A clinical trial in patients with the liver disease caused by the hepatitis C virus for assessment of safety and efficacy of one injection of test product RG-101 given in combination with test product GSK2878175 that is to be taken by mouth once daily for 6, 9, or 12 weeks

• Register: EUCTR
• Last refreshed on: 2 October 2017
• Main ID: EUCTR2015-004702-42-HU
• Date of registration: 19/11/2015
• Prospective Registration: Yes
• Primary sponsor: Regulus Therapeutics Inc.
• Public title: A clinical trial in patients with the liver disease caused by the hepatitis C virus for assessment of safety and efficacy of one injection of test product RG-101 given in combination with test product GSK2878175 that is to be taken by mouth once daily for 6, 9, or 12 weeks
• Scientific title: A Multi-Center, Parallel Group, Open-Label, Phase 2 Study to Evaluate the Efficacy and Safety of a Single Subcutaneous Injection of RG-101 Combined with Oral GSK2878175 Taken Once Daily for 6, 9, or 12 Weeks in Treatment Naïve, Genotype 1 and 3, Chronic Hepatitis C Patients
• Date of first enrolment: 15/01/2016
• Target sample size: 24
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-004702-42
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Greece, Hungary, Serbia, Spain

Contacts

• Name: Clinical Trials Info
• Affiliation: Accelsiors CRO and Consultancy Services Ltd

• Name: Clinical Trials Info
• Affiliation: Accelsiors CRO and Consultancy Services Ltd

Key inclusion & exclusion criteria

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
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.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Virus Diseases [C02]

Treatment Naïve, Genotype 1 and 3, Chronic Hepatitis C Patients
MedDRA version: 19.0 Level: LLT Classification code 10076831 Term: Chronic hepatitis C genotype 3 System Organ Class: 100000004862
MedDRA version: 19.0 Level: LLT Classification code 10074391 Term: Chronic hepatitis C virus genotype 1 System Organ Class: 100000004862

Intervention(s)

Product Code: RG-101
Pharmaceutical Form: Solution for injection
Current Sponsor code: RG2459
Other descriptive name: RG2459
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 150-

Product Code: GSK2878175
Pharmaceutical Form: Tablet
Current Sponsor code: GSK2878175
Other descriptive name: GSK2878175A, where ‘A’ denotes the free acid
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Week 12

Secondary Objective: • 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.

Main Objective: 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.

Primary end point(s): Proportion of subjects with SVR12 in HCV genotypes 1 and 3

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Week 12, week 24, week 48

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.

Secondary ID(s)

RG101-04

Source(s) of Monetary Support

Regulus Therapeutics Inc.