| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment Naïve, Genotype 1 and 3, Chronic Hepatitis C Patients |
|
| E.1.1.1 | Medical condition in easily understood language |
| Liver disease caused by the hepatitis C virus, Genotype 1 and 3 |
|
| 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 | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10076831 |
| E.1.2 | Term | Chronic hepatitis C genotype 3 |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10074391 |
| E.1.2 | Term | Chronic hepatitis C virus genotype 1 |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the efficacy of a single subcutaneous (s.c.) injection of 4 mg/kg RG-101 when given in combination with oral GSK2878175 20 mg/day taken for 6, 9, or 12 weeks in subjects with hepatitis C virus (HCV) genotypes 1 and 3, in terms of proportion of subjects with sustained virologic response (SVR) at 12 weeks after end of treatment (SVR12) with GSK2878175. |
|
| E.2.2 | Secondary objectives of the trial |
• To assess the safety and tolerability of RG-101 when given in combination with oral GSK2878175 taken for 6, 9, or 12 weeks in subjects with HCV genotypes 1 and 3;
• To assess the efficacy of a single injection of 4 mg/kg RG-101 when given in combination with oral GSK2878175 20 mg/day taken for 6, 9, or 12 weeks in subjects with HCV genotypes 1 and 3, in terms of proportion of subjects with sustained virologic response at 24 and 48 weeks after end of treatment (SVR24 and SVR48, respectively) with GSK2878175;
• To assess the time to viral load clearance in each of the genotypes and treatment arms;
• To assess plasma concentrations or pharmacokinetics (PK) of GSK2878175 and RG-101 related moieties [unconjugated (consisting of RG1649 and/or RG1649A), conjugated (consisting of RG2459 and/or its N acetylgalactosamine [GalNAc]-on metabolites), and/or a total combined concentration of unconjugated and conjugated moieties] at selected sampling time points only.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Adults aged 18 to 75 (inclusive) infected with HCV genotype 1 or 3;
2. Body mass index (BMI): 18.0 – 35.0 kg/m2;
[BMI (kg/m2) = Body weight (kg) ÷ Height2 (m2)];
3. Clinical and laboratory findings consistent with a clinical diagnosis of CHC, including:
• Previous documentation of positive HCV serology (HCV antibody or HCV RNA) at least 24 weeks prior to enrolment,
or
• Positive HCV serology (HCV antibody or HCV RNA) less than 24 weeks with a prior remote risk factor (more than 24 weeks prior to Screening) for the acquisition of hepatitis C,
and
• Serum HCV RNA ≥ 375,000 copies/mL or ≥ 75,000 IU/mL at Screening;
4. Subjects must have been treatment-naïve and had not received prior treatment with any interferon, immunomodulatory agent, or direct acting antiviral agent (DAA) or ribavirin containing regimen for HCV;
5. Screening hematology, clinical chemistries, coagulation and urinalysis are not clinically significant and the following criteria are met:
• Platelets > 100x109/L
• Total white blood cells > 3.0x109/L and absolute neutrophil count > 1.5x109/L
• Hemoglobin > 10.95 g/dL for females and > 11.92 g/dL for males
• Total and direct bilirubin < 1.5x upper level of normal (ULN)
• Alanine aminotransferase (ALAT) < 5x ULN
• Aspartate aminotransferase (ASAT) < 5x ULN
• ALP < 2x ULN
• Albumin ≥ 3.5 g/dL
• Serum creatinine within normal limits or increased up to 1.5x ULN and estimated creatinine clearance rate as calculated by the Cockcroft-Gault formula > 60 mL/min.
Cockroft-Gault formula: ((140 – age) x weight (in kilograms) x constant) / serum creatinine (in µmol/L), where constant is 1.23 for men and 1.04 for women
Note: At the discretion of the Investigator, screening laboratory testing may be repeated once to confirm out of-range (exclusionary) results.
