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. |
La indicación propuesta para lonafarnib coadministrado con ritonavir es para el tratamiento de la infección crónica por VHD. Aproximadamente el 5% de las personas infectadas con VHB están infectadas con VHD en todo el mundo. La infección crónica por VHD provoca una enfermedad hepática más grave que la monoinfección por VHB, se asocia con una progresión acelerada de la fibrosis y tiene un mayor riesgo de desarrollar carcinoma hepatocelular. |
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E.1.1.1 | Medical condition in easily understood language |
The proposed study is for the treatment of patients with chronic HDV infection. |
El estudio propuesto es para el tratamiento de pacientes con infección crónica por VHD. |
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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 |
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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. |
Los objetivos principales son los siguientes: • Comparar la combinación de la tasa de respuesta virológica y bioquímica en el FdT (semana 48) en pacientes que reciben 50 mg de LNF/100 mg de RTV dos veces al día, frente a los pacientes que reciben placebo. • Comparar la combinación de la tasa de respuesta virológica y bioquímica en el FdT (semana 48) en pacientes que reciben 50 mg de LNF/100 mg de RTV dos veces al día con 180 microgramos de PEG IFN-alfa-2a una vez CS, frente a los pacientes que reciben placebo. |
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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 |
Los objetivos secundarios son los siguientes: • Respuesta virológica • Respuesta bioquímica • Respuesta histológica • Respuesta virológica del límite mínimo de cuantificación (LMC) • Combinación de la respuesta virológica y bioquímica • Respuesta virológica y bioquímica independientes • Calidad de vida • Seguridad |
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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) at study entry. Note: Non-genotype 1 HDV will be capped at 15% of total enrollment. Patients with a screening HDV RNA viral load ≤ 4 log10 will make up between 35% and 45% of the total population. 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. Need to be able to read and understand language where the patient is participating in the study. 6. Need to be 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: • Progestogen injection (eg, Depo-Provera®) 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). |
Criterios de inclusión 1. Participantes con una infección crónica del VHD de, al menos, 6 meses de duración documentada mediante un análisis positivo del Ac del VHD y ARN del VHD ≥500 IU/ml por una reacción en cadena de la polimerasa cuantitativa (qPCR) a la entrada del estudio. Nota: El VHD sin genotipo 1 se limitará al 15 % del total de sujetos inscritos. Los pacientes con una carga viral de ARN del VHD ≤4 log10 de la selección supondrán entre el 35 % y el 45 % del total de la población. 2. La supresión demostrable del ADN del VHB (<20 IU/ml) después de, al menos, 12 semanas del tratamiento con nucleós(t)idos anti-VHB con entecavir o tenofovir antes de empezar el tratamiento. 3. ALT en suero >1,3 x del LSN y <10 x LSN. 4. Participantes con la voluntad y la capacidad para entender y cumplir con los procedimientos del estudio y otorgar el consentimiento informado por escrito. 5. Participantes con capacidad para leer y comprender el idioma del participante que está en el estudio. 6. Participantes con la capacidad para autoadministrarse la medicación por vía oral y mediante una inyección SC. 7. Los hombres y las mujeres participantes que tengan 18 años o más. 8. Participantes con un IMC de ≥18 kg/m2 y peso ≥45 kg. 9. Participantes que cuenten con una biopsia hepática en un plazo de 45 días a partir del día 1 que demuestre que padecen una hepatitis crónica. Si no se dispone de una biopsia del hígado, los pacientes deberán estar dispuestos a dar su consentimiento y no tener contraindicaciones en dicha biopsia. 10. Participantes cuyos ECG demuestren que no padecen isquemia aguda o una anomalía CS y un intervalo QT corregido según la fórmula de corrección de Fridericia (QTcF) <450 ms. 11. Exploración normal cuando la retina está dilatada. 12. Las pacientes de sexo femenino sexualmente activas y en edad fértil y los pacientes varones sexualmente activos y con parejas en edad fértil deben aceptar usar métodos anticonceptivos adecuados durante el estudio. Las mujeres en edad fértil son todas aquellas que no sean estériles quirúrgicamente, aquellas que tengan documentación médica de insuficiencia ovárica o que sean postmenopáusicas durante al menos 1 año. Para pacientes de sexo femenino: • Inyecciones de progesterona (p. ej., Depo-Provera®) durante ≥3 meses antes de la selección Y un método de barrera (uso de preservativo [pareja de sexo masculino], un diafragma con espermicida o un capuchón cervicouterino con espermicida) desde la selección; • DIU o un SIU durante ≥3 meses antes de la selección Y un método de barrera (uso de preservativo [pareja de sexo masculino], un diafragma con espermicida