| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Hepatitis D Virus (HDV) Infection. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Hepatitis D Infection. |
| Chronische Hepatitis D Infektion |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objectives of the study are to
- Evaluate the safety and tolerability of the following dose-titration regimen of
lonafarnib in combination with ritonavir over the 24-week Treatment Period:
* lonafarnib/ritonavir starting at 50 mg bid/100 mg twice daily (bid) and escalated to
* lonafarnib/ritonavir 75 mg bid/100 mg bid and then to 100 mg bid/100 mg bid as
tolerated
- Evaluate the pharmacodynamic activity (change in hepatitis D viral [HDV] load) of
the dose-titration regimen of lonafarnib in combination with ritonavir over the
24-week Treatment Period |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are to evaluate the effect of the dose-titration regimen of lonafarnib/ritonavir on the following:
- Pharmacokinetics (PK)
- Change in alanine aminotransferase (ALT) levels
- Change in hepatitis B virus (HBV) DNA levels
Exploratory objectives of the study are to evaluate the effects of the dose-titration regimen of
lonafarnib/ritonavir on immunologic parameters during treatment. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A patient may be included in this study if he or she meets all of the following criteria:
1. Willing and able to comply with study procedures and provide written informed consent.
2. Male or female, 18 to 65 years of age, inclusive.
3. Has a body mass index (BMI) of ≥18 kg/m2 and has a body weight of ≥45 kg.
4. Chronic HDV infection documented by a positive HDV antibody (Ab) test of at least 6 months duration and detectable HDV RNA by qPCR at study entry.
5. Liver biopsy 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. Liver biopsy will be performed during screening.
6. ALT <10x ULN
7. Electrocardiogram (ECG) demonstrating no acute ischemia or clinically significant abnormality and a QT interval corrected for heart rate (QTc) of < 450 ms using Fridericia correction (ICH Guidance for Industry E14: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs).
8. Females who meet the following criteria may be eligible to enter the study:
a. Of nonchildbearing potential—defined as women who are surgically sterile (have had bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), have medically documented ovarian failure, or are postmenopausal (amenorrheic for more than 2 years, age appropriate, and confirmed by follicle-stimulating hormone [FSH] level indicating a postmenopausal state).
b. Of childbearing potential—defined as women who have an intact uterus and ovaries and are within 1 year since the last menstrual period who
– Are not pregnant and have negative serum pregnancy test at screening and a negative urine pregnancy test on the Baseline/Day 1 Visit before randomization.
– Are not lactating or breastfeeding.
– Agree to use two of the following contraceptive methods until at least 90 days after last dose of study drug, of which at least one must be a barrier method:
- Hormonal contraceptives for at least 3 months before the start of screening and for at least 90 days after last dose of study drug.
- Intrauterine device (IUD) in place for at least 3 months before the start of screening and until at least 90 days after last dose of study drug.
- Double-barrier methods (use of condom [male partner] with either diaphragm with spermicide or cervical cap with spermicide) from the start of screening until 90 days after last dose of study drug.
- Surgical sterilization of the partner (vasectomy for 1 month before the start of screening and, throughout study and for at least 90 days after last dose of study drug).
9. Males with female partners who are of childbearing potential (see above) who meet the following criteria may be eligible to enter the study:
a. Are surgically sterile
or
b. Agree to practice two effective forms of birth control from those listed below from the start of screening until at least 90 days after their last dose of study drug, at least one of which must be a barrier method:
– Consistently and correctly use a condom
and
– Their partner must agree to use a hormonal contraceptive or a nonhormonal
barrier method (IUD or diaphragm with spermicide or cervical cap with
spermicide). |
|
| E.4 | Principal exclusion criteria |
1. Participation in a trial with or use of any investigational agent within 30 days of
start of screening
2. Pregnant or lactating/breastfeeding
3. Previous use of lonafarnib
4. Co-infected with HIV or active infection with HCV
5. Positive results for HIV or HCV Ab at screening. Patients with positive HCV Ab at screening are allowed if they have completed a curative antiviral regimen and are documented to be HCV RNA negative (undetectable) at least 3 months before and at screening
6. Active jaundice defined by total bilirubin level >2.0 mg/dL and known not to have Gilberts disease
7. A CPT score of >6-based on screening lab results
8. Decompensated liver disease or cirrhosis as defined by the presence of any of the following on screening lab tests:
a. Bilirubin level >2.0 mg/dL
b. Albumin level <3.0 g/dL
c. Platelet count <90,000 cells/mm3
d. International normalized ratio (INR) ≥1.5
9. History of bleeding esophageal varices, ascites, or hepatic encephalopathy
10. Patients with any of the following abnormal lab test results at screening:
a. White blood cell count <3,000 cells/mm3
b. Absolute neutrophil count <1500 cells/mm3
c. Hemoglobin <11 g/dL for women and <12 g/dL for men
d. Abnormal thyroid-stimulating hormone, T4, or T3 levels; unless the patient is stable on thyroid hormone replacement therapy.
