| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
The proposed indication for lonafarnib coadministered with ritonavir is for the treatment of chronic HDV infection.
Approximately 5% of HBV-infected individuals are infected with HDV worldwide. Chronic HDV infection leads to more severe liver disease than HBV mono-infection, is associated with accelerated fibrosis progression, and has a higher risk of developing hepatocellular carcinoma. Currently no satisfactory therapy for HDV infection exist. |
|
| E.1.1.1 | Medical condition in easily understood language |
| The proposed study is for the treatment of patients with chronic HDV infection. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019763 |
| E.1.2 | Term | Hepatitis delta |
| E.1.2 | System Organ Class | 100000004862 |
|
| 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 are as follows:
• To compare the composite virologic and biochemical response rate at end-of-treatment (EOT) (Week 48) in patients who receive LNF 50 mg/RTV 100 mg BID vs patients who receive placebo.
• To compare the composite virologic and biochemical response rate at EOT (Week 48) in patients who receive LNF 50 mg/RTV 100 mg BID with PEG IFN-alfa-2a 180 mcg QW vs patients who receive placebo.
Composite virologic and biochemical response is defined as a ≥ 2 log10 reduction in HDV ribonucleic acid (RNA) level and alanine aminotransferase (ALT) normalization relative to baseline. Meeting either primary objective will lead to an efficacy conclusion. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are as follows (see Protocol for details):
• Virologic Response
• Biochemical Response
• Histologic Response
• Lower Limit of Quantitation (LLOQ) Virologic Response
• Composite Virologic and Biochemical Response
• Individual Virologic and Biochemical Response
• Quality of Life
• Safety
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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.
Non-genotype 1 HDV will be capped at 15% of total enrollment.
2. Demonstrable suppression of HBV DNA (< 20 IU/mL) following a
minimum 12 weeks of anti-HBV nucleos(t)ide treatment with entecavir
or tenofovir (TDF or TAF) prior to initiating study therapy.
3. Serum ALT > 1.0 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/m2 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:
• Progestin-based hormonal contraception (implant, injection, oral)
associated with inhibition of ovulation for ≥ 3 months before screening.
Use of a progestin-based implant or injection method requires the
additional use of a barrier method (use of condom [male partner] or
diaphragm with spermicide or cervical cap with spermicide) from
screening. Use of a progestin-only, oral method requires the additional
use of double barrier methods (use of condom [male partner] with either
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). |
|
| E.4 | Principal exclusion criteria |
1.Participation in a clinical trial with, or use of, any investigational agent within 30 days or 5 half-lives, whichever is longer, before screening2.Previous use of LNF within 12 months before pre-screening/screening3.Female patients who are pregnant or breastfeeding. Male patients with female sexual partners who are pregnant
4.Current or previous history of Child-Pugh Class B/C
5.Co-infected with HIV/HCV
6.Positive results for HIV/HCV Ab at screening. They are allowed if they have completed a curative antiviral regimen and have documented undetectable HCV RNA for at least 3 months
7.History of 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. When the spleen measures larger than 12cm and the PI believes the subject meets all other non cirrhotic criteria, a discussion with the Medical Monitor (MM) is warranted for inclusion
8.Current evidence or history of ascites requiring diuretics or paracentesis, or hepatic encephalopathy
9.Any of the abnormal laboratory test results:
Platelet count <90,000cells/mm3
White blood cell (WBC) count <3,000cells/mm3
Absolute neutrophil count (ANC) <1,500cells/mm3
Hemoglobin: <11g/dL for women, <12g/dL for men
Confirmed creatinine clearance
Alpha-fetoprotein ≥100ng/mL
Abnormal TSH or total T4 levels (Patients with well-controlled thyroid function may be enrolled)
Bilirubin ≥ 2 mg/dL
10.Evidence of another form of viral hepatitis or liver disease
11.History of hepatocellular carcinoma
12.Patients with:
Current eating disorder
Evidence of alcohol substance use disorder or excessive intake, defined as:
−>20g/day for females or
−>30g/day for males
Blood alcohol concentration >0.08%
Drug abuse within the previous 6 months, with the exception of cannabinoids and their derivatives
13.Prior history or current evidence of:
Immunologically mediated disease that requires more than intermittent nonsteroidal anti-inflammatory medications for management or that requires chronic use of systemic corticosteroids in the 6 months (periodic use of oral steroid taper and inhaled asthma medications are allowed)
Retinal disorder or clinically relevant ophthalmic disorder
Any malignancy within 5 years (Exceptions are malignancies surgically excised with curative intent and/or evidence of being disease free for at least 5 years, or successfully treated in-situ carcinoma of the cervix)
Cardiomyopathy or significant ischemic cardiac or cerebrovascular disease
Chronic pulmonary disease associated with functional impairment, ratio <0.7
Pancreatitis or colitis
Severe or uncontrolled psychiatric disorder
Bone marrow or solid organ transplantation (For patients who are stable for 1 year post-transplantation and do not require immunosuppressive therapy(ies) enrollment may be considered)
14.Other significant medical condition that may require intervention during the study. Patients with any serious condition that 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 should be discussed
16.Any prescription, over-the-counter (OTC) product, or herbal product that is not approved by the MM
17.Consumption of grapefruit, Seville oranges, or product that contains these within 14 days
18.Therapy with an immunomodulatory agent, IFN-α, cytotoxic agent, or chronic systemic corticosteroids within 12 months of screening and during the study (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
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 any substances that are part of the study
24.Concomitant use (within 2 weeks of Day 1 and throughout study
conduct) of any medications or foods:
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
Known sensitive substrates of OCT1 with a narrow therapeutic index
Drugs known to prolong the PR or QT interval
25.Concomitant use of medications contraindicated in the prescribing
information for study drugs |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• To compare the composite virologic and biochemical response rate at end-of-treatment (EOT) (Week 48) in patients who receive LNF 50 mg/RTV 100 mg BID vs patients who receive placebo.
• To compare the composite virologic and biochemical response rate at EOT (Week 48) in patients who receive LNF 50 mg/RTV 100 mg BID with PEG IFN-alfa-2a 180 mcg QW vs patients who receive placebo.
Composite virologic and biochemical response is defined as a ≥ 2 log10 reduction in HDV ribonucleic acid (RNA) level and alanine aminotransferase (ALT) normalization relative to baseline. Meeting
either primary objective will lead to an efficacy conclusión. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Virologic Response
• Biochemical Response
• Histologic Response
• Lower Limit of Quantitation (LLOQ) Virologic Response
• Composite Virologic and Biochemical Response
• Individual Virologic and Biochemical Response
• Quality of Life
• Safety |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Week 48 and week 24 post treatment |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 38 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Israel |
| Mongolia |
| New Zealand |
| Pakistan |
| Taiwan |
| United States |
| France |
| Sweden |
| Bulgaria |
| Romania |
| Spain |
| Switzerland |
| Germany |
| Greece |
| Italy |
| Belgium |
| Moldova, Republic of |
| Turkey |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| Last visit from last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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