronic HDV infection (CHD) which presents an unmet medical need. The off-label use of pegylated interferon alpha (Alpha) for the treatment of CHD has so far been explored in several small single-arm studies and in 2 randomized controlled clinical trials, showing limited efficacy and high relapse rates. In addition, Alpha is associated with a poor tolerability profile and its use is limited in patients with advanced disease.
Lonafarnib (LNF), a FT inhibitor has been evaluated in over 2,000 subjects in clinical studies, comprising more than fifty Phase 1 and Phase 2 studies and two Phase 3 studies, with healthy subjects and patients with HDV, cancer, Hutchinson-Gilford progeria syndrome (HGPS) and progeroid laminopathies. Treatment with LNF has been administered as continuous (up to 11 years in HGPS) and intermittent therapy (exceeding one year in cancer patients).
The use of LNF in CHD has been assessed in a proof of concept study, a series of four phase 2 clinical trials (the LOWR program) and an on-going phase 3 clinical trial (D-LIVR study).
Hypothesis: that treatment with LNF50/RTV200 QD for 48 weeks will be safe and lead to a reduction in HDV RNA levels at end of treatment and end of follow up.
Procedures: At baseline, systems review, physical examination, vital signs (temperature, blood pressure, pulse rate per minute), anthropometric measurements (weight, height and BMI) and ECG will be performed. Information regarding the use of alcohol and drugs, symptoms and use of concomitant medications collected. Blood will be drawn for testing of local CBC, chemistry, coagulation studies, HDV antibody and RNA levels, HCV antibody (\& RNA if necessary), HBsAg levels, HBeAg status, HBV DNA levels, liver elastography and ultrasound. All blood tests besides HDV RNA levels, will be performed at a local lab. HDV RNA level testing will be performed at a central laboratory. Pregnancy test will be performed in females of child-bearing potential. Trial medications will be dispensed. Use of anti-HBV therapy (tenofovir or entecavir) will be confirmed.
Follow up visits will be conducted at week 4, 12, 24, 36 and 48 of treatment and at 24 weeks after stopping treatment and will include systems review, ECG recordings, evaluation of concomitant medications use, adverse events monitoring and assessment of compliance with trial medications and anti HBV therapy. In addition, blood will be drawn for measurement of CBC, chemistry panel, coagulation tests and HDV RNA and HBV DNA levels at each visit. Trial medications will be dispensed at each visit during the treatment phase of trial.
Adverse events and concomitant medications will be collected throughout the trial.
Data to capture:
* Demographic data: Gender, age, ethnicity, country of birth
* Detailed medical history: including currently prescribed medications, recently administered medications, dispensing date, past medications use and dispensing date, past medical diagnosis including diagnosis date, past medical procedures including procedure date, allergies.
* Habits: history of recreational drugs and alcohol consumption (using CAGE questionnaire).
* Clinical evaluation: Systems review, anthropometric measurements (weight, height and BMI), physical examination, vital signs, symptom questionnaire and AE assessment.
* Blood tests: Complete blood count, biochemistry panel, coagulation tests, anti-HDV antibody, anti HCV antibody, HDV RNA, HBV DNA.
Safety data collected during the trial (e.g., AEs and laboratory test results) will be monitored on an ongoing basis by the trial team.