11. Significant renal dysfunction, defined as serum creatinine concentration ≥1.5 times the ULN or an estimated glomerular filtration rate < 80 mL/min at screening, based on the Cockcroft-Gault equation
12. Evidence of another form of viral hepatitis (not including HBV or HCV) or another form of liver disease
13. Evidence of hepatocellular carcinoma
14. Patients with any one of the following:
a. An eating disorder or alcohol abuse within the past 2 years
b. Excessive alcohol 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). 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)
15. In the opinion of the Investigator, an alcohol use pattern that will interfere with study conduct
16. Drug abuse within the previous 6 months before the screening visit with the exception of medically prescribed cannabinoids and their derivatives
17. History or clinical evidence of any of the following:
a. Immunologically mediated disease that requires more than
intermittent nonsteroidal anti-inflammatory medications for management or that requires use of systemic corticosteroids in prior 6 months
b. History of or evidence of retinal disorder or clinically relevant ophthalmic disorder
c. Any malignancy within 5 years of the start of screening. Exceptions are superficial dermatologic malignancies
d. Significant or unstable cardiac disease
e. Chronic pulmonary disease associated with functional impairment
f. Pancreatitis
g. Severe or uncontrolled psychiatric disease, incl severe depression, history of
suicidal ideation, suicidal attempts, or psychosis requiring medication and/or hospitalization
18. Solid organ transplantation, incl liver
19. Use of alpha interferon, either interferon alfa-2a or interferon alfa-2b, or pegylated interferon alfa-2a or pegylated interferon alfa-2b within 2 months before the start of screening
20. Concomitant use of any of the following:
a. Medications or foods that are known moderate or strong inducers or
inhibitors of CYP3A4 or CYP2C19
b. Drugs known to prolong the PR or QT interval unless otherwise
described in protocol (i.e. Ondansetron).
c. Receipt of systemic immunosuppressive therapy within the 3 months
before start of screening.
d. Statins, due to inhibition of mevalonate synthesis, which reduces protein prenylation
e. Medications contraindicated in the prescribing information for ritonavir:
– Alpha1-adrenoreceptor antagonist: alfuzosin HCL
– Analgesics: pethidine, piroxicam, propoxyphene
– Antiarrhythmics: amiodarone, flecainide, propafenone, quinidine, bepridil, encainide
– Antibiotic: fusidic acid
– Antifungal: voriconazole
– Antihistamines: astemizole, terfenadine
– Antimycobacterial: rifabutin
– Ergot derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine
– Gastrointestinal motility agent: cisapride
– Herbal products: St. Johns wort (hypericum perforatum)
– HMG-CoA reductase inhibitors: lovastatin, simvastatin
– Antipsychotics/Neuroleptic: clozapine, pimozide, quetiapine
– Phosphodiesterase type 5 enzyme inhibitor: sildenafil only
when used for the treatment of pulmonary arterial hypertension, avanafil,
vardenafil
– Sedative/hypnotics: clorazepate, diazepam, estazolam, flurazepam, oral
midazolam, triazolam
f. History or evidence for any intolerance or hypersensitivity to lonafarnib, ritonavir, or other substances that are part of the study medication
21 . Other significant medical condition that may require intervention during
the study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The purpose of this study is to evaluate the safety and tolerability of the dose-titration regimen of lonafarnib in combination with ritonavir over the 24-week treatment period. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Week 0 (Day 1), Week 1 (Day 8 ± 2 d), Week 2 (Day 15 ± 2 d), Week 4
(Day 29 ± 2 d), Week 6 (Day 43 ± 2 d), Week 8 (Day 57 ± 5 d), Week 12 (Day 85 ± 5 d),
Week 16 (Day 113 ± 5 d), Week 20 (Day 141 ± 5 d), and Week 24 (Day 169 ± 5 d). |
|
| E.5.2 | Secondary end point(s) |
In addition, the PD activity (ie, change in HDV viral load) of the lonafarnib/ritonavir dose-titration regimen over the 24-week Treatment Period will be evaluated.
Secondary evaluations will include the effect the lonafarnib/ritonavir dose-titration regimen on
PK characteristics, ALT levels, and HBV DNA levels. Exploratory evaluations will include the effects of the lonafarnib/ritonavir dose-titration regimen on immunologic parameters during treatment. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 0 (Day 1), Week 1 (Day 8 ± 2 d), Week 2 (Day 15 ± 2 d), Week 4
(Day 29 ± 2 d), Week 6 (Day 43 ± 2 d), Week 8 (Day 57 ± 5 d), Week 12 (Day 85 ± 5 d),
Week 16 (Day 113 ± 5 d), Week 20 (Day 141 ± 5 d), and Week 24 (Day 169 ± 5 d). |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
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