o un capuchón cervicouterino con espermicida) desde la selección; • esterilización quirúrgica de la pareja (vasectomía ≥1 mes antes de la selección) Y un método de barrera (uso de preservativo [pareja de sexo masculino], un diafragma con espermicida o capuchón cervicouterino con espermicida) desde la selección, o • métodos de doble barrera (uso de preservativo [pareja de sexo masculino] junto con un diafragma con espermicida o un capuchón cervicouterino con espermicida) desde la selección. Para los pacientes varones: • esterilización quirúrgica (vasectomía ≥1 mes antes de la selección) Y un método de barrera (uso de preservativo, un diafragma con espermicida o un capuchón cervicouterino con espermicida) desde la selección, o • el uso correcto y de forma eficaz del preservativo a partir de la selección Y la pareja de sexo femenino debe aceptar usar un anticonceptivo hormonal, un sin barrera ni hormonas (p. ej., DIU de cobre) o un método de barrera sin hormonas (p. ej., diafragma con espermicida o capuchón cervicouterino con espermicida). |
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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 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. 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.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) 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: Medications or foods that are known moderate or strong inducers of CYP3A or sensitive substrates of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, UGT1A1, P-gp, and OCT1 Drugs known to prolong the PR or QT interval Statins (with the exception of pravastatin). 25.Concomitant use of medications contraindicated in the prescribing information for study drugs
Any requests for rescreening, after a screening failure, need to be discussed with the PI + MM |
Criterios de exclusión Criterios de exclusión generales 1. La participación en un ensayo clínico con, o en el que se use, cualquier fármaco en investigación en el plazo de 30 días o 5 semividas, lo que dure más, antes de la selección. 2. El uso previo de LNF en un plazo de 12 meses antes de la preselección/selección o durante el estudio. 3. Pacientes embarazadas o en periodo de lactancia. Las pacientes de sexo femenino deben tener un resultado negativo en una prueba en suero en la selección y una prueba de embarazo en orina negativa (sensibilidad mínima de 25 UI/l o unidades equivalentes de gonadotropina coriónica humana [GCh]) al inicio, en el plazo de 24 horas antes del inicio de la administración de cualquier fármaco en investigación. Los pacientes de sexo masculino con parejas que estén embarazadas. -Exclusiones en función de la enfermedad (vease en el protocolo) -Exclusiones en función del uso de medicación concomitante (vease en el protocolo) Nota: Se debe comentar con el investigador principal y el supervisor médico cualquier solicitud para la repetición de la selección después de un fallo de selección. |
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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. |
- Evaluar la combinación de la respuesta virológica y bioquímica, la tasa de respuesta histológica y la tasa de respuesta virológica del LMC al FdT (semana 48) en pacientes que reciben 50 mg de LNF/100 mg de RTV dos veces al día, frente a pacientes que reciben 50 mg de LNF/100 mg de RTV dos veces al día con 180 microgramos de PEG IFN-alfa-2a CS. - Evaluar la combinación de la respuesta virológica y bioquímica, la tasa de respuesta histológica y la tasa de respuesta virológica del LMC al FdT (semana 48) en pacientes que reciben 50 mg de LNF/100 mg de RTV dos veces al día con 180 microgramos de PEG IFN-alfa-2a CS, frente a pacientes que reciben 180 microgramos de PEG IFN-alfa-2a CS. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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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 |
•Respuesta Virológica •Respuesta bioquímica •Respuesta histológica •Respuesta virológica del límite mínimo de cuantificación (LMC) •Combinación de la respuesta virológica y bioquímica •Respuesta virológica y bioquímica independientes •Calidad de vida •Seguridad |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 48 and week 24 post treatment |
Semana 48 y semana 24 después del tratamiento |
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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 |
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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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
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 |
Belgium |
Bulgaria |
Canada |
France |
Germany |
Greece |
Israel |
Italy |
Moldova, Republic of |
New Zealand |
Pakistan |
Romania |
Spain |
Switzerland |
Taiwan |
Turkey |
United Kingdom |
United States |
Vietnam |
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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
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Last visit from last subject |
Última visita del último paciente |
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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 |