6. Female subjects must be of non-childbearing potential and must have undergone one of the following sterilization procedures at least 6 months prior to dosing:
a. hysteroscopic sterilization;
b. bilateral tubal ligation or bilateral salpingectomy;
c. hysterectomy;
d. bilateral oophorectomy;
or be postmenopausal with amenorrhea for at least 1 year prior to dosing and follicle-stimulating hormone (FSH) serum levels consistent with postmenopausal status as per Investigator judgment;
7. Male subjects with female partners of childbearing potential must use one of the following contraception methods from the time of the first dose of study medication to the last follow-up visit in the Short Term Follow-up Period (12 weeks after the last dose of study medication):
a. Male condom plus partner use of one of the following highly effective contraceptives:
• Contraceptive subdermal implant;
• Intrauterine device (IUD) or intrauterine system (IUS);
• Combined estrogen and progestogen oral contraceptive;
• Injectable progestogen;
• Contraceptive vaginal ring;
• Percutaneous contraceptive patches;
b. Documented sterilization of the male subject. For this definition, “documented” refers to the outcome of the Investigator's/designee’s review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject’s medical records;
c. Abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception;
8. Negative results on the screening alcohol saliva test. Subjects should be able and willing to limit the alcohol intake to a maximum of 5 units per week during the whole study period (1 unit of alcohol equals approximately 250 mL of beer, 100 mL of wine or 35 mL of spirits);
9. Negative results on the following screening laboratory tests: urine drug screen [opiates, cocaine, heroin, amphetamines (including ecstasy), barbiturates, benzodiazepines, tricyclic antidepressants; exceptions are cannabinoids and methadone], hepatitis B surface antigen (HBsAg), and human immunodeficiency virus (HIV) antibody. (At the investigator’s discretion subjects prescribed benzodiazepines, tricyclic antidepressants and opiates may be allowed.);
10. Based on single or averaged QTc values of triplicate electrocardiograms (ECGs) obtained over a brief recording period:
• QT interval corrected according to Fridericia’s formula (QTcF) < 450 msec; or
• QTcF < 480 msec in subjects with Bundle Branch Block;
11. The following screening values for vital signs parameters:
• Systolic blood pressure within the range of 90-140 mmHg;
• Diastolic blood pressure within the range of 45-90 mmHg; and
• Heart rate within the range of 50-100 bpm for female subjects or 45-100 bpm for male subjects;
12. Willingness to sign the ICF and obvious ability (mental and physical) to adhere to all study procedures. |
|
| E.4 | Principal exclusion criteria |
1. Other known cause of liver disease except for CHC;
2. History or symptoms of decompensated liver disease: Child-Pugh Class B or C, including ascites, hepatic encephalopathy, esophageal variceal bleeding, cirrhosis, or other signs of hepatic insufficiency or portal hypertension;
3. History of hepatocellular carcinoma or current liver mass consistent with malignancy on imaging studies;
4. Serum alpha-fetoprotein (AFP) > 50 ng/mL at Screening;
5. Concurrent clinically significant medical diagnosis (other than hepatitis C-related conditions) that would potentially interfere with the subjects study compliance or confound study results including but not limited to: significant or unstable cardiac disease (e.g., prolonged QT syndrome [torsades de pointe], unstable angina, myocardial infarction, diastolic dysfunction, congestive heart failure, significant arrhythmia, coronary heart disease, and/or clinically significant ECG abnormalities); cancer; uncontrolled seizure disorder; ascites; chronic infection other than HCV (e.g., tuberculosis); uncontrolled diabetes, and/or uncontrolled thyroid disease;
6. Evidence of cirrhosis, as determined by any one of the following:
a. FibroSure/FibroTest score >0.58 or Fibroscan score indicative of cirrhosis (≥14.5 kPa); or
b. Liver biopsy with a fibrosis stage indicative of cirrhosis as classified by a local pathologist (defined as Knodell > 3, Metavir > 2, Ishak > 4, or Batts and Ludwig > 2). Both incomplete and transition to cirrhosis (e.g., Metavir score 3) are considered as cirrhosis; or
c. History of ascites, hepatic encephalopathy, or esophagogastric varices;
7. Concurrent social conditions (e.g., drugs, alcohol) which would potentially interfere with the subject’s study compliance;
8. Use of anticonvulsants, antimycobacterials, analeptics and herbal supplements that may interact with the bioavailability of the investigational product or oral DAA agents; or other alternative medicines that may have influence on the disease outcome;
9. Mental handicap or history of or current significant psychiatric disease (which might impair ability to provide informed consent);
10. Clinically significant illness within 30 days prior to Screening;
11. Have used an investigational drug or has participated in an investigational study with a licensed drug within 30 days or 5 half lives, whichever is longer, prior to study drug administration;
12. History of relevant drug and/or food allergies;
13. Donation of more than 500 mL of blood within 60 days prior to drug administration. Donation of more than 1.5 liters of blood (for men) / more than 1.0 liter of blood (for women) in the 6 months prior to Screening;
14. The following family history of cardiac disease:
• prolonged QT syndrome (Torsade de Pointes) or sudden cardiac death;
• first-degree relative with myocardial infarction at premature age (≤ 45 years for male relative; ≤ 55 years for female relative);
15. Evidence of clinically significant pulmonary disease, as determined by any of the following:
a. Known (past or current) history of significant asthma, emphysema, chronic obstructive pulmonary disease, and/or interstitial lung disease; or
b. Abnormal pretreatment spirometry results. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects with SVR12 in HCV genotypes 1 and 3 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Viral load related
• Proportion of subjects with SVR24 and SVR48 in HCV genotypes 1 and 3;
• Time to viral load clearance in each of the genotypes and treatment arms;
• Proportion of relapsed subjects in each HCV genotype;
• Proportion of non-responders and partial responders;
• Proportion of subjects with viral resistance development at 48 weeks post end of GSK175 treatment or early termination;
• Change in viral loads across visits.
Biochemical response related
• Changes in liver enzymes during the study course;
• Changes in lipid profile during the study course;
• Changes in hematology and blood chemistry.
Pulmonary safety related
• Changes in pulmonary function.
Pharmacokinetic and pharmacokinetic/pharmacodynamic endpoints
• Measured plasma concentrations or PK of RG-101 related moieties [unconjugated (consisting of RG1649 and/or RG1649A), conjugated (consisting of RG2459 and/or its GalNAc-on metabolites), and/or a total combined concentration of unconjugated and conjugated moieties] at selected sampling time points;
• Measured plasma concentrations or PK of GSK2878175. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Week 12, week 24, week 48 |
|
| 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 | Yes |
| 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) | 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 | Yes |
| 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 | 3 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| 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 |
| Greece |
| Hungary |
| Serbia |
| Spain |
|
| 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
|
| Last visit of the last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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